The American Psychiatric Publishing

TEXTBOOK OF
GERIATRIC PSYCHIATRY
FIFTH EDITION
The American Psychiatric Publishing
 TEXTBOOK OF
GERIATRIC PSYCHIATRY
FIFTH EDITION

EDITED BY
David C. Steffens, M.D., M.H.S.
Dan G. Blazer, M.D., Ph.D.
Mugdha E. Thakur, M.D.
Note: The authors have worked to ensure that all information in this book is
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Library of Congress Cataloging-in-Publication Data

The American Psychiatric Publishing textbook of geriatric psychiatry /
Edited by
David C. Steffens, Dan G. Blazer, Mugdha E. Thakur. — Fifth edition.
p. ; cm.
Textbook of geriatric psychiatry
Includes bibliographical references and index.
ISBN 978-1-58562-484-3 (hardcover : alk. paper)
I. Steffens, David C., 1962–, editor. II. Blazer, Dan G., II (Dan German),
1944–, editor.
III. Thakur, Mugdha E., 1969–, editor. IV. Title: Textbook of geriatric
psychiatry.
[DNLM: 1. Mental Disorders. 2. Aged. 3. Aging—physiology. 4.
Geriatric Psychiatry—
methods. WT 150]
RC451.4.A5
618.97′689—dc23
2015002913
British Library Cataloguing in Publication Data
A CIP record is available from the British Library.
 Contents
Contributors
Preface

PART I
Introduction to Geriatric Psychiatry

1 Demography and Epidemiology of Psychiatric Disorders in Late

Life
Celia F. Hybels, Ph.D.
Dan G. Blazer, M.D., Ph.D.

2 Physiological and Clinical Considerations of Geriatric Patient

Care
Robert M. Kaiser, M.D., M.H.Sc.

3 Genomics in Geriatric Psychiatry

Aaron M. Koenig, M.D.
Robert A. Sweet, M.D.

PART II
Evaluation of Psychiatric Disorders in Late Life

4 The Psychiatric Interview of Older Adults

Dan G. Blazer, M.D., Ph.D.
5 Use of the Laboratory in the Diagnostic Workup of Older Adults
Sophia Wang, M.D.
Mugdha E. Thakur, M.D.
P. Murali Doraiswamy, M.B.B.S., F.R.C.P.

6 Neuropsychological Assessment of Late-Life Cognitive

Disorders
Kathleen A. Welsh-Bohmer, Ph.D.
Deborah K. Attix, Ph.D.

PART III
Presentation of Psychiatric Disorders in Late Life

7 Delirium
Jane S. Saczynski, Ph.D.
Sharon K. Inouye, M.D., M.P.H.

8 Dementia and Mild Neurocognitive Disorders

Eitan Z. Kimchi, M.D.
Constantine G. Lyketsos, M.D., M.H.S.

9 Depressive Disorders
Dan G. Blazer, M.D., Ph.D.
David C. Steffens, M.D., M.H.S.

0 Bipolar and Related Disorders

John L. Beyer, M.D.

1 Schizophrenia Spectrum and Other Psychotic Disorders

Jeanne E. Maglione, M.D., Ph.D.
Ipsit V. Vahia, M.D.
Dilip V. Jeste, M.D.
2 Anxiety, Obsessive-Compulsive, and Trauma-Related Disorders
Eric J. Lenze, M.D.
Jan Mohlman, Ph.D.
Julie Loebach Wetherell, Ph.D.

3 Somatic Symptom and Related Disorders

Marc E. Agronin, M.D.

4 Sexuality and Aging

Marc E. Agronin, M.D.

5 Bereavement
Moria J. Smoski, Ph.D.
Stephanie T. Jenal, Ph.D.
Larry W. Thompson, Ph.D.

6 Sleep and Circadian Rhythm Disorders

Andrew D. Krystal, M.D., M.S.
Mugdha E. Thakur, M.D.

7 Substance-Related and Addictive Disorders

Shahrzad Mavandadi, Ph.D.
David W. Oslin, M.D.

8 Personality Disorders
Thomas E. Oxman, M.D.

9 Agitation in Older Adults

Mugdha E. Thakur, M.D.
Lisa P. Gwyther, M.S.W., L.C.S.W.
 PART IV
Treatment of Psychiatric Disorders in Late Life

0 Psychopharmacology
Benoit H. Mulsant, M.D.
Bruce G. Pollock, M.D., Ph.D.

1 Electroconvulsive Therapy and Other Forms of Brain Stimulation

Richard D. Weiner, M.D., Ph.D.
Mustafa M. Husain, M.B.

2 Nutrition and Physical Activity

Kathryn Porter Starr, Ph.D., R.D.
Connie Watkins Bales, Ph.D., R.D.
Martha E. Payne, Ph.D., R.D., M.P.H.

3 Individual and Group Psychotherapy

Moria J. Smoski, Ph.D.
Patricia A. Areán, Ph.D.

4 Working With Families of Older Adults

Lisa P. Gwyther, M.S.W., L.C.S.W.
Diane E. Meglin, M.S.W., L.C.S.W., D.C.S.W.

5 Clinical Psychiatry in the Nursing Home

Joel E. Streim, M.D.

Index
 Contributors
Marc E. Agronin, M.D.
Medical Director for Mental Health and Clinical Research, Miami Jewish
Health Systems; Affiliate Associate Professor of Psychiatry and Neurology,
University of Miami Miller School of Medicine, Miami, Florida

Patricia A. Areán, Ph.D.

Professor, Department of Psychiatry, University of California, San
Francisco, San Francisco, California

Deborah K. Attix, Ph.D.

Associate Professor of Medical Psychology, Department of Psychiatry and
Behavioral Sciences, and Director, Clinical Neuropsychology Service,
Division of Neurology, Duke University Medical Center, Durham, North
Carolina

Connie Watkins Bales, Ph.D., R.D.

Associate Director for Education and Evaluation, Geriatrics Research,
Education, and Clinical Center (GRECC), Durham VA Medical Center;
Professor, Department of Medicine, Duke University Medical Center,
Durham, North Carolina

John L. Beyer, M.D.

Assistant Professor of Psychiatry, Duke University Medical Center,
Durham, North Carolina

Dan G. Blazer, M.D., Ph.D.

J.P. Gibbons Professor of Psychiatry Emeritus, Department of Psychiatry
and Behavioral Sciences, Duke University Medical Center, Durham, North
Carolina

P. Murali Doraiswamy, M.B.B.S., F.R.C.P.

Professor of Psychiatry, Duke University Medical Center, Durham, North
Carolina

Lisa P. Gwyther, M.S.W., L.C.S.W.

Associate Professor, Department of Psychiatry and Behavioral Sciences,
Duke University Medical Center, Durham, North Carolina

Mustafa M. Husain, M.B.

Professor, Department of Psychiatry and Behavioral Sciences, Duke
University Medical Center, Durham, North Carolina; Professor of
Psychiatry, Neurology & Neuroscience, University of Texas–Southwestern
Medical Center, Dallas, Texas

Celia F. Hybels, Ph.D.

Associate Professor, Department of Psychiatry and Behavioral Sciences,
Center for the Study of Aging and Human Development, Duke University
Medical Center, Durham, North Carolina

Sharon K. Inouye, M.D., M.P.H.

Professor of Medicine, Department of Medicine, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, Massachusetts; Director
and Milton and Shirley F. Levy Family Chair, Aging Brain Center, Institute
for Aging Research, Hebrew SeniorLife, Boston, Massachusetts

Stephanie T. Jenal, Ph.D.

Assistant Professor, Department of Psychiatry and Behavioral Sciences,
Duke University Medical Center, Durham, North Carolina

Dilip V. Jeste, M.D.

Estelle and Edgar Levi Chair in Aging; Director, Sam and Rose Stein
Institute for Research on Aging; Distinguished Professor of Psychiatry and
Neurosciences, Department of Psychiatry, University of California, San
Diego; Chief, Division of Geriatric Psychiatry, VA San Diego Healthcare
System, San Diego, California

Robert M. Kaiser, M.D., M.H.Sc.

Attending Physician, Geriatrics and Extended Care, and Medical Director,
Home-Based Primary Care Program, Washington D.C. Veterans Affairs
Medical Center; Associate Professor of Medicine and Associate Director,
Fellowship in Geriatric Medicine, George Washington University School of
Medicine, Washington, D.C.

Eitan Z. Kimchi, M.D.

Faculty, Johns Hopkins University School of Medicine, Baltimore,
Maryland

Aaron M. Koenig, M.D.

Geriatric Psychiatry Fellow, Perelman School of Medicine at the University
of Pennsylvania, Philadelphia, Pennsylvania

Andrew D. Krystal, M.D., M.S.

Director, Sleep Research Laboratory, and Professor, Department of
Psychiatry and Behavioral Sciences, Duke University Medical Center,
Durham, North Carolina

Eric J. Lenze, M.D.

Professor of Psychiatry, Washington University School of Medicine, St.
Louis, Missouri

Constantine G. Lyketsos, M.D., M.H.S.

The Elizabeth Plank Althouse Professor and Chair of Psychiatry for Johns
Hopkins Bayview, Department of Psychiatry and Behavioral Sciences,
Johns Hopkins University School of Medicine, Baltimore, Maryland

Jeanne E. Maglione, M.D., Ph.D.

Adult and Geriatric Psychiatrist, VA San Diego Healthcare System, San
Diego, California

Shahrzad Mavandadi, Ph.D.

Investigator, Philadelphia VA Medical Center VISN 4 Mental Illness
Research, Education, and Clinical Center; and Adjunct Assistant Professor,
Department of Psychiatry, University of Pennsylvania, Philadelphia,
Pennsylvania

Diane E. Meglin, M.S.W., L.C.S.W., D.C.S.W.

Associate, Department of Psychiatry and Behavioral Sciences, and Clinical
Social Worker, Department of Social Work, Duke University Medical
Center, Durham, North Carolina

Jan Mohlman, Ph.D.

Associate Professor, Department of Psychology, William Paterson
University, Wayne, New Jersey

Benoit H. Mulsant, M.D.

Physician in Chief, Centre for Addiction and Mental Health, Toronto,
Ontario, Canada; Professor and Vice-Chair, Department of Psychiatry,
University of Toronto, Toronto, Ontario, Canada

David W. Oslin, M.D.

Professor of Psychiatry, University of Pennsylvania and Philadelphia VA
Medical Center VISN 4 Mental Illness Research, Education, and Clinical
Center, Philadelphia, Pennsylvania

Thomas E. Oxman, M.D.

Professor Emeritus of Psychiatry, Geisel School of Medicine at Dartmouth,
Hanover, New Hampshire

Martha E. Payne, Ph.D., R.D., M.P.H.

Associate Professor, Department of Psychiatry and Behavioral Sciences,
Duke University, Durham, North Carolina

Bruce G. Pollock, M.D., Ph.D.

Vice President, Research, Centre for Addiction and Mental Health, Toronto,
Ontario, Canada; Professor and Director, Division of Geriatric Psychiatry,
Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Jane S. Saczynski, Ph.D.

Associate Professor of Medicine, Division of Geriatric Medicine, and
Associate Professor, Department of Quantitative Health Sciences, Division
of Epidemiology of Chronic Diseases and Vulnerable Populations,
University of Massachusetts Medical School, Worcester, Massachusetts

Moria J. Smoski, Ph.D.

Assistant Professor, Department of Psychiatry and Behavioral Sciences,
Duke University Medical Center, Durham, North Carolina

Kathryn Porter Starr, Ph.D., R.D.

National Institutes of Health Postdoctoral Fellow, Center for the Study of
Aging and Human Development, Duke University School of Medicine,
Durham, North Carolina

David C. Steffens, M.D., M.H.S.

Professor and Chairman, Department of Psychiatry, University of
Connecticut Health Center, Farmington, Connecticut

Joel E. Streim, M.D.

Professor of Psychiatry, Department of Psychiatry, University of
Pennsylvania; VISN 4 Mental Illness Research, Education, and Clinical
Center, Philadelphia VA Medical Center, Philadelphia, Pennsylvania

Robert A. Sweet, M.D.

Professor of Psychiatry and Neurology, University of Pittsburgh; Co-
Associate Director for Research, Mental Illness Research, Education, and
Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania

Mugdha E. Thakur, M.D.

Associate Professor, Department of Psychiatry and Behavioral Sciences,
Duke University Medical Center, Durham, North Carolina

Larry W. Thompson, Ph.D.

Professor Emeritus, Department of Medicine; Professor, Active Duty,
Department of Psychiatry and Behavioral Sciences; Stanford University
School of Medicine, Stanford, California
Ipsit V. Vahia, M.D.
Assistant Clinical Professor, Stein Institute for Research on Aging,
Department of Psychiatry, University of California, San Diego; VA San
Diego Healthcare System, San Diego, California

Sophia Wang, M.D.

Assistant Professor of Psychiatry, Duke University Medical Center, Durham
Veterans Affairs Medical Center, Durham, North Carolina

Richard D. Weiner, M.D., Ph.D.

Professor, Department of Psychiatry and Behavioral Sciences, Duke
University Medical School; Chief, Mental Health Service Line, Durham VA
Medical Center, Durham, North Carolina

Kathleen A. Welsh-Bohmer, Ph.D.

Professor of Medical Psychology, Department of Psychiatry, and Director,
The Joseph and Kathleen Bryan Alzheimer’s Disease Research Center,
Division of Neurology, Department of Medicine, Duke University Medical
Center, Durham, North Carolina

Julie Loebach Wetherell, Ph.D.

Professor of Psychiatry, University of California, San Diego; Staff
Psychologist, VA San Diego Healthcare System, San Diego, California

Disclosure of Interests
The following contributors to this book have indicated a financial interest
in or other affiliation with a commercial supporter, a manufacturer of a
commercial product, a provider of a commercial service, a
nongovernmental organization, and/or a government agency, as listed
below:

John L. Beyer, M.D. Research support: Forest, Merck, National Institute

of Mental Health, Repligen, Takeda. Consultant: Merck.
Aaron M. Koenig, M.D. Research support: American Psychiatric Institute
for Research and Education (APIRE)/Janssen Resident Psychiatric
 Research Scholars program.
Eric J. Lenze, M.D. Research support: Lundbeck, Roche.
Constantine G. Lyketsos, M.D., M.H.S. Grant support (research or
CME): Associated Jewish Federation of Baltimore, Astra-Zeneca,
Bristol-Myers, Eisai, Elan, Forest, Functional Neuromodulation,
Glaxo-Smith-Kline, Lilly, National Football League, National Institute
on Aging, National Institute of Mental Health, Novartis, Ortho-
McNeil, Pfizer, Weinberg Foundation. Consultant/Advisor: Abvie,
Adlyfe, Astra-Zeneca, Avanir, Bristol-Myers Squibb, Eisai, Elan,
Forest, Genentech, Glaxo-Smith Kline, Janssen, Lilly, Lundbeck,
Merz, NFL Benefits Office, National Football League Players
Association, Novartis, Orion, Pfizer, Supernus, Takeda, Wyeth,
Zinfandel. Honorarium or travel support: Forest, Glaxo-Smith-Kline,
Health Monitor, Pfizer.
Benoit H. Mulsant, M.D. Research support: Canadian Institutes of Health
Research, U.S. National Institutes of Health (NIH), Bristol-Myers
Squibb (medications for an NIH-funded clinical trial), Pfizer
(medications for an NIH-funded clinical trial). Stock ownership:
General Electric (<$5,000).
Bruce G. Pollock, M.D., Ph.D. Research support: U.S. National Institutes
of Health, Canadian Institutes of Health Research, Foundation of the
Centre for Addiction and Mental Health.
David C. Steffens, M.D., M.H.S. Consultant: Janssen.

The following authors have no competing interests to report:

Marc E. Agronin, M.D.

Patricia A. Areán, Ph.D.
Deborah K. Attix, Ph.D.
Connie Watkins Bales, Ph.D., R.D.
Dan G. Blazer, M.D., Ph.D.
P. Murali Doraiswamy, M.B.B.S., F.R.C.P.
Lisa P. Gwyther, M.S.W., L.C.S.W.
Mustafa M. Husain, M.B.
Celia F. Hybels, Ph.D.
Sharon K. Inouye, M.D., M.P.H.
Stephanie T. Jenal, Ph.D.
Dilip V. Jeste, M.D.
Robert M. Kaiser, M.D., M.H.Sc.
Eitan Z. Kimchi, M.D.
Andrew D. Krystal, M.D., M.S.
Jeanne E. Maglione, M.D., Ph.D.
Shahrzad Mavandadi, Ph.D.
Diane E. Meglin, M.S.W., L.C.S.W., D.C.S.W.
Jan Mohlman, Ph.D.
David W. Oslin, M.D.
Thomas E. Oxman, M.D.
Martha E. Payne, Ph.D., R.D., M.P.H.
Jane S. Saczynski, Ph.D.
Moria J. Smoski, Ph.D.
Kathryn Porter Starr, Ph.D., R.D.
Joel E. Streim, M.D.
Robert A. Sweet, M.D.
Mugdha E. Thakur, M.D.
Larry W. Thompson, Ph.D.
Ipsit V. Vahia, M.D.
Sophia Wang, M.D.
Richard D. Weiner, M.D., Ph.D.
Kathleen A. Welsh-Bohmer, Ph.D.
Julie Loebach Wetherell, Ph.D.
 Preface

With the current edition of The American Psychiatric Publishing

Textbook of Geriatric Psychiatry, Drs. Blazer and Steffens welcome Dr.
Mugdha E. Thakur as a co-editor. Dr. Thakur brings both broad clinical
knowledge in geriatric psychiatry as well as specific expertise in treatment
of agitation and sleep disorders. This version of the textbook builds on prior
editions led by Drs. Ewald W. Busse and Dan G. Blazer, the editors for the
first two editions. With Dr. Steffens now serving as the lead editor, he,
along with Drs. Blazer and Thakur have sought to continue the eclectic,
interdisciplinary, and developmental perspective that has been the hallmark
of the Textbook, while keeping pace with the latest scientific and clinical
developments in the field.
This edition does capture recent advances in assessment, treatment and
biological understanding of late life neuropsychiatric disorders. The reader
will find both new information and updates of alterations of existing
materials. The first edition of this textbook, entitled Geriatric Psychiatry,
was published in 1989; the second edition and third editions were published
in 1996 and 2004, respectively, with the title The American Psychiatric
Press Textbook of Geriatric Psychiatry. The American Psychiatric
Publishing Textbook of Geriatric Psychiatry, Fourth Edition, was published
in 2009, and the fifth edition retains this title. The decision to publish a
fourth edition was catalyzed by two forces: the recognition of significant
developments in the field; and the anticipated publication of the Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). With
this edition, we aimed to equip both the scholar and the clinician with the
current state of scientific understanding as well as the practical skills and
knowledge base required for dealing with mental disorders in late life. In
addition, we wanted to provide an update for DSM-5, highlighting areas of
particular salience in older populations.
 As in previous editions, the chapters are presented in a sequential and
integrated fashion, which we have found enhances the accessibility and
usefulness of the information presented. The contributors include both basic
and clinical scholars who have a clear ability to make complex material
understandable to our readers. We maintained an eclectic orientation
regarding theory and practice in geriatric psychiatry. Although most
contributors are psychiatrists, we also called on colleagues from relevant
biomedical and behavioral disciplines—especially for chapters covering the
basic sciences—because of their expertise and ability to incorporate such
knowledge into a comprehensive approach to patient care.
We targeted this text to psychiatrists and other health professionals who
have an interest in and a commitment to older adults. This book is of
particular value to candidates seeking certification in geriatrics from the
American Board of Psychiatry and Neurology, the American Board of
Internal Medicine, and the American Board of Family Practice. All of these
bodies’ examinations place considerable emphasis on geriatric psychiatry
and the behavioral aspects of aging.
David Steffens
Farmington, Connecticut

Dan Blazer and Mugdha Thakur

Durham, North Carolina
 PART I

Introduction to Geriatric Psychiatry

 CHAPTER 1

Demography and Epidemiology of

Psychiatric Disorders in Late Life
Celia F. Hybels, Ph.D.
Dan G. Blazer, M.D., Ph.D.

Epidemiology of psychiatric disorders in late life is the study of the

distribution of psychiatric disorders and psychiatric symptoms among older
adults and the variables that affect the distribution. In this chapter, the
findings of demographers and epidemiologists are reviewed as they relate to
the care of older adults with psychiatric impairments. Because the
determinants or factors that affect these disorders are covered in later
chapters that are specifically devoted to the disorders, we include in this
chapter only cursory descriptions to provide a sense of how epidemiology
informs such studies.

Demography
In 2010, approximately 40 million persons ages 65 years and older lived in
the United States, accounting for 13% of the population. The number of
persons in this age group has steadily increased, from 3.1 million in 1900
and 12.3 million in 1950 to the current estimate. With the aging of the baby
boomer cohort (those born between 1946 and 1964), the size of the elderly
population is projected to continue to increase over the next several decades
and to reach 72.1 million by the year 2030 and 88.5 million by 2050,
accounting for an estimated 20.2% of the population. Even more
astounding, the number of oldest old, or persons ages 85 years and older,
was 5.5 million in 2010 and was projected to reach 19.0 million by 2050
(Federal Interagency Forum on Aging-Related Statistics 2012).
In 2009, about 3% of adults ages 65 years and older resided in
community housing with at least one service available, whereas 4% resided
in long-term-care facilities. Among individuals ages 85 years and older, 8%
resided in community housing with services and 14% resided in long-term
care facilities (Federal Interagency Forum on Aging-Related Statistics
2012). Many of these residents are placed in residential care because of
psychiatric disorders, especially the behavior problems that result from
Alzheimer’s disease.
The current older population of the United States is predominantly
female and white. In 2010, women accounted for 57% of the population
ages 65 years and older and 67% of those ages 85 years and older (Federal
Interagency Forum on Aging-Related Statistics 2012). The racial and ethnic
composition of the older population is projected to change over the next
several decades. In 2010, approximately 80% of individuals ages 65 years
and older were non-Hispanic white, 8% non-Hispanic black, 7% Hispanic,
3% Asian, and 2% other race/ethnic group. By 2050, the proportion of non-
Hispanic blacks is projected to be 12%, Asians 9%, and Hispanics of any
race 20%, whereas the proportion of non-Hispanic whites is expected to
decrease to 58% (Federal Interagency Forum on Aging-Related Statistics
2012).
Life expectancy in the United States in 1900 was 50.7 years for women
and 47.9 years for men, whereas the life expectancy at birth in 2009 was
80.9 years for women and 76.0 for men. In 2009, a person age 65 could
expect to live an average of 19.2 more years, and a person age 85 could
expect to live 6.7 additional years (Federal Interagency Forum on Aging-
Related Statistics 2012).
The percentage of older adults in the labor force—those who are either
working or looking for work—has changed over the last five decades. The
percentage of men ages 65–69 in the labor force declined from 40.9% in
1963 to 24.4% in 1985 and then increased to 37.4% in 2011. The
percentage of men ages 70 years and older in the labor force declined from
20.8% in 1963 to 10.5% in 1985 and then increased to 15.4% in 2011. The
percentage of women ages 65–69 years in the labor force increased from
16.5% in 1963 to 27.3% in 2011 (Federal Interagency Forum on Aging-
Related Statistics 2012). Whether or not older adults choose to remain in or
leave the workforce, the effect of an aging population on the economy of
the United States—not to mention the need for health care—will be
dramatic.
If an older person develops a psychiatric disorder, the disorder may
become chronic and the person may live many years with a decreased
quality of life because of psychiatric morbidity. In addition, the great
majority of older persons with psychiatric disorders experience a comorbid
physical illness. Currently, the proportion of younger and middle-aged
adults with a psychiatric disorder is higher than the proportion of older
adults with a psychiatric disorder, suggesting that as the younger adults age,
the proportion of older adults with a lifetime psychiatric disorder may also
increase and create a potential crisis in geriatric mental health (Jeste et al.
1999).
What can psychiatric epidemiological studies contribute to mental health
services for older adults? Morris (1975) suggested the following uses of
epidemiology:

• Identify cases (e.g., determine whether the symptom pattern of depression

in elderly persons can be readily identified in community-dwelling and
clinical populations of older adults)
• Reveal the distribution of psychiatric disorders in the population (e.g.,
determine the prevalence and/or incidence of dementia)
• Trace historical trends of mental illness among elderly persons (e.g., find
out whether the incidence of suicide has increased among this population
over the past 10 years)
• Determine the etiology of psychiatric disorders in late life (e.g., determine
whether social factors contribute more to the etiology of late-life
psychiatric disorders than to such disorders in midlife, given lower
potential for genetic contributions)
• Examine the use of psychiatric and other mental health services by elderly
persons (e.g., establish whether psychiatrically impaired older adults in
the community underutilize psychiatric services)

Each of these functions of epidemiology is reviewed in this chapter.

Case Identification
Clinicians constantly face the task of distinguishing abnormality from
normality. Although most epidemiologists and clinicians agree on the core
symptoms of psychiatric disorders throughout the life cycle, the absolute
distinction between cases and noncases—that is, persons who require
psychiatric attention versus those who do not require such care—is not
easily established. Many of the symptoms and signs of a psychiatric
disorder in late life may be ubiquitous with the aging process, thus blurring
the distinction between cases and noncases. Epidemiologists can assist the
clinician in identifying meaningful clusters of symptoms and significant
degrees of symptom severity. Case identification is also the foundation of
descriptive epidemiology. “Cases” are the numerator of the equation from
which prevalence (the proportion of disease that is present in the population
during a specified time period) and incidence (the proportion of new cases
that develop in a population at risk over a specified time period such as 1
year) are derived from community and clinical samples (the denominator).
What is a case? Copeland (1981) suggested that this question be turned
by epidemiologists, with advantage, to “A case for what?” The choice of a
construct for a case depends on the particular scientific or clinical inquiry of
the investigator. If, to determine a value of a new short-acting sedative-
hypnotic agent, the clinician wishes to identify a group of older adults with
initial insomnia, the prevalence and severity of a target symptom (initial
insomnia) define the case. The sleep difficulty may result from several
different underlying disorders, but diagnosis would be irrelevant to the
purpose of the study. For most clinicians, however, the goal of case
identification is to identify subjects experiencing uniform underlying
psychopathology, as is implicit in DSM-5 (American Psychiatric
Association 2013).
Diagnostic categories that approximate true disease processes have
several characteristics, including the following (Weissman and Klerman
1978):

1. A category should be distinguished on the basis of patterns of

symptomatology (e.g., the clustering of symptoms in vascular depression
[Alexopoulos et al. 1997]).
2. A category should predict the outcome of a disorder (e.g., Alzheimer’s
disease should predict a steady decline in cognitive functioning [Shoghi-
 Jadid et al. 2002]).
3. A category should reflect underlying biological reality, confirmed by
family and genetic studies (e.g., Alzheimer’s disease [Roses 1994]).
4. Laboratory studies should eventually validate a diagnostic category (e.g.,
the use of specific imaging studies to diagnose Alzheimer’s disease
[Roses 1997]).
5. The classification scheme should identify persons who may respond to a
specific therapeutic intervention, such as a particular form of
psychotherapy or a specific group of medications (e.g., the use of
combined pharmacotherapy and interpersonal psychotherapy to treat
late-life depression [Reynolds et al. 1999]).

The goal of DSM-5 is to provide categories that eventually will meet

each of these characteristics. At present, however, these categories are
defined by operational criteria (e.g., the symptom criteria for the diagnosis
of major depression). One method of case identification is the use of
diagnostic instruments. These instruments (usually standardized interviews)
have been developed and used in community- and clinic-based
epidemiological studies to identify persons with symptoms that meet these
criteria. The Composite International Diagnostic Interview (CIDI; World
Health Organization 1990), the Structured Clinical Interview for DSM-IV
(First et al. 1997), and the Diagnostic Interview Schedule (DIS; Robins et
al. 1981) are examples of these instruments.
For example, the World Mental Health Survey version of the CIDI was
used in the National Comorbidity Survey Replication (NCS-R), which
reported that the lifetime prevalence of major depressive disorder was
10.6% among participants ages 60 years and older compared with 15.4%
among those ages 18–29 years, 19.8% among those ages 30–44 years, and
18.8% among those ages 45–59 years (Kessler et al. 2005). The DIS was
used in the landmark Epidemiologic Catchment Area (ECA) study
conducted in the 1980s, from which a 1-month estimate of the prevalence of
affective disorders in persons ages 65 years and older was 2.5% (compared
with 6.4% for persons ages 25–44 years) (Regier et al. 1988).
A second approach to case identification is the use of self-administered
symptom scales and personality inventories. Frequently used scales in
epidemiological surveys include the Center for Epidemiologic Studies—
Depression Scale (Radloff 1977), the Patient Health Questionnaire
(Kroenke et al. 2001), and the Geriatric Depression Scale (Yesavage et al.
1982–1983), which screen for depressive symptoms, and the Mini-Mental
State Examination (Folstein et al. 1975), which screens for cognitive
impairment. The advantage of these scales is that, unlike diagnostic
interviews, they do not subjectively assign patients to a particular diagnostic
category; a disadvantage is the lack of diagnostic specificity that can be
achieved with their use. For example, the severity of depressive symptoms
after the loss of a loved one may be similar to that associated with a major
depressive episode with melancholia; however, a symptom checklist cannot
be used to distinguish one from the other, although the diagnosis of, and
intervention for, these two disorders would be very different. For example,
Blazer et al. (1991) estimated the prevalence of clinically significant
depression symptoms among community-dwelling elderly persons in North
Carolina to be 9%, although most of these individuals would not receive a
diagnosis of major depression.
Other authors define a case on the basis of severity of physical,
psychological, and social impairment secondary to the symptoms. This
approach to case identification is less popular among clinicians, who are
more inclined to treat a disease than to improve functioning. Improved
function, in theory, should derive from remission of the disease.
Nevertheless, function has special relevance in the care of older adults,
especially the oldest old (Blazer 2000). When managing chronic psychiatric
disorders, such as primary degenerative dementia of the Alzheimer’s type,
the improvement or maintenance of physical, psychological, and social
functioning is a clinician’s primary goal (Hazzard 1994). Family members
are often more concerned with improved functioning than with alleviation
of symptoms. Improved sleep and appetite and a decline in suicidal ideation
in a depressed older adult may not translate into the family’s perception that
the individual has recovered from a depressive episode. Rather, the family
may focus on the quality of interpersonal interactions and social
functioning.
Whichever approach is used to identify cases, most clinicians and
clinical investigators want to achieve perfection in the separation of cases
from noncases (e.g., case identification is critical for entry into a clinical
trial). The epidemiological method depends, for the most part, on a clear
distinction between cases and noncases (Kleinbaum et al. 1982), yet most
older adults do not ideally fit the psychiatric diagnoses they receive (Strauss
et al. 1979).
Regardless of the diagnostic system, unusual or borderline cases exist
that cannot be clearly placed in a single category. This has led some
investigators to consider the possibility of “fuzzy sets” as a means by which
cases can be more realistically distinguished (Blazer et al. 1989). Not
infrequently, older adults manifest more than one disease simultaneously
(e.g., major depression and dementia). In addition, the prescribed categories
of DSM-5 do not always match the symptoms that individuals in this
population may be experiencing; generalized anxiety, for instance, is not
always disentangled from a major depressive episode in an agitated older
adult. Krishnan (2007) suggested that it may be advantageous to separate
etiology from clinical manifestation in future classification of disease.
Most natural clustering of older individuals into categories is
perceptually “fuzzy” (Rosch 1978), because natural processes rarely show
necessary and sufficient criteria for sharp distinctions. Boundaries between
closely related categories are ill defined. Some of the methods of case
identification, such as the symptom checklist and standardized interview
approaches that archive symptoms, are adaptive to the development of
clusters of both symptoms and subjects with fuzzy boundaries. For
example, depressed elderly persons are more likely to express cognitive
dysfunction than are depressed middle-aged persons, yet cognitive
dysfunction is part of the depressive syndrome across the life cycle (Blazer
et al. 1988). Therefore, psychiatric syndromes—rather than discrete
disorders—are more realistic as diagnostic entities in geriatric psychiatry.
The most common of these syndromes are memory loss, confusion,
depression, anxiety, suspiciousness and agitation, sleep disturbance, and
hypochondriasis (Blazer 2000).
Some researchers have focused on latent subtypes of psychiatric
disorders, which offer different directions in case definition, suggesting that
cases may differ in their symptom presentation or risk factors within a
disorder. For example, Lyketsos et al. (2001) identified three latent classes
of neuropsychiatric disturbance in a sample of older adults with
Alzheimer’s disease.
A diagnosis must be reliable and valid for it to be a useful means of
communicating clinical information. To pass the test of reliability, a
diagnosis must be consistent and repeatable. Standardized or operational
methods for identifying psychiatric symptoms and the availability of
specific criteria for psychiatric diagnoses have greatly improved the
reliability of case identification by psychiatrists and by lay interviewers in
psychiatric epidemiological surveys. Reliability, however, does not ensure
validity—that is, the test of whether a case identified by a particular method
reflects underlying reality (Blazer 2000).

Distribution of Psychiatric Disorders

Epidemiological studies of psychiatric impairment in older adults have
generally concentrated on either overall mental health functioning or the
distribution of specific psychiatric disorders in the population. Reports from
these studies usually begin as general observations of the association of
impairment or specific disorders to characteristics such as age, gender,
race/ethnicity, and socioeconomic status. These trends provide the template
for more in-depth studies of the hereditary, biological, and psychosocial
contributors to the etiology of disorders and the effect of the distribution of
the disorders on mental health care utilization. Frequencies of disorders
within the population are usually presented in terms of prevalence. Almost
all epidemiological studies provide estimates of prevalence or incidence
based on community samples of larger populations. Smaller studies of the
prevalence of impairment or specific disorders in institutional or clinical
settings provide important data about service use. Longitudinal
epidemiological studies of older adults can also provide data on the
incidence of impairment or psychiatric disorders, as well as outcomes
associated with specific psychiatric disorders.
One of the landmark studies of the prevalence of psychiatric disorders in
the United States was the ECA survey conducted in the 1980s. The National
Institute of Mental Health (NIMH) established the ECA program to
determine the prevalence of specific psychiatric disorders in both
community and institutional populations (Regier et al. 1984). Data were
collected in five communities, and the DIS was used to identify persons
who met criteria for specific disorders. DIS diagnoses were based on DSM-
III criteria (American Psychiatric Association 1980), the nomenclature in
effect at the time the data were collected. More than 18,000 persons were
interviewed in the ECA study, including 5,702 persons who were ages 65
years and older. All disorders, with the exception of cognitive impairment,
were more prevalent in younger or middle-aged adults than in older adults.
Of those ages 65 and older, 12.3% (13.6% of the women and 10.5% of the
men) met criteria for one or more psychiatric disorders in the month prior to
the interview. The two most prevalent disorders in this age group were any
anxiety disorder (5.5%) and severe cognitive impairment (4.9%) (Regier et
al. 1988).
Several large-scale epidemiological surveys provide more recent
estimates of lifetime and current prevalence of psychiatric disorders. These
large-scale studies have added to the rich data provided earlier by the ECA
surveys and by numerous smaller studies conducted in various geographic
locations. The National Epidemiologic Survey on Alcohol and Related
Conditions (NESARC) was sponsored by the National Institute on Alcohol
Abuse and Alcoholism. From 2001 to 2002, in-person interviews were
conducted with 43,093 participants ages 18 years and older, and the data
were weighted to represent the U.S. population at the time of the 2000
census, enabling national estimates of the prevalence of psychiatric
disorders using DSM-IV criteria (American Psychiatric Association 1994)
(Grant et al. 2005b). The diagnostic interview used was the Alcohol Use
Disorder and Associated Disabilities Interview Schedule—DSM-IV Version
(Grant et al. 2001). A 3-year follow-up (Wave 2) was conducted in 2004–
2005.
The World Health Organization (WHO) World Mental Health (WMH)
surveys were conducted from 2001 to 2003 in 14 countries, and a total of
60,463 adults were interviewed. DSM-IV psychiatric diagnoses were
assessed using the WMH version of the WHO Composite International
Diagnostic Interview (Demyttenaere et al. 2004; Kessler and Ustün 2004).
In the United States, the WMH survey was called the National Comorbidity
Survey Replication (NCS-R) and included data from 9,282 adults ages 18
years and older (Kessler et al. 2005).
The Collaborative Psychiatric Epidemiology Surveys (CPES) initiative
sponsored by NIMH combined three nationally representative studies that
used the same research methods: the NCS-R (described in the previous
paragraph), the National Survey of American Life, and the National Latino
and Asian American Study, all conducted in the United States between
2001 and 2003 (Heeringa et al. 2004). The CPES provided the opportunity
to examine the prevalence of major depression by racial/ethnic group and
immigration status. The 12-month prevalence of major depression among
individuals ages 65–74 years was 5.1% among those born in foreign
countries compared with 4.3% among those born in the United States,
whereas the lifetime prevalence was higher among participants born in the
United States (15.9%) than among those born in foreign countries (11.7%).
The lifetime prevalence of major depression among individuals ages 65–74
years was highest among Cubans (14.7%), Chinese (14.1%), Puerto Ricans
(14.0%), and whites (12.8%) compared with Mexican Americans (10.1%),
Vietnamese (8.7%), African Americans (5.6%), Black Caribbeans (5.3%),
and Filipinos (<0.01%) (González et al. 2010).
Overall, psychiatric disorders are found at a lower prevalence among
older adults than among individuals at other stages of the life cycle. Gum et
al. (2009) reported the prevalence of anxiety, mood, and substance disorders
among those ages 65 years and older in the NCS-R. The prevalence of any
of these disorders was 8.5%. This prevalence was lower than that reported
for individuals ages 18–44 years (27.6%) or those ages 45–64 years
(22.4%). Among individuals ages 65 and older, 6.3% had one of these
disorders, 1.3% had two disorders, and 0.9% had three or more disorders.
Although the prevalence of these disorders was lower among older
individuals, those at higher risk (e.g., the medically ill and those in long-
term care facilities) were not represented in the study.
Specific disorders are addressed in detail in subsequent chapters, but
Tables 1–1 through 1–5 provide summaries of the prevalence of psychiatric
symptoms and disorders in both community and clinical populations based
on selected studies conducted in the United States and other countries over
the last several decades.
The prevalence of broadly defined cognitive impairment in selected
community and institutional populations of older adults is presented in
Table 1–1 and ranges from 7.4% in community studies to 15.7% in primary
care samples. Since the late 1990s, much attention has focused on
“cognitive impairment no dementia” (CIND) and mild cognitive
impairment (MCI), and the studies listed in Table 1–1 report CIND/MCI
prevalence estimates ranging from 2% to 39%, depending on the age group
assessed and the research setting (community vs. institutional). These data
indicate that the prevalence of cognitive impairment is higher in samples
that include patients from primary care or residential care facilities. Also, as
shown in Table 1–1, some studies have focused on the prevalence of
different subtypes of MCI (e.g., amnestic MCI, other MCI).

TABLE 1–1. Prevalence of cognitive impairment in community and

institutional populations of older adults
Study Sample N Age Prevalence
(years)
Sachdev et al. Community—Sydney Memory 757 70+ MCI=39.1%
2012 and Aging Study
Plassman et al. Community—Aging, 856 >70 MCI/CIND=22.2%
2008 Demographic, and Memory
Study
Trollor et al. 2007 Community—Australian 1,792 65+ 7.4%
representative sample
Manly et al. 2005 Community sample in New York 1,315 65+ Amnestic MCI=5.0%
Other MCI=2.1%–6.2%
Ganguli et al. 2004 Community—Monongahela 1,248 Mean=74.6 Amnestic MCI=2.9%–
Valley Independent Elders 4.0% over 10 years
Survey
Busse et al. 2003 Community sample in Germany 1,045 75+ MCI=3.1%
Age-associated
cognitive
decline=8.8%
Lopez et al. 2003 Community—Cardiovascular 2,470 65+ MCI=19% <75 years
Health Study—Cognition Study MCI=29% 85+ years
Hänninen et al. Community and institution— 806 60–76 MCI=5.3%
2002 Population-based sample in
eastern Finland
Graham et al. 1997 Community and institution— 2,914 65+ CIND=16.8%
Canadian Study of Health and
Aging
Callahan et al. Primary care patients in Indiana 3,594 60+ 15.7%
1995
Note. CIND=cognitive impairment no dementia; MCI=mild cognitive impairment.

It is important to note that the studies in Table 1–1 reporting the

prevalence of cognitive impairment measured cognitive function using
standardized screening tests. Therefore, these studies do not report the
prevalence of dementia or Alzheimer’s disease or actual cerebral
impairment, although some of the recent studies have augmented their test
results with imaging data (e.g., Lopez et al. 2003). The prevalence of
cognitive impairment as assessed through these screening tests can be
affected by the educational level of the population being studied, as well as
by other sociocultural factors that may affect performance on cognitive
tasks.
The prevalence of dementia and Alzheimer’s disease in both community
and institutional samples is shown in Table 1–2. Overall, the prevalence of
dementia is lower than that of cognitive impairment or MCI, and is
estimated to be 0%–23% in the community. The prevalence of dementia in
primary care samples is higher than observed in community samples
(Olafsdóttir et al. 2001) and lower than that observed in long-term care
facilities, which often have a higher mean age (Bland et al. 1988; Rovner et
al. 1986).
In the East Boston Established Populations for Epidemiologic Studies of
the Elderly (EPESE), the prevalence of probable Alzheimer’s disease
increased with age. Specifically, the prevalence was 3.0% in those ages 65–
74 years, 18.7% in those ages 75–84 years, and 47.2% in those ages 85
years and older (Evans et al. 1989). In recent years, research has focused
more on earlier stages of cognitive decline, such as MCI, than the
prevalence of subtypes of dementia (Panza et al. 2005) assessed using
techniques such as imaging data (Feldman and Jacova 2005), resulting in
fewer studies of the prevalence of Alzheimer’s disease. In DSM-5, MCI has
been subsumed under the new diagnostic criteria of mild neurocognitive
disorder; however, there are not extant community-based studies using
these criteria (which are so recently published).
The prevalence of psychiatric symptoms in community samples of older
adults is presented in Table 1–3. The most frequently reported symptoms
are generally problems with sleep and feelings of anxiety. Psychotic
symptoms are less prevalent than anxiety symptoms in community samples
but may be as high as 10% in the oldest old. Although the prevalence of
alcohol use in older adults is low, binge drinking is more common among
older adults with subsyndromal alcohol use than among those with no
symptoms and is higher than expected in this age group (Blazer and Wu
2011).
Numerous studies have reported a high prevalence of depressive
symptoms among older adults. As shown in Table 1–3, the prevalence of
depressive symptoms may be as high as 25.6% in community samples. The
prevalence is even higher in residential care settings (Anstey et al. 2007)
and is generally higher in females than males (Black et al. 1998).
Across the entire life cycle, many psychiatric symptoms, especially
hypochondriasis and sleep disorders, have their highest frequencies among
elderly individuals. A relatively high frequency of certain symptoms in
elderly populations, however, does not necessarily signify an increased
frequency of specific psychiatric disorders. The paradox of relatively high
reports of depressive symptoms and relatively low reports of the prevalence
of major depressive episodes illustrates this point. In the NESARC Wave I,
using individuals ages 65 years and older as the reference group, the odds
of lifetime subsyndromal depression with limited symptoms were lower
among those younger than age 65 years (odds ratio [OR]=0.76 for ages 18–
29 years; OR=0.77 for ages 30–44; OR=0.97 for ages 45–64). The odds of
lifetime major depression, however, were higher among those younger than
age 65 years (OR=1.91 for ages 18–29 years; OR=2.05 for ages 30–44;
OR=2.26 for ages 45–64) (Pietrzak et al. 2013).

TABLE 1–2. Prevalence of dementia and Alzheimer’s disease in

community and institutional populations
Study Sample N Age Prevalence
(years)
Li et al. 2007 Community-dwelling elderly 1,593 60+ Dementia=2.51%
in Beijing, China
Plassman et al. Community—Aging, 856 >70 Dementia=13.9%
2007 Demographics, and
Memory Study
Stevens et al. 2002 Community residents of 1,085 65+ Dementia=9.86%
Islington, United Kingdom Among those with
dementia:
Alzheimer’s
disease=31.3%
Vascular
dementia=21.9%
Dementia with
Lewy
bodies=10.9%
Frontal lobe
dementia=7.8%
Olafsdóttir et al. Primary care center in 350 70+ Dementia=16.0%
2001 Sweden
Riedel-Heller et al. Community and institution— 1,692 75+ DSM-III-R
2001 Leipzig Longitudinal Study dementia=17.4%
of the Aged ICD-10
dementia=12.4%
Canadian Study of Community and institution— 10,263 65+ Dementia=8.0%
Health and Aging Canada Alzheimer’s
Working Group disease=5.1%
1994
Heeren et al. 1991 Community residents of 1,259 85+ Dementia=23.0%
Leiden, The Netherlands (11.0% with moderate
or severe dementia)
Evans et al. 1989 Community—East Boston 467 65+ 10.3% probable
Established Populations for Alzheimer’s disease
Epidemiologic Studies of
the Elderly
Bland et al. 1988 Community and institution— 358 65+ Severe cognitive
Edmonton, Alberta, Canada community impairment:
199 Community=0.0%
institutions
Institution=42.0%
female, 36.1% male

TABLE 1–3. Prevalence of psychiatric symptoms in community

populations of older adults
Study Sample N Age Symptoms/syndrome Prevalence
(years)
Blazer and Wu Community— 6,289 65+ Alcohol dependence 5.2%
2011 National symptoms
Survey on
Drug Use
and Health
Anstey et al. Community 1,116 65+ Depressive symptoms 14.4% community
2007 and 32.0% institution
institution—
Australia
Stek et al. 2004 Community— 500 85+ Depressive symptoms 15.4%
Leiden 85+
Study
Ostling and Community 347 85+ Psychotic symptoms 10.1% (delusions 5.5%,
Skoog 2002 and hallucinations
institution— 6.9%, paranoid ideation
Sweden 6.9%)
Black et al. 1998 Community— 2,823 65+ Depressive symptoms 25.6% (male 17.3%,
Hispanic female 31.9%)
EPESE
Forsell and Community 966 78+ Feelings of anxiety 24.4%
Winblad 1998 and
institution—
Stockholm
Beekman et al. Community— 3,056 55–85 Minor depression 12.9%
1995 Longitudinal
Aging
Studies
Amsterdam
Cornoni-Huntley Community— 3,673 65+ Trouble falling asleep 14.1%
et al. 1986 Iowa EPESE
Awakening during 33.7%
night
Daytime sleepiness 30.7%
Christenson and Community— 997 65+ Persecutory ideation 4%
Blazer 1984 North
Carolina
Note. EPESE=Established Populations for Epidemiologic Studies of the Elderly.

Diagnostic categories, such as those found in DSM-5, are clusters of

symptoms and signs that derive their validity not from the overall weight of
symptomatology but rather from regularities in the clustering of history, the
persistence of symptoms over time, a predictable outcome, a common
pathophysiology, and possible biochemical disturbances. As biological
markers of psychiatric disorders are identified and refined, laboratory
diagnostic techniques will provide information that is complementary to the
symptoms reported. As knowledge progresses in the area of nomenclature,
new categories of symptoms may be lumped together to define a particular
syndrome. Symptoms, the most objective clinical indicators of
psychopathology, may reflect more than one diagnostic entity; however,
symptoms also may not be associated with any disorder of interest to the
clinician. For example, decreased appetite can result from several sources.
At a given time, grief reactions, more frequent in late life than at other
stages of the life cycle, may be virtually indistinguishable from major
depressive episodes if appetite alone is considered. Loss of appetite also
accompanies major life adjustments such as forced change of residence or a
decline in economic resources. Most commonly, loss of appetite in late life
is a result of poor physical health.
The prevalence of selected psychiatric disorders in community
populations, shown in Table 1–4, is lower than the prevalence of related
psychiatric symptoms (see Table 1–3). The disorder with the highest 12-
month prevalence among participants ages 65 years and older reported from
the NESARC was specific phobia (7.5%) (Stinson et al. 2007), whereas the
disorder with the highest lifetime prevalence was any alcohol use disorder
(16.1%) (Hasin et al. 2007). In the NCS-R, the disorder with the highest 12-
month prevalence among adults ages 65 and older was also specific phobia
(4.7%) (Gum et al. 2009). The disorder with the highest lifetime prevalence
among participants ages 60 years and older was major depression (10.6%)
(Kessler et al. 2005). The presentation of studies in Table 1–4 provides an
opportunity to note several important points to consider when comparing
prevalence estimates across studies. Lifetime prevalence is generally higher
than but can be equal to point prevalence. Similarly, prevalence is
dependent on both the incidence and duration of the disorder within the
period of risk, so 12-month prevalence is generally higher than 1-month
prevalence. Prevalence estimates also can vary depending on the diagnostic
instruments used (which may explain in part the differences between the
lifetime prevalence estimates reported in the NCS-R and the NESARC).
As shown in Table 1–4, the current prevalence of major depression
reported from these studies ranges from around 1% to 3%. The prevalence
is higher in older women than in men (Gum et al. 2009). The current
prevalence of anxiety disorders is higher than that of major depression, and
the estimates depend in part on whether specific phobia is included. As
shown in Table 1–4, the current prevalence of individual disorders is
highest for specific phobia (approximately 4%–8%) and lowest for panic
disorder (<1%). The current prevalence of generalized anxiety disorder is
approximately 1%. The prevalence of any anxiety disorder among adults
ages 65 years and older in the NCS-R was 7.0%, with a higher prevalence
in women (10.4%) than in men (2.4%) (Gum et al. 2009). As shown in
Table 1–4, the current prevalence of alcohol abuse/dependence is low
(0.3%–1.5%). Similarly, the 1-month prevalence of schizophrenia among
persons ages 65 years and older in the ECA study was 0.1% (Regier et al.
1988).
The virtual absence of alcohol abuse or dependence in individuals 65
years and older may reflect selective mortality. It may also reflect changes
in drinking patterns (the lifetime prevalence in the NESARC was 16.1%,
whereas the 12-month prevalence was 1.5%) (Hasin et al. 2007). On the
other hand, the low prevalence of both alcohol abuse and schizophrenia
may also reflect the case-finding techniques used. For example, the
investigators in the ECA, the NCS-R, and the NESARC studies did not
attempt to assess the homeless population. Also, the community data do not
include individuals in institutions, and many persons in late life with
chronic schizophrenia may be institutionalized. To obtain prevalence
estimates, it can be useful to assess other populations. For example, in a
study from the Netherlands (Meesters et al. 2012), the 12-month prevalence
estimates of schizophrenia spectrum disorders in individuals ages 60 years
and older who were in contact with mental health services in one
psychiatric catchment area were as follows: 0.71% for all schizophrenia
disorders, 0.55% for schizophrenia, 0.14% for schizoaffective disorder, and
0.03% for delusional disorder. The 12-month prevalence of early-onset
schizophrenia was 0.35%, of late-onset schizophrenia was 0.14%, and of
very-late-onset schizophrenia-like psychosis was 0.05%.
Another question derives from the prevalence data for older adults: Do
unique late-life symptom presentations render the DSM-5 inadequate as a
system of nomenclature? DSM-5 provides age-specific categories for
children but not for elderly persons. Clinicians who work with older adults,
however, have often commented that depression may be masked in late life
by symptoms of poor physical health or dementia. However, there is no
compelling evidence for developing a new classification specific to older
adults. Although DSM may not identify all persons with significant
psychiatric symptoms, those older persons who do qualify for a DSM
diagnosis are not unlike persons at other stages of the life cycle (Blazer
1980a; Blazer et al. 1987a). The deficiency inherent in DSM-5 is that it
poorly differentiates psychiatric symptoms from symptoms that signify the
presence of physical illness and impaired cognition—a situation that may
also occur in younger individuals, although it is far more common as a
diagnostic problem in late life than in middle life.
The prevalence of psychiatric symptoms and disorders, especially major
depression, in treatment settings is presented in Table 1–5. The prevalence
of both symptoms and disorders is much higher than is found in community
populations. The prevalence of major depression in nursing homes or long-
term-care facilities is estimated to be 6.0% to over 14.0%, and the
prevalence of minor depression is estimated to be as high as 30.5%. Data
collected using the Minimum Data Set showed the prevalence of mental
health conditions in older nursing home residents to be high: depression
49.6%, anxiety disorders 16.1%, bipolar disorder 2.8%, and schizophrenia
3.6% (Eden et al. 2012). The prevalence of major depression in both acute
care hospitals and primary care is also higher than that found in the
community. Many older adults may be selectively admitted to medical
inpatient units or long-term-care facilities. The lower prevalence in the
community, therefore, should not lull clinicians into believing that
psychiatric problems are of little consequence to older adults.

TABLE 1–4. Prevalence of selected psychiatric disorders in community

populations of older adults
Study Sample N Age Disorder Period Prevalence
(years)
Gum et Community— 9,282 65+ Major depression 12 2.3%
al. National Representative Dysthymia months 0.5%
2009 Comorbidity U.S. sample age Bipolar disorder 0.2%
Survey 18+ (1,461 age
Replication 65+)
Panic disorder 0.7%
Agoraphobia without 0.4%
panic
Specific phobia 4.7%
Social phobia 2.3%
Generalized anxiety 1.2%
disorder
PTSD 0.4%
Any substance use <0.01%
disorder
Kessler Community— 9,282 60+ Major depression Lifetime 10.6%
et al. National Representative Dysthymia 1.3%
2005 Comorbidity U.S. sample age Panic disorder 2.0%
Survey 18+ (1,837 age
Replication 60+)
Agoraphobia without 1.0%
panic
Specific phobia 7.5%
Social phobia 6.6%
Generalized anxiety 3.6%
disorder
PTSD 2.5%
Obsessive-compulsive 0.7%
disorder
Alcohol abuse 6.2%
 Alcohol dependence 2.2%
Hasin et Community— 43,093 65+ Major depression 12 2.7%
al. NESARC months
2005
Representative Lifetime 8.2%
U.S. sample age
18+ (8,205 age
65+)
Grant et Social anxiety disorder 12 1.6%
al. months
2005a
Lifetime 3.0%
Grant et Generalized anxiety 12 1.0%
al. disorder months
2005b
Lifetime 2.6%
Grant et Panic disorder 12 0.8%
al. months
2006
Lifetime 2.8%
Hasin et Alcohol use disorder 12 1.5%
al. months
2007
Lifetime 16.1%
Stinson Specific phobia 12 7.5%
et al. months
2007
Regier et Community— 18,571 age 18+ 65+ Major depression 1 month 0.7%
al. Epidemiologic (5,702 age 65+) Dysthymia 1.8%
1988 Catchment Any anxiety disorder 5.5%
Area in five
U.S.
communities
Phobic disorder 4.8%
Schizophrenia 0.1%
Alcohol 0.9%
abuse/dependence
Trollor et Community— 1,792 65+ Major depression 1 month 1.2%
al. Australian Dysthymia 0.2%
2007 National Panic 0.3%
Mental Health disorder/agoraphobia
and Well-Being
Survey
Social phobia 0.1%
Generalized anxiety 0.8%
 disorder
PTSD 0.2%
Alcohol 0.3%
abuse/dependence
Bland et Community— 358 65+ Major depression Current 1.2%
al. Edmonton,
1988 Alberta,
Canada
Phobic disorder 3.0%
Panic disorder 0.3%
Note. NESARC=National Epidemiologic Survey on Alcohol and Related Conditions;
PTSD=posttraumatic stress disorder.

Fewer data regarding the incidence of psychiatric disorders in late life

are available because most disorders begin early in adulthood. Among
individuals ages 60 years and older, the 3-year incidence of DSM-IV
disorders reported from Wave 2 of the NESARC was 3.28% for major
depression, 0.76% for panic disorder, 1.35% for specific phobia, 0.58% for
social phobia, 1.63% for generalized anxiety disorder, 3.38% for nicotine
dependence, 1.02% for alcohol abuse, 0.40% for alcohol dependence, and
0.29% for drug abuse/dependence (Chou et al. 2011). The 1-year incidence
(per 100 person-years) reported from the ECA among individuals age 65 or
older was 1.25 for major depression, 0.04 for panic disorder, 4.29 for
phobic disorder, and 0.63 for alcohol abuse/dependence (Eaton et al. 1989).
In a study of 875 nondepressed older adults with a mean age of 85 years,
the 3-year incidence of depression was 4.1% (Forsell and Winblad 1999).
Henderson et al. (1997) reported that the 3- to 6-year incidence of
depression in a sample of community-dwelling elderly individuals ages 70
years and older was 2.5%. The 2-year incidence of depression defined by
the Geriatric Depression Scale (not necessarily first-onset depression) was
8.4% in adults ages 65 years and older in a community sample in London
(Harris et al. 2006). Incidence of depression differs by gender. In a Swedish
population of adults followed from age 70 to age 85, the incidence of first-
onset depression was 12 per 1,000 person-years for men and 30 per 1,000
person-years for women (Palsson et al. 2001). The incidence of
schizophrenia among older adults is estimated to be 3 new cases per
100,000 persons per year (Copeland et al. 1998). Bachman et al. (1993)
reported that the 5-year incidence of dementia from a community survey
was 7 per 1,000 in individuals ages 65–69 years and 118 per 1,000 in those
ages 85–89 years. A similar increase with age in the 1-year incidence of
Alzheimer’s disease was reported from the East Boston EPESE: 0.6% in
individuals ages 65–69 years and 8.4% in those ages 85 years and older
(Hebert et al. 1995).

Historical Studies
Psychiatrists typically follow patients for relatively short periods during the
course of their illnesses. In addition, they usually interact with each patient
within a relatively brief window of historical time. Epidemiological studies
add a historical perspective to current cross-sectional findings in population
and clinical surveys. Historical studies in psychiatric epidemiology are rare.
Temporal changes that occur with most behaviors that are of psychiatric
interest must be determined over years rather than months. Longitudinal
studies introduce problems of loss to follow-up. With the caveat that case
identification methods change over time and place, rendering the detection
of historical trends subject to misclassification error, historical studies have
contributed importantly to estimating the separate effects of age, historical
events, and cohort behavior on the incidence of mental illness. For example,
the benefits of historical studies can be seen in trends of suicide mortality
among older adults.

TABLE 1–5. Prevalence of selected psychiatric symptoms and disorders

among older adults in selected treatment settings
Study Sample N Age Disorder Prevalence
(years)
McCusker et Two acute care 380 65+ Major depression 14.2%–
al. 2005 hospitals in Minor depression 44.5%
Montreal 7.9%–9.4%
Smalbrugge AGED Study 333 55+ Any anxiety 5.7%
et al. 2005 —nursing disorder 4.2%
home Subthreshold 29.7%
patients on anxiety disorder
somatic Anxiety symptoms
wards in The
Netherlands
Jongenelis et AGED Study 333 55+ Major depression 8.1%
al. 2004 —nursing Minor depression 14.1%
home 24%
 patients on Subclinical
somatic depression
wards in The
Netherlands
Sheehan et al. Primary care 140 65+ Hypochondriacal 5%
2003 sample in neurosis
England
Bruce et al. Elderly home 539 65+ Major depression 13.5%
2002 health care
patients in
New York
Teresi et al. Nursing home 319 Mean=84.5 Major depression 14.4%
2001 sample in
New York
Lyness et al. Primary care 224 60+ Major depression 6.5%
1999 sample in Minor depression 5.2%
New York
Parmelee et Nursing home 708 Mean=84 Major depression 12.4%
al. 1989 and Minor depression 30.5%
congregate
housing
sample in
Pennsylvania
Note. AGED=Amsterdam Groningen Elderly Depression.

Suicide mortality is positively correlated with age. Suicide mortality in

the United States in 2010 was almost twice as high for men ages 65 years
and older (29.0 per 100,000 men) than for men ages 15–24 years (16.9 per
100,000 men). Suicide mortality has long been lower among women than
among men. In 2010, the suicide rate was 3.9 per 100,000 women ages 15–
24 years versus 4.2 per 100,000 women ages 65 years and older (National
Center for Health Statistics 2012).
Pooled data obscure significant differences among older persons across
gender, racial, and ethnic subgroups. For example, in 2010 in the United
States, suicide rates among men ages 65 years and older varied by race and
ethnicity: the suicide rate for non-Hispanic white men was 32.7 per
100,000, compared with 8.3 for non-Hispanic black men, 14.9 for Asian
men, and 15.7 for Hispanic men. Rates for women ages 65 years and older
were 4.7 for non-Hispanic white women, 4.3 for Asian women, and 2.2 for
Hispanic women (National Center for Health Statistics 2012).
Age-related increases in suicide rates have flattened over the past
century. Although suicide has continued generally to increase with age,
later-born cohorts demonstrate lower suicide rates as they age across time
than earlier cohorts. For example, the suicide rate among U.S. adults ages
65 years and older was 30.0 per 100,000 in 1950 but decreased to 14.9 per
100,000 in 2010. One trend causing concern, however, is the increase in
suicide deaths among middle-aged adults in the United States between 1999
and 2010 (Centers for Disease Control and Prevention 2013). From 1999 to
2010, the age-adjusted suicide rate for individuals ages 35–64 years
increased by 28.4%, from 13.7 per 100,000 population to 17.6 (P<0.001).
Among men, the greatest increases were observed among those ages 50–54
years (49.4%, from 20.6 to 30.7) and those ages 55–59 years (47.8%, from
20.3 to 30.0). Among women, the greatest increase was among those ages
60–64 years (59.7%, from 4.4 to 7.0). The rise in suicide rates among those
approaching late life may be due in part to the economic downtown during
the period from 1999 to 2010, to a cohort effect (in that baby boomers had
higher suicide rates during adolescence and may represent a cohort at
greater risk), and to a rising incidence of opioid overdose associated with
increased availability (Centers for Disease Control and Prevention 2013).
Figure 1–1 shows the suicide rates per 100,000 population by decade from
1950 to 2010 for white men; the recent increase among middle-aged white
men (ages 55–64 years) is shown in the graph.
Interpretations of the findings from historical studies are often prey to
the ecological fallacy, which assumes that putative exposures and effects
measured in aggregates and not for individuals are causal. That suicide
prevention measures coincide with a drop in suicide mortality rates—or
conversely that economic recession coincides with a rise in rates—does not
indicate causality. Such conclusions require well-designed etiological
studies.
FIGURE 1–1. Suicide trends among older white men in the United States
from 1950 to 2010.
Source. National Center for Health Statistics 2012.

Etiological Studies
One of the basic contributions of epidemiology is to identify determinants
of disease or to identify causal factors that can offer the possibility of
disease prevention. Within geriatric psychiatry, it is important to identify
factors that can either predispose individuals to developing psychiatric
disorders or precipitate the recurrence of such disorders. These disorders
may have their initial onset in late life, or the disorders may have an early
onset and recur later in life. Other factors can be identified that are
associated with the prevalence of a disorder, but the antecedent-consequent
relationship has not been established. For practical purposes in this
discussion, we identify all of these as risk factors. These factors generally
fall into several categories, including genetic or biological factors,
environmental or chemical factors, and social factors. Examples of each are
provided in the following subsections. In addition, the presence of a
comorbid physical or mental condition or disorder often leads to the
development of psychiatric symptoms or another disorder, and these are
described in chapters related to specific disorders throughout this textbook.

Genetic Factors
The genetic predisposition to psychiatric disorders is covered in other
chapters of this textbook (e.g., see Chapter 3, “Genomics in Geriatric
Psychiatry”) and is not reviewed here. Research that focuses on the
interaction between genetic and environmental factors and the occurrence
of disease (Hernandez and Blazer 2006), however, can potentially offer new
information on the etiology of psychiatric disorders. For example, Hendrie
et al. (2004) reported a significant association between the ε4 allele of the
apolipoprotein E gene (APOE*E4) and Alzheimer’s disease in African
Americans in Indianapolis, Indiana, but these alleles were not associated
with an increased risk for Alzheimer’s disease among Yoruba living in
Ibadan, Nigeria, suggesting that the interaction between gene and
environment may play a role in the etiology of the disease. Gatz et al.
(1992) studied genetic and environmental contributions to self-reported
depressive symptoms in older adults in a sample of twin pairs. Genetic
influence accounted for 16% of the variance in depression score and for
19% of the variance in psychomotor and somatic complaints, but
heritability was minimal for depressed mood and well-being. Although
shared experiences contributed to the variance, the most important correlate
of late-life depressive symptoms was nonshared experiences.

Physical Agents in the Environment

Physical agents in the environment may lead to cognitive problems and
other psychiatric symptoms. One such relationship is the effect of diet on
psychiatric disorder. Susser and Lin (1992) examined the risk of
schizophrenia onset in birth cohorts exposed to prenatal food deprivation
during the Dutch Hunger Winter of 1944–1945. They reported an increased
risk of schizophrenia among women who were born during this period in
areas of the country exposed to severe famine. Researchers later examined
the effect of this Dutch famine on brain morphology and found that
nutritional deficiency during the first trimester of gestation was associated
with brain abnormalities, particularly white matter hyperintensities, and
with aberrant early brain development in patients with schizophrenia,
suggesting that stunted brain development during the first trimester may be
a risk factor for developing schizophrenia (Hulshoff Pol et al. 2000).
Environmental agents such as bodily injuries can also be factors. One
association that has received much recent attention is the role of head
trauma (traumatic brain injury) in the later onset of mild and major
neurocognitive impairment. In one study, documented moderate or severe
brain injuries in early life were associated with a twofold increase in
Alzheimer’s disease and other neurocognitive disorders (Plassman et al.
2000). These findings on the consequences of head injury have been
extended to individuals at high risk for such trauma, such as football players
(Strain et al. 2013) and military personnel exposed to blast injuries (Barnes
et al. 2014).

Social Factors
By far the most frequently investigated environmental factors associated
with psychiatric disorders are social factors. Many investigators believe that
the changing roles and circumstances of older adults can cause stress and
thereby contribute to the onset of psychiatric disorders and cognitive
difficulties. In a study of 986 community-dwelling older adults, Blazer
(1980b) found the crude estimate of relative risk for mental health
impairment to be 2.14, given a life event score of 150 or greater on the
Schedule of Recent Events (Holmes and Rahe 1967). A relative risk of 1.73
(P<0.01) was estimated when a binary regression procedure was used,
controlling for physical health, economic status, social support, and age. In
a study of individuals ages 55 years and older, Murrell et al. (1983) found
that social factors, including widowhood, divorce, separation, and
decreased income, were related to depressive symptomatology in the
community. In the Hispanic EPESE, economic stressors and conditions
such as chronic financial strain were associated with depressive symptoms
in Mexican American elders (Black et al. 1998).
In the Longitudinal Aging Study Amsterdam, major depression was
associated with unmarried status, functional limitation, perceived
loneliness, internal locus of control, poorer self-perceived health, and lack
of instrumental social support (Beekman et al. 1995). In the Duke ECA
study, the recent experience of negative life events and poor social support
were associated with major depression (Blazer et al. 1987b). Perceived
health and loneliness were some of the correlates of depressive symptoms
in the Leiden 85-plus study (Stek et al. 2004). Depression has also been
linked with variables suggesting increased dependency (Anstey et al. 2007).
Impairment or dissatisfaction with one’s social network has been reported
to be associated with anxiety symptoms in late life (Forsell and Winblad
1998). Nevertheless, the study of social factors in relation to psychiatric
disorders must not be viewed simplistically. The mitigating effect of social
support, the perception of a stressful life event (as well as the actual
occurrence of the event), the expectancy of an event, and the perceived
importance of an event all may contribute to the effect of environmental
stress on the older adult.
In the study of social factors associated with psychiatric disorders across
the life cycle, context is essential. One study of the social and
environmental characteristics of a healthy community involved an in-depth
evaluation of selected Chicago neighborhoods (not specifically older adults)
(Sampson 2003). The investigators found that physical and mental health
were facilitated by the capacity of residents to achieve social control over
their environment and to engage in collective action for the common good.
They found that the strong ties among neighbors necessary for such
proactive action are no longer the norm in many urban communities
because friends and social support networks are not organized locally.
Given this reality, the investigators proposed a “collective efficacy theory,”
in which they focused on the combination of working trust and shared
willingness of residents to intervene in social control, a move away from
reliance on personal ties. They placed the emphasis on shared beliefs in a
neighborhood’s conjoint capability for action to achieve an effect. This type
of approach may be especially relevant to communal housing arrangements
for older adults.

Summary
From these examples, it is clear that both psychiatric disorders and
symptoms in late life can have multiple causes and that these factors may
interact with one another to produce adverse outcomes. Skoog (2004)
suggested that the science of epidemiology has much to contribute to
increased knowledge of the etiology of mental disorders in older adults and
that to maximize that contribution, future population studies should be
longitudinal and should include assessments of psychosocial risk factors as
well as biological markers such as brain imaging, neurochemical analyses,
and genetic information.

Health Service Utilization

Community-based epidemiological studies provide an opportunity not only
to estimate the prevalence of psychiatric disorders but also to examine
service use among those with psychiatric symptoms or disorders. Shapiro et
al. (1984) found that in three ECA communities (New Haven, Connecticut;
Baltimore, Maryland; and St. Louis, Missouri), 6%–7% of older adults had
made a visit to a health care provider for mental health reasons during the
previous 6 months. Those in the group age 65 years or older—even if they
were identified in the community as having a DSM-III psychiatric disorder
or severe cognitive impairment—infrequently received care from mental
health specialists. German et al. (1985) analyzed the ECA data from
Baltimore in greater detail. Of those persons younger than age 65 years,
8.7% had made a visit to a specialty or primary care provider for mental
health care during the 6 months prior to the interview. For those ages 64–74
years, the rate was 4.2%; of those ages 75 and older, only 1.4% received
such care. In the age 75 and older group, not one person among the 292
individuals interviewed saw a specialty mental health care provider. The
investigators concluded that the likeliest source of care for older individuals
with emotional or psychiatric problems was their primary care provider,
within the context of a visit for physical medical problems.
Since the ECA was conducted, the United States has seen changes in the
service sectors used for mental health care, with the general medical sector
experiencing the largest proportional increase (Wang et al. 2006). In the
NCS-R, participants ages 60 years and older were less likely than those in
younger age groups to receive any mental health treatment in the previous
12 months. Among individuals who received treatment, those ages 60 years
and older were less likely to receive treatment in the health care setting, and
those older adults who did receive treatment in the health care setting were
less likely to receive treatment in a mental health specialty (Wang et al.
2005b). Being in an older cohort was also associated with failure to make
initial treatment contact for mental health treatment after initial onset of the
disorder and with delay among those who eventually made treatment
contact (Wang et al. 2005a). Klap et al. (2003) reported that older adults
who met criteria for a psychiatric disorder were less likely than younger
adults to perceive a need for mental health care, to receive specialty mental
health care or counseling, and to receive referrals from primary care to
mental health specialty care. Older patients seen in primary care who
receive a diagnosis of depression are more likely to have increased total
ambulatory costs, tests, and consultations than older primary care patients
without this diagnosis (Luber et al. 2001).
In the CPES, racial differences in mental health service use were noted
among adults ages 60 years and older. Twenty percent of whites compared
with 13% of blacks reported using mental health services within the
specialty mental health sector, the general medicine sector, or any other
service sector within the past year. Differences by region, however, were
only significant in the South, where white elders were twice as likely as
blacks to use mental health services (Kim et al. 2013). Addressing cultural
beliefs about the causes of mental illness and treatment preferences may
help reduce these racial/ethnic disparities (Jimenez et al. 2012).
In contrast to less treatment use by older adults than by younger adults,
psychotropic drug use is higher among older than among younger
individuals. For example, the prevalence of past-month psychotropic drug
use reported in the National Health and Nutrition Examination Survey
(NHANES) 1999–2002 was 6.6% among adults ages 17–39 years
compared with 14.9% among adults ages 60 years and older (Paulose-Ram
et al. 2007). According to NHANES studies conducted in different years,
the use of antidepressants has increased across all age groups. Although the
use of antidepressants among individuals ages 60 years and older increased
from 3.2% in 1988–1994 to 9.5% in 1999–2002, the use of antianxiety,
sedative, and hypnotic medications in this age group remained relatively
stable (Paulose-Ram et al. 2007). In the CPES, the use of antidepressants
among individuals ages 65 years and older was much higher among whites
(7.8%) than among blacks (3.9%) (González et al. 2008).
Even though a high proportion of older adults use psychotropic
medications, their disorders, such as depression, remain untreated. In a
study of health maintenance organization enrollees, Unützer et al. (2000)
found that 4%–7% of the older adults received treatment for depression but
that most of the older individuals with probable depression did not receive
treatment.
The value of community surveys does not end with a description of
patterns of health services use. Such investigations are especially useful for
determining the need for service for noninstitutionalized and
institutionalized elderly persons. By sampling elderly community-dwelling
populations, researchers can collect data on the proportion of older
individuals with impairment, those with a need or perceived need for
services, and the current use of services. This information can be used by
government and private agencies to chart effective assessment, treatment,
and prevention patterns. This use is especially relevant to the care of older
individuals because they tend to be isolated, their psychiatric impairment
may be masked, and they are less active advocates for their mental health
needs than are younger persons.
A report by the Institute of Medicine (Eden et al. 2012) documented the
inadequacy of the U.S. mental health workforce to meet the needs of older
adults into the twenty-first century. Persons who take care of the mentally
ill elderly population, such as psychiatrists, psychologists, social workers,
nurses, primary care physicians, and direct care workers, not only are
insufficient in numbers but also are ill prepared in terms of training and
support. Financial support for many programs that were designed to
enhance this workforce has been phased out because of budget cuts. In
addition, enhancing this workforce is most fragmented at present, and an
economy of effort cannot be reached until the challenge of supporting this
workforce is organized and centralized, especially by the federal
government.
In summary, studies of older adults have shown that the prevalence of
psychiatric disorders and psychiatric symptoms in older adults are
significant, and this has implications for all types of health service
utilization.

Conclusion
The number of persons age 65 years or older is expected to increase over
the next several decades. Projections show that a higher proportion of these
older adults than observed in previous generations will have experienced a
DSM disorder in their lifetime, putting them at risk for chronic or recurrent
disorders. Epidemiological studies, particularly large-scale, community-
based surveys, can provide clues as to the etiology of these disorders by
observing risk factors as they occur in the general population. These
surveys can also provide important information about the use of health
services among older individuals and help quantify areas where there is
need.

Key Points
• The proportion of older adults in the United States is expected to
dramatically increase over the next 50 years and to be accompanied by
an increase in the number of older adults with psychiatric disorders.
• The prevalence of clinically significant psychiatric symptoms is
generally higher than the prevalence of psychiatric disorders, and the
prevalence of both symptoms and disorders is higher in clinical samples
than in community samples. Psychiatric syndromes, rather than
disorders, are the more realistic diagnostic entities in geriatric psychiatry.
• Alzheimer’s disease is the most prevalent form of dementia, and its
prevalence increases with age.
• Sleep problems, anxiety symptoms, and depressive symptoms are the
most prevalent psychiatric symptoms among older adults.
• The frequency of binge drinking is higher than expected among older
adults.
• Besides dementia, anxiety disorders (particularly phobic disorders) are
the most prevalent psychiatric disorders in older adults in community
samples.
• Genetic, environmental, and social factors, as well as their interaction,
can predispose individuals to psychiatric disorders in late life or be risk
factors for the recurrence of psychiatric symptoms.
• The high suicide rate among older adults is due primarily to the high rate
in older white males.
 • Older adults are less likely than younger adults to seek treatment for
mental health problems, and if treatment is sought, it is likely to be
within the primary care setting.
• Even though a high proportion of older adults use psychotropic
medications, psychiatric disorders, particularly depression, are generally
untreated in older persons.

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Suggested Readings
Eden J, Le M, Maslow K, Blazer D: The Mental Health and Substance Use
Workforce for Older Adults: In Whose Hands? Washington, DC,
National Academies Press, 2012
Gum AM, King-Kallimanis B, Kohn R: Prevalence of mood, anxiety, and
substance-abuse disorders for older Americans in the National
Comorbidity Survey-Replication. Am J Geriatr Psychiatry 17(9):769–
781, 2009
Jeste DV, Alexopoulos GS, Bartels SJ, et al: Consensus statement on the
upcoming crisis in geriatric mental health: research agenda for the next
2 decades. Arch Gen Psychiatry 56(9):848–853, 1999
Kessler RC, Berglund P, Demler O, et al: Lifetime prevalence and age-of-
onset distributions of DSM-IV disorders in the National Comorbidity
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Wang PS, Lane M, Olfson M, et al: Twelve-month use of mental health
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 CHAPTER 2

Physiological and Clinical Considerations

of Geriatric Patient Care
Robert M. Kaiser, M.D., M.H.Sc.

Grow old along with me! The best is yet to be…

—Robert Browning
Will you still need me, Will you still feed me When I’m sixty-four?

—John Lennon and Paul McCartney

The long-anticipated retirement of the generation born after World

War II, the baby boomers, has begun. People older than age 65 years
constitute one of the fastest-growing segments of the U.S. population, with
an American now turning 65 every 8 seconds (Fried 2000; O’Connor et al.
2010; Werner 2011). By the year 2030, there will be 72.1 million older
persons in the United States, nearly double the number there were in 2000
(Administration on Aging 2012; Fried 2000; Hall 1997; Vaillant and
Mukamal 2001). The conquest of childhood infectious disease,
improvements in sanitation, and better nutrition all have contributed to
increased survival (McKeown 1979), and medical innovation also has had a
beneficial effect on morbidity and mortality (Hunink et al. 1997). People
are living longer, and the numbers of elderly grow with each passing year.
The average life span has lengthened significantly (Fried 2000; Hall 1997;
Vaillant and Mukamal 2001). The enactment of Social Security, Medicare,
and Medicaid legislation in the last century greatly reduced poverty and
improved access to health care among elderly individuals (Emanuel 2014).
Reaching the age of 100 years is no longer the anomaly it once was, and
centenarians have become the focus of rigorous scientific investigation
(Perls 2005). Careful and sophisticated longitudinal studies of elderly
populations in the United States, such as the Established Populations for the
Epidemiologic Studies of the Elderly (Cornoni-Huntley et al. 1986) and the
Baltimore Longitudinal Study of Aging (Shock 1984), have addressed how
and why people are living to the eighth decade and beyond. Basic science
has yielded fundamental anatomical, physiological, and genetic information
about the aging process. As a result, a more complete picture of what aging
entails has emerged.
The hallmarks of physiological change in elderly people are twofold:
impaired homeostasis (also called homeostenosis) and increased
vulnerability because of decreased reserve capacity (Armbrecht 2001;
Taffet 1999). Homeostasis—that is, the ability of the organism to maintain a
steady state—lessens with time. Consider two straightforward,
representative examples: First, in elderly individuals, the baroreceptor
reflex, which triggers vasoconstriction in order to maintain normal blood
pressure, is less robust, and elderly people are less able to respond quickly
to intravascular volume depletion. Second, when faced with repelling an
invading microorganism, an older patient is less able to mount a strong
immune response, thereby making it more difficult to fight infection
effectively. Both of these situations clearly show that altered physiology
leads the elderly patient to be more susceptible to harm. In the first example
above, an older individual might become lightheaded and possibly fall to
the floor; in the second situation, the inability to repel a virulent
streptococcus might lead to a severe upper respiratory infection or perhaps
even a life-threatening pneumonia.
“Grow old along with me! The best is yet to be,” proclaims Robert
Browning optimistically in his famous poem. One might endorse
Browning’s belief that human relationships become deeper and richer with
time, but the inevitability of physiological decline is also a reality that all
humans must face as they age. Lennon and McCartney’s rather endearing
song, which has a young man wondering what life will be like in the
seventh decade, underscores that widespread apprehension about
approaching infirmity (and McCartney himself has aged so successfully and
gracefully that he has reached the milestone of longevity he imagined five
decades ago). As individuals age, they cannot expect—as can some aspiring
Olympic athletes—to run faster, throw farther, and leap higher. Age brings
with it expected decrements in function. This chapter details the various
physiological changes that occur with “normal” aging—in other words,
those progressive changes that take place over time but not as a result of
disease. The following topics are covered:

• Physiological changes in the major organ systems

• Special implications for prescribing medications in elderly patients
because of age-related physiological changes
• Chronic diseases
• Geriatric syndromes
• Fundamental principles of geriatric assessment that follow from those
expected physiological changes

Physiological Changes in Major Organ Systems

Sensory Systems: Vision and Hearing

Older adults develop significant age-related changes in the eye, which have
important effects on vision. The weakening of the ciliary muscle, combined
with decreased curvature of the lens, results in a loss of accommodation;
therefore, it becomes difficult for an individual to focus on near objects, and
bifocals may be needed. It is also difficult for elderly people to adapt to
light because of rigidity of the pupil and increasing size and opacity of the
lens. As the lens changes with age, the increased scattering of light
produces glare, which may be bothersome to elderly people. The pupil
becomes smaller in diameter (more miotic) with age, due to atrophy of the
dilator muscle fibers and increased rigidity of the blood vessels of the iris.
This anatomical alteration in the pupil, combined with the increased
thickness of the lens, contributes to the impairment of the visual
performance of older persons at twilight. The growth in lens thickness
causes a change in the absorption of light, with a decreased sensitivity at the
violet end of the spectrum and a decreased ability to distinguish between
blues and greens. Elderly people also show a decline in their ability to view
objects at rest (static acuity) and in motion (dynamic acuity). Reportedly,
93.5% of individuals ages 40–44 years have a corrected visual acuity of
20/20 or better, compared with 41.9% of individuals ages 70–74 years
(Weymouth 1960). With age, the lens opacifies (i.e., becomes less
transparent as a result of protein aggregations), and a cataract can form.
Elderly patients are also at risk for age-related macular degeneration, which
causes loss of central vision when drusen (yellowish-white deposits)
accumulate in the retina. Age-related macular degeneration is the most
common cause of blindness in elderly people (Harvey 2003;Hubschman et
al. 2009).
In addition to changes in vision, older adults can expect alterations in the
ear, which may lead to hearing loss in both high and low frequencies. In the
middle ear, thickening of the tympanic membrane and degenerative changes
in the ossicles occur, but these changes have an insignificant effect on
function. In the inner ear, cochlear neurons are lost, and changes in the
organ of Corti, basilar membrane, stria vascularis, and spiral ligament also
affect hearing. The degeneration of the organ of Corti is associated with
high-frequency sensorineural hearing loss, whereas atrophy of the stria
vascularis may cause hearing loss across all frequencies. The stiffening of
the basilar membrane and atrophy of the spiral ligament both can result in
loss of speech discrimination (Huang and Tang 2010).

Cardiovascular System
The heart and blood vessels of aging individuals undergo significant
anatomical alterations. These structural changes lead to changes in function.
In addition, age-associated changes occur in the autonomic nervous system
and in the response of the cardiovascular system to it, and these changes
have important physiological effects. The ability of the heart to beat faster
and pump efficiently and the ease with which blood vessels dilate or
constrict are markedly affected. Both cardiac output and cardiac reserve
decrease (O’Rourke and Hashimoto 2006; Seals and Esler 2000).
With age, human blood vessels stiffen. Anatomically, the intima and
media both thicken with age, but according to autopsy studies, this
thickening occurs disproportionately in the intima, with intimal hyperplasia
observed. Oxidative stress and vascular inflammation may both contribute
to endothelial changes and dysfunction. The vessels are thicker and less
distensible. The ability of arterial vessels to transmit blood is not
appreciably affected, but the cushioning effect of the arterial system is
adversely altered. The physiological results are a greater pulse wave
velocity, early reflected pulse waves, and higher systolic blood pressures
and aortic pulse pressures in older individuals. Higher pressures can
increase the load on the heart and lead to left ventricular enlargement as
well as increased left ventricular oxygen requirements, thereby increasing
the risk of congestive heart failure. There is an increased need for coronary
blood flow oxygen, but there is a decreased ability to provide such flow due
to decreased aortic pressure during diastole as well as a reduced period of
diastole. This situation may cause cardiac ischemia by worsening
ventricular function and cardiac perfusion during diastole. Increased
pressures can also result in damage to the endothelium and media in the
microcirculation of the brain and kidneys and may be connected with organ
dysfunction (O’Rourke and Hashimoto 2006; Ungvari et al. 2010).
The function of the heart during exercise, including the force and rate of
contraction, is mediated by the sympathetic nervous system. Age-related
changes in that system affect the adaptability of the heart and blood vessels
to stress. In general, sympathetic nervous system activity rises in elderly
patients, as evidenced by higher circulating levels of norepinephrine.
Norepinephrine fills cardiac and vascular surface cell receptors, making
them less sensitive. The β-adrenergic response of the heart during exercise
is attenuated; a lower maximum heart rate and decreased force of
contraction are the result. Similarly, large arteries do not respond as well to
β-adrenergic stimulation, and their ability to dilate is reduced (Lakatta
1999; Seals and Esler 2000).
The older heart dilates during exercise to increase end-diastolic volume
and maintain stroke volume, but cardiac output nonetheless declines with
age. Because the heart stiffens, it empties less completely. This is the result
of several factors, including increased afterload, decreased contractility of
the heart, and the reduced inotropic effect of β-adrenergic stimulation to the
heart. The decline in cardiac output also adversely affects oxygen use in
older adults. The decline in cardiac function with age may explain 50% of
the reduction in maximum oxygen consumption that occurs (Lakatta 1999).

Respiratory System
As individuals age, the chest wall becomes stiffer and less compliant. From
age 24 to age 75 years, compliance declines by 31%. A number of factors
contribute to stiffening of the chest wall, including degenerative joint
disease and the calcification of the costal cartilages and chondrosternal
junction. In older individuals, osteoporosis may cause partial or wedge
fractures of the vertebrae, with resulting kyphosis and an increase in the
anteroposterior diameter of the thorax; these physical alterations can in turn
adversely affect chest wall mechanics. When an older individual generates a
breath, the relative contribution of the diaphragm and abdominal muscles is
increased compared with the thoracic muscles, as a result of decreased chest
wall compliance. Respiratory muscle function also declines because of
changes in the rib cage, decreased chest wall compliance, and decreased
elastic recoil of the lung. Respiratory muscles weaken with age, as a result
of nutritional deficiencies, anatomical changes in skeletal muscle, and
physiological decline (Janssens 2005; Sharma and Goodwin 2006).
Changes in the lung itself and in the control of breathing negatively
affect the respiratory system. A loss of elastic tissue in the lung occurs, with
a loss of elastic recoil, and the alveolar ducts and respiratory bronchioles
enlarge. This enlargement leads to a loss of alveolar surface area; less tissue
is available for gas exchange, and partial pressure of oxygen (PO2)
decreases with age but the decline is not uniform. The diffusing capacity of
the lung also declines. Higher closing volumes make full expansion of the
airways more difficult, especially in the dependent areas of the lung. The
loss of surface area combined with decreased expansion results in
ventilation-perfusion mismatch and decreased oxygenation. The control of
breathing is also altered in elderly patients. Low oxygen tension and high
carbon dioxide levels fail to provide the same physiological stimulus to
breathe, but the decreased response to hypercapnia is not consistent in all
studies.
In older people, the lung is less able to guard itself against infection
(Taffet 1999). The mucociliary tree lining the respiratory tract is slower in
trapping and expelling invading particles and microorganisms (Ho et al.
2001). With age, the person’s ability to generate a sufficiently strong cough
declines. The development of higher closing volumes further complicates
defense against infection by making it harder to expel secretions from the
lower areas of the lungs.
 Some studies suggest that exercise training can slow the respiratory
decline that occurs with aging. The age-related decrease in maximum
oxygen consumption, as well as the decreased responsiveness to low
oxygen tension or high carbon dioxide levels, can improve with exercise.
Although exercise is helpful, it cannot prevent the eventual decline in
pulmonary function (Schwartz and Kohrt 2003). The extent to which
exercise is helpful may not be consistent across all groups of older patients
(Sharma and Goodwin 2006).

Gastrointestinal System
As people age, numerous anatomical changes take place throughout the
gastrointestinal tract, some of which are functionally significant (Firth and
Prather 2002; Hall and Wiley 2003; Majumdar et al. 1997; Taffet 1999).
The production of saliva declines with age. A recent study demonstrated
that healthy adults ages 70 years and older have lower levels of stimulated
whole saliva than do adults ages 50 years and younger (Smith et al. 2013).
In older individuals, receding gums make the teeth more susceptible to
dental caries and subsequent tooth loss. The mastication of food may be
incomplete. There are fewer myenteric ganglion cells, which affects the
coordination of swallowing and may predispose some elderly patients to
aspiration. The strength of esophageal contractions is diminished, but food
nonetheless traverses the length of the esophagus uneventfully. The
production of acid and pepsin by the stomach is mostly preserved. Both the
stomach and the small intestine do not dilate as easily as a bolus of food
enters, and transit through the large bowel may be slower. The small bowel
is less effective at absorbing vitamins and minerals (e.g., vitamin D,
calcium, and iron) and sugars (e.g., xylose and lactose). The motor function
of the colon is not significantly affected by aging.
The liver, gallbladder, and pancreas continue to function well in elderly
patients (Hall and Wiley 2003; Majumdar et al. 1997; Oskvig 1999; Taffet
1999). The liver loses hepatocytes and becomes smaller; those cells
remaining are less able to regenerate. In general, the liver’s ability to
manufacture binding proteins and metabolize drugs is stable, although
considerable variability can be found across individuals. The liver makes
fewer vitamin K–dependent clotting factors. Liver transaminases and
alkaline phosphatase remain unchanged. Few significant anatomical
changes occur in the gallbladder, and its function remains intact. In the
aging pancreas, there is parenchymal fibrosis, acinar atrophy, and fatty
infiltration but no resulting impairment in the synthesis of pancreatic
enzymes and bicarbonate. The role of the pancreas in digestive function is
therefore unaffected.

Endocrine System
Prolactin
Levels of prolactin in aging women have been reported to increase,
decrease, or remain the same, whereas those in aging men are slightly
increased. None of these changes is believed to have an effect on normal
function (Gruenewald and Matsumoto 2003).

Antidiuretic Hormone
Aging causes significant changes in antidiuretic hormone (ADH) and the
body’s response to it, which alter the older patient’s ability to excrete free
water—resulting in hyponatremia—or to prevent volume losses—resulting
in dehydration. Basal ADH levels are normal to increased in older
individuals; because renal free water clearance decreases with age,
hyponatremia can more easily occur. However, when volume loss takes
place, with subsequent hypotension, less ADH is released in older
individuals. In this particular clinical situation, other age-related changes
are also at work to produce dehydration: 1) the kidney is less responsive to
ADH, which impairs its effort to make more concentrated urine, and 2)
aldosterone activity decreases and natriuretic hormone activity increases,
both of which inhibit renal conservation of sodium and restoration of
normal volume. The impaired thirst mechanism in elderly individuals
further exacerbates this scenario by preventing them from drinking
adequate amounts of fluid to correct free water losses, thereby contributing
further to dehydration (Gruenewald and Matsumoto 2003; Oskvig 1999;
Perry 1999).

Corticotropin and Cortisol

Basal corticotropin levels are normal in elderly people. Neither the
corticotropin pulse frequency nor its circadian rhythm of secretion is
altered. Stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by
exogenous corticotropin produces the expected cortisol response, but the
cortisol secretion rate actually declines. Cortisol levels remain the same
because of a decrease in the cortisol metabolic clearance rate. When
subjected to stress, the HPA axis produces higher peak cortisol levels,
which then dissipate more slowly; this occurs because the negative
feedback of cortisol on the HPA axis is less effective (Gruenewald and
Matsumoto 2003).

Adrenal Androgens
Both dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate
(DHEA-S) decrease significantly in older individuals. DHEA production
peaks at age 20 years and then declines (Fried and Walston 2003;
Gruenewald and Matsumoto 2003).

Adrenal Medulla and Sympathetic Nervous System

In older individuals, secretion of norepinephrine increases and clearance
decreases; plasma levels therefore increase. Epinephrine secretion and
clearance both increase with age, so the level of epinephrine does not
change. The level of sympathetic nervous system activity is increased in
older individuals, but both α-adrenergic and β-adrenergic receptors are less
sensitive to stimulation (Gruenewald and Matsumoto 2003; Oskvig 1999;
Seals and Esler 2000).

Renin, Angiotensin, and Aldosterone

An age-related decrease in plasma renin activity leads to reduced
aldosterone secretion; aldosterone levels are thus reduced significantly. The
rise in natriuretic hormone secretion in older adults also serves to decrease
aldosterone levels; higher levels of natriuretic hormone suppress renin
secretion, plasma renin activity, and angiotensin II, further lowering
aldosterone secretion. In addition, natriuretic hormone itself can inhibit
aldosterone secretion. The ability of corticotropin to stimulate aldosterone
secretion is unchanged in the aging adult. The overall decrease in
aldosterone adversely affects sodium retention in the kidney and
predisposes elderly people to dehydration, as discussed earlier in the
subsection “Antidiuretic Hormone.” Another consequence of lower
aldosterone levels is an increased likelihood of hyperkalemia (Gruenewald
and Matsumoto 2003).

Growth Hormone
Growth hormone levels peak at puberty and then decrease by 14% per
decade. Both a decrease in growth hormone–releasing hormone secretion
and an increase in somatostatin are responsible for the decline in growth
hormone. Insulin-like growth factor (IGF-1), which is produced by the liver
and mediates the actions of growth hormone in the body, also diminishes
gradually, at a rate of 7%–13% per decade. The decline in growth hormone
with age may result in a decrease in both lean body mass and bone mass
(Gruenewald and Matsumoto 2003; Perry 1999).

Parathyroid Hormone, Vitamin D, and Calcium Regulation

Older adults generally consume insufficient calcium in their diet; in
addition, calcium is less efficiently absorbed in the small intestine. Vitamin
D is essential to that absorption, and levels of both 25-hydroxy vitamin D
(25D) and 1,25-dihydroxy vitamin D (1,25D) decrease as a result of several
factors, including 1) decreased sunlight exposure and less efficient
photoconversion in the skin of 2-dehydrocholesterol to vitamin D3; 2)
insufficient dietary intake of vitamin D; 3) intestinal malabsorption of, or
resistance to, vitamin D; 4) decreased 1-α-hydroxylase activity in the
kidney; and 5) the use of medications that cause the liver to break down
vitamin D.
The decline in both serum calcium and 1,25D levels triggers a
compensatory increase in parathyroid hormone (PTH). PTH then 1)
stimulates osteoclasts to resorb bone and 2) acts on the renal distal tubule to
promote calcium reabsorption, thereby increasing serum calcium levels.
PTH levels are higher in elderly individuals because of increased secretion
and decreased renal clearance. This is thought to represent a form of
secondary, rather than primary, hyperparathyroidism and can have a
deleterious effect on bone mass in older patients (Perry 1999; Prestwood
and Duque 2003).
Testosterone
As men age, the number of Leydig cells in the testis declines and
testosterone secretion gradually decreases. Two other factors influence the
age-related decline in testosterone: 1) a loss of the circadian variation in
testosterone levels and 2) an increase in sex hormone–binding globulin
levels, which limits the amount of free testosterone available. The action of
the hypothalamus and pituitary on the testis also may be affected by aging.
The pituitary in some older men may be less responsive to gonadotropin-
releasing hormone, with lower follicle-stimulating hormone and luteinizing
hormone levels as a result. The overall decline in testosterone causes a
decrease in both the number of Sertoli’s cells and daily sperm production;
the sperm produced may have defects in motility as well as chromosomal
abnormalities. The volume of the seminiferous tubules and the testis itself
also decreases. Both libido and fertility may decline. Declining testosterone
levels are thought to have less effect on sexual function than chronic
medical or psychiatric illness, vascular disease, neuropathy, or medications.
Declining testosterone may indeed adversely affect bone mass as well as
muscle mass and strength in older men. The changes in testosterone
secretion are common but not universal, and some men have normal serum
testosterone levels as they age (Gruenewald and Matsumoto 2003; Perry
1999). Testing for testosterone deficiency is generally recommended only
for those patients with clinical symptoms of hypogonadism, including both
specific symptoms—decreased libido, erectile dysfunction, loss of body
hair, small testes, loss of height, and reduced muscle size and strength—and
nonspecific symptoms—decreased energy, depression, anemia, and decline
in physical performance (Bhasin et al. 2010; Sadovsky et al. 2007).
Screening of all patients with erectile dysfunction for testosterone
deficiency is not universally endorsed by experts; in fact, only 2% of men
with erectile dysfunction have an endocrine disorder (Sadovsky et al. 2007).
The Endocrine Society has established clinical practice guidelines for
testosterone replacement (Bhasin et al. 2010). Replacement has a number of
potential benefits, including improved libido, sexual functioning, and sense
of well-being, as well as increased muscle mass and strength and better
physical functioning (Matsumoto 2002). However, testosterone replacement
is associated with a greater risk of all-cause mortality, myocardial
infarction, and ischemic stroke 3 years after angiography, as noted in a
recent study (Vigen et al. 2013).

Estrogen
Estrogen declines precipitously with menopause. Both fibrosis and
involution of the ovary, as well as atrophy of the uterus and vagina, take
place. The number of ovarian follicles declines, and a corresponding
decrease in the secretion of both estrogen and androgens occurs; after
menopause, the ratio of estrogens to androgens decreases. Menopause is
also marked by an alteration in gonadotropin-releasing hormone secretion
and high follicle-stimulating hormone levels, although luteinizing hormone
levels remain the same. The loss of estrogen affects bone mass and places
women at risk for osteoporosis. Women also lose the beneficial effects of
estrogen on lipids, with rising low-density lipoprotein levels, and are at
higher risk for cardiovascular disease. The lack of estrogen causes atrophy
of the vaginal endothelium; the endothelium thins, less lubrication occurs
with intercourse, and dyspareunia can result (Gruenewald and Matsumoto
2003; Perry 1999; Taffet 1999). The results of a widely cited randomized
clinical trial, the Women’s Health Initiative, demonstrated that estrogen
replacement in postmenopausal women did not produce the expected
reductions in cardiovascular events, stroke, fractures, and dementia that had
been anticipated based on previous observational studies (Grimes and Lobo
2002; Nelson et al. 2002). Some obstetricians and gynecologists have
nonetheless suggested that estrogen can be safely prescribed, at lower
dosages than those given in the Women’s Health Initiative trial, for the
relief of common postmenopausal symptoms such as hot flashes (Grimes
and Lobo 2002).

Thyroid
Although there are age-related changes in the thyroid gland, these changes
have no corresponding effect on thyroid function. The aging thyroid is more
fibrotic and nodular in composition and decreases in size. Overall, thyroid-
stimulating hormone tends to rise with age. Thyroid autoantibodies tend to
be higher in women than in men. Although the thyroid continues to make
sufficient amounts of thyroxine (T4), it fails to metabolize T4 as well. The
synthesis of T4 actually declines, but its level is unchanged. Peripheral
deiodination of T4 to triiodothyronine (T3) also decreases, and the level of
T3 declines by 10%–20% in elderly people. Reverse T3 levels do not
change. Thyroxine-binding globulin levels remain normal with age
(McNabney and Fedarko 2013;Veldhuis 2013).

Insulin
Elderly patients have a tendency toward hyperglycemia. Circulating insulin
levels may rise but are less efficiently utilized. Although insulin secretion
by the pancreatic β cells is preserved with age, insulin clearance declines
and insulin levels increase. Peripheral uptake of insulin is affected by
insulin resistance in peripheral tissues; some of these tissues, particularly
adipocytes, have fewer receptors, thereby decreasing their sensitivity to
insulin.
The presence in the bloodstream of free fatty acids and inflammatory
adipocytokines may also contribute to pancreatic β cell dysfunction. Elderly
individuals have decreased muscle mass and a higher percentage of fat and
therefore an increased number of adipocytes. These notable changes in
insulin secretion and tissue sensitivity in the periphery may lead to observed
increases in fasting glucose in older individuals. Another factor that leads to
higher glucose levels is that IGF-1, which acts at insulin receptors to
promote glucose uptake, is less abundant in older adults (Halter 2003; Perry
1999; Rizvi 2007; Taffet 1999). A number of other factors contribute to the
increased prevalence of glucose intolerance and type II diabetes mellitus in
elderly people, including changes in body composition, a reduction in
physical activity, and increased comorbid illness and medication use.
According to the Centers for Disease Control and Prevention (2014a), the
incidence of diagnosed diabetes in the U.S. population ages 65–79 years
was 15.4% in 2011.

Musculoskeletal System
In general, elderly people are weaker and less muscular. Sarcopenia, a
decline in skeletal muscle mass, occurs. In the fourth decade, both muscle
mass and strength begin to decrease. There are smaller numbers of type II
fast-twitch fibers and fewer motor units and synapses; slow muscle fibers
predominate. The motor units may enlarge. There are fewer and smaller
ventral spinal motor neurons in the cervical and lumbar regions. Age,
however, does not affect conduction velocity. Biochemical changes also
occur, with decreased activity of glycolytic enzymes, including
triosephosphate dehydrogenase, lactate dehydrogenase, glycerophosphate
dehydrogenase, and citrate synthase. Exercise may modify age-associated
changes in muscle mass and strength. Sarcopenia places older people at risk
for significant physical disability and a decline in their ability to perform
activities of daily living (ADLs) and may ultimately undermine their ability
to live independently (Loeser and Delbono 2003; Taffet 1999).
Elderly people also develop demonstrable changes in cartilage, tendons,
and ligaments. Cartilage becomes less cellular with age. Alterations in the
structure of proteoglycans affect the ability of these molecules to bind water
and maintain the hydration of cartilage. Cartilage weakens as the number of
proteoglycan monomers decreases and the protein links between the
monomers are broken. An increase in collagen cross-linking and in the
diameter of collagen fibrils occurs, which makes collagen stiffer; this
stiffness results in the compression of proteoglycans, which further
interferes with water retention. The overall effect of age-related changes in
cartilage is to decrease both its tensile strength and its stiffness, adversely
affecting its response to mechanical stress (Loeser and Delbono 2003;
Taffet 1999).
Older tendons and ligaments may be stiffer because of an increase in
cross-linking of type I collagen, and their water content is also decreased.
These alterations may make them less able to withstand mechanical stress
and more susceptible to fatigue. Biomechanical studies confirm the
weakening of tendons and ligaments with age. These changes may decrease
the range of motion of joints in older adults and make them more prone to
tendonitis, ligament tears, and ligament ruptures (Loeser and Delbono 2003;
Taffet 1999).
Age-related changes in the structure of both cortical and trabecular bone
occur. Cortical bone becomes thinner and more porous; trabecular bone also
thins, and whole trabeculae are lost. Bones are therefore weaker. As an
individual ages, the number of osteoblasts and osteocytes may decrease.
Osteoclasts continue to function normally. Mechanical strain, an important
stimulus to bone formation, has less of an effect in older people, and less
bone is made. Older individuals are at increased risk for bone loss. Without
estrogen replacement, women can lose significant bone mass after
menopause. Elderly men with testosterone deficiency also may develop
osteoporosis. Other factors that contribute to bone loss in both men and
women include low peak bone density, poor calcium intake, secondary
hyperparathyroidism (as discussed earlier), and insufficient exercise
(Prestwood and Duque 2003). Bisphosphonates have been studied
extensively and widely prescribed to treat osteoporosis, although reports of
unusual fractures in patients on long-term therapy have led to
reconsideration of exactly how long these medications should be prescribed
(Whitaker et al. 2012). Concern about the routine use of calcium
supplementation and the resultant increased risk of coronary artery disease
has also been raised in a systematic review (Bolland et al. 2010).

Hematological and Immune Systems

Despite a decrease in bone marrow mass, the aging adult does not lose the
ability to produce normal numbers of red blood cells, white blood cells, and
platelets; however, when challenged to produce more red blood cells by the
occurrence of blood loss or by the presence of hypoxic conditions, the bone
marrow is less able to respond quickly. Red blood cells and white blood
cells retain normal function. The red blood cell’s capacity to carry oxygen is
essentially unchanged. The white blood cell continues to engulf and kill
bacteria, but the respiratory burst activity of polymorphonuclear neutrophils
decreases with age. Platelets, however, may be more sensitive to substances
that trigger them to form blood clots. Although the prothrombin time and
partial thromboplastin time are unchanged, fibrinogen increases, and factor
VII, factor VIII, and D-dimer are all elevated (Chatta and Lipschitz 2003;
Taffet 1999).
When confronted with a new infection, older people are less able to
mount an adequate cell-mediated response. With age, the thymus decreases
in size, the number of T lymphocytes is diminished, and the individual’s
capacity to respond is adversely affected. Although the number of memory
T lymphocytes increases with age, these are less easily activated. Natural
killer cells do not function as well with age, with decreased cytotoxicity and
reduced production of cytokines and chemokines. The humoral, or
antibody, response in elderly people is also impaired. Older adults respond
less vigorously to the first presentation of an antigen as well as to the
reintroduction of antigen. There is decreased production of
immunoglobulin-producing B lymphocytes and a loss of immunoglobulin
diversity and affinity. These decreased primary and secondary responses
may explain why older adults respond less well to vaccination (Aw et al.
2007; Miller 1999; Taffet 1999).
The body’s primary defenses against infection are also affected by age.
The thinner skin of elderly people is more vulnerable to injury; when the
integrity of this barrier is compromised, surface bacteria may enter,
resulting in cellulitis or a potentially serious bacteremia. The mucous
membranes of the genitourinary and respiratory tracts of elderly people may
become more easily colonized with gram-negative organisms, thereby
serving as a potential source of infection. In urine, the amount,
concentration, and acidity of urea are decreased, depriving the urine of an
intrinsic defense against possible bacterial infection. Microorganisms also
may find their way into the body by other means; those elderly patients with
swallowing dysfunction may subsequently aspirate bacteria from the oral
cavity, or those unable to produce an adequate cough will leave infectious
material in the airways (Taffet 1999).

Renal System
As a person ages, a progressive decrease occurs in the size of the kidney
due to fatty infiltration, fibrosis, and the dropout of cortical nephrons. The
rate of decline of nephrons is 0.5%–1.0% per year; by age 60, 30%–50% of
functioning glomeruli have been eliminated. Cortical nephrons become
diffusely sclerotic. Glomeruli outside the cortex have fewer capillary loops
and epithelial cells, but more mesangial cells. Other areas of the kidney
may also be affected; interstitial fibrosis may adversely affect the renal
pyramids. These losses do not automatically lead to a failure of the kidney
to keep fluids and electrolytes in balance, but decreased reserve capacity
does predispose the kidney to possible dysfunction or failure. Creatinine
clearance, a widely accepted measure of kidney function, declines 7.5%–
10.0% per decade (Oskvig 1999; Taffet 1999; Weinstein and Anderson
2010).
These anatomical changes have important physiological consequences,
including the decreased ability of the kidney to acidify urine or to excrete
an acid or a water load. The response of the renin-angiotensin-aldosterone
system is less supple, renin activity declines, and less renin is produced in
the face of decreased intravascular volume or a depletion of salt. The
kidney is able to maintain its output of erythropoietin, but the hydroxylation
of vitamin D declines. Levels of atrial natriuretic peptide rise. The kidney
less reliably metabolizes hormones such as glucagon, calcitonin, and
parathyroid hormone; drug metabolism is also significantly affected
(Oskvig 1999; Taffet 1999; Weinstein and Anderson 2010), as discussed in
the next subsection, “Effects of Aging on Pharmacokinetics and
Pharmacodynamics.”

Considerations in Geriatric Prescribing

Effects of Aging on Pharmacokinetics and Pharmacodynamics

The effect of aging on pharmacokinetics (absorption, volume of
distribution, clearance rate, and elimination half-life) and
pharmacodynamics (the effect of a drug at a given dose) is crucial to
understanding how drugs should be prescribed in the elderly patient
(Schwartz 1999; Semla and Rochon 2006).

Pharmacokinetics
Absorption
Age has no significant effect on drug absorption. Although acid secretion,
gastrointestinal perfusion, and membrane transport all may decrease and
thereby lower absorption, gastrointestinal transit time is prolonged and
increases absorption, and thus no net change occurs.
Volume of Distribution
The volume of distribution is significantly affected by the changes in body
mass and total body water that occur with aging. Older patients, with
decreased lean body mass and total body water, have a smaller volume of
distribution. This is particularly relevant when choosing proper dosages for
drugs, such as antibiotics or lithium, that are primarily distributed in water.
Protein binding also can affect the volume of distribution; it is generally
unaffected by age. In frail elderly patients, there may be significant
decreases in albumin levels, which affect the binding of potentially harmful
drugs such as warfarin, which must be vigilantly titrated.
Clearance Rate
With age, renal mass and renal blood flow are decreased, resulting in a
decline in glomerular filtration rate and creatinine clearance. This decrease
in clearance can alter the rate at which drugs are excreted, and dosages must
be appropriately adjusted. Certain drugs, such as nonsteroidal anti-
inflammatory drugs and angiotensin-converting enzyme inhibitors, also
may alter renal blood flow and thereby depress kidney function. Hepatic
drug clearance is decreased by an age-related decline in hepatic blood flow;
oxidative metabolism in the cytochrome P450 system is slower, thereby
affecting elimination, but conjugation is not slower. Underlying hepatic
disease and drug interactions also may significantly affect the metabolism
of drugs by the liver.
Elimination Half-Life
The elimination half-life—the time required for the drug concentration to
decrease by half—of certain drugs increases in older adults. This may
require adjustment of the drug dosing interval. For example, aspirin, certain
antibiotics (e.g., vancomycin), digoxin, and the calcium channel blockers
(diltiazem, felodipine, and nifedipine) all have higher elimination half-lives,
and the dosages must be adjusted downward.

Pharmacodynamics
The pharmacodynamic effects of drugs in elderly patients must also be
considered. Frequently, older adults are more sensitive to medications, and
drugs often must be given in lower doses. For example, because their
response to anticholinergic drugs is increased, elderly individuals develop
side effects, including constipation, urinary retention, and delirium, more
frequently than do younger individuals. Other notable examples of drugs
with enhanced pharmacodynamic effects in elderly people include
diazepam, morphine, and theophylline.

Chronic Disease in Older Adults

Some chronic diseases are more prevalent in older people, and these
predominantly occur as a result of usual aging. The cumulative effect of
environment and heredity on the individual over time makes these diseases
more common, and they account for significant morbidity and mortality.
Among the most formidable and omnipresent are cardiovascular disease,
cerebrovascular disease, and cancer. Hypercholesterolemia and
hypertension are frequently diagnosed. As people age, weight and the
incidence of obesity increase; patients are at higher risk for the development
of type 2 diabetes mellitus. Aging also leads to an increased occurrence of
joint problems, particularly osteoarthritis, which can result in chronic pain
and the need for joint replacement. Elderly people can develop cataracts
and macular degeneration and therefore impaired vision; hearing loss,
caused by either previous noise exposure or age-related anatomical changes
in the ear, is also prevalent. Postmenopausal women and some hypogonadal
elderly men are prone to develop osteoporosis. Benign prostatic
hypertrophy, often with resultant urinary frequency and nocturia, becomes
more of a clinical problem as men age. Polymyalgia rheumatica and
temporal arteritis are collagen vascular diseases that occur often in elderly
patients. The increasing prevalence of multisystem disease in the older
patient can impose a substantial burden on the individual; in the face of
already diminished physiological reserves, such an individual is
considerably more vulnerable to declining health (Fried 2000).

Geriatric Syndromes
Several common syndromes—known generally as geriatric syndromes—
are found more frequently in older patients. Elderly people can be
predisposed to delirium, a waxing and waning disorder of inattention, and
many elderly patients develop dementia, which doubles in the population
every 5 years after age 65. Falls are multifactorial phenomena that increase
with age. Both elderly men and elderly women often develop chronic
difficulty with control of urination, or urinary incontinence. The tendency
of elderly people to use multiple drugs—or polypharmacy—is also a well-
known geriatric syndrome. Frailty is a complex geriatric syndrome in which
the health of the elderly individual declines after cumulative loss of
physiological reserve, with sarcopenia, osteopenia, weight loss, and
progressive functional deterioration. Five of the most characteristic geriatric
syndromes—dementia, falls, urinary incontinence, polypharmacy, and
frailty—are discussed in the following subsections.

Memory Loss and Dementia

Various studies have documented a decline in cognitive function with age.
Such decline may occur in several areas, including intelligence, ability to
maintain attention, language, memory, learning, visuospatial function, and
psychomotor function. These deficits do not occur uniformly across all
areas and do not occur in every person. Although the capacity to recognize
words does not change in older age, elderly adults are less able to name
items. Short-term, or working, memory is unaffected, but there may be
problems in accessing data from long-term memory. The time needed to
learn new information is increased for older adults. Visuospatial tasks are
more difficult, and both motor speed and response times decline with aging.
Some evidence suggests that executive function, or the ability to conceive,
organize, and carry out a plan or activity, may remain intact in elderly
people (Craft et al. 2003).
Dementia is a prevalent condition in elderly people but not a result of
normal aging (Morris 1999). Dementia is defined as the development of
significant deficits in two or more areas of cognition—an impairment of
memory and at least one other area, such as abstract thinking, judgment,
language, or visuospatial ability—that are severe enough to affect the
individual’s day-to-day functioning (Nyenhuis and Gorelick 1998). With
the inevitable decline in intellectual functioning and in the ability to
perform ADLs that occurs, dementia poses particular challenges for the
clinician and special burdens for caregivers. In 2010, an expert panel
convened by the National Institute on Aging and the Alzheimer’s
Association called for changes in diagnostic criteria for Alzheimer’s disease
that would lead to earlier and more precise detection of disease
(Alzheimer’s Association 2010). It is now acknowledged that Alzheimer’s
disease may have both amnestic and nonamnestic presentations (McKhann
et al. 2011).
Two-thirds of all dementia is caused by Alzheimer’s disease.
Alzheimer’s disease is present in about 5% of the population over age 65
years; beyond that age, the prevalence of the disease doubles every 5 years
(Klafki et al. 2006). Vascular dementia accounts for 15%–25% of dementia
cases (Gómez-Tortosa et al. 1998), and Lewy body dementia constitutes
10% of cases. The natural history and symptomatology of dementia vary
according to its etiology (Marin et al. 2002).
The accurate diagnosis of dementia requires a comprehensive assessment
by the clinician, including a detailed history; thorough physical,
neurological, and mental status examinations; and a depression screen.
Because the patient may have significant deficits, the history needs to be
gathered from the patient along with someone who is extremely familiar
with the history of the patient’s illness, medications, and social history. The
evaluating clinician should order laboratory studies to rule out vitamin B12
deficiency, syphilis, and hypothyroidism and should examine the patient for
evidence of anemia, electrolyte abnormalities, renal failure, and liver
dysfunction. This laboratory evaluation enables the clinician to detect
reversible causes of dementia and uncover evidence of metabolic
abnormalities that might point to a diagnosis of delirium rather than
dementia (Marin et al. 2002).
Above all, the treatment of dementia involves the building of a proper
support system for the patient. Medications can also be considered.
Acetylcholinesterase inhibitors, including donepezil, galantamine, and
rivastigmine, have shown some effectiveness in clinical trials of patients
with mild to moderate Alzheimer’s disease, with documented
improvements in the Alzheimer’s Disease Assessment Scale Cognitive
Subscale score (Birks 2006), but the overall effects of these drugs may be
modest (Raina et al. 2008). Combination treatment with
acetylcholinesterase inhibitors and memantine has been more effective than
treatment with acetylcholinesterase inhibitors alone (Farrimond et al. 2012).
Although ambitious research efforts continue, clinical trials of several drugs
for Alzheimer’s disease, including semagacestat (a γ-secretase inhibitor)
and solanezumab (a humanized monoclonal antibody that preferentially
binds soluble forms of amyloid), have failed (Doody et al. 2013, 2014). A
Phase 3 trial is ongoing for nasal insulin (Clinical Trials.gov 2014b). A trial
of solanezumab with presymptomatic patients is also in progress (Clinical
Trials.gov 2014a).
Patients with Alzheimer’s disease are at risk for the development of
depressive symptoms as well as major depression, for which clinicians can
provide effective medical treatment. Because agitation is also a prevalent
symptom, particularly in patients with late disease, this symptom also may
require treatment; atypical antipsychotic agents such as risperidone may be
helpful in this context (Defilippi and Crismon 2000; Tune 2001).
Nonpharmacological approaches to behavioral problems have also been
rigorously studied and found to be effective (Karlin et al. 2014; Logsdon et
al. 2005; Teri et al. 2005).

Falls
Falls are a common phenomenon in older patients; every year, one-half of
all nursing home residents and one-third of all community-dwelling elderly
have a fall. These falls produce notable morbidity: 20%–30% of falls result
in moderate to severe injuries such as lacerations, hip fractures, and head
trauma (Centers for Disease Control 2014b). Half of the persons who fall
experience minor injuries. In the aftermath of falls, disability may result.
People who fall frequently are at risk for a decline in their ADLs and
instrumental ADLs (IADLs) (assessment of such functions is discussed
later in this chapter in the subsection “Fundamentals of Geriatric
Assessment”). A decline in these functions can ultimately undermine
independence and also might result in hospitalization. The leading cause of
death from injury in adults over age 65 is complications resulting from falls
(Berry and Kiel 2013; Fried 2000; King and Tinetti 1995; Rubenstein and
Josephson 2006; Rubenstein et al. 1994).
Falls are generally multifactorial and are caused by 1) intrinsic factors,
2) situational factors, 3) extrinsic factors, and 4) medications (Alexander
1999; King and Tinetti 1995). Intrinsic factors are disease-specific deficits
in an individual patient that might contribute to falling; these factors include
neurological problems (central, neuromuscular, vestibular, visual, and
proprioceptive) as well as systemic illness. Situational factors relate to the
particular activity that is taking place. Extrinsic factors relate to the
demands and hazards of a particular environment. Medications may
adversely affect mental status, cognition, balance, circulation, and
neuromuscular function and therefore predispose patients to falls.
The proper evaluation of a fall requires 1) taking a detailed history and
review of systems and 2) performing a thorough physical examination and
neurological examination (Rubenstein and Josephson 2006). The fall may
indeed be a nonspecific presentation of a serious medical condition such as
cardiac ischemia, infection, intravascular volume depletion, or
hypothyroidism, and these should be initially considered. The clinician
should ask about any symptoms and situational or extrinsic factors that
might have led to the fall and determine exactly how the fall occurred. A
medication list should be compiled. The physical examination should rule
out any cardiac abnormalities; the neurological examination must carefully
assess the patient for any deficits in vision, strength, sensation, joint
mobility, balance, cerebellar function, gait, or proprioception.
The prevention of falls focuses on altering both intrinsic and extrinsic
factors (Gillespie et al. 2003; King and Tinetti 1995; Rubenstein and
Josephson 2006). With regard to intrinsic factors, one can 1) prescribe
medication appropriately, 2) optimally treat disease, 3) improve balance and
gait through physical therapy, and 4) improve conditioning and strength
through exercise. With regard to extrinsic factors, one can 1) improve the
environment by reducing or eliminating hazards, 2) monitor patients more
carefully by increasing staff supervision and using motion detection, 3)
eliminate restraints and the risk of injury they pose, 4) encourage patients to
wear hip protectors, and 5) install protective flooring. Preventing falls
ultimately requires multiple steps to produce successful results.
A meta-analysis of five randomized clinical trials suggested that vitamin
D supplementation may reduce the risk of falls in ambulatory or
institutionalized older individuals by more than 20% (Bischoff-Ferrari et al.
2004).

Urinary Incontinence
Urinary incontinence is a prevalent condition in older adults that causes
significant morbidity and affects quality of life (DuBeau 2006; Tannenbaum
et al. 2001). One-half of all nursing home residents and up to one-third of
persons older than age 65 years who reside in the community carry the
diagnosis. It is a condition with multiple causes, including age-related
changes, genitourinary tract abnormalities, and coexisting illnesses.
Urinary incontinence can be classified into two main categories: 1)
transient incontinence and 2) established incontinence. Transient
incontinence is reversible and can be easily treated. For example, transient
incontinence, which could be a consequence of an acute urinary tract
infection, inadequately controlled diabetes mellitus, or a recent prescription
of a diuretic, will resolve with the correction of those conditions.
Established incontinence is divided into the following three subcategories:

• Urge incontinence. This is the most prevalent form of incontinence in the

older patient. Urge incontinence results from detrusor overactivity,
sometimes with simultaneous impaired contractility. Detrusor overactivity
is more common with aging but can also occur for other reasons,
including neurological dysfunction (e.g., stroke) or irritation of the
bladder (secondary to cancer, urolithiasis, or infection); it can also occur
in elderly patients without other illnesses. Patients usually complain of a
sudden urge to urinate. They also classically have urinary frequency and
nocturia. They experience varying amounts of leakage.
• Stress incontinence. This problem occurs when increased abdominal
pressure, triggered by cough or sneezing, results in urinary leakage. It
happens commonly in women with weak pelvic muscles, although it also
may occur as a consequence of failed anti-incontinence surgery or vaginal
mucosal atrophy in women or prostatectomy in men. It is a frequent form
of incontinence among elderly women, ranking second.
• Overflow incontinence. Detrusor underactivity or bladder outlet
obstruction can produce overflow incontinence. Detrusor underactivity
can be caused by fibrosis of the detrusor muscle, peripheral neuropathy,
disc herniation, or spinal stenosis. Detrusor underactivity is an infrequent
cause of urinary incontinence in older individuals. Urethral strictures,
benign prostatic hypertrophy, and prostate cancer can cause bladder outlet
obstruction in elderly men; this form of incontinence is the second most
prevalent in this population. Bladder outlet obstruction in women occurs
much less frequently; the etiology is either the presence of a large
cystocele or a history of anti-incontinence surgery.

In general, the treatment of incontinence in elderly individuals begins

with behavioral interventions, which are followed by medical treatment.
Surgery is considered the last option and is appropriate only for stress
incontinence or outlet obstruction. Because urinary incontinence in older
adults is invariably the result of more than one cause, clinicians must
appreciate that a single intervention may not be effective. Medications must
be reviewed to determine whether they are contributing to the individual’s
incontinence. Patients must be cautioned against intake of fluids such as
alcohol, coffee, tea, and soft drinks, which stimulate urination. Fluid
restriction at bedtime may be appropriate to decrease nocturia.
Several specific interventions can be undertaken to treat the three forms
of established incontinence:

• Urge incontinence is best treated by frequent voluntary voiding and

bladder retraining. Patients are placed on a voiding schedule that
corresponds to their usual minimal interval of urination. They are taught
how to voluntarily inhibit the urge to void. The goal of therapy is to
increase gradually the interval between urination. For patients with
cognitive impairment, bladder retraining is not appropriate; instead, timed
voiding, scheduled voiding, or prompted voiding is instituted to decrease
episodes of incontinence. For those who fail behavioral methods,
medications such as oxybutynin, tolterodine, solifenacin, or imipramine
may be helpful, but patients should be monitored carefully for
anticholinergic side effects.
• Stress incontinence is also amenable to nonmedical therapy. The mainstay
of this approach is strengthening the pelvic muscles that support the
urethra by performing repeated isometric exercises, thereby preventing
urinary leakage. The patient should be referred to a physical therapist to
initiate an exercise program. In some cases, medical treatment also may be
helpful. In women, oral or topical estrogen sometimes has been beneficial.
Propanolamine also can be a useful adjunct, although this is not an option
in patients with hypertension. For women who fail physical therapy and
medical treatment, surgery remains another option.
• Overflow incontinence in men is most often the result of outlet obstruction
due to benign prostatic hypertrophy, which can be treated by medical and
surgical modalities. In clinical trials, α-adrenergic blocking agents have
been proven most effective for benign prostatic hypertrophy, although
finasteride may be used as a second-line treatment. Transurethral resection
of the prostate and prostatectomy are the available options for cases that
fail to respond to medical therapy. In women, previous vaginal or urethral
surgery may be the cause of overflow incontinence; this is surgically
correctable by lysis of adhesions or unilateral suture removal. For cases of
overflow incontinence caused by detrusor underactivity, appropriate
interventions include avoidance of constipation as well as careful
management of medications to exclude those that adversely affect detrusor
 function. Intermittent catheterization is most often recommended for
treatment of detrusor underactivity.

Incontinence can ultimately have harmful medical consequences,

including pressure ulcers, cellulitis, falls, and fractures. It can interfere with
sleep. It can also result in sexual dysfunction and depression. The proper
treatment of incontinence is therefore important and can yield significant
benefits.

Polypharmacy
Polypharmacy, defined as the simultaneous use of multiple medications or
the prescribing of more medications than is clinically appropriate, is a
common problem in older adults (Hanlon et al. 2001; Stewart 2001). The
high use of drugs by elderly individuals is attributable to several factors.
Older patients more commonly have chronic illness and experience more
symptoms. The elderly are also more frequent consumers of medical care.
Drug use is also influenced by individual physician prescribing practices
and by drug advertising. According to studies conducted in outpatients,
elderly patients typically use 3.1–7.9 prescription and nonprescription drugs
simultaneously. Polypharmacy carries with it certain consequences,
including adverse drug reactions, drug interactions, and patient
noncompliance; polypharmacy also increases the incidence of geriatric
syndromes such as urinary incontinence, falls, cognitive impairment, and
delirium.
Clinicians should take several steps to ensure that medicines are
prescribed appropriately. They should take a careful, comprehensive
medication history, including allergies and adverse drug reactions. Current
use of alcohol, tobacco, and recreational drugs should be documented.
Medications should be prescribed only if they have a known benefit, and
they should be given at the lowest effective dose. Instructions about
medication use should be communicated clearly to patients. Patients who
are taking medication should be carefully monitored for therapeutic
effectiveness and for side effects (Semla and Rochon 2006). In a systematic
review of 14 clinical trials on optimizing prescribing in older individuals,
Spinewine et al. (2007) reported that certain clinical interventions,
including geriatric medicine services, the participation of a pharmacist in
clinical care, and computerized decision support, had beneficial effects on
prescribing. In 2012, an expert panel of the American Geriatrics Society
revised the Beers Criteria for Potentially Inappropriate Medication Use in
Older Adults and issued new evidence-based guidelines (American
Geriatrics Society 2012 Beers Criteria Update Expert Panel 2012).

Frailty
The sum effect of physiological decline in the older individual, combined
with the cumulative and simultaneous burden of chronic disease, may result
in the geriatric syndrome known as frailty (Cohen 2000; Hamerman 1999;
Morley et al. 2006). Frailty has been defined by Fried and Walston (2003)
as “a state of age-related physiologic vulnerability resulting from impaired
homeostatic mechanisms and a reduced capacity of the organism to
withstand stress” (p. 1489). Older patients have less pulmonary, cardiac,
and renal reserve. They are less able to mount an effective immune
response. They also have higher sympathetic nervous tone, which may
increase cortisol production and further impair the immune system. In older
patients, cortisol also may have catabolic effects on bone and muscle and
result in insulin resistance. Elderly patients also may have higher levels of
circulating cytokines—such as interleukin-6, interleukin-1B, and tumor
necrosis factor-α—which also may have deleterious catabolic effects on
muscle. Changes in neuroendocrine function—the decline in sex steroids,
growth hormone, and DHEA—can have corresponding negative effects on
the size and strength of muscle and, in the case of estrogen and testosterone,
on bone mass. The frail older individual is characteristically weak as a
result of declining muscle and bone mass; a tendency toward a sedentary
state may lead to deconditioning, further weakness, and fatigue. Poor oral
intake may lead to weight loss and nutritional compromise, adding even
more to the tendency to tire easily. Progressive weakness may adversely
affect the patient’s balance and ability to ambulate. Ultimately, the frail
older individual loses the capacity to function independently and may
require skilled assistance in a facility outside the home. Frailty also carries
with it a higher risk of medical illness and mortality (Fried and Walston
2003).
Geriatric Assessment
The presentation of acute illness in older adults may not be typical of that in
younger adults, and diagnosis in the geriatric patient therefore poses special
challenges. For example, the geriatric patient may experience a change in
mental status that suggests an acute neurological event but is instead due to
pneumonia, urinary tract infection, myocardial infarction, or an adverse
reaction to medication. The symptoms of the older patient are very often
nonspecific. The astute clinician must consider this carefully when
constructing a differential diagnosis. Something as straightforward as
functional decline might signal a more serious medical problem. The
physiological changes that occur in elderly people also may markedly alter
how patients present. Older persons may not always develop fever and
leukocytosis in response to infection, and the clinician must recognize other
clues. The decline in functional reserve in many organ systems may
predispose elderly people to harm even when a precipitating event seems
minor. An elderly person with an impaired thirst mechanism may not
replenish water losses quickly enough on a hot summer day, and
dehydration could then happen very suddenly. The challenges of
deciphering symptoms and preventing harm are heightened by the difficulty
of gathering information from elderly patients. Those who are capable of
giving a good history may be reluctant to report that anything is wrong;
they may be depressed, fearful of a new diagnosis, convinced that their
problem is nothing but “old age,” or skeptical that any doctor or medical
system can help them. In some cases, medical illness can exacerbate
psychiatric illness—making the depressed patient more disengaged or the
schizophrenic patient more agitated—and clinicians must be willing to
consider diagnoses beyond mere worsening of an ongoing psychiatric
condition and other possibilities.
The effective evaluation and treatment of the geriatric patient—from the
fully functioning community-dwelling older adult to the frail older adult in
decline—require a global approach, which includes, but reaches beyond, a
consideration of the patient’s medical problems. Reuben (2003) defined
geriatric assessment as a comprehensive patient evaluation, conducted by
an individual clinician or an interdisciplinary team, which considers the
effect of key medical, social, psychological, and environmental factors on
health and pays careful attention to function. During the medical
assessment, the clinician performs a complete history and physical
examination. He or she reviews the medication list for appropriateness and
evidence of poly-pharmacy; checks for deficits in vision, hearing,
ambulation, and balance; and screens for common geriatric problems such
as falling, incontinence, and malnutrition. Vision is tested with Snellen’s
eye chart. Hearing is screened with the whispering voice test or a handheld
audiometer. The patient’s weight and height are measured, and the body
mass index is calculated. In addition to the standard neurological
examination, the patient’s mobility and balance can be determined by a “get
up and go” test; the patient is asked to stand, walk 10 feet, turn around,
return, and be seated. The task is timed; a time greater than 20 seconds
suggests that more extensive evaluation is needed.
Cognitive assessment is performed with the Mini-Mental State
Examination (Folstein et al. 1975). The Geriatric Depression Scale
(Yesavage et al. 1983) is used to screen for depression. Fundamental day-to-
day functioning is determined by documenting ADLs—bathing, dressing,
toileting, feeding, and transferring—and IADLs—driving, shopping,
cooking, housekeeping, using the telephone, and managing finances. The
clinician also must gather other important information about function: 1)
the extent, strength, and reliability of the patient’s social support system
(most often the patient’s family); 2) the patient’s economic resources; and
3) the safety of the patient’s home and its proximity to medical care and
other essential services. The patient’s spiritual preferences and needs are
also assessed. After the assessment is completed, recommendations are
developed and a care plan is implemented.
Although the results across clinical trials have not been consistent, the
effectiveness of comprehensive geriatric assessment and management has
been validated in several studies. Increased diagnostic accuracy has been
noted. Patients have shown significant improvements in functional status.
Affect and cognition have improved. The use of health care services, as
measured by nursing home days, hospital services, and medical costs, has
been reduced. The use of medications has improved, with fewer drugs being
prescribed (Hanlon et al. 2001; Reuben 2003; Spinewine et al. 2007; Stuck
et al. 1993). In-home geriatric assessment of older patients may postpone
the onset of disability, as well as reduce the number of patients requiring
permanent placement in nursing homes (Stuck et al. 1995). A multi-
institutional randomized controlled trial of geriatric evaluation and
management units in the Veterans Affairs Health Care System showed a
positive effect on functional status and quality of life for inpatients and on
mental health and quality of life for outpatients, with overall costs
equivalent to those for usual care, but had no effect on morbidity or
mortality (Cohen et al. 2002). As suggested by the evidence, comprehensive
geriatric assessment and management may serve as a useful tool for the
diagnosis and care of older patients, and the geriatrician has a valuable and
essential role in the evaluation and treatment of this population.

Conclusion
With longevity, all older adults face the prospect of progressive
physiological decline and increased vulnerability. This may result in
significant sensory deficits, increased susceptibility to illness, and less
robust intellectual and physical abilities. Those entering their seventh,
eighth, and ninth decades of life must confront many challenges to their
health and independence, but human beings are eminently adaptable and
resilient (Dubos 1965). Old age should not automatically lead to isolation
and infirmity; instead, it can be a time of happiness, creativity, and
fulfillment (Cohen et al. 2006). For many, the challenges of aging can be
met—insightfully and optimistically—by drawing on years of personal
experience and accumulated wisdom (Brooks 2014). Obtaining good
interdisciplinary geriatric care—care that enlists older individuals (and their
families) as equal partners and systematically addresses their medical,
social, psychological, and functional needs—may also be beneficial in
aging well and in ensuring that quality of life is as high as possible.

Key Points
• People older than age 65 years constitute one of the fastest-growing
segments of the U.S. population, and the average life span has
lengthened significantly.
• The hallmarks of physiological change in older adults are twofold:
impaired homeostasis (also called homeostenosis) and increased
 vulnerability because of decreased reserve capacity.
• The time needed for older adults to learn new information increases, and
they may have more difficulty accessing data from long-term memory.
• Older persons develop significant age-related changes in vision—
including decreases in accommodation, ability to adapt to light, color
discrimination, and visual acuity—and in hearing, with loss of hearing
ability in both high and low frequencies.
• Aging results in arterial stiffening and subsequent increased systolic
blood pressure and aortic pulse pressure, with resultant susceptibility to
left ventricular hypertrophy, cardiac ischemia, left ventricular failure,
cerebrovascular ischemia, and renal dysfunction.
• The immune response of the older individual is less vigorous, with
decreased cell-mediated response, impaired humoral response, and
increased susceptibility to infection.
• The decline in renal clearance and the increase in the elimination half-
life in elderly people may require adjustment of the dosing interval of
medications; because older adults are more sensitive to medications,
drugs must often be given in lower doses.
• Some chronic diseases are more prevalent in older adults, predominantly
occurring as a result of usual aging; these include obesity, hypertension,
hypercholesterolemia, type 2 diabetes mellitus, osteoarthritis,
cerebrovascular disease, cardiovascular disease, and cancer.
• Several common syndromes—known generally as geriatric syndromes—
are found more frequently in older patients, including dementia, falls,
urinary incontinence, polypharmacy, and frailty.
• The effectiveness of comprehensive geriatric assessment and
management has been validated in several large randomized studies, and
the geriatrician has a valuable and essential role in the evaluation and
treatment of this population.

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 CHAPTER 3

Genomics in Geriatric Psychiatry

Aaron M. Koenig, M.D.
Robert A. Sweet, M.D.

The flow of events leading from variation in a gene sequence to the

development of the various cognitive, behavioral, and emotional criteria
that encompass psychiatric disorders of later life is not straightforward.
However, the understanding of these processes is well under way and has
the potential to significantly influence the practice of geriatric psychiatry in
the twenty-first century. The completion of the Human Genome Project a
decade ago marked a milestone in the field of genomics. Since then, the
field has rapidly moved forward, with the first genomic mapping of a living
human followed by the more recent availability of direct-to-consumer
genome sequencing. Personalized genome sequencing (Levy et al. 2007) is
a reality that will have a profound impact on the field. Family, twin, and
adoption studies have demonstrated robust genetic influences in
schizophrenia, bipolar disorders, and Alzheimer’s disease (AD), and
conventional and newer approaches have advanced the understanding of the
specific genetic components of these disorders. In this chapter, we have
attempted to 1) summarize key advances in genomic science, 2) provide an
introduction to the growing field of genomic medicine (especially as it
relates to genetic testing), and 3) review the current state of understanding
of genetics of mental disorders of aging and later life.
Advances in Genomic Science: Background and
Context
The field of genomics has come a long way since Gregor Mendel’s first
work with pea plants in the mid-nineteenth century. In fact, the field is
rapidly evolving. Given these developments, it is important for the reader to
understand and appreciate the general framework of genomic science,
especially as groundwork is being laid for new genetically informed
diagnostic and interventional developments that will likely arrive in coming
years. With this in mind, we have provided a brief summary of recent
advances in the field, beginning with a discussion of the Human Genome
Project, and continuing with a discussion of our understanding of functional
and structural variation within the human genome. In addition, we have
provided a table of important terminology and definitions (Table 3–1) to
assist the reader in understanding this somewhat technical yet important
topic.

Lessons From the Human Genome Project

One of the fundamental insights arising from the sequencing of the human
genome was the discovery that the number of protein-coding genes (around
20,000) was several-fold less than expected, encompassing less than 2% of
human DNA. With the subsequent discovery that genes are surprisingly
conserved across mammalian species, investigators have begun to look
within and across species for other sources of variation within the genome.
From this process has emerged an awareness of the functional role of the
remainder of the genome, the so-called silent or noncoding DNA (ncDNA)
that is never translated into protein. In addition, this process has led to the
realization that structural variation—including deletions and replications of
segments of chromosomes—makes up the largest proportion (as measured
in base pairs) of variation within humans and between humans and other
primates (Cheng et al. 2005; Levy et al. 2007; Samonte and Eichler 2002).
Over the past decade, it has become apparent that a large degree of
complexity in the human genome results from the regulation of gene
transcription (the conversion of DNA to RNA) and gene splicing (which
alters the isoform of the resulting translated protein). This regulation was
known to occur via sites within nontranscribed DNA sequences (e.g.,
promoter sequences) and within transcribed yet noncoding portions of the
messenger RNA sequence (e.g., splice sites at the boundaries of introns and
exons) but has been supplemented by a recent explosion of understanding
regarding the extent to which ncDNA sequences are transcribed into
noncoding RNA (ncRNA) (Carninci et al. 2005) and the breadth of cellular
mechanisms under the control of ncRNA. It is now known, for example,
that ncRNAs serve critical roles as transcriptional and post-transcriptional
regulators, facilitating normal development and physiology and, when
dysfunctional, contributing to disease (Taft et al. 2010). Taken together,
these recent discoveries emphasize the need to move beyond the confines of
protein-coding genes and highlight the fact that continued investigation of
ncRNA function will be necessary for a comprehensive understanding of
genetic diseases (Taft et al. 2010).

Single-Nucleotide Polymorphisms
Until relatively recently, the majority of known disease-causing mutations
involved single DNA nucleotide changes (single-nucleotide polymorphisms
[SNPs]) in coding DNA that resulted in an altered amino acid sequence of
the translated protein. However, there is now greater recognition of the
contribution of SNPs in ncDNA sequences to disease risk and expression.
Koboldt and Miller (2007), for example, mapped more than 9 million SNPs
to gene sequences and ncDNA sequences of functional significance,
including transcription factor binding sites, exon splicing enhancers or
silencers, transcribed ncRNA, regulatory-potential sequences, and ncRNA
binding sites. They found that SNPs in coding DNA that altered protein
structure had significantly decreased allele frequencies and increased
population specificity (providing evidence of a functional effect, subject to
natural selection). Furthermore, they observed the same pattern among
SNPs in ncDNA that mapped to transcription factor binding sites, ncRNA
binding elements, regulatory-potential sequences, and splice sites, with
substitutions in ncRNA binding or splice sites being more likely to show
evidence of selection than coding SNPs. Subsequent discoveries have led
ncRNA to be implicated in several diseases that affect the brain, such as
schizophrenia, in which the strongest genetic findings to date are an
association of disease with genetic variation located within the gene for
microRNA 137 (Schizophrenia Psychiatric GWAS Consortium 2011).

TABLE 3–1. Definitions of importance

Allele One of a number of different forms of the same gene. Alleles may or may
not result in different observable phenotypic traits.
Base pair The building blocks of the DNA double helix, each containing two
complementary nucleotides.
Complex disease A disease that arises from complex interactions between multiple genes
and/or environmental factors.
Dominance A key concept in Mendelian inheritance, referring to the relationship
between alleles of a single gene. In a dominant gene, one allele
(dominant) masks the phenotypic expression of a second allele
(recessive) at the same location.
Gene expression The general process by which information from a nucleotide sequence is
synthesized into a functional gene product (e.g., a protein). Gene
expression includes the processes of transcription, splicing, translation,
and posttranslational modification.
Gene splicing A regulated process during gene expression that results in a single gene
coding for multiple proteins. During splicing, particular portions of a
gene are included in (or excluded from) the final messenger RNA
produced from the nucleotide sequence. Because proteins translated from
alternatively spliced RNAs contain different amino acid sequences,
splicing allows the synthesis of many more proteins than would be
expected from the human genome’s approximately 20,000 protein-coding
genes.
Gene transcription The first step of gene expression, during which a segment of DNA is
copied into RNA by the enzyme RNA polymerase. During transcription,
a DNA sequence is read by RNA polymerase, which produces a
complementary, antiparallel RNA strand called a primary transcript.
Gene translation Part of the process of gene expression, during which the primary transcript
is decoded to produce a specific amino acid chain that will later fold into
an active protein.
Genome-wide An examination of many common genetic variants in different individuals
association study to determine if any variant is associated with the disease of interest.
Genotype The genetic makeup of an organism.
Haplotype A combination of alleles that are often inherited together, due to their close
physical proximity on a chromosome.
Mendelian disease A disease that displays a predictable, single-gene pattern of inheritance
(e.g., autosomal dominant, autosomal recessive).
Mutation Change in the nucleotide sequence of a genome. Mutations result from
unrepaired damage to nucleotides, errors in replication, or insertion or
deletion of segments by mobile genetic units. Mutations are considered to
be rare events and may or may not result in discernible changes in
phenotype.
Noncoding RNA RNA sequences that do not function as messenger, transfer, or ribosomal
(ncRNA) RNAs. ncRNAs serve many functions (e.g., regulation of gene
expression).
Nonsynonymous The substitution of one base pair for another in an exon of a gene coding
substitution (mutation) for protein, such that the produced amino acid sequence is modified. In a
synonymous substitution, on the other hand, the base pair substitution
does not result in a change in the amino acid sequence.
Penetrance The proportion of individuals carrying a particular genotype that also
expresses an associated phenotype. In medical genetics, penetrance is
defined as the proportion of individuals with the mutation who exhibit
clinical symptoms.
Phenotype The observable composite of an organism’s genetic characteristics and
traits.
Polymorphism The simultaneous occurrence in the same population of two or more forms
of a gene in proportions that are not maintained by spontaneous mutation
or immigration. Polymorphisms are actively and steadily maintained by
natural selection and are considered to be more common than mutations.
Single-nucleotide A sequence variation occurring when a single nucleotide in the genome
polymorphism differs between members of a species or paired chromosomes.
Structural variation Variation in the structure of an organism’s chromosome, usually involving
changes such as deletions, duplications (copy-number variants),
insertions, and translocations.

Copy-Number Variation
Efforts to screen the human genome have shown that large segments of
DNA may also be deleted or duplicated (Inoue and Lupski 2002; Lupski
2007), resulting in changes in the number of genes within these regions and
disrupting gene structure at deletion or duplication breakpoints (Neumann
et al. 2006). Diseases caused by genomic rearrangements that result in an
altered number of gene copies (copy-number variation [CNV]) are often
referred to as genomic disorders. Efforts to map genomic variation in the
complete human genome have identified CNVs in 1,400 regions that
overlap with 14.5% of genes associated with human disease (Redon et al.
2006). CNV is known to be associated with a number of
neurodevelopmental and neurodegenerative disorders, including sporadic
and familial cases (Redon et al. 2006; Sebat et al. 2007). Familial early-
onset cases of AD and Parkinson’s disease (PD) due to CNV, for example,
are described later in this chapter (see “Genetics of Mental Disorders of
Aging and Later Life”). Too often, however, reports have been limited to
the discovery of regions containing CNVs, without identifying the specific
DNA sequence resulting in illness (the latter of which remains an important
area of study for the field).

Genome-Wide Association Studies

The efforts of the International HapMap Project (2014) to identify
contiguous blocks within the genome that are relatively invariant across
individuals and populations have been critical to recent successes in
identifying genetic variation associated with a number of complex diseases.
The relative constancy of each haplotype block allows for all genetic
sequence contained within it to be represented by a single tag SNP, such
that the entire genome can be thoroughly interrogated for association with
disease (genome-wide association) by about 106 tag SNPs, a number that is
substantially smaller than the approximately 3 billion nucleotides within the
genome. Successful genome-wide association studies (GWASs) to date are
notable for several shared features (Coon et al. 2007; Parkes et al. 2007;
Todd et al. 2007; Wellcome Trust Case Control Consortium 2007; Zeggini
et al. 2007), including use of ultra-high-density genotyping chips; DNA
samples obtained from large and phenotypically well-characterized cohorts;
and care taken to minimize bias stemming from potential population
heterogeneity, genotyping errors, and DNA quality control issues. As these
studies examine the entire genome, an important outcome includes the
discovery of new gene associations previously unrecognized as contributory
to the disease being studied. In addition, the associated SNPs are often
found in ncDNA that might not have otherwise been examined (Wellcome
Trust Case Control Consortium 2007). Because most identified variants
contribute modestly to disease risk (i.e., odds ratios of 1.2–1.5), detecting
effects of such small size requires many thousands of subjects with well-
defined phenotypes. Importantly, because the associations are with tag
SNPs, finding a significant association does not identify the exact genetic
variant that contributes to disease risk, although it strongly suggests that the
genetic variant lies somewhere within the “tagged” haplotype block.

De Novo Mutations
Although genetic risk is thought to be passed down through families, it is
also true that new (i.e., de novo) mutations or structural rearrangements
may occur in a parental gamete (sperm or egg) and thus first manifest in an
affected offspring. Rates of de novo mutations are increased, for example,
by increasing paternal age, whereas increasing maternal age is a risk factor
for de novo structural alterations such as trisomy 21, which results in Down
syndrome.

A Practical Framework: Genetics for the Clinician

As a brief summary, genetic variation with relevance for disease may be
common (typically defined by occurrence in > 1% of the population) or rare
(in < 1%); may alter single nucleotides (SNPs or mutations) or cause larger
structural rearrangements (e.g., CNVs or translocations); may impact amino
acids within the protein sequence (nonsynonymous) or alter ncDNA; and
may be transmitted through families to the affected individual or arise de
novo within an individual (and then be transmitted to offspring). In
addition, two other concepts are important for understanding the
relationship between genetic alterations and disease risk. First, genetic
disorders may be Mendelian in nature, following a clear pattern of
dominant or recessive inheritance of a single genetic mutation through
many generations within a family. Mendelian patterns of inheritance are
seen in many familial types of neurodegenerative illness. The majority of
psychiatric conditions of later life, however, are complex diseases,
influenced by multiple genes, environmental risk factors, and the interaction
between the two. Second, the effect of a specific genetic variation on
disease risk may be extremely large (e.g., with complete penetrance, 100%
of individuals with the genetic lesion who live to the age of risk develop the
disease), moderate (e.g., a three- to fourfold increase in risk for AD due to
having an allele that produces the ε4 type of apolipoprotein E [APOE*E4]),
or even very small (e.g., the 5%–10% increase in disease risk often seen for
common variants detected in GWASs of complex diseases) (Figure 3–1).
Information provided by the nature of the genetic variation itself, the
pattern of inheritance (Mendelian vs. complex), and the magnitude of the
genetic effect on risk enables the clinician to appreciate, interpret, and
communicate the association between a genetic variant and a clinical
disorder. For example, a rare nonsynonymous mutation with high
penetrance in a Mendelian disease can be identified by studying a large
family pedigree and will have implications for patient prognosis and family
planning. Alternatively, a common nonsynonymous variant of moderate
effect in a complex disease will be readily detected in a case-control study
and may contribute substantially to overall population risk but have unclear
implications for an individual patient with regard to prognosis and family
planning.

Genomic Medicine and Genetic Testing

The field of genomic medicine—or using an individual patient’s genotypic
information in his or her clinical care—is rapidly evolving (Manolio et al.
2013). Although the role of this information in the practice of geriatric
psychiatry has yet to be fully realized, the pace of developments will likely
accelerate over the coming years. Cancer medicine, for example, offers an
important and promising model for other fields hoping to integrate genetics
into clinical practice. Research has shown that human malignancy is a
condition derived from somatic aberrations in the human genome, and these
findings are helping to drive the development of more precise and effective
therapies (Patel et al. 2013). Advances in cancer genomics have
demonstrated that tumors originating from the same organ can be stratified
into subclasses, often with different clinical outcomes with regard to
prognosis (i.e., indolent vs. aggressive) and response to therapies (Hudson
2013). Relating genomic alterations to clinical presentations offers the
potential to guide clinical decisions based on knowledge of the molecular,
genetic, and functional alterations specific to each patient. As advances
continue to be made, it is the hope that similar discoveries and
developments will be applicable to the field of geriatric psychiatry.
Currently, genetic tests for a number of neuropsychiatric disorders of
later life are commercially available. However, the use of such testing in the
real-world clinical setting involves several hurdles. Although costs continue
to fall, genetic testing remains an expensive endeavor, often with limited
coverage and reimbursement by health insurance plans. In addition,
although the 2008 Genetic Information Nondiscrimination Act now protects
against genetic discrimination by health insurance companies and
employers, it does not protect against genetic discrimination related to long-
term care or life insurance (Goldman 2012). Deciding whether genetic
testing is appropriate for a particular clinical scenario involves a balance of
benefit and risk. Furthermore, testing requires informed consent and must
be guided by an experienced genetic counselor. The impact of genetic
results often differs for each member of the family, and the counselor will
explain the importance of identifying who should be privy to the results and
educate the patient about how a negative result relates to his or her
diagnosis.

FIGURE 3–1. Relationship between frequency of a variant and its

penetrance (i.e., the magnitude of its effect on risk).
Gray shading indicates variants likely to be detected by current approaches. GWAS=genome-wide
association study.

Before genetic testing is ordered, the patient, family, and health care
team must discuss a number of issues (Goldman 2012, p. 504):

• Will the test contribute to diagnosis and/or treatment of the disorder?

• Does the patient have the capacity to consent?
• Who else in the family should be present (or consulted) for a discussion of
possible genetic etiology and testing?
• What will be the effect of testing on other family members, and do they
want to know?
 It may be helpful to consider these overarching issues while reading
about individual clinical disorders in the following sections.

Genetics of Mental Disorders of Aging and Later

Life

Alzheimer’s Disease
AD—or, in DSM-5, neurocognitive disorder due to Alzheimer’s disease—is
the predominant cause of dementia in the United States, with over 5 million
people affected. The etiology of AD remains unclear, although significant
strides have been made using gene mapping efforts. Success has been most
notable for Mendelian familial early-onset AD (EOAD), which comprises a
minority (less than 5%) of all AD cases (Goldman et al. 2011). However,
recent success in identifying genetic variants in AD has led to a deeper
understanding of the biology of the disorder, and has potential therapeutic
implications for both EOAD and late-onset AD (LOAD).

Early-Onset Alzheimer’s Disease

Genetics and implications for mechanisms of disease and drug target
identification. Rare nonsynonymous mutations at three genetic loci
associated with EOAD have been identified. The first to be found was the
amyloid precursor protein gene APP located on chromosome 21 (Goate et
al. 1991). Since then, more than 30 different mutations in APP have been
identified, each of which may contribute to the development of EOAD
(Alzheimer Disease and Frontotemporal Dementia Mutation Database
2014). Individuals with one of these mutations generally experience onset
of disease between ages 40 and 60, although later age at onset can occur
(Theuns et al. 2006). More recently, families with duplications of APP—
leaving the mutation carrier with three copies of the gene on their two
chromosomes—have been reported (Rovelet-Lecrux et al. 2006; Sleegers et
al. 2006), with these families experiencing EOAD associated with cerebral
amyloid angiopathy and intracerebral hemorrhage. Although the
identification of mutations in APP has been important in advancing our
understanding of the genetic causes of AD, all APP mutations and
duplications reported to date account for disease in fewer than 100 families
worldwide (Alzheimer Disease and Frontotemporal Dementia Mutation
Database 2014).
A second AD locus was found on chromosome 14 (Schellenberg et al.
1992; St George-Hyslop et al. 1992) and is now called presenilin 1 (PSEN1)
(Sherrington et al. 1995). More than 180 mutations in the PSEN1 locus
have been reported in hundreds of families throughout the world
(Alzheimer Disease and Frontotemporal Dementia Mutation Database
2014). Onset of symptoms for those with PSEN1 mutations is often before
age 50 years, but later ages have also been reported. As with APP
mutations, PSEN1 mutations appear to act as autosomal dominant traits
with nearly complete penetrance (Cruts et al. 1998). However, there has
been at least one report of possible nonpenetrance of a PSEN1 mutation in a
healthy 68-year-old member of a pedigree with multiple affected members
(Rossor et al. 1996).
A third EOAD gene has been localized to chromosome 1 and is known
as presenilin 2 (PSEN2) (Levy-Lahad et al. 1995a, 1995b). Mutations in
PSEN2 appear to be rare, with only a few families of varying ethnicity
having been identified. Although PSEN2 mutations are autosomal
dominant, they may not be fully penetrant, with demonstrated penetrance
rates of about 95% (Goldman et al. 2011). PSEN2 mutations generally lead
to onset of AD symptoms before age 65 years.
The proportion of EOAD cases attributable to mutations in APP, PSEN1,
and PSEN2 remains unclear. Some reports have suggested that PSEN1
mutations account for most familial EOAD cases (Campion et al. 1995,
1999; Hutton et al. 1996), whereas others have reported that a more realistic
estimate is 20% or fewer of such cases, with PSEN2 and APP accounting
for 1% and 5%, respectively (Cruts et al. 1998). Because not all families
with autosomal dominant EOAD have identifiable mutations in PSEN1,
PSEN2, or APP, it is likely that there are additional genes that influence the
pathophysiology of EOAD (Goldman et al. 2011).
Although an appreciation for the role of amyloid β protein (Aβ) in AD
preceded the identification of AD genes (Glenner and Wong 1984), the
identification of causative mutations in EOAD has confirmed the primacy
of this mechanism. Aβ is generated by the processing of APP protein, the
product of the APP gene. In some families, AD results from simple
duplication of APP. Also, AD pathology develops in individuals with Down
syndrome unless the trisomy of chromosome 21 occurs distal to the location
of APP (Prasher et al. 1998). As evidenced by the results of animal and in
vitro studies, the expressions of the identified mutations in APP, PSEN1,
and PSEN2 that lead to EOAD all result in overproduction of the toxic 42
amino acid species of Aβ, Aβ42 (Hardy 2006; Selkoe et al. 2004). More
important for therapeutic implications are the contributions of these genetic
findings to an understanding of how APP protein is metabolized to Aβ42 in
the brain. In brief, the APP protein is cleaved by three enzymes: α-, β-, and
γ-secretase. Cleavage by β-secretase and then γ-secretase generates Aβ,
whereas cleavage by α-secretase prevents generation of Aβ. The
identification of a mutation in APP that selectively enhances metabolism of
APP protein by β-secretase (known as the Swedish mutation) provided the
assay necessary for the successful identification of β-secretase (Vassar et al.
1999). β-Secretase inhibitors are an active area of drug development in AD
(Guo and Hobbs 2006). Continuous administration of β-secretase inhibitors
has been shown to improve age-related cognitive decline in transgenic AD
mice, and several β-secretase inhibitors have also entered early-phase
clinical trials (Ghosh et al. 2012).
Similarly, the identification of AD-causing mutations in proteins PSEN1
and PSEN2 led to a search for their function and ultimately converged on
their identification as constituents of the proteolytic site in γ-secretase
(Hardy 2006; Selkoe et al. 2004). Efforts to identify γ-secretase inhibitors
for the treatment of AD are also under way (Eder et al. 2007), although
these are not as far advanced as the development of β-secretase inhibitors
due to potential toxicity associated with inhibiting the actions of γ-secretase
on proteins other than APP, such as Notch protein. Studies in both
transgenic and nontransgenic animal models of AD have shown that oral γ-
secretase inhibitors are able to lower brain Aβ concentrations, but
behavioral studies remain scarce, with only one study indicating positive
cognitive effects. The most studied γ-secretase inhibitor, semagacestat, was
shown to decrease the generation of Aβ in a dose-dependent manner in the
cerebrospinal fluid of healthy humans (Imbimbo and Giardina 2011).
Unfortunately, two large Phase 3 clinical trials of semagacestat in patients
with mild to moderate AD were halted due to detrimental effects on
cognition and functioning in patients receiving the drug (Imbimbo and
Giardina 2011). These effects were ascribed mainly to the accumulation of
the neurotoxic precursor of Aβ (the carboxy-terminal fragment of APP
protein, or CTFβ) resulting from the block of γ-secretase cleavage activity
on APP protein (Imbimbo and Giardina 2011). Two large Phase 3 studies
with tarenflurbil, a putative γ-secretase modulator, were also negative in
patients with mild AD. The failure of tarenflurbil was ascribed to low
potency and brain penetration. Despite these setbacks, new “Notch-sparing”
γ-secretase inhibitors and more potent γ-secretase modulators are being
developed, with the hope of overcoming previous limitations (Imbimbo and
Giardina 2011).

Testing for EOAD-associated genes. Presymptomatic testing for

autosomal dominant EOAD is most informative when a mutation has been
confirmed in a symptomatic family member. In general, clear genotype-
phenotype correlations cannot be made for PSEN1, PSEN2, and APP, the
three previously mentioned EOAD causative genes, and age at onset may
vary by more than 20 years within the same family. Although several
mutations in PSEN1, PSEN2, and APP have been reported to demonstrate
distinct clinical or neuropathological phenotypes, care must be taken when
interpreting test results, because mutations may have variable expression
across individuals (Goldman et al. 2011). The ongoing Dominantly
Inherited Alzheimer Network Trial is just one example of the exciting
potential for EOAD genetics to influence diagnosis and treatment. This
study, currently in progress, is recruiting individuals with known EOAD
mutations and individuals with parents or siblings with known EOAD
mutations. Investigators are testing two experimental drugs for EOAD to
assess their safety, side-effect profile, and impact on potential AD
biomarkers. The hope is that the results of this trial will have implications
for future diagnosis and management of EOAD, as well as for the
development of treatments for the more common sporadic (late-onset) form
of AD (Alzheimer’s Disease Education and Referral Center 2014).

Late-Onset Alzheimer’s Disease

Genetics. In contrast to EOAD variants, LOAD is a complex disorder that
results from the effects of multiple genes, likely interacting with pertinent
environmental risk factors. As a result, LOAD can present as either a
familial disorder or a sporadic disorder. A number of genes appear to be
associated with LOAD. The most well known, APOE, is clearly associated
with LOAD, with increased risk of AD found in individuals carrying
APOE*E4 in both familial and sporadic cases (Brousseau et al. 1994;
Mayeux et al. 1993; Rebeck et al. 1993; Saunders et al. 1993; Schmechel et
al. 1993). Although APOE*E4 is most associated with an increased risk for
LOAD, it has also been associated with EOAD (for an overview, see
Goldman et al. 2011). As the number of ε4 alleles increases from 0 to 2, the
risk for AD increases and the mean age at onset of AD is earlier (Corder et
al. 1993). These findings were confirmed in a meta-analysis of more than
14,000 subjects recruited from clinical, community, and brain bank sources
(Farrer et al. 1997). Although the effect of APOE*E4 on increased risk for
LOAD was evident in both sexes and in all age and ethnic groups, the
magnitude of the risk varied by age and ethnicity. The risk appeared to be
attenuated in older individuals and in African Americans and Hispanics
(relative to Caucasians), whereas the risk conferred by APOE*E4 was
increased in individuals of Japanese ethnicity (Farrer et al. 1997).
The strength of the relationship between APOE*E4 and risk for LOAD
cannot be overstated. Approximately 50%–70% of people with AD carry at
least one ε4 allele, and APOE*E4 accounts for up to 50% of the genetic
contribution to late-onset AD (Pericak-Vance and Haines 1995). Typical
estimates suggest a 2- to 3-fold increased risk for ε4 heterozygotes (with
estimates for homozygotes varying from 2- to 10-fold increased risk). Many
studies of the effects of the ε4 allele suggest that it influences the age at
which AD occurs, rather than the overall lifetime risk. Several studies have
also suggested that the presence of an ε2 allele may play a protective role
against the development of AD (Goldman et al. 2011). Nevertheless,
carrying one or two APOE*E4 alleles does not translate into certain
development of AD. It has been estimated that of the APOE*E4
homozygotes who are disease-free at age 65, at most 50% will develop AD
within their lifetime (Henderson et al. 1995; Seshadri et al. 1997).
At least half of the genetic contribution to LOAD is due to genes other
than APOE. A large number of linkage analyses of families with multiple
individuals affected by LOAD have been conducted, and many regions in
the genome have been implicated as possibly harboring LOAD-relevant
genes. Recent large GWASs have identified, in addition to APOE, other
potential genetic loci for LOAD, including CR1, BIN1, and CLU (Kamboh
et al. 2012). However, the genetic effect attributable to these loci is about
50%, indicating that additional risk genes for LOAD have yet to be
identified. A recent and exciting meta-analysis of GWASs identified 11 new
genetic loci with suspected relationships to LOAD. These loci reinforced
the importance of previously suspected key players in AD (e.g., APP
protein and tau) and, in combination with earlier findings, have highlighted
the role of inflammation in AD (Lambert et al. 2013). Strong efforts in
sequencing and post-GWAS analyses, however, will be required to fully
characterize the candidate genes and functional variants responsible for the
association of these loci with AD risk, as well as to understand their roles in
the pathophysiology of AD (Lambert et al. 2013). For example, such efforts
recently identified rare variants in the TREM2 gene as being associated with
increased AD risk (Guerreiro et al. 2013; Jonsson et al. 2013).

Testing for APOE*E4 and other LOAD-associated genes. In general, the

addition of APOE*E4 testing to a clinical dementia assessment lowers the
sensitivity and enhances the specificity of an AD diagnosis (Ertekin-Taner
2007), ultimately reducing the false-positive rate. However, in individuals
with normal cognition or mild cognitive impairment, APOE*E4 testing
appears to be an insufficient predictor (on its own) of subsequent AD and
may offer little benefit over cognitive testing in predicting a subsequent
dementia diagnosis (Cervilla et al. 2004; Klages et al. 2003). For this reason
and others, APOE genotyping is not routinely offered in the clinical setting.
Because the ε4 allele is neither necessary nor sufficient to cause AD,
numerous consensus statements have recommended against using APOE
genotyping for predicting AD risk. The primary reasons for this
recommendation include the aforementioned low sensitivity of testing, the
limited availability of treatment options, and the difficult nature of
effectively conveying probabilistic risk (Goldman et al. 2011). Currently,
routine genetic testing in AD is advised only for suspected cases of EOAD
(when the presenting affected individual is a young or middle-aged adult).
A number of ongoing studies, however, are evaluating the advantages and
disadvantages of similar testing in LOAD (Farlow and Foroud 2013). For
example, genotyping may eventually play a role in treatment selection,
given that it has been observed that therapeutic response to cholinesterase
inhibitors may be linked to the presence of certain APOE alleles (with
APOE*E4 carriers being poor responders), and carriers of defective
cytochrome P450 2D (CYP2D) polymorphic variants may exhibit altered
metabolism of cholinesterase inhibitors (Alagiakrishnan et al. 2012).
Neuropsychiatric Symptoms in Alzheimer’s Disease
Nearly all individuals with AD will develop neuropsychiatric symptoms at
some point in their illness, with depression, aggression, and psychosis being
the most common (Devanand et al. 1997; Swearer et al. 1988; Wragg and
Jeste 1989). Such symptoms invariably cause distress for the individual
who experiences them, as well as for family and caregivers (Kaufer et al.
1998). Psychotic symptoms occur in approximately 50% of individuals with
AD, and pharmacotherapies for AD with psychosis have limited efficacy
and may increase short-term mortality (Murray et al. 2014). In addition,
psychosis in AD indicates a more severe phenotype, with more rapid
cognitive decline beginning even before the onset of psychotic symptoms
(Murray et al. 2014).
A number of investigators have been interested in whether psychosis and
other behavioral disturbances in LOAD may result from the interaction of
genetic variation with the neurodegenerative process. Tunstall et al. (2000),
for example, reported on the significant genotypic influence on mood in
AD, but found evidence for familiality of AD-related psychosis to be
equivocal. In contrast, Sweet et al. (2002) found a significant association
between the presence of psychotic symptoms in probands and their siblings
in a cohort of 371 subjects with AD and 461 siblings also diagnosed with
AD, recruited and characterized as part of the National Institute of Mental
Health AD Genetics Initiative. Such work has led to an estimated
heritability of psychosis in AD of 61% (Bacanu et al. 2005). The familial
aggregation of psychosis in AD has since been confirmed in independent
samples (Hollingworth et al. 2007; Sweet et al. 2010). Furthermore, Sweet
et al. (2010) found that the presence of psychosis in AD was significantly,
albeit modestly, correlated with the severity of other behavioral symptoms,
raising the possibility that there may be some overlapping genetic
determinants.
Motivated by the observation of the heritability of psychosis in AD,
Hollingworth et al. (2012) undertook an analysis of three GWASs to
identify loci that increase susceptibility to psychosis in AD. The strongest
evidence for an association was observed in an intergenic region on
chromosome 4. Additional SNPs upstream of SLC2A9 and within VSNL1
showed strong evidence for an association when compared with controls
without psychosis. Such preliminary findings warrant further investigation
within larger and better-characterized samples (Hollingworth et al. 2012).

Other Neurodegenerative Illnesses of Later Life

Substantial progress has been made in the identification of genetic variation
that contributes to the risk of other common neurodegenerative diseases of
later life. As for AD, much of this progress has resulted from identification
of variants that contribute to the risk of highly heritable, familial forms of
these illnesses.

Frontotemporal Dementia
Frontotemporal dementia (FTD)—or, in DSM-5, neurocognitive disorder
due to frontotemporal lobar degeneration—is a clinically and pathologically
heterogeneous group of non-Alzheimer dementias whose underlying
pathology includes progressive degeneration of the prefrontal and anterior
temporal lobes (Neary et al. 2005). There are three main clinical syndromes
of FTD, characterized by leading features at presentation (Warren et al.
2013). About half of FTD cases present with behavioral change, referred to
as behavioral variant FTD. The remainder present with language decline
(primary progressive aphasia) characterized either by impaired speech
production (progressive nonfluent aphasia) or impaired word
comprehension and semantic memory (semantic dementia). It should be
noted, however, that a fair amount of overlap exists across these syndromes
(Warren et al. 2013). In contrast to AD—the most common dementia of
later life—FTD often presents in later middle age, with memory being
initially well maintained. Behavioral or personality changes that occur in
individuals with FTD are often mistaken for a primary psychiatric disorder,
particularly if the changes are accompanied by psychotic features. Clues
that such features are harbingers of FTD include absence of prior
psychiatric history, as well as the emergence of more specific symptoms
such as changes in eating behavior or social faux pas (Warren et al. 2013).
Nearly all FTD cases result from one of two major types of
neurodegenerative lesions: 1) tau-positive inclusions and 2) ubiquitin-
positive inclusions, shown to contain transactive response (TAR) DNA-
binding protein 43 (TDP-43) (Neumann et al. 2006). The neuropathological
findings of FTD overlap with those of several other neurodegenerative
disorders; for example, tau-positive inclusions are also seen in progressive
supranuclear palsy and corticobasal degeneration, and TDP-43–positive
inclusions are often seen with motor neuron disease.
FTD has been the subject of extensive genetic investigation. A positive
family history is present in up to 50% of cases (Bird et al. 2003; Chow et al.
1999). Mutations in one of several genes can result in FTD, which typically
demonstrates an autosomal dominant pattern of transmission. Major causes
of FTD include mutations in the following genes: MAPT, PGRN or GRN,
and C9orf72 (Wang et al. 2013). A minority of cases are caused by
mutations in the following genes: TDP-43, VCP, CHMP2B, and FUS. In
addition, involvement of the APOE gene locus has been reported (Wang et
al. 2013). A significant discovery identified mutation in C9orf72 (DeJesus-
Hernandez et al. 2011) as perhaps the most common genetic abnormality in
both familial behavioral variant FTD (11.7% of cases) and motor neuron
disease (23.5%). This new mutation is an expansion of a noncoding
GGGGCC hexanucleotide repeat located in chromosome 9p (Dobson-Stone
et al. 2012).
Testing for frontotemporal dementia–associated genes. Definitive
diagnosis of FTD (and AD, for that matter) can be made only at autopsy,
but genetics may be used to increase diagnostic and prognostic accuracy
(Farlow and Foroud 2013). MAPT, GRN, and C9orf72 may be easily
sequenced for mutations that lead to FTD and together account for a
majority of familial cases. Families concerned about the possibility of FTD
developing in future generations frequently ask their physician to order
genetic testing (Chow and Alobaidy 2013). As always, a referral to a
genetic counselor should precede the collection of samples for testing
(Chow and Alobaidy 2013).
The first step in determining the order for genetic testing for FTD is to
take a detailed family history (Goldman 2012). As with AD, testing for
autosomal dominant genes is less likely to yield a mutational finding
without a known or suspected family history of FTD. However, PGRN and
C9orf72 mutations have been found in sporadic cases (Goldman 2012).
Genetic testing for FTD is also greatly facilitated by having a pathological
diagnosis on an affected family member, because autopsy results can guide
genetic testing by eliminating the need to test certain genes.
 FTD genotyping may soon play a role in treatment selection for FTD.
Several preliminary reports have proposed the use of antisense
oligonucleotides (ASOs; short synthetic single DNA strands designed to
bind their complementary sequence) to reduce levels of RNA containing the
pathological hexanucleotide repeat in chromosome 9p (Lagier-Tourenne et
al. 2013). ASO therapies may treat gain-of-function disorders by silencing
the causative gene, either by acting on both alleles for nonessential genes or
by selectively acting on the mutant allele in the case of essential genes
(Fernandes et al. 2013). For certain loss-of-function diseases, there is also
the possibility of using ASOs for splice modulation, which can in certain
cases restore the gene function or otherwise compensate for its loss
(Fernandes et al. 2013).

Parkinson’s Disease
PD is a progressive neurodegenerative disorder that affects 1%–2% of the
population ages 65 years and older (de Rijk et al. 1997). It is characterized
by motor symptoms that include akinesia, rest tremor, rigidity, and
disturbance of postural reflexes. Many cases of PD are thought to arise
sporadically; as a result, the risk for first-degree family members of
individuals with PD is increased only two- to threefold, and only in families
with an early age at onset (Gasser 2005). Mutations in multiple genes have
been identified that appear to cause PD via a Mendelian mode of
inheritance. As with AD, however, these mutations account for a small
number of affected families and are primarily associated with earlier
lifetime onset (for reviews, see Gasser 2005; Hardy et al. 2006).
Autosomal dominant PD is robustly associated with mutations in the
following genes: SNCA, LRRK2, EIF4G1, and VPS35. Recessive PD is
associated with mutations in PARK2, PINK1, and DJ1/PARK7 (Puschmann
2013). Changes in a long list of additional genes have also been suggested,
including genes for hereditary ataxias, frontotemporal dementia, dopa-
responsive dystonia, and other conditions. Point mutations and
multiplications in SNCA, the gene encoding α-synuclein protein, cause
cognitive or psychiatric symptoms and parkinsonism, with widespread α-
synuclein pathology in the central and peripheral nervous system
(Puschmann 2013). LRRK2 mutations may lead to a clinical phenotype
closely resembling idiopathic PD, with a variety of neuropathology.
Mutations in PARK2, PINK1, and DJ1/PARK7, on the other hand, may
cause early-onset parkinsonism with limited risk for cognitive decline.
Carriers of mutations in the other genes may develop parkinsonism with or
without additional symptoms, but rarely a disease resembling PD. Although
some mutations occur with high frequency in specific populations, all are
very rare. Therefore, the genetic etiology of the majority of cases of
sporadic or hereditary PD remains unknown on a more global scale
(Puschmann 2013).
In a two-stage meta-analysis, the International Parkinson’s Disease
Genomics Consortium and Wellcome Trust Case Control Consortium 2
(2011) identified several new potential genetic loci for PD. The researchers
identified five additional PD risk loci—PARK16/1q32, FGF20/8p22,
STX1B/16p11, STBD1/4q21, and GPNMB/ 7p15—the first two of which
had been suggested by previous association studies. Using data from
postmortem brain samples assayed for gene expression and methylation, the
investigators were able to identify methylation and expression changes
associated with PD risk variants within PARK16/1q32, GPNMB/7p15, and
STX1B/16p11 loci, suggesting potential molecular mechanisms and
candidate genes at these locations.
Testing for Parkinson’s disease–associated genes. Currently, genetic
testing is available for a number of PD-related genes, including SNCA,
LRRK2 (PARK8), PARK2, PARK7, and PINK1 (Athena Diagnostics 2014).
Routine testing is not recommended at this time, however, due to lack of
disease-modifying therapies and still evolving research on the role and
utility of testing in clinical decision making. If an individual or family is
interested in pursuing testing, it is recommended that this is guided by a
genetic counselor with experience in working with patients with familial
history of PD.

Psychiatric Disorders of Adulthood:

Schizophrenia, Bipolar Disorders, and Major
Depressive Disorder
The major idiopathic psychiatric disorders of adulthood—schizophrenia,
bipolar disorders, and major depressive disorder—are complex disorders
with likely genetic contributions to their etiologies. Major depressive
disorder shows evidence of a moderate genetic contribution, with estimates
of its heritability at around 37% (Bienvenu et al. 2011). In contrast,
schizophrenia and bipolar disorders demonstrate substantially greater
heritability, estimated at 81% and 85%, respectively (Bienvenu et al. 2011).
It is important to note, however, that these three diagnostic categories are
not genetically distinct. Family studies have shown substantial overlap in
risk for schizophrenia and bipolar disorders and for bipolar disorders and
major depressive disorder, although the overlap between schizophrenia and
major depressive disorder is more modest (Cross-Disorder Group of the
Psychiatric Genomics Consortium and Genetic Risk Outcome of Psychosis
[GROUP] Consortium 2013; Cross-Disorder Group of the Psychiatric
Genomics Consortium et al. 2013). These observations have been extended
to unrelated individuals diagnosed with these disorders (or with autism
spectrum disorder and attention-deficit/hyperactivity disorder [ADHD]) by
examining the proportion of shared genotypes at nearly 1 million common
variants (Cross-Disorder Group of the Psychiatric Genomics Consortium
and Genetic Risk Outcome of Psychosis [GROUP] Consortium 2013;
Cross-Disorder Group of the Psychiatric Genomics Consortium et al. 2013).
Evidence demonstrated a high degree of shared genotypes between
schizophrenia and bipolar disorders, a moderate degree between bipolar
disorders and major depressive disorder, and a moderate degree between
schizophrenia and major depressive disorder. In addition, a moderate degree
of genetic correlation existed between major depressive disorder and
ADHD, and a small degree was present between schizophrenia and autism
spectrum disorder. These findings are consistent with the notion that there
are common genetic variants (and, by implication, conserved functional
consequences of these variants) that nonspecifically increase the risk for
schizophrenia, bipolar disorders, and major depressive disorder, and such
findings have led to further attempts to pool diagnoses to enhance power to
detect shared variants (Cross-Disorder Group of the Psychiatric Genomics
Consortium and Genetic Risk Outcome of Psychosis [GROUP] Consortium
2013). Similarly, studies have revealed evidence of shared liability to rare
structural variation (copy number variation) between schizophrenia, bipolar
disorders, autism spectrum disorders, and intellectual disability (Malhotra
and Sebat 2012).
 Because the search for specific underlying genetic contributions to these
disorders is an area of substantial ongoing research effort (and, as such, is
rapidly evolving), we have not attempted to generate a comprehensive
summary of all recent findings. Instead, we have focused on findings that
are well established or that will guide future studies. It should be noted that
studies summarized below are not specific to late-life (or late-onset)
disease, but instead focus on schizophrenia, bipolar disorders, and major
depressive disorder across the lifespan.

Rare Mutations
Efforts to identify rare variants with high penetrance leading to Mendelian
forms of disease have proved successful for neurodegenerative disorders
but unfortunately have not yielded definitive results for schizophrenia,
bipolar disorders, or major depressive disorder. In recent years, efforts have
shifted to the detection of rare de novo variants, with most studies to date
having focused on schizophrenia. This shift has been motivated in part by
the recognition that many individuals with schizophrenia do not have
family histories of the disorder, as well as the fact that schizophrenia has
persisted in the population despite conferring lower reproductive success.
Both of these observations may be explained by an excess of de novo
mutations (Xu et al. 2011). Efforts in this area have met with some
preliminary successes, suggesting there may be enrichment of de novo
mutations that disrupt genes involved in brain development and/or synaptic
function (Gulsuner et al. 2013; Kenny et al. 2014; Xu et al. 2012).
However, these studies have been limited by the fact that most identified
mutations are both individually rare and not fully penetrant, meaning that
they occur to some extent in unaffected individuals as well. The result is
that substantially larger numbers of subjects will need to be genotyped for
many of these rare variants before clear evidence of causality for any of
these genes can be established. It is expected that such studies will be
forthcoming.

Structural Variants
A number of studies have established that individuals with schizophrenia
have a greater frequency of genetic structural variation than do individuals
without schizophrenia; data for bipolar disorders are less striking but also
consistent with a greater frequency of structural variation (Malhotra and
Sebat 2012; Sullivan et al. 2012). Similar findings have not emerged for
major depressive disorder. Not only is the overall burden of structural
variants increased in schizophrenia, but alterations at a number of specific
genomic loci have been replicated across studies (Malhotra and Sebat
2012). Such loci have included confirmation of a previously known
association of increased risk for schizophrenia in individuals with a large
deletion at chromosome (chr) 22q11.2, which is associated with the
developmental disorder velocardiofacial (i.e., DiGeorge) syndrome, in
which about 25% of individuals develop schizophrenia. Other loci with
replicated structural variations associated with increased risk of
schizophrenia, and in some cases with bipolar disorders and recurrent
depression, include deletions at chr1q21.1, chr3q29, and chr15q13.3.
However, the implications of these and other similar findings for a more
specific biological understanding of schizophrenia and bipolar disorders are
not entirely clear, because these deletions are also associated with increased
risk for intellectual disability, developmental disorders, and autism
spectrum disorders. In addition, these loci contain many genes within the
deleted regions, and therefore determining the actual genetic changes that
lead to neuropsychiatric impairment remains a challenge.
With regard to the latter issue, there have been several structural variants
that seem to implicate a single gene or a limited set of genes. Among the
most intensively studied of these has been a reciprocal translocation
between chr1 and chr11 that disrupts DISC1, as well as ncRNAs DISC2 and
DISC1FP1 (Thomson et al. 2013). The translocation between chr1 and
chr11 has been found in a single large Scottish family, in which carriers of
the translocation have increased rates of schizophrenia, recurrent major
depressive disorder, and bipolar disorders (Blackwood et al. 2001).
However, the translocation is not fully penetrant, because carriers are
unaffected. This finding has spurred extensive examination of the genetics
of DISC1 in other individuals and families. These studies, which have
encompassed assessments of structural variation, rare mutations, and
common variants, have provided supportive but not unequivocal evidence
for an association of DISC1 with schizophrenia, depressive disorders, and
autism spectrum disorders (Thomson et al. 2013). Nevertheless, as one of
the best single-gene candidates for causation of mental illness, DISC1 has
been the subject of increasingly expansive investigations of its functionality
(Thomson et al. 2013).
Deletions and duplications affecting the gene NRXN1 have likewise been
described in schizophrenia but are also known to occur in autism spectrum
disorder, intellectual disability, and seizure disorder (Doherty et al. 2012).
Similarly, a duplication affecting the vasoactive intestinal peptide receptor 2
gene (VIPR2)—which, despite its name, is expressed and functions in the
brain—has been associated with schizophrenia and autism spectrum
disorders but not with bipolar disorders (Vacic et al. 2011). The fact that
these duplications increase the amount of VIPR2 expressed raises the
question of whether antagonists could be developed as potential targeted
therapeutics for schizophrenia.

Common Variants
Until very recently, most studies of common variants focused on candidate
genes identified by their known function or position within chromosomal
regions showing linkage to disease in gene mapping studies. However, the
extent to which these earlier reports may represent true associations remains
unclear, due to many biases inherent in such approaches. The field has since
moved toward the use of GWASs, which, by controlling for multiple
hypothesis testing, increases the confidence that significant associations are
true positives. However, GWASs also require large samples to detect
significant associations. Therefore, recent international efforts to combine
all moderate-sized GWASs in psychiatric illness into a large analysis via the
Psychiatric Genomics Consortium are under way and have generated a
series of analyses with increasing sample size. The most recent analysis of
common variation in schizophrenia involved 36,989 subjects with
schizophrenia and 113,075 control subjects. Investigators found 108
significantly associated genomic loci, implicating multiple genes and
ncRNAs as possibly associated with increased risk for schizophrenia
(Schizophrenia Working Group of the Psychiatric Genomics Consortium
2014). A number of these findings have highlighted consistent trends
observed in earlier studies. First and foremost has been the significant
association of schizophrenia and bipolar disorders with genes involved in
calcium signaling, including the calcium channel, voltage-dependent, L
type, alpha 1C subunit gene (CACNA1C) and the calcium channel, voltage-
dependent, beta 2 subunit gene (CACNB2). These findings have clear
potential therapeutic implications (e.g., for agents active at these receptors),
although much work remains necessary to elucidate the biological
mechanisms underlying these associations. A second important and
consistent finding was the identification of associations with variants in the
DRD2 gene and in genes affecting glutamate signaling (e.g. GRM3,
GRIN2A, SRR, GRIA1), supporting prior hypothesized dopaminergic and
glutamatergic mechanisms in disease.
Genetic studies have also found schizophrenia to be associated with the
ncRNA miR-137, a microRNA that acts to reduce expression of multiple
gene targets and is also associated with increased risk for schizophrenia
(Ripke et al. 2013). In addition, many genes associated with schizophrenia
are themselves potentially regulated by miR-137. This publication also
found many potential associations of another class of RNA—long ncRNA
(lncRNA)—with risk for schizophrenia. The functions of lncRNA are still
being uncovered but are expected to have a role in the regulation of gene
transcription, further highlighting the extent to which genetic variation in
schizophrenia may act through complex regulation of gene expression
rather than through alterations in specific protein sequences (Cookson et al.
2009). Finally, as in previous studies, recent investigations have found the
major histocompatibility complex to be associated with schizophrenia,
although the complex genetics of the major histocompatibility complex
make the implications of this association somewhat unclear at this time.
The efforts of the Psychiatric Genomics Consortium have also led to the
aforementioned discovery of shared common genetic variation among
individuals with schizophrenia, bipolar disorders, major depressive
disorder, and other disorders (see beginning of section “Psychiatric
Disorders of Adulthood: Schizophrenia, Bipolar Disorders, and Major
Depressive Disorder”), and efforts to identify genetic variation that may
contribute to risk across disorders have since been under way. The largest of
these to date examined 33,332 individual cases diagnosed with bipolar
disorders, major depressive disorder, schizophrenia, autism spectrum
disorder, or ADHD, as well as 27,888 healthy controls of European ancestry
(Cross-Disorder Group of the Psychiatric Genomics Consortium and
Genetic Risk Outcome of Psychosis [GROUP] Consortium 2013).
Significant associations with SNPs in ITIH3, AS3MT, and CACNB2 were
found, with similar associations to risk for all five disorders. In addition, a
significant association with a SNP in CACNA1C was driven by the
schizophrenia and bipolar groups. In contrast to these shared genetic
associations, no studies have identified significant associations of common
variants with major depressive disorder alone.
The inability to detect an association of common variants with major
depressive disorder alone, as well as reports of the relatively lower
heritability of major depressive disorder in comparison with schizophrenia
or bipolar disorders, likely reflects a greater role of environmental
precipitants in this syndrome. Identifying genetic variants that contribute to
major depressive disorder may require the study of groups of individuals
whose major depressive disorder occurs in the context of a specific or a
limited set of environmental factors. For example, a recent finding that
attracted a great deal of attention in studies of major depressive disorder
was the report that short alleles of a 44-base-pair insertion/deletion
polymorphism in the serotonin transporter gene SLC6A4 moderated
environmental effects on depression, increasing the risk for depression
induced by stressful life events or childhood maltreatment (Caspi et al.
2003). The possibility that genetic variation in SLC6A4 might influence
stress reactivity has been supported by several smaller studies using
different approaches (see review in Levinson 2006). However, two
subsequent large-scale studies were unable to replicate these findings
(Gillespie et al. 2005; Surtees et al. 2006). More recent meta-analyses have
continued to provide conflicting results, adding uncertainty to the
relationship between genetic variation in SLC6A4, stressful life events, and
major depressive disorder (Karg et al. 2011). Despite the lack of
convergence on SLC6A4, this approach could be used to identify common
variants using GWASs, if sufficiently large samples characterized for
environmental exposure to stressful events could be identified.
The consideration of specified environmental factors may have particular
relevance for the study of the genetics of late-life depression. Whereas
some environmental stressors that are common in late life (e.g.,
bereavement) may share mechanisms with early life stressors, other
important environmental contributors to late-life depression, such as
cerebrovascular disease, are likely to interact with a different set of genetic
variants. There have been some efforts to detect common variants that may
interact with cerebrovascular disease to alter the risk for late-life depression
(reviewed in Chapter 9, “Depressive Disorders”). At present, these studies
have been limited in sample size and to the study of a subset of SNPs
occurring in a few candidate genes. Therefore, they must be interpreted
with caution, because these designs are prone to generate both false-positive
and false-negative results when common variants are considered.
Nevertheless, such work is accelerating, driven by advances in the
identification of genetic variants associated with ischemic and large artery
stroke (Dichgans et al. 2014).

Conclusion
Medical genetics has entered the postgenomics era: the pace at which
genetic variants are being discovered continues to accelerate, and such
discoveries are beginning to inform the development of novel and much-
needed interventions. With faster and increasingly inexpensive genomic
approaches becoming available, untangling the genetic underpinnings of
some of the more complex disorders in geriatric psychiatry will ideally soon
follow. Although the impact of these developments on practicing geriatric
psychiatrists has so far been limited, it will soon be felt. The potential for
genomics to contribute to individualized clinical care has long been
recognized, and many optimistic scenarios for its use have been proposed.
In fact, several academic medical centers and integrated health systems
have already embarked on the implementation of genomic medicine in
clinical practice (Manolio et al. 2013).
Although advancements in medical genomics continue, it is important
for us to emphasize the reasons why identifying genes that lead to the
development of complex disorders remains a challenging process. The flow
of events leading from variation in the sequence of a gene to the
development of multiple cognitive, emotional, and behavioral criteria that
define the complex neuropsychiatric disorders of later life is not linear or
straightforward. Genes encode proteins, which act within extensive
biochemical networks in which changes may be amplified or compensated
for by the effects of other proteins or environmental factors. The net result
is that the magnitude of an increase in disease risk for a complex disorder
due to any single genetic variation will be relatively small, suggesting that
the ability to predict clinical outcomes for individual patients will be quite
limited, even if one knows that a patient carries a genetic variation
associated with the disease of interest.
Given current limitations in the availability of disease-modifying
therapies for a number of neurodegenerative illnesses, as well as the
complex ethical considerations involved in genomic medicine, clinicians
must carefully consider the appropriateness of ordering genetic tests for
their patients. Because both positive and negative findings may have
significant implications for patients and their families, thorough genetic
counseling is advised before and after genetic testing is performed. Methods
for screening and diagnosing neurodegenerative illnesses will continue to
improve as additional genes are identified and correlated with increasingly
specific phenotypes, and such discoveries will hopefully inform the
development of preventive and disease-modifying therapies (Farlow and
Foroud 2013). Geriatric psychiatrists will need to be familiar with these
developments so as to effectively counsel their patients and continue to
provide state-of-the-art care.

Key Points
• The discovery of rare disease-causing mutations has been instrumental in
furthering the understanding of the neurobiology of a number of
neuropsychiatric disorders of later life, including Alzheimer’s disease,
frontotemporal dementia, and Parkinson’s disease. Furthermore, the pace
of discovery in these areas continues to accelerate.
• Many neuropsychiatric disorders of later life—including the most
common presentations of the dementias—are genetically complex
diseases, resulting from the interaction of multiple genes and
environmental factors. Such complexity limits the definitive
identification of contributory genes and reduces the ability to use genetic
information to predict clinical outcomes. Nevertheless, important strides
in this area are continuing to be made.
• Genetic testing may be useful for some of the aforementioned disorders,
including early-onset Alzheimer’s disease and frontotemporal dementia,
and the likelihood of identifying causal mutations in individuals affected
by these disorders increases in the presence of a positive family history.
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 PART II

Evaluation of Psychiatric Disorders in

Late Life
 CHAPTER 4

The Psychiatric Interview of Older Adults

Dan G. Blazer, M.D., Ph.D.

The foundation of the diagnostic workup of the older adult

experiencing a psychiatric disorder is the diagnostic interview.
Unfortunately, in this age of increasing technology in the laboratory and
standardization of interview techniques, the art of the clinical interview has
suffered. Also, time pressures limit the ability of clinicians to perform a
thorough diagnostic workup. Nevertheless, such a workup will save
valuable time over the course of an older adult’s illness. In this chapter, I
review the core of the psychiatric interview, including history taking,
assessment of the family, and the mental status examination; describe
structured interview schedules and rating scales that are of value in the
assessment of older adults; and outline techniques for communicating
effectively with older adults.

History
The elements of a diagnostic workup of the elderly patient are presented in
Table 4–1. To obtain historical information, the clinician should first
interview the patient, if that is feasible, and then ask the patient’s
permission to interview family members. Members from at least two
generations, if available for interview, can expand the perspective on the
older adult’s impairment. If the patient has difficulty providing an accurate
or understandable history, the clinician should concentrate especially on
eliciting the symptoms or problems that the patient perceives as being most
disabling, then fill the historical gap with data from the family.

Present Illness
DSM-5 (American Psychiatric Association 2013) provides the clinician
with a useful catalog of symptoms and behaviors of psychiatric interest that
are relevant to the diagnosis of the present illness. Symptoms are bits of
data—the most visible part of the clinical picture and generally the part
most easily agreed on among clinicians. Symptoms should be defined in
such a way that if multiple clinicians independently obtain equivalent
information, they would have minimal disagreement about the presence or
absence of a symptom. The decision about whether those symptoms form a
syndrome or derive from a particular etiology must be determined
independently of the data collection on symptoms.

TABLE 4–1. Psychiatric interview of the elderly patient

History
Present illness
Past history
Family history
Context
Medication history
Medical history
Family assessment
Mental status examination

Even so, the clinical interaction may be confounded by bias when a

clinician communicates with an older adult about psychiatric symptoms. As
many insightful clinicians, such as Eisenberg (1977), have recognized,
physicians diagnose and treat diseases—that is, abnormalities in the
structure and function of body organs and systems. Patients have illnesses
—experiences of disvalued changes in states of being and in social
function. Disease and illness do not maintain a one-to-one relationship.
Factors that determine who becomes a patient and who does not can be
understood only by expanding horizons beyond symptoms. During the
process of becoming a patient, the older adult, usually with the advice of
others, forms a self-diagnosis of his or her problem and makes a judgment
about the degree of ill-being perceived. For some, illness is perceived when
a specific discomfort is experienced. For others, illness reflects a general
perception of physical or social alienation and despair. Given that few
uniform, satisfactory definitions of illness (or ill-being) exist, it is not
surprising that terms for wellness (or well-being) also mean different things
to different people. The historical background and the values of the older
adult in a social class and culture contribute to the formation of constructs
regarding the nature of the problem, the cause, and the possibility for
recovery.
For these reasons, the clinician must take care to avoid accepting the
patient’s explanation for a given problem or set of problems. Statements
such as “I guess I’m just getting old and there’s nothing really to worry
about” or “Most people slow down when they get to be my age” can lull the
clinician into complacency about what may be a treatable psychiatric
disorder. On the other hand, the advent of new and disturbing symptoms in
an older adult between office visits can exhaust the clinician’s patience,
thereby derailing pursuit of the problem. For example, the older adult with
illness anxiety disorder whose awakenings during the night are increasing
may insist that this symptom be treated with a sedative and plead with the
clinician not to allow continual suffering. In the clinician’s view, however,
the symptom is a normal accompaniment of old age and therefore should be
accepted. Distress over changes in functioning, such as sexual functioning,
may overwhelm the older adult patient and, especially if the clinician is
perceived as unconcerned, may precipitate self-medication or even a suicide
attempt.
To prevent attitudinal biases when eliciting reports by the older adult
(which may result in missing the symptoms and signs of a treatable
psychiatric disorder), the clinician must include in the initial interview a
review of the more important psychiatric symptoms in a relatively
structured format. Common symptoms that should be reviewed include
excessive weakness or lethargy; depressed mood or “the blues”; memory
problems; difficulty concentrating; feelings of helplessness, hopelessness,
and uselessness; isolation; suspicion of others; anxiety and agitation; sleep
problems; and appetite problems and weight loss. Less common yet critical
symptoms that should be reviewed include the presence or absence of
suicidal thoughts, profound anhedonia, impulsive behavior (“I can’t control
myself”), confusion, delusions, and hallucinations.
The review of symptoms is most valuable when considered in the
context of symptom presentation: When did the symptoms begin? How
long have they lasted? Has their severity changed over time? Are there
physical or environmental events that precipitate the symptoms? What
steps, if any, have been taken to try to correct the symptoms? Have any of
these interventions proved successful? Do the symptoms vary during the
day (diurnal variation)? Do they vary during the week or with seasons of
the year? Do the symptoms form clusters—that is, are they associated with
one another? Which symptoms appear ego-syntonic, and which appear ego-
dystonic? As symptoms are reviewed, a specific time frame facilitates focus
on the present illness. Having a 1-month or 6-month window enables the
patient to review symptoms and events temporally—an approach not
usually taken by distressed elders, who tend to concentrate on immediate
sufferings.
Critical to the assessment of the present illness is an assessment of
function and change in function. The two parameters that are most
important (and not included in usual assessments of physical and
psychiatric illness) are social functioning and activities of daily living.
Questions should be asked about the social interaction of the older adult,
such as the frequency of his or her visits outside the home, telephone calls,
and visits from family and friends. Many scales have been developed to
assess activities of daily living; however, in the interview, the clinician can
simply ask about the patient’s ability to get around (e.g., walk inside and
outside the house), to perform certain physical activities independently
(e.g., bathe, dress, shave, brush teeth, select clothes), and to do instrumental
activities (e.g., cook, maintain a bank account, shop, drive). It is also
important to assess how often the elder actually engages in these activities;
for example, the ability to walk outside does not always translate to outside
exercise.

Past History
Next, the clinician must review the past history of symptoms and episodes.
Has the individual had similar episodes in the past? How long did the
episodes last? When did they occur? How many times in the patient’s
lifetime have such episodes occurred? Unfortunately, the older adult may
not equate present distress with past episodes that are symptomatically
similar, so the perspective of the family is especially valuable in the attempt
to link current and past episodes.
Other psychiatric and medical problems should be reviewed as well,
especially medical illnesses that have led to hospitalization and the use of
medication. Not infrequently, an older adult has experienced a major illness
or trauma in childhood or as a younger adult but views this information as
being of no relevance to the present episode and therefore dismisses it.
Probes to elicit these data are essential. Older adults may ignore or even
forget past psychiatric difficulties, especially if these difficulties were
disguised. For example, mood swings in early or middle life may have
occurred during periods of excessive and productive activity, episodes of
excessive alcohol intake, or periods of vague, undiagnosed physical
problems. Previous periods of overt disability in usual activities may flag
those episodes. An older person sometimes becomes angry or irritated when
the clinician continues to probe. Reassurance regarding the importance of
obtaining this information will generally suffice, except when dealing with
a patient who cannot tolerate the discomfort and distress, even for brief
periods. Older persons who have chronic and moderately severe anxiety or
a histrionic personality style, as well as distressed Alzheimer’s patients,
tolerate their symptoms poorly.

Family History
The distribution of psychiatric symptoms and illnesses in the family should
be determined next. The older person with symptoms consistent with major
neurocognitive impairment may have a family history of a disorder such as
major neurocognitive disorder due to Alzheimer’s disease. The genogram
can be valuable for charting the distribution of mental illness and other
relevant behaviors throughout the family tree. This genogram should
include parents, blood-related aunts and uncles, brothers and sisters,
spouse(s), children, grandchildren, and great-grandchildren (recognizing
that data from many family members will not be complete). A history
should be obtained about institutionalization, significant memory problems
in family members, hospitalization for a nervous breakdown or depressive
disorder, suicide, alcohol abuse and dependence, electroconvulsive therapy,
long-term residence in a mental health facility (and possibly a diagnosis of
schizophrenia), and use of mental health services by family members
(Blazer 1984).
Of relevance to the pharmacological treatment of certain disorders—
especially depression—in older adults is the tendency of individuals in a
family to respond therapeutically to the same pharmacological agent. If the
older adult has a depressive disorder and if biological relatives have been
treated effectively for depression, the clinician should determine what
pharmacological agent was used to treat the depression. For example, a
positive response to sertraline in a family member of the depressed older
patient could make sertraline the drug of choice in treating that patient,
assuming side effects are not at issue (Ayd 1975).
Accurate genetic information can be better obtained when family
members from more than one generation are interviewed. Many psychiatric
disorders are characterized by a variety of symptoms, so asking the patient
or one family member for a history of depression is insufficient. Research
on the genetic expression of psychiatric disorders in families requires the
psychiatric investigator to interview directly as many family members as
possible to determine accurately the distribution of disorders throughout the
family. Such detailed family assessment is not feasible for clinicians, yet a
telephone call to a relative with permission from the patient may become a
standard of clinical assessment as the genetics of psychiatric disorders are
clarified.

Context
Psychiatric disorders occur in a biomedical and psychosocial context.
Although the clinician will try to determine what medical problems the
patient has experienced, it is possible to overlook a variation in the relative
contribution of these medical disorders to psychopathology or to overlook
the psychosocial contribution to the onset and continuance of the problem.
Has the spouse of the older adult undergone a change? Are the middle-aged
children managing high stress, such as simultaneously caring for an
emotionally disturbed child and the loss of employment? Are the
grandchildren placing emotional stress on the elderly patient, perhaps by
requesting money? Has the economic status of the older adult deteriorated?
Has the availability of medical care changed? Although many psychiatric
disorders are biologically driven, they do not occur in a psychosocial
vacuum. Environmental precipitants remain important in the web of
causation leading to the onset of an episode of emotional distress and are
critical to the assessment of the older adult.

Medication History
It is essential to evaluate the medication history of the older adult. A careful
review of current and past medications by the clinician, a nurse, or a
physician’s assistant is essential. The older person should be asked to bring
to the appointment all pill bottles, a list of medications taken, and the
dosage schedule. A comparison between the written schedule and the pill
containers will frequently expose some discrepancy. Both prescription and
over-the-counter drugs, such as laxatives and vitamins, should be recorded.
The clinician can then identify the medications that potentially lead to drug-
drug interactions and ask about them during subsequent patient visits.
Most elderly persons take a variety of medicines simultaneously, and the
potential for drug-drug interaction is high. For example, concomitant use of
fluoxetine and warfarin has been associated with an increase in the half-life
of warfarin, which could lead to severe bruising (although this finding is not
well documented). Some medications prescribed for older persons—such as
the β-blocker propranolol and calcium channel blockers—can exacerbate or
produce depressive symptoms.
Older persons are less likely than younger persons to have a substance
use disorder, but a careful history of alcohol and drug intake (especially
nonprescription use of prescription medications) is essential to the
diagnostic workup. Although older persons do not usually volunteer
information about their substance intake, they are generally forthcoming
when asked about their drinking habits.

Medical History
Given the high likelihood of comorbid medical problems associated with
psychiatric disorders in late life, a comprehensive medical history is
essential. Most older persons see a primary care physician regularly
(although decreasing payments from Medicare render this assumption less
accurate each year). The geriatric psychiatrist should obtain medical
records, if possible. Major illnesses should be recorded. A brief phone call
to the primary care physician can be extremely useful.

Family Assessment
Clinicians working with older adults must be equipped to evaluate the
family—both its functionality and its potential as a resource for the older
adult. Geriatric psychiatry, almost by definition, is family psychiatry. The
family assessment is best done, if possible, in conjunction with a social
worker. Just as an elevated white blood cell count is not pathognomonic for
a particular infectious agent yet is critical to the diagnosis, the complaint
that “my family no longer loves me” does not reveal the specific problems
in the family yet does highlight the need to assess the potential of that
family for providing care and support for the older adult (Blazer 1984). The
purpose of a comprehensive diagnostic family workup is to determine the
nature of the family structure in interaction, the presence or absence of a
crisis in the family, and the type and amount of support available to the
older adult.
A primary goal of the clinician, as advocate for the older adult with
psychiatric disturbance, is to facilitate family support for the elder during a
time of disability. At least four parameters of support are important for the
clinician to evaluate as the treatment plan evolves: 1) the availability of
family members to the older person over time; 2) the tangible services
provided by the family to the older person; 3) the perception of family
support by the older patient (and therefore the willingness of the patient to
cooperate and accept support); and 4) tolerance by the family of specific
behaviors that derive from the psychiatric disorder.
The clinician should ask the older person, “If you become ill, is there a
family member who will take care of you for a short period of time?” Next,
the availability of family members who can care for the older adult over an
extended period should be determined. If a particular member is designated
as the primary caregiver, plans for respite care should be discussed. Given
the increased focus on short hospital stays and the documented higher levels
of impairment on discharge, the availability of family members becomes
essential to the effective care of the older adult after hospitalization for a
psychiatric disorder or a combined medical and psychiatric disorder.
 What specific, tangible services can be provided to the older adult by
family members? Even the most devoted spouse can be limited in the
delivery of certain services because, for example, he or she does not drive a
car, and therefore cannot provide transportation, or is not physically strong
enough to provide certain types of nursing care. Generic services of special
importance in at-home support of the older adult with psychiatric
impairment include transportation; nursing services (e.g., administering
medications at home); physical therapy; checking on or continuous
supervision of the patient; homemaker and household services; meal
preparation; administrative, legal, and protective services; financial
assistance; living quarters; and coordination of the delivery of services.
These services are considered generic because they can be defined in terms
of their activities, regardless of who provides each service. Assessing the
range and extent of service delivery by the family to the older person with
functional impairment provides a convenient barometer of the economic,
social, and emotional burdens placed on the family.
Regardless of the level and types of services provided by the family to
the older person, if these services are to be effective, it is beneficial for the
older individual to perceive that he or she lives in a supportive environment.
Intangible supports include the perception of a dependable network,
participation or interaction in the network, a sense of belonging to the
network, intimacy with network members, and a sense of usefulness to the
family (Blazer and Kaplan 1983). The sense of usefulness may be of less
importance to some older adults who believe they have contributed to the
family for many years and therefore deserve reciprocal services in their
waning years. Unfortunately, family members, frequently stressed across
generations, may not recognize this reciprocal responsibility.
Family tolerance of specific behaviors may not correlate with overall
support. Every person has a level of tolerance for specific behaviors that are
especially difficult to manage. Sanford (1975) found that the following
behaviors were tolerated by families of older persons with impairments (in
decreasing percentages): incontinence of urine (81%), personality conflicts
(54%), falls (52%), physically aggressive behavior (44%), inability to walk
unaided (33%), daytime wandering (33%), and sleep disturbance (16%).
These relative frequencies may appear counterintuitive, because
incontinence is generally considered particularly aversive to family
members; however, although the outcome of incontinence can be corrected
easily enough, a few nights of no sleep can easily extend family members
beyond their capabilities for serving a parent, sibling, or spouse.

Mental Status Examination

Physicians and other clinicians are at times hesitant to perform a structured
mental status examination, fearing that the effort will insult or irritate the
patient or that the patient will view the examination as a waste of time.
Nevertheless, the mental status examination of the older psychiatric patient
is central to the diagnostic workup. Many aspects of this examination can
be assessed during the history-taking interview.
Appearance may be affected by the older patient’s psychiatric symptoms
(e.g., the depressed patient may neglect grooming), cognitive status (e.g.,
the patient with dementia may be unable to match clothes or even put on
clothes appropriately), and environment (e.g., a nursing home patient may
not be groomed as well as a patient living at home with a spouse).
Affect and mood can usually be assessed by observing the patient during
the interview. Affect is the feeling tone that accompanies the patient’s
cognitive output (Linn 1980). Affect may fluctuate during the interview;
however, the older person is more likely to demonstrate a constriction of
affect. Mood, the state that underlies overt affect and is sustained over time,
is usually apparent by the end of the interview. For example, the affect of a
depressed older adult may not reach the degree of dysphoria seen in
younger persons (as evidenced by crying spells or protestations of
uncontrollable despair), yet the depressed mood is usually sustained and
discernible from beginning to end.
Psychomotor activity may be agitated or retarded. Psychomotor
retardation or underactivity is characteristic of major depression and severe
schizophreniform symptoms, as well as of some variants of primary
degenerative neurocognitive disorder. Psychiatrically impaired older
persons, except some who have advanced neurocognitive disorder, are more
likely to exhibit hyperactivity or agitation. Those who are depressed will
appear uneasy, move their hands frequently, and have difficulty remaining
seated through the interview. Patients with mild to moderate neurocognitive
disorder, especially those with vascular neurocognitive disorder, will be
easily distracted, rise from a seated position, and/or walk around the room
or even out of the room. Pacing is often observed when the older adult is
admitted to a hospital ward. Agitation can usually be distinguished from
anxiety, for the agitated individual does not complain of a sense of
impending doom or dread. In patients with psychomotor dysfunction,
movement generally relieves the immediate discomfort, although it does not
correct the underlying disturbance. Occasionally, the older adult with
psychomotor retardation may actually be experiencing a disturbance in
consciousness and may even reach an almost stuporous state. The patient
may not be easily aroused, but when aroused, he or she will respond by
grimacing or withdrawal.
Perception is the awareness of objects in relation to each other and
follows stimulation of peripheral sense organs (Linn 1980). Disturbances of
perception include hallucinations—that is, false sensory perceptions not
associated with real or external stimuli. For example, a paranoid older
person may perceive invasion of his or her house at night by individuals
who disarrange belongings and abuse him or her sexually. Hallucinations
often take the form of false auditory perceptions, false perceptions of
movement or body sensation (e.g., palpitations), and false perceptions of
smell, taste, and touch. The older patient who is severely depressed may
have frank auditory hallucinations that condemn or encourage self-
destructive behavior.
Disturbances in thought content are the most prominent disturbances of
cognition noted in older patients with psychosis. The depressed patient
often develops beliefs that are inconsistent with the objective information
obtained from family members about the patient’s abilities and social
resources. Meyers and Greenberg (1986) found delusional depression to be
more prevalent among older depressed patients than among middle-aged
adults. Of 161 patients with endogenous depression, 72 (45%) were found
to be delusional. Delusions included beliefs such as “I’ve lost my mind,”
“My body is disintegrating,” “I have an incurable illness,” and “I have
caused some great harm.” Even after elderly persons recover from
depression, they may still experience periodic recurrences of delusional
thoughts, which can be most disturbing to otherwise rational older adults.
Older patients appear less likely to experience delusional remorse, guilt, or
persecution.
Even if delusions are not obvious, preoccupation with a particular
thought or idea is common among depressed elderly persons. Such
preoccupation is closely associated with obsessional thinking or irresistible
intrusion of thoughts into the conscious mind. Although the older adult
rarely acts on these thoughts compulsively, the guilt-provoking or self-
accusing thoughts may occasionally become so difficult to bear that the
person considers, attempts, or succeeds in committing suicide.
Disturbances of thought progression accompany disturbances of content.
Evaluation of the content and process of cognition may uncover
disturbances such as problems with the structure of associations, the speed
of associations, and the content of thought. Thinking is a goal-directed flow
of ideas, symbols, and associations initiated in response to environmental
stimuli, a perceived problem, or a task that requires progression to a logical
or reality-based conclusion (Linn 1980). The older adult who is compulsive
or has schizophrenia may pathologically repeat the same word or idea in
response to a variety of probes, as may the patient who has major
neurocognitive disorder. Some older adults with a neurocognitive disorder
exhibit circumstantiality—that is, the introduction of many apparently
irrelevant details to cover a lack of clarity and memory problems.
Interviews with patients who have this problem can be most frustrating
because they proceed at a very slow pace. On other occasions, elderly
patients may appear incoherent, with no logical connection to their
thoughts, or they may produce irrelevant answers. The intrusion of thoughts
from previous conversations into a current conversation is a prime example
of the disturbance in association found in patients with major
neurocognitive disorder associated with Alzheimer’s disease. This symptom
is not typical of other neurocognitive disorders, such as that associated with
Huntington’s disease. However, in the absence of a neurocognitive disorder,
even paranoid older adults do not generally demonstrate a significant
disturbance in the structure of associations.
Suicidal thoughts are critical to assess in the elderly patient with
psychiatric impairment. Although thoughts of death are common in late life,
spontaneous revelations of suicidal thoughts are rare. A stepwise probe is
the best means of assessing the presence of suicidal ideation (Blazer 1982).
First, the clinician should ask the patient if he or she has ever thought that
life was not worth living. If so, has the patient considered acting on that
thought? If so, how would the patient attempt to inflict such harm? If
definite plans are revealed, the clinician should probe to determine whether
the implements for a suicide attempt are available. For example, if a patient
has considered shooting himself, the clinician should ask, “Do you have a
gun available and loaded at home?” Suicidal ideation in an older adult is
always of concern, but intervention is necessary when suicide has been
considered seriously and the implements are available.
Assessment of memory and cognitive status is most accurately performed
through neuropsychological testing. However, the psychiatric interview of
the older adult must include a reasonable assessment. Although older adults
may not complain of memory dysfunction, they are more likely than
younger patients to have problems with memory, concentration, and
intellect. There are brief, informal means of testing cognitive functioning
that should be included in the diagnostic workup. The clinician proceeding
through an evaluation of memory and intellect must also remember that
poor performance may reflect psychic distress or a lack of education, as
opposed to intellectual disability or neurocognitive disorder. In addition, to
rule out the potential confounding of agitation and anxiety, testing can be
performed on more than one occasion. More formal brief testing, such as
with the Mini-Mental State Examination (Folstein et al. 1975), provides a
baseline from which performance can be documented over time.
Testing of memory is based on three essential processes: 1) registration
(the ability to record an experience in the central nervous system), 2)
retention (the persistence and permanence of a registered experience), and
3) recall (the ability to summon consciously the registered experience and
report it) (Linn 1980). Registration, apart from recall, is difficult to evaluate
directly. Occasionally, events or information that the older adult denies
remembering will appear spontaneously during other parts of the interview.
Registration usually is not impaired except in patients with a major
neurocognitive disorder.
Retention, on the other hand, can be blocked by both psychic distress and
brain dysfunction. Lack of retention is especially relevant to the
unimportant data often asked for on a mental status examination. For
example, requesting the older adult to remember three objects for 5 minutes
will frequently reveal a deficit if the older adult has little motivation to
attempt the task.
Disturbances of recall can be tested directly in a number of ways. The
most common are tests of orientation to time, place, person, and situation.
Most persons continually orient themselves through radio, television, and
reading material, as well as through conversations with others. Some
elderly persons may be isolated through sensory impairment or lack of
social contact; poor orientation in these patients may represent deficits in
the physical and social environment rather than brain dysfunction.
Immediate recall can be tested by asking the older person to repeat a word,
phrase, or series of numbers, but it can also be tested in conjunction with
cognitive skills by requesting that a word be spelled backward or that
elements of a story be recalled.
During the mental status examination, intelligence can be assessed only
superficially. Tests of simple arithmetic calculation and fund of knowledge,
supplemented by portions of well-known psychiatric tests, are helpful. The
classic test for calculation is to ask a patient to subtract 7 from 100 and to
repeat this operation on the succession of remainders. Usually, five
calculations are sufficient to determine the older adult’s ability to complete
this task. If the older adult fails the task, a less exacting test is to request the
patient to subtract 3 from 20 and to repeat this operation on the succession
of remainders until 0 is reached. These examinations must not be rushed,
because older persons may not perform as well when they perceive time
pressure. A capacity for abstract thinking is often tested by asking the
patient to interpret a well-known proverb, such as “A rolling stone gathers
no moss.” A more accurate test of abstraction, however, is classifying
objects in a common category. For example, the patient is asked to state the
similarity between an apple and a pear. Whereas naming objects from a
category, such as fruits, is retained despite moderate and sometimes marked
declines in cognition, the opposite process of classifying two different
objects in a common category is not retained as well.

Rating Scales and Standardized Interviews

Rating scales and standardized or structured interviews have progressively
been incorporated into the diagnostic assessment of the elderly psychiatric
patient. Such rating procedures have increased in popularity as the need has
increased for systematic, reproducible diagnoses for third-party carriers
(part of the impetus for the dramatic change in nomenclature evidenced in
DSM-5) and for a standard means of assessing change in clinical status. A
thorough review in this chapter of all instruments that are used is not
possible. Therefore, selected instruments are presented and evaluated in this
section, chosen either because they have special relevance to the geriatric
patient or because they are widely used.

Screens for Neurocognitive Disorders

A number of standardized assessment methods for delirium have emerged.
Perhaps the best and the most easily used is the Confusion Assessment
Method (Inouye et al. 1990). The scale assesses nine characteristics of
delirium, such as acute onset (evidence of such onset), fluctuating course
(behavior change during the day), inattention (trouble in focusing),
disorganized thinking (presence of rambling or irrelevant conversations and
illogical flow of ideas), and altered level of consciousness (rated from alert
to comatose). Diagnosis of delirium according to DSM-IV-TR criteria
(American Psychiatric Association 2000) can be derived from the scale.
Two interviewer-administered cognitive screens for neurocognitive
disorder have been popular in both clinical and community studies. The
Montreal Cognitive Assessment (MoCA; Nasreddine et al. 2005), a one-
page, 30-point assessment, is used to assess several cognitive domains
relevant to neurocognitive disorders. The short-term memory recall task
includes two learning trials of five nouns and delayed recall after
approximately 5 minutes. Visuospatial abilities are assessed using a clock-
drawing task and a three-dimensional cube copy. Multiple aspects of
executive functions are assessed using an alternation task such as moving
from numbers to letters in a systematic process, a phonemic fluency task,
and a two-item verbal abstraction task. Attention, concentration, and
working memory are evaluated using a sustained attention task, a serial
subtraction task, and digits forward and backward. Language is assessed
using a three-item confrontation naming task with low-familiarity animals
(lion, camel, rhinoceros), repetition of two syntactically complex sentences,
and the aforementioned fluency task. Finally, orientation to time and place
is evaluated. The Mini-Mental State Examination (Folstein et al. 1975) is a
30-item screening instrument that assesses orientation, registration,
attention and calculation, recall, and language. It requires 5–10 minutes to
administer. Seven to 12 errors suggest mild to moderate cognitive
impairment, and 13 or more errors indicate severe impairment. This
instrument is perhaps the most frequently used standardized screening
instrument in clinical practice.
 A number of clinical assessment procedures for neurocognitive disorders
have emerged. These are generally administered by neuropsychologists and
accompanied by imaging studies and even explorations of biomarkers, such
as scans for amyloid. For example, a scale assessing whether a
neurocognitive disorder is due to vascular causes was suggested by
Hachinski et al. (1975). In this study, cerebral blood flow in patients with
primary degenerative dementia was compared with that in patients with
vascular dementia. Certain clinical features were determined to be more
associated with multi-infarct dementia, and each of these features was
assigned a score of 1 or 2. The 2-point clinical features were abrupt onset,
fluctuating course, history of strokes, focal neurological symptoms, and
focal neurological signs. The 1-point features were stepwise deterioration,
nocturnal confusion, relative preservation of personality, depression,
somatic complaints, emotional incontinence, history of hypertension, and
evidence of associated atherosclerosis. A score of 7 or greater was highly
suggestive of multi-infarct dementia. However, given the frequent overlap
of multiple small infarcts and primary degenerative dementia, as well as the
difficulty of assessing these items effectively, most investigators have
ceased to rely on the Hachinski scale for clinical use.

Depression Rating Scales

A number of self-rating depression scales have been used to screen for
depression in patients at all stages of the life cycle; most of these scales
have been studied in older populations. The most widely used of the current
instruments in community studies is the Center for Epidemiologic Studies
Depression Scale (CES-D; Radloff 1977). The scale consists of 20
behaviors and feelings, and the patient indicates how frequently each was
experienced over the past week (from no days to most days). In a factor-
analytic study of the CES-D in a community population, four factors were
identified: somatic symptoms, positive affect, negative affect, and
interpersonal relationships (Ross and Mirowsky 1984). The disaggregation
of these factors and the exploration of their interaction are significant steps
forward in understanding the results derived from symptom scales such as
the CES-D in older populations. For example, the somatic items (e.g., loss
of interest, poor appetite) are more likely to be associated with a course of
depressive episodes similar to that described for major depression with
melancholia, and the positive-affect items are more likely to be associated
with life satisfaction scores.
The Geriatric Depression Scale (GDS) was developed because the CES-
D presents problems for older persons who have difficulty selecting one of
four forced-response items (Yesavage et al. 1982–1983). The GDS is a 30-
item scale that permits patients to rate items as either present or absent; it
includes questions about symptoms such as cognitive complaints, self-
image, and losses. Items selected were thought to have relevance to late-life
depression. The GDS has not been used extensively in community
populations and is not as well standardized as the CES-D, but many
clinicians prefer its yes/no format to the CES-D’s frequency ratings.
A scale that has received considerable attention clinically, having been
standardized in clinical but not community populations, is the Montgomery-
Åsberg Rating Scale for Depression (Montgomery and Åsberg 1979). This
scale concentrates on 10 symptoms of depression; the clinician rates each
symptom on a scale of 0–6 (for a range of scores between 0 and 60). The
symptoms include apparent sadness, reported sadness, inattention, reduced
sleep, reduced appetite, concentration difficulties, lassitude, inability to feel,
pessimistic thoughts, and suicidal thoughts.

General Assessment Scales

A number of general assessment scales of psychiatric status (occasionally
combined with functioning in other areas) have been found to be useful in
both community and clinical populations. DSM-5 has adopted the World
Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) to
assess disability in adults age 18 years and older (World Health
Organization 2010; the scale is also available in DSM-5 Section III,
“Emerging Measures and Models”). This 36-item self-assessment is divided
into six areas of function: understanding and communicating, getting
around, self-care, getting along with people, life activities (i.e., household,
work, and/or school activities), and participation in society.
The Geriatric Mental State Schedule (Copeland et al. 1976), an
adaptation of the Present State Exam (Wing et al. 1974) and the Psychiatric
Status Schedule (Spitzer et al. 1968), is a semistructured interviewing guide
that allows the rater to inventory symptoms associated with psychiatric
disorders. More than 500 ratings are made on the basis of information
obtained by a highly trained interviewer, who elicits reports of symptoms
from the month preceding the evaluation. Data are computerized to derive
psychiatric diagnoses (Copeland et al. 1986). The instrument measures
depression, impaired memory, selected neurological symptoms such as
aphasia, and disorientation.
The Older Americans Resources and Services (OARS) Multidimensional
Functional Assessment Questionnaire (Duke University Center for the
Study of Aging and Human Development 1978), administered by a lay
interviewer, produces functional impairment ratings in five dimensions:
mental health, physical health, social functioning, economic functioning,
and activities of daily living. In one community survey using OARS (Blazer
1978a), 13% of persons in the community were found to have mental health
impairment. The OARS instrument was developed to integrate functional
measures across a series of parameters relevant to older adults; it has been
used widely in both community and clinical surveys. With the recent
emphasis on discrete psychiatric disorders, however, the instrument has not
been as widely used by mental health workers as it might otherwise have
been.
Any discussion of clinical rating scales is not complete without a
discussion of the Abnormal Involuntary Movement Scale (AIMS; National
Institute of Mental Health 1975). There has been an increased incidence of
tardive dyskinesia among older adults, coupled with the need for better
documentation of this outcome due to prolonged use of antipsychotic
agents. Regular ratings of patients on the AIMS by clinicians have therefore
become essential to the practice of inpatient and outpatient geriatric
psychiatry. The scale consists of seven movement disorders; the presence
and severity of each is rated from none to severe. Three items require a
global judgment: severity of abnormal movements, incapacitation due to
abnormal movements, and the patient’s awareness of abnormal movements.
Current problems with teeth or dentures are also assessed. Procedures are
described to increase the reliability of this rating scale.

Structured Diagnostic Interviews

A number of structured interview schedules are available for both clinical
and community diagnosis. These interview schedules have allowed
increased reliability of the identification of particular symptoms and
psychiatric diagnoses; however, if one adheres closely to the structured
interview, the richness inherent in the unstructured interview tends to be
lost. Comments made by the patient during the evaluation that could be
used to trace relevant associations must be ignored to push through the
interview schedule. Most of these interviews require more time than the
traditional unstructured first session with the patient.
The most frequently used structured interview instrument in the United
States is the Structured Clinical Interview for DSM-IV (SCID; First et al.
1997). This instrument is easily adaptable to DSM-IV (American
Psychiatric Association 1994) and DSM-IV-TR; adaptation to DSM-5 is in
progress. Although specific questions are suggested for probing most areas
of interest, the interviewer using the SCID has the flexibility to ask
additional questions and can use any available data to assign a diagnosis.
The interviewer must have clinical training but does not have to be a
psychiatrist. Many of the symptoms may not be relevant to older adults
(especially the extensive probes for psychotic symptoms), and the interview
frequently takes 2.5–3 hours to administer. Nevertheless, the experience
gained by the clinician in using this instrument can contribute to a more
effective clinical practice.
The Diagnostic Interview Schedule for DSM-IV (DIS-IV; Robins et al.
2000) is a highly structured, computer-scored interview that can be
administered by a lay interviewer and allows psychiatric diagnoses to be
made according to DSM-IV criteria and Feighner criteria (Feighner et al.
1972). The DIS-IV questions probe for the presence or absence of
symptoms or behaviors relevant to a series of psychiatric disorders, the
severity of the symptoms, and the putative cause of the symptoms.
Diagnoses of cognitive impairment, schizophrenia or schizophreniform
disorder, major depression, generalized anxiety disorder, panic disorder,
agoraphobia, obsessive-compulsive disorder, dysthymic disorder,
somatization disorder, alcohol abuse and/or dependence, and other
substance abuse and/or dependence can be made from Axis I of DSM-IV. A
diagnosis of antisocial personality disorder (Axis II) can also be made. The
instrument has proved reasonably reliable in clinical populations for both
current and lifetime diagnoses.
The range of disorders probed by the DIS-IV questions, coupled with the
instrument’s relative ease of administration (it generally takes 45–90
minutes to administer to an older adult), has made it popular for use in
clinical studies. In addition, community-based comparative data are
available on a large sample from the Epidemiologic Catchment Area study
(Myers et al. 1984; Regier et al. 1984). The DIS-IV can be supplemented
with additional questions to probe for specific symptoms, such as
melancholic symptoms, and additional data on sleep disorders for depressed
older adults. No problems have arisen when the instrument is used among
older adults in the community. In general, the memory decay that occurs in
elderly persons causes no more of a performance problem on this
instrument than on others. Nevertheless, the DIS-IV is of less value in the
study of institutional populations and in reconstruction of lifetime history
regardless of setting, because memory problems cannot be circumvented by
clinical judgment. Supplementary data can be added to the instrument for
developing a standardized diagnosis. A shortened version of the DIS-IV
that has been used in more recent epidemiological surveys is the World
Mental Health Survey Initiative Version of the World Health Organization
Composite International Diagnostic Interview (CIDI) (Kessler and Ustün
2004; Kessler et al. 2005).

Effective Communication With the Older Adult

The clinician who works with the older adult should be cognizant of factors
relating to both the patient and the clinician that may produce barriers to
effective communication (Blazer 1978b). Many older persons experience a
relatively high level of anxiety yet do not complain of this symptom. Stress
deriving from a new situation, such as visiting a clinician’s office or being
interviewed in a hospital, may intensify such anxiety and subsequently
impair effective communication. Perceptual problems, such as hearing and
visual impairment, may exacerbate disorientation and complicate the
communication of problems to the clinician. Elderly persons are more likely
to withhold information than to hazard answers that may be incorrect—in
other words, older persons tend to be more cautious. Elderly persons
frequently take longer to respond to inquiries and resist the clinician who
attempts to rush through the history-taking interview.
The elderly patient may perceive the physician unrealistically, on the
basis of previous life experiences (i.e., transference may occur). Although
the older patient will sometimes accept the role of child, viewing the
physician as parent, the patient is initially more likely to view the clinician
as the idealized child who can provide reciprocal care to the previously
capable but now impaired parent. Splitting between the physician
(idealized) and the child of the patient (devalued) may subsequently occur.
Also, the clinician may perceive the older adult patient incorrectly because
of fears of aging and death or because of previous negative experiences
with his or her own parents. For a clinician to work effectively with older
adults, these personal feelings should be discussed during training—and
afterward.
Once physician and patient attitudes have been recognized and
acknowledged, certain techniques have generally proved to be valuable in
communicating with the elderly patient. These techniques should not be
implemented indiscriminately, however, for the variation in the population
of older adults is significant. First, the older person should be approached
with respect. The clinician should knock before entering a patient’s room
and should greet the patient by surname (e.g., Mr. Jones, Mrs. Smith) rather
than by a given name, unless the clinician also wishes to be addressed by a
given name.
After taking a position near the older person—near enough to reach out
and touch the patient—the clinician should speak clearly and slowly and
use simple sentences in case the person’s hearing is impaired. Because of
hearing problems, older patients may understand conversation better over
the telephone than in person. By placing the receiver against the mastoid
bone, the patient with otosclerosis can take advantage of preserved bone
conduction.
The interview should be paced so that the older individual has enough
time to respond to questions. Most older individuals are not uncomfortable
with silence, because it gives them a welcome opportunity to formulate
their answers to questions and elaborate certain points they may wish to
emphasize. Nonverbal communication is frequently a key to effective
communication with elderly individuals, because they may be reticent about
revealing affect verbally. The patient’s facial expressions, gestures,
postures, and long silences may provide clues to the clinician about issues
that are unspoken.
One key to successful communication with an older adult is a
willingness to continue working as a professional with that person. Older
adults—possibly unlike some of their children and grandchildren—place a
great deal of stress on loyalty and continuity. Most elderly patients do not
require large amounts of time from clinicians, and those who are more
demanding can usually be controlled through structure in the interview.

Key Points
• The diagnostic interview is the cornerstone of assessment and treatment
assignment for the older adult with psychiatric impairment.
• A thorough medication history, although it takes time to obtain, saves
valuable time and complications in the treatment of psychiatric disorders
in older adults.
• Functional status (i.e., the ability to perform usual activities of daily
living) is often as important as diagnosis in tracking the progress of
treatment of psychiatric disorders in older adults.
• Geriatric psychiatry is family psychiatry.
• What is gained in reliability by using a structured diagnostic interview is
offset by the loss of valuable information about the subjective feelings of
the older adult and the context of the emergence of symptoms.
• Speak clearly and slowly but not in a patronizing way to the older adult,
who might have a hearing impairment.

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Suggested Readings
Blazer DG: Techniques for communicating with your elderly patient.
Geriatrics 33:79–80, 83–84, 1978
Inouye SK: Clarifying confusion: the Confusion Assessment Method: a new
method for detection of delirium. Ann Intern Med 113:941–950, 1990
Nasreddine ZS, Phillips NA, Bédirian V, et al: The Montreal Cognitive
Assessment (MoCA): a brief screening tool for mild cognitive
impairment. J Am Geriatr Soc 53:695–699, 2005
Othmer E, Othmer SC, Othmer JP: Psychiatric interview, history and
mental status examination, in Kaplan and Sadock’s Comprehensive
Textbook of Psychiatry, Vol 1. Edited by Sadock BJ, Sadock VA.
Philadelphia, PA, Lippincott Williams and Wilkins, 2005, pp 794–826
 CHAPTER 5

Use of the Laboratory in the Diagnostic

Workup of Older Adults
Sophia Wang, M.D.
Mugdha E. Thakur, M.D.
P. Murali Doraiswamy, M.B.B.S., F.R.C.P.

Laboratory testing is an essential component of the psychiatric

evaluation of elderly individuals, who often present with comorbid medical
illnesses. The laboratory does not replace the clinician; there is no test that
is pathognomonic for a primary psychiatric illness. However, laboratory
testing does aid in the evaluation of comorbidities that complicate or
contribute to a psychiatric diagnosis.
There has been significant growth in the number and quality of
diagnostic tools available. Progress in research and technology, particularly
in imaging technology and genetic testing, has advanced rapidly over the
past decade. Regardless of the tools available, however, we must balance
what we can do with what we should do, as guided by our clinical
judgment, relative risk to the patient, and cost expenditure. When all risks
are considered, the decision to proceed with a test should be based on the
clinical presentation and on how the test results may change a treatment
plan.
The following discussion of specific diagnostic tests is not an exhaustive
review. We focus on tests currently being used or being considered for
clinical use. We hope this chapter will assist the clinician in selecting
laboratory tests that are appropriate for the individual patient.
Serologic Tests
Basic clinical chemistry and hematologic screens are routine for all hospital
admissions and many outpatient evaluations. Although these screens
infrequently identify causes of primary psychiatric disorders, they are
critical for identifying previously undiagnosed or poorly controlled medical
illnesses that may contribute to mental status changes, such as in dementia
or delirium. These tests should also be monitored when patients are taking
medications that may result in potentially dangerous abnormalities. For
most of these tests, the only risks are associated with blood draws, which
may result in transient pain, bruising, and occasional bleeding or fainting.
These risks are reduced, but not totally eliminated, by skilled phlebotomists.

Hematologic Tests
A complete blood cell count (CBC) is a standard part of any evaluation. It
screens for multiple problems, including infections and anemia. It also
provides a platelet count, a value important to monitor in psychiatric
medications associated with thrombocytopenia, such as divalproex sodium
or carbamazepine. This concern is particularly important in elderly patients,
because the risk of drug-induced thrombocytopenia may increase with age.
Lithium, in contrast, may result in mild leukocytosis. Because of the risk of
agranulocytosis, CBC testing is required weekly or biweekly for patients
taking clozapine and may be needed more frequently if the patient develops
signs of infection. Mirtazapine can also lead to agranulocytosis in rare
cases, and although routine CBC monitoring is not indicated, it should be
pursued if a patient develops sore throat, fever, stomatitis, or other signs of
infection.

Chemistry Tests
Most general chemistry panels have a variety of values that may be helpful
in medical evaluations. Blood glucose values may reveal hyperinsulinemia
and hypoglycemia, which may produce anxiety and weakness; more
commonly these tests show hyperglycemia, which may be associated with
diabetes and result in lethargy or, in severe cases, delirium, diabetic coma,
or ketoacidosis. This testing is critical for the diagnosis of diabetes, which
can be diagnosed with 1) an overnight fasting glucose greater than 126
mg/dL, 2) a random plasma glucose greater than 200 mg/dL with symptoms
of diabetes, or 3) an oral glucose tolerance test resulting in a plasma glucose
over 200 mg/dL 2 hours after a 75-g glucose load.
Kidney function tests are equally important. Blood urea nitrogen and
creatinine will be elevated in kidney failure and in hypovolemic states such
as dehydration. These tests also must be performed before initiating lithium
therapy because of lithium’s potential for nephrotoxicity.
General chemistry panels also measure serum sodium, potassium, and
other electrolytes. Hyponatremia—commonly defined as a serum sodium
concentration less than 135 mEq/L—has been reported with selective
serotonin reuptake inhibitors (SSRIs), particularly in the elderly. The signs
and symptoms of hyponatremia result from neurological dysfunction
secondary to cerebral edema. Acute hyponatremia can start with nausea and
malaise when the plasma sodium concentration falls below 125–130 mEq/L
and progresses rapidly to coma and respiratory arrest if the plasma sodium
concentration falls below 115–120 mEq/L. In chronic hyponatremia, the
brain cells adapt to the edema, and symptoms are much less severe. Patients
may be asymptomatic despite a plasma sodium concentration that is
persistently as low as 115–120 mEq/L. When symptoms do occur in
individuals with such low sodium concentrations, they are relatively
nonspecific (e.g., fatigue, nausea, dizziness, gait disturbances, forgetfulness,
confusion, lethargy, muscle cramps). The clinician should be vigilant to this
risk in older adults when they begin taking SSRIs. Of all the electrolyte
abnormalities, potassium disorders may be the most crucial to identify.
These rarely cause psychiatric symptoms but may result in severe cardiac
arrhythmias. Although not always included in routine chemistry screens,
calcium and magnesium levels are also important to consider, because
abnormal levels may result in paranoid ideation or frank psychosis. Any or
all of these results may be abnormal in patients undergoing hemodialysis.

TABLE 5–1. Guidelines for screening and monitoring of patients taking

second-generation antipsychoticsa
Assessment Frequency
At baseline and annually
Personal and family historyb
Weight At baseline, every 4 weeks for 12 weeks, then quarterly
Waist circumferencec At baseline and annually
Blood pressure At baseline, at 12 weeks, and annually
Fasting plasma glucose At baseline, at 12 weeks, and annually
Fasting lipid profile At baseline, at 12 weeks, and every 5 years
aMore frequent assessments may need to be done based on clinical status.
bPersonal and family history includes obesity, diabetes, dyslipidemia, hypertension, and
cardiovascular disease.
cWaist circumference is measured at umbilicus.
Source. American Diabetes Association et al. 2004.

Because second-generation antipsychotics can lead to weight gain and

diabetes, a set of guidelines has been proposed to screen and monitor
patients who are taking these drugs (Table 5–1) (American Diabetes
Association et al. 2004). These guidelines should be routinely incorporated
into clinical practice by all geropsychiatrists. Additionally, when patients
develop abdominal pain while being treated with atypical antipsychotics or
valproic acid, their amylase and lipase levels should be checked to rule out
pancreatitis. Liver function tests should be monitored periodically in
patients taking valproic acid. There have been case reports of both
venlafaxine and duloxetine causing elevated hepatic enzymes and even
hepatic failure. Liver function tests should be obtained in patients taking
these drugs who develop symptoms of liver disease.

Serologic Tests for Syphilis

Although syphilis was nearly eliminated in the United States in 2000, the
rate of primary and secondary syphilis cases steadily increased between
2001 and 2013, mainly due to higher rates among gay, bisexual, and other
men who have sex with men (Centers for Disease Control and Prevention
2014). Men from this demographic group who are infected with HIV and
are of lower socioeconomic status are at especially high risk of syphilis
infection. According to the American Academy of Neurology’s guidelines
for diagnosis of dementia, unless the patient has some specific risk factor
(e.g., another sexually transmitted disease) or evidence of prior syphilitic
infection or unless the patient resides in one of the few areas in the United
States with high numbers of syphilis cases, screening for the disorder in
patients with dementia is not justified (Knopman et al. 2001). If a clinician
suspects syphilis infection, the Venereal Disease Research Laboratory and
the rapid plasmin reagin tests are screening tools for infection with
Treponema pallidum, the cause of syphilis. These tests are unfortunately
nonspecific; false-positive results may occur in acute infections and chronic
illnesses such as systemic lupus erythematosus. More specific tests, the
fluorescent treponemal antibody and the microhemagglutination assay for
Treponema pallidum, may distinguish false-positive from true-positive
results and may aid in diagnosing late syphilis when blood and even
cerebrospinal fluid (CSF) reagin tests are negative.

Human Immunodeficiency Virus Testing

According to the Centers for Disease Control and Prevention (2013), HIV
infection has become a significant issue in the geriatric population. About
30% of HIV infections occur in individuals ages 50 years and older, and
17% of new HIV diagnoses are made in this age group.
The diagnosis of AIDS in elderly individuals is complicated; like
syphilis, AIDS has been described as a “great imitator” because its clinical
presentation may mimic that of other diseases (Sabin 1987). AIDS may
mimic not only medical illnesses but also neuropsychiatric disorders,
because AIDS may result in dementia.
There is no evidence that HIV treatment for elderly AIDS patients
should differ from that for younger patients. It is therefore the role of the
geriatric psychiatrist to assist the internist by screening for risk factors, such
as a history of sexually transmitted diseases, intravenous drug use, risky
sexual behavior, or a history of blood transfusions, particularly if they
occurred prior to the early 1990s. We recommend HIV testing for
individuals who have these risk factors or those who present with atypical
neuropsychiatric symptoms. For patients for whom testing is warranted, the
psychiatrist will also play an important role in counseling the patients about
the reasons behind testing, and then providing further counseling as the test
results are reported.
Thyroid Function Tests
To understand the significance of thyroid test results, one must first
understand the hormones themselves. Secretion of the thyroid hormones
thyroxine (T4) and triiodothyronine (T3) is regulated by pituitary gland
secretion of thyroid-stimulating hormone (TSH). TSH secretion, in turn, is
controlled through negative feedback by thyroid hormones. Both T4 and T3
are reversibly bound to the plasma protein thyroxine-binding globulin, and
only the small unbound fraction exerts its physiological effects.
A serum TSH test is the most frequently used screen for thyroid disease;
it is an excellent screening test because of its high negative predictive value
(Klee and Hay 1997). However, many medications may result in increased
TSH levels (amiodarone, estrogens) or decreased TSH levels
(glucocorticoids, phenytoin), and altered TSH levels may also be seen in
patients with acute nonthyroidal illness or systemic stress. A physical
examination and measurement of T4, T3, and TSH may be required for a
definitive diagnosis of thyroid disease (Table 5–2). TSH testing should be
done in all older adults presenting with neuropsychiatric symptoms because
hypothyroidism may cause symptoms of depression, fatigue, and impaired
cognition, and hyperthyroidism can cause symptoms of anxiety or even
psychosis. Older women in particular have a high prevalence of
hypothyroidism. Patients who are taking lithium should have their TSH
level checked every 6 months.

TABLE 5–2. Patterns of thyroid function tests

TSH Free T4 T3 Suggested diagnosis
Normal Normal Normal Euthyroid
High Low Low or normal Primary hypothyroidism
High Normal Normal Subclinical hypothyroidism
Low High or normal High Hyperthyroidism
Note. TSH=thyroid-stimulating hormone; T3=triiodothyronine; T4=thyroxine.

Vitamin B12, Folate, and Homocysteine

Measurement of serum vitamin B12 and folate levels is an integral part of
the laboratory evaluation. The prevalence of B12 deficiency increases with
age; the deficiency is present in up to 15% of the elderly population.
Although macrocytic anemia is a well-known sign of B12 deficiency, it is a
later presentation in most cases, with neuropsychiatric symptoms presenting
much earlier.
Vitamin B12 and folate deficiencies may result in neuropsychiatric
disturbances, including depression, psychosis, or cognitive deficits. In
patients with dementia, B12 deficiencies often result in delirium or
disorientation. Low levels of these vitamins may also result in visuospatial
and word fluency deficits (Robins Wahlin et al. 2001) and even greater
behavioral disturbances in patients with Alzheimer’s disease (AD) (Meins
et al. 2000).
However, vitamin B12 and folate levels may not tell the entire story;
there is also considerable interest in homocysteine. Serum homocysteine
levels may serve as a functional indicator of B12 and folate status, because
both vitamins are needed to convert homocysteine to methionine in one-
carbon metabolism in brain tissue. Hyperhomocysteinemia is prevalent in
elderly persons, and high serum levels of homocysteine can be attributed to
an inadequate supply of B12 and folate, even in the presence of low normal
serum levels (Selhub et al. 2000). High levels of homocysteine have also
been associated with increased risk of occlusive vascular disease,
thrombosis, and stroke (Boushey et al. 1995). Hyperhomocysteinemia is
further associated with cognitive dysfunction (Leblhuber et al. 2000; Selhub
et al. 2000), although not all authors have found this association (Ravaglia
et al. 2000). In a longitudinal study of 965 older individuals, a lower
incidence of AD was noted among those subjects in the highest quartile of
total folate intake, after adjustments for age, sex, education, ethnicity, and
other comorbidities. Neither vitamin B6 nor vitamin B12 intake was
associated with risk of AD (Luchsinger et al. 2007). Results on whether
vitamin supplementation to reduce plasma homocysteine levels also leads to
improved cognition are mixed, with some studies showing benefit (Durga et
al. 2007; Nilsson et al. 2001) and others showing no benefit despite lowered
homocysteine levels (McMahon et al. 2006).
Toxicology
When an acute change occurs in an individual’s mental status, an
investigation of the cause of the change must include the possible ingestion
of a substance. This consideration is particularly important in individuals
with a history of substance abuse or with a history of depression for whom
there is the risk of medication overdose.
When mental status changes in an individual who is taking medications
such as lithium, phenytoin, tricyclic antidepressants (TCAs), or any
medication that requires monitoring of blood levels, those levels should be
checked. Toxic levels of many pharmacological agents may cause a variety
of psychiatric or life-threatening medical conditions. Likewise, levels for
common over-the-counter medications such as acetaminophen and
salicylates can be tested. Concomitantly, a serum alcohol level should also
be drawn. Depending on the individual’s history, even a negative result may
be critical if there is the possibility of withdrawal. Finally, urine can be
tested for prescription medications, such as benzodiazepines, barbiturates,
and opioids, as well as illicit substances, such as cocaine and marijuana.
Advanced age does not preclude addiction.

Urinalysis
A urinalysis is an inexpensive, noninvasive test that provides a significant
amount of information. It determines the urine’s specific gravity, which
may indicate dehydration, and also tests for glucose and ketones, important
in the evaluation of diabetic patients. In the elderly population, the most
important use of urinalysis may be as a screening tool for urinary tract
infections (UTIs). A UTI is suggested when a microscopic examination
shows high levels of white blood cells, bacteria, positive leukocyte esterase
and nitrite, and possibly red blood cells; high numbers of epithelial cells
make the results difficult to interpret, because their presence suggests
contamination. A urine culture is a definitive means of diagnosing a UTI
and will identify the infecting organism and its susceptibility to
antimicrobial treatments. Approximately 20% of admissions from the
community to geropsychiatry units may have UTIs, and many cases of UTI
result in a delirium that improves with appropriate antibiotic treatment
(Levkoff et al. 1991; Manepalli et al. 1990).

Cerebrospinal Fluid Analysis and Plasma Assays

for Dementia
Although one of the most common diagnostic uses of CSF analysis is the
workup of suspected central nervous system infections (such as meningitis),
CSF analysis is now playing an increasingly important role of the
assessment of patients with dementia. In patients with AD and mild
cognitive impairment (MCI) due to AD, CSF levels of β-amyloid peptide
1–42 are reduced, whereas levels of phosphorylated tau (p-tau) and total tau
(t-tau) are increased (Blennow et al. 2010; Hansson et al. 2006). Increased
p-tau is more specific for AD than β-amyloid but less sensitive (Hansson et
al. 2006; Maddalena et al. 2003). Tau elevations, however, can also be
found in other conditions such as frontotemporal lobar degeneration
(FTLD) and Parkinson-plus syndromes. Other promising assays for AD
include CSF measurement of β-amyloid oligomers and amyloid precursor
proteins. The combination of these CSF biomarkers may improve accuracy
in the diagnosis of AD. Although CSF biomarkers are not part of the
routine dementia workup, they may be considered in special circumstances
when clinicians have difficulty distinguishing among various types of
dementia and when such biomarker measurements are available. National
Institute on Aging–Alzheimer’s Association guidelines for diagnosing AD
have also focused on the use of plasma and CSF biomarkers and
neuroimaging for the early detection of preclinical AD and MCI due to AD
(Jack et al. 2011). Research studies, most notably Alzheimer’s Disease
Neuroimaging Initiative 2, are under way to better characterize the utility of
these biomarkers in the context of neuropsychological testing and
neuroimaging.
A number of assays have been developed for early-onset and rapidly
progressive dementias. Two promising assays for FTLD include the
measurement of plasma levels of progranulin (PGRN) and transactive
response DNA-binding protein of 43 kDa molecular weight (TDP-43).
Mutations of PGRN have been associated with FTLD with tau-negative,
ubiquitin-positive inclusions (Forman et al. 2006), and lower plasma levels
of PGRN are predictive of PGRN mutations in patients with FTLD and
asymptomatic family members (Finch et al. 2009). TDP-43 proteinopathy
has also been associated with both FLTD and amyotrophic lateral sclerosis,
which suggests these are two processes on a disease continuum (Neumann
et al. 2006). Elevated levels of TDP-43 in the CSF and plasma are seen in
FTLD, amyotrophic lateral sclerosis, and AD; plasma levels of
phosphorylated TDP-43 may be more specific for FTLD (Foulds et al.
2009).
Hsich et al. (1996) described an immunoassay for the detection of the
14-3-3 protein in CSF that had a specificity of 99% and a sensitivity of 96%
for the diagnosis of Creutzfeldt-Jakob disease (CJD) among patients with
dementia. CSF 14-3-3 protein assay has been found to be superior to
electroencephalography or magnetic resonance imaging (MRI) in
identifying cases of CJD (Poser et al. 1999). However, other acute
neurological conditions such as stroke, viral encephalitis, and
paraneoplastic neurological disorders can provide false-positive results.
Nevertheless, the American Academy of Neurology recommends testing for
CSF 14-3-3 protein for confirming or rejecting the diagnosis of CJD in
clinically appropriate circumstances (Knopman et al. 2001).

Electrocardiogram
An electrocardiogram (ECG) provides a graphic representation of the
heart’s electrical activity, obtained via surface electrodes placed in specific
locations on the patient’s chest. This placement makes possible a graph of
electrical activity from a variety of spatial perspectives. In psychiatry, the
most important roles of the ECG include screening for cardiovascular
disease that may preclude the use of specific medications and monitoring
for drug-induced electrocardiographic changes either from standard doses
or from overdose. Electrocardiographic changes associated with specific
psychotropic medications are summarized in Table 5–3.
The TCAs are well known to be cardiotoxic in overdose; even at
therapeutic doses, their use is considered unsafe in patients with
cardiovascular disease, particularly ischemic disease. Although the most
common cardiovascular complication of TCAs is orthostatic hypotension,
TCAs have the same pharmacological properties as type IA
antiarrhythmics, such as quinidine and procainamide. TCAs slow
conduction at the bundle of His; individuals with preexisting bundle branch
block who take TCAs are at increased risk for atrioventricular block. Even
therapeutic levels are associated with prolonged PR intervals and QRS
complexes; these results may be more pronounced in elderly individuals
because the incidence and severity of adverse drug reactions increase with
age. If TCAs are used, baseline and frequent follow-up ECGs should be
obtained.

TABLE 5–3. Common electrocardiographic abnormalities associated

with psychotropic medications
Medication Electrocardiographic change
Antipsychotics (typical or Increased QTc interval
atypical agents)
Potential for torsades de pointes
β-Blockers Bradycardia
Lithium Sick sinus syndrome
Sinoatrial block
Tricyclic antidepressants Increased PR, QRS, or QT intervals
Atrioventricular block

Lithium may also result in electrocardiographic changes, and ECGs are

recommended before starting and regularly while taking lithium. Lithium
appears to most affect the sinus node, and even at therapeutic levels it may
result in sick sinus syndrome or sinoatrial block, either of which may occur
early or later in treatment. At higher levels, there have been reports of sinus
arrest and asystole.
Antipsychotics also result in electrocardiographic changes; about 25% of
individuals receiving antipsychotics exhibit electrocardiographic
abnormalities (Thomas 1994). Although many of these changes have
historically been considered benign, there is increased concern that
prolongation of the QT interval (when corrected for heart rate, the QTc
interval) may contribute to potentially fatal ventricular arrhythmias,
particularly torsades de pointes. QTc values are typically around 400
milliseconds in duration; values lower than this are considered normal.
Because the greater the duration, the greater the risk of torsades, 500
milliseconds is frequently used as a cutoff. It is important to note that other
medications also affect the QTc interval and produce an additive effect
when combined with an antipsychotic. This phenomenon may be seen with
almost any antipsychotic agent but is most likely to be associated with
thioridazine and haloperidol among typical antipsychotics and with
ziprasidone among atypical antipsychotics. Unfortunately, there are
currently concerns about QTc prolongation for all atypical antipsychotic
agents.
In 2011, the U.S. Food and Drug Administration (FDA) posted a black
box warning recommending against dosages of citalopram over 40 mg/day
(20 mg/day in patients ages 60 years and older) because of the risk of QTc
prolongation and torsades de points. Further studies have had mixed
findings; one study questioned whether there was truly a concern with
citalopram (Zivin et al. 2013), whereas another study found modest
prolongation not only for citalopram but also for escitalopram and
amitriptyline (Castro et al. 2013). Further studies will be needed to address
the effects of citalopram and other antidepressants on QTc and torsades de
pointes. Until more data are available, physicians should continue to discuss
the black box warning with their patients before the initiation of citalopram
(and possibly escitalopram).
Notably, there are various methodologies of how to correctly calculate
the QTc interval for an individual. For each person, the QT decreases as the
heart rate increases. The formula for correction is QT/RRc, in which
RR=the RR interval and c=the correction factor. According to the FDA, the
most accurate proposed method is to calculate this correction factor for an
individual based on 50–100 pretreatment ECGs, and this is the
recommended approach for Phase I ECG trials (U.S. Food and Drug
Administration 2005). Other methodologies for calculation include the
population-based approaches, such as the Bazett, Fridericia, linear
regression, and nonlinear regression techniques. The Bazett QT correction
formula is most frequently used in clinical practice and in the medical
literature, but clinicians should be aware that this type of correction tends to
be inaccurate at the extreme ranges (both elevated and low).
Routine ECGs for all patients receiving antipsychotics are not currently
recommended, but it is wise to be prudent. A careful history for cardiac
illness, family history, or syncope should be obtained for all patients. ECGs
should be considered more carefully when patients have other risk factors,
such as heart failure, bradycardia, electrolyte imbalance (particularly with
low levels of potassium and magnesium), female sex, old age, hepatic or
renal impairment, and slow metabolizer status. ECG and/or electrolytes
should be performed in patients with risk factors, and citalopram should be
discontinued if the QTc persistently exceeds 500 milliseconds.
With few exceptions, an ECG should always be obtained in cases of
potential medication overdose, even when the medication used is not
associated with arrhythmias. ECGs are important because some medications
may affect heart rhythm in overdose when they would not do so at usual
doses. Also, suicidal patients often do not report all the medications that
they have used to overdose; suicide attempts may be impulsive, and patients
who have an altered mental status may not be able to provide a complete
report.

Imaging Studies
Plain film radiographs remain an integral piece of the diagnostic imaging
performed in geriatric psychiatry. Such techniques are most commonly used
to detect lung pathology that may contribute to mental status changes or to
detect bone fractures. Plain film radiographs are critical for individuals who
have both severe dementia and either a recent history of falls or newly
developed limb immobility.
A number of more recently developed imaging techniques have greatly
enhanced diagnostic abilities. These techniques are costly, so they should
not be used without a good rationale that includes why they are needed and
how the specific findings may affect a patient’s treatment plan. The
following discussion focuses on two commonly used structural imaging
techniques: computed tomography (CT) and MRI. Because these techniques
are also discussed in other chapters of this book, we focus on the scientific
basis behind these tools and provide information to support their clinical
use, particularly in brain imaging, and to facilitate providing informed
consent.
Other imaging techniques such as single-photon emission computed
tomography (SPECT) and functional MRI are used mostly in research and
have limited clinical use, and therefore are not discussed here. Amyloid
imaging agents involving positron emission tomography (PET) are also
used primarily in research, but because of the number of ongoing clinical
research trials being done to establish their utility, a brief discussion is
included later.

Computed Tomography
Computed tomography is a general term for several radiographic techniques
that result in the computer-assisted generation of a series of images showing
slices of an organ or body region, such as the brain or abdomen. The CT
scanner uses a small X-ray device that rotates around the body region of
interest in a fixed plane; these signals are sent to a computer that produces
the corresponding cross-sectional slice for that plane. The computer can
create sections in axial, coronal, and sagittal alignments. More recent
advances in software and display systems have led to many useful clinical
applications, including virtual CT colonoscopy or angiography.
When used to examine brain structure, CT can allow for the ready
identification of many structures, although it does have limitations. By
measuring differences in density, it can distinguish among CSF, blood,
bone, gray matter, and white matter. CT is particularly useful for
demonstrating bone abnormalities (such as skull fractures), areas of
hemorrhage (such as a subdural hematoma), and the mass effect from
various lesions. It can also display atrophy or ventricular enlargement.
However, CT is not very useful for visualizing posterior fossa or brain stem
structures because of surrounding bone.
A typical concern of patients is radiation exposure. CT scans require the
use of a limited amount of radiation; any given CT procedure results in a
radiation exposure, but that exposure is well below governmental
recommendations for individuals who work around radiation. However,
these recommendations do not consider multiple CT scans (thus multiple
radiation exposures) or CT studies that overlap scanned regions, a technique
that increases the radiation dose. CT imaging should be used when
appropriate, but other assessment techniques that may result in lower
radiation exposure should also be considered.

Magnetic Resonance Imaging

Whereas CT scanners rely on radiation, in MRI, the scanner creates a
magnetic field that is 3,000–25,000 times the strength of the earth’s natural
magnetic field. The underlying principle behind MRI is that the nuclei of
identifiable endogenous isotopes (such as hydrogen or phosphorous) behave
like tiny spinning magnets. Strong magnetic fields alter this behavior, and
an MRI scanner can identify the resultant change.
When a patient is put into the strong, static magnetic field generated by
the MRI scanner, his or her nuclei align parallel to the field. Because the
nuclei are also spinning, they wobble randomly around the field; different
molecules can be identified because their nuclei wobble at different
frequencies. A second, oscillating magnetic field is then applied at a right
angle to the first. This field affects only the nuclei that are in resonance with
it—that is, the nuclei that wobble at the field’s frequency. This second field
forces those resonant nuclei to wobble in unison. When this field is
deactivated, the nuclei return to their original positions, and the
synchronized movement creates a voltage that can be measured and
displayed. Measurements taken at various times during the procedure
produce the different magnetic resonance images.

TABLE 5–4. Neuroimaging in geriatric psychiatry

Suspected condition Indicated neuroimaging study
Sudden loss of consciousness Noncontrast CT scan
Pituitary tumor MRI
(hyperprolactinemia)
Old vs. new lacunar infarct Diffusion weighted imaging
Hippocampal atrophy Coronal thin slice MRI
Wernicke’s encephalopathy MRI to rule out midbrain hemorrhage
Note. CT=computed tomography; MRI=magnetic resonance imaging.

MRI has advantages and disadvantages when compared with CT. MRI
produces higher-resolution images and can obtain good detail in regions
(such as the posterior fossa) that are poorly visualized on CT. Additionally,
no radiation is involved in MRI. Unfortunately, the procedure is more
grueling than CT because the patient must remain motionless for a longer
period of time in a smaller, enclosed space. This may be difficult for
individuals who are claustrophobic. Additionally, the magnetic device must
be housed in an area devoid of iron, and staff and patients must not carry or
wear certain metals or have them embedded in their bodies. Moreover, MRI
tends to be more costly than CT imaging in most institutions.
 In the psychiatric workup of a geriatric patient (Table 5–4), MRI should
be considered when the clinician suspects small lesions in regions difficult
to visualize—for example, to obtain evidence of midbrain hemorrhage in a
patient with suspected Wernicke’s encephalopathy, or to confirm a
suspected pituitary tumor in an individual with hyperprolactinemia, which
may be seen in association with risperidone and other high-potency
antipsychotic agents. Hyperprolactinemia carries the risks of osteopenia,
sexual dysfunction, amenorrhea, breast enlargement, and possibly cardiac
disease and breast cancer. Switching from high-potency to low-potency
antipsychotic drugs such as quetiapine or aripiprazole has been shown not
only to normalize prolactin but also in some instances to reverse menstrual
function or other symptoms (Shim et al. 2007). MRI can also easily identify
vascular pathology, including lacunar infarcts, and it is better than CT for
defining exact anatomical localization.
A limitation of CT and MRI is that neither can differentiate between
acute and chronic lesions. Diffusion-weighted imaging (DWI) overcomes
this difficulty. DWI is based on the capacity of fast MRI to detect a signal
related to the movement of water molecules between two closely spaced
radiofrequency pulses (diffusion). This technique can detect abnormalities
due to ischemia within 3–30 minutes of onset, whereas conventional MRI
and CT images would still appear normal. Therefore, DWI is helpful in
defining the clinically appropriate infarct when multiple subcortical infarcts
of various ages are present.
The American Academy of Neurology recommends routine use of
structural neuroimaging (noncontrast head CT or MRI) in the initial
evaluation of all patients with dementia (Knopman et al. 2001). Recent
studies also suggest novel uses for MRI in dementia. Schuff et al. (2009)
showed that in the Alzheimer’s Disease Neuroimaging Initiative cohort,
patients with MCI and AD show progressive hippocampal loss over 6
months and then accelerated loss over 1 year. NeuroQuant, an FDA-
approved software program, automatically quantifies volumes of brain
structures and may be useful for measuring progressive hippocampal loss in
patients. MRI measurements of cortical thickness, ventricular volume, and
mean diffusivity may also help to distinguish normal pressure
hydrocephalus from other neurodegenerative disorders (Ivkovic et al. 2013;
Moore et al. 2012).
Positron Emission Tomography Imaging
PET imaging has recently been incorporated into dementia workup, and
imaging agents that specifically bind amyloid or tau are being studied to
determine their clinical utility. The main risk of PET imaging is exposure
from radioactive imaging agents, which currently are mostly
18fluorodeoxyglucose (FDG) based and have a half-life of about 110
minutes. PET has two important advantages: high sensitivity and
quantification of distribution of the radioactive tracer; its main disadvantage
is the lack of spatial resolution. MRI has several important advantages:
high-resolution imaging of structures, excellent anatomical contrast for soft
tissue structures, and other useful measurements such as perfusion,
diffusivity, and spectroscopy. PET-MRI hybrid imaging combines the
advantages of each imaging modality but is currently limited by lack of
availability to many patients.

FDG-PET Imaging
FDG-PET imaging can be useful in distinguishing AD from frontotemporal
dementia (FTD) when the clinical diagnosis is unclear. On FDG-PET
imaging, AD causes hypometabolism predominantly in posterior
temporoparietal association and posterior cingulate cortices, whereas FTD
causes hypometabolism in the frontal lobes and anterior temporal and
anterior cingulate cortices. In one study, visual interpretation of FDG-PET
metabolic and statistical maps was superior to clinical assessment, with a
diagnostic accuracy of 89.6% (Foster et al. 2007). Medicare has approved
payment for FDG-PET imaging in patients who meet the criteria for both
AD and FTD and need clarification of their diagnosis.

Amyloid PET Imaging

Florbetapir, flumetamol, and florbetaben (a chemical cousin of florbetapir)
are FDA-approved fluorine-based radioactive PET imaging agents that bind
to brain β-amyloid plaque and are indicated to detect the presence of β-
amyloid neuritic plaques in people with progressive cognitive decline.
There are no major differences among these agents. Because amyloid PET
scans expose patients to radioactivity (equivalent to 100 or more X-ray
examinations), it is not recommended that patients have multiple scans
during their lifetime. The scans are interpreted visually as positive,
negative, or indeterminate by an experienced reader. Readers vary in their
interpretation and expertise; for this reason, there is a risk of a wrong
interpretation. Furthermore, a negative scan only indicates the state at the
time of the scan and does not preclude that a scan would be positive a year
or so later. β-Amyloid plaques are currently required for a confirmatory
diagnosis of Alzheimer’s dementia; a negative scan indicating a low
probability of β-amyloid plaques may point to other causes for the person’s
dementia. The negative predictive value of amyloid scans for future
progression is high. The positive predictive value of amyloid scans is close
to 50%; therefore, positive scans themselves do not necessarily mean that
the patient has AD (Zannas et al. 2012). Positive scans can be seen in
numerous conditions, such as dementia with Lewy bodies, late-stage
Parkinson’s dementia, and prion disorders, and even in normal elderly
individuals who carry an allele producing the ε4 type of apolipoprotein E.
The effect of amyloid scans on changing patient management or diagnosis
was tested in a multicenter uncontrolled study with some promising results
but needs to be confirmed further in controlled studies (Grundman et al.
2013). About 30% of all cognitively normal elderly individuals and 40%–
50% of subjects with MCI will have a positive scan, and studies suggest
that people with a positive scan progress faster than do those with a
negative scan (Doraiswamy et al. 2012). However, until further study, these
scans are not indicated for use to screen cognitively normal individuals or
to predict future decline in at-risk individuals. Currently, Medicare and
insurance companies do not reimburse these scans, except in special
circumstances, and further effectiveness studies are under way to determine
appropriate coverage.

Tau PET Imaging

Tau PET imaging is also actively being developed with hopes of
understanding the role of tau tangles in the pathophysiology of AD. Further
studies are needed to determine the specificity of tau imaging agents and
the forms of tau to which they bind, as well as to validate findings with
postmortem studies (Chien et al. 2014).
Electroencephalography
Electroencephalography is a technique in which scalp electrodes allow the
measurement of cortical electrical activity. A skilled reader can interpret the
electroencephalographic (EEG) waveforms to identify the presence of
epileptic activity, the slowing of electrical activity, or a patient’s sleep stage.
EEG testing is most useful in a psychiatric evaluation of individuals with
known or suspected seizure disorders. Although a history of brain injury or
trauma with mental status changes or psychosis may be an important
indication for an EEG evaluation, imaging studies are generally preferred
for diagnostic clarification in these situations.
In elderly individuals, EEG changes occur in both delirium and
dementia, but these changes are not specific to a given diagnosis. In
delirium, except that caused by alcohol or sedative-hypnotic withdrawal,
electroencephalograms typically display slowing of the posterior dominant
rhythm and increased generalized slow-wave activity.
Electroencephalography has limited clinical use in this area because the
diagnosis of delirium is typically made clinically, increased slow-wave
activity is seen in other disorders, and the electroencephalogram provides
minimal information about the causes of delirium. However, EEG testing is
useful for distinguishing between depression and “quiet” delirium because
no EEG changes are seen in depression, whereas generalized slowing is
seen in delirium.
Likewise, there are EEG changes in dementia. AD results in multiple
changes in EEG parameters. Although Kowalski et al. (2001)) reported that
the degree of EEG change (slowing of normal background activity) is
correlated with cognitive impairment, there are also reports that worsening
of EEG results does not always parallel the clinical deterioration. Various
treatments, including cholinesterase inhibitors, may mitigate EEG changes
in individuals with mild dementia (Kogan et al. 2001). However, significant
negative correlations have been found between frontal theta activity and
hippocampal volumes (Grunwald et al. 2001). Although
electroencephalography currently has limited clinical utility, the
COGNISION trial is under way to determine whether electrical signals
produced during task performance (event-related potentials) may be helpful
for the diagnosis of AD (National Institute on Aging 2010).
 EEG testing may be useful, however, when CJD is a consideration in the
differential diagnosis. CJD is a rare, rapidly progressive prion disease
characterized by dementia and neurological signs that may include gait
disturbances and myoclonus. Electroencephalography may play an
important role in diagnosing this disease: periodic sharp-wave complexes
are strongly associated with CJD, with a sensitivity of 67% and a specificity
of 86% (Steinhoff et al. 1996). Although electroencephalography is an
important diagnostic tool when considering CJD, it is important to
remember that periodic sharp-wave complexes may also occur in AD and
dementia with Lewy bodies.

Genetic Testing
Genetics in geriatric psychiatry is covered in more detail in Chapter 3,
“Genomics in Geriatric Psychiatry.” In this section, intended to serve as an
introduction to genetic testing, we briefly discuss a well-researched test
examining for APOE alleles, pharmacogenomics, and ethical and
psychological concerns related to genetic testing.

APOE Testing
Extensive research has attempted to identify genetic markers for AD.
Mutations on chromosomes 1, 14, and 21 have been linked to rare forms of
early-onset familial AD; such findings may help families make decisions
about pregnancies. One of the most studied genes for AD is APOE. This
gene encodes for an astrocyte-secreted plasma protein that is involved in
cholesterol transport. APOE may also play a role in the regeneration of
injured nerve tissue. There are three possible alleles (ε2, ε3, ε4) of the
APOE gene that may be combined in a heterozygous (ε2/ε3, ε2/ε4, ε3/ε4) or
homozygous (ε2/ε2, ε3/ε3, ε4/ε4) fashion.
Multiple epidemiological studies have documented that the presence of
the ε4 allele is a risk factor for AD. Additionally, the presence of ε4 alleles
increases the specificity of the diagnosis of AD. Despite these associations,
the presence of an ε4 allele, even a homozygous ε4/ε4 genotype, is not
diagnostic for AD. The APOE story may be even more complicated; Roses
et al. (2010) found that another factor, TOMM40 poly-T polymorphism,
may be linked to APOE and that together these may affect the mean age at
onset of AD. A clinical trial is under way to further validate this finding.
APOE testing is not currently recommended to predict dementia risk in
asymptomatic individuals. Arguments against routine testing include the
lack of an effective treatment to modify the disease course and the lack of
evidence that APOE status may influence current supportive treatments.

Pharmacogenomics
Most pharmacogenetic tests are designed to detect certain alleles that may
be correlated with psychotropic response or serious psychotropic-related
adverse events. The first FDA-approved pharmacogenetics test, the
AmpliChipR CYP450 Test made by Roche Diagnostics, includes the
assessment of 27 alleles in cytochrome P450, family 2, subfamily D,
polypeptide 6 gene CYP2D6 (Malhotra et al. 2012). This assessment of the
CYP2D6 allele is purportedly helpful for clinicians who are trying to
determine an appropriate starting dose for numerous psychotropic drugs
(including several SSRIs, TCAs, and antipsychotics) that are metabolized
by CYP2D6. Ultra-rapid metabolizers (about 1% of the population) may
require higher dosages to have therapeutic levels, whereas poor
metabolizers (about 7%–10% of Caucasians and 1% of Asians) may require
lower dosages to achieve similar levels. A number of studies have also
examined various alleles to try to detect those individuals who are at higher
risk for serious adverse events, such as metabolic syndrome, from taking
antipsychotics (Malhotra et al. 2012). Currently, based on the available
studies, the FDA recommends performing the HLA-B*1502 allele test for
carbamazepine-induced Stevens-Johnson syndrome only for individuals of
Asian descent.
Psychiatrists should ask themselves a few questions before ordering the
results of a pharmacogenetics test for clinical purposes. First, is the patient
from the specific population in which the test has been shown to be valid?
For example, the HLA-B*1502 allele test was validated in Asian but not
Caucasian populations. Second, what is the evidence for predictive power
of the test in the clinical (vs. the laboratory) setting? Demonstration of
biologically accurate results and quality control is an essential part of any
laboratory test but does not necessarily equate to clinical validity. Third,
what is the likelihood that the pharmacogenomic test will sufficiently
explain the observed phenotype? Although an allele may be associated with
a high risk of an adverse outcome, it may not explain the majority of cases
seen.
Additionally, as discussed in the next section, ethical and psychological
concerns must be considered. Does the patient fully appreciate the
implications of undergoing such tests in the clinical setting? For example, a
patient may agree to the release of test results to a health insurance
company or another third party, believing at the time that the test is
designed for a particular purpose (e.g., detection of risk of weight gain from
anti-psychotics). However, future studies may show that this allele is
associated with development of an unrelated disease process such as cancer,
and this discovery may have consequences that the patient did not anticipate
if proper counseling was not received. Therefore, collaboration with a
genetics counselor is essential before any genetic testing is performed in the
clinical—and arguably in the research—setting.

Ethical and Psychological Concerns in Genetic Testing

The results of genetic testing may have significant psychological, social,
and personal repercussions. These possible effects are likely to be of less
concern for a patient already diagnosed with dementia than for his or her
family members faced with the risk of inheriting the disease. The offspring
of a patient with AD are at increased risk for the disease based on family
history alone. If a parent with AD is found to be homozygous for the APOE
ε4 allele, the children, who will have at least one copy of the allele, have at
least two to three times the average risk of developing AD. Unfortunately,
this knowledge does not allow offspring to anticipate with certainty whether
and when they will develop AD. Also, no treatment is available to APOE ε4
allele carriers to prevent the disease.
A positive family history of late-onset AD has been associated with a
distinctive phenotype in MCI—namely, lower levels of β-amyloid 42 and
higher levels of t-tau in the CSF—suggesting that other genetic factors are
present besides APOE (Lampert et al. 2013). Previously, family members
were discouraged from being tested due to stigmatization or worry because
of increased risk of AD. However, a number of AD prevention trials are
now being geared toward asymptomatic individuals at higher risk for
dementia (usually with a family history), so interested individuals may wish
to discuss the issue with their physicians and genetic counselors.
 Beyond personal and psychological concerns, there are also financial
concerns. Genetic testing should be confidential. The inappropriate release
of such information could result in job loss or lack of insurability. While the
Genetic Information Nondiscrimination Act of 2008 prohibits health
insurers from engaging in genetic discrimination, some health insurance
organizations and providers of long-term-care insurance, life insurance, or
disability insurance are exempt from this prohibition (National Human
Genome Research Institute 2014). Medical and life insurance in particular
might be exceedingly difficult to obtain if insurance agencies gain access to
this information.
In the end, however, genetic testing is yet another tool at the disposal of
patients and clinicians. It is a tool with much untapped potential. It also
carries significant risks that are different from the risks associated with
other laboratory tests described in this chapter. As with other procedures,
clinicians must make sure that patients or patients’ families clearly
understand not only the benefits but also the risks before they proceed with
testing.

Omics Technologies
Since the inception of the Human Genome Project, high-throughput omics
technologies have shown immense promise to revolutionize medicine in the
decades to come. There is, however, an absence of widespread use and
acceptance of these tests in the clinical setting for various reasons,
including need for replication, need for demonstration of validity in the
general population, and costs. Nevertheless, given the high likelihood that
psychiatrists will have patients who will ask to have these tests performed
or will bring in results of these tests from elsewhere, it is important that
clinicians have a basic conceptual understanding of the general purpose and
challenges that may arise in the interpretation of these omics technologies.
Given the rapid development of this field, an exhaustive review is not
possible. Nevertheless, many of the same questions regarding the clinical
interpretation of pharmacogenetic tests (see earlier section
“Pharmacogenomics”) can also be applied to the other omics technologies.
The purpose of the omics technologies is to examine the changes that
can occur at different levels within an organism due to both physiological
and pathophysiological processes. Table 5–5 briefly describes various
omics technologies (Valdes et al. 2013). The overall concept is that these
technologies sample the process of how the organism is functioning from
the beginning product (the genome) to its end product (its metabolites), as
well as in between (epigenomics, transcriptomics, and proteomics). These
findings can be used to determine at which stage(s) critical differences or
modifications associated with certain types of outcomes (particularly in
diseases or adverse medication effects) may arise.

TABLE 5–5. Omics technologies

Omic technology Example
Genomics Examination of somatic differences in the nucleus and mitochondria
genomes
Epigenomics Examination of epigenetic changes (including DNA methylation and
histone modification) that affect whether parts of the DNA
sequences can be transcribed
Transcriptomics (expression Examination of RNA transcripts, namely the expression of genomic
profiling) material, including microRNAs, which can negatively regulate or
degrade transcripts
Proteomics Examination of proteins, including posttranslational modifications
such as phosphorylation, ubiquination, and glycosylation, that can
affect the proteins’ functioning
Metabolomics Examination of metabolic content of cell or organism (including
changes in protein, nucleic acid, carbohydrates, and lipids)
Source. Valdes et al. 2013.

Conclusion
Laboratory testing can provide invaluable information in both the diagnosis
and the treatment of geriatric psychiatry patients. Clinicians should
carefully interpret laboratory values in the context of patients’ histories and
other available data. The role of neuroimaging, CSF biomarkers, and
various “omics” in clinical care is the focus of future research and will
revolutionize the care of the geriatric psychiatric patient. Future directions
for laboratory values include detection of populations who may be at risk
for certain psychiatric disorders (e.g., dementia) and prediction of which
individuals may respond or not respond to certain treatments for psychiatric
disorders.
 Key Points
• Laboratory testing is an essential component of the psychiatric
evaluation for elderly individuals, who often present with comorbid
medical illnesses.
• Laboratory tests are also useful in monitoring medication side effects.
New guidelines have been proposed to monitor patients taking atypical
antipsychotics.
• Neuroimaging is useful in evaluation of a variety of neuropsychiatric
illnesses including, but not limited to, dementia.
• Genetic testing has great potential in geriatric psychiatry but currently
has limited clinical utility. Important ethical issues should be considered
when using genetic testing.

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 CHAPTER 6

Neuropsychological Assessment of Late-

Life Cognitive Disorders
Kathleen A. Welsh-Bohmer, Ph.D.
Deborah K. Attix, Ph.D.

Alzheimer’s disease (AD) is by far the most common neurocognitive

disorder of aging. Affecting nearly 10% of the population over age 65
years, AD is estimated to have a prevalence of 25%–40% in individuals
who are age 85 years or older (Hebert et al. 2013). Because of its slow and
insidious onset, the early stages of AD can be confused with relatively
benign memory impairments associated with normal aging.
Advances in disease biomarkers for AD have led to changes that bolster
diagnostic confidence over the course of the disease (Albert et al. 2011;
McKhann et al. 2011; Sperling et al. 2011). At present, AD biomarkers in
an asymptomatic individual are confined to research use because these
indicators do not currently provide reliable information at the individual
levels as to whether symptoms will develop and over what time frame. In
this new diagnostic context, neuropsychological assessment continues to
play a central role in the diagnosis of neurocognitive disorders, in the
detection of mild neurocognitive disorders likely to transition to a more
fully expressed syndrome (Gomar et al. 2011), and in the differentiation
among the plethora of cognitive disorders that can interfere with functional
ability and quality of life (Knopman et al. 2001; Weintraub et al. 2012). The
neuropsychological assessment offers a sensitive, reliable, and noninvasive
approach to early symptom verification as well as a potentially cost-
effective means for managing patients with memory disorders (Welsh-
Bohmer et al. 2003).
Our goals in this chapter are 1) to describe in detail the instances in
which neuropsychological assessment can be most useful in geriatric
settings, 2) to discuss the neuropsychological examination process and
common instruments applied in this context, and 3) to summarize the
neurobehavioral presentations of common disorders in geriatric practices,
specifically the profiles of normal aging, various common neurocognitive
disorders of later life, and depression.

Neuropsychological Assessment in Geriatric

Settings
Memory complaints in later life are common, often reflecting the effects of
normal aging of the nervous system. An acute public awareness of AD
heightens the fear that relatively benign changes in speed of processing and
word retrieval are a harbinger of an imminent major neurocognitive
disorder. Drawing the line between healthy aging and early brain disease is
difficult. The inclusion of fluid and imaging AD biomarkers in the
diagnosis of the disease may provide more clarity in a variety of situations
where there is diagnostic ambiguity. Diagnosis of major or mild
neurocognitive disorder due to AD begins with the identification of the
clinical phenotype and the exclusion of reasonable medical explanations.
Consideration of cerebrospinal fluid biomarkers of the two proteins
implicated in AD, amyloid-β peptide and tau, along with structural and
functional neuroimaging studies, secures the diagnosis of either early- or
later-stage AD (Albert et al. 2011; McKhann et al. 2011; Sperling et al.
2011).
Despite the advances in useful disease biomarkers, a diagnosis of AD
continues to rest heavily on clinical assessment of the presenting syndrome.
With early symptomatic disease and the presence of significant disease
comorbidities, each of which can interfere with cognition and function,
neuropsychological assessment may be needed. In geriatric practices,
patients are referred for neuropsychological evaluation for four common
reasons, which are not mutually exclusive. The first and by far most
frequent reason for referral is to assist in the diagnosis of a cognitive
disorder. Specifically, the examination is used to verify the presence or
absence of a cognitive syndrome (e.g., major or mild neurocognitive
disorder) and to determine the likely differential diagnostic possibilities
based on the behavioral profile (e.g., AD vs. vascular neurocognitive
impairment). The second reason for neuropsychological testing is to
establish an objective baseline for purposes of tracking changes in
mentation over time; this baseline is useful in clarifying diagnostic
assignments due to neurodegenerative diseases such as AD in which the
establishment of progression is essential. The neuropsychological
examination in this context can also be used to monitor treatment response.
A third common referral reason for testing is to guide clinical care
decisions, including the determination of functional capacities and
competency (see Koltai and Welsh-Bohmer 2000). Issues typically
confronted by a geriatric evaluation include medication management and a
patient’s ability to live independently, manage finances, and drive safely.
Finally, the neuropsychological evaluation can be used to guide appropriate
therapeutic interventions. Based on the results of testing, identified
cognitive strengths and weaknesses can be used for designing appropriate
rehabilitation approaches, such as those involving compensatory strategies
or psychotherapy (for full discussion, see Attix and Welsh-Bohmer 2006).
The actual neuropsychological evaluation process can vary in form
across clinical practices, depending in part on the populations typically
served (e.g., a Spanish-speaking population vs. native English speakers) and
in part on the training emphasis of the neuropsychologist administering the
examination. The approach can use a fixed battery or may use more flexible
methods tailored to the referral issue. Regardless, there are standard
features that are applied uniformly across neuropsychological settings to
ensure that all testable areas of cognition are assessed (Lezak et al. 2012).
The evaluation typically begins with a diagnostic interview to identify the
major referral issues and obvious symptoms. In this interview, a patient’s
orientation to situation, language, behavioral organization, memory, mood,
and affect are observed within a naturalistic context. With patient consent,
family members generally are also interviewed separately to determine
changes in functional ability and to clarify historical and medical
information. In the formal testing session, 10 central domains of cognition
and behavior are generally assessed: orientation, intelligence, language
expression and comprehension, episodic learning and memory, attention
and concentration, higher executive functions, visuoperception,
constructional, and spatial abilities, sensorimotor integration, personality
and behavior, and mood and anxiety. Neuropsychological tests that are
commonly used to assess these various functional domains are listed in
Table 6–1. From the battery of tests, a profile of performance can be
constructed, examined in reference to normative standards, and then
interpreted relative to the established behavioral profiles of known
neurobehavioral syndromes.
Simplifying the geriatric assessment are several neuropsychological
batteries designed for use with elderly patients and the availability of
appropriate normative information (for a review, see Strauss et al. 2006).
Among these are the Mattis Dementia Rating Scale (Mattis et al. 2002) and
the neuropsychological battery from the Consortium to Establish a Registry
for Alzheimer’s Disease (Morris et al. 1989). Both assessments are
relatively brief and sensitive to early stages of AD neurocognitive disorder.
Additionally, they both offer presentation formats, such as the use of large
print and an oral format, to minimize the influences of sensory confounding
(see Welsh-Bohmer and Mohs 1997). The Neuropsychological Assessment
Battery is another measure that provides a broad assessment of key domains
with normative information for individuals ages 18–97 years (Stern and
White 2003). Although not specifically designed for the geriatric
population, this instrument has the advantage of co-normed subtests,
simplifying interpretation of performance across tests.
It must be emphasized that the neuropsychological examination is not
simply a process of actuarial comparisons to normative tables. The
neuropsychological evaluation, as with other forms of clinical diagnosis,
rests on an inferential process. The neuropsychological diagnosis is an
iterative process that incorporates multiple sources of information to arrive
at diagnostic impressions (see Potter and Attix 2006). In assessing a
geriatric patient, the psychologist must first determine the patient’s likely
premorbid ability to determine whether any observed changes are newly
acquired for that individual or reflect long-standing weaknesses. Once this
has been established, the presence of cognitive impairment is determined in
reference to appropriate normative values from similarly aged individuals
with comparable education level or intellectual function (Steinberg and
Bieliauskas 2005). Consideration is given to any potential confounding
influences to test performance, including subject motivation factors,
extratest factors (e.g., interruptions), and other test behaviors that might
interfere with optimal function (e.g., anxiety). The interpretation of the
likely medical and psychological contributions to the cognitive profile
requires a good appreciation of brain-behavior organization. The
neuropsychologist must consider whether the results obtained make sense
from a functional anatomical perspective and then analyze the profile to
determine its conformity to known neurobehavioral syndromes, such as
normal aging, mild neurocognitive disorder, AD, and depression. Before
final diagnostic determination, consideration is given to other attendant
data, such as medical history, ancillary studies (including imaging data),
and informant report of functional change. The combined information is
more useful in differentiating normal aging from early neurocognitive
disorder and improves diagnostic accuracy (Tschanz et al. 2000). The next
sections of this chapter summarize the neuropsychology of normal aging
and the differentiation of various common forms of late-life neurocognitive
disorder. Separately from this, we also consider in some detail the
neuropsychology of geriatric mood disorders and the contribution of
depressive disorders to the presentation of neurocognitive disorders.

TABLE 6–1. Common neuropsychological tests used in geriatric

assessment
Domain Tests commonly used References
Orientation/global Mini-Mental State Examination Folstein et al. 1975
mental status
Montreal Cognitive Assessment Nasreddine 2010
Alzheimer’s Disease Assessment Scale— Mohs and Cohen 1988
Cognitive
Intellect Wechsler Adult Intelligence Scale, 4th Edition Wechsler 2009a
(WAIS-IV)
Language Category/semantic fluency (e.g., animal fluency) Strauss et al. 2006
Lexical fluency (e.g., FAS test or Controlled Oral Benton and Hamsher
Word—CFL test) 1983
Boston Naming Test Kaplan et al. 1978
Multilingual Naming Test Gollan et al. 2012
Memory Wechsler Memory Scale, 4th Edition (WMS-IV) Wechsler 2009b
California Verbal Learning Test, 2nd Edition Delis et al. 2000
Hopkins Verbal Learning Test—Revised Brandt and Benedict
2001
 Consortium to Establish a Registry for Welsh-Bohmer and
Alzheimer’s Disease Word List Memory Test Mohs 1997
Rey Auditory Verbal Learning Test Ivnik et al. 1992
Brief Visuospatial Memory Test—Revised Benedict 1997
Buschke Selective Reminding Test Strauss et al. 2006
Attention/concentration Subtests from the WMS-IV and WAIS-IV Lezak et al. 2012
Executive function Trail Making Test Reitan 1958
Color Trail Making Test D’Elia et al. 1996
Stroop Color and Word Test Golden and Freshwater
2002
Symbol Digit Modalities Test Smith 1968
Short Category Test Wetzel and Boll 1987
Wisconsin Card Sorting Test Berg 1948
Visuoperception Benton Facial Recognition Test Benton et al. 1983
Judgment of Line Orientation Test Benton et al. 1981
Tests of Constructional Praxis Lezak et al. 2012
Sensorimotor abilities Grooved Pegboard Strauss et al. 2006
Finger Oscillation Heaton et al. 1991
Personality and behavior Minnesota Multiphasic Personality Inventory—2 Hathaway and
McKinley 1951
Frontal Assessment Battery Cohen et al. 2012
Mood and anxiety Geriatric Depression Scale Yesavage et al. 1983
Beck Depression Inventory–II Beck et al. 1996
Beck Anxiety Inventory Beck and Steer 1993

Neuropsychology of Normal Aging

Cognitive complaints are both more frequent and more worrisome in later
adulthood, given the high age-associated prevalence of neurodegenerative
conditions. However, comparisons of cognitive performance across the
adult age span (20–80 years) illustrate incremental declines with advancing
age across many cognitive domains (Drachman 2006; Finch 2009;
Salthouse 2009). Compared with young adults, older individuals show
selective losses in functions related to speed and efficiency of information
processing. Particularly vulnerable are memory retrieval abilities,
attentional capacity, executive skills, and divergent thinking such as
working memory and multitasking (Samson and Barnes 2013; Salthouse
1996; van Hooren et al. 2007). On formal neuropsychological testing,
memory measures involving delayed free recall are typically affected (Craik
and Rose 2012), although not to the pronounced extent found in AD (Welsh
et al. 1991). Unlike individuals with neurocognitive disorder due to AD,
older adults without neurocognitive disorders typically demonstrate intact
memory ability on tests such as cued recall and delayed recognition. This
profile of performance suggests different mechanisms underlying the
memory loss of normal aging and AD. In AD, the problem appears to
involve the consolidation or storage of new information into long-term
memory stores. In normal aging, the principal problem appears to be
primarily in the efficient accessing of recently stored information.
Therefore, procedures providing structural support for recall (e.g.,
recognition) facilitate the retrieval process. In addition to having a decline
in memory, normal older individuals also show some decrements compared
with younger cohorts on tests of visuoperceptual, visuospatial, and
constructional functions (Eslinger et al. 1985; Howieson et al. 1993; Park
and Schwarz 1999). These modest declines are seen on tests involving
visual analysis and integration, such as the Block Design subtest of the
Wechsler Adult Intelligence Scale, 4th Edition (WAIS-IV; Wechsler 2009a),
and similar integrative tests involving visual processing. Performance on
measures of executive control (e.g., Trail Making Test; Reitan and Wolfson
2004), language retrieval (e.g., verbal fluency), and divided attention (e.g.,
Digit Span subtest from WAIS-IV) also tends to be lower in older groups
compared with their younger counterparts (Salthouse 2010).
A number of explanations for age-related cognitive change have been
suggested, none of which are mutually exclusive. All basically support a
premise of a broad explanatory mechanism for age-related cognitive change
rather than unique and specific changes in restricted cognitive domains.
Speed of central processing has been one popular unifying notion, given
that the majority of tasks affected in aging involve motor responses or
reaction times (Salthouse 2005). Empirical studies support slowed central
processing as a leading explanation for cognitive change with aging (Finkel
et al. 2007). Another explanation posits that the profile of cognitive change
in normal aging is the result of a loss in fluid abilities—that is, skills that
require novel problem solving and flexible thought (Botwinick 1977; Horn
1982); by contrast, well-rehearsed verbal abilities—so-called crystallized
skills—are less susceptible to age-associated change. Refinements of this
hypothesis have conceptualized normal aging as a selective vulnerability in
frontal, dysexecutive processes (Daigneault and Braun 1993). This notion is
consistent with the behavioral difficulties observed, suggesting subtle
impairments in integrative and retrieval functions, and is also supported by
neuroimaging (Coffey et al. 1992; Gur et al. 1987; Langley and Madden
2000; Tisserand 2003) and histopathological findings (Haug et al. 1983)
within the frontal-subcortical brain connections. Although this hypothesis is
conceptually appealing and capable of explaining much of the observed
change with aging, some work suggests that the deficits may not be
localizable in their entirety to a single brain system. Rather, cognitive
decline is conceptualized as a process occurring across the lifespan,
involving failures in distributed brain networks (Finkel et al. 2007; Reuter-
Lorenz and Park 2010; Salthouse 2010). A significant problem in the
interpretation of the earlier studies is that many did not routinely screen for
nervous system disorders or operationalize their criteria for normal aging.
Work continues to identify the nature of the mechanisms that underlie age-
related cognitive change and the association of these mechanisms with
brain diseases common to aging, specifically AD (Reuter-Lorenz and Park
2010; Samson and Barnes 2013).

Differentiating Common Forms of Neurocognitive

Disorder in Late Life
AD is the leading cause of late-life neurocognitive disorder, accounting for
50%–75% of all cases identified within community-based cohort and
population-based series (Breitner 2006; Ebly et al. 1994; Gascón-Bayarri et
al. 2007). Vascular neurocognitive disorder occurs either alone or in
combination with AD in 12%–30% of the cases (Lobo et al. 2000; Román
2003), whereas neurocognitive disorder with Lewy bodies accounts for
3%–26% of the cases (Lippa et al. 2007; McKeith et al. 2005; Zaccai et al.
2005). Rare disorders of late life, such as frontotemporal lobar
degeneration, account for an additional 3%–5% of the reported cases of
neurocognitive disorders (Cairns et al. 2007; Johnson et al. 2005). Illnesses
such as hydrocephalus, metabolic disorders, and infectious diseases are
etiologically tied to the remaining cases (Holman et al. 1995; Savolainen et
al. 1999). The cognitive profiles of the various neurocognitive disorder
subtypes are to some extent overlapping, but there are unique features to
many of them that can be of diagnostic utility. These characteristics are
summarized in Table 6–2.

Alzheimer’s Disease
The presentation of AD neurocognitive disorder is dominated by a
pronounced impairment in recent memory processing, which remains the
most affected area of mentation in the majority of cases. This difficulty is
now understood to arise from the selective involvement of the medial
temporal lobe early in the illness (Braak and Braak 1991; Hyman et al.
1984), giving rise to impaired consolidation of newly learned information
into more permanent memory stores located across interconnected
neocortical structures. On formal neuropsychological testing, the memory
problem of AD is manifest as a rapid forgetting of new information after
very brief delays of 5 minutes or more (Welsh et al. 1991). Patients in the
mild prodrome of the illness often show the characteristic memory disorder
of more fully expressed disease and may show other mild deficits in
executive function, language expression, visuoperception, and attention
(Bäckman et al. 2005; Hayden et al. 2005; Twamley et al. 2006). At this
early symptomatic stage, a diagnosis of mild cognitive impairment due to
AD can be made (Albert et al. 2011). A diagnosis of mild cognitive
impairment due to AD is synonymous with prodromal AD, a diagnostic
label used in Europe (Dubois et al. 2010), and with DSM-5 mild
neurocognitive disorder due to AD (American Psychiatric Association
2013).
As AD progresses, other areas of cognition become progressively more
involved, reflecting the specific spread of neuropathological involvement to
the lateral temporal areas, parietal cortex, and frontal neocortical areas
(Small et al. 2000; Storandt et al. 2006; Welsh et al. 1992). With the
advancement of symptomatic disease and as decline in independent
function becomes apparent, a diagnosis of major neurocognitive disorder
due to AD can be made (McKhann et al. 2011). At this stage, the
prototypical changes appear in expressive language, visuospatial function,
higher executive control, and semantic knowledge (Weintraub et al. 2012).
At later stages of the illness, anomia with impaired semantic fluency (e.g.,
generation of names of animals) is generally seen on examination. Word
search and circumlocution tendencies are common in conversational
speech, whereas speech comprehension itself is better preserved, as are all
other fundamental elements of communication (Weintraub et al. 2012).
Visuospatial problems become more prominent in later stages of illness,
resulting in dressing apraxia, difficulty in recognizing objects or people, and
problems in performing familiar motor acts (Cronin-Golomb and Amick
2001). Subtle problems in spatial processing and visual motion detection
can occur early and may be detectable only on formal examination
(Mapstone et al. 2003). Visuospatial problems can be illuminated by tests of
spatial judgment and visual organization (Rizzo et al. 2000). In everyday
settings, visuospatial problems may manifest as intermittent topographical
dis-orientation, leading to difficulties in finding familiar routes while
driving (Rizzo et al. 1997). Figure 6–1 compares the memory loss
characterizing AD and mild cognitive impairment with that characterizing
normal aging.

TABLE 6–2. Clinical neurocognitive syndromes and associated

neuropsychological profiles
Neurocognitive syndrome and Neuropsychological profile Examples of tests fit for
characteristics purposea
Normal aging
Subjective memory complaints Impaired fluid abilities (novel WAIS-IV Performance IQ tests
Annoying but not disabling problem solving) Lexical fluency, immediate recall
problems Deficiencies in memory retrieval of word lists
Frequent problems with name Decreased general speed of Speeded tests from WAIS-IV
retrieval processing WAIS-IV Digit Span Backward,
Minor difficulties in recalling Lowered performance on Trail Making Test
detailed events executive tasks and Symbol substitution tasks
visuospatial skills/visuomotor
speed
Mild cognitive impairment—amnesic form
Subjective memory complaints Memory performance 1.5 SD Wechsler Memory Scale, 4th
Noticeable change in memory below age-matched peers Edition
as noted by informants Otherwise intact neurocognitive CVLT-II
Clinical Dementia Rating score function or only minimal Rey Auditory Verbal Learning
of 0.5 (mild, questionable losses (<1.5 SD) Test
dementia) (Hughes et al. Functional disorder limited to Hopkins Verbal Learning Test—
1982) mild interference from the Revised
Problem not disabling memory difficulty Buschke Selective Reminding
Test
Alzheimer’s disease
 Insidious onset Impaired memory consolidation Particularly episodic memory
Progressive impairment with rapid forgetting tests (e.g., CVLT-II, Brief
Prominent memory impairment Diminished executive skills Visuospatial Memory Test—
Possible disorders: aphasia, Impaired semantic fluency and Revised) and tests of novel
apraxia, agnosia naming problem solving and abstraction
Impaired visuospatial analysis (WAIS-IV), Trail Making Test,
and praxis WAIS-IV Digit Span,
constructional praxis (copying
of figures)
Frontotemporal neurocognitive disorder
Prominent Pronounced executive Wisconsin Card Sorting Test
personality/behavioral impairments Cognitive Short Category Test
change inflexibility Stroop Color Word Test
Disinhibition or apathy Impaired sequencing Frontal Assessment Battery
Impaired judgment/insight Perseverative, imitative,
Normal mental status initially utilization behaviors
Poor use of feedback
Prone to interference
Less obvious memory
impairments
Lewy body neurocognitive disorder
Fluctuations in alertness/acute Memory impairment of Particularly important are tests of
confusional state Alzheimer’s disease but with visuospatial organization, such
Visual hallucinations some partial saving as constructional praxis tests
Memory impairment Pronounced apraxia, visuospatial (e.g., clock drawing, WAIS-IV
Parkinsonian signs difficulties Performance subtests, copy of
Neuroleptic sensitivity Rapidly increasing quantifiable the Rey-Osterrieth figure
Falls resulting from orthostatic deficits in many cases [Osterrieth 1944])
hypotension
Vascular neurocognitive disorder
Variation of symptoms with Language/memory retrieval Particular attention to
subtype difficulties common discrepancies on memory test
Focality on examination Benefit from structural (CVLT-II) between intact
Abrupt onset support/cueing recognition and cued recall but
In multi-infarct neurocognitive Asymmetric motor impaired free recall
disorder, stepwise speed/dexterity Trail Making Test, WAIS-IV
progression Executive inefficiencies Digit Span Backward
Parkinson’s disease neurocognitive disorder
Extrapyramidal motor Slowed performance Wisconsin Card Sorting Test
disturbance Retrieval memory deficit Trail Making Test, WAIS-IV
Gait dysfunction and frequent Executive deficiencies (slowed Digit Span Backward, and
falls sequencing, impaired lexical animal and other verbal fluency
Bradykinesia fluency) tests
Bradyphrenia Impaired fine motor speed Benton Visual Retention Test or
(asymmetry common) similar copy test; Judgment of
Constructional deficits Line Orientation Test
Huntington’s disease
Early age at onset (midlife) Slowed performance CVLT-II
Choreiform movements Memory difficulty in retrieval Wisconsin Card Sorting Test,
Neurocognitive disorder Benefit from retrieval supports Trail Making Test, WAIS-IV
Bradyphrenia (recognition OK) Digit Span Backward, and
Executive compromises animal and other verbal fluency
Poor verbal fluency/preserved tests
naming Motor testing; Finger Oscillation,
Grooved Pegboard
Progressive supranuclear palsy
Extrapyramidal syndrome but Mild dysexecutive symptoms: Wisconsin Card Sorting Test,
no tremor impaired sequencing, fluency, Trail Making Test, WAIS-IV
Ophthalmic abnormalities flexibility Digit Span Backward, and
(limited downgaze) Motor slowing animal and other verbal fluency
Axial rigidity Memory weakness characterized tests
Pseudobulbar palsy as inefficiencies in storage and Benton Visual Retention Test or
Frequent falls retrieval similar copy test; Judgment of
Line Orientation Test
Normal-pressure hydrocephalus
Memory impairment Slowed information processing Special attention to CVLT-II
Gait disturbance Memory retrieval problems (recall vs. recognition)
Incontinence Benefit from retrieval supports Naming and verbal fluency
Creutzfeldt-Jakob disease
Typically, rapid onset and Rapidly evolving neurocognitive WAIS-IV processing speed and
course disorder perceptual organization tasks
Neurocognitive disorder with Subtypes with a profile akin to Judgment of Line Orientation
pyramidal and Alzheimer’s disease or a Test
extrapyramidal signs pronounced complex Constructional tasks
Transient spikes on visuospatial disorder (Balint’s
electroencephalogram syndrome)
Neurocognitive disorder
associated with geriatric
depression
Affective disorder Impaired performance on Special attention to
Psychomotor slowing effortful processing tasks CVLT-II (recall vs. recognition)
Memory complaints Impaired attention, Naming and verbal fluency
Cognitive complaints linked concentration, sequencing, Effort across all tests
temporally to the depressive cognitive flexibility, and
disorder executive control
Retrieval memory difficulty
Memory improvement with
cueing/recognition
Behavioral tendencies to
abandon tasks, poor
motivation
Note. CVLT-II= California Verbal Learning Test, 2nd Edition; SD=standard deviation; WAIS-
IV=Wechsler Adult Intelligence Scale, 4th Edition.
aAuthor citations are included in this table only for tests not listed in Table 6–1.

FIGURE 6–1. Profiles of neuropsychological test performance by

patients with mild cognitive impairment (MCI) and by patients with
moderate Alzheimer’s disease (AD).
Bars indicate the performance of patients with MCI (n=153) and moderately impaired AD patients
(n=277) on the subtests of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD;
Tariot 1996) neuropsychological battery, compared with the performance of nonimpaired elderly
control subjects (n=158) of similar age, sex, and education. The overall neuropsychological test
performance of the AD sample is well below that of both patients with MCI and subjects
experiencing normal aging. Patients with MCI performed at normal levels on naming and praxis.
Learning and verbal fluency were mildly affected in this group, falling at 71% of normal. Memory
was particularly affected in both AD and MCI. Verbal recall on the CERAD Word List Memory test
was 45% of normal in the MCI sample and only 28% for the AD patients. Visual memory was 51%
of normal in MCI and 23% in AD.
Source. Data derived from the Cache County Study of Memory sample (K.A. Welsh-Bohmer,
unpublished).

Cerebrovascular Disease
The neuropsychological profile of vascular dementia differs in many
respects from that of AD, the largest difference being the absence of the
profound memory impairment that is a hallmark of AD (Tierney et al.
2001). The presentation of vascular neurocognitive disorders will vary
according to the type and extent of the vascular compromise—multiple
infarctions, a single strategic stroke, microvascular disease, cerebral
hypoperfusion, hemorrhage, or combinations of these etiologies (Cohen et
al. 2002). Multi-infarct dementia, arising from multiple large- and small-
vessel strokes, will demonstrate a pattern of multifocal impairments on
testing that respect the cerebral territories involved by the infarctions (Chui
et al. 1992; Román et al. 1993). In disorders attributed to diffuse small-
vessel disease (e.g., Binswanger’s disease), the pattern shown on testing
reflects the disruption in the dorsolateral prefrontal and subcortical circuitry
(Kramer et al. 2002). Memory is involved, but the deficits are often patchy
in nature. Patients may show impaired recollection of some recent event but
show a surprising memory of some other occurrence transpiring within the
same time frame. On formal neuropsychological testing, the pattern on
memory testing is one of inefficient acquisition of new information leading
to a flattened learning curve over repeating trials (Looi and Sachdev 1999;
Padovani et al. 1995). Recall performance can be quite low, similar to that
seen in AD and mild cognitive impairment, but rapid forgetting is not a
typical feature (Hayden et al. 2005; Matsuda et al. 1998). The information
acquired, albeit limited, is generally retained, so that savings scores
between a final learning trial and a later delayed recall trial generally are
high. Finally, recognition improves dramatically with a recognition format,
suggesting a primary difficulty in retrieval rather than in storage or
consolidation of new information (Hayden et al. 2005). Beyond memory,
dysexecutive functions are typically involved, leading to slowed
sequencing, cognitive inflexibility, and decreased verbal fluency (Mathias
and Burke 2009). Asymmetries on sensory motor function or deficits in
coordination also are frequently demonstrated.

Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD) refers to a heterogeneous group
of neurodegenerative conditions that are genetically, clinically, and
neuropathologically diverse and represent collectively a major non-AD
neurocognitive disorder. The onset of disease is typically in the presenium,
distinguishing it from AD, in which the typical age at onset appears to
occur later (i.e., after age 65). The exact prevalence of FTLD in late old age
has not been conclusively established, but several studies suggest that it
accounts for approximately 10%–20% of the early-onset major
neurocognitive disorders (for a review, see Seltman and Matthews 2012).
The neuropathological features of FTLD are heterogeneous, but uniformly
the histological changes and atrophy are confined to the frontal and anterior
temporal cortices.
Clinically, from the outset, the neuropsychological profile of FTLD is
distinct from that of AD or any other form of major neurocognitive disorder
(Weintraub et al. 2012). There are typically prominent early changes in
behavior, personality, or language as opposed to impairments in memory
and other aspects of cognition. As a consequence of impaired judgment and
social inappropriateness, patients with FTLD may have tremendous
difficulties in their everyday lives, but on formal psychometric screening
they may score entirely within normal limits. A number of investigations
have delineated the cognitive profile of these disorders (Pachana et al.
1996) and indicate double dissociations between FTLD and AD.
Specifically, in AD, there is classic rapid forgetting; in FTLD, there is
impairment in executive function. The dysexecutive syndrome of FTLD is
characterized by slowed information processing, cognitive rigidity,
diminished abstract reasoning, poor response inhibition, and impaired
planning. At the neurobehavioral level, there are major changes in
personality and general social decorum. Disinhibition or its converse,
behavioral apathy and inertia, frequently occurs. Insight into impairment
and into personality change is also affected, and this capacity commonly is
disturbed early in the course of FTLD (Rankin et al. 2005). This behavior
pattern contrasts with that of AD, in which insight is generally lost later in
the neurodegenerative process (Salmon et al. 2008). In fact, appreciation of
memory impairment and other symptoms may be quite acute early in the
disease and be a harbinger of the progressive disorder (Geerlings et al.
1999). In instances of FTLD aphasia, the profile may be distinguished from
similar vascular disorders with aphasia based on a history of insidious onset
and indolent change. Imaging is often necessary to rule out stroke and to
visualize focal brain atrophy.
There is considerable clinical variability in the presentation of FTLD,
and at least three different subtypes of FTLD are now described based on
common clinical and neuropsychological features (Seltman and Matthews
2012; Warren et al. 2013): 1) a so-called behavioral variant, 2) semantic
dementia, and 3) progressive nonfluent aphasia. FTLD can also be
segregated into two subtypes based on regional brain involvement of
predominantly the frontal or temporal neocortices (e.g., Seeley et al. 2005).
Otherwise, the neuropathological features of FTLD appear heterogeneous
(Brun et al. 1994; Cairns et al. 2007; Jackson and Lowe 1996).
Microvacuolation, neuronal loss, cortical thinning, and gliosis are often
observed on gross and histological examination. Three major pathogenic
proteins are implicated in FTLD: phosphorylated tau, transactive response
DNA-binding protein 43 (TDP-43), and fused in sarcoma protein (FUS).
With immunohistochemistry, some cases show the spherical Pick bodies
with tau-positive inclusions. However, the majority of cases stain positive
for ubiquitin (TDP-43), not tau, and invariably are without these Pick
bodies. Clinicopathological studies that are beginning to emerge suggest
that the clinical expression of some forms of FTLD may be related to the
molecular pathology. Some forms of progressive aphasia have demonstrated
a relationship to the tauopathies (Cairns et al. 2007), semantic dementia to
TDP-43–associated pathology, and some behavioral variants of FTLD to
FUS-associated pathology (Warren et al. 2013). Work continues in this area,
having implications for efforts to identify biomarkers that would help
distinguish the early clinical expression of FTLD from primary psychiatric
and other neurological disorders.
It should be underscored that the subtypes do not always present
distinctly and that there can be a combination of symptoms. Additionally,
there are other types of frontal lobe disorders, which can include early-onset
neurocognitive disorder associated with motor neuron disease, such as
amyotrophic lateral sclerosis with dementia. There are also various
degenerative conditions with secondary frontal lobe effects. Vascular
conditions such as subcortical ischemic vascular dementia or Binswanger’s
disease (see the earlier “Cerebrovascular Disease” section) often present
with frontal lobe impairments, which are likely secondary to the disruption
of subcortical white matter pathways.

Parkinson’s Disease and Lewy Body Disease

Patients with Parkinson’s disease commonly have cognitive complaints, and
many go on to develop a major neurocognitive disorder. Although the
cumulative prevalence estimates of Parkinson’s disease dementia (PDD)
remain unclear, some estimates suggest that 10%–30% of patients newly
diagnosed with Parkinson’s disease develop functional impairment within 3
years (Reid et al. 1996; Williams-Gray et al. 2007). Related to PDD is
dementia with Lewy bodies (DLB), a progressive neurological condition
that is heralded by cognitive, behavioral, and functional impairments, as
opposed to extrapyramidal motor symptoms, and is associated with a
disorder of α-synuclein metabolism. The disorder has been referred to by a
variety of names—diffuse Lewy body dementia, senile dementia of the
Lewy body type, and the Lewy body variant of AD—depending in large
measure on what the regional distribution of the neuropathology is and
whether amyloid plaques co-occur (McKeith et al. 2005; Zaccai et al.
2005). The recognition that DLB and PDD share a common biology has led
to their being grouped together and referred to collectively as Lewy body
dementias (LBDs) (Lippa et al. 2007).
Clinically, PDD and DLB present differently, but they share a core
symptom complex that allows their recognition and distinction from AD
(Geser et al. 2005). In PDD, the prevailing features are parkinsonism,
akinetic rigidity, and generalized slowing in motor movement/initiation and
thought processes (bradykinesia and bradyphrenia, respectively). DLB, in
contrast, is characterized by early fluctuations in cognition and attention,
recurrent and persistent visual hallucinations, and extrapyramidal motor
symptoms. Diagnosing the conditions rests on the relative occurrence of
dementia with respect to the extrapyramidal motor symptoms. In PDD the
symptoms of dementia emerge in the context of a previously established
diagnosis of Parkinson’s disease, whereas in DLB the symptoms of
cognitive and functional impairments either predate or follow the onset of
parkinsonian symptoms within a 1-year time interval.
On neuropsychological evaluation, the cognitive impairments of PDD
and DLB are similar, but the profiles can be differentiated from those
typically observed in AD (Tröster 2008; Welsh-Bohmer and Warren 2006).
Both PDD and DLB are characterized by a pattern of memory retrieval
problems and mild dysexecutive disturbances, which early in the course are
less dramatic and globally impairing than the cognitive deficits of AD
(Hamilton et al. 2004). Visuospatial disturbances are commonly observed
early in the course of the LBDs (Ballard et al. 1999; Hanson et al. 1990;
Salmon et al. 1996), but expressive language such as naming tends to be
better preserved than in AD (Ballard et al. 1999; Heyman et al. 1999).
Despite these differences on neuropsychological testing, making a solid
differential diagnosis based solely on the cognitive profile alone will be
difficult (Monza et al. 1998; Soliveri et al. 2000; Testa et al. 2001),
particularly in the very early stages. The integration of the clinical
examination findings (which includes history and review of systems, motor
examination, cognitive findings, behavioral ratings, psychiatric interview,
and supportive laboratory studies such as neuroimaging) is necessary to
clarify these disorders from one another and to make an accurate diagnosis
early in the process (Litvan et al. 2012). In this context, particular attention
to the history of symptoms (e.g., fluctuations in ability throughout the day)
and to the presence or absence of defined behavioral impairments is crucial
to the diagnosis (Geser et al. 2005; Pillon et al. 1991). Cognitively impaired
patients with Parkinson’s disease can be differentiated from patients with
AD by the comparatively increased apathy observed in the former group
and memory impairment within the latter (Cahn-Weiner et al. 2002),
whereas presence of visual hallucinations not associated with treatment can
help distinguish LBD from PDD (Aarsland et al. 2001). Visual
hallucinations can occur in AD but are uncommon in the earliest stages;
hence, their presence in a neurocognitive process signals another etiological
cause such as LBD.

Geriatric Depression and Neurocognitive

Disorders
Two of the most common uses of neuropsychological assessment for elderly
patients are evaluating memory disorders and determining the role of
depression. By itself, serious depression in elderly people can result in
disabling cognitive impairment, or what has been called dementia of
depression or pseudodementia (see Breitner and Welsh 1995). The problem
of geriatric depression is fairly common, with some epidemiologically
based studies suggesting that nearly one-third (28%) of elderly individuals
older than 65 years exhibit prominent affective syndromes (Lyketsos et al.
2001). Depression also frequently co-occurs in the context of a range of
medical disorders, including AD, stroke and cerebrovascular conditions,
and Parkinson’s disease, complicating the diagnosis of these disorders and
exacerbating functional loss associated with each (Diniz et al. 2013;
Krishnan 2000; Migliorelli et al. 1995; Reichman and Coyne 1995).
Distinguishing between depression and other conditions in elderly people
can be challenging but is assisted by a thorough screening of both
depressive symptoms and cognitive status.
When screening fails to give a clear picture of the contribution of
depression to the cognitive picture, neuropsychological examination can
assist. It must be noted that depression in late life is clinically
heterogeneous, with variable concordance between severity of depressive
symptoms and level of cognitive impairment (Alexopoulos et al. 2002;
Butters et al. 2008). Despite the heterogeneity, there are some distinctive
neurocognitive and behavioral changes that appear ascribable to the
condition of late-life depression and that are characteristic of a rather large
subgroup of patients who present without neurological disease (Beats et al.
1996; Lockwood et al. 2002). The neurocognitive profile tends to be one of
a dysexecutive syndrome with impairments in planning, organization,
initiation, sequencing, working memory, and behavioral shifting in response
to feedback. Short-term memory and visuospatial skills are also disturbed,
in part because of the attentional and organizational compromises.
Behaviorally, these patients show apathy and psychomotor retardation as
opposed to prominent mood dysphoria of younger counterparts.
On formal neuropsychological testing, these patients show impairments
on tests sensitive to frontal lobe function. Difficulties can be readily seen on
tests of selective and sustained attention, verbal fluency, inhibitory control,
and set shifting (Boone et al. 1994, 1995; Lockwood et al. 2002). Memory
is impaired on both acquisition and recall, leading to a profile characterized
by a flattened learning curve and impaired free recall of previously learned
information after brief delays (Hart et al. 1987). Recognition memory is
better preserved but can be characterized by false-negative tendencies (not
recognizing previous target material). The memory disturbance of
depression is distinguished from AD by the impaired acquisition and
recognition elements. In AD, acquisition is relatively better preserved,
whereas recognition is characterized by false-positive tendencies
(recognizing foils incorrectly as previously presented targets). The profile
of impairment in depression leads to the impression of generalized
cognitive inefficiency and suppression of performance. Other qualitative
differences also may be seen in the performance of these two groups; in
depressed patients there is often a heightened tendency to abandon effortful
tests.
Importantly, even with treatment, not all of the cognitive impairments
associated with geriatric depression remit (Butters et al. 2000). In the older
patient, this may be due to the co-occurrence of another disease process,
such as AD or cerebrovascular disease (Butters et al. 2008). Although far
from conclusive, a number of studies report that depression in elderly
people exerts a discernible additional effect on cognition and functional
independence and may be a risk factor for later cognitive decline (Steffens
et al. 2006). Neuropsychological evaluation of elderly patients can provide
clinically useful information regarding the nature of the cognitive failures,
differential diagnostic information, and a baseline for future comparisons.
The information is useful in diagnosis and management, regardless of
whether all of the cognitive change detected is reversible.

Conclusion
The neuropsychological evaluation provides a useful and cost-effective
management approach for diagnosis and management of the growing
geriatric population with memory complaints. A neuropsychological
evaluation is not needed in most major neurocognitive disorders in which
symptoms are obvious and the diagnosis is secure. It can be enormously
useful, however, in more complex, less straightforward diagnostic
situations, such as in early AD detection or in geriatric depression. By its
objective nature, the neuropsychological examination has strong
applications in medical management, providing information regarding
patient capacities and deficits that is important for choosing intervention
approaches and for guiding future decision making with respect to
competency and safety.

Key Points
• The neuropsychological presentation of Alzheimer’s disease is
characterized by a pronounced deficit in the consolidation of new
information from short-term, immediate memory to a more permanent
 store. Thus, the deficit early in the disorder is a problem of rapid
forgetting of newly learned information.
• The profile of normal cognitive aging is characterized by modest
declines on executive function tests, in large measure because of
inefficiencies in multi-task processing and declines in perceptual motor
speed.
• Frontotemporal lobar degeneration is characterized by profound
functional and behavioral changes. The neurocognitive deficits
associated with the disorder, particularly in the early stages, may be
difficult to discern with mental status instruments. Neuropsychological
testing targeting executive functions can tease out the impairments in
behavioral regulation, disinhibition, perseveration, judgment, and
abstraction.
• The neuropsychological deficits associated with neurocognitive disorder
due to Parkinson’s disease are clinically very similar to those of a closely
aligned condition, neurocognitive disorder with Lewy bodies. However,
the neuropsychological profiles of these conditions can be distinguished
from that of neurocognitive disorder due to Alzheimer’s disease.
Visuospatial deficits are common early in neurocognitive disorder due
Parkinson’s disease and neurocognitive disorder with Lewy bodies, and
the memory disorders are less severe than those of Alzheimer’s disease.
• Geriatric depression can cause significant impairments in the efficiency
of cognitive processing, leading to selective problems in sustained
attention, concentration, and memory. It is a risk factor for cognitive
decline to dementia. When co-occurring with progressive neurological
disorders, such as Alzheimer’s disease or vascular neurocognitive
disorder, depression can lead to excess disability and an overall
reduction in the quality of life that might otherwise be achieved.

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 PART III

Presentation of Psychiatric Disorders in

Late Life
 CHAPTER 7

Delirium
Jane S. Saczynski, Ph.D.
Sharon K. Inouye, M.D., M.P.H.

Delirium, defined as an acute and sudden change in attention and

overall cognitive function, is a serious medical problem for older persons—
and one that is often fatal (Inouye et al. 2014b). Delirium is the most
frequent complication affecting hospitalized patients ages 65 years and
older. Despite its high prevalence and incidence, it often goes unrecognized.
Hospitalized patients with delirium have a worse prognosis than patients
without delirium and are at an increased risk of developing long-term
cognitive and functional decline (Pandharipande et al. 2013; Rudolph et al.
2009; Saczynski et al. 2012), which leads to additional posthospitalization
treatment costs, including institutionalization, rehabilitation services, and
home health care (Inouye et al. 2014b). Because it is preventable in up to
40% of cases (Inouye et al. 1999; Marcantonio et al. 2001), delirium is
increasingly the target for interventions to prevent its associated burden of
downstream complications and costs and therefore is now included on the
patient safety agenda (Wachter 2012) and as an indicator of health care
quality for older patients (National Quality Measures 2003). Delirium is a
costly condition, with total annual health care costs related to delirium and
its complications estimated at over $164 billion (Leslie et al. 2008).

Epidemiology
Delirium is often the only sign of an acute and serious medical condition
affecting a patient, and it most commonly occurs in frail older persons with
multiple comorbidities. Table 7–1 presents the prevalence rates (present on
admission) and incidence rates (new onset) of delirium in various patient
populations. The highest incidence rates were observed in the intensive care
unit (ICU) and postoperative and palliative care settings. Although high,
these rates likely represent underestimates of true incidence rates, because
many studies of delirium exclude patients with cognitive impairment or
dementia at baseline. In general medical and geriatric wards, the rates of
prevalence of delirium (present on admission) must be added to the
incidence rates to yield the overall occurrence rates of delirium in these
populations of 29%–64% (see Table 7–1). The prevalence of delirium in the
community setting is relatively low (1%–2%), but its onset usually brings
the patient to emergency care (Inouye et al. 2014b). On presentation to the
emergency department, delirium is present in 8%–17% of all seniors and in
40% of nursing home residents (Inouye et al. 2014b).
Delirium is consistently associated with higher mortality rates across all
nonsurgical populations, including general medical, geriatric, intensive
care, stroke, dementia, nursing home, and emergency department (see Table
7–1). Delirium in the ICU is associated with a 2- to 4-fold increased risk of
death both in and out of the hospital and with cognitive impairment for up
to 12 months after discharge; patients who develop delirium while on
general medical or geriatric wards are at 1.5-fold increased risk for death in
the year following hospitalization; and delirium in the emergency
department is associated with a 70% increased risk of death during the first
6 months after the visit (Inouye et al. 2014b; Pandharipande et al. 2013).
Postoperative cognitive impairment is common among surgical patients
who develop delirium, with impairments lasting up to 1 year
postoperatively, and physical function is impaired for 30 days or more after
discharge among surgical and nonsurgical patients who develop delirium
(Rudolph et al. 2009; Saczynski et al. 2012). Prevalent delirium at
admission to post-acute care is associated with a 5-fold increased risk of 6-
month mortality (Marcantonio et al. 2005).

Diagnosis, Assessment, and Workup

The diagnostic criteria for delirium that appear in DSM-5 (American
Psychiatric Association 2013) (Table 7–2) and the International Statistical
Classification of Diseases and Related Health Problems, 10th Revision
(ICD-10; World Health Organization 1993) (Table 7–3), are generally
accepted as the current diagnostic standards. Expert consensus was used to
develop the DSM-5 criteria, and sensitivity and specificity estimates of the
criteria have not yet been reported.
Over 24 delirium instruments have been used in published studies
(Adamis et al. 2010). The Confusion Assessment Method (CAM; Inouye et
al. 1990) is the most widely used instrument for the identification of
delirium and provides a simple diagnostic algorithm (Table 7–4) (Wei et al.
2008; Wong et al. 2010). The CAM algorithm has been validated in high-
quality studies of over 1,000 patients and has a sensitivity of 94%,
specificity of 89%, and high interrater reliability. The CAM has been
translated into at least 12 languages; has been used in more than 4,000
published studies (Inouye et al. 2014b); has been adapted for use in the ICU
(Ely et al. 2001), emergency departments (Han et al. 2009), and nursing
homes; and is now included as part of the Minimum Data Set (Centers for
Medicare and Medicaid Services 2010). Several behavioral checklists for
symptoms of delirium that are used, particularly in nursing-based studies,
include the Delirium Observation Screening Scale (Schuurmans et al.
2003), the Nursing Delirium Screening Checklist (Gaudreau et al. 2005),
and the NEECHAM Confusion Scale (Neelon et al. 1996). Delirium
severity is most widely measured using the Delirium Rating Scale
(Trzepacz et al. 1988, 2001) and the Memorial Delirium Assessment Scale
(Breitbart et al. 1997). A new severity instrument based on the CAM is now
available (Inouye et al. 2014a). A chart method for retrospective
identification of delirium has been validated (Inouye et al. 2005), but its
sensitivity is limited compared with interview-based methods. A combined
method (including both chart review and direct patient interview) captures
the broadest number of patients with delirium (Saczynski et al. 2014). The
Family Confusion Assessment Method has been developed and validated as
a way to identify delirium from reports of informal caregivers (Steis et al.
2012).

TABLE 7–1. Incidence, prevalence, and outcomes of delirium

Population Prevalence (range),* Outcomes (adjusted RR†)
incidence (range)
Surgical
Cardiac — Cognitive dysfunction (RR=1.7)
Functional decline (RR=1.9)
11%–46%
Noncardiac — Functional decline (RR=2.1)
Cognitive dysfunction (RR=1.6)
13%–50%
Orthopedic 17% Dementia/cognitive dysfunction
(RR=6.4–41.2)
12%–51% Institutionalization (RR=5.6)
Medical
General medical 18%–35% Mortality (RR=1.5–1.6)
Functional decline (RR=1.5)
11%–14%
Geriatric units 25% Falls (RR=1.3)
Mortality (RR=1.9)
20%–29% Institutionalization (RR=2.5)
Intensive care 7%–50% Mortality (RR=1.4–13.0)
Longer LOS (RR=1.4–2.1)
19%–82% Extended mechanical ventilation
(RR=8.6)
Stroke — Mortality (RR=2.0)
Any of 3 outcomes: increased LOS,
10%–27% functional impairment, or death
(RR=2.1)
Dementia 18% Cognitive decline (RR=1.6–3.1)
Institutionalization (RR=9.3)
56% Mortality (RR=5.4)
Palliative care/cancer — —
47%
Nursing home/postacute care 14% Mortality (RR=4.9)

20%–22%
Emergency department 8%–17% Mortality (RR=1.7)

—
Note. LOS=length of stay; RR=relative risk.
*The sum of both prevalence (present on admission) and incidence (new onset) yields the overall
occurrence rates of delirium in each setting.
†Adjusted relative risks were derived from studies that provided adjustment for at least one
covariable.
Source. Reprinted (with modifications) from Inouye SK, Westendorp RG, Saczynski JS, et al:
“Delirium in Elderly People.” The Lancet 383(9920):911–922, 2014 with permission from Elsevier.

TABLE 7–2. DSM-5 diagnostic criteria for delirium

A. A disturbance in attention (i.e., reduced ability to direct, focus, sustain,
and shift attention) and awareness (reduced orientation to the
environment).
B. The disturbance develops over a short period of time (usually hours to a
few days), represents a change from baseline attention and awareness,
and tends to fluctuate in severity during the course of a day.
C. An additional disturbance in cognition (e.g., memory deficit,
disorientation, language, visuospatial ability, or perception).
D. The disturbances in Criteria A and C are not better explained by another
preexisting, established, or evolving neurocognitive disorder and do not
occur in the context of a severely reduced level of arousal, such as coma.
E. There is evidence from the history, physical examination, or laboratory
findings that the disturbance is a direct physiological consequence of
another medical condition, substance intoxication or withdrawal (i.e.,
due to a drug of abuse or to a medication), or exposure to a toxin, or is
due to multiple etiologies.
Specify whether:
Substance intoxication delirium
Substance withdrawal delirium
Medication-induced delirium
Delirium due to another medical condition
Delirium due to multiple etiologies
Specify if:
Acute
Persistent
Specify if:
Hyperactive
Hypoactive
Mixed level of activity
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the
full criteria set, including specifier descriptions and coding and reporting procedures.
Source. DSM-5 criteria for delirium reprinted from Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, pp. 596–598.
Used with permission. Copyright © 2013 American Psychiatric Association.
TABLE 7–3. ICD-10 diagnostic criteria for delirium
For definite diagnosis, symptoms, mild or severe, should be present in each
one of the following areas:
1. Impairment of consciousness and attention (on a continuum from
clouding to coma; reduced ability to direct, focus, sustain, and shift
attention).
2. Global disturbance of cognition (perceptual distortions, illusions, and
hallucinations—most often visual; impairment of abstract thinking and
comprehension, with or without transient delusions, but typically with
some degree of incoherence; impairment of immediate recall and of
recent memory but with relatively intact remote memory; disorientation
for time as well as, in more severe cases, for place and person).
3. Psychomotor disturbances (hypo- or hyperactivity and unpredictable
shifts from one to the other; increased reaction time; increased or
decreased flow of speech; enhanced startle reaction).
4. Disturbance of the sleep-wake cycle (insomnia or, in severe cases, total
sleep loss or reversal of the sleep-wake cycle; daytime drowsiness;
nocturnal worsening of symptoms; disturbing dreams or nightmares,
which may continue as hallucinations after awakening).
5. Emotional disturbances, e.g., depression, anxiety or fear, irritability,
euphoria, apathy, or wondering perplexity.
Source. Reprinted from The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic
Criteria for Research. Geneva, Switzerland, World Health Organization, 1993. Used with
permission.

Delirium goes unrecognized by clinicians in up to 70% of patients who

develop this condition (Inouye et al. 2001); therefore, careful clinical
assessment for this condition is imperative. Identification of delirium relies
on insightful clinical judgment combined with a thorough medical
evaluation. The clinician should assess for recent changes or updates in
medication regimen, new infections, or recent development of medical
illnesses that may contribute to delirium. Sudden and acute onset,
fluctuating course, and alteration in attention are the central features of
delirium. Therefore, it is important to establish a patient’s level of baseline
cognitive functioning and the course of cognitive change when evaluating
for the presence of delirium. A detailed and in-depth background interview
with a proxy informant, such as a family member, caregiver, or medical
professional who knows the patient, proves invaluable when documenting
change in a patient’s mental status. To distinguish delirium from dementia,
which can be very challenging, it is important to differentiate between 1)
cognitive changes that increase and decrease in severity over a period of
days, which is indicative of delirium, and 2) changes that are more chronic
and progressive over a period of months to years, which is indicative of
dementia.

TABLE 7–4. Confusion Assessment Method (CAM) diagnostic

algorithma
Feature 1. Acute onset and fluctuating course
This feature is usually obtained from a reliable reporter, such as a family
member, caregiver, or nurse, and is shown by a positive response to this
question: Is there evidence of an acute change in mental status from the
patient’s baseline?
Feature 2. Inattention
This feature is shown by a positive response to this question: Did the
patient have difficulty focusing attention, for example, being easily
distractible, or have difficulty keeping track of what was being said?
Feature 3. Disorganized thinking
This feature is shown by a positive response to this question: Was the
patient’s thinking disorganized or incoherent, such as rambling or
irrelevant conversation, unclear or illogical flow of ideas, or
unpredictable switching from subject to subject?
Feature 4. Altered level of consciousness
This feature is shown by any answer other than “alert” to this question:
Overall, how would you rate this patient’s level of consciousness? (alert
[normal], vigilant [hyperalert], lethargic [drowsy, easily aroused], stupor
[difficult to arouse], or coma [unarousable])
aThe CAM ratings should be completed following brief cognitive assessment of the patient, such as
with the Mini Mental State Exam (Folstein et al. 1975). The diagnosis of delirium by CAM requires
the presence of features 1 and 2 and of either 3 or 4.
Source. Adapted from Inouye SK, Vandyck CH, Alessi CA, et al.: “Clarifying Confusion: The
Confusion Assessment Method—A New Method for Detection of Delirium.” Annals of Internal
Medicine 113:941–948, 1990. Used with permission.

The cognitive evaluation for delirium should encompass the following

domains: global cognitive changes, impairment in attention, disorganized
thought process, and altered level of consciousness. Global cognitive
changes associated with delirium can be assessed through simple cognitive
testing, combined with close clinical observations of behavior during test
administration, such as the patient’s ease and fluidity and ability to
complete tasks. Brief cognitive screening should be conducted with formal
cognitive screening tests, such as the Short Portable Mental Status
Questionnaire (Pfeiffer 1975), Mini-Cog (Borson et al. 2000), or Montreal
Cognitive Assessment (Nasreddine et al. 2005). If time is extremely limited,
then a basic screening can be done, which involves assessment of
orientation along with an attention task, such as backward naming of the
days of the week (allow 0 errors) or of the months of the year (allow 1
error), serial 7s (allow 1 error on five subtractions), or digit span backwards
(normal: ≥3 digits backward).
It is important not to underestimate the waxing and waning periods of
delirium, because periods of lucidity and reversal of symptoms can often be
deceiving. Impairment in attention, a hallmark feature of delirium, is
clinically manifested through the patient’s difficulty in focusing on the task
at hand, maintaining or following a conversation, and/or shifting of
attention, often leading to perseveration on a previous topic or task.
Disorganized thought is present when the patient’s speech is incoherent or
jumbled and when the patient lacks a clear or logical presentation of ideas;
this problem can be similar to the “word salad” phenomenon seen in
schizophrenia and other formal thought disorders. Alteration in
consciousness is highly variable and can range from an agitated or
aggressive state to one of lethargy or stupor. Other disturbances in cognition
include deficits identified on cognitive assessment, such as memory deficit,
disorientation, impairments in language or visuospatial ability, and
perceptual disturbances such as hallucinations (visual, auditory, or tactile).
Other clinical features commonly associated with delirium that are not
included as key diagnostic criteria are psychomotor agitation, paranoid
delusions, sleep-wake cycle disruption, and emotional lability.
Clinically, delirium typically presents in one of three major forms:
hypoactive, hyperactive, or mixed. The hypoactive form, which is more
common in older patients, is characterized by lethargy and reduced
psychomotor functioning. It is important to note that the hypoactive form of
delirium is associated with an overall poorer prognosis and often goes
unrecognized by clinicians and caregivers (Inouye et al. 2001). The reduced
level of patient activity associated with hypoactive delirium is often
attributed to low mood or fatigue, which may contribute to its misdiagnosis
or underrecognition. The hyperactive form of delirium is characterized by
agitation, increased vigilance, and often concomitant hallucinations. The
hyperactive form rarely goes unnoticed by caregivers or clinicians. In the
mixed form of delirium, patients fluctuate between the hypoactive and the
hyperactive forms. The mixed form creates a challenge in distinguishing
symptoms of delirium from symptoms of other psychotic or mood
disorders.
Table 7–5 summarizes the suggested workup for delirium. Several
fundamental points in the evaluation of delirium are worthy of special
emphasis. Often, delirium may be the initial and only sign of a serious and
life-threatening underlying illness, such as sepsis, pneumonia, or
myocardial infarction. Further complicating the evaluation of older patients
is the occult or atypical presentation of disease in older persons. For
instance, an octogenarian with myocardial infarction presents more often
with delirium than with classic symptoms of chest pain or shortness of
breath. Thus, a patient presenting with delirium should be screened for
acute physiological disturbance such as hypoxemia, low blood glucose, and
high arterial carbon dioxide. Another important principle is that the
diagnostic evaluation (e.g., laboratory testing, neuroimaging) must be
targeted based on the patient’s history and physical examination; an
untargeted battery of testing is likely to result in low diagnostic yield
(Hirano et al. 2006). For example, in patients with an identified medical
etiology of delirium or with preexisting dementia, over 98% will have a
normal brain scan (Hufschmidt and Shabarin 2008).
The clinician’s most important and difficult task is to differentiate
delirium from dementia. Dementia is a strong risk factor for delirium,
increasing the risk by two- to fivefold on hospital admission (see Table 7–7
below). Patients with dementia who develop a superimposed delirium
experience a more rapid progression of cognitive dysfunction and worse
long-term prognosis (Fick and Foreman 2000; Jackson et al. 2004). The key
diagnostic feature that aids in distinguishing these two conditions is that
delirium has an acute and rapid onset, whereas dementia is much more
gradual in progression. Alterations in attention and changes in level of
consciousness also point to a diagnosis of delirium. However, establishing
the occurrence of those changes can be difficult if no baseline cognitive
data are available or if preexisting cognitive deficits are reported by an
informant. If the differentiation cannot be made with certainty, then given
the life-threatening nature of delirium, the patient should be treated as
delirious until proven otherwise.
Other important diagnoses that must be differentiated from delirium
include psychiatric conditions such as depression, mania, and nonorganic
psychotic disorders such as schizophrenia. In general, these conditions do
not develop suddenly in the context of a medical illness. Although
hallucinations and perceptual disturbances can occur within the context of
delirium, alterations in attention and global cognitive impairment are the
key features that help to differentiate delirium from other psychiatric
conditions. Differentiating among diagnoses is critical because delirium
carries a more serious prognosis without proper evaluation and
management. For example, treatment for certain conditions such as
depression or affective disorders may involve the use of drugs with
anticholinergic activity, which in turn could exacerbate an unrecognized
case of delirium. Establishing the diagnosis can be difficult when the
clinician is faced with symptoms that are subtle, when a background history
is unavailable, or when the clinician is faced with an uncooperative patient.
Again, given the seriousness of delirium and the fact that certain medical
treatments may actually worsen symptoms, it is best for the clinician to
assume that delirium is present until further diagnostic information is
available.
The electroencephalogram has limited sensitivity and specificity in the
diagnosis of delirium. However, delirium does result in a characteristic
pattern of diffuse slowing with increased theta and delta activity and poor
organization of background rhythm that correlates with severity of delirium.
Electroencephalography can be particularly useful to differentiate organic
etiologies from functional or psychiatric disorders in patients who are
difficult to assess, to evaluate deteriorating mental status in patients with
dementia, and to identify occult seizures (e.g., nonconvulsive status
epilepticus or atypical complex partial seizures) (Jacobson and Jerrier 2000;
Jenssen 2005).
TABLE 7–5. Evaluation of suspected delirium
History Baseline cognitive function and recent
changes in mental status (e.g., family,
staff)
Recent changes in condition, new diagnoses,
review of systems
Review all current medications, including
over-the-counter medications and herbal
remedies
Review any new medications and drug
interactions
Review alcohol and benzodiazepine use
Assess for pain and discomfort (including,
urinary retention, constipation, thirst)
Vital signs Include temperature, oxygen saturation,
fingerstick glucose
Postural vital signs as needed
Physical and neurological Search for signs of occult infection,
examination dehydration, acute abdomen, deep vein
thrombosis, other acute illness. Assess for
sensory impairments.
Search for focal neurological changes and
meningeal signs
Targeted laboratory Based on history and physical examination,
evaluation (selected tests consider:
based on clues from Laboratory tests: CBC, electrolytes,
history and physical) calcium, glucose, renal function, liver
function, thyroid function, urinalysis,
cultures of urine, blood, sputum, drug
levels, toxicology screen, ammonia
level, vitamin B12 level, cortisol level
Arterial blood gas
Electrocardiography
 Chest X-ray
Lumbar puncture reserved for evaluation
of fever with headache, and meningeal
signs, or suspicion of encephalitis
Targeted neuroimaging Assess focal neurological changes, since
(selected patients) stroke can present as delirium
Suspicion of encephalitis for temporal lobe
changes
History or signs of head trauma
Electroencephalography Evaluate for occult seizures
(selected patients) Differentiate psychiatric condition from
delirium
Note. CBC=complete blood count.
Source. Reprinted from Inouye SK, Westendorp RG, Saczynski JS, et al: “Delirium in Elderly
People.” The Lancet 383(9920):911–922, 2014, with permission from Elsevier.

No specific laboratory tests currently exist that will aid in the definitive
identification of delirium. The laboratory evaluation for delirium is
intended to identify contributing factors that will need to be addressed, and
the approach should be guided by astute clinical judgment and tailored to
the individual situation. Laboratory tests that should be considered in the
delirium evaluation include complete blood count, electrolytes, kidney and
liver function, oxygen saturation, and glucose levels. Evaluation of occult
infection can be obtained through blood cultures, urinalysis, and urine
culture. Other laboratory tests, such as thyroid function, arterial blood gas,
vitamin B12 level, cortisol level, drug levels, toxicology screen, and
ammonia levels, may be helpful in identifying factors that contribute to
delirium. An electrocardiogram and/or chest radiograph may prove useful
in patients with cardiac or respiratory diseases.
In general, the routine use of neuroimaging in delirium is not
recommended, because the overall diagnostic yield is low, and the findings
from neuroimaging change the management of patients in less than 10% of
cases (Hirao et al. 2006). Brain imaging techniques—computed
tomography (CT), positron emission tomography (PET), single-photon
emission computed tomography (SPECT), and magnetic resonance imaging
(MRI)—have low diagnostic yield in unselected patients but are
recommended in cases of head trauma or injury, for evaluation of new focal
neurological symptoms, for assessment for suspected encephalitis, or for
evaluation of fever of unknown origin. Cerebrospinal fluid examination,
accomplished through lumbar puncture, may be useful in cases where the
suspicion of meningitis, encephalitis, or subarachnoid hemorrhage is high
(Marcantonio 2011). It may also be indicated in cases where delirium is
persistent or where no etiology of delirium can be identified.

Pathophysiology of Delirium
The fundamental pathophysiological mechanisms of delirium remain
unclear, and because each episode of delirium has a unique set of
contributors representing different causal mechanisms, it is unlikely that a
single cause or pathophysiological mechanism for delirium will be
identified. Increasing evidence suggests that several sets of biological
factors interact and result in disruption of large-scale neuronal networks in
the brain, leading to acute confusion, cognitive dysfunction, and delirium
(Watt et al. 2013). Table 7–6 presents the mechanisms potentially
contributing to delirium and their level of evidence.
Although many neurotransmitters are implicated in delirium (Gaudreau
and Gagnon 2005), the most frequently considered mechanism of delirium
is dysfunction in the cholinergic system. Acetylcholine plays a key role in
mediating consciousness and attentional processes. Given that delirium is
manifested by an acute confusional state, often with alterations of
consciousness, it is likely to have a cholinergic basis. Evidence for the
cholinergic connection includes findings that anticholinergic drugs can
induce delirium in humans and animals and that serum anticholinergic
activity is increased in patients with delirium (Hshieh et al. 2008; Lauretani
et al. 2010). Also, cholinesterase inhibitors have been found to reduce
symptoms of delirium in some studies (Gleason 2003; Wengel et al. 1998).
Chronic stress induced by severe illness, trauma, or surgery involves
sympathetic and immune system activation that may lead to delirium; this
activation may include increased activity of the hypothalamic-pituitary-
adrenal axis with hypercortisolism, release of cerebral cytokines that alter
neurotransmitter systems, alterations in the thyroid axis, and modification
of blood-brain barrier permeability (Hughes et al. 2012). Neuroimaging
studies, using either CT or MRI, have demonstrated structural abnormalities
in the brains of patients with delirium, especially in the splenium of the
corpus callosum, thalamus, and right temporal lobe (Bogousslavsky et al.
1988; Doherty et al. 2005; Naughton et al. 1997; Ogasawara et al. 2005;
Takanashi et al. 2006). Advanced neuroimaging techniques find overall and
regional perfusion abnormalities in the brains of people with delirium (Fong
et al. 2006; Pfister et al. 2008). Functional imaging may help to distinguish
structural damage resulting from an episode of delirium from preexisting
changes (Choi et al. 2012).

TABLE 7–6. Potential pathophysiological contributors to delirium

Biological factor Type of data Review
available published
Neurotransmitters
Acetylcholine, dopamine, melatonin E, O Yes
Gamma-aminobutyric-acid (GABA) E, O No
Tryptophan, serotonin O Yes
Glutamate, N-methyl-D-aspartate (NMDA) O No
Epinephrine/norepinephrine H No
Pro-inflammatory markers
Interferon (IFN) α or β E Yes
Interleukin 6 (IL-6), 8 (IL-8) O Yes
Interleukin 10 (IL-10) O No
Tumor necrosis factor (TNF-α), interleukin 1-β (IL 1-β), H Yes
prostaglandin E (E2, EP1–4)

Physiological stressors
Cortisol, S100B, neopterin, hypoxia O No
Metabolic disorders
Lactic acidosis E, O No
Hypo- or hyperglycemia O No
Insulin-like growth factor 1 (IGF-1) O Yes
Hypercapnia H Yes
Electrolyte disorders
Sodium, calcium, magnesium E, O No
Genetic factors
Apolipoprotein E (ApoE), dopamine transporter receptor O Yes
Glucocorticoid receptor O No
Toll-like receptor 4 H No
Note. E=Experimental—Controlled data available in humans (e.g., clinical trials and/or inference
from unintended side effects of medications); O=Observational—Only observational data available
in humans; H=Hypothetical—Studies not yet available in humans to support the mechanism.
Source. Reprinted from Inouye SK, Westendorp RG, Saczynski JS, et al: “Delirium in Elderly
People.” The Lancet 383(9920):911–922, 2014, with permission from Elsevier.

Risk Factors for Delirium

Although a single factor may lead to delirium, more commonly delirium is
multifactorial in older persons (Inouye and Charpentier 1996). To facilitate
immediate and effective diagnosis and treatment of delirium, it is important
to identify all multifactorial contributors. The development of delirium
involves the complex interrelationship between the multiple predisposing
factors that make a patient vulnerable and exposure to noxious insults or
precipitating factors (Figure 7–1). For example, a single dose of a sedative
drug given to a patient who is cognitively impaired or severely ill may lead
to delirium. However, a patient without severe illness or cognitive
impairment has greater resistance to developing delirium unless he or she is
repeatedly exposed to multiple insults such as surgery, anesthesia, and
psychoactive medications (Gleason 2003). Addressing only a single
noxious insult or factor may not aid in improving delirium. Rather,
multicomponent approaches will be most effective for both prevention and
treatment (O’Mahony et al. 2011).
Table 7–7 presents predisposing and precipitating factors identified in
prospectively validated prediction models. The leading risk factors
consistently identified at admission in both medical and noncardiac surgery
populations were dementia or cognitive impairment, functional impairment,
vision impairment, history of alcohol abuse, and advanced age (>70 years).
Comorbidity burden or presence of specific comorbidities (e.g., stroke,
depression) was associated with an increased risk in all patient populations.
In the ICU studies, younger individuals were included and baseline factors
(e.g., dementia, functional impairment) were not significant independent
predictors. Precipitating factors varied more across patient populations. In
medical patients, polypharmacy, psychoactive medication use, and physical
restraints were the leading factors, conferring up to a 4.5-fold increased
risk. Abnormal laboratory values were risk factors in all populations,
conferring an increased risk of between 40% and 500%.

Medications and Delirium

Medication use contributes to delirium in more than 40% of cases (Inouye
1994; Inouye and Charpentier 1996). A list of medications identified in the
Beers Criteria by the American Geriatrics Society (2012) as causing or
exacerbating delirium are listed in Table 7–8. The medications most
frequently associated with delirium are those with psychoactive effects,
such as sedative-hypnotics, anxiolytics, narcotics, and histamine type 2 (H2)
blockers. Drugs with anticholinergic effects, including antipsychotics,
antihistamines, antidepressants, antiparkinsonian agents, and
anticonvulsants, are also commonly associated with delirium. Previous
studies, including validated risk prediction models, have demonstrated that
the use of psychoactive medication results in a fourfold increased risk of
delirium, whereas the use of two or more psychoactive medications is
associated with a fivefold increased risk (Inouye and Charpentier 1996).
Sedative-hypnotic drugs are associated with a 3- to 12-fold increased risk of
delirium, narcotics with a threefold risk, and anticholinergic drugs with a 5-
to 12-fold risk (Agostini and Inouye 2003; Foy et al. 1995; Schor et al.
1992). A systematic review of prospective studies identified opioids,
benzodiazepines, dihydropyridines, and antihistamines as increasing the
risk of delirium (Clegg and Young 2011).
FIGURE 7–1. Multifactorial model of delirium in older persons.
Note. The onset of delirium involves a complex interaction between the patient’s baseline
vulnerability (predisposing factors) present on admission and precipitating factors or noxious insults
occurring during hospitalization. See text for details.
Source. Reprinted from Inouye SK, Westendorp RG, Saczynski JS, et al: “Delirium in Elderly
People.” The Lancet 383(9920):911–922, 2014, with permission from Elsevier.

Polypharmacy leads to a proportionately greater risk for developing

delirium. The increased risk is related to the direct toxicity of the
medications themselves, as well as to the increased risk of drug-drug and
drug-disease interactions. Some homeopathic or herbal therapies, especially
those used for mood disorders (e.g., St. John’s wort, kava kava), may
increase the risk of delirium, especially when used in combination with
prescribed psychoactive medications. Given the role of medications in
contributing to the development of delirium, it is essential to conduct a
complete review of all prescription and over-the-counter medications a
patient is taking. The majority of older patients take several prescribed
medications during hospitalization, increasing the risk for drug-drug and
disease-drug interactions. Medications with known psychoactive effects
should be discontinued or minimized whenever possible. At the very least,
steps should be taken to reduce dosage or to substitute medications with
less toxic potential. In aging adults, medications may cause adverse effects
even when given at the recommended dosages and with serum drug levels
that are within the “therapeutic range.” Determining if the patient has a
history of chronic sedative use or alcohol dependence is critical in assessing
for withdrawal risk.
TABLE 7–7. Risk factors for delirium from validated predictive models
Surgery
Risk factors General Noncardiac Cardiac Intensive
medicine care unit
Predisposing factors
Dementia 2.3–4.7 2.8 — —
Cognitive impairment 2.1–2.8 3.5–4.2 1.3 —
History of delirium — 3.0 — —
Functional impairment 4.0 2.5–3.5 — —
Vision impairment 2.1–3.5 1.1–3.0 — —
Hearing impairment — 1.3 — —
Comorbidity/severity of illness 1.3–5.6 4.3 — 1.1
Depression 3.2 — 1.2 —
History of transient ischemia/stroke — — 1.6 —
Alcohol abuse 5.7 1.4–3.3 — —
Older age (≥75 years) 4.0 3.3–6.6 — 1.1

Precipitating factors
Medications
Multiple medications added 2.9 — — —
Psychoactive medication use 4.5 — — —
Sedative-hypnotics — — — 4.5
Use of physical restraints 3.2–4.4 — — —
Use of bladder catheter 2.4 — — —
Physiological
Elevated serum urea 5.1 — — 1.1
Elevated BUN/creatinine ratio 2.0 2.9 — —
Abnormal serum albumin — — 1.4 —
Abnormal sodium, glucose, or — 3.4 — —
potassium
Metabolic acidosis — — — 1.4
Infection — — — 3.1
Any iatrogenic event 1.9 — — —
Surgery
Aortic aneurysm — 8.3 — —
Noncardiac thoracic — 3.5 — —
Neurosurgery — — — 4.5
Trauma admission — — — 3.4
 Urgent admission — — — 1.5
Coma — — — 1.8–21.3
Note. Data are relative risks. Some data are reported as ranges. BUN=blood urea nitrogen.
Source. Reprinted from Inouye SK, Westendorp RG, Saczynski JS, et al: “Delirium in Elderly
People.” The Lancet 383(9920):911–922, 2014, with permission from Elsevier.

TABLE 7–8. Drugs to avoid in delirium: Beers Criteria

All tricyclic antidepressants
Anticholinergics
Antihistamines
Antiparkinsonian agents
Muscle relaxants
Antidepressants
Antipsychotics
Antimuscarinics
Antispasmodics
Benzodiazepines (short-, intermediate-, and long-acting)
Nonbenzodiazepine hypnotics
Corticosteroids
Histamine type 2 (H2) receptor antagonists
Meperidine
Sedative-hypnotics
Thioridazine
Source. American Geriatrics Society 2012.

Prevention and Management of Delirium

Pharmacological Prevention and Management
Although clinical trials have used a variety of pharmacological approaches,
at present there is no convincing, reproducible evidence that any of these
treatments are clearly effective for either prevention or treatment of
delirium. Many published pharmacological trials report no difference in
delirium rates (Inouye et al. 2014b). In the majority of trials that showed a
reduced rate of delirium following targeted pharmacological treatment,
there was no corresponding impact on clinical outcomes, such as ICU or
hospital length of stay, hospital complications, or mortality, or clinical
outcomes were not measured. For instance, a randomized controlled trial of
haloperidol versus placebo in 457 noncardiac surgery patients in the ICU
showed reduced incidence of delirium (haloperidol 15.3% vs. placebo
23.2%, P=0.03) but no difference in length of hospital stay, postoperative
complications, or mortality (Wang et al. 2012). Similarly, several trials have
reported that treatment resulted in potentially worse outcomes: olanzapine
reduced incidence of delirium compared with placebo in 400 patients
following hip replacement but resulted in greater duration and severity of
delirium (Larsen et al. 2010), and rivastigmine resulted in higher delirium
duration and mortality in 104 ICU patients (van Eijk et al. 2010). Notably,
published trials use different approaches to the assessment of delirium and
evaluate diverse patient populations; therefore, generalizing findings is
difficult. Given the preponderance of evidence, however, pharmacological
approaches to prevention and treatment are not recommended at this time
(Barr et al. 2013; O’Mahony et al. 2011).

Nonpharmacological Prevention and Management

Primary prevention—that is, preventing delirium before it develops—is the
most effective strategy to alleviate symptoms associated with delirium. The
Hospital Elder Life Program (HELP; www.hospitalelderlifeprogram.org)
utilizes a multicomponent targeted intervention approach to aid in
preventing delirium and is the most widely disseminated approach to
delirium prevention (Inouye et al. 1999, 2006). HELP is a hospital-wide
program that was designed to implement delirium prevention strategies and
to promote an overall increase in quality of medical care for older persons.
The HELP interventions include the following: reorientation, therapeutic
activities, reduction of psychoactive medications, early mobilization,
promotion of sleep, maintaining of hydration and nutrition, and provision of
vision and hearing adaptations. The program is implemented by a skilled
interdisciplinary team, assisted by nursing staff and often trained
volunteers.
In general, nonpharmacological approaches, such as those used in the
HELP protocols, should be implemented as the first-line treatment of
delirium (Table 7–9). Nonpharmacological treatment approaches include
reorientation (e.g., using orientation boards, clocks, calendars), behavioral
interventions, encouraging the presence of family members, and
transferring a disruptive patient to a private room or closer to the nurse’s
station for increased supervision. Consistent and compassionate staff are
essential in facilitating contact and communication with the patient through
frequent verbal reorienting strategies, clear instructions, frequent eye
contact, and the inclusion of patients as much as possible in all decision
making regarding their daily and medical care. Sensory deficits should be
assessed and then corrected by ensuring that all assistive devices, such as
eyeglasses and hearing aids, are readily available, functioning, and being
used properly by the patient. The use of physical restraints should be
minimized due to their role in prolonging delirium, worsening agitation,
and increasing complications such as strangulation (Inouye et al. 2007).
Strategies that increase the patient’s mobility, self-care, and independence
should be promoted.
Geriatric assessment followed by consultation has also been successful
in preventing and treating delirium. For instance, a trial of a proactive
geriatric consultation resulted in a 40% reduction in the risk of delirium in
patients following hip fracture (Marcantonio et al. 2001). The consultative
strategy focused on 10 domains: adequate brain oxygen delivery, fluid and
electrolyte balance, pain management, reduction in psychoactive
medications, bowel and bladder function, nutrition, early mobilization,
prevention of postoperative complications, appropriate environmental
stimuli, and treatment of delirium. Controlled trials of educational strategies
targeted toward training staff to assess, prevent, identify, and treat delirium
have demonstrated positive results in increasing recognition and reducing
episodes and duration of delirium (Marcantonio et al. 2010; Milisen et al.
2001; Tabet et al. 2005). Controlled trials of multifactorial interventions,
which usually consist of a combination of staff education and treatments
tailored to meet the individual needs of patients, have demonstrated
reductions in delirium rate and/or duration (Bergmann et al. 2005; Deschodt
et al. 2012; Lundström et al. 2005; Naughton et al. 2005; Pitkälä et al.
2006). Other approaches include interventions delivered by family members
and mobility or rehabilitation interventions, both of which were
demonstrated to be effective for prevention of delirium (Caplan et al. 2006;
Martinez et al. 2012; Schweickert et al. 2009).

TABLE 7–9. Initial management of delirium

Medication adjustments Reduce or remove psychoactive medications
 (e.g., anticholinergics, sedative-hypnotics,
opioids); lower dosages; avoid PRNs
Substitute less toxic alternatives
Use nonpharmacological approaches for
sleep and anxiety, including music,
massage, relaxation techniques
Address acute medical issues Treat problems identified in workup (e.g.,
infection, metabolic disorders)
Maintain hydration and nutrition
Treat hypoxia
Reorientation strategies Encourage family involvement; use sitters as
needed
Address sensory impairment; provide
eyeglasses, hearing aids, interpreters
Maintain safe mobility Avoid use of physical restraints, tethers, and
bed alarms, which can increase delirium
and agitation
Ambulate patient at least 3 times per day;
active range of motion
Encourage self-care and regular
communication
Normalize sleep-wake cycle Daytime: discourage napping, encourage
exposure to bright light
Facilitate uninterrupted period for sleep at
night
Quiet room at night with low level lighting;
nonpharmacological sleep protocol
Pharmacological management Reserve for patients with severe agitation,
(severe agitation or which will result in interruption of
psychosis only) essential medical therapies (e.g.,
intubation) or severe psychotic symptoms
Start low doses and titrate until effect
achieved; haloperidol 0.25–0.5 mg po/im
 bid preferred; atypical antipsychotics
close in effectiveness
Note. bid=twice daily; CBC=complete blood count; im=intramuscular; mgs=milligrams; po=by
mouth; PRN=as needed medication.
Source. Reprinted from Inouye SK, Westendorp RG, Saczynski JS, et al: “Delirium in Elderly
People.” The Lancet 383(9920):911–922, 2014, with permission from Elsevier.

Key Points
• Delirium is a common problem for older hospitalized persons.
• Delirium is the most frequent complication affecting surgical and
nonsurgical older patient populations and often goes unrecognized.
• Patients with delirium have a worse prognosis than comparable patients
without delirium and an increased risk of developing long-term cognitive
and functional decline.
• It is important to establish a patient’s level of baseline cognitive
functioning and course of cognitive change when evaluating for
delirium.
• The Confusion Assessment Method provides a simple diagnostic
algorithm and has become widely used for identification of delirium.
• Although delirium can be caused by a single factor, it is usually
multifactorial.
• Existing cognitive impairment and dementia are the leading risk factors
for development of delirium.
• Nonpharmacological approaches should be implemented as the first line
of treatment for delirium.
• Certain medications can induce or exacerbate an episode of delirium.
• Pharmacological management of delirium should be reserved for patients
with severe agitation.

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Suggested Readings
American Geriatrics Society: American Geriatrics Society updated Beers
Criteria for potentially inappropriate medication use in older adults. J
Am Geriatr Soc 60:616–631, 2012 22376048
Inouye SK, Bogardus ST Jr, Charpentier PA, et al: A multicomponent
intervention to prevent delirium in hospitalized older patients. N Engl J
Med 340(9):669–676, 1999 10053175
Inouye SK, Baker DI, Fugal P, et al: Dissemination of the hospital elder life
program: implementation, adaptation, and successes. J Am Geriatr Soc
54(10):1492–1499, 2006 17038065
Inouye SK, Westendorp RG, Saczynski JS, et al: Delirium in elderly people.
Lancet 383(9920):911–922, 2014 23992774
Wong CL, Holroyd-Leduc J, Simel DL, et al: Does this patient have
delirium? Value of bedside instruments. JAMA 304(7):779–786, 2010
20716741
 CHAPTER 8

Dementia and Mild Neurocognitive Disorders

Eitan Z. Kimchi, M.D.
Constantine G. Lyketsos, M.D., M.H.S.

Dementia is a clinical syndrome that can be caused by a range of diseases or

injuries to the brain. Although it can affect young people, it is most commonly
seen in older individuals because dementia prevalence increases with age.
Alzheimer’s Disease International estimates that approximately 35.6 million
individuals were living with dementia worldwide in 2010 (Prince et al. 2013);
considering its high prevalence and worldwide distribution, dementia should
now be considered a pandemic. Given the dramatic growth of the older
population (for instance by 2050, the number of people ages 60 years and older
worldwide will have increased by 1.25 billion and account for 22% of the
world’s population), the number of people living with dementia worldwide is
expected to approximately double every 20 years to 65.7 million in 2030 and
115.4 million in 2050 (Prince et al. 2013) (Figure 8–1). The Alzheimer’s
Association (Theis et al. 2013) estimates that 5.2 million Americans are living
with Alzheimer’s disease (AD), the single most common cause of dementia.
About 11% of people ages 65 years and older and about 32% of the oldest old
(those age 85 and older) has AD. AD is the sixth leading cause of death in the
United States (Theis et al. 2013). Given the chronicity of dementia, with
estimates of its duration ranging from 3–4 years in community settings (Graham
et al. 1997) to 10–12 years in clinical settings (Rabins et al. 2006), it poses a
unique public health problem with serious effects on its victims, their families,
and society at large. For example, the Alzheimer’s Association (Theis et al.
2013) estimated that in the United States, annual direct and indirect expenses of
caring for people with AD and other dementias will soar from an estimated $203
billion in 2013 to a projected $1.2 trillion annually by 2050.
 In this chapter, we discuss definitions, clinical presentation, evaluation, and
differential diagnosis of dementia and related cognitive disorders; describe
specific dementia syndromes according to their etiology; and discuss treatment
approaches, including treatments that may be on the horizon. For an in-depth
discussion of the clinical management of dementia, we recommend Practical
Dementia Care by Rabins et al. (2006).

FIGURE 8–1. Projected prevalence of dementia worldwide.

Source. Data from Prince M, Bryce R, Albanese E, et al.: “The Global Prevalence of Dementia: A
Systematic Review and Metaanalysis.” Alzheimer’s and Dementia 9(1):63–75, 2013.

Definitions
Table 8–1 provides definitions espoused by the American Association for
Geriatric Psychiatry (Lyketsos et al. 2006). Clinical syndromes such as dementia
and cognitive impairment not dementia (CIND) are differentiated from clinical
subsyndromes such as mild cognitive impairment (MCI). The table also clarifies
that AD refers to a process of characteristic pathological changes in the brain
that presumably causes (or influences) the observed dementia syndrome.
Although these definitions are important to the clinical world, one should
recognize that uncertainty remains about linking cognitive decline to brain
pathology. Many studies demonstrate relationships between specific anatomical
distributions of neuropathological markers and specific domains of cognitive
function (e.g., the presence of medial temporal neurofibrillary tangles affects
primarily episodic memory) (Dowling et al. 2011). Other studies show that even
older individuals without cognitive impairment can accumulate significant
neuropathological changes of AD, cerebral infarctions, and Lewy bodies
(Bennett et al. 2012; Negash et al. 2011). In fact, in a study undertaken to
examine the relationship of AD pathology, cerebral infarcts, and Lewy body
pathology to cognition in individuals without cognitive impairment, nearly all
individuals had AD pathology (more than 75% exhibiting amyloid) and a
significant percentage had macroscopic infarctions (22%), microscopic
infarctions (24%), and Lewy body pathology (13%) (Bennett et al. 2012).
Furthermore, up to one-third of individuals without dementia can have AD
lesions that meet criteria for intermediate or even high likelihood of AD (Negash
et al. 2011). In community settings, up to 88% of individuals with dementia or
cognitive impairment who come to autopsy have mixed rather than unitary brain
pathologies, including a combination of AD lesions (neocortical neurofibrillary
tangles and neuritic plaques), microvascular infarcts (microinfarcts and lacunar
infarcts), neocortical Lewy bodies, hippocampal sclerosis, and generalized brain
atrophy (White 2009). Although microvascular infarcts predominate as the sole
or dominant lesion in 33.8% of patients with dementia or cognitive impairment,
AD lesions predominate in 18.6% of these individuals and codominant lesions
(most often AD and microvascular) predominate in 14.2% (White 2009).

TABLE 8–1. Definitions related to dementia

Alzheimer’s A dementia syndrome that has gradual onset and slow
dementia progression and is best explained as caused by Alzheimer’s
disease.
Alzheimer’s A brain disease characterized by plaques, tangles, and neuronal
disease loss.
Cognitive A clinical syndrome consisting of apparent or measurable
impairment decline in memory or other cognitive abilities, with little
not dementia impact on day-to-day functioning. Does not meet criteria for
(CIND) dementia.
Dementia A clinical syndrome consisting of global cognitive decline and
memory deficits, plus at least one other area of cognition
 affected. Significant effect on day-to-day functioning.
Syndrome is present in the absence of delirium.
Mild cognitive A clinical subsyndrome of CIND, most likely the prodrome to
impairment Alzheimer’s dementia. Can be amnestic (having memory
deficits) or nonamnestic.
Source. Adapted from Lyketsos CG, Colenda CC, Beck C, et al.: “Position Statement of the American
Association for Geriatric Psychiatry Regarding Principles of Care for Patients With Dementia Resulting
From Alzheimer Disease.” American Journal of Geriatric Psychiatry 14:561–572, 2006. Used with
permission.

Clinical Presentation, Evaluation, and Differential

Diagnosis

Clinical Presentation of the Dementia Syndrome

Dementia, being a syndrome, is defined entirely on clinical grounds. Table 8–2
lists the four critical elements of the dementia syndrome. First, dementia affects
cognition, which is defined as the mental processes used to obtain knowledge or
to become aware of and interact with the environment. These processes include
perception, imagination, judgment, memory, and language, as well as the
processes people use to think, organize, and learn. Second, cognition is affected
globally, meaning that for the dementia syndrome to be present, several areas of
cognition (e.g., complex attention, learning, procedural or explicit memory,
language, social awareness) must be affected. Third, to differentiate dementia
from mental retardation, the cognitive symptoms must represent a cognitive
decline for the individual. The decline must be substantial enough to be of
concern to an individual, a knowledgeable informant, or the clinician; be
quantitatively demonstrable by standardized neuropsychological testing or
clinical assessment; and affect the person’s daily functioning, operationalized as
basic or instrumental activities of daily living (ADLs). Fourth, because delirium
can cause the full range of cognitive symptoms associated with dementia, it is
critical that the cognitive syndrome be present in the absence of delirium.
DSM-5 (American Psychiatric Association 2013) has largely moved away
from the term dementia in favor of major neurocognitive disorder. However, it
acknowledges that the two terms are substantially congruent. The diagnostic
criteria for major neurocognitive disorder, which parallel the key elements of the
dementia syndrome, are listed in Table 8–3. Clinicians have recently started to
deemphasize the concept of the four A’s of cognitive impairment (amnesia,
aphasia, apraxia, and agnosia) in favor of the following cognitive domains:
complex attention, executive function, learning and memory, language,
perceptual-motor, and social cognition. Patients must demonstrate significant
decline in cognitive function in one or more of these cognitive domains for a
diagnosis of major or mild neurocognitive disorder. The exception is major
neurocognitive disorder due to AD, in which a decline in at least two domains is
required. DSM-5 primarily subtypes major neurocognitive disorders based on
the known or presumed etiology or pathological entity (e.g., AD, frontotemporal
lobar degeneration, Lewy body disease) underlying the cognitive decline. The
degree of functional impairment determines the severity of the dementia (mild,
moderate, or severe).

TABLE 8–2. The four key elements of the dementia syndrome

1. Dementia affects cognition.
2. Cognition is affected globally.
3. Decline from prior baseline significantly affects functioning.
4. Delirium is absent.

Although the dementia syndrome is defined around cognitive disturbances,

patients with dementia have a wider range of impairments that are of relevance
to themselves, their daily life, and their caregivers. These include functional,
neuropsychiatric (behavioral), and neurological impairments.

Functional Impairments
Patients with dementia have problems in their social and interpersonal
functioning and in their ability to live independently. Patients with milder
dementia have difficulties with instrumental activities of daily living (IADLs),
such as preparing a meal, balancing a checkbook, shopping, and driving.
Patients with more severe dementia develop impairments in their basic ADLs,
such as eating, toileting, dressing, and transferring. Changes in functional
abilities are associated with cognitive decline (Royall et al. 2007). Furthermore,
they have prognostic significance because declining functional abilities impact
caregiver burden and are associated with institutionalization (Massoud 2007).

Neuropsychiatric Impairments
Dementia has also been associated with neuropsychiatric symptoms (NPSs).
These are generally grouped into four types: 1) affective and motivational
symptoms, such as depression (affecting up to 50% of individuals with
dementia), apathy, anxiety, and irritability; 2) psychotic symptoms, such as
delusions or perceptual disturbances; 3) disturbances of basic drives, including
feeding, sleep, and sexuality; and 4) unexpected, socially inappropriate, or
disinhibited behaviors. The latter behaviors, such as spontaneous violence,
uncharacteristic vocalizations, intrusiveness, and wandering, typically arise in
more severe dementia; they represent behavioral manifestations of loss of
executive control, sometimes referred to as executive dysfunction syndrome
(Lyketsos et al. 2004). Research has found that over the course of a progressive
dementia, essentially all patients develop one or more of the NPSs (Okura et al.
2010; Steinberg et al. 2008). These symptoms are associated with a decline in
function and cognition among patients that may ultimately lead to increased
mortality (Levy et al. 2012). Furthermore, the severity of NPSs is a strong
predictor of caregiver burden (Bergvall et al. 2011), with increased rates of
depression, anxiety, stress, loss of sleep, medical illness, and mortality among
caregivers (Levy et al. 2012). Caregiver burden, in turn, results in greater usage
of institutionalization for patients with dementia (Levy et al. 2012).

TABLE 8–3. DSM-5 diagnostic criteria for major neurocognitive disorder

A. Evidence of significant cognitive decline from a previous level of
performance in one or more cognitive domains (complex attention, executive
function, learning and memory, language, perceptual-motor, or social
cognition) based on:
1. Concern of the individual, a knowledgeable informant, or the clinician that
there has been a significant decline in cognitive function; and
2. A substantial impairment in cognitive performance, preferably documented
by standardized neuropsychological testing or, in its absence, another
quantified clinical assessment.
B. The cognitive deficits interfere with independence in everyday activities (i.e.,
at a minimum, requiring assistance with complex instrumental activities of
daily living such as paying bills or managing medications).
C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not better explained by another mental disorder
(e.g., major depressive disorder, schizophrenia).
Specify whether due to:
 Alzheimer’s disease
Frontotemporal lobar degeneration
Lewy body disease
Vascular disease
Traumatic brain injury
Substance/medication use
HIV infection
Prion disease
Parkinson’s disease
Huntington’s disease
Another medical condition
Multiple etiologies
Unspecified
Specify:
Without behavioral disturbance
With behavioral disturbance
Specify current severity:
Mild
Moderate
Severe
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full
criteria set, including specifier descriptions and coding and reporting procedures.

Source. DSM-5 criteria for major neurocognitive disorder reprinted from Diagnostic and Statistical Manual
of Mental Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, pp. 602–605.
Used with permission. Copyright © 2013 American Psychiatric Association.

Neurological Impairments
Patients with dementia develop a range of neurological impairments. Depending
on the cause of dementia and specifically on the parts of the brain affected over
time, a range of neurological symptoms may occur. Most common are gait
disorders, especially unstable, ataxic, or labored gait. Other symptoms include
incontinence, focal findings, seizures, and, less commonly, cranial nerve
findings.

Clinical Presentation of Milder Cognitive Syndromes

Epidemiological studies have found that large numbers of older people have
mild decline in one or more cognitive domains, such as memory, attention, and
thinking, that do not compromise everyday activities and functioning—that is,
their independence is preserved—and thus do not satisfy criteria for dementia.
Nevertheless, the cognitive impairment is greater than expected for the person’s
age and education such that tasks require more time or effort to complete than
previously. Impairments may be demonstrable on cognitive assessments and are
often troubling to the individual or to family members. The population-based
Mayo Clinic Study of Aging reported the prevalence of mild impairments to be
16% among elderly subjects ages 70–89 years and free of dementia (Petersen et
al. 2009). Several terms have evolved to refer to these impairments: age-
associated memory impairment, age-associated cognitive decline, CIND, and
MCI. Impairments can be further divided into amnestic or nonamnestic
subtypes, depending on whether significant impairments in memory are present.
The core clinical features of MCI, as identified by the National Institute on
Aging–Alzheimer’s Association (NIA-AA), are listed in Table 8–4 (Albert et al.
2011). Paralleling the change from favoring the term major neurocognitive
disorder over dementia, DSM-5 has largely moved away from the term mild
cognitive impairment in favor of mild neurocognitive disorder, while
acknowledging the congruency of the two terms. The DSM-5 diagnostic criteria
for mild neurocognitive disorder are listed in Table 8–5. NPSs are more
common in patients with MCI than in individuals with normal cognition. These
symptoms include depression (most common), irritability, anxiety, agitation,
apathy, and delusions. In one population-based study in Cache County, Utah, the
presence of at least one NPS (even of mild severity) was a risk factor for
conversion from CIND to all-cause dementia (Peters et al. 2013). Few individual
NPSs had predictive value of conversion; however, nighttime behaviors were a
risk factor for all-cause dementia and for AD, and hallucinations were a risk
factor for vascular dementia. Several prior studies have also linked specific
NPSs, such as major depression and anxiety, to conversion of CIND/MCI to
dementia. For instance, in one study, increasing levels of anxiety doubled the
risk of conversion (Palmer et al. 2007).

TABLE 8–4. National Institute on Aging—Alzheimer’s Association’s

proposed clinical and cognitive criteria for mild cognitive
impairment
Cognitive concern reflecting a historical or observed decline in cognition over
time, as reported by a patient, informant, or clinician
Objective evidence of impairment in one or more cognitive domains (typically
including memory)
Preservation of independence in functional abilities
No dementia
Source. Adapted from Albert et al. 2011.

TABLE 8–5. DSM-5 diagnostic criteria for mild neurocognitive disorder

A. Evidence of modest cognitive decline from a previous level of performance
in one or more cognitive domains (complex attention, executive function,
learning and memory, language, perceptual-motor, or social cognition) based
on:
1. Concern of the individual, a knowledgeable informant, or the clinician that
there has been a mild decline in cognitive function; and
2. A modest impairment in cognitive performance, preferably documented by
standardized neuropsychological testing or, in its absence, another
quantified clinical assessment.
B. The cognitive deficits do not interfere with capacity for independence in
everyday activities (i.e., complex instrumental activities of daily living such
as paying bills or managing medications are preserved, but greater effort,
compensatory strategies, or accommodation may be required).
C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not better explained by another mental disorder
(e.g., major depressive disorder, schizophrenia).
Specify whether due to:
Alzheimer’s disease
Frontotemporal lobar degeneration
Lewy body disease
Vascular disease
Traumatic brain injury
Substance/medication use
HIV infection
Prion disease
Parkinson’s disease
Huntington’s disease
Another medical condition
Multiple etiologies
 Unspecified
Specify:
Without behavioral disturbance
With behavioral disturbance
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full
criteria set, including specifier descriptions and coding and reporting procedures.

Source. DSM-5 criteria for mild neurocognitive disorder reprinted from Diagnostic and Statistical Manual
of Mental Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, pp. 605–606.
Used with permission. Copyright © 2013 American Psychiatric Association.

Long-term follow-up studies suggest that although one-third of individuals

with MCI improve to the point that their cognitive impairments are no longer
detectable in the next few years, the majority go on to develop dementia
(Rosenberg et al. 2006). Approximately 46% of individuals with MCI developed
dementia within 3 years, compared with only 3% of individuals of the same age
who did not have MCI at the beginning of the study (Tschanz et al. 2006). These
findings are consistent with the idea that most patients who develop progressive
dementia do so in stages and typically go through a prodromal period of milder
cognitive impairment. Pathological studies have confirmed that after long-term
follow-up, large numbers of patients who meet criteria for MCI have AD
pathology. Risk factors for conversion of MCI to dementia include greater
cognitive and functional impairment, advancing age, male gender, marital status
(never married), years of education (inverse relationship), being a carrier of the
allele producing the ε4 type of apolipoprotein E (APOE*E4), cerebrospinal fluid
(CSF) markers or positron emission tomography (PET) scan patterns compatible
with AD, positive amyloid imaging, and the presence of anxiety and other NPSs
(Palmer et al. 2007; Peters et al. 2013; Petersen et al. 2009; Tschanz et al. 2006).
The prodromal period most often, but not exclusively, starts with cognitive
symptoms characteristic of the specific cause of dementia. For example,
amnestic MCI, the most common subtype of MCI (Petersen et al. 2009), appears
to be a precursor to AD. In fact, the NIA-AA (Albert et al. 2011) has proposed
terminology for classifying individuals with MCI due to AD with varying
degrees of certainty, based on the presence or absence of AD biomarkers. As
with major neurocognitive disorders, DSM-5 primarily subtypes mild
neurocognitive disorders based on the known or presumed etiology underlying
the cognitive decline. The term vascular cognitive impairment (Bowler and
Hachinski 1995; Hachinski 1994, 2007) was coined to refer to nondementia
disturbances associated with cerebrovascular disease, likely the prodrome of
vascular dementia. Whereas MCI, the prodrome of AD, appears to have
primarily cortical features, vascular cognitive impairment, the prodrome of
vascular dementia, typically affects executive functions (Hayden et al. 2006).

Conducting an Evaluation
Although a detailed discussion of how to evaluate a patient with suspected
dementia is beyond the scope of this chapter, we highlight critical aspects of the
evaluation, with a focus on taking a history, conducting a cognitive assessment,
and using diagnostic tests. A thorough discussion of the evaluation of the patient
with suspected dementia, including reasons for doing an evaluation, the setting
for the evaluation, and ways to communicate the diagnosis to the patient and
caregiver, is provided in Practical Dementia Care (Rabins et al. 2006).

History Taking
Because dementia is diagnosed clinically, a thorough medical history is
essential. A patient with suspected dementia may have difficulty providing
history due to language problems, memory disturbance, or anosognosia (lack of
insight). Therefore, it is critical to involve a reliable informant during history
taking. Informants need to be people who know the patient well, such as family
members. Because informants themselves can be influenced by their own mental
states, such as depression or denial of the situation, it is often useful to speak
with more than one informant to confirm or challenge discrepancies between the
history and the evaluation of the patient.
It is critical to date and elucidate the type of onset of cognitive symptoms
(e.g., insidious onset, abrupt onset following traumatic brain injury [TBI]), as
well as establish the progression of symptoms over time (e.g., gradual, stepwise,
or nonprogressive decline). Comparing the severity of the patient’s current
impairment with its duration often influences the differential diagnosis. For
instance, a slowly progressive dementia over years with insidious onset may
point to Alzheimer’s dementia, whereas a dementia that progresses rapidly over
months may point to dementia due to prion disease. Clinicians need to resolve
discrepancies in reports of severity and duration because they portend different
prognoses and recommendations. It is often more feasible to determine when the
patient was last well rather than when symptoms first started. Many times,
informants minimize early symptoms by attributing them to “normal aging.” It is
also important to remember that the history should systematically evaluate for
the presence or absence of the broader dementia syndrome presentation, as
discussed in the earlier section “Clinical Presentation of the Dementia
Syndrome.” Therefore, the history should assess for cortical and subcortical
cognitive symptoms; functional losses in social, interpersonal, and daily
functioning; the full range of NPSs; and neurological deficits.

Cognitive Assessment
Conducting a cognitive assessment is the central aspect of the evaluation. Many
specialists tend to use the Mini-Mental State Examination (MMSE; Folstein et
al. 1975) as their primary tool because it is brief, easy to use, and well known.
The MMSE, however, is inefficient in evaluating patients with milder cognitive
symptoms or mild dementia, especially those with subcortical features. This is
because the MMSE has ceiling effects, especially for premorbidly well-educated
and intelligent individuals, and has limitations in evaluating executive control
function. Furthermore, the MMSE is unable to discriminate subtle degrees of
impairment in severe dementia. We recommend that specialists in geriatric
psychiatry and other clinicians who work with patients broaden their use of
bedside standardized assessments. The Modified Mini-Mental State (3MS; Teng
and Chui 1987) and the Montreal Cognitive Assessment (MoCA; Nasreddine et
al. 2005) are two bedside cognitive tests that provide a more comprehensive
assessment of cognition. The 3MS and MoCA have many advantages: several
translations exist, and they have been validated in various languages; they assess
abstract thinking, delayed recall, and verbal fluency better than the MMSE; and
they have well-known population norms. In addition, for closer assessments of
executive functioning, geriatric psychiatrists should consider incorporating the
following three measures in every dementia evaluation: the Clock Drawing test
(van der Burg et al. 2004), the Frontal Assessment Battery (Dubois et al. 2000),
and the Mental Alternation Test (Jones et al. 1993).
Neuropsychological testing is often useful for differentiating dementia from
milder cognitive syndromes or normal aging or for clarifying the etiology of the
cognitive disorder. However, neuropsychological testing is not needed in every
case, assuming that the clinician conducts a standardized assessment using tools
similar to those discussed above. If neuropsychological testing is needed, the
clinician should have in mind specific questions that he or she wishes to address,
such as how to clarify the differential diagnosis or how to set the stage for
monitoring prognosis or response to treatment.

Differential Diagnosis and Diagnostic Testing

A key aspect of the dementia evaluation is forming a complete differential
diagnosis of the syndrome. Figure 8–2 provides a useful flowchart for this
purpose. The first decision is whether any of the observed cognitive changes are
disproportionate to normal aging. This can be determined by reviewing the
patient’s history or by assessing the patient’s performance against well-known
norms for age and education. If the cognitive changes are beyond age
appropriate, the next question is whether the patient meets criteria for major
neurocognitive disorder such as those listed in DSM-5. If the patient does not
meet these criteria, then either CIND (which might be further subtyped as MCI
or vascular cognitive impairment) or delirium is present. If dementia is present,
the geriatric psychiatrist will determine whether it is cortical or subcortical;
consider whether it is progressive or nonprogressive; rate its severity; and assess
the degree of functional impairments, the presence or absence of NPSs and their
specific phenomenology, and the presence or absence of motor and other
neurological symptoms. Finally, the clinician establishes the presumptive cause
of the dementia.
The severity of the dementia, typically labeled mild, moderate, or severe, is
guided by the score on the MMSE (or equivalent such as the MoCA) or degree
of functional impairment. An MMSE score of 20–24 or difficulties with IADLs
suggest mild dementia; an MMSE score of 13–20 or difficulties with basic
ADLs suggest moderate dementia; and an MMSE score of 12 or less or
complete functional dependence indicates severe dementia. NPSs can be
assessed by history, mental status examination, and/or standardized tools such as
the Neuropsychiatric Inventory—Clinician rating scale (NPI-C; de Medeiros et
al. 2010). Occupational therapists are skilled at assessing functional impairment
and often use scales such as the Assessment of Motor and Processing Skills
(AMPS; Fisher 2003). A complete neurological evaluation is central to assessing
neurological conditions that may cause or be the sequelae of a cognitive
disorder.
Further workup using laboratory studies and brain imaging is needed in most
cases of dementia. A basic dementia screen typically involves laboratory studies
and brain imaging. The American Academy of Neurology (Knopman et al.
2001) and the National Institute for Health and Care Excellence (2011)
recommend obtaining a metabolic panel, liver function test, complete blood
count, thyroid function studies, vitamin B12 levels, and folate levels. In at-risk
populations or if the clinical picture indicates, the clinician may consider
additional tests, such as heavy metal screen, HIV, syphilis serology, toxicology,
electrocardiogram, and chest radiograph, to determine possible underlying
pathology.
Urinalysis is useful when the clinician suspects delirium as part of the
differential diagnosis. CSF analysis is not routinely part of a dementia workup
unless the clinician suspects Creutzfeldt-Jakob disease (CJD) or other forms of
rapidly progressive dementias. Likewise, electroencephalography is not part of a
routine dementia workup unless frontotemporal lobar degeneration (FTLD),
CJD, or delirium is suspected. Brain biopsies are indicated only in cases in
which dementia is thought to be secondary to a potentially reversible condition
that cannot be diagnosed in any other way (National Institute for Health and
Care Excellence 2012).

FIGURE 8–2. Flowchart in the diagnosis of dementia.

Note. CIND=cognitive impairment not dementia; MCI=mild cognitive impairment; NPS = neuropsychiatric
symptoms; VCI=vascular cognitive impairment.

The type of brain imaging to be used remains controversial. Most clinicians

suggest that computed tomography (CT) of the head is adequate to exclude other
cerebral pathologies; others feel it is important to perform magnetic resonance
imaging (MRI), especially when cortical or subcortical vascular disease may be
involved. In the near future, quantification of specific MRI components, such as
hippocampal or medial parietal cortical atrophy, will provide information that is
important to the differential diagnosis, prognosis, and treatment options.
Functional brain imaging using functional MRI (fMRI), PET, or single-photon
emission computed tomography (SPECT) has come into broader use and is
reimbursed by Medicare under specific circumstances. These types of imaging
reveal distinct regions of low metabolism and hypoperfusion and are most useful
in the differential diagnosis of dementia caused by AD, cerebrovascular disease,
Lewy body disease, or FTLD, if the rest of the clinical picture is inconclusive.
Various amyloid PET tracers, such as 18F-AV-45 (also known as florbetapir) and
Pittsburgh compound B (PiB), which measure amyloid lesion burden in the
brain by binding to amyloid-β (Aβ), can aid in the diagnosis and prognosis of
AD, and differentiate AD from other causes of dementia. In 2012, the U.S. Food
and Drug Administration (FDA) approved florbetapir for this purpose. The long
half-life of 18F allows florbetapir to accumulate considerably more in the brains
of patients with AD (Wong et al. 2010). In 2013, the FDA also approved 18F-
flutemetamol, an 18F-labeled derivative of the parent molecule PiB.
Other biomarkers, such as CSF tau and Aβ levels, continue to be used in
research and will likely have clinical applications in the future. The same is true
for genetic testing. Although APOE genotyping is not used in clinical settings
universally, it might have greater utility in the near future for tailoring treatment
options. Some studies suggest that certain medications may be more effective in
specific APOE subgroups (Petersen et al. 2005). Testing for specific genetic
mutations associated with AD also has its place in the rare instances in which
there is a clear familial autosomal dominant case of Alzheimer’s dementia and
knowledge of the specific genetic mutation involved might be useful to the
patient or the patient’s progeny following appropriate counseling.
Over 100 different disease processes have been associated with dementia
(Rabins et al. 2006). Most cases of dementia can be adequately assessed through
the patient’s history and the diagnostic testing approach discussed previously in
this section. In the past, dementias were often categorized as either treatable or
nontreatable. This differentiation is no longer useful for two reasons. First, the
reversibility of a “treatable dementia” depends on the severity of brain damage
that has occurred. For example, dementia resulting from moderate to severe
vitamin B12 deficiency, hypothyroidism, or normal-pressure hydrocephalus does
not reverse when treated. Second, the implication that AD, vascular dementia,
and other dementias are not treatable is incorrect. Although these cases tend to
be progressive despite available treatments, applying treatments makes a big
difference to patients, caregivers, and families, because treatments may attenuate
progression, reduce symptoms, and improve quality of life.
Specific Dementias
The more common causes of dementia are listed in Table 8–6. AD is generally
considered to be the most prevalent cause of dementia. Other common causes
include cerebrovascular disease, Lewy body disease, and FTLD. Less common
causes include normal-pressure hydrocephalus, prion diseases (e.g., CJD), TBI
(common in the young, however), AIDS, Huntington disease, primary
progressive aphasia, corticobasal degeneration, and dementia of depression
(previously referred to as pseudodementia). In this section, we highlight the
most common, as well as some of the less common, causes of dementia. An
extended discussion of all of the above causes of dementia is beyond the scope
of this chapter.

Dementia Due to Alzheimer’s Disease

Alzheimer’s dementia is the most common form of dementia. Depending on the
population series, 50%–70% of people with dementia are diagnosed clinically as
having dementia due to AD (Ranginwala et al. 2008). Experts can typically
make the clinical diagnosis of AD reliably. However, whereas the vast majority
of patients meet pathological criteria for AD, a significant number have other
pathological findings, such as cerebrovascular infarcts, Lewy bodies, and
lacunes.
The prevalence of Alzheimer’s dementia is closely tied to age, which is the
primary risk factor. Other reported risk factors include head injury or TBI,
reduced cognitive reserve capacity of the brain, limited educational or
occupational attainment, cerebrovascular disease, hyperlipidemia, hypertension,
atherosclerosis, coronary heart disease, atrial fibrillation, smoking, obesity, and
diabetes. A possible risk factor is homocysteinemia. Some but not all
epidemiological studies have suggested that dietary intake of folate and vitamin
B12, antioxidants (especially vitamins C and D), moderate alcohol (especially
red wine), nonsteroidal anti-inflammatory agents, and estrogen during the
perimenopausal period are associated with reduced risk of AD.
A major risk factor for AD is genetics, with 70%–80% of the disease being
heritable, as supported by twin studies (Blennow et al. 2006). AD is a
heterogeneous genetic disorder with familial and sporadic forms. The familial
forms follow classical autosomal dominant inheritance and typically have their
onset before age 65 years. The familial forms are linked with several mutations
in genes associated with amyloid precursor protein (APP) on chromosome 21,
the presenilin 1 gene PSEN1 on chromosome 14, or the presenilin 2 gene PSEN2
on chromosome 1 (Figure 8–3). Mutations in PSEN1 account for 18%–55% of
early-onset familial AD cases, whereas mutations in PSEN2 and APP are less
common (Nowrangi et al. 2011). Taken together, these genes account for one-
half to two-thirds of the familial cases, suggesting that many autosomal
dominant genes are unknown. Researchers are currently studying the
mechanisms by which these genetic loci interact.
Many genes, most unidentified, likely increase risk but do not determine the
absolute occurrence of sporadic, late-onset AD (LOAD). The most well-known
gene, APOE, is a genetic risk factor for LOAD. APOE*E4 is associated with
more than 50% of cases of AD (Nowrangi et al. 2011). Individuals who are
heterozygous carriers of APOE*E4 have three times the risk of developing AD,
whereas individuals who are homozygous APOE*E4 carriers have 15 times the
risk compared with non-APOE*E4 carriers. APOE*E4 probably operates mainly
by modifying the age at onset through uncertain molecular mechanisms
(Breitner et al. 1999). Another major gene associated with LOAD is the sortilin-
related receptor gene SORL1. This gene, which is probably involved in amyloid
clearance, has also been identified as a risk factor (Rogaeva et al. 2007). The
SORL1 protein may alter intracellular trafficking of APP, causing aggregated
Aβ to accumulate, and ultimately causing cell death (Nowrangi et al. 2011).

TABLE 8–6. The most common causes of dementia

Causes Hallmark features
Alzheimer’s A brain disease characterized by plaques, tangles, and
disease neuronal loss. Insidious onset. Slow progressive cognitive
and functional decline. Neuropsychiatric symptoms are
nearly universal.
Cerebrovascular Known as vascular dementia or multi-infarct dementia.
disease Controversial nosological entity due to lack of agreed-upon
neuropathological definition. Heterogeneous group of
dementias. Stepwise progression with variable rates of
decline. Symptoms overlap with those of Alzheimer’s
disease. Focal neurological signs. Apathy and depression
are common.
Lewy body Examples include Parkinson’s disease dementia and dementia
disorders with Lewy bodies. α-Synuclein aggregates in neurons.
Progressive cognitive decline, fluctuating cognition, visual
hallucinations, parkinsonian features, rapid eye movement
 sleep disorder, and severe neuroleptic sensitivity are
common.
Frontotemporal Previously referred to as Pick’s disease. Clinically and
lobar pathologically heterogeneous. Most common presentations
degeneration are behavioral variant frontotemporal dementia and primary
progressive aphasia. Focal degeneration of frontal and
temporal lobes. Hyperphosphorylated tau protein or
transactive response DNA binding protein TDP-43
inclusions. Knife-edge atrophy on magnetic resonance
imaging. Progressive change in personality, behavior, and
language. Motor impairment syndromes co-occur. Typically
a more rapid rate of decline than with Alzheimer’s disease.

Since 2009, genome-wide association studies (GWASs) have revolutionized

the ability to identify biological pathways potentially involved in AD (Medway
and Morgan 2014). GWAS studies compare the entire genome of patients with a
disease to those without, to determine whether specific alleles occur in greater
frequency in patients with the disease and are thus more likely to be associated
with the disease. Determining a causal allele strengthens the ability to identify
candidate genes that increase the risk of specific disease phenotypes and to
attribute risk to each gene. GWASs have led to the discovery of new LOAD
alleles, each common (minor allele frequency of greater than 5%) and
transmitting modest genetic effects (Medway and Morgan 2014). In the largest
GWAS meta-analysis of LOAD to date, the International Genomics of
Alzheimer’s Project recently reported 11 new Alzheimer’s susceptibility loci
(CASS4, CELF1, FERMT2, HLA-DRB5/HLA-DRB1, INPP5D, MEF2C, NME8,
PTK2B, SLC24A4/RIN3, SORL1, and ZCWPW1) (Lambert et al. 2013). The
study also confirmed eight (CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A,
PICALM, and ABCA7) of the nine previously reported genome-wide
associations in addition to APOE. Drawing on over 74,000 samples, the meta-
analysis was sufficiently powered to reveal new risk alleles previously
concealed due to low frequency or weak genetic effects. Although some genes
cannot be attributed to pathways that are biologically relevant to LOAD, many
susceptibility loci can be linked to pathways involving cholesterol metabolism,
synaptic vesicle recycling/endocytosis, and immune system function (see Figure
8–3). These pathways may modify amyloid aggregation and/or clearance.
Alternatively, some of these genes may act through non-amyloid mechanisms.
Although GWASs are useful at detecting common variants with weak to modest
effects, these studies have limitations in detecting rare variants that may confer
large genetic effects. Alternative technology (e.g., next-generation sequencing)
may be used in tandem with GWASs to detect these uncommon variants in small
cohorts (Medway and Morgan 2014).

FIGURE 8–3. Pathways implicated in Alzheimer’s disease (AD).

The familial form of AD is linked with several mutations in genes associated with PSEN1, PSEN2, and
APP, all involved in the amyloid processing pathway (“the amyloid cascade”). Various pathways
(cholesterol metabolism, endocytosis, and immune system) are linked with the more common nonfamilial,
late-onset AD (LOAD). Each of these pathways is represented by candidate genes as shown in the figure.
Note. FAD=familial Alzheimer’s disease; LOAD=late-onset Alzheimer’s disease.
Source. Reprinted from Medway C, Morgan K: “Review: The Genetics of Alzheimer’s Disease: Putting
Flesh on the Bones.” Neuropathology and Applied Neurobiology 40(2):97–105, 2014.

The current hypothesis is that Alzheimer’s dementia is a heterogeneous

condition representing a range of etiologies involving different interactions
between different sets of genetic and environmental risk factors (Blennow et al.
2006). At one end of the spectrum are individuals with familial disease, for
whom genes such as APOE influence the age at onset and who will develop the
disease if they live long enough. At the other end of the spectrum are individuals
with a weak predisposition, perhaps carriers of few or no risk genes but in whom
the occurrence of environmental risk factors is critical to the onset of
Alzheimer’s pathology and the later dementia. As an example of gene-
environment interactions, individuals with TBI may be at increased risk of
progressive dementia if they also carry one or more APOE*E4 alleles (Isoniemi
et al. 2006).
The natural history of Alzheimer’s dementia has been well described from
tertiary clinical centers. Time from diagnosis to death in these settings is on the
order of 10–12 years, with considerable variability around this median estimate.
Population studies from Canada and the United States suggest that a significant
proportion of patients with dementia do not make it to clinical centers and that if
all patients in this group are included, the median time from onset of symptoms
to death in patients with dementia is on the order of 3–5 years (Wolfson et al.
2001). A significant number of patients exhibit slow progression after the onset
of dementia. In the Cache County Memory Study, 25%–30% of individuals with
AD exhibited limited to no progression from milder stages of dementia even 3–5
years after onset (Tschanz et al. 2011). Likewise, only about 25% of individuals
with AD ever progressed to severe dementia, with the majority dying prior to
that point (Rabins et al. 2013).
There is also significant variability of cognitive and functional decline in
Alzheimer’s dementia. For instance, although the annual rate of cognitive
decline on the MMSE as reported in most studies is 3 points, the mean rate of
decline in the Cache County Memory Study was 1.5 points (Tschanz et al.
2013). Furthermore, 30%–56% of individuals in this study exhibited a slow rate
of decline in one or more domains (cognitive, functional, and behavioral),
declining no more than 1 point per year on the measures of each domain
(Tschanz et al. 2011).
In the Cache County Memory Study, many factors appeared to influence the
progression of Alzheimer’s dementia cognitively, functionally, and behaviorally.
Women and individuals in both the youngest and oldest age-at-onset cohorts
exhibited faster declines (Rabins et al. 2013; Tschanz et al. 2013). It is possible
that factors such as a more severe form of AD in younger persons and/or greater
comorbidity in the oldest cohort influence the rate of progression. Neither being
a carrier of APOE*E4 nor years of education affected the rate of progression in
any of the three domains (Rabins et al. 2013). Other studies reported mixed
results for both risk factors (see Tschanz et al. 2013). Individuals with unstable
or poorly controlled general health performed cognitively and behaviorally
worse over the course of dementia (Tschanz et al. 2013). Specifically,
hypertension, atrial fibrillation, angina, and myocardial infarctions were all
associated with faster cognitive and functional decline, particularly among older
individuals. Several medical treatments—statins, antihypertensive medications,
and history of coronary artery bypass graft—are associated with slower rates of
cognitive and functional decline in AD. In general, cholinesterase inhibitors and
memantine, taken by approximately 22% of the cohort, were associated with
higher baseline cognitive scores but did not affect rate of decline (Tschanz et al.
2011). However, among women APOE*E4 carriers, greater duration of
treatment with a cholinesterase inhibitor was associated with slower cognitive
and functional decline (Tschanz et al. 2013).
Caregiver and care environment factors influenced the clinical course of
individuals with AD in the Cache County Memory Study (Tschanz et al. 2013).
Participant engagement in more cognitively stimulating activities was associated
with slower cognitive decline early in the course of AD. Likewise, a closer
caregiver and care recipient relationship was associated with both slower
cognitive and functional decline. AD participants cared for by an adult child
with a neurotic personality trait exhibited faster cognitive decline. Conversely,
AD participants cared for by an adult child with high extraversion scores
exhibited slower rates of decline, and AD participants whose caregivers reported
regular use of problem-solving coping strategies demonstrated a slower rate of
cognitive and functional decline.
Despite the variability in their rate of decline, patients who progress show a
typical pattern, with loss of memory occurring fairly early, followed by the
development of agnosia, apraxia, and aphasia. Patients also follow predictable
progression in functional impairments and, in later stages, universally develop
problems with mobility and continence. In terminal stages, patients with AD
may live a long time, sometimes years, in near-vegetative states if they are in
good general health and receive good care.
NPSs are nearly universal. They tend to be persistent in that around 80% of
individuals with NPSs at baseline will show at least one symptom over an 18-
month interval (Tschanz et al. 2013). Over time, the prevalence of NPSs
increases; the most common symptoms are depression, apathy, agitation, and
restlessness (at least one of these symptoms is manifested in approximately 75%
of individuals), followed by sundowning and verbal outbursts (manifested in
approximately 50% of individuals) (Scarmeas et al. 2007; Steinberg et al. 2008;
Tschanz et al. 2011). Several cohort studies suggest that affective, psychotic, and
sleep symptoms relapse and remit through the course of Alzheimer’s dementia
and are very troubling for patients and caregivers (Rabins et al. 2006; Steinberg
et al. 2008). Apathy, in contrast, appears to be a steadily accumulating symptom
in that many, but not all, patients gradually develop persistent and pervasive
apathy (Steinberg et al. 2008). Overall, the presence of NPSs tends to increase
over time (Scarmeas et al. 2007).
During the past several decades, studies have explored the possibility of
neuropsychiatric subsyndromes in Alzheimer’s dementia (Canevelli et al. 2013).
For example, increasing evidence over the past 10 years suggests that AD with
psychosis may represent a distinct phenotype with a genetic basis (Geda et al.
2013). By examining the internal structure of the Neuropsychiatric Inventory,
researchers have classified NPSs into specific clusters. The practical
implications of identifying possible clusters or subsyndromes include more
adequately comprehending neurobiological correlates and psychosocial
determinants of NPSs, as well as tailoring therapeutic interventions to specific
phenotypes and subsyndromes (Canevelli et al. 2013). Neurobiological data
support the notion of specific clusters of NPSs by recognizing that there are
three major neurobiological models relevant to NPSs in AD: the frontal-
subcortical circuits, corticocortical networks, and the monoaminergic system
(Geda et al. 2013). Specific NPSs have been associated with lesions involving
crucial structures or tracks in a network mediating a particular behavior (Geda et
al. 2013). For instance, disinhibition or apathy can be observed from lesions
involving the frontal-subcortical circuits, even if the lesion is far away from the
frontal cortex (Geda et al. 2013). Reflecting the evidence that NPSs tend to
cluster into distinct groups, the Neuropsychiatric Syndromes of AD Professional
Interest Area (NPS-PIA) of the International Society to Advance Alzheimer’s
Research and Treatment organized NPSs around five syndromic areas:
depression, apathy, sleep, agitation, and psychosis (Geda et al. 2013). The NPS-
PIA has prepared specific reviews and recommendations for each syndrome,
while recognizing that syndromes will overlap with one another (Geda et al.
2013).
Depression affects up to 50% of persons with dementia over the course of the
illness (Schwarz et al. 2012). It is the most common symptom early in the course
of dementia, affecting 29% of individuals (Tschanz et al. 2013). A potentially
devastating and debilitating illness, depression tends to be underrecognized and
highly correlated with increased health care utilization, increased risk of suicide,
decreased quality of life for the affected individual and caregiver, and greater
severity and acceleration of cognitive impairment (Sepehry et al. 2012). Among
individuals with AD, the risk for depression increases with older age, female
gender, and less education (Treiber et al. 2008).
 Apathy affects a large proportion of individuals with dementia. In the Cache
County Study, apathy was among the most frequently reported NPSs, with 20%
of individuals exhibiting apathy at baseline and 51% exhibiting the symptom at
5-year follow-up (Steinberg et al. 2008). It was consistently the most severe
symptom at each evaluated time point. Apathy affects up to 70% of individuals
with mild to moderate AD and up to 90% of individuals with late-stage AD
(Berman et al. 2012). It tends to appear early in dementia, increase with illness
severity, and persist throughout the illness. Risk factors for apathy include
greater severity of cognitive and functional impairment, older age, and stroke
(Treiber et al. 2008). Strokes may damage areas such as the prefrontal cortex or
related neural pathways involved in planning and execution of goal-directed
behaviors (Treiber et al. 2008). Apathy is significantly associated with
subsequent development of depression, consisting of inactivity, loss of
confidence, learned helplessness, and poor response to rehabilitation due to lack
of motivation (Berman et al. 2012). Understandably, apathy is associated with
poorer quality of life for patients and caregivers (Berman et al. 2012).
Up to half of all individuals with AD experience sleep disorders (Camargos
et al. 2014; Roth 2012). Sleep disorders reduce patients’ quality of life, can
magnify their cognitive impairments and mood dysregulation, contribute to loss
of function, are a primary reason for institutionalization, and increase
caregivers’ burden. The most common sleep disorder associated with AD is
irregular sleep-wake rhythm, a circadian rhythm disorder (Roth 2012). Patients
with irregular sleep-wake rhythm lack a well-defined sleep period (e.g., they
might alternate between sleeping for 2–3 hours and remaining awake for 2–3
hours throughout an entire 24-hour cycle). Other common sleep disorders
among individuals with AD include sundowning, nighttime wandering,
difficulty with sleep onset and/or maintenance, and an increased diurnal
distribution of sleep (as opposed to an overall decreased amount of sleep)
(Camargos et al. 2014; Roth 2012). Electroencephalograms (EEGs) of
individuals with AD demonstrate increased stage I sleep, non–rapid eye
movement dedifferentiation in later stages, and reduced rapid eye movement
quantity in late stages. Causes of sleep disorders in AD are multifactorial.
Various brain hormones and systems (e.g., suprachiasmatic nucleus, vasopressin,
pineal gland, and melatonin systems) critical for the regulation of the sleep-wake
cycle are affected by the disease. For instance, in some patients with AD, the
suprachiasmatic nucleus demonstrates tangles and neuronal cell loss with
reactive gliosis (Roth 2012). Also, individuals with AD who are homozygous
APOE*E4 carriers demonstrate greater reductions in melatonin levels compared
with those who have the alleles APOE*E3 and APOE*E4. On the other hand,
individuals with AD often have changes in zeitgebers (environmental cues
critical for reinforcing circadian rhythm patterns), such as disturbed patterns of
light exposure, as a consequence of inactivity and inadequate stimulation at
home or in nursing homes.
Detailed discussions of the causes and common presentations of agitation and
psychosis in dementia appear in Chapter 19, “Agitation and Suspiciousness,”
and Chapter 11, “Schizophrenia Spectrum and Other Psychotic Disorders,”
respectively.
The Predictors Study, a population-based study that recruited individuals
mostly in relatively early stages of AD, demonstrated that symptoms such as
agitation, restlessness, and wandering, were associated with faster cognitive
decline (Scarmeas et al. 2007). Agitation and restlessness were also associated
with faster functional decline, whereas wandering was associated with faster
functional decline and institutionalization. Other studies demonstrated that
apathy, depression, and psychosis predict subsequent rapid cognitive decline. In
the Cache County Memory Study, individuals who demonstrated clinically
significant symptoms in at least one domain on the Neuropsychiatric Inventory
were more likely to progress to severe AD and progressed more rapidly than
individuals with only mild symptoms or no symptoms at all (Rabins et al. 2013).
Several studies have reported that genetic factors (most notably APOE*E4)
confer an increased risk of NPSs in AD, including aggression, depression, and
psychosis. However, the majority of studies have not demonstrated a
relationship between APOE genotype and NPSs (Treiber et al. 2008).
What is unclear is whether there is a causal relationship between NPSs and
disease severity or between treatments targeting symptoms and disease severity,
or whether symptoms and treatments interact together to influence disease
severity. Also, it is unknown whether pharmacological or nonpharmacological
interventions targeting NPSs influence the rate of progression to severe AD.
Whether there is an association between NPSs and mortality remains
controversial (Rabins et al. 2013; Scarmeas et al. 2007).
The brain changes seen in Alzheimer’s dementia are well known. Even in
early stages of the disease, brain imaging studies show volume reduction in the
hippocampus bilaterally, and this reduction appears to progress with the illness.
In early stages of the disease, brain imaging using fluorodeoxyglucose PET
typically shows bitemporoparietal and often frontal hypoperfusion. This
hypoperfusion eventually spreads throughout the brain as the disease progresses.
PET or SPECT of neurotransmitters involving the cholinergic, dopaminergic,
and serotonergic systems shows neurotransmitter loss even in living patients in
early stages of Alzheimer’s dementia (Sabbagh et al. 2006). More recently,
researchers and clinicians have been able to image amyloid deposition in the
brain using florbetapir, PiB, FDDNP, and other PET or SPECT ligands. Using
these ligands, researchers have found that by the time dementia begins, there is
already an abundant deposition of amyloid, which does not necessarily increase
over time and is not necessarily specific to Alzheimer’s dementia (Engler et al.
2006). The deposition of amyloid may be fairly extensive by the time early
symptoms appear, suggesting a time course of many years, perhaps decades, of
brain changes between pathological onset and clinical expression of dementia
(Blennow et al. 2006).
Pathologically, the characteristic lesions of AD include senile or neuritic
plaques containing Aβ and neurofibrillary tangles comprised of
hyperphosphorylated tau proteins, with associated loss of neurons in several
neurotransmitter systems: cholinergic, serotonergic, and dopaminergic. These
changes typically occur early in the disease and affect both the nuclei and the
cortical projections of neurons. Over time, these changes result in synaptic
dysfunction. Until recently, the dominant hypothesis about etiopathogenesis
suggested an amyloid cascade in which the increased production or decreased
clearance of Aβ in the brain causes the disease, as shown in Figure 8–4A
(Pimplikar 2009). Aβ40 and Aβ42 peptides accumulate, resulting in aggregation
and formation of insoluble plaques; this triggers a cascade of deleterious
changes, resulting in neuronal death (Pimplikar 2009). This hypothesis, which
dominated research for over 20 years (Selkoe 1991), is now evolving to that
depicted in Figure 8–4B (Morelli et al. 2012; Mucke and Selkoe 2012;
Pimplikar 2009).
Aβ peptides are derived in the amyloidogenic pathway of APP (Morelli et al.
2012). APP, a transmembrane glycoprotein, is present on most neurons. Its
function is unknown. In the nonamyloidogenic APP pathway, α-secretase
followed by γ-secretase cleaves APP within the Aβ peptide region, preventing
Aβ generation (Morelli et al. 2012). In the amyloidogenic pathway, APP
undergoes site-specific sequential proteolysis by β-secretase followed by γ-
secretase (the core proteins of which are presenilins 1 and 2) (Morelli et al.
2012). APP is rapidly processed (speed in excess of 10
molecules/neuron/second), and the vast majority of its metabolism is deposited
in the extracellular space (Moghekar et al. 2011). Aβ40 and Aβ42 peptides
predominate in the fragments released following proteolysis by β-secretase and
γ-secretase. Aβ is likewise secreted into the extracellular space at extremely high
rates (2–4 molecules/neuron/second) (Moghekar et al. 2011). Aβ42, a longer
form of Aβ, is more prone to aggregate and to form plaques (see Figure 8–5)
(Pimplikar 2009). Aβ42 accumulates close to the synaptic cleft and is thought to
lead over time to synaptic disconnection, the loss of neurotransmitter systems,
and the emergence of symptoms. Plaques contain other proteins, such as APOE.
One hypothesis is that some APOE*E4, in particular, acts as an amyloid catalyst
or “pathological chaperone” (Morelli et al. 2012). Although many mutations in
APP or presenilin 1 result in increased levels of Aβ42, some mutations in
presenilin 1 decrease the Aβ40 levels, thus effectively changing the ratio of Aβ40
to Aβ42 (Pimplikar 2009). There is evidence to suggest that the increase in the
ratio of Aβ42 to Aβ40, rather than the absolute level of Aβ42, is pathogenic and
triggers events ultimately leading to the disease (Figure 8–5) (Pimplikar 2009).
Indeed, some studies suggest that the increased ratio of Aβ42 to Aβ40 is
inversely related to the age at onset of AD (Bentahir et al. 2006).
FIGURE 8–4. Reassessing the amyloid hypothesis.
(A) The classical view of the amyloid hypothesis. Aβ is the primary cause of AD. Increased production or
decreased degradation results in accumulation of Aβ, triggering downstream deleterious events. Over time,
these events result in synaptic dysfunction and cause AD. The working model is that blocking the effects of
Aβ will prevent all downstream events and prevent AD. (B) A modified amyloid hypothesis, more
consistent with the presently available data. Both Aβ and non-Aβ factors (green boxes) cause deleterious
events leading to AD. Aβ no longer occupies the top position and is not considered to be the sole instigator
of downstream events. One corollary of this theory is that blocking the effects of Aβ will not necessarily
prevent AD.
Note. Aβ=amyloid-beta.
Source. Reprinted from Pimplikar SW: “Reassessing the Amyloid Cascade Hypothesis of Alzheimer’s
Disease.” International Journal of Biochemistry and Cell Biology 41(6):1261–1268, 2009. Used with
permission.

FIGURE 8–5. Main tenets of the amyloid hypothesis in the pathogenesis of

Alzheimer’s disease.
The amyloid hypothesis suggests that Aβ is the primary cause of AD. The original proposal was that
increased levels of Aβ resulted in plaque formation (1), causing AD. Subsequent observations suggested
that it is the increased levels of Aβ42 that are pathogenic and cause AD (2). Other research suggests that
the ratio of Aβ42 to Aβ40 is pathogenic (3). Newer research has focused on the idea that Aβ forms soluble
oligomers that are pathogenic and cause AD (4).
Note. Aβ=amyloid-beta; AD=Alzheimer’s disease.
Source. Reprinted from Pimplikar SW: “Reassessing the Amyloid Cascade Hypothesis of Alzheimer’s
Disease.” International Journal of Biochemistry and Cell Biology 41(6):1261–1268, 2009. Used with
permission.

Patients may develop end-stage dementia despite having no evidence of

amyloid plaque (Holmes et al. 2008). Moreover, cognitively normal individuals
may demonstrate substantial amounts of senile plaques (Villemagne et al. 2008).
There are also increasing data to support that insoluble plaques are not
necessarily the cause of the disease (Pimplikar 2009). Newer research has
focused on soluble forms of Aβ, referred to as Aβ oligomers. Aβ oligomers are
believed to be a particularly biologically active form of Aβ, and there is
evidence to indicate that it is the disease-causing pathogenic agent (see Figure
8–5) (Walsh and Selkoe 2007). Other data suggest that presenilin 1 mutations
alone can trigger the toxic events seen in AD and that the increased
concentration of Aβ and senile plaques may only be a secondary effect
(Pimplikar 2009).
 The manifestation of AD symptomatology probably depends more on the
brain location and neurotransmitter systems affected than on the cause of the
pathology present (Lyketsos 2006). Neuritic plaques first begin in the frontal
cortex before spreading over the entire cortical region; on the other hand, tau
and neurofibrillary tangles first appear in the limbic system before spreading to
the cortex (Pimplikar 2009). Although Aβ is associated with brain neuronal
changes, it may also bind to other brain cells, such as microglia, and cause
neuronal injury (Mucke and Selkoe 2012). High levels of Aβ can structurally
and functionally alter microglia, astrocytes, and the endothelial and smooth
muscle cells of cerebral blood vessels (Mucke and Selkoe 2012). Other
downstream factors involved in progression include glutamatergic toxicity, lipid
peroxidation products, and the loss of trophic factor. The precise mechanisms by
which Aβ contributes to neuronal dysfunction and ultimately death are still
unknown (Mucke and Selkoe 2012).
Because Alzheimer’s pathology likely begins many years and perhaps
decades before the onset of symptoms, there is an opportunity for prevention
once future advances make it possible to diagnose the disease through the use of
biomarkers before symptom onset. Also, the distribution of the neuropathology
appears to change with the course of the disease such that it begins in the mesial
temporal lobe and then disseminates widely throughout the brain. The tissue loss
that follows can become extensive, so that patients dying with advanced AD
have atrophic brains and significantly enlarged ventricles. These changes during
the course of the disease may mean that different treatments will have
differential efficacy at different phases of the disease.

Dementia Due to Cerebrovascular Disease (Vascular Dementia)

Vascular dementia continues to be a controversial nosological entity, in part
because of the absence of clear neuropathological agreement about it. Also, it is
difficult to differentiate on clinical grounds alone those patients who have
dementia due to AD from those who have vascular dementia. Further
complicating the differentiation, abundant evidence suggests that
cerebrovascular risk factors and diseases influence both the progression of
dementia due to AD (e.g., Mielke et al. 2007) and the emergence of Alzheimer’s
pathology in the brain (e.g., Beach et al. 2007). Most patients with vascular
dementia who come to autopsy have mixed pathology, often with significant AD
pathology (Jellinger and Attems 2006).
Vascular dementia, therefore, is best understood as a heterogeneous group of
dementias. At one end of the spectrum are patients with pure genetic forms, such
as 1) cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy and 2) mitochondrial encephalopathy with lactic acidosis
and strokelike episodes. At the other end are patients who develop dementia
after multiple strokes in which significant portions of the brain are damaged.
Between those two endpoints are patients with mixtures of pathologies and
clinical presentations that impact one another (e.g., smaller strokes or chronic
subcortical hypoxia might both damage brain tissue and lead to the onset and
progression of Alzheimer’s pathology). Genes and risk factors that predispose
individuals to cerebrovascular disorders are also risk factors for vascular
dementia. These include diseases of the large and small vessels of the brain,
diabetes, hypertension, and atrial fibrillation and other cardiac diseases.
The clinical presentation of vascular dementia is variable. More often than
not, it can resemble that of AD. Typically, it presents in fits and spurts, often
with acute or subacute onset after a cerebrovascular event. A mix of symptoms
is usually present, often including apathy, depression, and motor symptoms.
Among patients with vascular dementia or dementia due to AD who have
similar MMSE scores, those with vascular dementia are usually more
functionally impaired. Gait disorders, parkinsonism, and incontinence are early
features of vascular dementia.
The diagnosis of vascular dementia is based on a typical clinical history and
associated physical examination findings. The diagnosis requires brain imaging
that shows completed infarcts or lacunes in brain areas associated with the
cognitive changes. One should be able to demonstrate a temporal relationship
between the brain vascular disease and the cognitive changes, but this might be
difficult. Radiological findings of white matter change alone, with no evidence
of completed strokes or associated examination findings (e.g., focal motor
symptoms or a gait disorder), are not supportive of a diagnosis of vascular
dementia. White matter changes, as seen on MRI, are common in cognitively
normal older people (Longstreth et al. 2005). The diagnosis becomes more
complex when patients with established Alzheimer’s dementia develop strokes;
many such patients also meet criteria for a diagnosis of vascular dementia.
Results from the Nun Study (Snowdon et al. 1997) and the Religious Order
Study (Schneider et al. 2004) suggested that for a given degree of Alzheimer’s
pathology, dementia is more severe in the presence of comorbid cerebrovascular
disease.
Little is known about the progression of clinically diagnosed vascular
dementia. Therefore, we can only make speculative comments here. Clinical
anecdotes suggest that many patients with vascular dementia can have a
nonprogressive condition for many years as long as they do not have other
strokes. However, other patients decline rather precipitously, and most patients
have variably slower rates of progressive decline.

Lewy Body Disorders

In 2007, a consensus panel (Lippa et al. 2007) proposed the term Lewy body
disorders as an umbrella term for Parkinson’s disease (PD), Parkinson’s disease
dementia (PDD), and dementia with Lewy bodies (DLB). This proposal
appropriately recognizes the existence of a spectrum of dementias associated
with Lewy body disease of the brain whose shared pathology involves
impairments in α-synuclein metabolism. In these three conditions, also termed
synucleinopathies, α-synuclein aggregates to form insoluble fibrils. α-Synuclein,
a synaptic protein, is the primary structural component of Lewy body filaments.
Lewy bodies, in turn, are cytoplasmic, eosinophilic, round or oblong neuronal
inclusions. Lewy bodies (as well as Lewy neurites, related proteinaceous
structures comprised of α-synuclein) develop in discrete regions throughout the
brain stem, diencephalon, basal ganglia, and neocortex (Ballard et al. 2013).
Neuronal degeneration, cognitive impairment, and eventually dementia ensue in
all Lewy body disorders. The sequence of events involved is poorly known.
One of the complicating factors in determining a diagnosis is that many
patients with Lewy body pathologies have coexisting pathologies, in particular
Alzheimer’s and vascular pathologies. For instance, approximately half of PDD
patients meet neuropathological criteria for AD (Sabbagh et al. 2009). Amyloid
plaques are typically seen in DLB (although not as dense as in AD), and
neurofibrillary tangles can be found in some DLB cases. Parkinsonian features
can be seen in AD although typically late in the disease course. Furthermore,
patients with AD are often treated with psychotropic medications that cause
long-lasting extrapyramidal side effects, even after the drugs are discontinued.
The clinical presentations of PDD and DLB can be similar. Patients develop a
progressive subcortical dementia with the following hallmark features: executive
dysfunction, cognitive fluctuations, inattention, visuospatial dysfunction,
parkinsonism, visual hallucinations, and sleep disturbances (McKeith et al.
2005).

Dementia With Lewy Bodies

Dementia with Lewy bodies is the second most common type of progressive
dementia after AD. DLB accounts for approximately 20% of late-onset dementia
cases (Ballard et al. 2013), generally affects individuals age 60 or older, and
becomes more prevalent with age. The Dementia With Lewy Bodies Consortium
continues to systematically update diagnostic and management
recommendations for DLB. The third report of the consortium highlights the
central, core, and suggestive features that comprise the diagnostic criteria for
probable and possible DLB (McKeith et al. 2005). The central feature is a
progressive cognitive decline that eventually ends in dementia. Whereas AD
typically presents with memory loss initially, DLB’s early deficits are in
attention, executive, and visuospatial abilities. Core features include fluctuating
cognition with variations in attention and levels of alertness, recurrent well-
formed visual hallucinations, and parkinsonian features. Suggestive features
include rapid eye movement (REM) sleep behavior disorder, severe sensitivity
to neuroleptics, and low dopamine transporter uptake in the basal ganglia as
demonstrated on PET or SPECT imaging. The diagnostic criteria for probable
DLB require one of the following:

• The presence of dementia plus at least two core features

• The presence of dementia plus one core feature and one suggestive feature

The diagnostic criteria for possible DLB require the presence of dementia
plus one core or suggestive feature. The DLB Consortium also provided a long
list of supportive features which lack diagnostic specificity but can support the
clinical diagnosis of DLB (McKeith et al. 2005). Examples of such supportive
features include falls, syncope, transient and unexplained loss of consciousness,
severe autonomic dysfunction, hallucinations (other than visual) or delusions,
depression, or brain imaging or EEG findings consistent with the diagnosis.
Fluctuating cognition occurs in about 60%–80% of people with DLB
(McKeith et al. 1996) and is often mistaken for delirium. The symptoms and
their duration vary between individuals and even within the same person.
Symptoms range widely from episodes resembling blackouts of absence seizures
to speech changes seen in strokes. They can last from seconds to days. Recurrent
visual hallucinations occur in over half of DLB cases (Simard and van Reekum
2004) and are the most frequently reported psychotic symptom. Hallucinations
tend to be images of people, animals, or objects (Ballard et al. 2013) but can be
as simple as shapes in the corner of one’s eye. They can occur at any time but
are more common at night and are not typically distressing unless accompanied
by delusions or occurring in severely demented individuals (Ballard et al. 2013).
Parkinsonian features are similar to those found in PD (e.g., dyskinesias,
rigidity, gait disorders, tremor) and occur in almost 70% of individuals with
DLB (Aarsland et al. 2001).
 If dementia and parkinsonism coexist, the differential diagnosis is sorted out
by examining the relative course of the cognitive and motor symptoms. The
emergence of dementia after many years of motor symptoms supports a
diagnosis of PDD. In contrast, the early presence of dementia in a patient with
motor parkinsonism supports a diagnosis of DLB. Researchers use a 1-year
interval between onset of PD and onset of dementia to differentiate PDD from
DLB.
Many patients with Alzheimer’s dementia develop a clinical DLB picture,
reflected in the neuropathology, and many DLB patients have concurrent
Alzheimer’s dementia pathology. Daytime drowsiness and naps, staring spells,
and episodes of disorganized speech have high positive predictive value for the
diagnosis of DLB over Alzheimer’s dementia (Ferman et al. 2004). Both visual
hallucinations and delusions are more common in DLB (as well as in PDD) than
in Alzheimer’s dementia and have high positive predictive value. In fact, visual
hallucinations may be the most clinically useful feature to distinguish DLB from
AD (Tiraboschi et al. 2006). Neuroleptic sensitivity is much more common and
severe in DLB than in AD. Autonomic dysfunction, such as urinary
incontinence, tends to be an early sign in DLB, whereas it often occurs in late
stages of AD.
Although the progression of DLB tends to be similar overall to that of
Alzheimer’s dementia, the course of DLB is more variable. Because many
patients have a more fulminant course, some experts believe that DLB has a
worse prognosis than Alzheimer’s dementia (McKeith et al. 2004). DLB is
associated with considerable suffering for patients and families, in part because
of common, difficult-to-treat, and persistent NPSs (hallucinations, delusions,
and affective symptoms). Patients also tend to become affected early with
balance, sleep, and motor disorders and to become confined in their mobility.

Parkinson’s Disease Dementia

PDD refers to patients who have had PD for many years and then develop
dementia most likely caused by the PD itself. With the advent of the use of L-
dopa to help control Parkinson’s motoric symptoms, it has become apparent that
some of the most common and impairing symptoms of PD are in the cognitive
realm. PDD is associated with excess disability, reduced quality of life,
increased risk for psychosis, increased nursing home admission and therefore
disease-related costs, increased mortality, and increased caregiver burden (Emre
2003). Patients with PD typically show impairments in executive functioning
(e.g., problem solving, set shifting, and planning), deficiencies in attention, and
poor fluency. They also have memory impairments, affecting working memory
and the organization and retrieval of explicit memory. Memory retrieval is often
improved by cuing. Some individuals have visuospatial difficulties arising out of
problems with set shifting and the need for high executive demand to complete
visuospatial tests.
The average time from onset of PD to the development of dementia is
approximately 10 years (Hughes et al. 2000). At least 75% of patients with PD
who survive for more than 10 years will develop dementia. Risk factors for the
development of dementia in individuals with PD include old age, PD onset after
age 60 years, duration of PD, severity of motor symptoms (particularly postural
and gait disturbances), REM sleep behavior disorder, visual hallucinations
(which increase the risk of developing dementia by 20-fold) (Galvin et al. 2006),
and MCI. Once individuals with PD begin to demonstrate cognitive impairment,
their MMSE scores decline by an average of 2.4 points per year (Kandiah et al.
2009). However, because the MMSE is not very sensitive to detecting executive
dysfunction, patients may have significant cognitive impairment even with
normal MMSE scores. The MoCA may be a more sensitive tool for identifying
early cognitive impairment in PD (Zadikoff et al. 2008).
FIGURE 8–6. Common pathways linking Parkinson’s disease with
Alzheimer’s disease.
Source. Reprinted by permission from Macmillan Publishers LTD: Nature Genetics (Shulman JM, De Jager
PL: “Evidence for a Common Pathway Linking Neurodegenerative Diseases.” Nature Genetics
41(12):1261–1262, 2009), copyright 2009.

Classically, neuropathological staging of PD is based in part on a predictable

neuroanatomical spread of Lewy body pathology, starting with the olfactory
system and lower brain stem and eventually progressing to the cortex (Braak et
al. 2004). Although the neuropathological stage of PD generally correlates with
the severity of dementia, some patients may develop cognitive decline despite
mild cortical pathology, whereas others may have normal cognitive function
despite widespread cortical pathology (Braak et al. 2005). Although high rates
of Alzheimer’s pathology appear to be present in patients with PD and dementia,
this linkage remains controversial because of the different findings in various
autopsy series. One proposed theory linking PD and AD is that the pathways of
β-amyloid, tau, and α-synuclein aggregation may potentiate each other, leading
to neuronal dysfunction and cell death (Figure 8–6) (Shulman and De Jager
2009). Metzler-Baddeley (2007) provides more information.
 Cognitive impairment in PD has been associated with deficits in several
neurotransmitter systems, including dopaminergic, cholinergic, serotonergic, and
noradrenergic. Many studies have demonstrated a relationship between
frontostriatal dopaminergic pathways and working memory (e.g., Cools and
D’Esposito 2011). Although dopaminergic medications may promote mild
improvement on short-term memory tests early in the disease course, they are
unlikely to be helpful in moderate to severe cases of PDD (Morrison et al.
2004). Cholinergic systems appear to have an important role in the cognitive
decline associated with PDD. PET scans have demonstrated cholinergic
dysfunction in the cerebral cortex, beginning in early PD and becoming more
widespread in PDD (Shimada et al. 2009). Cholinesterase inhibitors modestly
improve cognitive function in PDD, leading to the FDA’s approval of the
cholinesterase inhibitor rivastigmine for treatment of PDD.
NPSs are common in PD both with and without dementia. These symptoms
include depression, psychosis, anxiety, impulse control disorders, disorders of
sleep and wakefulness, and apathy (Weintraub and Burn 2011). Depression can
be seen in up to 40% of patients. Sleep disorders occur in up to 30% of patients
and include rapid eye movement sleep behavior disorders, nightmares, sleep
fragmentation, and daytime sleepiness. Visual hallucinations can be seen in up
to 50% of patients. Persecutory delusions are also quite common. Many
medications used to treat PD, such as anticholinergic agents, amantadine,
dopaminergic agents, and catechol O-methyltransferase (COMT) inhibitors, can
exacerbate visual hallucinations and delusions.

Dementia Due to Frontotemporal Lobar Degeneration

FTLD is in many ways the paradigmatic non-Alzheimer’s dementia and has
become a major focus of interest because of the appreciation that in individuals
younger than 65 years, FTLD is the second most common form of dementia,
with a rate of occurrence that is close to that of Alzheimer’s dementia (Neary et
al. 2005). Previously referred to as Pick’s disease, FTLD is a clinically and
pathologically heterogeneous disorder characterized by a progressive change in
personality, behavior, and language, and focal degeneration of the frontal and/or
temporal lobes. Less commonly, FTLD can also present with progressive motor
decline in addition to behavior and language deficits. As the condition
progresses and global dementia ensues, however, symptoms overlap and it
becomes increasingly difficult to group patients into one category of FTLD or
another.
 The most common presentation of FTLD is the behavioral variant (bvFTLD)
(Kertesz et al. 2007). It is characterized by progressive changes in personality
and behavior, as well as cognitive dysfunction. Patients may exhibit an amalgam
of executive dysfunction, such as social inappropriateness and disinhibition,
poor insight, hyperorality, changes in affect, emotional blunting and apathy, and
stereotyped behaviors. Because of the prevalence of apathy in this variant,
bvFTLD is often misdiagnosed as depression (Bertoux et al. 2012). Cognitive
tests, such as the MMSE, may not be able to reveal cognitive deficits early in the
course of bvFTLD.
The second most common presentation of FTLD is primary progressive
aphasia (PPA) (Kertesz et al. 2007). PPA is characterized by a prominent
progressive impairment in speech and language of insidious onset, with deficits
in speech production, naming, grammar, and/or word comprehension.
Behavioral features often develop in individuals with PPA. The three main
variants of PPA are progressive nonfluent aphasia, semantic dementia, and
logopenic progressive aphasia. Patients with progressive nonfluent aphasia
demonstrate anomia, impaired fluency, paraphasic errors, and agrammatism with
telegraphic speech. Language comprehension and repetition are spared early in
the course. Patients ultimately progress to mutism. Those with the semantic
dementia variant present with anomia, impaired single-word comprehension,
and semantic paraphasic errors. Semantic memory is also affected. Speech
production and repetition are spared. The third variant, logopenic progressive
aphasia, is characterized by a paucity of and slowed rate of speech, impairment
in single-word retrieval and repetition, and phonological paraphasias. Episodic
memory and calculation are often affected. Speech production, grammar, and
single-word comprehension are spared, at least early on.
Approximately 10%–15% of patients with FTLD also have motor neuron
disease. Individuals with the bvFTLD type are most often affected, and motor
symptoms can either precede or follow changes in behavior and personality.
Patients present with progressive lower motor neuron signs of muscular atrophy
and fasciculations preferentially affecting bulbar and upper extremity muscles.
The progression to death is hastened. One motor impairment syndrome that co-
occurs with FTLD is amyotrophic lateral sclerosis (ALS). Some patients with
FTLD develop ALS presentations (known as FTLD-ALS) as their disease
progresses, whereas some patients with ALS develop FTLD over their disease
course.
There is significant clinical, pathological, and genetic overlap between
FTLD-ALS and two atypical parkinsonian syndromes, progressive supranuclear
palsy and corticobasal syndrome (Seltman and Matthews 2012). Both
progressive supranuclear palsy and corticobasal syndrome have cognitive and
behavioral features that overlap with FTLD and are often classified in the
spectrum of FTLD clinical syndromes. Clinical features of progressive
supranuclear palsy include postural instability, axial rigidity, frequent falls,
bradykinesia, dysarthria, and supranuclear gaze deficits, as well as progressive
cognitive decline and apathy. Clinical features of corticobasal syndrome include
the simultaneous occurrence of asymmetrical cortical signs (e.g., limb apraxia,
myoclonus, alien limb phenomenon) and extrapyramidal signs (e.g.,
bradykinesia, tremor, limb rigidity, dystonia). Although progressive
supranuclear palsy is characterized by neuronal loss and atrophy in the basal
ganglia with relative sparing of the frontal cortex, the pattern of frontal lobe
atrophy in corticobasal syndrome closely resembles the pattern of FTLD.
Because some individuals with FTLD may manifest both extrapyramidal
symptoms and psychosis, they are not infrequently diagnosed as having DLB.
Individuals with FTLD may also exhibit hypersomnia, fluctuating cognition, and
sleep disorders (Claassen et al. 2008), leading to diagnosis of DLB.
Clinicopathological studies can be helpful in understanding the underlying
neurodegenerative process in patients who meet criteria for both FTLD and
DLB.
A revised consensus of neuropathological criteria takes into account advances
in both genetics and biochemistry and reflects the diversity of pathological
pictures (Cairns et al. 2007). Pathologically, FTLD is characterized by knife-
edge lobar atrophy, typically in the anterior temporal and posterior inferior areas
of the frontal lobes. Microscopically, neurons appear enlarged and vacuolar,
with extensive gliosis and loss of myelin. Neurons and glial cells may contain
abnormal cytoplasmic and/or nuclear protein inclusions. Inclusions tend to
comprise either hyperphosphorylated tau protein or transactive response DNA
binding protein 43 (TDP-43). Inclusions containing tau protein can be seen in
various disorders such as FTLD with Pick bodies, corticobasal degeneration,
progressive supranuclear palsy, and hippocampal sclerosis. Collectively, these
disorders are known as tauopathies.
FTLD is familial in a considerable number of patients, often in an autosomal
dominant pattern of inheritance. Mutations in the tau, progranulin, and ubiquitin
genes have been associated with the condition. Familial TDP-43 proteinopathy
is associated with defects in multiple genes and several neuropathological types
(Cairns et al. 2007).
FTLD is a clinical diagnosis. Although neuroimaging is not necessary to
establish the diagnosis of FTLD, it may support the diagnosis and is necessary to
exclude alternative pathology. FTLD is sometimes misdiagnosed as Alzheimer’s
dementia; however, clinicians can differentiate FTLD from Alzheimer’s
dementia via the early age at onset of FTLD (average age at onset is in the late
50s or early 60s), early prominent NPSs, and lack of significant memory or
visual spatial impairments. Other symptoms that support a diagnosis of FTLD
over Alzheimer’s dementia include abnormal eating behaviors, social
inappropriateness, degree of apathy, and stereotyped behaviors. FTLD is almost
invariably progressive, especially if language symptoms occur early on. In
clinical settings, the time from an FTLD diagnosis to death is on the order of 3–
5 years, which is shorter than the periods associated with Alzheimer’s dementia
(Chow et al. 2006). Also, compared with Alzheimer’s dementia, FTLD is a
greater burden to caregivers, given the disinhibited behaviors that are hard to
treat and require aggressive supervision to manage.

Less Common Dementias

Dementia Due to Normal-Pressure Hydrocephalus
The dementia of normal-pressure hydrocephalus (NPH) is a subcortical
dementia associated with a characteristic magnetic-like gait disorder,
incontinence, and cognitive dysfunction. Little is known about its epidemiology
and progression. It is estimated to have an annual incidence of 0.5–2 per million
individuals (Wilson and Williams 2006). Idiopathic NPH is most common after
age 60 years. Cognitive symptoms may include psychomotor slowing, executive
dysfunction, personality changes, inattention, impaired recall, and decreased fine
motor speed (Finney 2009). The condition is suspected when patients present
with the classic triad of findings and brain imaging reveals enlarged ventricles
disproportionate to cortical atrophy. The diagnosis is confirmed by a patient’s
response to either lumbar puncture drainage of a large volume (40–50 mL) of
CSF, response to an extended CSF drainage trial through a lumbar spinal
catheter, or measurement of resistance to CSF outflow during a lumbar puncture.
NPH is difficult to diagnose because gait difficulty, cognitive decline, urinary
incontinence, and enlarged ventricles (ventricle size increases with age) are all
common in the elderly and can have many causes; furthermore, there is no
combination of cardinal findings that is pathognomonic or specific for NPH
(Graff-Radford 2007). Because NPH is often seen in the elderly, a factor
complicating the diagnosis of NPH is that 75% of patients with idiopathic NPH
also meet clinical criteria for AD or vascular dementia (Bech-Azeddine et al.
2007). Moreover, a significant percentage of patients with idiopathic NPH
demonstrate positivity for biomarkers typically found in AD, such as Aβ
(Leinonen et al. 2012). Much interest has focused on efforts to diagnose and
treat NPH using shunts, as discussed in “Disease-Modifying Therapies” later in
this chapter.

Dementia Due to Prion Diseases and Other Rapidly Progressive

Dementias
Rapidly progressive dementias (RPDs) represent a heterogeneous group of
disorders that can be categorized by their underlying pathophysiology, including
neurodegenerative, inflammatory, vascular, toxic, metabolic, neoplastic, and
infectious causes (Woodruff 2007). Although relatively rare, human
transmissible spongiform encephalopathies, or prion diseases, are probably
foremost in the minds of clinicians when evaluating RPDs (Woodruff 2007).
Prion diseases represent a large portion of neurodegenerative causes of RPD
(Appleby and Lyketsos 2011; Geschwind et al. 2008). However, out of a
University of California, San Francisco, cohort of 178 patients with suspected
prion disease or other RPDs, 38% of patients were diagnosed with a nonprion
condition (Geschwind et al. 2008). The largest group of nonprion patients in the
cohort had neurodegenerative diseases (14.6% of the entire cohort and 39% of
all nonprion cases). These diseases included AD, DLB, FTLD, corticobasal
syndrome, and progressive supranuclear palsy. The second most common group
had autoimmune conditions (8.4% of the entire cohort and 22% of nonprion
cases). These included Hashimoto’s encephalopathy, antibody-mediated limbic
encephalitis associated with cancer (paraneoplastic) or without cancer
(nonparaneoplastic), multiple sclerosis, and neurosarcoidosis. The third most
common diagnosis was dementia of unknown cause (4.5% of the entire cohort
and 12% of nonprion cases). Several patients had encephalitis of presumed viral
etiology (enterovirus was confirmed in one patient). Other nonprion causes of
RPD included toxic-metabolic causes (e.g., methylmalonic acidemia,
encephalopathy secondary to alcohol intoxication, methotrexate toxicity),
encephalopathy associated with cancer but without evidence of autoantibodies,
and psychiatric conditions, among others.
Recent knowledge regarding prion protein transmission across species has
led to concerns about animal-to-human transmission of these proteins through
the diet, followed by incurable RPD. In the United States the annual incidence
of CJD, the most common human prion dementia, is roughly 1 per million
individuals (Holman et al. 2010). The incidence peaks between ages 65 and 74
years (Holman et al. 2010). Although most cases (75%–85%) of CJD are
sporadic, other forms include genetic (10%–22%) and acquired (iatrogenic and
variant CJD) (<1%–3%) (Appleby and Lyketsos 2011; Geschwind et al. 2008).
 The basic pathophysiology of the disease, partly worked out by Stanley
Prusiner (who won the Nobel Prize in Medicine for this work), is thought to
involve abnormal transformation of prion protein (PrPc) from its α-helical form
to a β-sheet form. The pathological prion protein (PrPres) reuses itself as a
template (prions do not require nucleic acids to replicate) to convert more PrPc
to PrPres. This leads to a snowball cascade with widespread dissemination of
these proteins, which become clumpy and toxic, leading to the classic
spongiform appearance of the nervous system. How this is brought about is
uncertain. It might occur spontaneously or result from interactions with mutant
prion proteins or those of other species that make their way into the human
brain. Some cases have resulted from transplanting affected organs. Little is
known about factors that initiate or accelerate these transitions, although some
of the familial cases appear to have been initiated by biological stress to the
brain through stroke, hypoxia, or TBI (Lyketsos 1999). At present, this disease is
incurable. The familial forms are a target of genetic counseling.
All mammals, including humans, carry the prion protein gene PRNP on the
short arm of chromosome 20. Several mutations in this gene have been reported
and are associated with a familial progressive dementia (Michalczyk and Ziman
2007), sometimes referred to as Gerstmann-Sträussler-Scheinker syndrome. In
1996, variant CJD was discovered in the United Kingdom. It was linked to
bovine spongiform encephalopathy, which was most likely transmitted to
humans by eating affected beef. By the end of 2005, approximately 190 human
cases had been identified (Collee et al. 2006). This epidemic appears to have
subsided.
CJD and Gerstmann-Sträussler-Scheinker syndrome have variable clinical
presentations, although the most characteristic presentation is that of RPD,
prominent gait disorder (e.g., ataxic gait), extrapyramidal symptoms, and motor
findings (e.g., myoclonus) early on. Early cognitive deficits involve memory,
concentration, judgment, and language (e.g., aphasia). Sleep disturbances, such
as insomnia, and visual disturbances, ranging from field defects to cortical
blindness, can occur as well (Puoti et al. 2012). Patients may display a gaze that
expresses apprehension or fear and may be hypersensitive (Puoti et al. 2012).
Patients become disabled rapidly and may experience difficulty in obtaining a
diagnosis because they often present with psychiatric symptoms such as
depression, anxiety, apathy, and executive dysfunction. In one-third of
individuals, vague complaints of fatigue, headache, sleep disturbance, vertigo,
malaise, weight loss, pain, depression, or behavioral changes precede the
dementia by weeks to months (Geschwind et al. 2008). However, obvious
impairments in gait, behavior, and cognition can be apparent over a matter of
days (Puoti et al. 2012). The median survival is 5 months, and approximately
85% of patients die within 1 year of symptom onset (Geschwind et al. 2008).
Although the time course of CJD is almost invariably rapid, cases in the
literature have been reported with longer courses, sometimes lasting years. The
familial cases, in particular, tend to run longer courses, as long as a decade in
younger individuals (Lyketsos 1999).
The only way to definitively confirm a diagnosis of sporadic prion disease in
living patients is through brain tissue biopsy. However, the combination of a
clinical assessment and either CSF assay or MRI imaging has sufficient
sensitivity and specificity to accurately diagnose the disease (Puoti et al. 2012).
That said, often up to 80% of prion disease cases, including genetic forms, are
initially misdiagnosed (Appleby and Lyketsos 2011). The rarity of the disease
often delays diagnosis. Furthermore, diagnostic patterns vary by country and/or
clinical center (e.g., community hospital vs. university hospital) (Appleby and
Lyketsos 2011). The Centers for Disease Control and Prevention (2010) has
published criteria for probable sporadic CJD, which are outlined in Table 8–7.
Although neurodegenerative dementias such as AD, DLB, and FTLD are
typically characterized by gradual onset and insidious progression, they can
sometimes present in a fulminant form, developing over months, with death
occurring in less than 3 years (Geschwind et al. 2008). These neurodegenerative
dementias can resemble CJD because of an overlap of motor symptoms
(particularly gait disturbances, extrapyramidal signs, and myoclonus) and
cognitive, behavioral, and psychiatric manifestations. EEG and CSF
abnormalities can likewise overlap. For instance, the periodic 1- to 2-Hz
triphasic sharp waves characteristically seen on EEG in CJD can also be seen,
although rarely, in end stages of AD or DLB, as well as in toxic-metabolic
conditions and in Hashimoto’s encephalopathy. Furthermore, this
electroencephalographic finding usually appears only in the later stages of CJD.
Thus, the EEG lacks sensitivity and specificity and misses many early and some
late cases. CSF findings in CJD are likewise neither sensitive nor specific for the
disease. False-positive results for CSF 14-3-3 protein can be seen in fulminant
AD cases. A more sensitive and specific test for CJD could be the combination
of fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging
(DWI) MRI sequences (Geschwind et al. 2008).

TABLE 8–7. CDC criteria for probable sporadic Creutzfeldt-Jakob disease

Rapidly progressive dementia
And
At least two of the following four features:
Myoclonus
Visual or cerebellar signs
Extrapyramidal or pyramidal signs
Akinetic mutism
And
A positive result on at least one of the following three laboratory tests:
Periodic sharp wave complexes on electroencephalogram during a disease of
any duration
Positive 14-3-3 cerebrospinal fluid assay in patients with a disease duration of
less than 2 years
Magnetic resonance imaging signal abnormalities in the caudate nucleus
and/or putamen on diffusion-weighted imaging or fluid-attenuated inversion
recovery
And
Routine investigations should not suggest an alternative diagnosis
Source. Adapted from Centers for Disease Control and Prevention 2010.

Autoimmune diseases of the brain causing limbic encephalopathy can also

resemble CJD. Symptoms include memory loss, depression, anxiety, personality
changes, emotional lability, and seizures. The clinician should consider a
paraneoplastic syndrome when there is a subacute or rapid development of
dementia, cancer risk factors, extrapyramidal or cerebellar symptoms, other
neurological symptoms, evidence of inflammation in CSF analysis, or a family
history of cancer (Geschwind et al. 2008). Detection of paraneoplastic
antibodies should prompt the clinician to aggressively investigate for the
corresponding tumors. Primary central nervous system vasculitis often presents
with headache, altered mentation, focal neurological signs, and CSF pleocytosis
(Geschwind et al. 2008). Vasculitides can be distinguished from CJD and other
RPDs by the presence of systemic manifestations or by specific brain MRI
abnormalities, such as brain hemorrhage or multiple infarctions of different
ages. Notably, even in the absence of gastrointestinal symptoms, celiac disease
can cause ataxia, NPSs, seizures, headaches, neuropathy, and dementia.
Geschwind et al. 2008) and Woodruff (2007) provide further information
regarding various causes of RPD, as well as diagnostic approaches, screening
tests, representative imaging abnormalities, and treatment options.
Treatment

Treatment for Milder Cognitive Syndromes

Memory clinics and primary care physicians anecdotally report that because of
the increased public awareness of dementia, patients are presenting with
increasingly milder cognitive symptoms to request diagnosis and treatment. At
present, there is little empirical knowledge about how to manage these patients
clinically. Most experts recommend continued observation and the use of
nonpharmacological therapies such as controlling vascular risk factors (e.g.,
healthy diet, exercise, smoking cessation), due to the relationship of
cardiovascular health to cognitive health; meditation; cognitive stimulation; and
cognitive rehabilitation (e.g., using memory cues and organizational aids).
Cooper et al. (2013) reviewed nonpharmacological interventions for MCI to
identify which had the best treatment evidence. The only type of
nonpharmacological intervention for which they found preliminary evidence
was a long-term group program of memory training, reminiscence and cognitive
stimulation, recreation, and social interaction, which improved cognition over 6
months. They found limited evidence that individual aerobic exercise programs
improve executive functioning and category fluency, or that computerized
cognitive training programs improve delayed recall. However, the studies using
computerized programs had multiple secondary outcomes, increasing the
possibility of a chance finding. Furthermore, Cooper and colleagues questioned
the clinical benefit of isolated improvements in these cognitive domains.
Nonetheless, exercise has been associated with favorable effects on neuronal
survivability and function, neuroinflammation, vascularization, neuroendocrine
response to stress, and brain amyloid burden (Baker et al. 2010). Cooper et al.
highlighted the limited generalizability of the nonpharmacological interventions
that they reviewed, most of which were underpowered and lacked sufficient
evidence of efficacy. A Cochrane review found that, compared with no
treatment, specific neuropsychological (“brain”) exercises designed to
strengthen memory in people with MCI did improve immediate and delayed
verbal recall (Martin et al. 2011); however, the effects were lost when the group
receiving exercises was compared with an active control group.
Various vitamins (e.g., vitamin B6, vitamin B12, folate, vitamin E),
supplements (e.g., Gingko biloba), and nonsteroidal anti-inflammatory drugs
(NSAIDs; e.g., rofecoxib, triflusal) have not been shown to reliably improve
cognition in patients with MCI or to prevent conversion to dementia. Nicotine
patches improved attention (and verbal recall as a secondary outcome) but not
global functioning over 6 months in a small study of nonsmokers (Newhouse et
al. 2012). In one study, piribedil, a dopamine receptor agonist, was more
effective than placebo on a cognitive primary outcome (defined as change in
MMSE score) over 3 months (Nagaraja and Jayashree 2001); however, the
criteria for MCI were not strict and the authors acknowledged that some
participants may have had dementia.
The results of at least one randomized trial suggest that the cholinesterase
inhibitor donepezil may delay progression to dementia, especially in patients
who are APOE*E4 carriers (Petersen et al. 2005), but this has not been
replicated or supported by other trials (Rosenberg et al. 2006). More recent
reviews and meta-analyses (e.g., Cooper et al. 2013; Russ and Morling 2012)
found very little evidence that cholinesterase inhibitors either affected
progression to dementia or improved cognitive scores in patients with MCI.
Furthermore, there was an increased risk of adverse events, particularly
gastrointestinal, in those who received cholinesterase inhibitors, as well as an
unexplained increased mortality rate with galantamine specifically (Cooper et al.
2013). Thus, in most cases, cholinesterase inhibitors should not be clinically
prescribed for individuals with MCI (Cooper et al. 2013; National Institute for
Health and Care Excellence 2012). We recommend initiating pharmacological
therapy only in cases in which there is strong evidence of likely benefit—for
example, when the patient appears to be about to transition to Alzheimer’s
dementia or when the cognitive impairment is particularly worrisome to the
patient. Rosenberg et al. (2006) and Cooper et al. (2013) provide more detailed
approaches to this issue.

The Four Pillars of Dementia Care

Dementia care has four basic elements, or pillars (Lyketsos et al. 2006). The first
pillar relates to management of key aspects of the disease with the goal of
reversing its effects or delaying its progression in the brain. Although few
disease therapies exist at present, several therapies are being developed for
different types of dementia targeted at underlying pathophysiological
mechanisms. The second pillar of dementia care relates to the management of its
symptoms, whether they are cognitive, neuropsychiatric, or functional. The final
two pillars involve providing supportive care to patients and caregivers in ways
that are systematic and evidence based.
The overall premise of this approach is that an effective, systematic care
model exists for patients with dementia resulting from AD (Lyketsos et al.
2006). This care model also has implications for patients suffering from other
forms of dementia. Until recently, dementia care interventions were few and
were provided on faith, with limited evidence of effectiveness. Evidence from
randomized trials now indicates that a dementia care “package” provides
significant benefits to patients and caregivers. Although rigorous well-controlled
trials to evaluate the efficacy of care interventions are sparse, several high-
quality trials of care coordination in dementia demonstrate modest to moderate
effects on patient quality of life, improving care quality, reduction of NPSs, and
reduction of caregiver burden, unmet needs, and depression (Samus et al. 2014).
Based on results from a randomized trial, Callahan et al. (2006) reported that in
primary care settings, guideline-based dementia care led to better patient and
caregiver outcomes, likely due to the more appropriate use of medications and
interventions that targeted both caregivers and patients. Long-term follow-up
studies (e.g., Mittelman et al. 2006) have demonstrated that caregiver-targeted
interventions (e.g., counseling and support programs) can prolong the time
patients spend in the community. An observational cohort (Lyketsos et al. 2007)
from the Maryland Assisted Living Study supported these findings, suggesting
that treatment for dementia might delay discharge from assisted living facilities
by as much as 7 months.
Multicomponent supportive dementia care programs can improve the
patient’s ability to age in place. In a recent 18-month randomized controlled
study (Maximizing Independence [MIND] at Home) of 303 community-living
elders, home-based dementia care delivered by community-based nonclinical
coordinators, supervised by geriatric clinicians, led to delays in transitioning
from home, reduced unmet needs, and improved self-reported quality of life
(Samus et al. 2014). The intervention was considered to be low risk with no
intervention-related adverse events. Over 18 months, participants in the
intervention group had a 51-day mean delay of transition out of their home, with
a 228-day median delay over an extended follow-up period (median of 26
months) compared with control participants. Given the positive effect of being
able to stay at home versus costly facilities (e.g., nursing homes or assisted
living placements), the findings imply a cost savings (Samus et al. 2014).
Furthermore, most contacts (72%) between the community-based coordinator
and another person (e.g., patient, study partner, health provider, clinician) were
phone based, which implies that benefits can be achieved in a potentially cost-
efficient manner (Samus et al. 2014). Tremont et al. (2013) is currently
investigating a cost-effective, telephone-based, multicomponent dementia
intervention to reduce distress in dementia caregivers. Nevertheless, in-person
visits are likely essential to visually identify a wide range of home and personal
safety needs (e.g., fall risk, medication use adherence, wander risk) and the
physical condition of participants and study partners (Samus et al. 2014).
An optimal dementia care team includes dementia care specialist,
occupational and physical therapists, nurse, psychologist, social worker, and
case manager, working closely with the primary care physician and caregivers.
One of the roles of the dementia care specialist, who is often a gerontologist or
geriatric psychiatrist, is to manage, both pharmacologically and
nonpharmacologically, the cognitive and neuropsychiatric symptoms that
accompany dementia. Nonpharmacological strategies can be very effective and
avoid risks and side effects associated with medications. Over time, however,
medications often become a necessary and integral part of symptom
management. A particularly useful and well-known adage for medication
management in geriatric patients is to start low and go slow. When initiating or
titrating medications, the care specialist should be mindful of the following:

1. Elderly patients have decreased renal clearance and slowed hepatic

metabolism.
2. Because elderly patients often have multiple medical illnesses and are taking
multiple medications, the clinician must evaluate potential drug-drug
interactions.
3. Because geriatric patients are at increased risk of orthostasis and falls in part
due to decreased vascular tone, medications contributing to orthostasis should
be used cautiously.
4. Deliriogenic medications (e.g., anticholinergics and benzodiazepines) should
be used judiciously and sparingly.

Disease-Modifying Therapies
Alzheimer’s Disease
As articulated in the principles of care of the American Association for Geriatric
Psychiatry (AAGP) (Lyketsos et al. 2006), estrogen, anti-inflammatory agents
(e.g., prednisone, NSAIDs), and Ginkgo biloba are not effective treatments for
Alzheimer’s dementia. One large randomized controlled trial (RCT)
demonstrated that high doses of the antioxidant vitamin E delays progression of
Alzheimer’s dementia, lengthening the time before onset of the next phase by 2
years (Sano et al. 1997). Given safety concerns about dosing, the AAGP
recommended considering vitamin E for Alzheimer’s dementia but avoiding
doses above 400 IU/day. In a recent study evaluating the use of high-dose (2,000
IU/day) vitamin E in patients with mild to moderate AD, Dysken et al. (2014)
found that vitamin E may slow functional decline and decrease caregiver burden
for some patients. Under investigation are the usefulness of other antioxidants
(vitamins C and D), folate to reduce homocystinemia, and dietary modifications.
One of the most effective therapies for AD is the aggressive management of
associated vascular risk factors such as blood pressure (particularly keeping
systolic blood pressure below 160 mm Hg), high cholesterol, diabetes, obesity,
and sedentary lifestyle (Mielke et al. 2007). Although statins have shown
promise as treatments for cognitive decline and dementia in observational
studies, several large RCTs (e.g., Trompet et al. 2010) did not show any
significant effect on cognition.
A better understanding of the etiopathogenesis of Alzheimer’s dementia has
led to the development of therapies targeting amyloid precursor protein
metabolism, Aβ1–42 deposition or clearance, and ways by which amyloid injures
neurons. For example, inhibition of the enzymes β-secretase and β-secretase
targets the metabolism of amyloid precursor protein. Two types of
immunotherapies under investigation include injecting amyloid to create host
immunity (active immunization) or injecting intravenous immunoglobulin
antibodies to clear amyloid from the brain (passive immunization). Examples of
the latter include bapineuzumab and solanezumab, monoclonal antibodies that
bind to soluble Aβ and promote Aβ removal from the brain through the
bloodstream. Lastly, there are antitau therapies targeting tau
hyperphosphorylation and the inhibition of tau aggregation. Mangialasche et al.
(2010) published a summary of FDA clinical trials of disease-modifying agents.
For the most part, clinical trials have not been successful at producing safe
disease-modifying therapies for AD. Given the complexity of AD, the central
hypothesis of “one protein, one drug, one disease” needs to be modified
(Mangialasche et al. 2010). There are complex interactions at every level of the
human body, from genes to organs, as well as interactions between the person
and the environment. Few people have “pure” AD; amyloid plaques and Lewy
bodies may interact in yet unknown ways. It is difficult to account for these
nonlinear and rather unpredictable interactions in clinical trials. Many clinical
trials aim to find a selective compound that acts on a specific disease target (e.g.,
Aβ) to produce a desired clinical effect. However, some RCTs demonstrate that
even when therapies completely remove amyloid plaques, patients may still
develop end-stage dementia, suggesting that clearing amyloid plaques alone
cannot repair already damaged neurons or stop clinical progression of AD
(Holmes et al. 2008). Researchers neither completely understand the functions
of Aβ nor know the upper and lower safe limits of Aβ (Carrillo et al. 2013).
Many drugs bind to more than one target, increasing the risk of unforeseen and
unwanted complications. On the other hand, many enzymes, such as β-secretase,
have many substrates. It is challenging to design a drug to target β-secretase
because of its many substrates, as well as because of its wide substrate-binding
domain and the need for drugs to be able to cross the blood-brain barrier to
modulate the enzyme (Mangialasche et al. 2010).
Mangialasche et al. (2010) highlight other barriers to producing successful
disease-modifying therapies, including the following:

1. RCT protocols can be costly and time-consuming for the patient and the
caregiver, thus increasing withdrawal rates.
2. There is a lack of validated biomarkers with established cutoffs.
3. Studies that have unsuccessful pre-clinical and clinical results are not always
published, leading to repetition of errors.
4. Some drugs with positive results in preclinical and early clinical testing failed
large phase 3 RCTs.
5. Designing selective compounds without intolerable and potentially toxic side
effects is difficult.
6. Some drugs are hindered by the inability to reach a therapeutic dosage, or
treatment duration may have been too short to result in an effect.
7. There are genetic differences among patients (e.g., APOE*E4 carriers or
cytochrome P450 variability).
8. Reliable evaluation of patients requires adequate training and monitoring of
RCT raters.
9. Even if a drug targets mild to moderate stages of AD, the disease could have
already advanced too far for detection of a disease-modifying effect.

Indeed, even by the time MCI develops, the pathological process may have
advanced too far for treatments to be preventive, and it may be necessary to
target the disease earlier, at the stage of subjective memory impairment (Cooper
et al. 2013).
Given that disease-modifying therapies have largely been unsuccessful, that
targeting patients even in early stages of dementia may prove too late, and that
physicians are increasingly able to diagnose AD in very early stages (i.e., in a
pre-symptomatic phase) using biomarkers, trials have started targeting
prevention of AD. Carrillo et al. (2013) describe various ongoing trials in their
early phases. The following are some examples:
1. The Anti-Amyloid Treatment for Asymptomatic AD Trial targets cognitively
normal adults ages 65–80 years with PET evidence of Aβ. Because the
subjects have evidence of Aβ, they are more likely to demonstrate cognitive
decline over time during the trial, making them a good target population for
prevention. Subjects will be randomly assigned to receive solanezumab or
placebo. The primary outcome measure will be the rate of cognitive decline.
2. The Centre for Studies on Prevention of AD at the Douglas Institute in
Montreal, Quebec, is testing various preventive interventions in people older
than 60 years with a family history of AD. Interventions include medications
such as intranasal insulin and naproxen, and lifestyle modifications such as
aerobic exercise and dietary changes. The goals are to find optimal biomarker
end points and to identify interventions that move biomarkers or mitigate
their progression.
3. The Australian Imaging Biomarkers and Lifestyle Flagship Study of Aging is
investigating the interaction between vascular and AD pathologies and
exploring the possibility of delaying AD by reducing vascular risk factors
through physical activity. The target population is individuals older than 60
years with subjective memory complaints or a diagnosis of MCI and at least
one cardiovascular risk factor.
4. The Multidomain Alzheimer Preventive Trial in France is testing the
protective effects of a multifactorial intervention consisting of nutritional
advice, cognitive and physical activity, and omega-3 treatment. The targeted
population includes frail (because of evidence linking frailty with cognitive
decline) or prefrail individuals without dementia, ages 70 years and older,
with subjective memory complaints and a limitation in at least one IADL.

Many risk factors contributing to the development of late-life dementia are

modifiable. Cognitive stimulation, complexity of occupation, an engaged
lifestyle, and a reduction of vascular risk factors (e.g., cholesterol and smoking)
may have protective effects (Carrillo et al. 2013).
Various prevention trials focus on different populations such as asymptomatic
individuals with AD pathology and presymptomatic individuals with dominant
mutations or other risk factors that increase the likelihood of developing AD
(Carrillo et al. 2013). However, these trials may not necessarily be generalizable
because they may represent two different pathological processes that may
respond differently to a given treatment. Furthermore, ethical issues arise in
prevention studies. At this point in time, we cannot predict whether a person
with AD pathology will definitively develop dementia. Both false positives and
false negatives can have detrimental effects on a person and his or her family.
Other Diseases
There are no disease-modifying treatments available for DLB, PDD, FTLD, or
CJD. Management of stroke risk, typically with anticoagulants and by mitigating
vascular risk factors, is fully indicated in treating patients with vascular
dementia or possibly Alzheimer’s dementia with relevant vascular
comorbidities. L-Dopa agonists may be effective at treating PDD. Some patients
with DLB may also have a partial response. Although L-dopa can precipitate or
exacerbate psychosis and somnolence, this risk is lower than with dopamine
agonists (Fernandez et al. 2003).
Although many patients with NPH have favorable outcomes that can be
enduring after shunt insertion, the beneficial effects typically involve gait and
continence but not cognition (Klassen and Ahlskog 2011). The response of
patients with NPH or AD to shunt insertion is poorer than that of patients
without neurodegenerative pathology (Hamilton et al. 2010). Indicators of
positive response to shunting include improvement in gait after a high-volume
lumbar puncture or high CSF flow pressure on continuous monitoring (Graff-
Radford 2007). Other positive prognostic factors include 1) short duration of
cognitive impairment, 2) a mild impairment in cognition, 3) the appearance of
gait disturbance prior to the onset of cognitive impairment, and 4) the presence
of a secondary cause for NPH (Graff-Radford 2007). Indicators of negative
response to shunting include 1) moderate or severe cognitive impairment, 2) the
presence of dementia for more than 2 years, 3) the appearance of cognitive
impairment before gait disturbance, 4) the presence of aphasia, and 5) the
patient’s abuse of alcohol (Graff-Radford 2007). The size of ventricle or the
severity of gait disorder is not a good predictor of outcome (Meier et al. 2006).
Up to 40%–50% of shunt patients experience complications from shunting. In a
Dutch study (Vanneste et al. 1992), the largest outcome study to date, notable
mortality was observed after shunt placement, with the risks of shunting
outweighing the benefits. No RCT has been conducted to evaluate the long-term
benefit of shunting. Although confirmatory diagnostic tests for NPH are
available, shunting for patients with NPH remains controversial due to an
absence of trials demonstrating long-term benefit.
Several RPDs already have disease-modifying treatments that can potentially
halt or reverse their disease process. However, no disease-modifying treatments
for prion diseases are as yet available. Appleby and Lyketsos (2011) highlighted
experimental trials of treatments for prion diseases. Researchers are identifying
potential novel approaches to treatment, such as vaccines, RNA interference,
and anti-inflammatory agents. One of the most popular approaches to treatment
is to block neuronal PrPc, which has been done successfully in animal models.
Most treatment studies of human prion diseases are case reports or case series.
They are hampered by disease heterogeneity, lack of standardized outcome
measures, low prevalence and statistical power, and rapid progression.
Furthermore, families may decline noncurative treatments due to the rapid
progression and severity of neurocognitive decline seen in prion diseases.
Individuals at risk of developing prion diseases (e.g., genetic forms of prion
diseases) are most likely to receive the greatest benefit from treatments. Thus,
the most important aspect of establishing treatment for RPD is an early and
accurate diagnosis. For instance, a brain fluorodeoxyglucose–PET scan study of
fatal familial insomnia mutation carriers demonstrated hypometabolism in the
thalamus 13–21 months prior to clinical symptoms (Cortelli et al. 2006). Once
therapeutics become available, early detection of prion diseases using
biomarkers could enable clinicians to administer effective treatments in
presymptomatic stages or prior to severe brain damage, allowing for a better
quality of life for patients.

Therapies for Cognitive Symptoms Associated With Dementia

The cholinesterase inhibitors, donepezil, rivastigmine, galantamine, and tacrine,
and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine are all
approved by the FDA for the symptomatic treatment of cognitive symptoms in
AD. These medications provide only modest and temporary stabilization of the
changes to cognition and ADLs associated with the disease. They do not reverse
or stop the degenerative process. Furthermore, the data are mixed as to whether
these medications improve long-term outcomes, such as the need for nursing
home admission.
Cholinesterase inhibitors inhibit the enzymes that degrade acetylcholine
(acetylcholinesterase and/or butyrylcholinesterase), effectively increasing the
concentration of acetylcholine at synaptic clefts in the brain. Acetylcholine is a
neurotransmitter hypothesized to be important in cognition. Donepezil,
rivastigmine, and galantamine are all approved for the treatment of mild to
moderate AD. Donepezil and the patch preparation of rivastigmine are approved
for the treatment of severe AD. Tacrine, the first agent approved for use in AD,
is no longer available in the United States because it can cause hepatotoxicity,
specifically a transient and reversible transaminitis. These medications are
available in a variety of formulations: oral immediate-release tablet or capsule,
once-daily dosing tablet (donepezil only), extended-release preparations
(memantine and galantamine), oral-disintegrating tablet (donepezil only),
solution (rivastigmine and galantamine), and transdermal patch form
(rivastigmine only).
Researchers have studied another cholinesterase inhibitor, huperzine, an over-
the-counter Chinese herb extract whose safety is poorly understood. A recent
meta-analysis (Yang et al. 2013) suggests that huperzine may have some
beneficial effects on cognitive function, daily living activities, and global
clinical assessment in patients with AD; however, the study acknowledges that
its findings should be interpreted with caution due to the poor methodological
quality of the trials included.
Memantine, which is hypothesized to work by preventing the excitotoxic
effects of glutamate in the brain, is approved for the treatment of moderate to
severe AD. It is available in oral immediate-release, extended-release, and
solution preparations.
A summary of the four FDA-approved medications available in the United
States for the treatment of cognitive symptoms is provided in Table 8–8.
The approved cholinesterase inhibitors appear to have comparable efficacy.
However, because each of the medications has individual pharmacological
particularities as well as pharmacokinetic and pharmacodynamic properties that
make them distinct, a patient may respond to one medication over another
(Massoud et al. 2011). Prior to the development of the patch delivery form of
rivastigmine, approved in the United States in 2007, and the extended-release
form of galantamine, there were important differences in toxicity that entered
into the clinical decision about which medication to use first. Rivastigmine also
has biological activity against butyrylcholinesterase. Galantamine is also an
allosteric modulator of the nicotinic receptors. Despite differences in biological
activity, in the absence of solid relevant clinical data, the choice of agent
continues to be driven by ease of use and titration, cost, and physician
experience.
There is ample evidence to recommend initiating a cholinesterase inhibitor
for the treatment of mild to moderate AD, provided that the agent appears to
have a worthwhile effect on cognitive, global, functional, or neuropsychiatric
symptoms, and that a dementia care specialist initiates and routinely reviews
treatment (National Institute for Health and Care Excellence 2011). Although
memantine is frequently prescribed off-label for mild AD, independent reviews
have found no differences between memantine and placebo on any outcome for
patients with mild AD (Schwarz et al. 2012). Furthermore, these reviews
detected only small differences on some outcomes in patients with moderate AD
taking memantine (Schwarz et al. 2012). Thus, many experts recommend
against memantine for mild AD but recommend it as an option for moderate AD
only for patients who are intolerant of or have a contraindication to
cholinesterase inhibitors (National Institute for Health and Care Excellence
2011).

TABLE 8–8. FDA-approved medications available in the United States for

the treatment of cognitive symptoms in Alzheimer’s dementia
Drug Disease stage Preparations Dosing Common side effects
and dosing tips
Donepezil All stages of AD Oral tablet Initially 5 Nausea,
Once-daily mg/day. vomiting,
tablet May diarrhea,
increase anorexia,
Oral-
to 10 weight loss,
disintegrating
mg/day dyspepsia,
tablet
after 4–6 insomnia, and
weeks. vagotonic
effects leading
to bradycardia
and heart
block. Dosage
may have to be
reduced in
cases of hepatic
impairment.
Rivastigmine Mild to moderate AD Oral capsule Initially 1.5 Nausea,
Transdermal patch Oral solution mg twice vomiting,
also approved for Transdermal daily. diarrhea,
severe AD Increase anorexia,
patch
by 3 mg abdominal
Oral tablet and
every 2 pain, weight
transdermal patch
weeks as loss, dyspepsia,
also approved for
tolerated dizziness,
mild to moderate
to headache,
Parkinson’s disease
maximum extrapyramidal
dementia
dose of 6 symptoms,
mg twice central nervous
daily. system
depression, and
vagotonic
 effects leading
to bradycardia
and heart
block.
Gastrointestinal
side effects
may be reduced
if taken with
food and
dosage titrated
slowly. If
treatment
stopped for
more than
several days,
start titration
over with
initial dosage.
Galantamine Mild to moderate AD Oral tablet Initially 4 Nausea,
Extended- mg twice vomiting,
release daily. diarrhea,
capsule Increase anorexia,
to 8 mg weight loss,
Oral solution
twice dyspepsia,
daily after muscle cramps,
4 weeks. and vagotonic
May effects leading
increase to bradycardia
to 12 mg and heart
twice block.
daily if Associated
indicated. with increased
mortality,
mainly due to
cardiovascular
events, in some
placebo-
controlled
trials.
 Gastrointestinal
side effects
may be reduced
if taken with
food and
dosage titrated
slowly. Caution
in patients with
renal or hepatic
impairments.
Memantine Moderate to severe Oral tablet Initially 5 Dizziness,
AD (monotherapy Extended- mg/day. headache,
and in combination release May confusion,
with capsule increase constipation,
acetylcholinesterase by 5 mg and fatigue.
Oral solution
inhibitor) weekly to Caution in
maximum patients with
dose of renal or hepatic
20 mg impairments.
twice Dosage may
daily. have to be
Dosages reduced in
over 5 mg cases of renal
should be impairment.
divided.
Note. AD=Alzheimer’s disease; FDA=U.S. Food and Drug Administration.

Source. Data from Stahl SM: Essential Psychopharmacology: The Prescriber’s Guide, Revised and
Updated Edition. New York, Cambridge University Press, 2006.

Several RCTs and withdrawal studies suggest that in patients with moderate
or severe AD, cholinesterase inhibitors are associated with clinically relevant
cognitive and functional benefits (Schwarz et al. 2012). The available evidence
also supports the use of memantine in patients with severe AD (National
Institute for Health and Care Excellence 2011; Schwarz et al. 2012). There is no
consensus, however, on when to switch from cholinesterase inhibitors to
memantine in individuals with severe AD (Schwarz et al. 2012).
Most experts recommend and data support initiating and titrating one of these
medications to the highest approved and tolerated dose, and assessing response
over 6–12 months (Rabins et al. 2006). Cholinesterase inhibitors lead to notable,
albeit temporary, symptomatic improvements in 10%–15% of cases.
Symptomatic improvements often last for 6–9 months. In clinical practice, the
judgment as to the response to treatment relies greatly on the expectations that
patients, their families, and their prescribing physicians have with this class of
medications (Massoud et al. 2011). Mild improvement or stabilization should be
considered an appropriate and realistic goal (Massoud et al. 2011). There is no
consensus, however, on how to estimate clinical efficacy (Schwarz et al. 2012).
There is debate, however, about whether patients should continue taking a
cholinesterase inhibitor for a longer period of time. In primary care settings in
the United States, most patients who start a prescription do not continue taking it
for more than a few months. Nevertheless, many experts recommend continuing
therapy once it begins because patients may develop a rapid cognitive and
functional decline when a cholinesterase inhibitor is discontinued (Schwarz et
al. 2012). It is unclear whether clinical deterioration following discontinuation
of a cholinesterase inhibitor is due to a loss of therapeutic effect or withdrawal
from the medication (Schwarz et al. 2012).
Other experts point out that some patients do well after a discontinuation trial
and that many benefit from switching agents. Massoud et al. (2011) reviewed
eight open-label or retrospective switching studies involving patients in the mild
to moderate stages of AD. In general, more than 50% of patients switched for
unsatisfactory response showed stabilization or improvement in global
evaluations, cognitive measures, and functional measures. Additionally, more
than 50% of individuals switched for intolerance tolerated the second agent. The
authors concluded that because cholinesterase inhibitors have individual
pharmacological properties, switching is a valid clinical choice for patients with
AD who either do not tolerate or have a lack of response to the initial agent.
They considered significant deterioration within the first 6 months of treatment
to represent a “lack of efficacy” and deterioration beyond the first 6 months of
treatment to represent “loss of efficacy” (measured by a decline of at least 2
points on the MMSE, as well as a documented deterioration in functional
autonomy, global impression, or behavior). The authors suggested that either a
lack or a loss of efficacy was a reasonable justification for switching agents. On
the other hand, they did not recommend switching for loss of response with the
initial cholinesterase inhibitors beyond 1 year of use, because this is most often
due to the natural course of AD (most evident during the transition from mild to
moderate or from moderate to severe stages). In these latter cases, the authors
recommended adding memantine to the cholinesterase inhibitor. In practice,
however, less than one-third of patients actually switch cholinesterase inhibitors.
One of the authors of this chapter (CGL) has followed a patient who benefited
from sequential use of four of the cholinesterase agents (huperzine, donepezil,
rivastigmine, and galantamine). Although clearly that was an extreme case,
which is probably quite rare, it points out that the issue of long-term therapy is
not a settled matter.
Although cholinesterase inhibitors and memantine are licensed for
monotherapy, combining the two types of drugs could theoretically potentiate
their benefits (Schwarz et al. 2012). Even though it is common practice to
combine cholinesterase inhibitors with memantine, many experts do not endorse
this practice because of a lack of clinical evidence to support additional benefit
(National Institute for Health and Care Excellence 2011; Schwarz et al. 2012).
Several randomized trials and observational studies demonstrated no additional
(or inconclusive) superiority of combination donepezil and memantine over
donepezil monotherapy (National Institute for Health and Care Excellence
2011).
Although clinical trials have suggested that cholinesterase inhibitors may be
of value in treating vascular dementia, none has been approved by the FDA for
that purpose. The results of one study suggest that compared with placebo,
donepezil is associated with increased mortality in vascular dementia. The
National Institute for Health and Care Excellence (2012) recommends that
cholinesterase inhibitors and memantine should not be prescribed clinically for
the treatment of cognitive decline in individuals with vascular dementia.
Both oral and transdermal preparations of rivastigmine have been approved
for the treatment of mild to moderate dementia in PDD. In a large, parallel-
group RCT of rivastigmine in PDD (Emre et al. 2004), patients who received
rivastigmine demonstrated an average 1-point advantage on the MMSE over the
24-week treatment period compared with those who received placebo. The
treatment group also demonstrated an average advantage of nearly 3 points on
the Alzheimer’s Disease Assessment Scale—Cognitive subscale, particularly in
areas of attention and executive function; 2 points on an ADLs scale; and 2
points on the total Neuropsychiatric Inventory score. In a Cochrane review of
cholinesterase inhibitors for PDD, DLB, and MCI associated with PD, Rolinski
et al. (2012) determined that current evidence supports the use of cholinesterase
inhibitors in patients with PDD, with a positive impact on global assessment,
cognitive function, NPSs, and ADLs. However, evidence from RCTs for
cholinesterase inhibitors other than rivastigmine is inconclusive (Ballard et al.
2011). Likewise, although memantine is well tolerated, it does not appear to
demonstrate positive effects on nonmotoric symptoms in PDD (Schwarz et al.
2012).
 Cholinesterase inhibitors have been effective in treating cognitive impairment
in DLB, although this is considered an off-label use. Furthermore, they have
demonstrated therapeutic benefit in treating hallucinations and are considered
first-line therapy for treating psychosis in DLB. Studies on use of memantine for
DLB have been inconclusive (Schwarz et al. 2012). At best, memantine seems
to provide modest positive global effects in DLB. However, benefits from
memantine treatment are rapidly lost following discontinuation.
Although no cholinesterase inhibitors have demonstrated value in treating
cognitive deficits in patients with FTLD, a medication trial is reasonable when
the underlying cause of dementia is unclear.

Therapies for Neuropsychiatric Symptoms in Dementia

NPSs are nearly universal in patients with dementia, affecting up to 98% of
individuals across dementia stages and etiologies (Kales et al. 2014; Lyketsos et
al. 2011). They are associated with poor patient outcomes, including excess
morbidity and mortality, more rapid disease progression, increased health care
utilization, and earlier nursing home placement. NPSs are also associated with
negative caregiver outcomes, including stress, depression, reduced employment,
and poorer quality of life. Thirty percent of the cost of caring for community-
dwelling patients with dementia can be directly attributed to NPS management.
Nevertheless, there continues to be uncertainty about how to manage these
symptoms. A detailed discussion of the evaluation and management of NPSs in
dementia is beyond the scope of this chapter. We articulate a few principles here
from Kales et al. (2014) and Lyketsos et al. (2011); Rabins et al. (2006) provide
a more in-depth discussion.
A useful mnemonic for the management of NPSs is DICE: Describe,
Investigate, Create, and Evaluate (Kales et al. 2014). The describe phase
involves an evaluation in which the patient, caregivers, and other relevant
informants accurately characterize what is occurring behaviorally. This phase
enables the provider to identify underlying patterns or contributory factors to the
behavior. Another important goal of this phase is to determine what aspects of
the NPSs are most disturbing or problematic for the patient and caregiver, as
well as to establish the treatment goal.
During the investigate phase, the clinician examines the patient and identifies
potential underlying and modifiable etiologies. Contributing factors include
undiagnosed medical conditions (e.g., pain, infections, constipation,
dehydration), medication side effects and drug-drug interactions, underlying
psychiatric comorbidity (e.g., depressive or anxiety disorders), limitations in
functional abilities, poor sleep hygiene, boredom, psychological factors (e.g.,
feelings of inadequacy, helplessness, fear), sensory impairments (e.g., hearing,
vision), and environmental factors (e.g., over- or understimulating environment,
lack of predictable routine, diminished pleasurable activities). Table 8–9 lists
major components contributing to NPSs. In general, most disturbances are
multifactorial, and it is best to address several contributing factors at once. The
workup for underlying causes often includes laboratory studies.
In the create phase, the person with dementia, the caregiver, and the
treatment team (provider, visiting nurse, social worker, occupational therapist)
collaborate to design and implement a treatment plan. The plan consists of
behavioral, environmental, pharmacological (prescribing medications and/or
discontinuing medications contributing to NPSs), and educational approaches
that target the identified causes. For example, a provider might treat a patient’s
urinary tract infection or constipation while simultaneously teaching the
caregiver not to rush the patient during toileting and to use a combination of
scheduled and prompted toileting for incontinence. A provider may educate a
caregiver about sleep hygiene while simultaneously tapering the patient’s
daytime sedating medications that contribute to excessive napping. The plan
should target physical problems (aggressively managing pain, constipation,
dehydration, sleep disturbances, sensory impairments, and infections),
underlying psychiatric conditions, safety concerns (e.g., putting safety knobs on
stoves, eliminating throw rugs, removing weapons, providing sufficient
lighting), and other environmental factors (e.g., establish structured routines and
meaningful activities for the patient). Caregivers provide important insight as to
what has worked for the patient and what has not. Taking into account the
patient’s interests, the team can more effectively tailor a patient-specific
treatment plan. Providers can assist caregivers by modeling problem solving,
giving constructive feedback, providing emotional support, validating that what
the caregivers are doing is important, and ensuring that they are taking care of
themselves.

TABLE 8–9. Contributing causes of neuropsychiatric symptoms

A biological stress or delirium that accompanies a recurrent or new medical
condition (e.g., constipation, urinary or upper respiratory infection, pain, poor
dentition, headaches, hunger, thirst)
An identifiable psychiatric syndrome that is either recurrent or associated with
the dementia
Aspects of the cognitive disturbance itself (e.g., a catastrophic reaction due to
 inability to express oneself vocally)
An environmental stressor (e.g., excessive noise or stimulation, unfamiliar
surroundings, not enough heat)
Unmet needs (e.g., hunger, thirst, feeling lonely)
Unsophisticated or intrusive caregiving (e.g., poor communication, being
rushed)
Medication side effects, whether from new medications or previously
prescribed medications

Finally, the evaluate phase involves assessing whether an intervention was

attempted and whether it was effective. If the caregiver implemented an
intervention, it is important to evaluate whether the NPSs improved, whether the
intervention helped to decrease the patient’s and caregiver’s distress, and
whether there were any unintended side effects or consequences. If the caregiver
did not implement an intervention, the provider should attempt to understand
why not and brainstorm solutions with the caregiver. If the intervention included
a psychotropic medication, the provider and caregiver should sequentially
monitor behaviors and potential new side effects, and consider a trial of tapering
the dose or discontinuing the medication to ensure that the medication continues
to be necessary.
Because of the increased risks inherent in using medications to treat NPSs in
patients with dementia, the clinician should consider using nonpharmacological
interventions as first-line therapy. The exception is in emergency situations
when NPSs could compromise the safety of the patient or others, in which case
the standard of care supports psychotropic use (Kales et al. 2014). Small studies
have shown modest benefit with aromatherapy, bright light therapy, music
therapy, controlled multisensory stimulation (Snoezelen rooms), animal-assisted
therapy, exercise programs, physical therapy, occupational therapy, and speech
therapy. Some of these therapies are useful during a treatment session but have
no longer-term benefits. Behavioral therapy using a behavioral monitoring log
can help identify triggers to avoid or manage, and can provide sustained
improvements in behavior in individuals with dementia. A Cochrane review and
meta-analysis (Moniz Cook et al. 2012) suggested that functional analysis
(where a therapist develops an understanding of the function or meaning behind
the patient’s distress and symptoms) is associated with a decrease in the
frequency of challenging behaviors and an improvement in the caregiver’s
reaction to them. However, it is too early to draw conclusions regarding the
efficacy of this method. A stable, structured, predictable environment that
avoids over- or understimulation can be very beneficial for a patient. Distraction,
redirection, removing environmental cues (e.g., car keys) for behaviors
caregivers want to discourage (e.g., driving), or offering simple choices can be
effective in decreasing agitation and anxiety. Educating caregivers and
professional staff about how to manage NPSs can lead to reductions in patients’
behavioral outbursts and less restraint use. Psychotherapy can be a useful
strategy, particularly in early dementia, with patients who are anxious,
depressed, or demoralized. Interventions with the best evidence to support their
use are outlined in Table 8–10.
Although extensive effort has been put into developing nonpharmacological
approaches, little controlled evidence is available to suggest that they work, and
they are often difficult to implement in real-world settings, especially in primary
or institutional care (Livingston et al. 2005). A study of newly admitted nursing
home residents demonstrated that within the first 3 months of admission, only
12% received nonpharmacological interventions, whereas 71% received at least
one psychotropic medication (Molinari et al. 2010). Furthermore, more than
15% were taking four or more psychotropic medications. Of those treated with
psychotropics, 64% had not received psychopharmacological treatment for the 6
months preceding admission and 71% had not received a psychiatric diagnosis
during the same time frame.
No pharmacotherapy has FDA approval for dementia-related NPSs. Despite
well-known, significant concerns about the safety and efficacy of psychotropic
medications in treating NPSs in individuals with dementia, clinicians commonly
use these drugs to manage these symptoms. Clinicians routinely prescribe these
medications without first methodically assessing potential underlying causes of
behaviors. Clinicians may use a “symptom cluster” approach, in which they
match a medication to a symptom that resembles a known symptom of an illness
(e.g., mood stabilizers for decreased sleep and pressured speech or
antidepressants for dysphoria and apathy). Because dementia is usually
progressive and NPSs can fluctuate over time, clinicians and caregivers may be
trying to hit a “moving target” with psychotropics. Caregivers frequently
attempt to manage several NPS disturbances concomitantly, often with more
than one medication, contributing to an unpredictable and undecipherable
outcome. Even in the few cases where psychotropics, specifically
antipsychotics, demonstrate modest efficacy in improving NPSs, the benefits
may be negated by significant adverse effects. Psychotropic medications are
unlikely to affect poor self-care or refusal of care, memory problems,
inattention, unfriendliness, repetitive verbalizations or questioning, shadowing,
or wandering (Kales et al. 2014). They are also unlikely to improve behaviors
that can ultimately be attributed to apraxia or agnosia (e.g., urinating in a trash
can because it resembles a toilet bowl). If medication treatments are indicated, it
is important to follow guidelines similar to those outlined in Table 8–11. Sink et
al. (2005) published a widely employed algorithm for using medications to treat
NPSs in dementia.

TABLE 8–10. General nonpharmacological strategies for managing

neuropsychiatric symptoms
Domain Key strategies
Behavior
management
Memory-related Identify self and others if patient does not remember names
problems (e.g., or is aphasic.
disorientation or Use memory aids (calendar or white board showing current
confusion with date).
object
Keep all objects for a task in a labeled container (e.g.,
recognition)
grooming).
Supervise medication taking and secure medications.
Present a single object at a time.
Paint doors to identify or disguise them.
Falling and poor Remove clutter or unnecessary objects.
balance Use a fall alert system if the patient can remember to
activate.
Consider referral to occupational therapy for home safety
evaluation and removal of tripping hazards.
Consider referral to physical therapy for simple balance
exercise.
Minimize alcohol intake.
Hearing voices or Evaluate hearing and adjust amplification of hearing aids.
noises (especially Evaluate quality and severity of auditory disturbances.
at night)
If hallucinations are present, evaluate whether they present
an actual threat to safety or function in deciding whether
to treat with antipsychotics.
Wandering or Educate caregiver about the need to supervise patient.
inability to Inform neighbors, fire department, and police of patient’s
respond to condition.
emergency
Develop emergency plan involving others if possible.
(difficulty calling
for help) Outfit with an ID bracelet (e.g., Alzheimer Safe Return
Program).
Identify potential triggers for elopement and modify them.
Nighttime Implement good sleep hygiene.
wakefulness, Evaluate environment for disturbances such as temperature,
turning on lights, noise, light, shadows, and level of comfort.
awaking
Eliminate caffeinated beverages (starting in the afternoon).
caregiver, feeling
insecure at night Create a structured schedule that includes exercise and
activities throughout the day.
Limit daytime napping.
Use night-light.
Create a quiet routine for bedtime that includes a calming
activity and calming music.
Address daytime loneliness and boredom that may
contribute to nighttime insecurities.
Hire nighttime assistance to enable caregiver to sleep.

Repetitive Respond using a calm, reassuring voice.

questioning Use a light touch to reassure, calm, or redirect.
Inform patient of events as they occur (vs. indicating what
will happen in the near or far future).
Use distraction.

Care management
Communication Use a calm, reassuring voice.
Avoid negative words and tone.
Use a light touch to reassure, calm, or redirect.
Allow patient sufficient time to respond to a question.
Help patient find words to express himself or herself.
 Offer simple choices (no more than two at a time).
Simplifying the Use labeling or other visual cues.
environment Remove unnecessary objects to reduce confusion with
tasks.
Eliminate noise and distractions while you are
communicating or when patient is engaging in an activity.
Use simple visual reminders (e.g., arrows pointing to
bathroom).
Caregiver Understand that patient behaviors are not intentional.
education and Learn how to relax the rules (e.g., baths do not have to
support happen daily; there is no right or wrong in performing
activities or tasks as long as the patient and caregiver are
safe).
Go along with patient’s view of what is true and avoid
arguing or trying to reason or convince.
Task structuring Break each task into very simple steps.
Provide one- to two-step simple verbal commands.
Use verbal or tactile prompts for each step.
Provide structured daily routines that are predictable.
Activities Engage patient with meaningful activities that tap into
preserved capabilities and previous interests.
Introduce activities involving repetitive motion (washing
windows, folding towels, and putting coins in container).
Guide and cue the patient to initiate, sequence, organize,
and complete tasks.
Note. Domains and strategies listed are potential approaches used in randomized clinical trials but are not
exhaustive. One strategy may be effective for one patient but not another. Only consider the above
strategies following a thorough assessment and diagnostic workup.

Source. Adapted from Gitlin LN, Kales HC, Lyketsos CG: “Nonpharmacologic Management of Behavioral
Symptoms in Dementia.” Journal of the American Medical Association 308(19):2020–2029, 2012. Used
with permission.

Several different classes of medications have been studied. For some of them,
safety concerns exist and efficacy remains uncertain. The use of both
conventional and atypical antipsychotics is controversial because their efficacy
is modest and they have been associated with side effects (including rapid
cognitive decline), a higher risk of cerebrovascular or cardiovascular events, and
mortality in patients with dementia (Schneider et al. 2005). The FDA has issued
black box warnings regarding the use of antipsychotics in treating patients with
dementia-related psychosis (U.S. Food and Drug Administration 2008). Both
conventional and atypical antipsychotics carry this increased mortality risk in
dementia, whereas other psychotropic medications, such as antidepressants and
anticonvulsants, do not.

TABLE 8–11. Guidelines for use of medications to treat neuropsychiatric

symptoms
Differentiate which disturbance is present; they are not all the same.
Consider possible contributing causes and the need for medical workup.
Implement nonpharmacological interventions concomitantly.
Use medications cautiously, with defined targets and close monitoring for
adverse effects potentially caused by psychotropic medications.
Educate caregivers to notify clinicians immediately should the patient develop
an adverse drug reaction.
Routinely review the risk-benefit ratio of treatment.
Avoid knee-jerk prescribing of psychotropics in response to symptoms to better
elicit the underlying cause(s).
Be mindful that select isolated disturbances are unlikely to respond to
medications.
Use of psychotropics should always be time limited, because symptoms may
resolve over time with or without pharmacological treatment.
Have in place a backup plan and a plan to deal with after-hours crises.
Source. Adapted from Gitlin LN, Kales HC, Lyketsos CG: “Nonpharmacologic Management of Behavioral
Symptoms in Dementia.” Journal of the American Medical Association 308(19):2020–2029, 2012. Used
with permission.

Antipsychotic medications are the core treatments of agitation and psychosis.

In the Clinical Antipsychotic Trial of International Effectiveness—Alzheimer’s
Disease, risperidone and olanzapine showed the most, albeit modest, benefit of
symptom reduction as assessed by various rating scales. Antipsychotics had no
effect on other outcomes such as cognition, functioning, or quality of life
(Sultzer et al. 2008). Although these antipsychotics are not contraindicated in
dementia, the risk-to-benefit ratio is high, and they should be used with caution
(Rabins and Lyketsos 2005). Some RCTs have demonstrated that antipsychotics
can be discontinued for the majority of individuals receiving chronic
antipsychotic therapy without a worsening of behavior (Seitz et al. 2013).
However, the Antipsychotic Discontinuation in AD trial showed that after
patients with AD and psychosis or agitation achieved and maintained treatment
response with risperidone (mean dose of 0.97 mg/day) for 4–8 months, a switch
from risperidone to placebo in a randomized, double-blind manner was
associated with a markedly increased risk of relapse relative to continuing
risperidone (Devanand et al. 2012). Predictors of successful discontinuation of
antipsychotics include lower baseline severity of NPSs and lower dosages of
antipsychotics to receive symptom control (Seitz et al. 2013). For a more
detailed description of the pharmacological treatment of agitation and psychosis
in the context of dementia, see Chapter 19, “Agitation and Suspiciousness,” and
Chapter 11, “Schizophrenia Spectrum and Other Psychotic Disorders,”
respectively, in this textbook.
Patients with DLB present an additional challenge to antipsychotic therapy
because they are extremely sensitive to the extrapyramidal side effects of all
antipsychotics except clozapine. Adverse events range from parkinsonism to
acute dystonia to neuroleptic malignant syndrome. Clinicians should avoid use
of conventional antipsychotics in patients with DLB. Similarly, although
antipsychotics can be useful in treating visual hallucinations and delusions
associated with PDD, they need to be used with caution due to the inherent risk
of exacerbating parkinsonian symptoms. Quetiapine and especially clozapine are
the least likely to worsen parkinsonism.
There is evidence to suggest that selective serotonin reuptake inhibitors
(SSRIs), such as citalopram (Porsteinsson et al. 2014; Seitz et al. 2013),
sertraline (Lyketsos et al. 2003), and escitalopram (Seitz et al. 2013), are
efficacious in treating agitation, depression, and apathy in patients with
Alzheimer’s dementia. Double-blind trials comparing the serotonin antagonist
and reuptake inhibitor trazodone with placebo, however, have not shown benefit
in the treatment of NPSs (Ballard and Corbett 2010). Although the rates of
adverse events with antidepressants may be less than those observed with
antipsychotics, antidepressants should in no way be considered harmless (Seitz
et al. 2013). In older adults serotonergic agents are associated with adverse
events, including injurious falls (evident even at low doses but increasing by as
much as threefold at higher doses), fractures, bleeding, and hyponatremia
(Schwarz et al. 2012; Seitz et al. 2013). There are also reports that SSRIs induce
an amotivational or apathy syndrome, which is reversible when the medication
is stopped or the dose decreased (Berman et al. 2012). Some observational
studies have demonstrated an increased risk of stroke and death as well (Seitz et
al. 2013).
Recent RCTs have demonstrated that citalopram and escitalopram may be as
effective as risperidone or perphenazine and more effective than placebo in
hospitalized populations with dementia and NPSs (Seitz et al. 2013). One recent
randomized placebo-controlled, double-blind trial, the Citalopram for Agitation
in Alzheimer Disease study, evaluated 186 patients with probable AD and
clinically significant agitation (Porsteinsson et al. 2014). Over 9 weeks,
compared with patients given placebo, patients treated with citalopram 30
mg/day showed a clinically relevant, significant reduction of agitation on several
rating scales. This improvement is comparable to that of antipsychotic drugs in
other trials (Porsteinsson et al. 2014). Adverse events were modest and
consistent with known side effects of SSRIs (e.g., gastrointestinal complaints,
respiratory tract infections, falls). Compared with patients given placebo,
patients treated with citalopram demonstrated a 1-point greater decline in
MMSE scores over 9 weeks. Although the clinical significance of this effect on
cognition is unclear, this decline is less than what experts consider to be a
minimum clinically significant change (1.4 points). It is also unclear whether the
cognitive effect continues beyond 9 weeks and whether citalopram adversely
affects the course of AD. One limitation of using citalopram (and escitalopram,
the active S-isomer of citalopram), however, is a dose-dependent risk of QT
prolongation, potentially leading to torsades de pointes. This risk generated an
FDA advisory warning in 2011 stating that citalopram should no longer be used
at daily dosages greater than 20 mg/day in individuals older than 60 years
because of the potential for cardiac electrical abnormalities (U.S. Food and Drug
Administration 2012). There are insufficient data on the efficacy of citalopram
for agitation at doses lower than 30 mg/day (Porsteinsson et al. 2014).
Evidence is limited regarding the efficacy of cholinesterase inhibitors and
memantine for NPSs, but these drugs may help delay the emergence of
symptoms or treat very mild symptoms. In general, they should not be
considered first-line agents in managing acute NPSs of moderate or greater
severity until better evidence of their efficacy emerges (Weintraub and Katz
2005).
Multiple meta-analyses suggest that evidence to support the use of
antidepressants to treat comorbid depression in AD is weak at best (Schwarz et
al. 2012; Sepehry et al. 2012). However, these meta-analyses were limited by
the heterogeneity of their included studies, with differing criteria for the
diagnosis of depression, the compound tested, and outcome measures for
depression. Many clinical trials also excluded more severely depressed patients,
likely limiting the apparent treatment benefit in these studies (Ballard and
Corbett 2010).
Choosing an antidepressant is complicated because of the frailty and
susceptibility to side effects of many individuals with dementia (Ballard and
Corbett 2010). Tricyclic antidepressants are limited by significant adverse
effects (e.g., confusion, falls due to orthostatic hypotension, cardiac
arrhythmias). There is only one study looking at venlafaxine, a serotonin-
norepinephrine reuptake inhibitor (SNRI), in the treatment of depression in
dementia. This small placebo-controlled, double-blind, randomized study
showed essentially no difference in improvement on a depression rating scale
between low-dosage venlafaxine (mean immediate-release doe of 75 mg/day,
with a range from 37.5 to 131.25 mg/day) and placebo groups at 6 weeks (de
Vasconcelos Cunha et al. 2007). There also was no statistically significant
difference in the incidence of adverse events between the groups. No clinical
studies have been done of either duloxetine, an SNRI, or bupropion, a
norepinephrine-dopamine reuptake inhibitor, for depression in dementia.
Randomized placebo-controlled trials of sertraline and mirtazapine have
demonstrated an absence of benefit of antidepressants over placebo after 3
months of treatment (Banerjee et al. 2011; Rosenberg et al. 2010; Weintraub et
al. 2010). Patients with AD and depression who received antidepressants did not
show improvement in global cognition (Sepehry et al. 2012); moreover, patients
treated with antidepressants experienced an increased rate of adverse events.
Experts emphasize, however, that the limited evidence of efficacy of
antidepressant therapy from clinical trials should not be used as a reason to
withhold antidepressant treatment from a patient with AD who is severely
depressed (Ballard and Corbett 2010). Various international organizations (e.g.,
British Psychological Society, Royal College of Psychiatrists, Canadian
Consensus Conference on Dementia) recommend treating an individual with
dementia and depression with antidepressants (giving preference to an SSRI or
to avoiding medications with anticholinergic effects) if the patient has had an
inadequate response to nonpharmacological interventions (e.g., increasing
pleasant activities and social interactions), after carefully assessing the risk-
benefit ratio (Sepehry et al. 2012). Although the duration of treatment is unclear,
a general rule of thumb is to treat major depression for at least 6 months.
Little is known about treating depression associated with other types of
dementia because most studies have focused on AD. SSRIs may be efficacious
in treating depression and anxiety associated with DLB. Observational studies
have demonstrated some benefit for SSRIs in reducing disinhibition, anxiety,
depression, impulsivity, repetitive behaviors, and eating disorders in patients
with FTLD. In the absence of any specific evidence guiding the treatment of
depression in other non-AD dementias, clinicians should follow the same
treatment approaches as they would for depression in AD (Ballard and Corbett
2010).
Few studies have examined treatments for apathy in dementia. Even fewer
have targeted apathy as a primary outcome. These studies tended to be open-
label, were underpowered, involved mixed dementias, and had a wide range of
definitions for apathy. Cholinesterase inhibitors have the best evidence for
improving or stabilizing apathy, with no clear indication that any one
cholinesterase inhibitor is superior to the other (Berman et al. 2012). There is
some evidence for modest benefits of memantine, mixed evidence for benefits of
atypical antipsychotics, and no good evidence to support using antidepressants,
antiepileptics, or traditional antipsychotics to treat apathy (Berman et al. 2012).
Potential adverse effects limit the use of these classes of medications. Despite a
perception that apathy is treatable with stimulants, only a handful of small
eligible trials of methylphenidate since 1975 have shown significant
improvement. The most recent study to evaluate methylphenidate in dementia,
the Apathy in Dementia Methylphenidate Trial, compared methylphenidate 20
mg/day to placebo in a 6-week, randomized, double-blind trial (Rosenberg et al.
2013). Methylphenidate treatment was associated with significant improvement
in two out of three efficacy outcomes. Global cognition trended toward
improvement with methylphenidate but was not statistically significant.
Although the methylphenidate group experienced minimal significant adverse
events overall, this group trended toward experiencing weight loss and greater
anxiety. Apathy tends to be chronic and progressive; for this reason, it is unclear
when to initiate treatment and how long to continue treatment. Treatment may
be useful if a patient’s quality of life can potentially be improved, if the patient
has excessive disability, or if a patient’s caregiver is significantly distressed or
burdened by the repercussions of this symptom (Berman et al. 2012). Long-term
therapy may be indicated if a patient demonstrates a positive response to
medications.
A comprehensive discussion on the treatment of sleep disorder in dementia is
beyond the scope of this chapter. A useful first step is to take an individualized
sleep inventory (Roth 2012). A widely used sleep inventory is the Epworth
Sleepiness Scale (Johns 1991). After identifying which type of sleep disorder
(e.g., difficulty falling asleep at night, excessive daytime sleepiness, restless leg
syndrome, obstructive sleep apnea) is present and which symptoms are most
pressing to the patient and/or caregiver, the dementia team can tailor treatments
to the specific disorder and symptoms. As a general rule, the team should
discontinue medications causing the symptoms, implement
behavioral/nonpharmacological measures (e.g., sleep hygiene, hiring nighttime
assistants to enable the caregiver to sleep, continuous positive airway pressure
therapy for obstructive sleep apnea), and attempt to identify underlying
problems and target specific issues before treating general symptoms (Camargos
et al. 2014; Roth 2012). There is a paucity of studies evaluating pharmacological
interventions of sleep disorders in dementia. Many of the extant studies have
been limited by a small sample size, retrospective data collection, open-label
testing, or the fact that sleep was evaluated as a secondary outcome (Camargos
et al. 2014). Trials evaluating the effects of triazolam, haloperidol, and
melatonin on sleep have had disappointing results (Camargos et al. 2014).
Quetiapine and mirtazapine are sometimes used to treat sleep difficulties (e.g.,
quetiapine may improve rapid eye movement sleep behavior disorder) but can
worsen restless legs syndrome and periodic limb movements of sleep (Roth
2012). The typical starting dose of quetiapine is 12.5 mg/day (increasing in
increments of 12.5 mg). The typical starting dose of mirtazapine is 7.5 mg/day,
and the dose can be increased by increments of 7.5 mg; however, it is important
to remember that higher doses tend to be less sedating (Roth 2012). A recent
double-blind, placebo-controlled study of trazodone in AD patients with sleep
disorders demonstrated promising results (Camargos et al. 2014). Compared
with individuals in the placebo group, individuals who received trazodone 50
mg/day slept 42.5 more minutes per night and experienced no drug effect on
daytime sleepiness, naps, cognition, or function. More in-depth discussions of
the etiology, evaluation, and treatment of sleep disorders in specific dementias
are provided in Chapter 16, “Sleep and Circadian Rhythm Disorders,” and in
Roth (2012).

Supportive Care for Patients

An estimated 60%–70% of older individuals with AD and other dementias live
in the community and are cared for by family members and friends (Theis et al.
2013). Nearly all (up to 99%) of community-residing individuals with dementia
have unmet needs for care, services, and support (Black et al. 2013). Unmet
dementia-related needs increase the risk of undesirable health outcomes, nursing
home placement, and death (Black et al. 2013). It is critical to provide
systematic supportive care to patients with dementia. The first step is for
patients, caregivers, and team members to collaborate to determine unmet care
needs. A needs assessment is an efficient tool to help identify these gaps. Once
an assessment is completed, the patient, caregiver, and team can prioritize unmet
needs by importance and feasibility, and then devise a tailored treatment plan to
meet these needs.
The MIND at Home study recently set out to determine the prevalence and
correlates of unmet needs in a sample of community-residing individuals with
dementia and their informal caregivers (Black et al. 2013). Using a dementia
care needs assessment (Black et al. 2008), evaluators were able to determine the
proportion of unmet items in six pre-specified need categories: evaluation and
treatment of memory symptoms, NPS management, home and personal safety,
general health and medical care, daily and meaningful activities, and legal issues
and advance care planning. Participants, study partners, and primary care
physicians received the written results of the assessment, which included
recommendations for each identified unmet need. Coordinators then conducted
an in-home visit with each participant and study partner; they reviewed and
prioritized needs and then developed a care plan. Care components could be
individually tailored to unmet needs and updated based on emergent needs of
either participants or caregivers. A coordinator helped guide the study partner
and/or participant (when appropriate) on implementing the plan. Ninety percent
of participants had unmet home and personal safety needs, particularly for
wander and fall risk management and for home safety evaluations. More than
60% of participants had unmet general health and medical care needs, including
the need to see their primary care provider, medical subspecialist, or a dental,
vision, or hearing specialist. Over 50% had unmet meaningful activities needs,
including the need for adult day care, attending senior centers, and in-home
activities. Forty-eight percent had unmet legal issues and advance care planning
needs. Almost 33% of participants had not received a prior evaluation or
diagnosis of dementia. Higher unmet needs for individuals with dementia was
significantly associated with nonwhite race, lower income, early-stage dementia
and less impairment in ADLs, more symptoms of depression, and caregivers
with lower education.
Table 8–12 lists supportive areas that a dementia care team should address in
every case (Lyketsos et al. 2006). Teams should educate patients, when
appropriate, about their condition, including giving them their diagnosis and
anticipated course. Early diagnosis can provide opportunities to initiate
treatments for dementia symptoms and to help individuals and families plan for
future care (Black et al. 2013). When patients, caregivers, and clinicians
recognize medical conditions earlier, the costs of care may be lowered, quality
of life improved, and hospitalizations prevented (Black et al. 2013). Supportive
care for patients should be aimed at preserving their dignity, maintaining optimal
physical and mental health, encouraging their abilities to persist for longer
periods of time, and making life easier for their caregivers. Teams should work
with caregivers to find safe environments that maximize remaining physical and
cognitive abilities, within the restrictions of the environment. Ideally,
environments would permit patients to be well nourished and hydrated, receive a
certain amount of activity and socialization, receive support for their ADLs and
IADLs, and maintain good sleep hygiene. In-home activities customized to the
interests and capabilities of individuals with dementia can significantly increase
their engagement, reduce NPSs, and reduce caregiver burden (Black et al. 2013).
An in-home occupational therapy assessment, using a functional assessment
method such as the Assessment of Motor and Processing Skills (Fisher 2003),
can provide useful data about a patient’s level-of-care needs and about home
safety. Additional information about providing supportive care for patients is
available in the book The 36-Hour Day by Mace and Rabins (2011) and from
the Alzheimer’s Association Web site (www.alz.org).
Community-dwelling adults with dementia generally receive more care from
caregivers as their disease progresses (Theis et al. 2013). The daunting tasks of
caregivers include assisting with ADLs, managing the individual’s safety and/or
NPSs, identifying and navigating a loose network of long-term care support
services, facilitating health care visits, advocating for the patient, and making
proxy financial and health care decisions (Black et al. 2013). All of this work
occurs within a context of loss—both losses for the individual with dementia
and losses for his or her caregiver (Black et al. 2013). These caregivers often
face greater burdens and stress than do caregivers of individuals with other
illnesses, and depression is common (Black et al. 2013). Caregiver burnout can
affect not only the caregiver but also the patient. Stress, deteriorating mental and
physical health, and financial hardships can have deleterious effects on the
patient. Caregiver stress is predictive of nursing home admission for individuals
with dementia, and unmet caregiver needs are associated with lower quality of
life (Black et al. 2013). In the MIND at Home study, almost all caregivers (97%)
had one or more unmet needs (Black et al. 2013). More than 85% of caregivers
had unmet needs for referrals to community resources (e.g., Alzheimer’s
Association) and caregiver education (e.g., developing caregiver skills and
learning how dementia impacts individuals and their loved ones). More than
40% of caregivers also had unmet needs for mental health care. Nonwhite race,
less education, and more symptoms of depression was significantly associated
with higher unmet caregiver needs.

TABLE 8–12. Supportive care for patients

Provide comfort and emotional support.
Address safety concerns with regard to driving, living alone, environmental
hazards (eliminating access to dangerous items), medications, falls, and
wandering (using a monitoring device).
Maintain a safe, predictable place to live with graded support (as little help as
possible), role modeling, and cueing for activities of daily living and
instrumental activities of daily living.
Provide structure, activity, and stimulation in day-to-day life to maximize
remaining abilities and function.
Provide environmental cues for behaviors (e.g., laying out clothing for self-
care).
Assist with decision making.
Aggressively manage medical comorbidities.
Maintain up-to-date advance directives and advance care planning decisions.
Provide good nursing care in advanced stages.

TABLE 8–13. Supportive care for the caregiver

Provide comfort and emotional support.
Educate the caregiver about dementia.
Instruct caregiver on the skills of caregiving and support him or her with
problem-solving techniques.
Ensure that an expert clinician is always available for consultation, especially
for crisis intervention.
Encourage respite from caregiving.
Encourage caregiver to maintain a social network.
Attend to the caregiver’s general and mental health, including scheduling
preventive health care visits.

Because caregivers are the lifeline of the patient and are greatly affected by
dementia, they should be involved intimately in the development and
implementation of any dementia care program. As with addressing unmet needs
of individuals with dementia, a needs assessment can serve as a useful
foundation to gather data on unmet caregiver needs. Table 8–13 lists key
intervention areas involving caregivers (Lyketsos et al. 2006; Rabins et al. 2006;
Selwood et al. 2007). Mittelman et al. (2006) highlight the importance of the
delivery of interventions to caregivers. Their work suggests that caregiver
interventions can have effect sizes as large as or larger than medications in
delaying out-of-home placement for patients with dementia. Central to good
dementia care is making sure that caregivers are educated about dementia, have
an understanding of the diagnosis, are able to access resources, use respite
appropriately, and have an expert available around the clock to help them in
times of crisis.

Key Points
• Dementia is an epidemic clinical syndrome consisting of global cognitive
decline and memory deficits, with at least one other area of cognition
affected.
• Dementia can be accurately diagnosed and differentiated from cognitive
impairment not dementia and mild cognitive impairment.
• Amnestic mild cognitive impairment is likely the prodrome to Alzheimer’s
dementia, the most common form of dementia.
• The evaluation and differential diagnosis of dementia and of mild
neurocognitive disorders involve an initial focus on defining the
phenomenology of the syndrome and its associated features, followed by a
workup for a putative clause.
• The four pillars of dementia treatment are disease treatment, symptom
treatments, supportive care for the patient, and supportive care for the
caregiver. All of these areas must be addressed in contemporary dementia
care. A needs assessment is an efficient tool to help identify unmet care
needs.
• The concept of treatable and nontreatable dementias is no longer relevant; all
dementias are treatable, albeit not necessarily curable. One of the most
effective therapies for Alzheimer’s disease is aggressively managing
associated vascular risk factors.
• The amyloid cascade hypothesis of Alzheimer’s disease is rapidly evolving,
impacting clinical trials. Trials have started targeting prevention of
Alzheimer’s disease with antiamyloid therapies.
• Neuropsychiatric symptoms are nearly universal across dementia stages and
etiologies. No pharmacotherapy has U.S. Food and Drug Administration
 approval for dementia-related neuropsychiatric symptoms.
Nonpharmacological interventions can be as effective as currently available
medications and should be considered first-line therapy except in emergency
situations.
• Disease-modifying therapies in Alzheimer’s disease have largely been
unsuccessful, and there are no disease-modifying treatments available for
dementia with Lewy bodies, Parkinson’s disease dementia, frontotemporal
lobar degeneration, or Creutzfeldt-Jakob disease. Cholinesterase inhibitors
provide only modest and temporary stabilization of the changes to cognition
and ADLs associated with the disease. They do not reverse or stop the
degenerative process.

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 CHAPTER 9

Depressive Disorders
Dan G. Blazer, M.D., Ph.D.
David C. Steffens, M.D., M.H.S.

Questions regarding depression in old age are frequently posed: Do

persons become more depressed as they grow older? Does depression
become more difficult to treat with increased age? Is depression more
difficult to identify in the older adult? The answers to these questions rest in
part with the definition of late-life depression. Depression in late life is not
a unitary construct. Depending on how depression is defined, the answers to
questions regarding late-life depression vary.
Depression can be construed in at least three ways, each of which has
clinical relevance for older adults. First, depression can be viewed as a
unitary phenomenon, with the various manifestations of depression forming
a continuum. Depression symptom checklists, such as the Center for
Epidemiologic Studies Depression Scale (CES-D; Radloff 1977) and the
Geriatric Depression Scale (GDS; Yesavage et al. 1982–1983), are useful in
determining the degree to which an individual suffers from depression in
late life.
Most modern investigators, however, find it difficult to conceive of
depression as phenomenologically homogeneous. A categorical approach,
as exemplified in DSM-5 (American Psychiatric Association 2013), has
been of more interest to modern clinicians. If one views the mood disorders
as a group of distinct entities or independent syndromes, with each being
mutually exclusive, diagnosis and management of depression are allied with
the traditional medical model. Given the availability of excellent, albeit
potentially dangerous, biological therapies for depressed older adults, the
categorical approach has been adopted by most geriatric psychiatrists.
Specific therapies can be prescribed for distinct diagnostic entities.
The third approach to the conceptualization of the depressed elder is a
functional approach: when depressive symptoms become so severe that
functioning is impaired, the case is considered worthy of clinical attention.
Social functioning, especially the performance of role responsibilities, has
been targeted as a critical variable in monitoring treatment. Examples of the
functional approach can be found in many surveys of community subjects,
such as the Older Adults Resources and Services assessment (Fillenbaum
1988; Shulman 1986). Functional capacity is a critical element for family
members, who do not view symptom remission alone as an essential marker
of improvement but rather consider a return to social involvement and
improved life satisfaction as critical signs. An older adult who sleeps better,
has a better appetite, and ceases to be suicidal may be determined to be
improved by the clinician but little improved by the family, if the patient’s
social isolation and disinterest in the social environment persist after
appropriate therapy. The clinician can use a V code to document problems
in the social environment, such as Problem Related to Living Alone
(V60.3).
Clinical entities classified with mood disorders in DSM-5 that are
relevant to depression in elderly patients include the following: 1) bipolar
and related disorders, 2) major depressive disorder (either with or without
psychotic features), 3) persistent depressive disorder (dysthymia), 4)
depressive episode with insufficient symptoms (previously called minor or
subsyndromal depression), 5) substance/medication-induced depressive
disorder, and 6) depressive disorder due to another medical condition.
Depressive symptoms are likewise present in other disorder categories in
DSM-5; for example, persistent complex bereavement disorder is listed
under the DSM-5 category “other specified trauma- and stressor-related
disorder” and also included in the DSM-5 chapter “Conditions for Further
Study”; and adjustment disorder with depressed mood is classified with the
DSM-5 trauma- and stressor-related disorders (Table 9–1).

TABLE 9–1. Subtypes of depression in later life

Bipolar and related disorders
Depressive disorders
Major depressive disorder (encompasses symptoms in response to a
significant loss that meet criteria for a major depressive episode)
Psychotic depression (i.e., major depressive disorder with psychotic
features)
Persistent depressive disorder (dysthymia)
Minor or subsyndromal depression (i.e., depressive episode with
insufficient symptoms)
Substance/medication-induced depressive disorder
Depressive disorder due to another medical condition
Trauma- and stressor-related disorders
Adjustment disorder with depressed mood
Persistent complex bereavement disorder (coded under “other specified
trauma-or stressor-related disorder”)

Manic episodes in later life may present with a mixture of manic,

dysphoric, and cognitive symptoms, with euphoria being less common (Post
1978). When mania is associated with significant changes in cognitive
function—so-called manic delirium—it may be difficult to distinguish from
organic conditions or schizophrenia (Shulman 1986). Such disorders are
often associated with substance or medication use and are so identified in
DSM-5.

Epidemiology
An overview of the epidemiology of psychiatric disorders in late life is
presented in Chapter 1, “Demography and Epidemiology of Psychiatric
Disorders in Late Life”; in this chapter, we discuss information relevant to
mood disorders. Using a community survey, investigators at Duke
University Medical Center attempted to untangle the different subtypes of
depression in late life (Blazer et al. 1987b). More than 1,300 older adults in
urban and rural communities who were age 60 or older were screened for
depressive symptomatology. Of the 27% reporting depressive symptoms,
19% had mild dysphoria only. Persons with symptomatic depression—that
is, subjects with more severe depressive symptoms—made up 4% of the
population. These individuals were primarily experiencing stressors, such
as physical illness and stressful life events. Only 2% had dysthymia, and
0.8% were experiencing a current major depressive episode. No cases of
current manic episode were identified.
In another study, the frequency of major depression in the community
was approximately 3.7% among individuals ages 75–84 and 2.1% among
those ages 75 years and older (Center for Multicultural Mental Health
Research 2012); 1.2% had a mixed depression and anxiety syndrome. These
data suggest that the DSM-5 depression categories do not apply to most
depressed older adults in the community. Surveys have confirmed the lower
frequency of major depression in the community (Kessler et al. 2005).
In hospital and long-term-care settings, the frequency of major
depression among older adults is much higher than in community settings.
Up to 21% of hospitalized elders meet criteria for a major depressive
episode, and an additional 20%–25% have minor (subsyndromal)
depression (Koenig et al. 1988). Rates of major depression among elderly
nursing home patients are even higher, exceeding 25% in some studies
(Parmelee et al. 1989).
How does one reconcile these seemingly disparate results? “Depression
in late life” remains a generic term that captures many constructs, some of
which are well defined and others of which are ill defined. The burden of
depression in elderly patients, as indicated by the just-described frequency
of significant depressive symptoms in community populations, is
unquestioned. Many older persons with atypical presentations of depression
do not meet criteria for major depression yet have clinically significant
depressive symptoms (Hybels et al. 2001).
The Epidemiologic Catchment Area surveys identified a bipolar disorder
in 9.7% of nursing home patients, which suggests that nursing homes may
have become a dumping ground for such patients (Weissman et al. 1991). In
clinical settings, a bipolar disorder has been identified in about 10%–25%
of geriatric patients with a mood disorder and 3%–10% of all older
psychiatric patients (Wylie et al. 1999; Young and Klerman 1992). About
5% of all individuals admitted as geropsychiatry inpatients present with
mania (Yassa et al. 1988).
Clinical Course
Episodes of depression across the life cycle, especially episodes of more
severe major depression, almost always remit or at least partially remit.
Nevertheless, depression is a chronic and recurrent illness. Data from a
community study from the Netherlands illustrate this chronicity. Among
subjects with clinically significant depressive symptoms, 23% improved,
44% experienced an unfavorable but fluctuating course, and 33%
experienced a severe and chronic course. In a second group of subjects with
less severe depression, 25% experienced a chronic course. Overall, 35% of
those subjects diagnosed with major depression and 52% of the subjects
diagnosed with DSM-IV dysthymic disorder experienced a chronic course
(Beekman et al. 2002).
Studies that have focused on older adults in clinical settings have found
similar chronicity (Alexopoulos et al. 1996; Baldwin and Jolley 1986;
Murphy 1983; Post 1962). In an early study, Post (1962) followed a clinical
sample for 6 years and found that 31% recovered and remained well over
the follow-up, 28% experienced at least one relapse but later recovered, and
23% only partially recovered, whereas 17% remained depressed throughout
the period of follow-up. Murphy (1983) followed a group of elderly
depressed subjects (many of whom were medically ill) over 1 year. Of those
subjects, 35% experienced a good outcome, 48% experienced a fluctuating
course or remained continuously ill, and 14% died. In an Australian study
of a group of elderly patients who were followed for 25 years after
experiencing severe depression earlier in life, only 12% fully remitted and
experienced no recurrences over the period of follow-up (Brodaty et al.
2001). The prognosis from clinical studies of depressed older adults with
late-life depression, however, is similar to that found among younger adults
if the older adult is not plagued with comorbid medical illness, functional
impairment, or cognitive impairment (Keller et al. 1982a, 1982b).
Comorbid depression is associated with a less favorable prognosis. For
example, when major depressive disorder is comorbid with persistent
depressive disorder (dysthymia), the prognosis is poor. Factors predicting
partial remission were similar to those predicting no remission, and poor
social support and functional limitations increased the risk for poor
outcome in these subjects (Hybels et al. 2005).
 Cognitive impairment is often associated with depressive symptoms.
When the depression improves, the cognitive impairment often improves as
well. Nevertheless, comorbid depression and cognitive impairment are a
risk factor for the later emergence of Alzheimer’s disease (Alexopoulos et
al. 1993). Therefore, early depressive symptoms associated with mild
cognitive impairment may represent a preclinical sign and should be
considered a risk for impending Alzheimer’s disease or vascular dementia
(Li et al. 2001). Depression can further complicate Alzheimer’s disease
over time by increasing disability and physical aggression, thereby
contributing to depression among caregivers (González-Salvador et al.
1999). Depressive symptoms resolve spontaneously without requiring
intensive therapy (such as medication therapy) at a greater frequency
among patients with Alzheimer’s disease than among older adults
experiencing depression and vascular dementia, in whom depressive
symptoms tend to be persistent and refractory to drug treatment (Li et al.
2001). Considerable study in recent years has focused on structural brain
changes and the outcome of depression in elderly individuals. For example,
Ribeiz et al. (2013) found that both a lower baseline score on the Mini-
Mental State Examination (MMSE; Folstein et al. 1975) and lower baseline
orbitofrontal cortex volume predicted a poorer outcome.
Depression and medical problems are frequently comorbid, and the
causal pathway may be bidirectional (Blazer and Hybels 2005). Depression,
for example, is a frequent and important contributing cause of weight loss
in late life (Morley and Kraenzle 1994). Frailty, leading to profound weight
loss, can in turn contribute to clinically important depressive symptoms
(Fried 1994). Many chronic medical illnesses are associated with
depression, including cardiovascular disease, diabetes, osteoporosis, and hip
fracture, to name a few (Blazer et al. 2002b; Lenze et al. 2007; Lyles 2001;
Williams et al. 2002). The mechanisms that explain the close association
between depression and physical illness in older adults are for the most part
not well documented. Clues, however, have emerged. For example, platelet
activation is increased in older depressed patients, especially those with a
specific polymorphism in the serotonin transporter–linked promoter region.
This polymorphism leads to higher levels of platelet aggregation and β-
thromboglobulin, both pathophysiological changes that increase the risk for
myocardial infarction (Whyte et al. 2001).
 Perhaps the best-established association between depression and
physical problems is that between depression and functional impairment
(Blazer et al. 1991; Bruce 2001). For example, in one study, older adults
who were depressed were 67% more likely than those who were not
depressed to experience impairment in activities of daily living and 73%
more likely to experience mobility restrictions 6 years following initial
evaluation (Penninx et al. 1999b). Disability, in turn, can increase the risk
for depressive symptoms (Kennedy et al. 1990; Roberts et al. 1997).
Explanations for this bidirectional association include the following: the
propensity for physical disability to lead to a higher frequency of negative
life events, which in turn increases the risk for depression; the loss of
independence and the concomitant need to depend on others; restricted
social and leisure activities secondary to physical disability; and the
isolation and reduced quality of social support often inherent with physical
disability (Blazer 1983). Functional decline, however, is not inevitable
when the older adult becomes depressed. For example, the instrumental
support provided to older adults, such as help in tasks necessary for daily
living, can be protective against the worsening of performance on
instrumental abilities, and therefore buffer against the onset of depression
(Hays et al. 2001).
Despite the frequency and clinical importance of late-life depression,
long-term psychiatric follow-up investigations involving survivors of severe
episodes of this disorder have been relatively scarce. The typical course of
major depression throughout the life cycle is remission and relapse. In
patients who have a history of recurrent episodes, new episodes tend to be
associated with similar symptoms and to last about as long as prior
episodes. Classic studies of depression suggest that the duration of major
depression throughout the life cycle is approximately 9 months if untreated
(Dunner 1985). As individuals age, however, they may experience episodes
more frequently, and these episodes can merge into a chronic condition.
Most clinicians and clinical investigators report that more than 70% of
elderly patients with major depression who are treated with antidepressant
medication (at an adequate dose for a sufficient time) recover from the
index episode of depression if the depression is uncomplicated by comorbid
factors. Reynolds et al. (1992) reported that treatment of physically healthy
depressed elders with combined interpersonal psychotherapy and
nortriptyline was associated with response rates nearing 80%. In a long-
term outcome study of treatment-resistant depression in older adults, 47%
of patients were clinically improved 15 months after treatment with an
antidepressant or electroconvulsive therapy (ECT); at 4-year follow-up, the
percentage had increased to 71% (Stoudemire et al. 1993). These optimistic
results are tempered by the fact that physical illness and impaired cognition
may complicate both the course of depression and the response to treatment
(Baldwin and Jolley 1986; Koenig et al. 1989a; Murphy et al. 1988). Once
an older patient has experienced one or more moderate to severe episodes
of major depressive disorder, he or she may need to continue antidepressant
therapy permanently to minimize the risk of relapse (Reynolds et al. 2006).
Persons with a persistent depressive disorder (dysthymia) experience a
more chronic clinical course than do persons with major depressive
disorder. By DSM-5 definition, an individual’s depressive symptoms must
last at least 2 years for a diagnosis of dysthymia to be made. An
undetermined percentage (as high as 4%–8%) of community-dwelling (and
possibly institutionalized) elders experience moderately severe depressive
symptoms for more than 2 years, although they report intermittent periods,
lasting longer than a few days, of relative freedom from depressive
symptoms. The severity of their symptoms is not great enough to meet the
criteria for major depressive disorder, and the intermittent symptom-free
periods disqualify them from the diagnosis of persistent depressive disorder
(dysthymia). Nevertheless, these individuals experience chronic depression.
Other older adults experience chronic depression secondary to medical or
even psychiatric disease (e.g., alcoholism, obsessive-compulsive disorder).
Each of these disorders contributes to residual depression in ambulatory
elderly individuals.
Factors associated with improved outcome in late-life depression include
a history of recovery from previous episodes, a family history of
depression, female gender, extroverted personality, current or recent
employment, absence of substance abuse, no history of major psychiatric
disorder, less severe depressive symptomatology, and absence of major life
events and serious medical illness (Baldwin and Jolley 1986; Cole et al.
1999; Post 1972). The results of a number of studies suggest a relationship
between social support during an index episode and outcome in
psychological distress and depression. Intuition suggests that adequate
support should enhance recovery from a severe or moderately severe
psychiatric disorder such as major depression. In a study involving 493
community respondents, Holahan and Moos (1981) found that decreases in
social support of family and within work environments were related to
increases in psychological maladjustment over a 1-year follow-up period.
Coping behavior may also affect the prognosis of late-life depression.
One of the coping behaviors most commonly used by recent generations of
older adults is religious involvement. In a study involving 100 middle-aged
or elderly adults, one-third of men and nearly two-thirds of women used
religious cognitions or behaviors to help them cope with a stressful period
(Koenig et al. 1988). A number of investigators have reported inverse
associations between religious coping and depressive symptoms in older
adults with or without medical illness (Braam et al. 1997b; Idler 1987;
Koenig 2007a; Koenig et al. 1992; Pressman et al. 1990). A study involving
850 hospitalized medically ill older adults found that those using religion to
cope were less likely to be depressed and more likely to experience
improvement in depressive symptoms over time (Koenig et al. 1992).
Religious involvement also appears to be a predictor of faster recovery from
depression in both community-dwelling and clinical samples of older adults
(Braam et al. 1997a; Koenig 2007b; Koenig et al. 1998).
Personality pathology is another measurable phenomenon that is known
to affect the outcome of major depression (Weissman et al. 1978).
Unfortunately, there are no published reports of personality as a predictor of
major depression outcome in elderly patients. In addition, studies with
mixed-age samples have generally been confounded by the interaction of
depressive symptomatology and personality variables at baseline
assessment—that is, a depressed affect may influence the underlying
personality. Given the stability of personality in late life, longitudinal
studies of relationships between personality and both onset and outcome of
major depression would be most helpful.
The outcome of bipolar disorder in elderly individuals remains virtually
unknown. In a long-term follow-up study involving 500 patients in Iowa,
Winokur (1975) found that bipolar disorder tended to occur in clusters over
time and speculated that early-onset bipolar illness may “burn itself out” in
time. Shulman and Post (1980) studied elderly patients with bipolar
disorder and found that only 8% had their first episode of mania before age
40. In a review of records of a small number of untreated patients with
severe and prolonged bipolar disorder, Cutler and Post (1982) found a
tendency toward more rapid recurrences late in the illness, with decreasing
periods of remission. In other words, if bipolar disorder reemerges in the
later years, the episodes of mania—or mania mixed with depression—may
once again cluster, just as the disorder typically clusters at earlier periods of
life. Most clinicians who have worked with patients with bipolar disorder in
late life recognize the tendency of these disorders to recur frequently for a
time, only to remit for an extended period.
Ambelas (1987) emphasized a relationship between life events and onset
of mania, noting that stressful events were more likely to precede early-
onset mania than late-onset mania. Likewise, Shulman (1989) stressed that
increased cerebral vulnerability due to organic insults (stroke, head trauma,
other brain insults) played a stronger role than life events in precipitating
late-onset mania (a factor that may also play a role in treatment resistance).
Young and Klerman (1992) emphasized the low rates of familial affective
disorder and the increased frequency of certain diseases and drug use
associated with late age at onset.
Controversy exists over whether age at onset of first manic episode
affects response to treatment. Glasser and Rabins (1984) described no
significant age-related differences in presentation or treatment response.
Young and Falk (1989) reported that late-onset mania was associated with
lower activity level, lower sexual drive, and less-disturbed thought
processes; however, they also found that older age was associated with
longer hospitalization, greater residual psychopathology, and poorer
response to pharmacotherapy. Eastham et al. (1998) suggested that elderly
patients with bipolar disorder often require lithium dosages that are 25%–
50% lower than those used in younger patients. Data on the use of valproic
acid in elderly patients with bipolar disorder are limited but encouraging.
There is almost no information on the use of carbamazepine or other drugs
in late-life bipolar disorder. ECT has been reported to be well tolerated and
effective in the treatment of these patients (Eastham et al. 1998).
All-cause mortality is a significant adverse outcome resulting from late-
life depression. In one review of multiple reports, 72% of the studies
demonstrated a positive association between depression and mortality in
elderly people (Schulz et al. 2002). In another review of 23 outcome studies
of depression in subjects ages 65 years and older, the pooled odds of dying
if subjects were depressed were 1.75 (Geerlings et al. 2002). A longer
follow-up predicted smaller effect size. Both severity and duration of
depressive symptoms predicted mortality in the elderly population in these
studies (Geerlings et al. 2002). For example, investigators from the
Epidemiologic Catchment Area study found a fourfold increase in the odds
of dying over a follow-up of 15 months if persons over age 55 years
experienced a mood disorder (Bruce and Leaf 1989). Also, community-
dwelling persons in the Netherlands who experienced both major and minor
depression were at increased risk for cardiac mortality (Penninx et al.
1999a).
The association between depression and mortality holds in many of these
studies, despite the addition of potentially confounding variables. In studies
from North Carolina and New York, however, investigators failed to find an
association (Blazer et al. 2001; Thomas et al. 1992).
One reason for the lack of association in some studies may be the
selection of specific control variables, especially chronic disease and
functional impairment. For example, in a study of the North Carolina
Established Populations for Epidemiologic Study of the Elderly cohort, the
unadjusted relative odds of mortality among depressed subjects at baseline
was 1.98 (Blazer et al. 2001). These odds moved toward unity when other
risk factors, such as chronic disease, were controlled, and when health
habits, cognitive impairment, functional impairment, and social support
were added to the model. Therefore, the specific control variables used in
mortality studies may determine the association between depression and
mortality.
The effect of depression on mortality may vary by sex. In elderly
Japanese American men but not women, depressive symptoms were a risk
for mortality in the physically healthy (Takeshita et al. 2002). In another
study, depressive symptoms were a significant risk factor for cardiovascular
but not cancer mortality in older women (Whooley and Browner 1998). In a
controversial report, investigators found that subthreshold depression, as
indicated by CES-D scores of 12–16, was not associated with mortality in
men but was negatively related to 3-year mortality in women (odds ratio
0.56) (Hybels et al. 2002). In other words, mild depressive symptoms were
protective in this highly controlled analysis of community-based data.
Murphy et al. (1988) examined all-cause mortality in a 4-year follow-up
study involving 120 depressed elderly psychiatric inpatients, comparing
them with 197 age- and gender-matched control subjects. Among the
depressed women, mortality was twice the expected rate; among the men, it
was three times the expected rate. Older men with physical health problems
and depression were significantly more likely to die than were similarly
aged, physically ill, nondepressed men. A study involving elderly veterans
hospitalized with medical illness found a significantly higher mortality rate
during hospitalization for 41 patients who were depressed than for 41
nondepressed patients matched for age, gender, and severity and type of
medical illness (Koenig et al. 1989b). Rovner et al. (1991) also found
higher death rates among elderly nursing home patients with depression.
Several other studies involving medically ill elderly patients like-wise
found greater mortality rates among those with depression than among
those without (Arfken et al. 1999; Black 1999; Covinsky et al. 1999).
These studies indicate higher rates of mortality for depressed elderly
patients (men in particular) with concurrent physical health problems; in
clinical samples, this relationship persisted after important covariates were
controlled. The association between late-life depression and mortality is
intuitively attractive, because older persons are thought to experience loss
of meaningful roles and emotional support through retirement, death of
friends or a spouse, decreased economic and material well-being, and
increased isolation and loneliness (Atchley 1989; Fassler and Gaviria
1978). When poor physical health compounds these age-related changes,
depression may be particularly prone to affect health outcomes.

Etiology1

Biological Origins
Genetics
The etiology of late-life affective disorders is undoubtedly multifactorial
(Table 9–2). Twin and family studies, along with studies focusing on
molecular genetics, provide strong evidence for a heritable contribution to
the etiology of major depression and bipolar disorder (Gatz et al. 1992).
Evidence that these genetic factors weigh heavily in the etiology of bipolar
disorders in late life is virtually nonexistent, although the biological nature
of this disorder would suggest some genetic contribution. Evidence from
studies of unipolar depression in late life suggests that the genetic
contribution is weaker in late-life depression than in depression at earlier
stages of the life cycle. In a study of elderly twins in Sweden, genetic
influences accounted for 16% of the variance in total depression scores on
the CES-D and 19% of the somatic symptoms. In contrast, genetic
influences minimally contributed to the variance of symptoms of depressed
mood and positive affect (Gatz et al. 1992).
Hypothesized genetic markers for late-life depression have usually not
stood the test of well-controlled studies, yet some studies present intriguing
possibilities. Many candidate genes, such as genes encoding enzymes for
serotonin synthesis, the norepinephrine transporter, and even the
neurotrophic factor, have been hypothesized and explored in animal studies.
As yet, however, these hypotheses await further testing in older adults with
depression (Smith et al. 2007). Some pharmacological studies with
depressed elders have shown associations between speed of response and
antidepressant side effects with the serotonin transporter promoter
polymorphism (Pollock 2000).
Despite many studies of the allele producing the ε4 type of
apolipoprotein E (APOE*E4), no association was found in a community
sample between APOE*E4 and depressive symptoms (Blazer et al. 2002a),
although in a clinical sample of 500 subjects, Yen et al. (2007) found that
APOE*E4 was associated with more severe depression, after adjusting for
vascular diseases and lipid profile. Investigators have also concentrated on
genes that may be associated with cerebrovascular lesions that are
associated with depression. In one study, subjects with late-onset major
depression exhibited a higher frequency of C677T mutation of the
methylene tetrahydrofolate reductase enzyme compared with control
subjects. This mutation may place older persons at risk for major depression
associated with cerebrovascular lesions (vascular depression) (Hickie et al.
2001). In another study, carriers of the C1166 allele of the type 1
angiotensin II receptor gene (AGTR1) had greater ratios of lesioned to
nonlesioned white matter tissue across multiple tracts (Taylor et al. 2013b).

TABLE 9–2. Origins of late-life depression

Biological risk factors
Genetics (e.g., abnormalities in the serotonin transporter gene)
Female sex
Neurotransmitter dysfunction (e.g., underactivity of serotonergic
neurotransmission)
 Endocrine changes (e.g., long-standing elevated blood levels of cortisol)
Vascular changes (e.g., vascular depression secondary to subcortical
vascular changes)
Medical illness (e.g., cardiovascular disease)
Other psychiatric disorders (e.g., long-standing anxiety disorder)
Psychological risk factors
Personality attributes (e.g., hopelessness, ambivalence)
Neuroticism
Cognitive distortions (e.g., feelings of abandonment when left alone for
short periods)
Social origins
Stressful life events (e.g., death of a close friend, change of residence)
Chronic stress or strain (e.g., residence in an unsafe neighborhood)
Low socioeconomic status

Neurotransmitter Dysfunction
Decreased activity of serotonergic neurotransmission has been the focus of
much research on the pathophysiology of depression in younger adults.
Dysfunctions in the transmission of norepinephrine and dopamine have also
been implicated. Serotonin activity, specifically 5-HT2A receptor binding,
decreases dramatically in a variety of brain regions through midlife, yet
there is less decrease from midlife to late life. 5-HT2A receptors in normal
subjects decreased markedly from young adulthood to midlife (70% from
the levels at age 20 years through the fifth decade) and then leveled off as
age advanced (Sheline et al. 2002). Activity of these receptors, however,
may vary with age.

Endocrine Changes
Hypersecretion of corticotropin-releasing factor (CRF) has been associated
with depression for many years across the life cycle. CRF is thought to
mediate sleep and appetite disturbances, reduced libido, and psychomotor
changes (Arborelius et al. 1999) and is diminished with normal aging
(Gottfries 1990). Aging is associated with an increased responsiveness of
dehydroepiandrosterone sulfate to CRF (Luisi et al. 1998).
Serum testosterone levels decline with aging (Liverman and Blazer
2004) and have been found to be even lower in elderly men with dysthymia
than in men without depressive symptoms (Seidman et al. 2002). The
efficacy of testosterone treatment for major depression in men, however,
has not been established (Liverman and Blazer 2004). In women,
improvement of mood has resulted from hormone replacement (Sherwin
and Gelfand 1985).
Endocrine dysregulation over time has been associated with anatomical
changes related to late-life depressive symptoms, suggesting a vicious cycle
downward to chronic and moderately severe depressive symptoms.
Depressive symptoms have been hypothesized to cause atrophy of the
hippocampus (Sapolsky 1996, 2001; Sheline et al. 1996; Steffens et al.
2002). Stress that accumulates over the life cycle may lead to a sustained
increase in secretion of cortisol, leading to loss of preexisting hippocampal
neurons (Sapolsky 1996). This loss may be prevented in part by use of
antidepressant medications (Czéh et al. 2001).

Vascular Depression
For many years vascular risk factors have been known to be associated with
depressive symptoms (Post 1962). Because major depression is a frequent
outcome of stroke (Robinson and Price 1982) and hypertension (Rabkin et
al. 1983), investigators have proposed a vascular-based depression among
elderly individuals (Coffey et al. 1990; Krishnan et al. 1988; Kumar et al.
2002; Olin et al. 2002; Post 1962). In a study of 139 depressed older
individuals, 54% met neuroimaging criteria for subcortical ischemic
vascular depression. Age was most strongly associated with the increased
prevalence of subcortical changes; also associated were lassitude, a history
of hypertension, and poorer outcome (Krishnan et al. 2004; Taylor et al.
2013a). In a U.S. sample, vascular depression was more prevalent among
African American elderly persons than among Caucasians (Reinliebb et al.
2014). Vascular depression is associated with white matter hyperintensities
(Guttmann et al. 1998; Krishnan et al. 1997). These lesions probably
contribute to the disruption of neural circuits associated with depression
(Taylor et al. 2013a).
Clinical symptoms and signs associated with these vascular impairments
resemble impairments found in frontal lobe syndromes. Magnetic resonance
imaging (MRI) of depressed patients has revealed structural abnormalities
in areas related to limbic-cortical-striatal-pallidal-thalamic-cortical
pathways (George et al. 1994), including the frontal lobes (Krishnan et al.
1993), caudate (Krishnan et al. 1992), and putamen (Husain et al. 1991;
Sheline 2003). In MRI studies of mood disorders, structures that make up
this tract show volume loss or structural abnormalities (Sheline 2003).

Medical and Psychiatric Comorbidity

Myocardial infarction and other heart conditions often lead to late-life
depression (Sullivan et al. 1997), as do diabetes (Blazer et al. 2002b), hip
fracture (Magaziner et al. 1990), and stroke (Robinson and Price 1982). In a
survey of community-dwelling Mexican Americans, depressive symptoms
were found to be associated with diabetes, arthritis, urinary incontinence,
bowel incontinence, kidney disease, and ulcers (Black et al. 1998). Poor
functional status secondary to physical illness and dementing disorders are
the most important causes of depressive symptoms in older adults (Bruce
2001; Hays et al. 1997). For example, in one longitudinal study, depressive
symptoms increased the risk for activities of daily living disability and
mobility disability by 67% and 73%, respectively, over 6 years (Penninx et
al. 1999b). Depressive symptoms are consistently associated with health
status in cross-sectional studies of older adults (Kraaij et al. 2002);
however, the association is not always clear-cut (Fiske et al. 2003). In one
study, for example, health status was associated with depressive symptoms,
but new illnesses in the previous 3 years did not consistently predict
increases in depressive symptoms (Fiske et al. 2003).
Late-life depression is frequently comorbid with other biologically
driven psychiatric disorders (although comorbidity with other disorders,
except dementia, is less frequent in late life than earlier in the life cycle),
and these other disorders may contribute to the depressive symptoms.
Alcohol use and major depression frequently co-occur, as would be
expected, in community studies of older adults (Devanand 2002). Anxiety
is a common symptom comorbid with depressive symptoms, whether or not
the depressive symptoms meet criteria for a depressive disorder (Blazer et
al. 1989).
Biological vulnerability to depressive symptoms and disorders appears to
be greater in late life than in midlife. Brain changes coupled with the
increased frequency of diseases known to be associated with depression are
typical of the aging process, especially as the individual advances into the
era of the oldest old (Blazer 2000). These biological factors may be related
to the finding from a systematic review that late-life depression is
associated with a significant risk of all-cause dementia, Alzheimer’s
disease, and vascular dementia (Diniz et al. 2013).

Psychological Origins
Psychological factors, such as personality attributes, neuroticism, cognitive
distortions, and emotional control, may contribute to the onset of late-life
depression but are not specific to the origins of depression in older
individuals. Therefore, we briefly address some related studies.
In a study comparing older patients with and without personality
disorder, Morse and Lynch (2004) found that those with a personality
disorder were four times more likely to continue with or experience a
reemergence of depressive symptoms. Specific personality traits were not
correlated with clinical features of depression, such as age at onset and
number of previous episodes. Nevertheless, some of the traits were
associated with depressive symptoms such as hopelessness. Basic
personality attributes often underlie the origin and expression of depressive
symptoms in older adults.
Neuroticism—a construct rarely studied by psychiatrists in North
America despite being popular in Europe and Australia—is consistently
associated with late-life depressive symptoms in cross-sectional and
longitudinal studies of community samples (Henderson et al. 1993, 1997;
Lyness et al. 2002) and older adults in residential homes (Eisses et al.
2004). Cognitive distortions (Beck 1967) are among the most studied
psychological origins of depression across the life cycle. Depressed
individuals may overreact to life events or misinterpret these events and
exaggerate their adverse outcome. For example, in a study of the experience
and impact of adverse life events, older patients with major depression
reported more adverse life events in the recent past and a greater negative
impact of these events (particularly for interpersonal conflicts) than did
comparison groups of elderly patients with dysthymia and healthy control
subjects (Devanand et al. 2002). It is not clear whether the reported impact
reflects an increased vulnerability to events or a bias in reporting due to
current depressed mood. In another study from a community sample,
elderly persons with more frequent depressive symptoms used acceptance,
rumination, and catastrophizing (maladaptive cognitive distortions) to a
higher extent and positive reappraisal to a lower extent than did those with
fewer symptoms (Kraaij and de Wilde 2001). Presence of neuroticism was
associated with poor mood and cognitive outcomes among treated older
patients followed up to 3 years (Steffens et al. 2013).
Beekman and colleagues, in the Longitudinal Aging Study Amsterdam
(Beekman et al. 1995), found that major and minor depression, as well as
the persistence and emergence of depressive symptoms over 3 years, were
predicted by external locus of control (Beekman et al. 2001). Higher levels
of mastery—that is, a perception of being able to accomplish tasks and
having control over one’s life—have been shown to have a direct
association with fewer depressive symptoms in older individuals and to
buffer the adverse impact of disability on depression (Jang et al. 2002).
Self-efficacy may have a direct effect and also may work indirectly through
its effect on social support to prevent depressive symptoms, as indicated in
a sample of older adults followed for 1 year (Holahan and Holahan 1987).
In a study of patients with insomnia and depression, dysfunctional beliefs
about not being able to function and needing to avoid activities after a night
of disrupted sleep were related to mental and physical fatigue (Carney et al.
2014).

Social Origins
In addition to having biological and psychological origins, late-life
depression derives from social origins, including stressful life events,
bereavement, chronic stress or strain, low socioeconomic status, and
impaired social support. The relative contribution of these factors appears to
vary across the life cycle.
Some years ago, Murphy (1982) found a strong association between both
severe life events (e.g., bereavement, life-threatening illness of someone
else, major personal illness) and social difficulties (e.g., difficulties in
health of someone close to subject, housing issues, marital and family
relationships) with the onset of late-life depression. Elders lacking a
confidant were especially vulnerable to the effects of life stress. Social
support may therefore buffer the effect of a stressful event. The association,
however, may not be straightforward. Based on a meta-analysis of 25
studies of the relationship between negative life events and depression in
late life, Kraaij et al. (2002) reported that the total number of life events and
the total number of daily hassles were strongly associated with depressive
symptoms, as would be expected. In contrast, sudden unexpected events
were not related to depression.
Compared with younger adults, older adults are at greater risk for
depressive symptoms secondary to stressful life events. At least three
factors, however, modify this risk. First, ongoing problems may have a
smaller effect on the risk for depression in older individuals than in younger
individuals (Bruce 2002). For example, in one study, the onset of depressive
symptoms was not associated with baseline psychosocial stressors but was
associated with factors that changed through time (Kennedy et al. 1990).
Second, stressful events that are predictable or “on-time” events often cause
less depression in older adults than in younger adults. For example, death of
a spouse is a severe and at times catastrophic event leading to depression.
For young or middle-aged adults, this event is unexpected and the
adjustment is especially difficult. Older adults, in contrast, recognize that
death of a spouse is expected (by observing their peers) and have actually
rehearsed the event, such as by considering what they might do if a spouse
dies. Third, many events that can lead to depression, such as divorce and
difficulties with the law, are more frequent early in life than in late life. In
one study, significant difficulty with the law (something more serious than a
traffic violation) was reported during the preceding year by 9% of younger
individuals but less than 1% of older individuals (Hughes et al. 1988).
Bereavement is a common cause of depressive symptoms in late life
(Clayton 1990; de Beurs et al. 2001; Prigerson et al. 1994). In a study of
1,810 community-dwelling older adults, onset of clinically significant
depressive symptoms over a 3-year follow-up was predicted by death of a
partner or other relatives (Prigerson et al. 1994). Although some studies
have found bereavement to predict depressive symptoms, others have not
(Prince et al. 1998).
 Yet another common cause of depression in later life is chronic strain.
For example, the prevalence of depressive symptoms in caregivers of
people with dementia is 43%–47% (Livingston et al. 1996; Waite et al.
2004). Therefore, providing support for caregivers is important to prevent
the onset and progression of depression in this vulnerable group of elders.
In cross-sectional analyses using data from a community study of older
Mexican Americans, financial strain was associated with level of depressive
symptoms (Black et al. 1998).
Lower socioeconomic status has been associated with depression across
the life cycle. Both the frequency of depressive symptoms and their
persistence over 2–4 years were associated with socioeconomic
disadvantage in a sample of community-dwelling adults ages 50 years and
older who originally met criteria for major depression (Mojtabai and Olfson
2004). In another study, although the level of education did not predict
emergence of depressive symptoms over 1 year, emergence of depression
over a 3-year period was predicted by lower level of education (Beekman et
al. 2001).
Social support is a multifactorial construct that includes perception,
structure of the social network, and tangible help and assistance (Turner and
Turner 1999). Perceived social support has proved to be the most robust
predictor of late-life depressive symptoms (Bruce 2002). Investigators from
Hong Kong, in a community study, found that depressive symptoms were
associated with impaired social support (including network size, network
composition, social contact frequency, satisfaction with social support, and
instrumental-emotional support) (Chi and Chou 2001). Findings from
another longitudinal study substantiated that poor social support predicted
depressive symptoms at follow-up after 3–6 years (Henderson et al. 1997).
The impact of social support on depression may vary by sex. In one study
of middle-aged and older patients, impaired social support was associated
with poorer outcome of major depression in older men but not older women
(George et al. 1989).
The clinician must not assume that older adults in general experience a
deficit in social support. Social support is perceived to be adequate by older
individuals, even among clinical samples (Blazer 1982). Old social
networks thin out, but new ones emerge for many people. Most older people
believe that they have enough contact with both family and friends and
assess the relationships that they have with their social networks as positive
(Cornoni-Huntley et al. 1990). Even so, when the social network is depleted
suddenly, either through loss of someone close to the older adult (e.g., a
spouse or child) or through a change in the quality of the relationship (e.g.,
a dispute within the family), impaired social support may emerge as a most
important contributor to late-life depression.
In a recent review of studies exploring social relations and depression in
late life, many of the factors already discussed were confirmed. By
considering factors across multiple domains, the investigators found that
social support, quality of social relations, and the presence of confidants
were the factors significantly associated with depression. In contrast the
quantitative aspects of social relations, such as frequency of contact, were
more inconsistent in association (Schwarzbach et al. 2014).
How does the clinician or investigator resolve the discrepancy between a
relatively lower frequency of major depression in the older adult
community with increased biological vulnerability, and perhaps only
slightly better social resources, compared with younger adults?
Psychological factors may modify the biological and social risks for
depression. Most older adults, for example, who experience a significant
physical illness do not become depressed. Older people may in general
possess psychological strengths that actually protect them from the onset of
clinically significant depressive symptoms. Two such potential strengths are
described below.
Socioemotional selectivity theory may explain differences across the life
cycle in the experience of events that lead to depression (Carstensen et al.
2000). The theory focuses on the perception by older individuals of time
left in life, rather than on past experiences. Younger adults have much to
learn and relatively long futures over which to learn. They are motivated by
pursuit of knowledge, even when this requires that they suppress emotional
well-being. In contrast, older individuals perceive that they have lived
longer than they should live and therefore deemphasize negative experience
and prioritize emotionally meaningful goals. In one study, negative
emotional experiences (e.g., the perception of stressors) declined from
young adulthood until around age 60 years (Carstensen et al. 2000). Periods
of highly positive emotional experience endured as meaningful among older
adults compared with younger adults.
Adults are also thought to acquire increased wisdom as they age.
Wisdom is a nebulous concept. Investigators with the Berlin Aging Group,
however, have operationalized wisdom and studied it in community
samples (Baltes and Staudinger 2000). Wisdom is an expert knowledge
system concerning the fundamental pragmatics of life, including knowledge
and judgment about the meaning and conduct of life and the orchestrating
of human development toward excellence while attending conjointly to
personal and collective well-being. Five criteria can be used to assess
wisdom: rich factual knowledge; rich procedural knowledge (e.g., the
ability to develop strategies for addressing problems); lifespan
contextualization (e.g., integrating life experiences); relativism of values
and life priorities (e.g., tolerance for differences in society); and recognition
and management of uncertainty (accepting that the future cannot be known
with certainty and that the ability to assess one’s sociocultural environment
is inherently constrained). Wisdom is thought to accumulate over the life
cycle if severe physical illness and cognitive impairment do not intervene.
Cumulative wisdom over time should protect older individuals from
spiraling down into depression when confronted with a complex of negative
experiences.

Diagnosis and Differential Diagnosis of Late-Life

Mood Disorders
Clinical entities included as mood disorders in DSM-5 that are relevant to
depression in elderly patients were listed in Table 9–1 (presented earlier in
this chapter) and are discussed in the following subsections. Depressive
symptoms are likewise present in other DSM-5 disorder categories, such as
persistent complex bereavement disorder (coded as an “other specified
trauma- and stressor-related disorder”) and adjustment disorder with
depressed mood.

Bipolar and Related Disorders

To meet criteria for a manic episode, an individual must exhibit three or
more (four or more if the mood is only irritable) of the following
symptoms: 1) inflated self-esteem or grandiosity, 2) decreased need for
sleep, 3) more talkativeness than usual, 4) flight of ideas, 5) distractibility,
6) increased goal-directed activity (e.g., at work) or psychomotor agitation,
and 7) excessive involvement in pleasurable activities with potential
adverse consequences (e.g., unrestricted buying episodes). However,
bipolar disorder varies somewhat with aging. Post (1978) found that most
elderly individuals with bipolar disorder exhibited a depressive admixture
with manic symptomatology. Spar et al. (1979) reported that manic elderly
individuals are atypical in presentation, with dysphoric mood and denial of
classic manic symptoms. Shulman (1986) described the special problem of
manic delirium. When an individual is experiencing a full-blown manic
episode, cognitive function is difficult to test, yet perseverative behavior,
catatonia-like symptoms, and even negativistic symptoms may emerge.
Manic episodes, therefore, must be distinguished (but often with difficulty)
from neurocognitive disorders, such as a delirium characterized by
hallucinations, delusions, and agitation (American Psychiatric Association
2013).

Major Depressive Disorder

The diagnosis of major depressive episode is made when the individual
exhibits one or both of two core symptoms—depressed mood and lack of
interest or pleasure—as well as four or more of the following symptoms, for
at least 2 weeks: significant weight loss, insomnia or hypersomnia,
psychomotor agitation or retardation, fatigue or loss of energy, feelings of
worthlessness or excessive or inappropriate guilt, diminished ability to
concentrate or make decisions, and recurrent thoughts of death or suicidal
ideation (American Psychiatric Association 2013). First-onset episodes of
major depression after age 60 years (referred to as late onset) are common,
making up about one-half of all episodes in older adults. Personality
abnormalities and a family history of psychiatric illness are more common
if the depression is early onset (i.e., the first episode occurs before age 60),
but for the most part, the phenomenology is no different between early-
onset and late-onset major depression (Brodaty et al. 2001).
In a study involving hospitalized patients with a diagnosis of major
depressive episodes with melancholia but without comorbid physical
impairment or cognitive impairment, the criterion symptoms of depression
and symptoms specifically associated with melancholia (or endogenous
depression) did not differ between individuals in midlife and those in late
life (Blazer et al. 1987a). Nevertheless, there may be subtle changes with
age, because melancholia (symptoms of noninteractiveness and
psychomotor retardation or agitation) emerges at a later age than
nonmelancholic symptoms. Psychomotor disturbances are the most distinct
in older persons (Parker et al. 2001).

Major Depressive Disorder With Mood-Congruent or Mood-

Incongruent Psychotic Features
Late-onset psychotic depression deserves special attention. Meyers et al.
(1984) studied the prevalence of delusions in 50 patients hospitalized for
endogenous major depression. Depressed patients with illness onset at age
60 years or later had delusions more frequently than did those with earlier
onset. Individuals with delusional depression tended to be older and to
respond to ECT, as opposed to tricyclic antidepressants (TCAs). Delusions
of persecution or of having an incurable illness are more common than
delusions associated with guilt. If guilt predominates in the delusional
picture, it usually involves some relatively trivial episode that occurred
many years before the onset of the depressive episode and was forgotten
over time, but is currently viewed as a major problem (Bridges 1986). For
example, a one-time sexual liaison, forgotten or forgiven by the spouse, is
resurrected by a patient with a fear of an ongoing venereal disease or cancer
or is associated with chronic and severe pain. Nihilistic delusions (delusions
of nothingness) may occur more commonly in late life. Focus on the
abdomen is common in an elderly patient with a delusional or psychotic
depression. Hallucinations are uncommon, however. The symptoms may be
mood congruent (content of delusions and hallucinations are consistent with
the typical depressive themes) or mood incongruent (not typical with
depressive themes).
Thakur et al. (1999) compared the clinical, demographic, and social
characteristics of psychotic and nonpsychotic depression in a tertiary care
sample of 674 elderly and younger patients. In this study, younger age,
psychomotor retardation, guilt, feelings of worthlessness, a history of
delusions in the past, and increased suicidal ideation and intent were found
more commonly in psychotic than in nonpsychotic patients, and these
associations were largely confirmed when sociodemographic variables were
controlled. Psychotic depression also tended to be associated with poor
social support and, not surprisingly, bipolar illness. Cerebrovascular risk
factors did not differ significantly between psychotic and nonpsychotic
patients.

Persistent Depressive Disorder (Dysthymia)

Every clinician who has worked with elderly patients has observed
persistent depression, characterized by significant and unremitting
depressive symptoms associated with apparently psychosocial causes. Like
major depressive disorder, persistent depressive disorder is diagnosed
across the life cycle. Although dysthymia requires fewer criteria symptoms
than does major depressive disorder, these symptoms must last 2 years or
more. Dysthymia and major depressive disorder often coexist, leading to a
“double depression.” Results of some research suggest that dysthymia in
older persons may differ from that in younger persons. Devanand et al.
(2000) examined 76 outpatients, ages 60 and older, who had dysthymic
disorder based on DSM-IV-TR criteria (American Psychiatric Association
2000). They found that less than one-third of the patients had a diagnosable
personality disorder. Personality disorder was associated with an earlier age
at onset of depressive illness, a greater lifetime history of comorbid Axis I
disorders, greater severity of depressive symptoms, and lower
socioeconomic status. The most common personality disorders were the
obsessive-compulsive and avoidant types—the personality disorders most
commonly found in elderly patients with major depression. The late onset
of dysthymia in many of the patients in the study, as well as the lack of
psychiatric comorbidity, caused the authors to conclude that dysthymia in
elderly individuals is different from dysthymia in younger persons.

Depressive Episode With Insufficient Symptoms (Minor or

Subsyndromal Depression)
Depressive episode with insufficient symptoms (previously called minor,
subsyndromal, or subthreshold depression) is coded under the DSM-5
category “other specified depressive disorder.” This diagnosis may be
assigned when an individual who has never met criteria for a mood disorder
experiences depressed affect and at least one other symptom of a major
depressive episode that persist for at least 2 weeks. Another definition of
subsyndromal depression is a CES-D (Radloff 1977) score of less than 16
(the threshold for clinically significant depression). Associations with
subsyndromal depression are similar to those for major depression,
including impaired physical functioning, disability days, poorer self-rated
health, use of psychotropic medications, perceived low social support,
female gender, and unmarried status (Beekman et al. 1995; Hybels et al.
2001). Other investigators have suggested a syndrome of depression
without sadness, thought to be more common in older adults (Gallo et al.
1997).

Depressive Disorder Due to Another Medical Condition

Depressive disorders have been associated with a variety of physical
illnesses, including cardiovascular disease (Glassman and Shapiro 1998;
Musselman et al. 1998), endocrine disturbances (Blazer et al. 2002b),
Parkinson’s disease (Zesiewicz et al. 1999), stroke (Robinson and Price
1982), and cancer (Spiegel 1996). Depressive symptoms and disorders are
common findings in surveys of general medical inpatients (Koenig et al.
1988). Controversy continues over the degree to which acute or chronic
medical illnesses cause depression because of direct physiological effects
on the brain or because of a psychological reaction to the disability and
other life changes evoked by these illnesses. To meet criteria for “due to
another medical condition,” there must be evidence that the mood
disturbance is a direct pathophysiological consequence of another medical
condition. Otherwise, the diagnosis of adjustment disorder with depressed
mood should be made.
The association between depression and physical illnesses may be
bidirectional. Physical functioning is highly correlated with depression in
cancer patients. In one study (Bukberg et al. 1984), among patients with a
Karnofsky score of 40 or less (i.e., patients who were most disabled),
almost 80% had major depression, whereas only 23% of those who scored
60 or better (i.e., had moderate to good function) had major depression.
Lower rates of depression (5%–13%) were found among ambulatory
outpatients with cancer (Koenig and Blazer 1992). Many studies
documenting high rates of depression in patients with cancer are
controversial because they often involve patients referred for treatment of
cancer, who may have more advanced or complicated illness. It is important
that myths about depression and cancer be dispelled. One myth is that all
cancer patients are depressed; another is that physicians should not bother
to treat depression because cancer patients should be depressed. In fact,
when cancer patients become depressed, mortality may increase (Brown et
al. 2003). With regard to hospitalized elderly individuals with cancer, at
least one study has shown substantially higher mortality for cancer patients
with major depression compared with nondepressed cancer patients
(Koenig et al. 1989b). Studies have also shown that “desire for hastened
death” among terminally ill cancer patients is significantly increased among
those who are depressed or feeling hopeless (Breitbart et al. 2000).
With regard to cardiovascular disease and depression, Schleifer et al.
(1989) conducted structured psychiatric interviews of 283 patients (mean
age 64 years) admitted to the coronary care unit for myocardial infarction.
The interviews were conducted using the Schedule for Affective Disorders
and Schizophrenia 8–10 days after infarction and again 3–4 months later.
Initially, 45% of the patients met the diagnostic criteria for minor or major
depression, including 18% with major depression; 3–4 months later, 33% of
patients continued to meet the criteria for depression, including 77% of
those who had initially met the criteria for major depression. In another
study, Frasure-Smith et al. (1993) followed 222 patients for 6 months after
myocardial infarction; depression was a significant predictor of mortality
(hazard ratio, 5.7; P<0.001), even after other relevant risk factors were
controlled. In an extensive review of this literature, Glassman and Shapiro
(1998) reported that 9 of 10 studies found increased cardiovascular
mortality in depressed patients; even when community-dwelling
populations were examined and prospectively followed, the relationship
between depression and cardiovascular mortality persisted (after controlling
for smoking and other risk factors).

Adjustment Disorder With Depressed Mood

The DSM-5 category of adjustment disorder with depressed mood is
reserved for those individuals who exhibit a maladaptive reaction to an
identifiable stressor. The relationship of the syndrome to the stressful event
is clear and within 3 months of the stressor. Typical stressors for older
adults include life events such as marital problems, difficulty with children,
loss of a social role, and an ill-advised change of residence. Retirement is
usually not a source of excessive stress for the older adult. Therefore, the
onset of significant depressive symptomatology and withdrawal from
activities after retirement may not indicate a true adjustment disorder. Of
much greater frequency is the development of depressive symptomatology
secondary to a physical illness. When an episode of depression
accompanies a physical illness and the level of symptoms dramatically
exceeds the expected level, a diagnosis of either adjustment disorder or
depression due to medical illness (discussed next) is indicated.

Diagnostic Workup of the Depressed Older Adult

At its core, the diagnosis of a mood disorder in older adults is made on the
basis of a history, augmented with a physical examination and fine-tuned by
laboratory studies (Blazer 2003) (Table 9–3). No biological markers or tests
are available to confirm the diagnosis of depression, yet some tests may
assist in identifying subtypes of depression; for example, MRI scans for
subcortical white matter hyperintensities can confirm the presence of
vascular depression (Krishnan et al. 1988) and polysomnography can
explain sleep disturbances. Of special importance in evaluating a depressed
older patient are the following: the duration of the current depressive
episode; the history of previous episodes; the history of drug and alcohol
abuse; response to previous therapeutic interventions for the depressive
illness; a family history of depression, suicide, and/or alcohol abuse; and
the severity of the depressive symptoms. Establishing some indication of
the risk of suicide is essential, because suicidal risk may determine where
the patient is treated.
Screening for depression is helpful, using standardized scales such as the
GDS (Yesavage et al. 1982–1983) and the CES-D (Radloff 1977). In
primary care settings, the clinical effectiveness of screening is mixed. One
reason is that clinical trials typically exclude the type of patients who are
most likely to present to the busy internist, such as the patient with
comorbid depression and medical illness. Although internists accept
responsibility for treating late-life depression, they frequently perceive their
clinical skills to be inadequate and are frustrated with their practice
environment (Callahan et al. 1992). Assessment of cognitive status is
critical to the evaluation of depressed older patients. Use of a screening
scale such as the MMSE is a good adjunct to the diagnostic workup
(Folstein et al. 1975).
 The physical examination must include a thorough neurological
examination to determine whether soft neurological signs (e.g., frontal
release signs) or laterality is present. Weight loss and psychomotor
retardation in the depressed older adult may lead to peroneal nerve palsy,
documented by electromyography and nerve conduction studies (Massey
and Bullock 1978). Because the older adult is less occupied with physical
activities and therefore tends to be sedentary, the peroneal nerve is subject
to chronic trauma.
The laboratory workup of the depressed older adult is important. It
should include a thyroid panel (triiodothyronine, thyroxine, and radioactive
iodine uptake) and determination of thyroid-stimulating hormone levels. A
blood screen enables the clinician to detect the presence of anemia.
However, at least one study has shown that red blood cell enlargement and
abnormalities are not good predictors of deficits in vitamin B12 or folate
(Mischoulon et al. 2000). Because both depressive and cognitive symptoms
can result from deficits in vitamin B12 or folate, it is important to obtain
levels of these vitamins.

TABLE 9–3. Diagnostic workup of late-life depression

Routine studies
Screening (especially in a primary care setting, use standard symptom
checklists such as the Geriatric Depression Scale [Yesavage et al. 1982–
1983] or the Center for Epidemiologic Studies Depression Scale
[Radloff 1977])
Thorough history and assessment, including present and past history of
depressive episodes, family history, medication history, and assessment
of psychological functioning and of social stressors; medical history,
including assessment of nutritional status, current medications, past and
current medical history, and functional status
Screening for cognitive impairment with an instrument such as the Mini-
Mental State Examination (Folstein et al. 1975)
Physical examination
Laboratory tests, such as chemistry screen and electrocardiogram if
antidepressants are prescribed (previous medical records may provide
these data)
Elective studies
Magnetic resonance imaging to establish the diagnosis of vascular
depression
Blood screens for evidence of vitamin deficiency such as a deficiency of
B12 or folate
Polysomnography when sleep abnormalities persist and cannot be
explained
Screening for thyroid dysfunction (triiodothyronine, thyroxine, radioactive
iodine uptake, thyroid-stimulating hormone levels)

Treatment
Treatment of depression in late life is four-pronged, involving
psychotherapy, pharmacotherapy, neurostimulation, and family therapy.
These four approaches are discussed in this section.

Psychotherapy
Cognitive-behavioral therapy (CBT) is the only psychotherapy that was
designed specifically to treat depression (Beck 1967). Even the more
recently developed technique of interpersonal therapy is primarily a
cognitive-behavioral orientation to improving interpersonal relationships
(Klerman et al. 1984). The advantage of using CBT in treating the older
adult is that the therapy is directive and time limited, usually involving
between 10 and 25 sessions. CBT has been found to be effective for
depressed elderly patients (Gallagher and Thompson 1982; Steuer et al.
1984) and for patients with chronic medical illnesses such as type II
diabetes (Lustman et al. 1998), heart disease (Kohn et al. 2000), and
irritable bowel syndrome (Boyce et al. 2000). It may be particularly useful
for patients who show only a partial response to antidepressant drug therapy
(Scott et al. 2000).
The goal of behavioral and cognitive therapies is to change behavior and
modes of thinking. This change is accomplished through behavioral
interventions such as weekly activity schedules, mastery and pleasure logs,
and graded task assignments. Cognitive approaches to the restructuring of
negative cognitions or automatic thoughts include subjecting these
cognitions to empirical reality testing, examining distortions (e.g.,
overgeneralizations, catastrophizing, dichotomous thinking), and generating
new ways of viewing one’s life (Steuer et al. 1984). Depressed patients
typically regard themselves and their present and future in somewhat
idiosyncratic or negative ways. Such patients believe that they are
inadequate or defective and think that unpleasant experiences are caused by
a problem with themselves and that they are therefore worthless, helpless,
and hopeless. This cognitive triad leads the older adult to believe that he or
she has a never-ending depression and that nothing pleasant will ever
happen again. The cognitive model presupposes that these symptoms of
depression are consequences of negative thinking patterns.
Thompson et al. (1987) randomly assigned 91 elderly individuals with
major depression to cognitive therapy, behavioral therapy, or brief dynamic
therapy (the latter stresses the importance of the patient-therapist
relationship and emphasizes realistic collaborative aspects of the
therapeutic alliance). Patients in each group underwent 16–20 sessions of
therapy conducted by expert clinicians; 20 additional patients were assigned
to a waiting-list control group. By the end of 6 weeks, 52% of the patients
in therapy were in complete remission, and 18% showed significant
improvement. All therapies were equally efficacious and superior to waiting
for treatment.
Results of empirical studies suggest that compared with control subjects,
elders who engage in psychotherapy experience incremental improvement.
Not only does the percentage of elderly individuals who respond to these
treatments compare favorably with the percentage of younger subjects who
respond, the degree of improvement appears equal to that obtained with
medications, especially for individuals with milder forms of depression.
Drug therapy is not appropriate for some elders, and cognitive therapy,
behavioral therapy, and brief dynamic psychotherapy are viable alternatives.
In addition, evidence has emerged that suggests that the long-term benefit
of CBT may be greater than that of pharmacotherapy, especially if the
medications are discontinued during the first year of treatment (Reynolds et
al. 1999).
Older adults who have minor depression or adjustment disorders, or who
experience dysphoria because of losses of various types, often require less
intensive forms of psychotherapy. Active listening and simple support may
be sufficient to help distressed elders cope with their situation. Because
religion is an important factor in the lives of many older adults, referral to a
pastoral counselor may be particularly helpful and acceptable (Koenig et al.
2004).

Pharmacotherapy
The use of selective serotonin reuptake inhibitors (SSRIs) has been growing
in elderly patients (with or without medical illness). Citalopram (Nyth and
Gottfries 1990), escitalopram (Gorwood et al. 2007), fluoxetine
(Heiligenstein et al. 1995), paroxetine (Bump et al. 2001), and sertraline
(Cohn et al. 1990) have been shown to be effective in treating geriatric
depression. SSRIs have also proved effective in depressed older adults who
have had a stroke (Cole et al. 2001) or who have vascular disease in general
(Krishnan et al. 2001) or Alzheimer’s disease (Lyketsos et al. 2000). These
agents have become the drugs of first choice for treating mild to moderate
forms of depression. Important advantages of the use of these drugs in
treating elderly patients are the lack of anticholinergic, orthostatic, and
cardiac side effects; lack of sedation; and safety in overdose. Nevertheless,
for a significant number of older adults, SSRIs cause other unacceptable
effects, including excessive activation and disturbance of sleep, tremor,
headache, significant gastrointestinal side effects, hyponatremia, and weight
loss.
Other agents that affect both the serotonergic and noradrenergic systems
are often considered the best second-line therapy if the patient’s response to
an SSRI is not adequate. Duloxetine (Raskin et al. 2008) and venlafaxine
(Staab and Evans 2000) have been shown to be effective in treating geriatric
depression.
TCAs are the agents of choice for some patients with more severe forms
of major depression who can tolerate the side effects and do not respond to
the medications mentioned above. Medications that are effective yet
relatively free of side effects (especially cardiovascular effects) are
preferred. In recent years, nortriptyline and desipramine have become the
more popular medications for treating older adults with endogenous or
melancholic major depression. However, doxepin remains a favorite among
many practitioners. It is recommended that all elderly patients have an
electrocardiogram (ECG) before initiation of treatment and again after
therapeutic blood levels have been achieved. If the ECG shows a second-
degree (or higher) block, a bifascicular bundle branch block, a left bundle
branch block, or a QTc interval greater than 480 milliseconds, treatment
with TCAs should not be initiated or should be stopped in patients already
taking these medications (Caravati and Bossart 1991; Stoudemire and
Atkinson 1988).
Antidepressant doses administered to persons in late life should be case
specific but are generally lower than those given to persons in midlife. As
shown in Table 9–4, starting therapeutic daily doses of antidepressants are
as follows: citalopram, 10–40 mg; fluoxetine, 5–20 mg; paroxetine, 10–30
mg; sertraline, 12.5–50 mg; mirtazapine, 7.5–30 mg; and venlafaxine, 37.5–
200 mg (in divided doses). With regard to TCAs, 25 mg of desipramine
orally twice a day or 25–50 mg of nortriptyline orally at bedtime is
frequently adequate for relieving depressive symptoms. Plasma levels of
TCAs can be helpful in determining dosing: desipramine levels greater than
125 ng/mL and nortriptyline levels of 50–150 ng/mL have been found to be
therapeutic.
Trazodone and bupropion (Weihs et al. 2000) are alternatives in patients
who cannot tolerate TCAs, SSRIs, or mixed agents like venlafaxine.
Trazodone has advantages over TCAs in that it is virtually free of
anticholinergic effects, and it has advantages over the newer antidepressants
in that it has strong sedative effects. Nevertheless, the drug is not without
side effects, including excessive daytime sedation, priapism (occasionally),
and significant orthostatic hypotension. The therapeutic daily dose of
trazodone is 300 mg or more, an amount that many older patients cannot
tolerate because of sedation. Bupropion can be effective in treating
depression in elderly people but generally is used once other medications
have proved ineffective. Bupropion therapy should be initiated at 75 mg
twice daily, with an increase to 150 mg twice daily (not to exceed 150 mg
in a single dose). Agitation is the most common side effect that troubles
older individuals. Two newer agents, vilazodone and vortioxetine, have
limited data in elderly patients. For both medications, no dose adjustment
on the basis of age is recommended.
Monoamine oxidase inhibitors (MAOIs) are another alternative to TCAs,
SSRIs, and mixed serotonergic/noradrenergic antidepressants. An important
consideration is that if MAOIs are being considered because of intolerance
to side effects of other antidepressants, older adults usually do not tolerate
MAOIs any better. If treatment with an MAOI is to follow treatment with
an SSRI, a minimum of 1–2 weeks (or 2–4 weeks following fluoxetine)
must elapse after discontinuation of SSRI therapy before initiation of
MAOI therapy, to avoid a serotonergic syndrome. If a patient’s depression
is severe and ECT is contemplated, use of an MAOI also precludes
initiation of ECT until 10–14 days after the drug is discontinued. Such a
delay may seriously impede clinical management of the suicidal elder.

TABLE 9–4. Pharmacological treatment of late-life depression

Medication Dosage
Selective serotonin reuptake inhibitors
Citalopram 10–40 mg/day
Escitalopram 10–20 mg/day
Fluoxetine 5–20 mg/day
Paroxetine 10–30 mg/day
Sertraline 12.5–50 mg/day
Serotonin-norepinephrine reuptake inhibitors
Duloxetine 20 mg bid
Levomilnacipran 40–120 mg/day
Mirtazapine 7.5–30 mg/day
Venlafaxine 37.5–200 mg tid
Tricyclic antidepressants
Desipramine 25 mg bid
Doxepin 100 mg at bedtime
Nortriptyline 25–50 mg at bedtime
Monoamine oxidase inhibitors
Phenelzine 15 mg bid to tid
Tranylcypromine 10 mg bid to tid
Other agents
 Bupropion 75–150 mg bid
Trazodone 300 mg/day
Vilazodone 40 mg/day
Vortioxetine 10–20 mg/day
Note. bid=twice daily; tid=three times daily.

Some clinicians prescribe low morning doses of stimulant medications,

such as 5 mg of methylphenidate, to improve mood in the apathetic older
adult. Although the effectiveness of stimulants has not been conclusively
demonstrated, these agents are generally safe at low doses, and rarely does
the clinician encounter an elder with a propensity to abuse stimulants or to
become addicted when these drugs are given once daily.
Additional information regarding psychopharmacological treatment of
the older adult is provided in Chapter 20, “Psychopharmacology.”

Neurostimulation
Electroconvulsive Therapy
ECT continues to be the most effective form of treatment for individuals
with more severe major depressive episodes (O’Connor et al. 2001). The
induction of a seizure via ECT appears to be effective in reversing a major
depression. ECT was first established as a treatment in 1938, but it is not
used as much as it was immediately after its development. Despite its
effectiveness, ECT is not the first-line treatment of choice for a patient with
major depression and should be prescribed only because other therapeutic
modalities have been ineffective. ECT has been shown to be effective in
selected individuals, primarily those who have major depression with
melancholia, and especially those who have major depression with
psychotic symptoms associated with agitation or withdrawal. Many older
adults with such syndromes either fail to respond to antidepressant
medications or experience toxicity (usually postural hypotension) when
taking antidepressants. The presence of self-destructive behavior, such as a
suicide attempt or refusal to eat, increases the necessity for intervening
effectively; in such situations, ECT may be the treatment of choice.
If ECT is selected as an intervention, the clinician must first discuss in
detail with the patient and the family the nature of the treatment and the
reasons for this recommendation. It is important to explain why ECT is
necessary; what procedures the patient will undergo during a course of
ECT; how many treatments can be expected; how long hospitalization will
continue; whether ECT can be performed on an outpatient basis; what the
risks and side effects of ECT are; and what results, both immediate and
long-term, can be expected. Even when an elderly patient is severely
depressed, careful and thoughtful discussion with the patient and family
will usually result in a willingness by the patient (often with encouragement
from the family) to undergo the course of ECT treatments. Once treatment
is begun, fears of ECT usually remit.
The medical workup before ECT includes acquisition of a complete
medical history, a physical examination, and consultation with a
cardiologist if any cardiac abnormalities are recognized. Knowledge of any
family history of psychiatric disorders, suicide, or treatment with ECT is
helpful in predicting a patient’s response to treatment. Laboratory
examination includes a complete blood count, a urinalysis, routine
chemistries, chest and spinal X rays (the latter to document previous
compression fractures), an ECG, and a computed tomography (CT) scan or
MRI (with CT or MRI available, an electroencephalogram and skull X ray
are not routinely required). The presence of some abnormalities seen in
magnetic resonance images does not militate against the use of ECT,
however. For example, a series of older adults with major depression were
found to have subcortical arteriosclerotic encephalopathy, as demonstrated
by MRI, but promptly improved after undergoing ECT (Coffey et al. 1987).
Before an older individual undergoes ECT, all medications should be
withdrawn, if possible. As noted in the pharmacotherapy section earlier in
this chapter, any MAOIs must be withdrawn 10–14 days before the
procedure to prevent any toxic interactions with the anesthetic used during
ECT. Reserpine and anticholinesterase drugs should also be withdrawn for
at least 1 week prior to ECT. Lithium carbonate, TCAs, antipsychotics, and
antianxiety agents (including sedative-hypnotics) are not absolutely
contraindicated in older patients who are to undergo ECT; however,
benzodiazepines increase the seizure threshold and should be avoided.
Generally, a short-acting barbiturate, such as chloral hydrate (500 mg orally
at bedtime), is the most appropriate sedative-hypnotic, although chloral
hydrate should not be given on the night preceding administration of ECT,
if possible. Use of low-dose haloperidol or thiothixene is probably the most
appropriate means of controlling severe agitation or psychotic symptoms
during the course of ECT treatment.
The basic techniques for ECT are well described. Thirty minutes before
treatment, an anticholinergic agent is administered intramuscularly to
prevent complications of cardiac arrhythmias and aspiration. Directly
before treatment, a short-acting anesthetic, such as thiopental or
methohexital, is administered until an eyelash response is no longer present.
Then a muscle relaxant, such as succinylcholine, is administered to prevent
severe muscle contractions. Investigators are increasingly using unilateral
electrode placement to the nondominant cerebral hemisphere, because
evidence has accumulated that less confusion occurs after unilateral
treatment than after bilateral treatment. Nevertheless, unilateral electrode
placement does not preclude development of memory difficulties. (Some
investigators question the efficacy of unilateral versus bilateral electrode
placement, but bilateral electrode placement has not been clearly
established as therapeutically superior to unilateral electrode placement.)
The electrical stimulus is applied, and the seizure is monitored either by
applying a tourniquet to one arm and observing the tonic and clonic
movements in the extremity peripheral to the tourniquet or by using direct
electroencephalographic monitoring. Direct electroencephalographic
monitoring is preferred, and a seizure lasting 25 seconds or more is required
for optimal results.
Seizure duration varies with age. In a study involving 228 patients
treated with ECT, Hinkle et al. (1986) found that of patients older than age
60 years, a greater percentage were likely to have a seizure of 30 seconds or
less. When ECT is repeated, use of caffeine may increase the likelihood of
inducing a seizure without the necessity of restimulation using higher
electrical parameters (which could lead to increased central nervous system
toxicity).
ECT treatments are generally administered three times per week, and
usually 6–12 treatments are necessary for adequate therapeutic response. A
clear improvement is often noted after one of the treatments, with the
patient reporting a remarkable improvement in mood and functioning. Two
or three treatments are generally given after the ECT administration that
leads to improvement.
The risks and side effects of ECT in elderly patients are similar to those
in the general population. Cardiovascular effects are of greatest concern and
include premature ventricular contractions, ventricular arrhythmias, and
transient systolic hypertension. Frequent monitoring during treatment
decreases the (already low) risk that one of these side effects will lead to
permanent problems. Confusion and amnesia often result after a treatment,
but the duration of this confusional episode is brief. Even with the use of
unilateral nondominant treatment, however, some patients have prolonged
memory difficulties. Headaches are a common symptom with ECT; they
usually respond to nonnarcotic analgesics. Status epilepticus and vertebral
compression fractures are some of the rare but more serious adverse effects.
Compression fractures are a particular risk in older women because of the
high incidence of osteoporosis in the postmenopausal population.
The overall success rate of ECT in patients who have not responded to
drug therapy is usually 80% or greater, and there is no evidence that
effectiveness is lower in older adults (Avery and Lubrano 1979). Wesner
and Winokur (1989) examined the influence of age on the natural history of
major depressive disorder and found that ECT reduced the rate of chronicity
when it was used in patients age 40 or older but, surprisingly, not in those
younger than age 40 years.
A review of records in Canada from 1992 to 2004 found that rates of
ECT use in elderly patients increased during the 1990s but then stabilized at
approximately 12.5 persons per year per 100,000 in the population
(Rapoport et al. 2006). Rosenbach et al. (1997) reported that the number of
beneficiaries receiving ECT increased from 12,000 in 1987 to 15,560 in
1992, an increase of more than 20% (after calculations were adjusted for
increased numbers of beneficiaries between 1987 and 1992). In a
prospective, multisite study, Tew et al. (1999) compared characteristics and
treatment outcomes of 133 adult (age 59 or younger), 63 young-old (ages
60–74 years), and 72 old-old (age 75 or older) patients treated with ECT for
major depression. They found that patients less than 60 years old had a
significantly lower rate of response to ECT (54%) than did young-old
patients (73%) or old-old patients (67%). The investigators concluded that
despite a higher level of physical illness and cognitive impairment, patients
age 75 or older who had severe major depression tolerated ECT in a manner
similar to the way in which younger patients tolerated the treatment, and the
old-old patients demonstrated a similar or even better response. There is
also evidence that ECT may be more effective and have fewer side effects
than antidepressants when used to treat depression in old-old patients
(Manly et al. 2000).
The relapse rate with no prophylactic intervention may exceed 50% in
the year after a course of ECT. This relapse rate can be decreased if
antidepressants or lithium carbonate is prescribed after the treatment.
Maintenance ECT may be necessary for some patients who exhibit a high
likelihood of recurrence despite use of prophylactic medication and/or who
experience high toxicity and therefore cannot tolerate prophylactic
medications. For such patients, weekly or monthly treatments (usually on
an outpatient basis) are prescribed, with careful monitoring of response and
side effects. Following an effective course of ECT, the combination of
continuation ECT and antidepressant drug therapy has been shown to have
greater efficacy than use of medications alone (Gagné et al. 2000).
Despite the effectiveness of ECT, few deny that treatment may lead to
memory difficulties. In a study by Frith et al. (1983), 70 severely depressed
patients were randomly assigned to eight real or sham ECT treatments and
were divided according to the degree of recovery from depression
afterward. Compared with nondepressed control subjects, the depressed
patients were impaired on a wide range of tests of memory and
concentration before treatment, but their performance on most tests
improved after treatment. Real ECT induced impairments in concentration,
short-term memory, and learning but significantly facilitated access to
remote memories. At 6-month follow-up, all differences between real and
sham ECT groups had disappeared.
Price and McAllister (1989) examined the efficacy of ECT in elderly
depressed patients with dementia. Overall, the patients achieved an 86%
response rate, with only 21% experiencing a significant worsening of
cognition; the cognition problems were transient in most cases. Of
particular importance is that 49% of the patients treated with ECT showed
improvement in memory function after treatment. Likewise, Stoudemire et
al. (1995) found that over time, ECT may lead to significant improvement
in memory of cognitively impaired older adults with depression. Although
data on the safety and efficacy of ECT in patients with concurrent medical
illness derive primarily from retrospective studies involving psychiatric
patients with stable disease, these data do support the use of ECT in patients
with cardiovascular, neurological, endocrine, or metabolic conditions, as
well as a variety of other conditions (Stoudemire et al. 1998).
Repetitive Transcranial Magnetic Stimulation
A recent advance in clinical neurostimulation is repetitive transcranial
magnetic stimulation (rTMS). As summarized in a review paper (Aleman
2013), rTMS involves generation of a time-varying magnetic field by a
current pulse through a simulator coil placed over the scalp, inducing
electric current intracranially, and thus neural activation. The intensity of
stimulation is set at a fixed percentage of the individual’s motor threshold,
measured as the output required to produce movement of thumb or fingers.
When generally agreed-upon guidelines for stimulation are followed, rTMS
appears to be a safe and well-tolerated treatment, with minimal risk of
inducing an epileptic seizure. When used to treat depression, the rTMS
stimulus is placed over the prefrontal cortex, in most cases over the
dorsolateral prefrontal cortex. Typical treatment includes a 20- to 40-minute
session, 5 days a week for 4–8 weeks. In adult populations with major
depression, results with rTMS are mixed, with most studies favoring active
rTMS treatment over a sham or control condition (Hovington et al. 2013).
Although studies of rTMS in geriatric depression are limited, one study
of MRI-defined vascular depression in elderly patients used active versus
sham rTMS (Jorge et al. 2008). The older depressed patients receiving
active stimulation experienced significantly greater improvement in
depression severity and had higher response rates compared with those
receiving sham rTMS. The investigators found that greater left and right
gray matter volumes were associated with response to rTMS.

Family Therapy
The final component of therapy for the depressed elderly patient is work
with the family. Not only may family dysfunction contribute to the
depressive symptoms experienced by the older individual, but family
support is critical to a successful outcome in the treatment of the depressed
elderly patient. A clinician must attend to 1) those members of the family
who will be available to the elderly person; 2) the frequency and quality of
interactions between the older adult and family members, as well as among
other family members; 3) the overall family atmosphere; 4) family values
regarding psychiatric disorders; 5) family support and tolerance of
symptoms (such as expressions of wishing not to live); and 6) stressors
encountered by the family other than the depression experienced by the
elder (Blazer 2002).
Most depressed elders do not resist interaction between the clinician and
family members. With the patient’s permission, the family should be
instructed regarding the nature of the depressive disorder and the potential
risks associated with depression in late life, especially suicide. Family
members can assist the clinician in observing changes in the patient’s
behavior, such as an increase in discomfort (either physical or emotional),
increased withdrawal and decreased verbalization, and preoccupation with
medications or weapons. The family can assist by removing possible
implements of suicide from places of easy access. The family can also take
responsibility for administering medications to an older adult who is
unreliable or whose potential for suicide is high.
Family members can benefit from simple instructions regarding how to
communicate with an elderly depressed patient. Methods of responding to
expressions of low self-esteem and pessimism, such as paraphrase and
expression of understanding without a sense of responsibility to intervene,
can be especially effective. Families can be taught, for example, to
acknowledge to the patient, “I hear what you are saying, and I understand.”
Behavioral techniques for dealing with demanding or overly dependent
elders can be taught to families as well. A depressed elder’s demand for
constant attention from a family member may necessitate “weaning” the
patient from continued contact.
When the symptoms of depression become so severe that hospitalization
is required, family members are valuable in facilitating hospitalization.
Without a proper alliance between clinician and family, a family may be
resistant to hospitalization and undermine the clinician’s attempts to treat
the older adult appropriately. It is usually necessary for the clinician to take
responsibility for saying that hospitalization is essential—that the situation
has reached the point at which the family has no choice. The clinician
informs the patient—in the presence of the family—of the necessity of
hospitalization, and the family in turn can support the clinician’s position.
In such a situation, the patient rarely resists hospitalization for long.

Conclusion
Depressive disorders are among the most frequent clinical problems
encountered by those who care for older adults. We perhaps know more
about these disorders in older adults, especially their successful treatment,
than any other late-life psychiatric disorders. In addition, we have improved
diagnostic capabilities and better treatments (especially treatments used in
combination) than we did 30 years ago. It is not an understatement to
suggest that where there is depression in later life, there is hope.

Key Points
• Late-life depression overall may not be as frequent as at other stages of
the life cycle, yet the frequency is much higher in physically and
cognitively impaired older adults than in community-based samples.
• The biopsychosocial model works well in placing the origins of late-life
depression in context. Most cases derive from a variety of causes.
• Older adults appear more vulnerable to biological causes of depression,
such as depression secondary to vascular lesions in the brain.
• Social causes of depression in older adults do not appear to be more
frequent but differ from social causes of depression in young or middle-
aged adults.
• Older adults who are cognitively intact may experience a buffering of
depression because of a lifetime of cumulative wisdom coupled with a
different view of events given their age.
• The diagnostic workup of the depressed older adult is centered on a
detailed history, ideally from the patient and family.
• For moderately severe depression, a combination of antidepressant
therapy and psychotherapy (e.g., interpersonal therapy) is optimal.
• Electroconvulsive therapy is indicated for more severe and treatment-
resistant depressive disorders in late life and is generally well tolerated.

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35:1241–1252, 2005.
 CHAPTER 10

Bipolar and Related Disorders

John L. Beyer, M.D.

Bipolar disorders can be severe, relapsing mental illnesses, sharing

characteristics with both major depressive disorder and schizophrenia. Like
depressive disorders, bipolar and related disorders feature recurrent
episodes of altered mood that interfere with cognition and functioning. Like
schizophrenia, bipolar disorders may be chronic conditions that often
involve psychotic episodes and similar pathological features. However,
bipolar disorders should not be considered to be part of a continuum
between schizophrenia and depressive disorders. Although bipolar disorders
have long been recognized as being separate psychiatric disorders, the past
decade has brought significant advancements in knowledge of these
conditions. New information is emerging regarding prevalence, genetics,
and treatment, and this information is both directing and challenging our
understanding of bipolar disorders in late life.

Diagnosis
Bipolar disorder is a cycling illness that affects an individual’s ability to
regulate moods, which may be manic, hypomanic, or depressed. Under the
DSM-5 rubric of bipolar and related disorders are five main entities: bipolar
I disorder, bipolar II disorder, cyclothymic disorder, substance/medication-
induced bipolar and related disorder, bipolar and related disorder due to
another medical condition, and other specified or unspecified bipolar and
related disorder (American Psychiatric Association 2013).
 For a diagnosis of bipolar I disorder, the patient must have experienced
at least one manic episode—that is, an alteration in mood that is euphoric,
expansive, or irritable and is associated with increased energy. These
changes must last for at least 1 week and be accompanied by three of the
seven associated symptoms listed in DSM-5 (e.g., decreased need for sleep,
racing thoughts, pressured speech, increased behaviors that may have high
likelihood for bad outcome). It is not necessary for a patient to have
experienced a depressive episode to be diagnosed with a bipolar disorder,
although the vast majority of patients with bipolar disorders have
experienced depression and many report it to be the most commonly
experienced mood problem.
For a diagnosis of bipolar II disorder, the patient must have experienced
one or more major depressive episodes and at least one hypomanic episode.
A hypomanic episode is defined as at least 4 days of altered mood
(expansive, euphoric, irritable) occurring with at least three of the seven
associated symptoms listed in DSM-5.
Bipolar I and bipolar II are the most recognized and most common
bipolar conditions. They are defined by symptom presentation and intensity.
The following two diagnoses are defined by the causes of the altered mood:
1) substance/medication-induced bipolar and related disorder refers to an
episode of altered mood that meets criteria for a manic episode but occurs
during or soon after substance intoxication or withdrawal, or after exposure
to a medication, and 2) bipolar and related disorder due to another medical
condition refers to an episode of altered mood that meets criteria for a
manic episode but is caused by a known medical condition.
Cyclothymic disorder is characterized by the presence, over a 2-year
period, of numerous periods of hypomanic symptoms (that do not meet
criteria for a hypomanic episode) and depressive symptoms (that do not
meet criteria for a major depressive episode). During this period, the person
has not been without these hypomanic or depressive symptoms for more
than 2 months at a time. It is unclear whether cyclothymia is truly a disorder
disease process, a temperament variation, or a premorbid state for bipolar II
disorder (Baldessarini et al. 2011), given that there is a 15%–50% risk that a
person with cyclothymic disorder will later meet criteria for bipolar I or
bipolar II disorder (American Psychiatric Association 2013).
Finally, the last two categories of bipolar disorders refer to episodes of
altered mood that interfere with functioning but do not completely meet
criteria for any disorder in the bipolar and related disorders diagnostic class.
Other specified bipolar and related disorders may include hypomanic
episodes that last only 2–3 days, or hypomanic episodes without a history of
major depressive episodes, or cyclothymia that has lasted less than 24
months. The diagnosis of unspecified bipolar and related disorder applies to
presentations in which symptoms characteristic of a bipolar disorder cause
clinical distress or impairment but do not meet the full criteria for any of the
specified disorders. For the most part, little is known about bipolar II and
related disorders in late life; therefore, all information presented in this
chapter focuses on bipolar I disorder unless otherwise noted.

Epidemiology and Clinical Presentation

Prevalence
The exact prevalence of bipolar disorder in late life is uncertain. Based on
five large-scale studies that used very different sampling methods, the
prevalence of bipolar disorder in the community has been generally
reported to range from 0.08% to 0.5%. The Epidemiologic Catchment Area
(ECA) study conducted in the early 1990s sampled 18,263 community-
dwelling Americans at five sites to determine the prevalence of mental
illnesses for those ages 15 years and older (Weissman et al. 1988). The
ECA study found that bipolar disorder for adults ages 65 years and older
had a 1-year prevalence range of 0.0%–0.5%, with a cross-site mean of
0.1%. This was markedly lower than the prevalence among young (ages
18–44 years; 1.4%) and middle-age (ages 45–64 years; 0.4%) adults.
Similarly, a large health maintenance organization administrative database
review containing almost 300,000 unique individuals found a prevalence of
0.25% for bipolar disorder in persons ages 65 years and older and a
prevalence rate of 0.46% in adults ages 40–64 years (Unützer et al. 1998).
Hirschfeld et al. (2003) sent the Mood Disorder Questionnaire (a validated
screening instrument for bipolar I and II disorders) to 127,000 people. For
the 85,258 responders, the overall screen rate for bipolar disorder was 3.4%,
but for adults ages 65 years and older, the screen rate was 0.5%. Klap et al.
(2003) conducted a telephone survey of 9,585 households and found a
prevalence rate of 0.08% for adults ages 65 years and older compared with
1.17% for adults ages 30–64 years. Finally, the National Comorbidity
Survey Replication studied the incidence of psychiatric disorders in
community-dwelling adults (Chou et al. 2011). Of the 2,575 participants
ages 55 years and older, the 3-month incidence rate was 0.54% for bipolar I
disorder and 0.34% for bipolar II disorder. Interestingly, each of these
surveys suggested that the prevalence of bipolar disorder declines with age
or in aging cohorts.
Winokur (1975) was the first to propose that manic patients may “burn
out” after a finite number of episodes. In a retrospective study, Angst et al.
(1973) described a finite number of episodes in patients with mania,
suggesting that the illness may be self-limiting. However, in a later
prospective study, Angst and Preisig (1995) followed 209 patients with
bipolar disorder over a period of 40 years until a median age of 68. They
found that manic episodes did not decrease with age and that many patients
continued to have episodes into their 60s. It should be noted that the decline
in prevalence rates of bipolar disorder with age is consistent with findings
for other mental illnesses, such as depression and schizophrenia.
Because most of the large-scale prevalence surveys have excluded
patients who were institutionalized in hospitals, nursing homes, or other
residential treatment centers, critics have suggested that the prevalence data
may underrepresent the true prevalence because older patients with mental
illness are more likely to require institutionalized care. Two surveys of
mental illness in nursing home patients found a prevalence of bipolar
disorder of 3%–10% (Koenig and Blazer 1992; Tariot et al. 1993). Speer
(1992) reported that bipolar disorder was present in 17.4% of residential
psychiatric programs for older adults.
Chart reviews of inpatient admissions revealed prevalence rates of
bipolar disorder among older adults in psychiatric inpatient treatment
settings to be 4.7%–18.5% (for a review of published surveys, see Depp and
Jeste 2004 and Dols et al. 2014a). The mean prevalence was 6.0%–8.7%,
although Depp et al. (2004) argued that this was likely to be an
underestimation, because many of the inpatient surveys did not include
bipolar depressed subjects or reported prevalence only for those whose
bipolar disorder began after age 60 years. In summary, the prevalence of
bipolar disorder may depend in part on the diagnostic criteria or
measurement used and on the population sampled. In general, community
surveys show that bipolar disorder appears to decrease with age, a change
consistent with the declines seen in other mental disorders. Nevertheless,
the proportion of older patients utilizing services (either inpatient or
outpatient) appears to be the same as in younger populations. Furthermore,
there may be increasing utilization of institutional care with age.

Gender
Epidemiological studies in the United States have indicated that bipolar
disorder is approximately equally common in men and women (American
Psychiatric Association 2000). Depp and Jeste (2004) pooled 17 studies
reporting various samples of late-life bipolar disorder and found that the
weighted mean of elderly women with bipolar disorder was 69% (range
45%–89%). However, they noted that this percentage was similar to the
gender ratio among older adults in the general population.

Comorbidity
Psychiatric Comorbidity
Psychiatric comorbidity is frequently seen in patients with bipolar disorder
and has been a major point of discussion in the literature on bipolar
disorder, yet there is very little information about its presence in late-life
bipolar disorder. Only a scattering of studies have looked at substance abuse
comorbidity, whereas individual reports (mostly regional or individual
hospital–based data) are available for personality disorders, posttraumatic
stress disorder (PTSD), and anxiety disorders. There are no published
reports on comorbid eating disorders or attention disorders, which have
been found to be significant in surveys of mixed-age subjects with bipolar
disorder.
Sajatovic et al. (2006) conducted a review of the national Veterans
Health Administration database to examine the prevalence of dementia,
PTSD, and anxiety disorders in older patients with bipolar disorder. They
identified 4,668 subjects with bipolar disorder (mean age 70 years); of
these, 4.5% had comorbid dementia, 5.4% had PTSD, and 9.4% had an
anxiety disorder. In the Netherlands, Dols et al. (2014b) looked at a cohort
of elderly patients with bipolar disorder and found that comorbid anxiety
disorders were relatively rare (1-month panic disorder, 2%; 1-month social
anxiety, 3%; 6-month general anxiety disorder, 5%). Lifetime alcohol
dependence was 24.8% and abuse 13.9% among those with bipolar
disorder.
The best evidence for the prevalence of comorbid substance abuse and
bipolar disorders comes from the National Comorbidity Study, in which
61% of individuals with bipolar disorder also had a substance use disorder
(Kessler et al. 1997). Unfortunately, this survey excluded adults older than
age 55 years from the data set. Cassidy et al. (2001) reviewed rates of
substance abuse in 392 patients who were hospitalized at a state psychiatric
facility for bipolar disorder. Nearly 60% had some history of lifetime
substance abuse (consistent with the finding of the National Comorbidity
Study), but in the 51 patients older than age 60, only 29% had a history of
lifetime substance abuse. Supporting this finding of lower-than-expected
substance abuse disorders in older patients with bipolar disorder are two
small inpatient retrospective studies (Ponce et al. 1999; Sajatovic et al.
1996), a review of elderly bipolar utilizers of mental health system
outpatient services (Depp et al. 2005), and a large review of the Veterans
Health Administration database (Sajatovic et al. 2006). The reason for this
unexpected finding is unclear.
Only one study has reviewed the presence of personality disorders
together with co-occurring late-life mental disorders. Molinari and
Marmion (1995) reviewed 76 geriatric outpatients and inpatients and found
that 63% of the patients had one of the personality disorders. Of the 27
subjects with bipolar disorder, 70% were found to have a personality
disorder. The authors suggest that the unusually high rate of personality
disorders may be due in part to the difficult and chronic patterns of affective
disorders.

Medical Comorbidity
Because of the high association that secondary mania has with late-life
bipolar disorder, there have been more studies assessing the presence of
comorbid medical problems—the most common being neurological
illnesses—than studies assessing psychiatric comorbidities. Depp and Jeste
(2004) reviewed eight studies that reported the presence of illness and noted
that despite a wide variety in reporting strategies, the sample-weighted
prevalence for neurological illnesses was 23.1%. Shulman et al. (1992)
compared 50 geriatric patients hospitalized for mania with 50 age-matched
patients hospitalized for unipolar depression. They found that the rates of
neurological illness in manic patients were significantly higher (36% vs.
8%), suggesting that neurological disease is a risk factor for the
development of mania in late life.
Other comorbid medical disorders are also common in bipolar disorder
and especially in late-life bipolar disorder. Lala and Sajatovic (2012)
reported that a mean of three to four medical conditions appeared to be the
norm in elderly patients with bipolar disorder. Regenold et al. (2002)
reviewed the inpatient charts of 243 older (ages 50–74 years) psychiatric
inpatients. They found that type II diabetes was present in 26% of those
with bipolar disorder, which is a much higher rate than in patients with
unipolar depression, patients with schizophrenia, and inpatients with bipolar
disorder in other studies (9.9% in mixed-age inpatient sample; Cassidy et al.
1999). Dols et al. (2014b) interviewed 101 elderly patients with bipolar
disorder (mean age 68.9±7.8 years) and found an average of 1.7 medical
comorbid conditions, predominately hypertension (27.8%), arthrosis
(29.1%), allergies (25.6%), and peripheral atherosclerotic disease (18.8%).
Only 21.8% had no somatic illnesses. Metabolic syndrome was found in
28.7% of patients.

Dementia
Dementia has become an increasing concern for older adults in general and
possibly a special concern for older adults with bipolar disorder. Studies of
four inpatient samples found that the rate of comorbid dementia was highly
variable, ranging from 3% to 25% (Broadhead and Jacoby 1990;
Himmelhoch et al. 1980; Ponce et al. 1999; Stone 1989). Sajatovic et al.
(2006) reported dementia in 4.5% of veterans treated for bipolar disorder
through the Veterans Health Administration system. Comorbidity does not
necessarily imply an association, which has been a particular concern for
late-life bipolar disorder. Tsai et al. (2003) reported that 30.7% of the early-
onset patients in their inpatient sample had Mini-Mental State Examination
(MMSE) scores below 24. Furthermore, Dhingra and Rabins (1991)
reviewed 25 elderly patients who had been hospitalized 5–7 years
previously for manic episodes and found that 32% experienced a significant
decline in their MMSE scores. Kocsis et al. (1993) followed 38 elderly
patients with bipolar disorder treated with lithium and found that rates of
cognitive and functional impairment were much higher than in the general
population.

Mortality
Individuals with mental illness at all ages have higher mortality rates, from
both natural and unnatural causes, than the general population (Laursen et
al. 2007). This is especially true for patients with bipolar disorder. Ramsey
et al. (2013) reported on the 26-year follow-up data of participants from the
Epidemiologic Catchment Area Study. They found that odds of mortality
for patients with lifetime manic spectrum episodes (either full manic,
hypomanic, or subthreshold manic symptoms) was much higher (odds ratio
1.4) than for those with no lifetime manic spectrum episodes. Dhingra and
Rabins (1991) found that mortality rates among elderly patients with
bipolar disorder who had been hospitalized 5–7 years previously were
higher than expected compared with population norms. Shulman et al.
(1992) found that the mortality rate over a 10- to 15-year follow-up for
elderly hospitalized patients with bipolar disorder was significantly higher
than that of elderly hospitalized unipolar depressed patients (50% vs. 20%),
suggesting that mania appears to have a poorer prognosis and to be a more
severe form of affective illness than unipolar depression.
In summary, psychiatric comorbidity is frequent in patients with bipolar
disorder, but the prevalence of the comorbidities in older patients with
bipolar disorder is relatively unknown. Substance abuse, the most common
and best-reported comorbid condition in the literature, appears less
commonly in older than younger patients with bipolar disorder. Lifetime
history also appears less commonly. Dementia and poorer cognitive
performance on neurological testing (see “Neurocognitive Testing”
subsection later in this chapter) are possibly increased, or apparent earlier,
in older adults with bipolar disorder. Medical comorbidity is also higher in
older adults with bipolar disorder (Beyer et al. 2005), with special concern
about neurological illness and diabetes. All of these problems may
contribute to higher mortality rates for patients with bipolar disorder than
for individuals without psychiatric illness and for unipolar depressed
patients.

Course
After reviewing studies that retrospectively looked at course of bipolar
disorder prior to hospitalization, Goodwin and Jamison (1990) reported that
depression was the initial episode more often in older adults than in
younger patients. Various investigators have described a latency period of
10–20 years between first depressed episode and onset of mania
(Broadhead and Jacoby 1990; Shulman and Post 1980; Shulman et al. 1992;
Snowdon 1991; Stone 1989). Kessing (2006), in a study of Denmark’s
health care utilization, found that first psychiatric hospitalizations for older
adults with bipolar disorder were much more likely to be for depressive
episodes than for manic episodes. Furthermore, older adults with bipolar
disorder appear to experience more mixed symptoms than the classic manic
presentation (Post 1968; Spar et al. 1979).
Previously, it was believed that elderly patients with bipolar disorder
may differ in symptom presentation from younger patients. However, a
review from the Systematic Treatment Enhancement Program for Bipolar
Disorder (STEP-BD) found no statistically significant association between
age and symptom presentation of acute depression or mood elevation or
psychosis (Al Jurdi et al. 2012).
As noted previously, Angst and Preisig (1995) followed 209
psychiatrically hospitalized patients with bipolar disorder over a 40-year
period until a median age of 68 years. Of these patients, only 16% had fully
recovered (defined as no episodes in the previous 5 years and a Global
Assessment of Functioning [GAF] Scale score above 60), whereas 26% had
no episodes but had GAF scores below 60. The largest group (36%) had
experienced episodes within the previous 5 years, and another 16%
exhibited a chronic course. Seven percent had committed suicide.
Interestingly, despite the high risk of suicide reported with aging and
among individuals with bipolar disorder, the risk of suicide in late-life
bipolar disorder appears lower than expected. Tsai et al. (2002) studied
suicide rates in Taiwan among patients with bipolar disorder and found that
the highest risk was during the first 7–12 years after the onset of the illness
and for individuals under age 35 years. Depp and Jeste (2004) suggested
that older patients with early-onset bipolar disorder may constitute a
“survivor cohort.” Young and Falk (1989) found that older patients with
mania who need hospitalization tend to have a slower resolution of
symptoms and a longer duration of hospitalization than do younger adult
patients.
 A study comparing health-related quality of life and functioning in
elderly adults with bipolar disorder (n=54) and a group without psychiatric
illness (n=38) found that even patients in remission from bipolar disorder
had quality-of-life scores lower than those of the normal comparison group.
Overall, bipolar disorder was associated with substantial disability,
comparable to schizophrenia, and incomplete improvement in functioning
even among those classified as remitters (Depp et al. 2006).
Similar to younger patients with bipolar disorder, older adults with the
disorder have a high use rate of mental health services. Sajatovic et al.
(1996) found that older patients with bipolar disorder were hospitalized at
the same rate as older patients with schizophrenia. Bartels et al. (2000)
found that older individuals with bipolar disorder used outpatient services
four times as often as a similarly aged group of individuals with unipolar
depression. Brennan et al. (2002) found that older veterans with comorbid
bipolar disorder and substance use disorders had an increased probability of
mental health care service use and readmission. However, Depp et al.
(2005) compared 2,903 elderly individuals with bipolar disorder who
received outpatient services with younger bipolar groups and found that the
elderly individuals were less likely to use inpatient, outpatient, and
emergency room psychiatric care but were more likely to use case
management and conservator services. Overall, the elderly bipolar group
had less substance use but more cognitive disorders and a lower global
functioning than the younger bipolar groups.

Age at Onset
The mean age at onset for bipolar disorder is in the late teens to early 20s
(Weissman et al. 1996). Although most studies have found bipolar disorder
to be unimodal in distribution, a few studies have noted two peaks for the
onset of mania, with the first occurring in the mid-20s and a second, smaller
peak occurring closer to middle age, in the late 40s (Angst 1978; Goodwin
and Jamison 1984; Petterson 1977). Others have suggested a trimodal
distribution pattern, with distinct groups represented by onset in late teens,
mid-20s, and early 40s (Bellivier et al. 2003).
Despite being phenotypically similar to the other age-at-onset subtypes,
the late-onset subtype has historically been viewed as an “organic” variant
of bipolar disorder. This may be due in part to the relative small number of
new-onset bipolar disorders in older adults (especially in late life) compared
with younger adults, as well as the known physical changes associated with
age, such as the suggestions that women may be at risk for first episodes
around the time of menopause (Angst 1978; Petterson 1977; Sibisi 1990;
Zis et al. 1979) and that men may have increased risk in their 70s (Spicer et
al. 1973) or 80s (Sibisi 1990), possibly due to neurological causes. Shulman
and Post (1980) reviewed the course of 67 elderly patients with bipolar
disorder whose first manic episode occurred around age 60; the authors
noted a pattern of an initial depressive episode in mid-life, followed by a
long latency period (mean of 15 years) before the onset of mania. They
hypothesized that this group may have underlying cerebral changes due to
aging that convert them to mania.
Many researchers have emphasized the importance of dividing bipolar
disorder into early- and late-onset subtypes, noting heuristic evidence of
differences in familial incidence of mood disorders, neurological disease,
and mortality. Patients with early-onset illness may have an increased
prevalence of close family members with affective disorders compared with
patients who had later-onset illness (Baron et al. 1981; Hopkinson 1964;
James 1977; Mendlewicz et al. 1972; Post 1968; Snowdon 1991; Stenstedt
1952; Taylor and Abrams 1973). Despite arguments that this would suggest
a higher genetic loading for early-onset patients and/or a higher incidence
of secondary bipolar disorder for late-onset patients, this issue is not clear
because other studies have not substantiated this finding (Broadhead and
Jacoby 1990; Carlson et al. 1977; Depp et al. 2004; Glasser and Rabins
1984; Hays et al. 1998; Tohen et al. 1994). Notably, even if the number of
affectively ill relatives is higher in the early-onset group, the percentage of
affectively ill relatives in the late-onset group is still considerable and
corresponds to the 4%–22% generally cited for the relatives of manic
patients (James 1977; Mendlewicz et al. 1972; Post 1968; Stenstedt 1952;
Taylor and Abrams 1973).
The existence of a relationship between late-onset illness and
neurological abnormalities is a much more consistent finding. Although the
definition of neurological illness varied in eight studies that examined this
issue, six of the studies showed significantly higher rates in the late-onset
patients (Almeida and Fenner 2002; Huang et al. 2012; Snowdon 1991;
Subramaniam et al. 2007; Tohen et al. 1994; Wylie et al. 1999), whereas the
other two studies showed trends toward increased levels of neurological
illness in late-onset patients (Broadhead and Jacoby 1990; Hays et al.
1998). Late-onset subjects were also more likely to have a higher risk for
mortality.
The importance of identifying a late-onset bipolar disorder as a distinct
syndrome has come under question. Besides the information listed above,
few meaningful differences have been found between early-onset and late-
onset groups, except for possibly less overall psychopathology and
improved treatment response (Carlson et al. 1977, 2000; Chu et al. 2010;
Depp et al. 2004; Leboyer et al. 2005). Furthermore, DSM-5 (American
Psychiatric Association 2013) does not make such a distinction.
Interestingly, some reports have suggested that age at onset may be a more
important differential for individuals with an early onset (before age 13;
Perlis et al. 2009) than for those with late onset.

Neurocognitive Testing
Cognitive dysfunctions are increasingly recognized as a core feature of
bipolar disorder. The affected abilities are most often noted in assessments
of executive function, verbal memory, and processing speed. These
dysfunctions are not solely related to residual mood effects, drug effects, or
other confounding factors but rather appear to be related to illness severity.
They are also apparent in first-degree relatives. These findings have
suggested that bipolar disorder may be associated with various
neurobiological factors that may reflect a neurodegenerative process (e.g.,
glutamatergic excitotoxicity, neuroinflammation, oxidative stress,
mitochondrial dysfunction). Adults with bipolar disorder exhibit a range of
cognitive deficits that persist across illness stages and during symptom
remission, the severity of which may rival those described in schizophrenia
(Balanzá-Martínez et al. 2005). Studies of older adults with bipolar disorder
have found patterns similar to that of younger adults with bipolar disorder:
deficits in executive functioning, working memory, verbal memory,
attention, construction, and processing speed (Aprahamian et al. 2014;
Delaloye et al. 2011; Gildengers et al. 2010; Gunning-Dixon et al. 2008;
Lewandowski et al. 2014; Samamé et al. 2013; Young et al. 2006). Depp et
al. (2007) suggested that the neurocognitive deficits in geriatric patients
with bipolar disorder were related to quality of life rather than to severity or
duration of psychiatric symptoms, suggesting that bipolar disorder often
involves disabling and enduring cognitive impairments. In a study by
Köhler et al. (2013), the presence of psychotic symptoms was associated
with poorer cognitive functioning and more rapid cognitive decline over a
6-year follow-up.
The course of cognitive functioning over the lifespan in adults with
bipolar disorder has been less clear. Some research has suggested that
compared with mentally healthy individuals of similar age and education,
older adults with bipolar disorder not only had worse performance but also
appeared to have a faster decline (Dhingra and Rabins 1991; Gildengers et
al. 2004, 2009). These findings would seem to support the hypothesis that
bipolar disorder may be related to a neurodegenerative (progressive)
process. However, other research has not found accelerated decline in older
adults with bipolar disorder (Delaloye et al. 2011; Depp et al. 2007). In the
largest longitudinal study, Gildengers et al. (2013) found that both older
adults with bipolar disorder and age-matched comparators exhibited a
decline in neuropsychological functioning over a 2-year follow-up period;
however, the bipolar group displayed worse cognitive function in all
domains at baseline and follow-up. The research group did not find an
accelerated decline in the bipolar group over time, suggesting that cognitive
impairment and associated functional disability of older adults with bipolar
disorder appear to be due to long-standing neuroprogressive processes
compounded by normal cognitive aging rather than a neurodegenerative
process.

Neuroimaging

Stroke
Compared with unipolar depression, mania following a stroke is relatively
uncommon. However, a controlled study of patients with secondary mania
showed that when manic symptoms are present, the right hemisphere of the
brain (both cortical and subcortical areas) is more frequently the site of the
lesion (Starkstein et al. 1987, 1991). Further research suggests that
development of mania after right-sided lesions occurs more often when the
basal region of the right temporal lobe is involved (Starkstein et al. 1990).
Huang et al. (2012) found that silent cerebral infarctions were frequently
observed in older adults with bipolar disorder but were often neglected or
unobserved, regardless of the patients’ age at onset.

Volumetric Neuroimaging
Neuroimaging in mixed-age subjects with bipolar disorder is still a rising
field, but as the literature has evolved, an emerging hypothesis for
understanding bipolar disorder has developed, suggesting that affective
instability may be the result of changes or altered processes in certain areas
of the brain (Phillips 2006). There appears to be increased activity among
the subcortical and limbic regions that make an initial assessment of
“emotional stimulus” (amygdala, anterior insula), resulting in increased
activity in regions associated with mood generation and decision processing
of the emotional material (ventromedial and ventrolateral prefrontal
cortices, ventral anterior cingulate gyrus). Finally, there is reduced activity
in regions that regulate these responses and attentional processes
(dorsomedial prefrontal cortices), causing the mood lability. Neuroimaging
results specific to late-life bipolar disorders have been relatively limited, but
the published studies have supported significant volumetric abnormalities in
certain areas that are consistent with the overall theory presented above.
Volumetric studies of total brain volumes for patients with bipolar
disorder have shown only limited changes. Young et al. (1999) compared 30
geriatric manic patients with control subjects but did not find any difference
in the ventricular-brain ratios. They did note that subjects with bipolar
disorder had greater cortical sulcal widening, which correlated with age at
onset and age at first manic episode. Tanaka et al. (1982) suggested that
atrophy may occur at an earlier age in subjects with bipolar disorder, despite
the fact that cortical atrophy in their elderly subjects with bipolar disorder
was similar to that in normal (healthy) control subjects. Beyer et al. (2004a)
also did not find any differences in total brain volume or lateral ventricular
volumes between elderly subjects with bipolar disorder and controls;
however, they did find a volume decrease in those with late-onset (after age
45 years) versus those with early-onset bipolar disease.
Other volumetric findings include smaller caudate (Beyer et al. 2004a)
and larger hippocampal (Beyer et al. 2004b) volumes in patients with late-
life bipolar disorder compared with controls. The latter finding appeared to
be consistent with use of lithium, suggesting a role for neuroprotection.
Magnetic Resonance Imaging Hyperintensities
Possibly related to strokes, “hyperintense” signals viewed on T2-weighted
magnetic resonance imaging (MRI) have been one of the earliest and most
consistent neuroimaging findings in the study of bipolar disorder.
Hyperintensities represent areas of neuronal cell death, although the
mechanism by which this occurs is unclear. Pathological examination has
found that hyperintensities could characterize areas of arteriosclerotic
disease, demyelination, loss of axons, arteriolar hyalinization, rarefaction,
infarctions, and necrosis (Bradley et al. 1984; Braffman et al. 1988;
Chimowitz et al. 1992; Fazekas et al. 1993; Fujikawa et al. 1997; George et
al. 1986). Fujikawa et al. (1997) coined the term silent cerebral ischemia to
refer to these hyperintensities. Electroencephalographic studies in patients
with dementia suggest that white matter hyperintensities may result in a
functional brain disconnection. Therefore, some researchers have suggested
that for patients with mood disorders, hyperintensities may “disconnect”
different pathways in the mood regulation circuits.
Dupont et al. (1987) were the first to report the presence of
hyperintensities in patients with bipolar disorder, and most (Altshuler et al.
1995; Aylward et al. 1994; Botteron et al. 1995; Dupont et al. 1990, 1995;
Figiel et al. 1991; Krabbendam et al. 2000; McDonald et al. 1991, 1999;
Swayze et al. 1990) but not all (Brown et al. 1992; Strakowski et al. 1993)
studies have supported this finding. Because of differences in study groups
and methodology, there is a wide range in frequency of T2 hyperintensities
found in subjects with bipolar disorder (5%–62%) and normal control
subjects (0%–42%). However, in all but one study, the odds ratio was in the
same direction and the overall effect size was highly significant (Bearden et
al. 2001). Two meta-analyses reported similar findings with common odds
ratios of 3.3 (Altshuler et al. 1995) and 3.29 (Videbech 1997), strongly
supporting the relationship between hyperintensities and bipolar disorder.
One group of researchers who did not find a relationship studied patients
with bipolar disorder at the time of their first hospitalization, although they
did find a trend toward the presence of hyperintensities (1.7 times higher
rate) (Strakowski et al. 1993). Interestingly, this finding is not inconsistent
with data from Aylward et al. (1994) and Hickie et al. (1995), who noted
that the presence of hyperintensities was significant only in an older
subgroup of patients with bipolar disorder (older than age 39 years), or
Dupont et al. (1995), who noted a correlation of hyperintensities only in
patients with mania onset after adolescence. Thus, increased age is related
to the presence of hyperintensities, a finding that is not unexpected because
hyperintensities are also seen in normal aging populations as well as in
subjects with unipolar depression.
The presence of hyperintensities not only is more common among
patients with bipolar disorder than among control subjects (Dupont et al.
1995) but remains significantly more common when medical risk factors
(e.g., hypertension, vascular disease) are controlled for (Altshuler et al.
1995; Hickie et al. 1995; McDonald et al. 1999). Specific studies of bipolar
disorder in late life have consistently found a higher presence of
hyperintensities in individuals with bipolar disorder than in control subjects.
In a study of patients older than age 50 years with mania, McDonald et al.
(1991) found no significant difference with respect to the presence of
hyperintensities between the patients with bipolar disorder and the control
sample, yet the mean number of large hyperintensities (>2.5 mm) was
significantly higher in the elderly patients with bipolar disorder. McDonald
et al. (1999), in a mixed bipolar sample that included elderly individuals,
found increased hyperintensities in the subependymal region, subcortical
gray nuclei, and deep white matter, whereas de Asis et al. (2006) found
increased hyperintensities in the frontal deep white matter in a group of
older individuals with bipolar disorder when compared with control
subjects. This increased number was especially prominent on the right side
in the late-onset group.
The presence of hyperintensities may be especially important in late-life
bipolar disorder because of their impact on treatment response and severity
of illness. Data from studies on bipolar disorder are very limited, but MRI
hyperintensities have been found to be associated with longer hospital stays
(Dupont et al. 1990) and more frequent rehospitalizations (McDonald et al.
1999). The role of hyperintensities in contributing to cognitive decline is
not clear. Some researchers (Bearden et al. 2001) have noted that
hyperintensities appear to be associated with cognitive impairment with
increasing age and chronicity of disorder. However, Rej et al. (2014)
dispute this, noting that in their small sample, cognitive dysfunction was not
associated with white matter hyperintensity burden or gray matter volume,
which suggests that other potential neuroprogressive pathways, such as
inflammation, mitochondrial dysfunction, serum anticholinergic burden,
and altered neurogenesis, may play a role.

Differential Diagnosis
There are five potential presentations of patients with late-life bipolar
disorder: 1) those who had early onset of bipolar disease and have now
reached old age; 2) those who previously experienced only episodes of
depression but have now switched to a manic episode; 3) those who have
never had an affective illness but develop mania because of a specific
medical or neurological event (e.g., head trauma, cerebrovascular accident,
hyperthyroidism); 4) those who have never been recognized as having
bipolar symptoms or who have been misdiagnosed with another disorder;
and 5) those who have never had an affective illness but develop mania for
unknown reasons. It is unknown how common each presentation may be,
although in the author’s personal experience, the most frequently
encountered presentation is that of a patient who developed bipolar disorder
earlier in life and is now seeking treatment. However, based on findings by
Hirschfeld et al. (2003), it is not uncommon for the diagnosis of bipolar
illness to have been missed previously.
Because the onset of bipolar disorder in late life is relatively uncommon,
every patient who presents with a new onset of mania should undergo a
good medical evaluation, with special emphasis on the neurological
examination. Because older adults may be receiving a higher number of
medications, these should be reviewed for possible temporal association. A
laboratory workup consisting of a thyroid panel and basic tests should also
be completed. Finally, consideration should be given to neuroimaging,
especially if the presentation is associated with psychosis.

Treatment
Treatment of bipolar disorder is often challenging for many reasons. In
addition to the challenge of medication management in older adults, elderly
patients with bipolar disorder often have incomplete response, recurrent
episodes, potentially severe psychopathology, and higher mortality rates.
Furthermore, the disease itself tends to cause problems with poor insight
and poor compliance with treatment. Finally, limited data are available on
use of medications and psychotherapies for older patients with bipolar
disorder. Many of the treatment practices are based on results from clinical
trials in younger populations that have been adapted for geriatric use.

Lithium
Lithium has traditionally been identified as the gold standard for treatment
of bipolar disorder and has been widely prescribed to older patients with the
disorder (Shulman et al. 2003; Umapathy et al. 2000). Because of the need
to better understand treatment in this vulnerable population, the National
Institute for Mental Health (NIMH) commissioned a study to evaluate the
efficacy and tolerability of lithium and valproate in late-life mania. Young
et al. (2012) conducted a blinded trial of 224 patients with mania over age
60 who were administered either lithium or valproate. They found that both
lithium and valproate were well tolerated and efficacious, but lithium was
associated with greater reduction in mania scores.
The recommended lithium level for acute mania in geriatric patients is
unclear. In the study by Young et al. (2012), the mean dose of lithium was
780±315 mg/day, with a mean serum concentration of 0.76±0.35 mEq/L.
However, some case series have suggested that elderly patients may
respond to lower lithium levels (0.5–0.8 mEq/L) than those recommended
for younger adults (0.6–1.2 mEq/L) (Chen et al. 1999; Prien et al. 1972;
Roose et al. 1979), whereas other studies have not found a difference
(DeBattista and Schatzberg 2006; Young et al. 1992).
Special care must be taken in dosing geriatric patients with lithium. With
aging, the renal clearance of lithium decreases and the elimination half-life
increases (Foster 1992; Shulman et al. 1987; Sproule et al. 2000).
Furthermore, medications commonly prescribed to the elderly, such as
thiazide diuretics, nonsteroidal anti-inflammatory agents, and angiotensin-
converting enzyme inhibitors, can increase lithium concentrations. Other
medications, such as theophylline, can decrease lithium concentrations.
Finally, because lithium use can contribute to hypothyroidism and a decline
in renal clearance, lithium should be used with caution in patients with
kidney problems or thyroid disorders.
 Lithium toxicity in elderly individuals is not uncommon (Foster 1992).
Commonly reported adverse effects of lithium in the elderly include
cognitive impairment, ataxia, urinary frequency, weight gain, edema,
tremor, and worsening of psoriasis and arthritis. Because of adverse effects
(including neurotoxicity) that can occur even at therapeutic levels,
appropriate lithium serum levels in the elderly are largely determined by
medical status, frailty, and conservative dosing (Sajatovic et al. 2005b;
Young et al. 2004).

Anticonvulsants
Physicians have increasingly been prescribing anticonvulsants for the
treatment of bipolar disorder. Since 1993, four anticonvulsants have been
approved by the U.S. Food and Drug Administration (FDA) to treat bipolar
disorder: valproate, carbamazepine, oxcarbazepine, and lamotrigine. For
information regarding the anticonvulsants, the literature is limited to case
reports and subanalyses of data from the inclusion of elderly patients in the
larger Phase III trials.

Valproate
Since 2000 there has been a marked increase in the prescription of valproate
for bipolar disorder, especially for elderly patients. In 1999, Oshima and
Higuchi proposed that lithium be the first choice in treatment guidelines for
geriatric bipolar disorder. However, Shulman et al. (2003) noted that
prescriptions of valproate for elderly patients with bipolar disorder
increased while prescriptions of lithium decreased, so that valproate is now
the most prescribed medication treatment for elderly persons with bipolar
disorder.
In the NIMH study on the tolerability and efficacy of lithium and
valproate in late-life mania (Young et al. 2012), valproate performed well
and was tolerated as well as lithium was. The mean daily dose was
1,200±550 mg/day, and the mean serum concentration was 74±21 μg/mL.
In general, the recommended blood level concentration for valproate in
adults is 50–120 μg/mL (Bowden et al. 2002), although Chen et al. (1999)
found that manic elderly patients who had a blood level concentration from
65–90 μg/mL improved more than patients with lower concentrations.
 As patients age, the elimination half-life of valproate may be prolonged
and the free fraction of plasma valproate increases. The clinical significance
of this is unknown, although it should be noted that usual laboratory tests
measure the total valproate level. Thus, the reported level may
underrepresent the actual dose available to the brain in geriatric patients
(Sajatovic et al. 2005b; Young et al. 2004). Common medications taken
concurrently may also influence the level of valproate: aspirin can increase
the valproate free fraction, and phenytoin and carbamazepine may decrease
the valproate level. In turn, valproate may affect other medications’ effects.
It can inhibit the metabolism of lamotrigine so that the dose of lamotrigine
may need to be lowered to minimize side effects. Valproate also may
increase the unbound fraction of warfarin; coagulation parameters should
therefore be monitored in patients undergoing anticoagulation therapy
(Panjehshahin et al. 1991).
The most common side effects associated with valproate are nausea,
somnolence, and weight gain. Less common side effects that may be
particularly important to geriatric patients are hair thinning,
thrombocytopenia, hepatotoxicity, and pancreatitis (the latter two are less
likely to occur with age) (Bowden et al. 2002). Notably, valproate is
available in sprinkle and liquid formulations for patients who have
difficulty swallowing. In addition, Regenold and Prasad (2001) have
reported on the intravenous use of valproate in three geriatric patients.

Carbamazepine
Carbamazepine was approved for the treatment of bipolar mania in 1996,
and the extended-release formulation was approved in 2005. Some
researchers have suggested that carbamazepine may be the preferred mood-
stabilizing agent, rather than lithium, for patients with secondary mania
(Evans et al. 1995; Sajatovic 2002); however, very little information is
available on the use of carbamazepine (in either preparation) for elderly
patients with bipolar disorder. Okuma et al. (1990) noted that seven elderly
patients with mania were included in a larger sample of 50 treated with
carbamazepine in a double-blind study that showed good efficacy.
Before initiating carbamazepine, the physician should check liver
enzymes, electrolytes, and complete blood cell count. Because
carbamazepine can also affect the heart’s rhythm, an electrocardiogram
should be considered. In elderly patients, carbamazepine may be started at
100 mg either once or twice daily and gradually increased every 3–5 days to
400–800 mg/day (McDonald 2000). Target serum levels are between 6 and
12 μg/L.
Carbamazepine is metabolized in the liver by cytochrome P450 (CYP)
enzyme 3A4/5. Because carbamazepine can induce its own metabolism,
dose increases may need to be adjusted in the first 1–2 months.
Furthermore, carbamazepine clearance is decreased in an age-dependent
manner, presumably due to a reduction in CYP 3A4/5 metabolism,
suggesting that elderly patients may require lower doses compared with
younger patients to achieve similar blood levels (Battino et al. 2003).
Notably, carbamazepine also may alter the pharmacokinetics of other
medications, including oral hormones, calcium channel blockers,
cimetidine, terfenadine, and erythromycin (Sajatovic 2002).
Possible adverse effects associated with carbamazepine include sedation,
ataxia, nystagmus/blurred vision, leukopenia, hyponatremia (secondary to
the syndrome of inappropriate antidiuretic hormone secretion [SIADH]),
and agranulocytosis. The FDA (U.S. Food and Drug Administration 2007)
has recommended that patients of Asian ancestry have a genetic blood test
to identify an inherited variant of the human leukocyte antigen allele HLA-
B*1502 (found almost exclusively in people of Asian ancestry) before
starting therapy. Patients testing positive should not be treated with
carbamazepine.

Lamotrigine
Lamotrigine was approved by the FDA in 2003 for the maintenance phase
of bipolar disorder. Sajatovic et al. (2005a) conducted a retrospective
analysis of two placebo-controlled, double-blind clinical trials for
maintenance therapy in bipolar disorder, focusing on 98 subjects who were
age 55 years or older. They found that, similar to the parent study,
lamotrigine significantly delayed the time to intervention for any mood
episode, whereas lithium and placebo did not. In a subanalysis of the type
of mood episode that was more likely to recur, the authors found that
lamotrigine was significantly more effective than lithium and placebo at
increasing time to intervention for depressive recurrences, but lithium
performed much better in increasing time to intervention for manic
episodes. Overall, the authors found that lamotrigine was well tolerated
(compared with lithium) by the older patients with bipolar disorder, and no
increased incidence of rash was noted (Sajatovic et al. 2007). In a follow-up
analysis evaluating clinical correlates of treatment response, Gildengers et
al. (2012) noted that lamotrigine worked best in depressed patients with
high cardiometabolic risk factors and a low level of manic symptoms with
their depression. A small case series (Robillard and Conn 2002) of five
female geriatric bipolar patients with depressive episodes suggested good
efficacy when lamotrigine was used as an augmenting agent as well.
Lamotrigine is metabolized in the liver and eliminated through the
hepatic glucuronide conjugation. Some minor decreases in hepatic
glucuronidation occur with aging, although their impact on lamotrigine
dosing in the elderly is not thought to be significant (Hussein and Posner
1997; Posner et al. 1991). Overall, lamotrigine is well tolerated, although
serious skin rashes (Stevens-Johnson syndrome) have been reported. It has
been suggested that lamotrigine may have fewer negative effects on
cognition than other anticonvulsant medications, which may be important
for some geriatric patients (Aldenkamp et al. 2003).

Antidepressants
Antidepressants are frequently prescribed for the treatment of bipolar
depression in elderly patients (Beyer et al. 2008), although the use of
antidepressants in bipolar disorder is a point of continued concern among
psychiatrists (Ghaemi 2012). Three issues highlight the controversy: 1) the
literature is ambiguous as to the efficacy of antidepressants in bipolar
depression, 2) antidepressants have the potential to induce a manic episode,
and 3) antidepressants may also induce a rapid-cycling course. Thase and
Denko (2008) reviewed the general literature, focusing especially on two
large clinical trials from the Stanley Foundation and the National Institute
of Mental Health (STEP-BD) that have attempted to clarify the benefits and
risks of antidepressant use in bipolar depression. The results of both trials
did not show that antidepressant augmentation of mood stabilizers
distinguished itself as more effective than placebo or the use of a second
mood stabilizer; however, possible benefit was noted for certain subgroups.
On the basis of the data, the authors were not able to recommend the use of
antidepressants or to conclude that antidepressants should be avoided
(Thase 2007).
Given these limitations, the American Psychiatric Association (2002)
has maintained its recommendations that primary treatment of bipolar
depression should be with a mood stabilizer and that antidepressant
augmentation of the mood stabilizer may be considered if there is limited or
no response.
There are no specific studies of the use of antidepressants in geriatric
populations. In a retrospective study of elderly inpatients who had
antidepressant-induced mania, Young et al. (2003) found that tricyclic
antidepressants were more likely than other antidepressants to induce
manias in late life, suggesting that the use of selective serotonin reuptake
inhibitors may be preferable in elderly patients.

Antipsychotic Agents
Atypical antipsychotic agents are increasingly being used for the treatment
of various phases of bipolar disorder. Olanzapine, risperidone, quetiapine
and quetiapine XR (extended release), ziprasidone, aripiprazole, and
asenapine are currently approved by the FDA for the treatment of acute
mania; olanzapine-fluoxetine combination, quetiapine and quetiapine XR,
and lurasidone are approved for the treatment of acute bipolar depression;
and olanzapine, aripiprazole, quetiapine and quetiapine XR, risperidone,
and ziprasidone are approved for maintenance phase treatment. However,
limited data are available about their efficacy in the geriatric population.
Beyer et al. (2001) reported on a pooled subanalysis of three double-
blind, placebo-controlled acute bipolar mania clinical trials with olanzapine,
focusing on subjects older than age 50 years. In comparison with placebo,
olanzapine was found to be efficacious for the treatment of acute mania
without any significant change in the side-effect profile. Information on
quetiapine, risperidone, clozapine, ziprasidone, aripiprazole, and asenapine
is much more limited. Case reports and open-label studies in geriatric
bipolar patient treatment are published for quetiapine (Madhusoodanan et
al. 2000), risperidone (Madhusoodanan et al. 1995, 1999), clozapine (Frye
et al. 1996; Shulman et al. 1997), and asenapine (Baruch et al. 2013). No
published reports are currently available for ziprasidone or aripiprazole.
 In general, a lower-dose strategy in the elderly has been recommended
for most atypical antipsychotics (Alexopoulos et al. 2004), although this
may be less of a concern in the acute state. A major concern regarding
atypical antipsychotic use is the potential risk of metabolic abnormalities
such as obesity, diabetes, and dyslipidemia. This risk may be less of a
concern for elderly patients because they have less propensity for weight
gain and other metabolic effects associated with atypical antipsychotics
(Meyer 2002). In 2006, a black box warning was added to each of the
atypical antipsychotic agents, indicating that their use in elderly patients
with dementia may be associated with a higher incidence of death. The
exact mechanism of the increased mortality risk is unknown, although it
may be due to increased infections and cardiovascular causes. Limited
information is available on the risk of death in patients with late-life bipolar
disorder. A review of the U.S. Department of Veterans Affairs registries for
older patients with bipolar disorders showed differences in mortality risks
for various atypical antipsychotics; patients given risperidone had the
highest mortality rate, whereas those given quetiapine had the lowest
(Bhalerao et al. 2012). Although the authors did not believe that the data
could currently be translated to recommendations for use of one agent over
another, they proposed that the findings suggested a cautious approach to
the use of any atypical antipsychotics in older adults and recommended
using them judiciously when traditional mood stabilizers and
psychotherapies do not fully address the patient’s needs.

Electroconvulsive Therapy
Electroconvulsive therapy (ECT) has long been known to be effective for
the treatment of bipolar disorder. However, very limited data are available
on the use of ECT in elderly patients with bipolar disorder, especially when
compared with the quantity of literature on ECT for unipolar depression.
McDonald and Thompson (2001) reported on a case series of three elderly
manic patients who also had some dementia and were resistant to
pharmacotherapy but did respond to ECT treatment. Little et al. (2004)
reported on a case series of depressed elderly patients, which included five
patients with bipolar depression, who were treated with bifrontal ECT.
 Key Points
• The prevalence of bipolar disorder, like other mental illnesses, decreases
with age. However, bipolar disorder in late life does continue to be a
frequent cause for admission to psychiatric inpatient facilities and
disruption of patients’ lives.
• The mortality rate for older adults with bipolar disorder is significantly
higher than that for the general population and for patients with unipolar
depression.
• The onset of bipolar disorder at a later age may be associated with fewer
genetic associations and more neurological illnesses.
• Treatment guidelines for late-life bipolar disorder are based primarily on
case reports and extrapolation from bipolar treatment in younger adults.
As in other geriatric treatment recommendations, the maxim “start low
and go slow” is applicable to late-life bipolar treatment.
• Elderly patients may require lower doses of lithium because of decreased
renal clearance.

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 CHAPTER 11

Schizophrenia Spectrum and Other

Psychotic Disorders
Jeanne E. Maglione, M.D., Ph.D.
Ipsit V. Vahia, M.D.
Dilip V. Jeste, M.D.

Delusions, hallucinations, and other psychotic symptoms can

accompany a number of conditions in late life. These symptoms may be
more common than previously thought; Swedish investigators found that in
a sample of 85-year-old people, the prevalence of psychotic symptoms was
10.1%, with 6.9% experiencing hallucinations, 5.5% having delusions, and
6.9% experiencing paranoid ideation (Ostling and Skoog 2002).
Conditions that cause acute psychotic symptoms that tend to resolve
when the underlying condition is treated are discussed elsewhere in this
volume (e.g., delirium is discussed in Chapter 7, “Delirium,” and drug-
induced psychosis is discussed in Chapter 20, “Psychopharmacology”). In
this chapter, we review the epidemiology, presentation, and treatment of
chronic late-life psychotic disorders that are not secondary to a mood
disorder or a general medical condition other than a neurocognitive
disorder. We discuss early-onset schizophrenia, late-onset schizophrenia,
very-late-onset schizophrenia-like psychosis (with onset after age 60),
delusional disorder, and psychosis related to a major neurocognitive
disorder such as Alzheimer’s disease (AD).

Schizophrenia
Early-Onset Schizophrenia
Typically, individuals with schizophrenia develop the disorder in the second
or third decade of life (American Psychiatric Association 2000). Although
mortality rates in general, and suicide and homicide rates in particular, are
higher among individuals with schizophrenia than in the general population
(Hannerz et al. 2001; Hiroeh et al. 2001; Joukamaa et al. 2001), many
people with early-onset schizophrenia are now living into older adulthood.
Therefore, most of the older adults with schizophrenia have had an early
onset followed by a chronic course of illness spanning several decades. The
prevalence of schizophrenia is approximately 0.6% among adults ages 45–
64 and 0.1%–0.5% among elderly individuals (Castle and Murray 1993;
Copeland et al. 1998; Keith et al. 1991).
Longitudinal follow-up of patients with schizophrenia indicates
considerable heterogeneity of outcomes. A minority of patients experience
remission of both positive and negative symptoms (Ciompi 1980; Harding
et al. 1987; Huber 1997). Auslander and Jeste (2004) reported that nearly
10% of community-dwelling older patients with schizophrenia met strict
research criteria for sustained remission. A small proportion of patients
experience deterioration of symptoms. The course in a majority of patients
is largely unchanged over time (Belitsky and McGlashan 1993; Cohen
1990; Harvey et al. 1999), although there is generally an improvement in
positive symptoms (Jeste et al. 2003). A possibility of survivor bias—that
is, that the sickest patients die young, and the hardier ones survive into
older age—should be kept in mind in studying older patients with early-
onset illness.
Factors associated with poor prognosis for early-onset schizophrenia
include chronicity, insidious onset, premorbid psychosocial or functional
deficits, and prominent negative symptoms (Ram et al. 1992). In a sample
of chronically institutionalized patients with schizophrenia, older age was
associated with lower levels of positive symptoms and higher levels of
negative symptoms (Davidson et al. 1995). However, Harding (2002) noted
that the strength of the association between predictors of outcome and
actual outcome in patients with schizophrenia weakens over time.

Cognition in Older Patients With Schizophrenia

The pattern of cognitive deficits in schizophrenia differs significantly from
that in AD; patients with AD have less efficient learning and more rapid
forgetting than patients with schizophrenia (Heaton et al. 2001). Among
community-dwelling older outpatients with schizophrenia, cognitive
functioning seems to remain relatively stable, other than the changes
expected from normal aging (Heaton et al. 2001). A small proportion of
chronically institutionalized older patients with schizophrenia have
cognitive decline greater than that expected for their age (Putnam and
Harvey 2000).

Depression in Older Patients With Schizophrenia

Depression is a common source of comorbidity in older patients with
schizophrenia. Studies have shown depressive symptoms to be distinct from
negative symptoms (Baynes et al. 2000). Depression is also a major
predictor of suicidality in this population (Montross et al. 2006).
Subsyndromal depression has been found to be associated with greater
morbidity (Diwan et al. 2007; Zisook et al. 2007). Detection and
management of subsyndromal depression may have an important role to
play in management of this population.

Functional Capacity
The level of functional impairment varies considerably among older adults
with schizophrenia. In a study of a group of middle-aged and older
schizophrenia outpatients, Palmer et al. (2002) found that 30% had been
employed at least part time since the onset of psychosis, 43% were current
drivers, and 73% were living independently. In general, worse
neuropsychological test performance, lower educational level, and negative
symptoms but not positive symptoms are associated with poorer functional
capacity in older outpatients with schizophrenia (Evans et al. 2003).

Quality of Life
Self-appraisal is considered to be essential in studies of quality of life for
patients with schizophrenia. Several studies have found poorer self-assessed
quality of life to be associated with depression, positive and negative
symptoms, cognitive deficits, financial strain, poor social support, and poor
social skills (Vahia et al. 2007). These findings suggest that a multimodal
approach to management of these patients is necessary to improve quality
of life.

Late-Onset Schizophrenia
Historically, schizophrenia has been considered a disease of younger
adulthood. Kraepelin (1971) termed schizophrenia dementia praecox to
distinguish it from organic disorders arising in late life and to indicate a
poor prognosis with a course of progressive deterioration. However, in later
years, Kraepelin himself observed that some cases arose for the first time in
older age and that progressive decline was not a universal feature of the
disease. Bleuler (1943) and Roth (1955) developed this concept further,
with studies showing the late-onset phenotype to be a distinct entity from
the early-onset form. A literature review found that approximately 23% of
patients with schizophrenia had an onset after age 40, with 3% being older
than age 60 years (Harris and Jeste 1988). An investigation involving first-
contact patients found that 29% of patients had an onset after age 44, with
12% reporting onset after age 64 (Howard et al. 1993). The consensus
statement by the International Late-Onset Schizophrenia Group suggested
that schizophrenia with an onset after age 40 should be called “late-onset
schizophrenia” and should be considered a subtype of schizophrenia rather
than a related disorder (Howard et al. 2000). Although DSM-III-R labeled
schizophrenia with onset after age 45 as a late-onset type (American
Psychiatric Association 1987), later DSM editions have not included age-
related specifiers or criteria (American Psychiatric Association 1994, 2000,
2013). DSM-5 states that “late-onset cases can still meet the diagnostic
criteria for schizophrenia, but it is not yet clear whether this is the same
condition as schizophrenia diagnosed prior to mid-life” (American
Psychiatric Association 2013, p. 103).
Risk factors and clinical presentation associated with late-onset
schizophrenia are similar to those associated with early-onset schizophrenia
(Brodaty et al. 1999; Jeste et al. 1995). Similar proportions of individuals
with early-onset or late-onset schizophrenia reported having a family
history of schizophrenia (10%–15%) (Jeste et al. 1997b). Levels of
childhood maladjustment, measured retrospectively, were similar in early-
and late-onset schizophrenia patients and higher in both groups than in
healthy subjects (Jeste et al. 1997b). Patients with early- and late-onset
schizophrenia have increased rates of minor physical anomalies relative to
healthy subjects (Lohr et al. 1997).
Women predominate among individuals with onset of schizophrenia in
middle to late life (Häfner et al. 1998; Jeste et al. 1997b). It has been
speculated that estrogen may serve as an endogenous antipsychotic,
masking schizophrenic symptoms in vulnerable women until after
menopause (Seeman 1996). However, investigations on efficacy of
hormone replacement therapy as an adjunct treatment for postmenopausal
women with psychosis have not had promising results (Kulkarni et al. 1996,
2001; Lindamer et al. 2001).
Neuroimaging studies show that compared with patients with early-onset
schizophrenia, patients with late-onset schizophrenia have more nonspecific
structural abnormalities, such as enlarged ventricles and increased white
matter hyperintensities (Sachdev et al. 1999) and a larger volume of
thalamus on magnetic resonance imaging (Corey-Bloom et al. 1995). A
single small study employing diffusion tensor imaging recently found
evidence of abnormal white matter integrity in the left parietal lobe and
right posterior cingulum in patients with late-onset schizophrenia (n = 20)
compared with age-matched healthy control subjects (n = 17), although
there were no associations between these abnormalities and symptom levels
(Chen et al. 2013). Other imaging studies have ruled out strokes, tumors, or
other abnormalities as potential causes of schizophrenia in late life (Rivkin
et al. 2000). Finally, long-term neuropsychological follow-up of a group of
patients with late-onset schizophrenia revealed no evidence of cognitive
decline, suggesting a neurodevelopmental rather than a neurodegenerative
process (Palmer et al. 2003).
Most studies have found that compared with patients with early-onset
disease, patients with late-onset schizophrenia have lower levels of positive
symptoms and a lower daily antipsychotic dose requirement (Vahia et al.
2010). Patients with late-onset schizophrenia tend to have more organized
delusions, auditory hallucinations or hallucinations with a running
commentary, and persecutory delusions with and without hallucinations
(Howard et al. 2000). Data from initial smaller studies suggested a higher
prevalence of the paranoid subtype of schizophrenia and lower levels of
negative symptoms on average among patients with late-onset
schizophrenia (approximately 75%) than among patients with early-onset
schizophrenia (approximately 50%) (Jeste et al. 1997b). However, a more
recent larger study from our center, including data collected over 20 years
comparing 744 early-onset schizophrenia and 110 late-onset schizophrenia
patients, found that the two groups had similar relative proportions of
patients with the paranoid subtype and no differences in severity of negative
symptoms (Vahia et al. 2010).
On neuropsychological testing, after correction for age, education, and
gender, patients with late-onset schizophrenia tend to have less impairment
in learning, abstraction, and flexibility in thinking than patients with early-
onset schizophrenia (Jeste et al. 1997b). Compared with patients with early-
onset schizophrenia, a greater proportion of patients with late-onset
schizophrenia have successful occupational and marital histories and
generally higher premorbid functioning.
Sensory deficits, particularly hearing loss, are associated with psychotic
symptoms in late life and have been proposed as a risk factor for late-onset
schizophrenia (Howard et al. 1994; Raghuram et al. 1980). However, other
data suggest that patients with either early- or late-onset schizophrenia may
be less likely than healthy older adults to receive appropriate correction for
vision and hearing impairments (Prager and Jeste 1993). Thus, uncorrected
sensory deficits may reflect generally poorer health care utilization by older
psychotic patients and may not be a potential cause of psychosis in the
elderly population.
In summary, early- and late-onset schizophrenia share similarities in
many key clinical characteristics. However, there are important differences,
including the greater proportion of women, lower average severity of
positive symptoms, and lower average antipsychotic dose requirement in
late-onset schizophrenia. More analyses of large data sets and studies
designed to elucidate the pathophysiological pathways underlying early-
and late-onset schizophrenia are needed to better understand how these two
groups differ from each other (Jeste et al. 2005).

Very-Late-Onset Schizophrenia-Like Psychosis

In its consensus statement, the International Late-Onset Schizophrenia
Group proposed the diagnostic term very-late-onset schizophrenia-like
psychosis (VLOSLP) for patients whose psychosis begins after age 60 years
(Howard et al. 2000). Table 11–1 compares risk factors for and clinical
features of early-onset schizophrenia, late-onset schizophrenia, and
VLOSLP. VLOSLP may be difficult to diagnose clinically because its
clinical picture can be confused with other conditions (e.g., delirium,
psychosis due to underlying medical illness). Nevertheless, new-onset
primary psychotic symptoms have been described in older adults. Indeed,
Cervantes et al. (2006) described a clinical case of primary-onset psychosis
in a 100-year-old patient.
Factors distinguishing individuals with VLOSLP from “true”
schizophrenia patients include a smaller genetic load, less evidence of early
childhood maladjustment, a relative lack of thought disorder and negative
symptoms (including blunted affect), a greater risk of tardive dyskinesia,
and evidence of a neurodegenerative rather than a neurodevelopmental
process (Andreasen 1999; Howard et al. 1997). Although the term was
initially considered a catchall phrase for several different entities, research
has since suggested that VLOSLP may be a distinct entity. It has been noted
to be more common in immigrant populations, suggesting that psychosocial
factors might play a role (Mitter et al. 2005). Imaging studies have shown
underlying focal white matter abnormalities in cerebral tracts (Jones et al.
2005). One study has suggested that the cognitive biases that are common
in younger individuals with delusions are absent in patients with VLOSLP
(Moore et al. 2006). A study by Mazeh et al. (2005) suggested that patients
with VLOSLP may have somewhat more stable cognitive and everyday
functioning than do chronically institutionalized elderly patients with
schizophrenia. In summary, clinical vigilance must be exercised when
treating apparent primary-onset psychotic symptoms in older patients, and
“organic” causes should be meticulously ruled out.

Delusional Disorder
At least 6% of older individuals have paranoid symptoms such as
persecutory delusions, but most of these individuals have a neurocognitive
disorder (Christenson and Blazer 1984; Forsell and Henderson 1998;
Henderson et al. 1998). The essential feature of a delusional disorder is a
nonbizarre delusion (e.g., a persecutory, somatic, erotomanic, grandiose, or
jealous delusion) without prominent auditory or visual hallucinations. The
symptoms must be present for at least 1 month. When delusional disorder
arises in late life, basic personality features, intellectual performance, and
occupational function are preserved, but social functioning is compromised.
To diagnose delusional disorder, the clinician must rule out delirium, major
neurocognitive disorder, psychotic disorder due to another medical
condition or due to substance or medication use, schizophrenia, and mood
disorders with psychotic features. The course of persecutory delusional
disorder is typically chronic, but individuals with other types of delusions
may have partial remissions and relapses.

TABLE 11–1. Comparison of early-onset schizophrenia, late-onset

schizophrenia, and very-late-onset schizophrenia-like
psychosis
Feature Early-onset Late-onset Very-late-onset
schizophrenia schizophrenia schizophrenia-like
psychosis
Age at onset Before age 40 Middle age (~40–60) Late life (60+)
Female preponderance – + ++
Negative symptoms ++ + –
Minor physical + + –
anomalies
Neuropsychological
impairment
Learning ++ + ?++
Retention – – ?++
Progressive – – ++
cognitive
deterioration
Brain structure – – ++
abnormalities (e.g.,
strokes, tumors)
Family history of + + –
schizophrenia
Early childhood + + –
maladjustment
Daily neuroleptic dose ++ + +
Risk of tardive + + ++
dyskinesia
Note. + = mildly present; ++=strongly present; ?++=probably strongly present, but limited data
exist;–=absent.
Source. Adapted from Palmer et al. 2001.
 According to DSM-5, the lifetime prevalence of delusional disorder is
estimated to be 0.2% and the most common subtype is persecutory. There
are no significant gender differences in the prevalence of delusional
disorder, although the jealous subtype may be more frequent in men than in
women (American Psychiatric Association 2013). The disorder typically
first appears in middle to late adulthood, with an average age at onset of
40–49 years for men and 60–69 years for women.
Risk factors for delusional disorder include a family history of
schizophrenia or avoidant, paranoid, or schizoid personality disorder
(Kendler and Davis 1981). Evidence supporting hearing loss as a risk factor
for paranoia is mixed (Cooper and Curry 1976; Moore 1981). In one
neuroimaging study, brain atrophy and white matter hyperintensities did not
distinguish older psychotic patients with somatic delusions from those
without such delusions (Rockwell et al. 1994). According to Maher (2005),
a subset of the population that is prone to primary perceptual abnormalities
may be prone to developing delusions as a result. Maher (2005) also
pointed out that “normal” persons may demonstrate “delusional” behavior
as a result of sensory disturbances. Evans et al. (1996) compared middle-
aged and older patients with schizophrenia or delusional disorder and found
no differences in neuropsychological impairment but more severe
psychopathology associated with delusional disorder. Finally, immigration
and low socioeconomic status may be risk factors for delusional disorder
(American Psychiatric Association 2000).

Psychosis of Alzheimer’s Disease

Based on a review of 55 studies, Ropacki and Jeste (2005) estimated the
median prevalence of psychosis in AD to be about 41% (range 12.2%–
74.1%). Psychosis is associated with more rapid cognitive decline. Some
studies found a significant association between psychosis and age, age at
onset of AD, and illness duration; however, gender, education, and family
history of dementia or psychiatric illness showed weak or inconsistent
relationships with psychosis. In a large sample of patients with probable
AD, Paulsen et al. (2000) found a cumulative incidence of psychotic
symptoms of 20% at 1 year, 36% at 2 years, 50% at 3 years, and 51% at 4
years. Delusions, especially of a persecutory nature, tend to be the most
common symptom (median prevalence 36%); visual hallucinations (median
prevalence 18.7%) and auditory hallucinations (median prevalence 9.2%)
are less common (Ropacki and Jeste 2005). These symptoms often need to
be inferred from the patient’s behavior, because the patient may be unable
to verbalize thoughts or perceptions due to cognitive impairment,
particularly in the later stages of the disease. In one large naturalistic study
of the course of psychotic symptoms in dementia, Devanand et al. (1997)
found that hallucinations and paranoid delusions were more persistent than
depressive symptoms over time but less prevalent and less persistent than
behavioral disturbances, particularly agitation.
In Table 11–2, characteristics associated with psychosis of AD are
compared with characteristics of schizophrenia in elderly patients (Jeste and
Finkel 2000). Two common psychotic symptoms in AD are
misidentification of caregivers and delusions of theft (Jeste et al. 2007).
Schneiderian first-rank symptoms, such as hearing multiple voices talking
to one another or hearing a running commentary on one’s actions, are rare
(Burns et al. 1990a, 1990b). Disorganization of speech and behavior and
negative symptoms are also uncommon (Jeste et al. 2007). Active suicidal
ideation and past history of psychosis are rare. Because psychotic
symptoms in patients with dementia tend to remit in the late stages of the
disease, very long-term maintenance therapy on antipsychotics is typically
unnecessary.
AD patients with psychosis and those without psychosis differ in several
important ways. Neuropsychologically, AD patients with psychosis have
shown greater impairment in executive functioning, more rapid cognitive
decline (Jeste et al. 1992; Stern et al. 1994), and greater prevalence of
extrapyramidal symptoms (Stern et al. 1994) than AD patients without
psychosis. Delusions in dementia have been associated with dysfunction in
paralimbic areas of the frontotemporal cortex (Sultzer 1996).
Neuropathologically, patients with psychosis related to a neurocognitive
disorder have shown increased neurodegenerative changes in the cortex,
increased norepinephrine in subcortical regions, and reduced serotonin
levels in both cortical and subcortical areas (Zubenko et al. 1991). In one
study, AD patients with psychosis had much higher levels of tau protein in
the entorhinal and temporal cortices than did nonpsychotic AD patients
(Mukaetova-Ladinska et al. 1995). Furthermore, Wilkosz et al. (2006)
suggested that the misidentification subtype and the paranoid subtype of
psychosis of AD may be distinct.

TABLE 11–2. Comparison of psychosis of Alzheimer’s disease (AD) with

schizophrenia in older patients
Feature Psychosis of AD Schizophrenia
Prevalence 35%–50% of AD Less than 1% of
patients general population
Bizarre or complex delusions Rare Frequent
Misidentification of Frequent Rare
caregivers
Common form of Visual Auditory
hallucinations
Schneiderian first-rank Rare Frequent
symptoms
Active suicidal ideation Rare Frequent
Past history of psychosis Rare Very common
Eventual remission of Frequent Uncommon
psychosis
Need for years of Uncommon Very common
maintenance on
antipsychotic medication
Usual optimal daily doses of
commonly used atypical
antipsychotics
Risperidone 0.75–1.5 mg 1.5–2.5 mg
Olanzapine 2.5–7.5 mg 7.5–12.5 mg
Recommended adjunctive Sensory enhancement, Cognitive-behavioral
psychosocial treatment structured therapy, social
activities, social skills trainingb
contact, behavior
therapya
aCohen-Mansfield 2001.
bGranholm et al. 2002; McQuaid et al. 2000.
Source. Adapted from Jeste DV, Finkel SI: “Psychosis of Alzheimer’s Disease and Related
Dementias: Diagnostic Criteria for a Distinct Syndrome.” American Journal of Geriatric Psychiatry
8:29–34, 2000. Used with permission.

Jeste and Finkel (2000) recommended specific diagnostic criteria for

psychosis of AD to facilitate epidemiological, clinical, and therapeutic
research. These criteria include the presence of visual or auditory
hallucinations or delusions, a primary diagnosis of AD, a duration of at
least 1 month, and a chronology indicating that symptoms of AD preceded
those of psychosis. Alternative causes of psychosis must be excluded, and
sufficient functional impairment should be present for this diagnosis to be
made. There is evidence for good interrater and test-retest reliability of
these criteria (Jeste et al. 2007).

Psychosis in Other Major Neurocognitive

Disorders
Psychosis is also common in other neurocognitive disorders. Visual
hallucinations and secondary delusions are common in Lewy body disease,
and vascular neurocognitive disorder may also be accompanied by
delusions or hallucinations (Schneider 1999). Naimark et al. (1996) found
psychotic symptoms in approximately one-third of a sample of patients with
Parkinson’s disease, with hallucinations being more common than
delusions. Psychosis in frontotemporal lobar degeneration is poorly
characterized but may be as common as psychosis in AD (Srikanth et al.
2005).

Treatment
The modern era of pharmacological treatment for schizophrenia and other
psychotic disorders began with the introduction of chlorpromazine in the
early 1950s. Although this and other conventional agents substantially
improved the positive symptoms of schizophrenia (e.g., hallucinations and
delusions), a number of treatment liabilities have been recognized over the
years, such as movement disorders, sedation, orthostatic hypotension, and
increased prolactin concentrations. In addition, older adults have a
significantly higher risk for developing tardive dyskinesia than do younger
adults, making use of conventional antipsychotics in this population highly
problematic.
Therefore, when atypical antipsychotics—which are associated with
significantly lower incidence of tardive dyskinesia—were introduced, they
were hailed as the drugs of choice for older adults with psychotic disorders.
However, these agents have since been linked to an increased risk of
metabolic dysfunction, including diabetes, dyslipidemia, and obesity,
thereby leading to a worsened cardiovascular risk profile. In elderly patients
with dementia, atypical antipsychotics have been associated with an
increased risk of cerebrovascular adverse events and mortality compared
with placebo; therefore, leading pharmaceutical regulatory agencies have
issued warnings about the use of these agents in patients with dementia
(Meeks and Jeste 2008). At the same time, because of the paucity of
evidence-based pharmacological treatment alternatives to antipsychotics for
patients with dementia, clinicians are restricted to off-label treatments,
which must be used with caution and close monitoring. Psychosocial
treatments for older adults with psychosis have been developed and tested
in randomized controlled trials (RCTs) and show promise as primary or
adjunctive treatments.

Treatment of Schizophrenia, Very-Late-Onset Schizophrenia-

Like Psychosis, and Delusional Disorder

Pharmacological Treatments
Pharmacotherapy for older adults with chronic psychotic disorders can be
challenging. Although few randomized, placebo-controlled, double-blind
clinical trials have been conducted in this population, some information has
become available. Maintenance pharmacotherapy is usually required for
older patients with schizophrenia due to risk of relapse. Because older
patients are at higher risk of adverse antipsychotic effects, due to age-
related pharmacokinetic and pharmacodynamic factors (Hämmerlein et al.
1998), coexisting medical illnesses, and concomitant medications, the
recommended starting and maintenance doses of antipsychotics in older
adults are much lower than the usual doses in younger adults (Lehman et al.
2004). Patients with late-onset schizophrenia respond well to low-dose
antipsychotic medication, requiring about 50% of the dose typically taken
by older patients with early-onset schizophrenia and 25%–33% of the dose
used in younger patients with schizophrenia.
Use of conventional or typical antipsychotics in older adults is
problematic because of the higher incidence of tardive dyskinesia in older
patients. Aging appears to be the most important risk factor for the
development of tardive dyskinesia (American Psychiatric Association 2000;
Yassa and Jeste 1992). The cumulative 1-year incidence of tardive
dyskinesia is 29% among older patients (mean age 65 years) despite low
dosing (Jeste et al. 1999b), whereas the annual cumulative incidence of
tardive dyskinesia in young adults is 4%–5% (Kane et al. 1993). The risk of
severe tardive dyskinesia is also higher in older patients (Caligiuri et al.
1997). Other side effects of conventional neuroleptics include sedation,
anticholinergic effects, cardiovascular effects including orthostatic
hypotension, parkinsonian reactions, and neuroleptic malignant syndrome.
Despite these side effects, occasionally a conventional antipsychotic may be
the most reasonable treatment option for an individual patient, and these
agents can be used at flexible, individualized low doses to minimize side
effects (Jeste et al. 1999b).
Few efficacy comparisons have been done of conventional
antipsychotics versus atypical antipsychotics in patients with schizophrenia
over age 65. In a study of 42 elderly inpatients, Howanitz et al. (1999)
found that clozapine (≤300 mg/day) and chlorpromazine (≤600 mg/day) had
similar efficacy. Kennedy et al. (2003) compared olanzapine (5–20 mg/day)
and haloperidol (5–20 mg/day) in a 6-week trial of 117 patients ages 60
years and older who had schizophrenia and related disorders. Olanzapine
(mean modal dose 11.9 mg/day) produced significantly greater
symptomatic improvement and was associated with fewer motor side
effects than haloperidol (mean modal dose 9.4 mg/day) (Kennedy et al.
2003). The National Institute of Mental Health’s Clinical Antipsychotic
Trials of Intervention Effectiveness (CATIE) study (Lieberman et al. 2005),
which included adults ages 18–65, found no significant differences in
effectiveness between the conventional antipsychotic perphenazine and the
atypical antipsychotics risperidone, olanzapine, quetiapine, or ziprasidone,
but it is unknown how these findings would translate to patients older than
age 65.
 Generally, atypical antipsychotics carry a much lower risk of tardive
dyskinesia than conventional neuroleptics, even when taken by very high-
risk patients such as middle-aged and older adults with borderline tardive
dyskinesia (Dolder and Jeste 2003; Jeste et al. 1999a). Clozapine has shown
efficacy in reducing tardive dyskinesia in patients with existing tardive
dyskinesia (Kane et al. 1993; Lieberman et al. 1991; Simpson et al. 1978;
Small et al. 1987); however, other side effects limit its use, particularly in
elderly patients. A beneficial effect of other atypical agents, specifically
risperidone and olanzapine, on preexisting tardive dyskinesia has also been
reported (Jeste et al. 1997a; Kinon et al. 2004; Littrell et al. 1998; Street et
al. 2000).
Atypical antipsychotics have a less favorable side-effect profile,
however, in terms of metabolic function. Common metabolic side effects
include excessive weight gain and obesity, glucose intolerance, new-onset
type II diabetes mellitus, diabetic ketoacidosis, and dyslipidemia (Allison et
al. 1999; Jin et al. 2002, 2004; Wirshing et al. 1998). Although there are no
guidelines for management of these side effects specifically in older
patients with schizophrenia, the monitoring recommendations developed by
the American Diabetes Association et al. (2004) are potentially applicable.
Because elderly patients tend to be at higher risk for cardiovascular disease
than younger patients, closer monitoring is necessary for older adults.
The short-term benefit of risperidone and olanzapine for treatment of
psychotic symptoms in middle-aged and older adults with schizophrenia has
been supported in several double-blind trials (Feldman et al. 2003; Jeste et
al. 2003; Riedel et al. 2009; Suzuki et al. 2011), and one short-term trial
suggests that paliperidone might be of benefit (Tzimos et al. 2008). Data
supporting the short-term benefit of other atypical antipsychotics come only
from open-label or retrospectively designed studies. Although clozapine has
been shown to have superior effectiveness than other antipsychotics in
younger adults (Jones et al. 2006; Lieberman et al. 2005), the medication is
difficult to use in elderly persons due to the risk of leukopenia and
agranulocytosis, as well as other side effects such as orthostasis, sedation,
and anticholinergic effects. The necessity of weekly blood draws also may
pose a problem for older patients.
Data from a study by Jin et al. (2012) raise serious concerns about the
longer-term safety and effectiveness of atypical antipsychotics in middle-
aged and older adults. The use of aripiprazole, olanzapine, quetiapine, and
risperidone was studied in 332 outpatients older than age 40 years who had
psychotic symptoms related to a variety of diagnoses, including
schizophrenia, mood disorders, posttraumatic stress disorder, or
neurocognitive disorder. The patients were followed for up to 2 years. The
high 1-year cumulative incidence of metabolic syndrome (36% in 1 year)
and high rates of both serious (23.7%) and nonserious (50.8%) adverse
events observed were particularly concerning given that no significant
improvement in psychopathology was detected. Over half of the study
participants discontinued their medication within 6 months, often due to
side effects (51.6%) or lack of efficacy (26%), and the quetiapine arm of the
study was discontinued early because the incidence of serious adverse
events was found to be twice that of the other three atypical antipsychotics.
The concerns about the long-term safety and efficacy of atypical
antipsychotics in middle-aged and older adults, combined with the data on
the increased risk of strokes and mortality in elderly patients with dementia
treated with atypical antipsychotics and the consequent U.S. Food and Drug
Administration (FDA) black box warnings (discussed in “Treatment of
Psychosis of Alzheimer’s Disease and Other Neurocognitive Disorders,”
later in this chapter), underscore the need for clinicians to exercise caution
when prescribing these drugs for older patients with schizophrenia. We
strongly recommend educating patients and their caregivers about the
potential risks and benefits of medications and encouraging shared decision
making. If the decision is made to use an antipsychotic medication, it is
generally best to start with a low initial dose (25%–50% of that used in a
younger patient) and titrate slowly. In patients who have been on stable
dosages of antipsychotic medications for long periods of time, clinicians
should consider gradual and incremental decreases to determine the lowest
effective dosage. Patients should be monitored closely for medication
effectiveness and for possible side effects.
Few data are available regarding the safety and effectiveness of
pharmacological treatment specifically of VLOSLP or delusional disorder
in older individuals. A single small retrospective case study of 8 outpatients
and 13 inpatients with VLOSLP concluded that atypical antipsychotics
(aripiprazole, risperidone, olanzapine, and quetiapine) could be helpful at
low dosages. Alexopoulos et al.’s (2004) survey of 48 experts in geriatric
care found antipsychotics to be the only recommended treatment for
delusional disorder in older adults, and the most favored recommendation
for older adults with delusional disorder was risperidone (0.75–2.5 mg/day),
followed by olanzapine (5–10 mg/day) and quetiapine (50–200 mg/day).
More research is required regarding pharmacological treatment of these
conditions in older adults.

Psychosocial Treatments
Over the past decade, effective psychosocial interventions for older adults
with chronic psychotic disorders have been developed. Granholm et al.
(2005) conducted an RCT to examine the effects of adding cognitive-
behavioral social skills training (CBSST) to treatment as usual for 76
middle-aged and elderly stable outpatients with schizophrenia. This training
intervention teaches cognitive and behavioral coping techniques, social
functioning skills, problem-solving techniques, and compensatory aids for
neurocognitive impairments. The investigators found that CBSST led to
significantly increased frequency of social functioning activities, greater
cognitive insight (more objectivity in reappraising psychotic symptoms),
and greater skill mastery. At 12-month follow-up, the CBSST group had
maintained their greater skill acquisition and performance of everyday
living skills. The greater cognitive insight seen in the CBSST group at the
end of the treatment was not maintained at 12-month follow-up, however,
suggesting a possible need for booster sessions (Granholm et al. 2007).
Patterson et al. (2006) conducted an RCT to compare a behavioral group
intervention called Functional Adaptation Skills Training (FAST) with a
time-equivalent attention control condition. FAST is a manualized
behavioral intervention designed to improve everyday living skills
(including medication management, social skills, communication skills,
organization and planning, transportation, and financial management) of
middle-aged and older adults with schizophrenia or schizoaffective
disorder. Compared with participants randomized to attention control, the
FAST group showed significant improvement in daily living skills and
social skills but not medication management. The FAST intervention has
also been culturally adapted and pilot-tested in middle-aged and older
Spanish-speaking Mexican American patients with schizophrenia or
schizoaffective disorder. This intervention, called Programa de
Entrenamiento para el Desarrollo de Aptitudes para Latinos (PEDAL), was
compared with a time-equivalent friendly support group in a randomized
controlled pilot study (Patterson et al. 2005). The PEDAL group
demonstrated a significant improvement in everyday living skills that was
maintained at 12-month follow-up.
Helping Older People Experience Success (HOPES), a 12-month
program combining social skills training and a nurse-administered
preventive health care program, was associated with improved community
living skills and functioning, greater self-efficacy, and lower levels of
negative symptoms in adults over age 50 with serious mental illness
including schizophrenia. Improvement in community living skills was
maintained at 3-year follow-up (Bartels et al. 2014; Mueser et al. 2010).
Following an examination of employment outcomes among middle-aged
and older adults with schizophrenia who each participated in one of three
types of work rehabilitation program, Twamley et al. (2005) reported that
the highest rates of volunteer or paid work (81%) and competitive/paid
work (69%) occurred for the patients who were placed in a job chosen with
a vocational counselor and who then received individualized on-site
support. The less successful programs (achieving at best a 44% rate of
volunteer or paid work) employed a train-then-place approach.

Treatment of Psychosis of Alzheimer’s Disease and Other

Neurocognitive Disorders
Atypical antipsychotics have for the most part replaced conventional
antipsychotics in treating psychosis, aggression, and agitation in patients
with neurocognitive disorders because of greater perceived tolerability,
lower risk for acute extrapyramidal symptoms, and comparatively lower
risk of tardive dyskinesia. Most antipsychotics that are prescribed for older
adults are for behavioral disturbances associated with neurocognitive
disorders, despite their lacking this FDA-approved indication (Weiss et al.
2000).
Atypical antipsychotics seem to have modest short-term efficacy for
treating psychosis of AD (Ballard and Waite 2006; Sink et al. 2005);
however, studies have not always found a significant advantage over
placebo in treating psychotic symptoms (Kindermann et al. 2002; Schneider
et al. 2006a). In the CATIE-AD trial—the largest (N = 421) non–industry-
sponsored trial of atypical antipsychotics for psychosis or
agitation/aggression in people with dementia—olanzapine, quetiapine, and
risperidone were no better than placebo for the primary outcome (time to
discontinuation for any reason) (Schneider et al. 2006b). Time to
discontinuation due to lack of efficacy favored olanzapine and risperidone,
whereas time to discontinuation due to adverse events favored placebo. In a
meta-analysis of RCTs of atypical antipsychotics in dementia, Schneider et
al. (2006a) reported that the number needed to treat ranged from 5 to 14,
depending on the outcome measure, criterion for improvement, and
methodology used. They found that the overall average treatment effect was
approximately 18%, which is remarkably similar to that reported in a meta-
analysis of conventional antipsychotics in this population (Schneider et al.
1990). In a more recent review, Ballard and Corbett (2013) identified 18
RCTs of atypical antipsychotic treatment of agitation and aggression in AD
over periods of 6–12 weeks. The authors identified five clinical trials
reporting statistically significant but clinically modest improvement in
aggression with risperidone at total doses up to 2 mg/day compared with
placebo. The evidence to support the benefit of risperidone for
nonaggressive symptoms was less consistent, and evidence to support the
value of other atypical antipsychotics was limited and conflicting.
Only a few RCTs have compared atypical and conventional
antipsychotics for treatment of neurocognitive disorders: three trials
compared risperidone with haloperidol (Chan et al. 2001; De Deyn et al.
1999; Suh et al. 2004), and one compared quetiapine with haloperidol
(Tariot et al. 2006). One of these found superior efficacy of the atypical
over the typical agent, and the others reported no significant differences
between the two types. In all four studies, haloperidol was associated with
more extrapyramidal symptoms.
In addition to the liabilities described above, the use of atypical
antipsychotics in elderly patients with dementia has been associated with
both cerebrovascular adverse events (CVAEs) and death, leading to black
box warnings by the FDA. Currently, risperidone, olanzapine, and
aripiprazole carry black box warnings for stroke risk in older patients with
neurocognitive disorders. The data for quetiapine in this population are
more limited than for risperidone, olanzapine, and aripiprazole. The
attribution of risk of CVAEs to atypical antipsychotics is limited, however,
in that these studies were not designed to determine a cause-and-effect
relationship between atypical antipsychotics and CVAEs, and serious
CVAEs were not operationally defined in the trials. Additionally,
retrospective database reviews (Gill et al. 2005; Herrmann et al. 2004) did
not find any difference in incidence of CVAEs for typical versus atypical
antipsychotic use, although these studies were not originally designed to
examine CVAE risk.
In May 2004, the FDA issued a black box warning that elderly patients
with dementia treated with atypical antipsychotic drugs are at an increased
risk for death compared with those treated with placebo. A 2005 meta-
analysis of 15 RCTs reported a mortality risk of 3.5% for patients treated
with atypical antipsychotics compared with a risk of 2.5% for patients given
placebo (odds ratio = 1.5; 95% confidence interval = 1.1–2.2) (Schneider et
al. 2005). The causes of death were most commonly cardiac or infectious,
the two most common causes of death in patients with dementia (Kammoun
et al. 2000; Keene et al. 2001). The data on mortality risk associated with
typical versus atypical antipsychotics have been mixed (Jeste et al. 2008).
Patients with Lewy body dementia and parkinsonian dementia are
especially sensitive to side effects such as extrapyramidal symptoms and
anticholinergic effects; therefore, very low doses and slow titration
schedules should be used to avoid worsening of motor symptoms (Stoppe et
al. 1999). Low-dose clozapine has demonstrated efficacy in reducing
symptoms of psychosis, and the drug does not worsen and can even
improve the parkinsonian tremor (Bonuccelli et al. 1997; Masand 2000;
Parkinson Study Group 1999; Pollak et al. 2004). Several trials of
olanzapine in patients with Parkinson’s disease have found worsened motor
function without demonstrable efficacy in treating psychosis (Chou et al.
2007; Miyasaki et al. 2006). Quetiapine does not appear to worsen motor
functioning, but data about its efficacy for psychosis in Parkinson’s disease
are mixed (Chou et al. 2007; Yeung et al. 2000). The limited data (generally
from small, open-label studies) on ziprasidone and aripiprazole do not
clearly support the use of these drugs in patients with movement disorders;
however, no large RCTs have been published to date (Chou et al. 2007).
One double-blind, placebo-controlled trial that addressed the treatment of
psychosis in dementia with Lewy bodies (N = 120) found that twice as
many patients treated with rivastigmine (up to 12 mg/day) (63%) versus
placebo (30%) had at least 30% improvement in delusions and
hallucinations without worsening of motor symptoms (McKeith et al.
2000).
 Nonuse of active treatment may be a reasonable option for some mild to
moderate cases, but in many clinical scenarios, this would be an
unacceptably risky alternative. Because of the concerns about safety and
effectiveness of antipsychotic medications discussed above and the lack of
alternative FDA-approved pharmacotherapies for treating psychosis in
patients with dementia, most current treatment guidelines recommend
nonpharmacological treatment of symptoms as a first-line approach to
management of these symptoms unless more aggressive management is
deemed necessary to preserve safety. Accordingly, a number of studies have
tested such promising interventions, although when strict inclusion criteria
are used, very few of these studies can be considered evidence based
because the results are often inconclusive (Ayalon et al. 2006; Livingston et
al. 2005). Recent reviews have highlighted several promising psychosocial
therapies (e.g., individualized daily social interactions and caregiver
training) (Ballard and Corbett 2013).

Conclusion
Chronic psychotic disorders of late life may include early-onset
schizophrenia (onset before age 40), late-onset schizophrenia (onset
between ages 40 and 60), very-late-onset schizophrenia-like psychosis
(onset after age 60), delusional disorder, and psychosis related to
Alzheimer’s disease or other neurocognitive disorders. Psychosocial
treatments have an important place as an adjunctive treatment for older
adults with psychosis. Aging is associated with increased risk for
antipsychotic-related adverse reactions. Compared with younger patients,
older adults have a much higher risk of developing tardive dyskinesia, and
atypical antipsychotics are associated with metabolic liabilities. There are
also concerns about the long-term safety and effectiveness of atypical
antipsychotics in older patients. No FDA-approved treatments are currently
available for psychosis and agitation in neurocognitive disorders, and
atypical antipsychotic use in this population has been associated with an
increased risk of cerebrovascular adverse events and mortality. Use of
pharmacological treatments for older adults with psychosis therefore
requires careful consideration of the potential risks and benefits as well as
shared decision making with patients and their caregivers.
 Key Points
• Schizophrenia may be classified by age at onset into early-onset
schizophrenia (onset before age 40), late-onset schizophrenia (onset
between ages 40 and 60), and very-late-onset schizophrenia-like
psychosis (onset after age 60).
• There is considerable heterogeneity of course and outcome with aging in
patients with early-onset schizophrenia, although there is generally an
improvement in positive symptoms.
• Patients with late-onset schizophrenia are similar to patients with early-
onset schizophrenia in terms of risk factors, clinical presentation, family
history of schizophrenia, and response to medications. However, women
are overrepresented among the late-onset patients. Also, late-onset
schizophrenia is characterized by lower average severity of positive
symptoms, and a lower average antipsychotic dose requirement.
• Very-late-onset schizophrenia-like psychosis is a heterogeneous entity
with varied etiology.
• Patients with psychosis of Alzheimer’s disease tend to have paranoid
delusions and visual or auditory hallucinations, as well as greater risk of
agitation, faster cognitive decline, and greater likelihood of being
institutionalized than patients with Alzheimer’s disease without
psychosis.
• Compared with younger patients, older adults have a much higher risk of
developing tardive dyskinesia. Although atypical antipsychotics are
associated with significantly lower risk of tardive dyskinesia than
conventional agents, they have problematic metabolic liabilities.
• Psychosocial treatments have an important place as an adjunctive
treatment for older adults with schizophrenia.
• There are currently no FDA-approved treatments for psychosis and
agitation in dementia; however, off-label use of medications, as well as
certain psychosocial interventions, may be appropriate.
• There are concerns about longer-term safety as well as effectiveness of
atypical antipsychotics in older patients with psychotic disorders.
 Additionally, atypical antipsychotic use in patients with dementia has
been associated with an increased risk of cerebrovascular adverse events
and mortality, leading the FDA to issue black box warnings for this
population.
• Principles of pharmacotherapy for older adults with psychosis include
careful consideration of indications, shared decision making, and use of
the lowest effective doses for the shortest possible time periods.

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 CHAPTER 12

Anxiety, Obsessive-Compulsive, and Trauma-

Related Disorders
Eric J. Lenze, M.D.
Jan Mohlman, Ph.D.
Julie Loebach Wetherell, Ph.D.

In this chapter we review the presentation, epidemiology, correlates, and

treatment of late-life anxiety, obsessive-compulsive, and trauma-related disorders. Since
publication of the last edition of this textbook in 2009, there have been many advances
in neuroscience as well as the introduction of DSM-5 (American Psychiatric
Association 2013) and of the Research Domain Criteria of the National Institute of
Mental Health (NIMH; Cuthbert 2014). There have also been advances in the
understanding of late-life anxiety disorders and related conditions. It is still the case that
much more is known about the pathophysiology and treatment of geriatric depression
than about geriatric anxiety disorders, mainly because of the dearth of longitudinal
and/or mechanistic studies that would shed light on aging-related pathophysiology of
the latter. On the other hand, with respect to treatment, several recent clinical trials now
support the use of treatments such as selective serotonin reuptake inhibitors (SSRIs) and
cognitive-behavioral therapy (CBT) for these common distressing and impairing
disorders. Accordingly, this chapter summarizes recent advances in knowledge about
the epidemiology and treatment of anxiety disorders in older adults and synthesizes
them into a body of information to guide clinicians and researchers.

Anxiety Disorders and Related Conditions in DSM-5:

Focus on Aging
The classification of and criteria for anxiety disorders have undergone some changes in
DSM-5, as listed in Table 12–1. Posttraumatic stress disorder (PTSD) was reclassified
as a trauma- and stressor-related disorder, and obsessive-compulsive disorder (OCD)
was reclassified as one of the obsessive-compulsive and related disorders. Additionally,
hoarding disorder, a relatively common problem in older adults, has been added in
DSM-5 (also as one of the obsessive-compulsive and related disorders). The major
changes (listed in Table 12–1) are likely to lead to an improvement in the detection of
geriatric anxiety disorders, largely due to the discontinuation of requiring that the
patient has insight that his or her anxiety is “excessive.”
An Advisory Committee to the DSM-5 Lifespan Disorders Work Group
recommended text revisions to improve the diagnosis and management of these
disorders (Mohlman et al. 2012). Highlights of these recommendations are summarized
in Table 12–2.

Epidemiology
Prevalence estimates of late-life anxiety disorders vary widely, ranging from the view
that they are relatively uncommon and, if present, are typically comorbid conditions
stemming from depression and/or cognitive decline to the opinion that anxiety disorders
are common and in fact the most prevalent disorders in older adults. Such disparate
opinions may stem from the wide variability in published prevalence estimates of
anxiety disorders and related conditions in community-dwelling older adults (Table 12–
3). For example, the National Comorbidity Survey Replication (NCS-R) found much
lower rates of all anxiety disorders in individuals ages 65 years and older compared
with their peak prevalence in individuals ages 18–44 years (Gum et al. 2009). In
contrast, the Longitudinal Aging Study Amsterdam (LASA; Beekman et al. 1998), one
of the largest epidemiological studies to focus on psychiatric disorders in elderly
persons, demonstrated that more than 10% of elderly adults had any anxiety disorder,
including generalized anxiety disorder (GAD), any phobic disorder, panic disorder,
and/or OCD, closer to estimates in younger adults. Other studies have found that all of
the anxiety disorders are less common in older adults, with many studies finding panic
disorder rare or nonexistent (Flint 1994). One study, the Australian National Mental
Health and Well-Being Survey (NMHWS), found that the prevalence of anxiety
disorders in elderly people varied almost threefold, depending on whether DSM-IV-TR
(American Psychiatric Association 2000) or ICD-10 (World Health Organization 1992)
criteria were used (Trollor et al. 2007).
As a whole, these epidemiological studies suggest that GAD is about as common in
older adults as in younger adults, whereas other anxiety disorders (as well as OCD and
possibly PTSD) are rarer in older adults. However, we view the prevalence estimates as
being limited by the well-known challenges in identifying anxiety disorders in this age
group (Wolitzky-Taylor et al. 2010). Chief among these challenges is that older adults
are less able as a group than younger adults to accurately identify anxiety symptoms
(Wetherell et al. 2009). Furthermore, avoidance and the “excessive” nature of anxiety,
which are two distinguishing features in DSM-IV (American Psychiatric Association
1994), are quite challenging to detect in older people, as described in Table 12–2.
Additionally, anxiety conditions germane to elderly persons—such as anxiety in the
context of dementia (Starkstein et al. 2007), anxiogenic medical conditions such as
heart disease (Todaro et al. 2007), fear of falling (Gagnon et al. 2005), and hoarding
syndrome (Saxena 2007)—may not be discerned by standard epidemiological
assessments or methodology. Thus, the prevalence and significance of such conditions
are currently unknown.

TABLE 12–1. DSM-5 changes of most relevance to older adults: anxiety, obsessive-
compulsive, and trauma-related disorders
Disorder Changes in DSM-5

Anxiety disorders
Specific phobia “Excessive or unreasonable” requirement has been removed
in favor of “out of proportion to the actual danger.”
Social anxiety disorder “Excessive or unreasonable” criterion has been removed in
(social phobia) favor of “out of proportion to the actual threat”; fear of
negative evaluation has been added.
Panic disorder, Panic disorder and agoraphobia are now diagnosed
agoraphobia separately. Panic disorder diagnosis is unchanged.
Agoraphobic diagnosis is more specific about feared
situations (public transportation, open spaces, enclosed
places, standing in line or being in a crowd, and being
outside home alone) and requires fear/anxiety “out of
proportion to the actual danger.”
Generalized anxiety “During depression” exclusion has been removed.
disorder
Obsessive-compulsive and related disorders
Obsessive-compulsive Disorder has been reclassified into obsessive-compulsive
disorder and related disorders. “Recognized as excessive or
unreasonable” requirement has been removed.
Hoarding disorder Disorder has been added in DSM-5, in obsessive-
compulsive and related disorders.
Trauma- and stressor-related disorders
Posttraumatic stress Disorder has been reclassified into trauma- and stressor-
disorder related disorders. Changes include greater specificity
regarding the nature of the traumatic experience (see
Table 12–12, criterion A). Diagnosis requires symptoms
of intrusion, avoidance, negative alterations in cognitions
or mood, and heightened arousal/reactivity. “Sense of
foreshortened future” symptom has been removed.
Age at Onset and Risk Factors for Anxiety Disorders and
Related Conditions
Published reviews of the literature have taken two different stances on the question of
age at onset of anxiety disorders. One camp describes them as rarely of late onset (Flint
2005a), pointing to studies indicating onset in childhood or early adulthood (Kessler et
al. 2007). Another camp has found in clinical samples of elderly persons that many
individuals have a later onset of anxiety disorder (Lenze et al. 2005a; Le Roux et al.
2005; Sheikh et al. 2004; van Zelst et al. 2003). For example, in a sample of 103
treatment-seeking elderly patients with GAD, the mean age at onset was 49 years, with
46% of cases being of late onset (Lenze et al. 2005a). Other evidence suggests a
bimodal distribution of onset, with approximately two-thirds of patients having onset in
childhood or adolescence and one-third developing the disorder for the first time at age
50 years or later (Blazer et al. 1991; Le Roux et al. 2005). The largest epidemiological
study to specifically examine the question of incident mental disorders in elderly found
that late-onset anxiety disorders are not rare (Chou et al. 2011).

TABLE 12–2. Enhancing diagnosis of anxiety disorders and related conditions in

older adults: recommendations of the Anxiety Disorders Advisory
Committee to the DSM-5 Lifespan Disorders Work Group
Disorder Recommendations to clinicians for diagnosis in older
adults
Specific phobia 1. Fear of falling increases substantially with age and may
meet criteria for specific phobia (or agoraphobia). In this
context, older adults may be reluctant to consider their
fear or avoidance behavior to be excessive.
2. Because older adults’ changing social environment and
roles, inquire about whether they are receiving formal or
informal home support as a result of phobic avoidance.
Social anxiety disorder 1. Give examples of anxiety in age-appropriate social
(social phobia) situations: anxiety associated with declines in sensory
functioning (hearing, vision), memory (e.g., remembering
people’s names), or embarrassment about appearance or
functioning due to medical conditions.
2. The detection of social impairment in this disorder is more
difficult with aging because of changes in social
environment and roles.
Panic disorder Older adults often have a weaker autonomic response, so
full-blown panic attacks may be less frequent or
nonexistent.
Agoraphobia 1. Because of lack of insight and avoidance behavior, an
older individual might not report having fear or anxiety in
the avoided situation. The clinician’s focus should
emphasize the avoidance behavior rather than intense
fear/anxiety.
2. Clients may not endorse fear/anxiety per se but may
instead state they are “cautious” or “careful.”
3. Functional consequences of agoraphobia can include
reduced home maintenance, difficulties managing one’s
health (missing medical appointments), and increased
reliance on caregivers.
4. New-onset agoraphobia is not uncommon after a
traumatic medical event such as a fall-related injury,
myocardial infarction, or stroke. There are no specific
medical conditions that preclude a diagnosis of
agoraphobia (vs. anxiety disorder associated with a
general medical condition).
Generalized anxiety 1. Use a broad array of terms to inquire about worry (e.g.,
disorder (GAD) anxiety, concerns, think too much, fret).
2. Give examples of worries and avoidance behaviors that
are age-appropriate. Probe the areas of health and
finances.
3. Do not ask whether worry is “excessive”; instead, inquire
whether friends and relatives believe the individual
worries too much, or whether the description of worries
suggests high frequency and severity.
4. When differentiating from depression, note that frequently
both disorders will be present and both will be foci of
treatment.
5. Co-occurring cognitive impairment will be common,
because GAD often precedes cognitive decline and vice
versa.
Obsessive-compulsive Older adults may report obsessions with content related to
disorder health and memory loss. This requires differentiation from
GAD or depression (with focus on cognitive concerns).
Hoarding disorder 1. Use terms other than “urges” to describe hoarding (e.g.,
“need to save,” “cannot part with,” “might need it in the
future”).
2. Clients may not describe their hoarding as a problem but
rather a consequence to early life events or learned
behaviors, or as part of their cultural norms.
 3. In cognitively impaired clients, repetitive behaviors may
be mistaken for hoarding symptoms.
Posttraumatic stress 1. Subthreshold (partial) PTSD is substantially more
disorder (PTSD) common than full PTSD. Older adults who continue to
have PTSD into older adults express fewer symptoms of
hyperarousal, avoidance, and numbing.
2. There is considerable comorbidity with dementia.
3. PTSD symptoms can persist for more than 50 years after a
traumatic event and symptoms exacerbated due to factors
such as worsening health and cognitive functioning, or
social isolation.
Source. Adapted from Mohlman J, Bryant C, Lenze EJ, et al.: “Improving Recognition of Late Life Anxiety
Disorders in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: Observations and
Recommendations of the Advisory Committee to the Lifespan Disorders Work Group.” International Journal of
Geriatric Psychiatry 27(6):549–556, 2012. Used with permission.

In a sense, both camps may be correct: aging may either protect from anxiety or
cause anxiety, depending on circumstances. Congruent with this assertion, some reports
have noted a decline in the propensity for negative affect (which underlies anxiety as
well as depression) from adulthood to “early” elderly years, with a subsequent rise in
the mid-70s (Charles et al. 2001; Teachman 2006). It has been suggested that aging
provides the opportunity to inoculate against the anxiety-producing nature of stressors
and to practice emotion regulation (Jarvik and Russell 1979). Additionally, aging may
reduce the propensity for anxiety because of degeneration in anxiety-producing brain
regions such as the locus coeruleus (Flint 1994). On the other hand, aging is associated
with a number of new stressors, such as chronic illness and disability (in self or loved
ones), that may be particularly anxiogenic. It is perhaps for this reason that GAD,
centrally defined by worry-related distress, seems to peak in prevalence in middle age
and frequently have a late age at onset. Also, age-related degeneration in brain regions
associated with adaptive responses to anxiety (e.g., the dorsolateral prefrontal cortex)
may reduce the ability of some to manage anxiogenic situations; findings of poststroke
GAD (Aström 1996) and cerebral lesions associated with late-onset OCD (Swoboda
and Jenike 1995) are congruent with this assertion. Along these lines, clinicians should
be aware that many prescription medications can induce anxiety (e.g., anticholinergics,
psychostimulants, steroids), and this possibility should be a part of any differential
diagnosis of new-onset anxiety in an elderly person. However, it is our clinical
experience that elderly persons, unless cognitively impaired, are usually quite insightful
when a medication they take causes clinically significant anxiety.

TABLE 12–3. Prevalence estimates of late-life anxiety disorders and related

conditions from epidemiological studies
Epidemiological studies in the elderly Young
adult
 ECA LASA AMSTEL CCHS NMHWSNCS-R comparator
groupa
N — 3,107 4,051 12,792 1,792 1,461 —
Age range 65 + 55–85 65–84 55 + 65 + 65 + 18–44
Prevalence
Any anxiety 5.5% 10.2% N/A N/A 4.4% 7.0% 20.7%
disorder
Any phobic 4.8% 3.1% N/A 1.3% (social) 0.6% 4.7% 9.7%
disorder 0.6% (social) (specific)
(e.g., specific (agoraphobia)
phobia,
social
phobia,
agoraphobia)
Panic disorder 0.1% 1.0% N/A 0.8% 0.8% 0.7% 3.2%
Generalized 1.9% 7.3% 3.2% N/A 2.4% 1.2% 2.8%
anxiety
disorder
Obsessive- 0.8% 0.6% N/A N/A 0.1% — 1.6%
compulsive
disorder
Posttraumatic N/A N/A — N/A 1.0% 0.4% 3.7%
stress
disorder
Note. AMSTEL=Amsterdam Study of the Elderly (Schoevers et al. 2003); CCHS=Canadian Community Health
Survey (Streiner et al. 2006); ECA=Epidemiologic Catchment Area (Regier et al. 1990); LASA=Longitudinal Aging
Study Amsterdam (Beekman et al. 1998); NCS-R=National Comorbidity Survey Replication (Byers et al. 2010);
NMHWS=(Australian) National Mental Health and Well-Being Study (Trollor et al. 2007). N/A=not applicable.
aAll prevalence estimates are from the NCS-R except that for obsessive-compulsive disorder, which is from the
ECA.

Another consideration is that some anxiety disorders presenting in later life may
have a different nature (Flint 2005b), owing to a potentially different etiology (much as
late-onset depression, often in the context of cerebrovascular disease, has different
phenomenology than the early-onset variety). Research has generally not found that age
at onset affects qualitative presentation of anxiety disorders (Sheikh et al. 2004;
Wetherell et al. 2003b), yet this in itself may be due to the use of DSM diagnoses
created for younger adults. In summary, late-onset anxiety disorders are probably more
common than appreciated (Chou et al. 2011), but the disorders may present differently
than in younger adults.
 Risk factors for anxiety disorders have been reported in elderly persons (Vink et al.
2008). They include female gender, neurotic personality, early life stress, and chronic
disability in self or spouse. However, research uncovering neurobiological risk factors
for late-life, or late-onset, anxiety has not been done. Therefore, the basic question of
who develops anxiety in older age is largely unanswered.

Shared Versus Distinct Clinical Features of Anxiety

Disorders and Related Conditions
Anxiety disorders are marked by elevated fear or worry and behavioral avoidance.
Within these broad criteria, the anxiety disorders have both shared and distinct features
as shown in Table 12–4. A few points regarding this table should be highlighted. First,
all of these disorders may be associated with some degree of avoidance (e.g., even in
GAD). However, most anxiety research now delineates the more overt situational fear
response from worry. Second, on the basis of these shared and distinct features, the
eight DSM-IV anxiety disorders—GAD, panic disorder, specific phobia, social phobia,
agoraphobia, OCD, PTSD, and acute stress disorder—could be divided into three main
categories according to the nature of their phenomenology: worry/distress disorders
(GAD, PTSD, and acute stress disorder), fear disorders (panic disorder and the
phobias), and OCD (Watson 2005). Finally, however, research in young and middle-
aged adults has suggested that these categories have shared (as well as distinct) genetic
diatheses, neurocircuitry, and neuroendocrine responses, in addition to shared (as well
as distinct) features with depression (Hettema 2008; Sylvester et al. 2012). Such
pathophysiological research increasingly questions this diagnostic grouping, which is
one of the bases for the NIMH Research Domain Criteria initiative that seeks to
understand mental disorders on a pathophysiological rather than purely diagnostic or
behavioral basis. In this respect, it should be emphasized that such pathophysiological
research is largely nonexistent in older adults; therefore, very little is known about the
appropriate subtyping of anxiety presentations in late life to distinguish or group
anxiety disorders based on underlying neurobiology. Nevertheless, in this section we
describe the changes to the various anxiety disorders, in DSM-5, with a focus on aging.

TABLE 12–4. Shared and distinct clinical features of anxiety disorders and related
conditions
Situational Situational Autonomic Anticipatory Obsessions Panic
fear avoidance arousal worry and attacks
compulsions
Specific X X X X X
phobia,
social
 anxiety
disorder
(social
phobia), and
agoraphobia
Panic disorder X X X X X
Generalized X
anxiety
disorder
Obsessive- X X X X
compulsive
disorder
Hoarding X
disorder
Posttraumatic X X X X
stress
disorder

Specific Anxiety Disorders and Related Conditions

Fear Disorders: Phobias and Panic Disorder

The fear disorders are marked by anxiety that is discrete (clearly episodic) and confined
to a specific situation, although in the case of agoraphobia, behavioral avoidance may
be continuous and without reference to specific triggers. The fear disorders are also
marked by autonomic arousal and situational avoidance.

Phobias
Phobias are marked by an excessive and unreasonable situational fear that is distressing
or impairing. Exposure to the feared situation is either avoided or endured only with
distress, even precipitating a panic attack in some instances.
Phobia may be difficult to detect in an older adult—particularly if the phobia has
been lifelong—because of lifestyle accommodation around it (e.g., avoiding social
situations in the case of social phobia). The available evidence suggests that specific
phobias (Table 12–5) are quite common in elderly persons, whereas social phobia is less
so.
The difficulty of diagnosing phobias is exemplified by fear of falling, a common
problem in elderly persons, which by its very name might be considered a phobia.
However, under DSM-IV criteria, this condition usually could not be diagnosable as a
phobia, in part because individuals who fear falling typically do not feel their fear to be
excessive or unreasonable (Gagnon et al. 2005). Under DSM-5 criteria, fear that is “out
of proportion to actual danger posed,” such as severe levels of fear and avoidance in
individuals who are at low objective fall risk, could be diagnosed as a phobia.
Social phobia (Table 12–6) has received little study in elderly persons. In the largest
examination of this condition, Cairney et al. (2007) found that aging was associated
with reduced prevalence of social phobia, although the condition still remained fairly
common in old age and qualitatively appeared strikingly similar to that in young adults.
Agoraphobia (Table 12–7) can present within the context of panic attacks but
frequently does not do so in elderly persons (McCabe et al. 2006). It can appear de novo
in the context of a stroke or other medical event, in which case it can be highly
disabling, leading to inhibition of activities necessary for restoration after the event
(Burvill et al. 1995). The condition itself might lead to decreased ability to detect it;
accordingly, studies of adults who are homebound or receiving home-based aging
services have found high rates of anxiety symptoms (Gum et al. 2009; Jayasinghe et al.
2013).

TABLE 12–5. DSM-5 diagnostic criteria for specific phobia

A. Marked fear or anxiety about a specific object or situation (e.g., flying, heights,
animals, receiving an injection, seeing blood).
Note: In children, the fear or anxiety may be expressed by crying, tantrums,
freezing, or clinging.
B. The phobic object or situation almost always provokes immediate fear or anxiety.
C. The phobic object or situation is actively avoided or endured with intense fear or
anxiety.
D. The fear or anxiety is out of proportion to the actual danger posed by the specific
object or situation and to the sociocultural context.
E. The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more.
F. The fear, anxiety, or avoidance causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
G. The disturbance is not better explained by the symptoms of another mental disorder,
including fear, anxiety, and avoidance of situations associated with panic-like
symptoms or other incapacitating symptoms (as in agoraphobia); objects or
situations related to obsessions (as in obsessive-compulsive disorder); reminders of
traumatic events (as in posttraumatic stress disorder); separation from home or
attachment figures (as in separation anxiety disorder); or social situations (as in
social anxiety disorder).
Specify if:
Animal
Natural environment
 Blood-injection-injury
Situational
Other
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set,
including specifier descriptions and coding and reporting procedures.
Source. DSM-5 criteria for specific phobia reprinted from Diagnostic and Statistical Manual of Mental Disorders,
5th Edition. Washington, DC, American Psychiatric Association, 2013, pp. 197–198. Used with permission.
Copyright © 2013 American Psychiatric Association.

Panic Disorder

Case Example
A 72-year-old woman was referred to geriatric psychiatry after she presented with complaints of “passing out” to
her primary care doctor. She described how, without warning, she would feel like she was losing consciousness.
The feeling was subjective and not tied to exertion, physical activity, or orthostatic changes. On further interview,
she reported that these episodes would last for approximately 15 minutes and would be associated with shortness
of breath, palpitations, tingling in her hands, and abdominal distress. She did not have any active cardiac
problems. These episodes occurred approximately monthly.
Since the onset of these symptoms, the woman’s family describes her as more “needy.” She unnecessarily
pays lots of attention to and closely monitors interoceptive sensations. She leaves her home less often, and when
she does, it is only with a family member present. She describes this change as related to crime in the
neighborhood and realistic worries about falling without someone to help her in case of an injury.

A panic attack is an episode of fear or intense anxiety accompanied by multiple

somatic and cognitive symptoms (e.g., feeling that one is losing control). Somatic
symptoms tend to be autonomic in nature (palpitations, sweating, chills, tremulousness)
and also include gastrointestinal distress, numbness and tingling in extremities, and
shortness of breath. Attacks build to peak intensity quickly (within 10 minutes at the
most) and last up to 30 minutes, although repeated panic attacks can occur. Attacks can
occur at any time, including nocturnally, when they cause sudden awakening.

TABLE 12–6. DSM-5 diagnostic criteria for social anxiety disorder (social phobia)
A. Marked fear or anxiety about one or more social situations in which the individual is
exposed to possible scrutiny by others. Examples include social interactions (e.g.,
having a conversation, meeting unfamiliar people), being observed (e.g., eating or
drinking), and performing in front of others (e.g., giving a speech).
Note: In children, the anxiety must occur in peer settings and not just during
interactions with adults.
B. The individual fears that he or she will act in a way or show anxiety symptoms that
will be negatively evaluated (i.e., will be humiliating or embarrassing; will lead to
rejection or offend others).
C. The social situations almost always provoke fear or anxiety.
Note: In children, the fear or anxiety may be expressed by crying, tantrums,
freezing, clinging, shrinking, or failing to speak in social situations.
D. The social situations are avoided or endured with intense fear or anxiety.
E. The fear or anxiety is out of proportion to the actual threat posed by the social
situation and to the sociocultural context.
F. The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more.
G. The fear, anxiety, or avoidance causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
H. The fear, anxiety, or avoidance is not attributable to the physiological effects of a
substance (e.g., a drug of abuse, a medication) or another medical condition.
I. The fear, anxiety, or avoidance is not better explained by the symptoms of another
mental disorder, such as panic disorder, body dysmorphic disorder, or autism
spectrum disorder.
J. If another medical condition (e.g., Parkinson’s disease, obesity, disfigurement from
burns or injury) is present, the fear, anxiety, or avoidance is clearly unrelated or is
excessive.
Specify if:
Performance only
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set,
including specifier descriptions and coding and reporting procedures.
Source. DSM-5 criteria for social anxiety disorder (social phobia) reprinted from Diagnostic and Statistical Manual
of Mental Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, pp. 202–203. Used with
permission. Copyright © 2013 American Psychiatric Association.

Panic disorder (Table 12–8) is the syndrome of recurrent panic attacks (at least some
of which are unexpected) associated with concern about having further attacks and,
often, avoidance of situations associated in the patient’s mind with attacks. This
avoidance can often lead to agoraphobia.
Most studies have found a low prevalence of panic disorder in older adults in the
community. This has led to a line of thinking that perhaps the aging process reduces
panic disorder prevalence or that mortality due to panic disorder reduces the likelihood
of its being present in older age groups (Flint 1994). Late-onset panic disorder appears
to be rare and may often be a prodrome of a medical or neurological problem. However,
this assertion is based on the disorder as defined in young adults and cannot exclude the
possibility that panic symptoms that do not meet criteria for panic disorder may be more
common in late life. Even this assertion has been questioned by epidemiological data
suggesting that incident panic disorder in late life, although not common, is not rare
(Chou et al. 2011).

TABLE 12–7. DSM-5 diagnostic criteria for agoraphobia

A. Marked fear or anxiety about two (or more) of the following five situations:
1. Using public transportation (e.g., automobiles, buses, trains, ships, planes).
2. Being in open spaces (e.g., parking lots, marketplaces, bridges).
 3. Being in enclosed places (e.g., shops, theaters, cinemas).
4. Standing in line or being in a crowd.
5. Being outside of the home alone.
B. The individual fears or avoids these situations because of thoughts that escape might
be difficult or help might not be available in the event of developing panic-like
symptoms or other incapacitating or embarrassing symptoms (e.g., fear of falling in
the elderly; fear of incontinence).
C. The agoraphobic situations almost always provoke fear or anxiety.
D. The agoraphobic situations are actively avoided, require the presence of a
companion, or are endured with intense fear or anxiety.
E. The fear or anxiety is out of proportion to the actual danger posed by the
agoraphobic situations and to the sociocultural context.
F. The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more.
G. The fear, anxiety, or avoidance causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
H. If another medical condition (e.g., inflammatory bowel disease, Parkinson’s disease)
is present, the fear, anxiety, or avoidance is clearly excessive.
I. The fear, anxiety, or avoidance is not better explained by the symptoms of another
mental disorder—for example, the symptoms are not confined to specific phobia,
situational type; do not involve only social situations (as in social anxiety disorder);
and are not related exclusively to obsessions (as in obsessive-compulsive disorder),
perceived defects or flaws in physical appearance (as in body dysmorphic disorder),
reminders of traumatic events (as in posttraumatic stress disorder), or fear of
separation (as in separation anxiety disorder).
Note: Agoraphobia is diagnosed irrespective of the presence of panic disorder. If an
individual’s presentation meets criteria for panic disorder and agoraphobia, both
diagnoses should be assigned.
Source. DSM-5 criteria for agoraphobia reprinted from Diagnostic and Statistical Manual of Mental Disorders, 5th
Edition. Washington, DC, American Psychiatric Association, 2013, pp. 217–218. Used with permission. Copyright ©
2013 American Psychiatric Association.

When panic disorder does occur in elderly persons, it tends to be associated with less
severe or less frequent panic attacks than in young adults, who frequently have daily
attacks (Sheikh et al. 2004). The lower severity of attacks may be because older adults
have less ability to mount a strong autonomic response (Flint et al. 2002). Nevertheless,
because the disability due to panic disorder tends to be related to the behavioral
avoidance rather than the frequency of attacks themselves, panic disorder can still be a
highly disabling condition in elderly persons.

TABLE 12–8. DSM-5 diagnostic criteria for panic disorder

A. Recurrent unexpected panic attacks. A panic attack is an abrupt surge of intense fear
 or intense discomfort that reaches a peak within minutes, and during which time four
(or more) of the following symptoms occur:
Note: The abrupt surge can occur from a calm state or an anxious state.
1. Palpitations, pounding heart, or accelerated heart rate.
2. Sweating.
3. Trembling or shaking.
4. Sensations of shortness of breath or smothering.
5. Feelings of choking.
6. Chest pain or discomfort.
7. Nausea or abdominal distress.
8. Feeling dizzy, unsteady, light-headed, or faint.
9. Chills or heat sensations.
10. Paresthesias (numbness or tingling sensations).
11. Derealization (feelings of unreality) or depersonalization (being detached from
oneself).
12. Fear of losing control or “going crazy.”
13. Fear of dying.
Note: Culture-specific symptoms (e.g., tinnitus, neck soreness, headache,
uncontrollable screaming or crying) may be seen. Such symptoms should not count
as one of the four required symptoms.
B. At least one of the attacks has been followed by 1 month (or more) of one or both of
the following:
1. Persistent concern or worry about additional panic attacks or their consequences
(e.g., losing control, having a heart attack, “going crazy”).
2. A significant maladaptive change in behavior related to the attacks (e.g., behaviors
designed to avoid having panic attacks, such as avoidance of exercise or
unfamiliar situations).
C. The disturbance is not attributable to the physiological effects of a substance (e.g., a
drug of abuse, a medication) or another medical condition (e.g., hyperthyroidism,
cardiopulmonary disorders).
D. The disturbance is not better explained by another mental disorder (e.g., the panic
attacks do not occur only in response to feared social situations, as in social anxiety
disorder; in response to circumscribed phobic objects or situations, as in specific
phobia; in response to obsessions, as in obsessive-compulsive disorder; in response
to reminders of traumatic events, as in posttraumatic stress disorder; or in response
to separation from attachment figures, as in separation anxiety disorder).
Source. DSM-5 criteria for panic disorder reprinted from Diagnostic and Statistical Manual of Mental Disorders, 5th
Edition. Washington, DC, American Psychiatric Association, 2013, pp. 208–209. Used with permission. Copyright ©
2013 American Psychiatric Association.

Generalized Anxiety Disorder

 Case Example
A 70-year-old woman was interviewed about anxiety by her family physician after she presented with concerns
about her memory and voiced a fear that she had Alzheimer’s disease. She admits to being “a worrier” all her life
but does not feel that her previous anxiety had been excessive or problematic. In the past 3 years, however, she
reports spending more time worrying and finding it more distressing and “difficult to turn my mind off.” This has
occurred in the context of caring for her husband, who has severe cardiac failure and often gets chest pain,
resulting in the need for immediate medical attention at any time of the day.
The patient also worries about her own health, her children’s health, the family’s finances, and other issues
(e.g., crime in the neighborhood). In the past 3 years, she has had poor sleep, finding it difficult to stop worrying
at night. She feels “tense” as well and has seen an orthopedist about “shoulder pain” that was thought to be
muscle tension. Her concentration is poor, although she does well with objective testing of memory and other
neuropsychological domains. Finally, she feels fatigued much of the day, resulting in workups for anemia and
other medical problems.

GAD is a common and impairing disorder in older adults; it is highly comorbid with
personality, mood, and other anxiety disorders (Mackenzie et al. 2011). The central
feature of GAD is worry or anticipation of future negative events. Also known as
anxious apprehension, worry is thought to be a separate form of anxiety from fear or
anxious arousal, as seen in the fear disorders (e.g., panic disorder). Phenomenologically,
they are quite different; worry may wax and wane but does not have the intense
episodic nature of panic attacks (although worry can itself precipitate panic attacks).
GAD has evolved diagnostically to be considered first a residual state of phobic/panic
anxiety, then a disorder in its own right, and now, in the DSM-5 era, as still an anxiety
disorder but a close relative to major depressive disorder (MDD). Worry in DSM-5–
diagnosed GAD must be excessive, be difficult to control, and cause distress (Table 12–
9). The actual content of worry in late-life GAD has been noted to be similar to that in
older adults without GAD—that is, concerns about health or disability, family
relationships, or finances (Diefenbach et al. 2001).
Associated features of GAD are muscle tension, restlessness (or feeling keyed up or
on edge), sleep difficulties, concentration problems (often thought by older adults to be
memory problems), fatigue, and irritability. GAD may wax and wane but is typically
chronic, unlike depressive episodes (Lenze et al. 2005a). Late-life GAD is associated
with impaired quality of life but low levels of professional help seeking in mental health
settings (Mackenzie et al. 2011). In our clinical experience, elderly persons with GAD
often present to primary care or specialty medical care with these associated symptoms,
which then become the targets of treatment (e.g., benzodiazepines for sleep, muscle
relaxants or even physical therapy referral for muscle tension, cholinesterase inhibitors
for cognitive complaints) rather than detection of the underlying anxiety syndrome
(Figure 12–1). As the figure depicts, this focus on treating symptoms may lead to
additional complications from the pharmacological or other management, in addition to
lack of treatment of the underlying disorder.

TABLE 12–9. DSM-5 diagnostic criteria for generalized anxiety disorder

A. Excessive anxiety and worry (apprehensive expectation), occurring more days than
not for at least 6 months, about a number of events or activities (such as work or
 school performance).
B. The individual finds it difficult to control the worry.
C. The anxiety and worry are associated with three (or more) of the following six
symptoms (with at least some symptoms having been present for more days than not
for the past 6 months):
Note: Only one item is required in children.
1. Restlessness or feeling keyed up or on edge.
2. Being easily fatigued.
3. Difficulty concentrating or mind going blank.
4. Irritability.
5. Muscle tension.
6. Sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying
sleep).
D. The anxiety, worry, or physical symptoms cause clinically significant distress or
impairment in social, occupational, or other important areas of functioning.
E. The disturbance is not attributable to the physiological effects of a substance (e.g., a
drug of abuse, a medication) or another medical condition (e.g., hyperthyroidism).
F. The disturbance is not better explained by another mental disorder (e.g., anxiety or
worry about having panic attacks in panic disorder, negative evaluation in social
anxiety disorder [social phobia], contamination or other obsessions in obsessive-
compulsive disorder, separation from attachment figures in separation anxiety
disorder, reminders of traumatic events in posttraumatic stress disorder, gaining
weight in anorexia nervosa, physical complaints in somatic symptom disorder,
perceived appearance flaws in body dysmorphic disorder, having a serious illness in
illness anxiety disorder, or the content of delusional beliefs in schizophrenia or
delusional disorder).
G. The disturbance causes clinically significant distress or impairment in social,
occupational, or other important areas of functioning.
Source. DSM-5 criteria for generalized anxiety disorder reprinted from Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, p. 222. Used with permission.
Copyright © 2013 American Psychiatric Association.

As described earlier in the section “Epidemiology,” prevalence estimates for GAD in

older adults vary widely across studies. Additionally, some studies have found that
“pure” GAD, which is not comorbid with MDD, is more common than the comorbid
condition (Beekman et al. 2000; Schoevers et al. 2003). The several-fold variation in
published estimates of late-life GAD may result from important qualitative differences
between the ways in which elderly persons versus younger adults describe anxiety. The
objects of worry for elderly persons with GAD are largely the same as those for older
adults without GAD: health, disability in self or spouse, and finances (Diefenbach et al.
2001). Because these are often realistic sources of concern in aging, older adults with
GAD may be unlikely to feel that their worry is excessive or is about minor issues, as
required by the GAD criteria, making its diagnosis difficult in epidemiological research
or in clinical practice. In working with older individuals, clinicians need to consider the
amount of worry, the difficulty the individual has in stopping it, and the degree of
distress or functional impairment related to worrying, rather than the degree to which
the worry is realistic versus excessive.

FIGURE 12–1. The iatrogenic outcomes of undetected and untreated generalized

anxiety disorder in older adults.
Note. BZD=benzodiazepine; GI=gastrointestinal.

In any event, GAD is one of the most common mental disorders in elderly persons,
and as noted earlier in the section “Age at Onset and Risk Factors for Anxiety
Disorders,” late-onset GAD is not uncommon (Chou et al. 2011). The disorder is even
more common in medical settings, as might be expected for any affective or anxiety
disorder (Todaro et al. 2007; Tolin et al. 2005). These findings, together with data
showing that elderly persons with anxiety disorders rarely present to specialty mental
health clinics (Ettner and Hermann 1997), suggest that primary and specialty medical
care, not psychiatric settings, are the places to find late-life GAD that is not comorbid
with depression (with attendant problems from this, as shown in Figure 12–1).
Symptoms that are common to GAD and MDD include impaired sleep and
concentration, low energy, and irritability. Additionally, low mood is a frequent feature
of GAD, and excessive worry is frequently seen in MDD. The underlying genetic
predisposition to both disorders is thought to be similar in older and younger adults
(Kendler et al. 1992, 2007). As a whole, there are several reasons for high comorbidity
between GAD and MDD, including bidirectional risk and shared underlying
neurocircuitry (Andreescu et al. 2013).
As previously noted in this section, GAD tends to be chronic rather than episodic.
Studies have found that the mean length of GAD symptoms in elderly persons
presenting for treatment ranged from 20 (Lenze et al. 2005a) to more than 30 years
(Stanley et al. 2003a; Wetherell et al. 2003a), whereas 9 years is the average among
younger adults (Wang et al. 2005). This chronicity fits with evidence showing that GAD
is one of the least likely mental disorders in the anxiety-affective spectrum to remit
spontaneously over time (Bruce et al. 2005). Other reports have suggested that in
elderly persons, chronic GAD tends to develop into a somatization condition (Rubio
and López-Ibor 2007) or mixed GAD and MDD (Schoevers et al. 2003).

Obsessive-Compulsive Disorder and Hoarding Disorder

Obsessive-Compulsive Disorder
Most epidemiological studies have concluded that OCD, marked by obsessions,
compulsions, or both (Table 12–10), is fairly uncommon in elderly persons and is rarely
of late onset. However, one report from the Epidemiologic Catchment Area data set
found a second peak of OCD incidence in women ages 65 and older (Nestadt et al.
1998). In any event, it has not been the topic of research in this age group (Velayudhan
and Katz 2006), beyond a few case reports and case series (e.g., Chacko et al. 2000;
Weiss and Jenike 2000). The case reports have often found cerebral lesions, often in the
basal ganglia, suggesting neurodegenerative disease as potential pathophysiology for
late-onset OCD. The observation of hoarding and similar compulsive behavior in
dementia, and the observation of greater neuropsychological impairment in late-onset
OCD (Hwang et al. 2007), adds to evidence of a connection between neurodegenerative
illness and late-onset OCD.
Genetic predisposition for OCD appears limited to individuals with early-onset
illness (Nestadt et al. 2000). Patients with a later onset of illness may be more likely to
respond to CBT for the disorder (Grant et al. 2007), although it is not clear that this
would be the case if there was overlying cognitive impairment (as would be expected
for patients with neurodegenerative disease).

Hoarding Disorder
Hoarding can be a disorder in its own right (Table 12–11) or can be a symptom of OCD.
Hoarding disorder is a common, often highly impairing, and sometimes dangerous
condition in older adults. Hoarding behavior is increasingly common and severe in old
age (Teachman 2006). Because hoarding is commonly seen in association with
dementia, debilitating physical conditions, and comorbid mental illness (Ayers et al.
2014a; Snowdon et al. 2007), clinicians should be sensitive to detecting hoarding
behavior in these contexts. In patients with dementia, clinicians need to delineate
repetitive behaviors from hoarding. True late-onset hoarding disorder is unlikely, but
because the disorder is progressive and rarely remits with age, its prevalence is highest
in oldest age groups (Ayers et al. 2010). For example, 15% of nursing home residents
and 25% of senior day care attendees display clinically significant hoarding behaviors.
Hoarding disorder may be difficult to detect in many older adults, who may deny
“urges” to save but may describe their hoarding by other phrases (e.g., need to save,
cannot part with). Similarly, they may not describe their hoarding as a psychiatric
problem but rather as a consequence of early life events or learned behaviors. Older
adults are often unaware that this is a treatable psychiatric problem and have not sought
or received treatment (Ayers et al. 2014b). Accurate recognition of and treatment for
hoarding are of growing concern, because hoarding is now considered a form of elder
self-abuse in several U.S. states (Dong et al. 2012). Therefore, hoarding disorder merits
greater efforts by clinicians to diagnose and manage it and by researchers to develop
better treatments.

TABLE 12–10. DSM-5 diagnostic criteria for obsessive-compulsive disorder

A. Presence of obsessions, compulsions, or both:

Obsessions are defined by (1) and (2):
1. Recurrent and persistent thoughts, urges, or images that are experienced, at some
time during the disturbance, as intrusive and unwanted, and that in most
individuals cause marked anxiety or distress.
2. The individual attempts to ignore or suppress such thoughts, urges, or images, or
to neutralize them with some other thought or action (i.e., by performing a
compulsion).
Compulsions are defined by (1) and (2):
1. Repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts
(e.g., praying, counting, repeating words silently) that the individual feels driven
to perform in response to an obsession or according to rules that must be applied
rigidly.
2. The behaviors or mental acts are aimed at preventing or reducing anxiety or
distress, or preventing some dreaded event or situation; however, these behaviors
or mental acts are not connected in a realistic way with what they are designed to
neutralize or prevent, or are clearly excessive.
Note: Young children may not be able to articulate the aims of these behaviors or
mental acts.
B. The obsessions or compulsions are time-consuming (e.g., take more than 1 hour per
day) or cause clinically significant distress or impairment in social, occupational, or
other important areas of functioning.
C. The obsessive-compulsive symptoms are not attributable to the physiological effects
of a substance (e.g., a drug of abuse, a medication) or another medical condition.
D. The disturbance is not better explained by the symptoms of another mental disorder
(e.g., excessive worries, as in generalized anxiety disorder; preoccupation with
appearance, as in body dysmorphic disorder; difficulty discarding or parting with
possessions, as in hoarding disorder; hair pulling, as in trichotillomania [hair-pulling
disorder]; skin picking, as in excoriation [skin-picking] disorder; stereotypies, as in
stereotypic movement disorder; ritualized eating behavior, as in eating disorders;
preoccupation with substances or gambling, as in substance-related and addictive
 disorders; preoccupation with having an illness, as in illness anxiety disorder; sexual
urges or fantasies, as in paraphilic disorders; impulses, as in disruptive, impulse-
control, and conduct disorders; guilty ruminations, as in major depressive disorder;
thought insertion or delusional preoccupations, as in schizophrenia spectrum and
other psychotic disorders; or repetitive patterns of behavior, as in autism spectrum
disorder).
Specify if:
With good or fair insight
With poor insight
With absent insight/delusional beliefs
Specify if:
Tic-related

Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set,
including specifier descriptions and coding and reporting procedures.
Source. DSM-5 criteria for obsessive-compulsive disorder reprinted from Diagnostic and Statistical Manual of
Mental Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, p. 237. Used with
permission. Copyright © 2013 American Psychiatric Association.

TABLE 12–11. DSM-5 diagnostic criteria for hoarding disorder

A. Persistent difficulty discarding or parting with possessions, regardless of their actual
value.
B. This difficulty is due to a perceived need to save the items and to distress associated
with discarding them.
C. The difficulty discarding possessions results in the accumulation of possessions that
congest and clutter active living areas and substantially compromises their intended
use. If living areas are uncluttered, it is only because of the interventions of third
parties (e.g., family members, cleaners, authorities).
D. The hoarding causes clinically significant distress or impairment in social,
occupational, or other important areas of functioning (including maintaining a safe
environment for self and others).
E. The hoarding is not attributable to another medical condition (e.g., brain injury,
cerebrovascular disease, Prader-Willi syndrome).
F. The hoarding is not better explained by the symptoms of another mental disorder
(e.g., obsessions in obsessive-compulsive disorder, decreased energy in major
depressive disorder, delusions in schizophrenia or another psychotic disorder,
cognitive deficits in major neurocognitive disorder, restricted interests in autism
spectrum disorder).
Specify if:
With excessive acquisition
Specify if:
 With good or fair insight
With poor insight
With absent insight/delusional beliefs
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set,
including specifier descriptions and coding and reporting procedures.
Source. DSM-5 criteria for hoarding disorder reprinted from Diagnostic and Statistical Manual of Mental Disorders,
5th Edition. Washington, DC, American Psychiatric Association, 2013, p. 247. Used with permission. Copyright ©
2013 American Psychiatric Association.

Posttraumatic Stress Disorder and Acute Stress Disorder

Case Example
A World War II veteran presented to the Veterans Affairs hospital for complaints related to a possible
diagnosis of PTSD. He said that during the invasion of Normandy in 1941, he was a land-sea transport
captain who delivered soldiers to Omaha Beach. Many of these soldiers, especially in the initial waves, were
killed by gunfire in front of him. He describes still visualizing bodies lapped against his ship by the waves.
He describes several symptoms related to this visualization: elevated anxiety and distress, nightmares, poor
concentration, irritability, and feelings of being detached or numb. These symptoms have worsened recently
as a number of his friends have passed away from illness.

PTSD is a chronic, often fluctuating disorder that adversely affects the quality of life
of older adults (Chopra et al. 2014) and may be a risk factor for dementia (Yaffe et al.
2010). PTSD is no longer categorized as an anxiety disorder in DSM-5; rather, it is now
one of the trauma- and stressor-related disorders. PTSD is characterized by exposure to
a traumatic event (an accident, violence, or natural event) (Table 12–12). The event
must have produced at least 1 month of symptoms in each of four clusters: 1) intrusion
(reexperiencing of the event via thoughts, flashbacks, or dreams), 2) avoidance
(avoiding thoughts of the event or situations that bring it to mind), 3) negative
alterations in cognitions or mood (feeling detached, having diminished interest in or
responsiveness to activities, being unable to experience positive emotions), and 4)
heightened arousal/reactivity (e.g., sleep disturbances, exaggerated startle, irritability).
If this syndrome is present but symptoms last less than 1 month, acute stress disorder is
diagnosed.
PTSD has received little study in older adults, despite the association of the disorder
with many types of traumatic experiences common in this age group, such as combat
experiences for military veterans (Frueh et al. 2007) or traumatic medical events (Dew
et al. 2001). In a study by Pietrzak et al. (2012a), the combined lifetime prevalence of
full or partial PTSD in older individuals was 10%. Also of note is an epidemiological
study that found that PTSD had the highest 12-month prevalence of any mental disorder
in older African American individuals (Ford et al. 2007). This finding may have
reflected methodological differences from other studies or real differences of minorities
from Caucasians in this age group. Overall, the research in late-life PTSD is far behind
its overall impact in terms of prevalence and morbidity (van Zelst et al. 2003).
In older adults, partial PTSD needs to be considered when diagnosing patients.
Although partial PTSD does not meet full PTSD criteria, it appears to be more than a
subsyndromal problem because it is associated with impaired psychosocial functioning
(Pietrzak et al. 2012).

Fear of Falling
A prime example of how DSM criteria have not mapped well onto geriatric syndromes
is fear of falling (e.g., Mohlman et al. 2012). Fear of falling is a common syndrome in
community-dwelling older adults; estimates are 7%–14%. Fear of falling consists of
moderate to severe fear with avoidance of multiple situations and activities (e.g.,
approximately 3% of older adults avoid leaving their houses or yards as a result of fear
of falling; Arfken et al. 1994).
The fear of falling is frequently excessive relative to objective fall risk. Many who
report fear have never experienced a fall and do not report any fall risk factors;
therefore, the diagnosis of agoraphobia could properly define many older adults with
fear of falling (McCabe et al. 2006; van Haastregt et al. 2008). The fear of falling is also
impairing, limiting mobility and contributing to functional decline and
institutionalization (Zijlstra et al. 2007). However, fear of falling does not map well
onto the pre–DSM-5 requirement of insight into excessiveness of the fear, which many
older patients lack. For example, Gagnon et al. (2005) found that only 1 of 48 subjects
with moderate or severe fear of falling considered their fear to be unreasonable, even
though the fear frequently resulted in the individuals’ avoidance of activities, in some
cases to the point of their being housebound (Flint 2005a). Fear of falling is common
and impairing and therefore hopefully will be encompassed more readily by the changes
with DSM-5, such as removal of the requirement of the patient’s insight into
“excessiveness” for many of the anxiety disorders.

TABLE 12–12. DSM-5 diagnostic criteria for posttraumatic stress disorder

A. Exposure to actual or threatened death, serious injury, or sexual violence in one (or
more) of the following ways:
1. Directly experiencing the traumatic event(s).
2. Witnessing, in person, the event(s) as it occurred to others.
3. Learning that the traumatic event(s) occurred to a close family member or close
friend. In cases of actual or threatened death of a family member or friend, the
event(s) must have been violent or accidental.
4. Experiencing repeated or extreme exposure to aversive details of the traumatic
event(s) (e.g., first responders collecting human remains; police officers repeatedly
exposed to details of child abuse).
Note: Criterion A4 does not apply to exposure through electronic media, television,
movies, or pictures, unless this exposure is work related.
B. Presence of one (or more) of the following intrusion symptoms associated with the
traumatic event(s), beginning after the traumatic event(s) occurred:
 1. Recurrent, involuntary, and intrusive distressing memories of the traumatic
event(s).
Note: In children older than 6 years, repetitive play may occur in which themes or
aspects of the traumatic event(s) are expressed.
2. Recurrent distressing dreams in which the content and/or affect of the dream are
related to the traumatic event(s).
Note: In children, there may be frightening dreams without recognizable content.
3. Dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if
the traumatic event(s) were recurring. (Such reactions may occur on a continuum,
with the most extreme expression being a complete loss of awareness of present
surroundings.)
Note: In children, trauma-specific reenactment may occur in play.
4. Intense or prolonged psychological distress at exposure to internal or external cues
that symbolize or resemble an aspect of the traumatic event(s).
5. Marked physiological reactions to internal or external cues that symbolize or
resemble an aspect of the traumatic event(s).
C. Persistent avoidance of stimuli associated with the traumatic event(s), beginning
after the traumatic event(s) occurred, as evidenced by one or both of the following:
1. Avoidance of or efforts to avoid distressing memories, thoughts, or feelings about
or closely associated with the traumatic event(s).
2. Avoidance of or efforts to avoid external reminders (people, places, conversations,
activities, objects, situations) that arouse distressing memories, thoughts, or
feelings about or closely associated with the traumatic event(s).
D. Negative alterations in cognitions and mood associated with the traumatic event(s),
beginning or worsening after the traumatic event(s) occurred, as evidenced by two
(or more) of the following:
1. Inability to remember an important aspect of the traumatic event(s) (typically due
to dissociative amnesia and not to other factors such as head injury, alcohol, or
drugs).
2. Persistent and exaggerated negative beliefs or expectations about oneself, others,
or the world (e.g., “I am bad,” “No one can be trusted,” “The world is completely
dangerous,” “My whole nervous system is permanently ruined”).
3. Persistent, distorted cognitions about the cause or consequences of the traumatic
event(s) that lead the individual to blame himself/herself or others.
4. Persistent negative emotional state (e.g., fear, horror, anger, guilt, or shame).
5. Markedly diminished interest or participation in significant activities.
6. Feelings of detachment or estrangement from others.
7. Persistent inability to experience positive emotions (e.g., inability to experience
happiness, satisfaction, or loving feelings).
E. Marked alterations in arousal and reactivity associated with the traumatic event(s),
beginning or worsening after the traumatic event(s) occurred, as evidenced by two
 (or more) of the following:
1. Irritable behavior and angry outbursts (with little or no provocation) typically
expressed as verbal or physical aggression toward people or objects.
2. Reckless or self-destructive behavior.
3. Hypervigilance.
4. Exaggerated startle response.
5. Problems with concentration.
6. Sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep).
F. Duration of the disturbance (Criteria B, C, D, and E) is more than 1 month.
G. The disturbance causes clinically significant distress or impairment in social,
occupational, or other important areas of functioning.
H. The disturbance is not attributable to the physiological effects of a substance (e.g.,
medication, alcohol) or another medical condition.
Specify whether:
With dissociative symptoms:
1. Depersonalization
2. Derealization
Specify if:
With delayed expression

Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set,
including specifier descriptions and coding and reporting procedures.

Source. DSM-5 criteria for posttraumatic stress disorder reprinted from Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, pp. 271–272. Used with
permission. Copyright © 2013 American Psychiatric Association.

Anxiety Disorders and Related Conditions in the Context of Comorbid

Medical Illness
Anxiety disorders may be of greatest public health significance in older adults when
they occur in the context of medical conditions. Because anxiety symptoms are highly
common in many medical illnesses and lead to increased disability and possibly
accelerated mortality, it should be of great importance for clinicians to accurately
diagnose anxiety disorders in these contexts. At the same time, anxiety disorders are
especially difficult to identify and diagnose in the context of medical conditions in older
adults.
The DSM criteria for diagnosing anxiety disorders such as GAD and panic disorder
have traditionally excluded a disturbance that is caused by another medical condition.
Clinically there is a concern that this exclusion may lead to underdiagnosis (and
resultant undertreatment) of the anxiety disorder in medically ill elderly individuals. If
anxiety is really a sign of an occult medical issue (hyperthyroidism, cardiac arrhythmia,
drug toxicity or withdrawal), it is most important to detect and correct the underlying
problem. DSM-5 includes a separate diagnosis for anxiety that is due to another medical
condition (Table 12–13), and the DSM-5 Lifespan Advisory Group created a list of
factors that might suggest that an anxiety disorder is actually due to rather than co-
occurring with a general medical condition (Table 12–14).

Comorbidity of Anxiety Disorders and Related Conditions

With Late-Life Depression
Much attention has been given to the issue of the comorbidity of anxiety and late-life
depression, because studies have consistently found that response to antidepressants is
delayed or diminished in late-life depression in the context of anxiety.
The term anxious depression refers to individuals with MDD and either a comorbid
anxiety disorder or significant anxiety symptoms. The LASA study—to our knowledge
the largest epidemiological study to examine comorbidity of anxiety disorders and
depression in elderly people—found that 48% of elderly persons with MDD also had a
current comorbid anxiety disorder, whereas approximately one-fourth of those with
anxiety disorders had MDD (Beekman et al. 2000). Likewise, rates of severe anxiety
symptoms have been seen in up to one-half of late-life MDD clinical samples (Lenze et
al. 2000; Mulsant et al. 1996). In an NCS-R study, King-Kallimanis et al. (2009) found
that anxiety and late-life depression are commonly comorbid.
The comorbidity is not surprising given the extensive symptomatic overlap of
anxiety disorders and related conditions (particularly GAD and PTSD) with MDD.
While classified in separate categories in DSM-5, MDD, persistent depressive disorder
(dysthymia), PTSD, and GAD are all centrally defined by distress from negative affect.
Many patients with late-life MDD develop significant anxiety only within the
depressive episode, whereas others have a long history of an anxiety disorder with later
onset of depression (Lenze et al. 2005a). Symptomatically, anxiety symptoms are more
stable than those of depression and more likely to lead to depressive symptoms than
vice versa (Wetherell et al. 2001). As a result, anxiety disorders might be a risk factor
for late-life depression (Hettema et al. 2006). When depression precedes or coexists
with the anxiety disorder, anxiety symptoms often persist after remission of depression
and increase risk for depressive relapse (Dombrovski et al. 2007; Flint and Rifat 1997).
The combination of anxiety and depression in elderly persons is a severe and often
treatment-resistant illness. Depressed elderly patients with comorbid anxiety have
greater somatic symptoms, greater suicidal ideation (Jeste et al. 2006; Lenze et al.
2000), and a higher risk of suicide (Allgulander and Lavori 1993). Many studies have
demonstrated a longer time to response in depression, and/or a reduced response rate,
when patients also have anxiety symptoms (Alexopoulos et al. 2005; Andreescu et al.
2007; Dew et al. 1997; Lenze et al. 2003; Mulsant et al. 1996) or an anxiety disorder
(Flint and Rifat 1997; Steffens and McQuoid 2005). One study found that even after
elderly patients achieved full remission from late-life depression, they were still more
likely to relapse if they had high levels of baseline anxiety symptoms (Andreescu et al.
2007). However, a meta-analysis on this topic concluded that comorbid anxiety
symptoms were not predictive of treatment resistance in late-life depression (Nelson et
al. 2009). The reason for the possible increase in depression nonremission in the
presence of co-occurring anxiety is unclear; it may simply be that the combination of
two disorders results in higher symptom levels, which reduces the chance of remitting
to “normal” levels of symptoms, or it may be that both anxiety and depressive
symptoms are treatment targets of some therapies (e.g., most antidepressants, CBT).
Thus, it may be that some features of anxiety (e.g., worry, avoidance) are a treatment-
relevant feature of affective disorders in elderly persons (impairing treatment adherence
or full remission), yet in many cases anxiety symptoms resolve along with the
depression. Eventually, translational research should better clarify the convergence of
anxiety and depression in late life (e.g., via functional neuroimaging) (Andreescu et al.
2011).

TABLE 12–13. DSM-5 diagnostic criteria for anxiety disorder due to another
medical condition
A. Panic attacks or anxiety is predominant in the clinical picture.
B. There is evidence from the history, physical examination, or laboratory findings that
the disturbance is the direct pathophysiological consequence of another medical
condition.
C. The disturbance is not better explained by another mental disorder.
D. The disturbance does not occur exclusively during the course of a delirium.
E. The disturbance causes clinically significant distress or impairment in social,
occupational, or other important areas of functioning.
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set,
including specifier descriptions and coding and reporting procedures.
Source. DSM-5 criteria for anxiety disorder due to another medical condition reprinted from Diagnostic and
Statistical Manual of Mental Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, p.
230. Used with permission. Copyright © 2013 American Psychiatric Association.

TABLE 12–14. Suggestions for delineating anxiety in the context of medical illness
and medication use
Factors implicating a physiological cause of anxiety in medically ill older adults
Anxiety symptoms arise de novo in absence of psychiatric history and risk factors
after diagnosis of physical illness.
Symptoms of a medical condition are known to mimic those of anxiety (e.g.,
hyperthyroidism, cardiac conditions).
Anxiety symptoms are a known side effect of recently started medication.
The patient is, or was until recently, taking sedatives or antianxiety medication
(leading to withdrawal symptoms).
 Anxiety symptoms have acute onset in the absence of other life events.
Factors implicating a psychological cause of anxiety in medically unwell older
adults
Anxiety symptoms predate physical illness.
Affective disorders predate physical illness.
Anxiety symptoms arise in the context of a chronic illness.
The patient has no recent new medications, medication changes, or issues with
adherence.
The patient has experienced a major life event or change in his or her circumstances.
The patient has one or more present risk factors for an anxiety disorder (e.g., high
score on measures of neuroticism, anxiety sensitivity).
Effect on functioning is characterized by avoidance or by increased anxiety when in
feared situation.
Source. Adapted from Mohlman J, Bryant C, Lenze EJ, et al.: “Improving Recognition of Late Life Anxiety
Disorders in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: Observations and
Recommendations of the Advisory Committee to the Lifespan Disorders Work Group.” International Journal of
Geriatric Psychiatry 27(6):549–556, 2012. Used with permission.

Neuropsychology and Neurobiology of Late-Life Anxiety

Disorders and Related Conditions
Defining anxiety in the presence of neurocognitive deficits is important in geriatric
patients, just as it is in depression. A bidirectional relationship between anxiety and
cognitive function has been posited (Beaudreau and O’Hara 2008; Wetherell et al. 2002;
Yaffe et al. 2010). Research in both GAD and PTSD in older adults has suggested that
primarily memory (short-term memory, recall) is adversely affected (Beaudreau and
O’Hara 2008; Butters et al. 2011; Caudle et al. 2007; Mantella et al. 2007; Mohlman et
al. 2013; Schuitevoerder et al. 2013; Yehuda et al. 2007). In contrast, in hoarding
disorder, executive function appears to be most adversely affected (Ayers et al. 2013).
One study of late-life GAD found executive deficits (Butters et al. 2011), but another
found that more severe worry was associated with better executive function on a
measure of inhibitory control (Price and Mohlman 2007). Other researchers have found
no difference between age-matched healthy control subjects and patients with GAD on
tests of executive functions (Mohlman et al. 2013). As a whole, these studies suggest
both similarities and differences between late-life anxiety and depression, but more
definitive research in this area is needed.
To date, few longitudinal studies of clinical anxiety disorders in late life have been
carried out that could examine cognitive decline (DeLuca et al. 2005; Sinoff and Werner
2003). However, studies examining links between negative affect with cognitive
impairment and decline consistently find that worry has the largest effect (Andreescu et
al. 2014; Pietrzak et al. 2012b; Rosenberg et al. 2013; Wilson et al. 2011). This
observational research is not able to discern whether anxiety is the cause or
consequence of cognitive decline; to our knowledge, no studies are under way to dissect
this complex and possibly bidirectional relationship.
Very little translational research has been carried out in late-life anxiety disorders.
Some studies have examined the hypothalamic-pituitary-adrenal axis in late-life GAD
because dysfunction in this axis is common in late-life depression (Sharma et al. 1988)
and in young adults with anxiety disorders. Late-life GAD is associated with 40%–50%
higher diurnal cortisol levels than are seen in healthy elderly persons (Mantella et al.
2008). Elevated cortisol in late-life GAD decreases with pharmacological treatment
(Lenze et al. 2011; Pomara et al. 2005) and is associated with improved memory (Lenze
et al. 2012), suggesting that neurohormonal stress response is an important part of the
pathophysiology of the disorder in aging. These findings of elevated cortisol in late-life
GAD may distinguish the disorder from PTSD, for which a study in a largely elderly
population found lower urinary cortisol in veterans with PTSD compared with those
without (Yehuda et al. 2007). That same study found no relationship of PTSD with
hippocampal volume. On the other hand, a recent large study of older adults found that
those with an anxiety disorder had a lower cortisol awakening response than those
without, with the effect being largest in GAD (Hek et al. 2013).
Although a considerable number of structural neuroimaging studies have been
carried out in patients with late-life depression (showing white matter hyperintensities
and specific volumetric changes, such as in the hippocampus), as described in Chapter
9, “Depressive Disorders,” similar studies have not been carried out in patients with
late-life anxiety disorders aside from a single small study in patients with GAD. In this
study, worry scores showed a positive association with volume of the medial
orbitofrontal cortex, a neural area known to be involved in emotional decision making
under uncertain conditions (Mohlman et al. 2009). To date, few functional
neuroimaging studies have been carried out in late-life anxiety disorders. One
preliminary task-related functional magnetic resonance imaging (fMRI) study found
deficient prefrontal attentional control (Price et al. 2011), and a preliminary functional
connectivity fMRI study showed aging and worry severity effects on default mode
network connectivity (Andreescu et al. 2013). This dearth of translational research in
late-life anxiety disorders is undoubtedly one of the major limitations in understanding
of these disorders, and further study is likely to lead to new and innovative treatment
options.

Guidelines for Diagnosing Anxiety Disorders and Related

Conditions in the Context of Neurocognitive Impairment
Anxiety is a frequent behavioral feature of dementia (Ballard et al. 2000), and
dementia-specific GAD criteria are available (Starkstein et al. 2007). GAD is a common
manifestation of dementia (Mintzer and Brawman-Mintzer 1996). Also, Ferretti et al.
(2001) reported that anxiety arising in the context of Alzheimer’s disease is often
comorbid with depression.
The course of anxiety in dementia is complex, in part because of the stages of
dementing illness (from presymptomatic to severe cognitive impairment) and in part
because of the likely bidirectional causality of anxiety and cognitive problems. When
anxiety symptoms have occurred for a long time (>10 years) before the cognitive
decline, this suggests a separate anxiety disorder (not a prodrome). When anxiety
symptoms and cognitive difficulties begin approximately concurrently, the anxiety may
either be a result of the disease course that gives rise to the cognitive decline or be due
to cognitive problems stemming from the anxiety and its neurobiological consequences.
Because anxiety symptoms can be a prodromal manifestation of dementia, new-onset
anxiety with mild cognitive impairment (or even subjective complaints) may portend a
developing disease process.
Several research groups have published findings that relate to anxiety and dementia.
Seignourel et al. (2008) reported that if patients with dementia have insight into their
mental decline (likely in the early stages), then anxiety is more likely to be present.
Bryant et al. (2013) found that as dementia becomes more severe, instead of anxiety,
agitation is more likely to be present. Finally, according to Yaffe et al. (2010), anxiety
that is triggered or associated with specific situations (e.g., phobias, PTSD) is unlikely
to be caused by cognitive decline, although a prior history of PTSD may be a risk factor
for developing dementia in old age.

Assessment Instruments for Anxiety in Older Adults

Epidemiological instruments in mental health often have low sensitivity in older adults
for a variety of reasons, including insight and recall issues. Table 12–15 provides
several recommendations for clinicians and researchers to improve sensitivity of
assessments. These recommendations are based on empirical research and clinical
experience (Mohlman et al. 2012).

Treatment
Anxiety disorders have a waning and waxing course in elderly adults, as in young
adults, but these disorders are unlikely to remit completely in older patients
(Schuurmans et al. 2005). Additionally, anxiety disorders produce quality-of-life
impairments and disability on par with that of late-life depression (de Beurs et al. 1999;
Wetherell et al. 2004) and may be risk factors for the development of anxious
depression, a severe and treatment-resistant illness. These issues suggest the importance
of treatment.
Despite the relative lack of treatment trials, the treatment of late-life anxiety
disorders has been the subject of reviews and meta-analyses (e.g., Pinquart and
Duberstein 2007; Wetherell et al. 2005b). The available evidence suggests that both
psychotherapy (primarily CBT) and pharmacotherapy are effective. However,
considerable gaps exist in the understanding of these treatments. As a result, various
authors have concluded that psychotherapy (Mohlman and Price 2006) or that
pharmacotherapy (Pinquart and Duberstein 2007) should be the first-line treatment, but
this issue is not yet resolved.

Psychotherapy
There is evidence that older adults with GAD can learn new skills in CBT and use them
effectively over time (Wetherell et al. 2005a). In the only study to simultaneously
compare CBT with a credible attention control condition and a waiting list for patients
with late-life GAD, CBT produced large effects on measures of anxiety, depression, and
quality of life relative to the waiting list, whereas the control condition produced small
to medium effects (Wetherell et al. 2003a). Other research has found that CBT is
effective compared with minimal-contact control subjects (Stanley et al. 2003a) or usual
care (Stanley et al. 2003b, 2009). These data show that CBT is an efficacious treatment
for GAD in older adults (although they do not prove that CBT is more effective than
other therapies). It is likely that relaxation therapy is the most effective part of CBT
(Thorp et al. 2009; Yoder et al. 2013); clinicians need to ensure the inclusion of this
relatively easily instructed component with older adults. In addition, in older patients
with PTSD, prolonged exposure therapy appears preliminarily to be effective (Thorp et
al. 2012), suggesting that exposure is an effective component of CBT at all ages.

TABLE 12–15. Guidelines for use of assessment tools for anxiety in older adults
Avoid a yes/no format for screening questions in favor of open-ended questions. A
yes/no screening question requires that subjects know exactly what the symptom is
referring to in context of their own experience.
Avoid numeric frequency/severity format of standard assessments, or supplement with
additional probes.
Avoid sets of questions whose response formats alternate between narrative and
numerical.
Use the term endorsed by the individual to describe anxiety as a concept (e.g.,
“nerves,” “concerns”).
Avoid lengthy, complex, or reverse-coded items.
Use personal timelines to aid in recall. Include informant reports.
Use a lower number of symptoms to meet cutoff or diagnostic criteria compared with
 young adults.

CBT for late-life anxiety typically includes education about anxiety and its
symptoms, relaxation skills, cognitive therapy, problem-solving skills training, exposure
exercises, and sleep hygiene instruction (Stanley et al. 2004). Adaptations for CBT in
elderly persons include increased repetition, increased time reviewing previous sessions
(Mohlman and Price 2006), and combining CBT with cognitive rehabilitation training
to enhance logic and reasoning skills (Mohlman 2008; Mohlman et al. 2013).
The evidence is mixed as to whether CBT is a superior treatment to other types of
psychotherapy for late-life anxiety (Barrowclough et al. 2001; Stanley et al. 1996;
Wetherell et al. 2003a). One study directly comparing CBT and pharmacotherapy for
late-life anxiety (mostly GAD and panic disorder) found a greater effect size for
pharmacotherapy (sertraline), although this study had a relatively small sample size
(Schuurmans et al. 2006). In contrast, a study comparing CBT to paroxetine for late-life
panic disorder found no differences in response rate between the treatments, with both
treatments leading to better outcomes than a waitlist control condition (Hendriks et al.
2010). This question of whether medication or psychotherapy is better remains
unresolved, but a more clinically salient question may be whether further enhancements
or a sequential approach of using medications and CBT would be more effective in
older adults. Addressing this issue, Wetherell et al. (2013b) found that augmenting SSRI
treatment with CBT improved worry symptoms and reduced relapse rates in older
adults with GAD. This report suggests that a combination of pharmacotherapy and
psychotherapy approaches may provide the greatest benefits for patients with this
disorder.
No controlled research on psychotherapy that focuses on anxiety conditions other
than GAD exists. Several studies have included patient samples with mixed anxiety
disorders, including panic disorder and social phobia, but none have published disorder-
specific results.

Pharmacotherapy
Some studies have found that benzodiazepines are efficacious in reducing anxiety
symptoms in late-life anxiety (Bresolin et al. 1988; Koepke et al. 1982). However, these
medications increase the risk of falls (e.g., Landi et al. 2005; Lenze et al. 2009a) and
cognitive impairment (Billioti de Gage et al. 2014). This is troubling, given their
widespread use in older adults (Olfson et al. 2014).
Antidepressants—particularly SSRIs, such as escitalopram, citalopram, and
sertraline, and serotonin-norepinephrine reuptake inhibitors, such as duloxetine and
venlafaxine—are considered first-line treatment for anxiety disorders in younger adults
because of these drugs’ lower potential for toxicity or abuse. To our knowledge, three
randomized controlled trials (of which two are pilot studies) have examined the efficacy
of the SSRIs for late-life anxiety disorders (Lenze et al. 2005b, 2009b; Schuurmans et
al. 2006). All of these demonstrated efficacy of SSRIs, although the largest (Lenze et al.
2009b) found only a small effect size. However, the maintenance (i.e., relapse-
prevention) efficacy of maintenance SSRI has been demonstrated, with an apparent
large effect size similar to what has been seen in late-life depression (Wetherell et al.
2013b).
Few studies have been published examining second-line strategies. Of these, the two
largest studies are multisite industry-led studies involving older patients with GAD:
Montgomery et al. (2008) found that pregabalin was efficacious in older adults (similar
to findings in young adults), and Mezhebovsky et al. (2013) found that extended-release
quetiapine was efficacious. Additionally, a small study of risperidone ([Moríñigo et al.
2005]) showed it to be efficacious as an augmentation strategy. None of these
medications, however, has been approved by the U.S. Food and Drug Administration
for treating GAD.
No published studies have focused exclusively on late-life PTSD, but a few studies
involving mixed-age populations, with mean ages ranging from 55 to 60 years, have
suggested that the antidepressants citalopram (English et al. 2006) and mirtazapine
(Chung et al. 2004) and the α-adrenergic blocker prazosin (Raskind et al. 2007) are
effective. Further research is needed to determine optimal treatment for PTSD in elderly
persons.

Treatments in the Future

To date, the proven treatments for late-life anxiety disorders are simply the same
treatments demonstrated to be effective in young adults. However, early-phase trials in
several areas suggest numerous innovations in the works. In brief, these include
Mindfulness-Based Stress Reduction (Lenze et al. 2014a), antiglucocorticoid therapy
(Lenze et al. 2014b), Internet-based therapy (Mewton et al. 2013), psychotherapy for
anxiety in the context of dementia (Stanley et al. 2013), and novel treatments for
hoarding disorder (Ayers et al. 2013) and for fear of falling (Wetherell et al. 2013a).
Further research into these treatments may lead to additional treatment directions in
late-life anxiety (Lenze and Wetherell 2009).

Clinical Management
Although medication, psychotherapy, and their combination have been shown to be
efficacious in acute and long-term treatment of late-life anxiety disorders, having this
knowledge base is only a small part of what therapists need for managing these
common and debilitating disorders. A list of important management issues for clinicians
is provided in Table 12–16 (Lenze and Wetherell 2011).
Detecting and diagnosing the patient’s anxiety (whether primary or comorbid) are of
utmost importance. Elderly persons with anxiety disorders may not be insightful or
conversant with terms used to define anxiety (e.g., panic, social anxiety). They often
feel that anxiety or fear is a realistic response to their environment or current stressors.
However, undetected anxiety is likely to persist and have a detrimental effect on
treatment of comorbid conditions, such as depression. Anecdotally, we have found that
asking about reactions to stress (e.g., “How do you feel in times of stress?”) is a useful
opener when asking elderly persons about anxiety symptoms. Patients who report
anxiety using terms such as anxious, concerned, or worried can then be asked
additional questions, such as “How often does it occur?” and “What do you do to
manage these feelings?” Asking whether anxiety is excessive or uncontrollable is
unlikely to be fruitful; instead, asking about a patient’s mechanisms to control anxiety
will elicit a more pertinent response. Patients with panic symptoms may not endorse
“panic attacks” when questioned, but they may admit to experiencing brief periods with
multiple physical symptoms (particularly autonomic symptoms such as palpitations).

TABLE 12–16. Principles for managing anxiety disorders in older adults

Assessment should measure severity (“target symptoms”) to provide objective criteria
for assessing response, and should assess comorbidity, prior treatment, cognitive
status, and need for a medical workup.
First-line treatment according to patient’s preference (including prior response),
provider preference and competence, and treatment availability.
Think twice about a benzodiazepine prescription. Warn of risks.
Educate the patient and family (and remind yourself) about anxiety (“the paper tiger”)
and treatment (benefits > risks; “call me”). Self-help helps.
Frequent follow-up, particularly within the first month of treatment or dose change, to
encourage adherence and monitor treatment response.
With medications, “start low, go slow”, but go—as aggressively as required to treat
symptoms to remission.
Consider augmentation treatment, refer to expert as needed.
Provide maintenance treatment appropriately.
Source. Adapted from Lenze and Wetherell 2011.

The clinician should discuss management with the patient while keeping in mind that
anxiety may affect the patient’s views about treatment. Patients’ reactions are
particularly an issue in relation to medications, especially antidepressants, which are
well known to have a stimulating or mildly anxiogenic effect initially before an
antianxiety effect occurs. Anecdotally, we have observed that most patients with late-
life anxiety report being sensitive to or intolerant of antidepressant medications if they
have tried them. Their claim of intolerance likely results from anticipatory concern
about side effects, vigilance toward interoceptive stimuli, and a tendency to
catastrophize about any interoceptive sensations they detect (even if unrelated to the
antidepressant). Therefore, clinicians need to counsel patients in advance about
medication side effects explicitly to reduce patients’ concerns that these might
somehow be toxic or incapacitating. Additionally, management requires close follow-up
after the onset or dosage titration of an antidepressant medication to ensure that the
patient is taking the medication and to address the patient’s perception of side effects.
Clinicians should realize that when a patient claims to have side effects, the patient may
actually be describing anxiety-related symptoms that preceded the start of the medicine
and that are now being attributed to the medicine. It is useful to inform the patient that
such symptoms are expected to get better and are not harmful.
The early use of benzodiazepines may produce a fast anxiolytic action, which could
improve compliance; however, the long-term use of these medications is discouraged in
favor of alternative treatments, such as SSRIs, other antidepressants, or psychotherapy.
Also, it should be noted that benzodiazepines may counteract the effects of
psychotherapy, particularly CBT (Westra and Stewart 1998).
In summary, the detection and management of anxiety disorders in elderly persons is
challenging, but the high prevalence and significant morbidity associated with these
disorders highlight the importance of understanding them. It is expected that as the
knowledge base (regarding diagnosis, etiology, and treatment) of these disorders
improves, anxiety disorders will become a core clinical issue in geriatric psychiatry,
much like dementia and depression.

Key Points
• Late-life anxiety disorders are more common than previously thought but may
escape detection unless specific strategies are used to enhance recognition.
• Antidepressants and psychotherapeutic treatments as well as their combination are
effective in older adults, but probably less so than in young adults.
• Increased vigilance is required of the clinician to manage anxiety in this age group.
• More research is needed to examine the nature, course, and treatment of these
common but still understudied syndromes.

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Suggested Readings
Beaudreau SA, O’Hara R: Late-life anxiety and cognitive impairment: a review. Am J
Geriatr Psychiatry 16(10):790–803, 2008
Lenze EJ, Wetherell JL: A lifespan view of anxiety disorders. Dialogues Clin Neurosci
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doubtful benefits [letter]. BMJ 349:g5205, 2009. Available at:
http://www.bmj.com/content/349/bmj.g5205/rr/777842. Accessed December 4,
2014.
Mohlman J, Bryant C, Lenze EJ, et al: Improving recognition of late life anxiety
disorders in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition:
observations and recommendations of the Advisory Committee to the Lifespan
Disorders Work Group. Int J Geriatr Psychiatry 27(6):549–556, 2012
Wetherell JL, Petkus AJ, White KS, et al: Antidepressant medication augmented with
cognitive-behavioral therapy for generalized anxiety disorder in older adults. Am J
Psychiatry 170(7):782–789, 2013
 CHAPTER 13

Somatic Symptom and Related Disorders

Marc E. Agronin, M.D.

Somatic symptom and related disorders comprise a heterogeneous

group of psychiatric illnesses characterized by prominent physical
symptoms or complaints that are associated with significant distress and
impairment. The conceptualization of these disorders under the category of
somatoform disorders in DSM-IV/DSM-IV-TR) (American Psychiatric
Association 1994, 2000) required that these somatic presentations lack
objective organic causes. This latter requirement has been deleted in DSM-
5, largely because somatic symptoms often do have related medical
conditions (American Psychiatric Association 2013). Even when such
associations have not been established, the assumption that they are present
has often led to patients being labeled in pejorative ways, as if they are
faking symptoms or somehow responsible for their own suffering.
The seven disorders encompassed in the DSM-5 category of somatic
symptom and related disorders are somatic symptom disorder, illness
anxiety disorder, conversion disorder (functional neurological symptom
disorder), psychological factors affecting other medical conditions,
factitious disorder, other specified somatic symptom and related disorder,
and unspecified somatic symptom and related disorder. DSM-IV disorders
that are subsumed under this new nomenclature include somatization
disorder, undifferentiated somatoform disorder, hypochondriasis, pain
disorder, and factitious disorders (which appeared in their own separate
category in DSM-IV). Body dysmorphic disorder is not included in the new
somatic symptom disorder category and is now classified as one of the
other specified obsessive-compulsive and related disorders.
Prevalence rates in the literature for what were previously labeled
somatoform disorders varied by diagnosis, but in general and across ages
these disorders have been seen in 16% of primary care outpatients and in
23% of outpatients with medically unexplained symptoms (de Waal et al.
2004; Smith et al. 2005). A comparison of DSM-5 and DSM-IV diagnoses
in a sample of patients suggests that prevalence rates are similar across the
old and new nomenclatures (Voigt et al. 2012).
Older individuals with somatic symptom and related disorders are seen
in all health care settings, where they frequently overuse medical services
and overburden general practitioners (de Waal et al. 2008;Puri and
Dimsdale 2011). They often come to the attention of a geriatric psychiatrist
after another clinician has attempted unsuccessfully to resolve their physical
symptoms. To date, the somatic symptom and related disorders have not
been well studied in late life, in part because many of the disorders tend to
begin in early adulthood. In addition, research involving older cohorts has
usually focused on reported somatic symptoms rather than on specific
diagnoses. A complicating factor is that somatoform symptoms in late life
are often obscured by comorbid physical and psychiatric illnesses. In
particular, these disorders have been strongly associated with stress,
depression, anxiety, psychological trauma, substance abuse, and personality
disorders (de Waal et al. 2004; Haftgoli et al. 2010; Hasin and Katz, 2007;
Sack et al. 2007; Tomenson et al. 2012). DSM-5 is trying to make the
diagnoses more parsimonious by eliminating the requirement for medically
unexplained symptoms, but additional research is needed to further
elucidate their characteristics under the new nomenclature.

Clinical Features
Prominent somatic symptoms that cause significant distress and impairment
are seen commonly in outpatient settings. When these symptoms shift from
transient expressions of somatic concern to more serious bodily
preoccupation and impairment, and begin to cause excessive emotional or
behavioral responses that are out of proportion to what would be expected
given the physical symptoms, somatic symptom disorder becomes a more
likely diagnosis. Somatic symptoms are experienced by the affected
individual as real physical sensations, pain, or discomfort, usually
indistinguishable from symptoms of actual medical disorders and frequently
coexisting with them. Associated psychological factors are presumed but
not always apparent, and patients vary in their degree of insight into such
factors. In many but not all cases, no clear organic causes emerge from
appropriate workup. Three important factors associated with all of the
disorders in this class are high sensitivity to somatic sensations and pain;
catastrophizing, in which there are excessive and unrealistic fears regarding
one’s health status; and excess functional disability associated with the
symptoms (Bortz 2008; Egloff et al. 2014).
Patients with somatic symptom and related disorders are often able to
accept that their symptoms may be functional and have psychological roots.
Unlike malingering, however, the disorders in this class do not represent
intentional, conscious attempts by patients to present physical symptoms in
order to achieve a specific goal (e.g., to get out of work). In DSM-IV,
somatoform disorders were classified separately from factitious disorders
such as Munchausen’s disease, because the etiologies of the former were
considered to be wholly unconscious and not always aimed at assuming the
sick role (as noted in the introduction to this chapter, factitious disorder
now falls under somatic symptom and related disorders). Neither do
somatoform disorders represent delusional thinking as found in psychotic
states. Somatic symptom and related disorders also differ from
psychosomatic disorders, which are characterized by actual disease states
with presumed psychological triggers.

Specific Somatic Symptom and Related Disorders

The somatic symptom and related disorder diagnostic categories of primary
relevance to the older patient that will be described in this section are
somatic symptom disorder, illness anxiety disorder, and conversion
disorder. The DSM-IV diagnoses pain disorder and undifferentiated
somatoform disorder have been removed, but these syndromes are
subsumed under the DSM-5 diagnosis somatic symptom disorder (with the
specifier “with predominant pain” appended in the case of pain disorder).
Body dysmorphic disorder is no longer considered a somatic symptom
disorder, and like factitious disorder, it is rare in the elderly. Neither will be
discussed in this chapter.

Somatic Symptom Disorder

Somatic symptom disorder in DSM-5 (Table 13–1) replaces somatization
disorder, which was characterized by multiple physical complaints, in
excess of what would be expected given the patient’s history and
examination findings. In somatization disorder, the patient’s complaints
could not be fully explained by medical workup and had to include pain at
four or more sites, as well as two gastrointestinal symptoms, one sexual
symptom, and one pseudoneurological symptom (other than pain). A term
previously used in the literature for this disorder was Briquet’s syndrome
(Liskow et al. 1986). In contrast, DSM-5 somatic symptom disorder is
characterized by one or more somatic symptoms that are distressing or
significantly disruptive to daily life, and are accompanied by excessive
thoughts, feelings, or behaviors related to the symptoms. In an older person,
localized pain or diffuse discomfort may be the main physical symptom, but
it is accompanied by persistent high levels of anxiety and excessive time
and energy devoted to it.
Symptoms of DSM-IV somatization disorder were postulated to begin
before age 30 and persist for years by the time of diagnosis. The disorder
was diagnosed almost exclusively in women, with prevalence rates ranging
from less than 1% to 3% (Faravelli et al. 1997; Rabinowitz et al. 2011).
High rates of the disorder have been noted among first-degree female
relatives of affected individuals and in certain medical conditions. For
example, definite or probable somatization disorder was diagnosed in 42%
of a sample of 50 medical outpatients with irritable bowel disease (Miller et
al. 2001). Associated problems include drug abuse and dependence,
depression and suicidality, disability, and multiple and unnecessary medical
treatments, including surgeries (Klengel et al. 2011; Kushwaha et al. 2014;
Rabinowitz et al. 2011; Yoshimasu 2012).
With somatization disorder, the most difficult diagnostic feature to
establish in elderly patients was the onset of symptoms before age 30 years,
because such history can rarely be accurately determined. This is no longer
a factor with the new classification. Determining what would be considered
an excessive reaction to somatic symptoms can be difficult in late life given
the high incidence of comorbid illnesses and the lack of appreciation for
“normal” reactions.
Somatization disorder tends to run a chronic course, with the majority of
individuals demonstrating consistent symptom patterns as they age, even
into later life (Pribor et al. 1994). Rabinowitz et al. (2011) found that older
individuals with somatization were more lonely, isolated, and dissatisfied
with the support they received from others.

TABLE 13–1. DSM-5 criteria for somatic symptom disorder

A. One or more somatic symptoms that are distressing or result in
significant disruption of daily life.
B. Excessive thoughts, feelings, or behaviors related to the somatic
symptoms or associated health concerns as manifested by at least one of
the following:
1. Disproportionate and persistent thoughts about the seriousness of
one’s symptoms.
2. Persistently high level of anxiety about health or symptoms.
3. Excessive time and energy devoted to these symptoms or health
concerns.
C. Although any one somatic symptom may not be continuously present,
the state of being symptomatic is persistent (typically more than 6
months).
Specify if:
With predominant pain
Specify if:
Persistent
Specify current severity:
Mild
Moderate
Severe
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the
full criteria set, including specifier descriptions and coding and reporting procedures.
Source. DSM-5 criteria for somatic symptom disorder reprinted from Diagnostic and Statistical
Manual of Mental Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013,
p. 311. Used with permission. Copyright © 2013 American Psychiatric Association.
 The DSM-IV diagnosis of undifferentiated somatoform disorder now
falls under the DSM-5 diagnosis of somatic symptom disorder. It was
previously defined by the presence of one or more physical complaints,
lasting at least 6 months, that could not be fully explained by appropriate
medical workup and that resulted in considerable social, occupational, or
functional impairment. Again, diagnosis is complicated in late life by the
frequency of comorbid medical disorders. Determining whether the
impairment is due to somatoform symptoms rather than comorbid medical
disorders is difficult—and may be nearly impossible in the case of many
debilitated elderly individuals. Prevalence rates for undifferentiated
somatoform disorder were not well established for any age group, although
one community study in Italy found a rate of 13.8%—significantly higher
than rates for every other somatoform disorder (Faravelli et al. 1997).
Patients with chronic pain were found to have quite high rates of DSM-IV
undifferentiated somatoform disorder (Aigner and Bach 1999).
Pain is the most common medical complaint in elderly persons, with
pain due to musculoskeletal disease (e.g., osteoarthritis, back pain,
headache) being the most common type (Deen 2008; Leveille et al. 2001).
Close to 50% of elderly individuals have chronic pain, and the percentage
approaches 70% for those in long-term care (Otis and McGeeney 2000). Up
to 17% suffer from substantial daily pain (Sawyer et al. 2007). Persistent
pain is associated with significant functional and social impairment (Scudds
and Ostbye 2001), as well as comorbid psychiatric symptoms, including
depression, insomnia, and substance abuse (Karp and Weiner 2011). Pain
assessment is often limited because of its dependence on subjective patient
reports, which can be influenced by numerous confounding factors in late
life, including dementia. Dementia may limit an individual’s ability to
verbalize pain, with the result that caregivers must rely on nonverbal
behaviors such as facial expressions, agitation or inactivity, or autonomic
responses (Scherder and Plooij 2012). It has also been proposed that the
pathological process in Alzheimer’s disease may alter pain perception,
perhaps by increasing the pain threshold (Scherder et al. 2001).
Pharmacological treatment of pain, however, can lead to additional
problems resulting from medication side effects and drug-drug interactions.
In the DSM-IV category of pain disorder, pain was the major focus of
the clinical presentation, and psychological factors were believed to play
critical roles in the onset, severity, exacerbation, or continuation of the pain.
Pain disorder would now be classified as somatic symptom disorder with
predominant pain. Even when there are specific causes of pain, diagnosis
hinges on identifying an overwhelming preoccupation with pain, sometimes
involving a pattern of treatment resistance.

Illness Anxiety Disorder

The DSM-5 category of illness anxiety disorder (Table 13–2) incorporates
the essence of what was previously labeled hypochondriasis. It is
characterized by an excessive preoccupation with having or acquiring a
serious illness, despite the fact that somatic symptoms are either not present
or, if present, are very mild in intensity. Key to this preoccupation is a high
level of anxiety about one’s health associated with excessive health-related
behaviors such as checking one’s body for signs of illness or maladaptive
avoidance of medical appointments or settings (American Psychiatric
Association 2013). It is believed that misinterpretation of normal bodily
sensations as indicative of severe illness is the main dynamic underlying
health anxiety disorder (Krautwurst et al. 2014).
Hypochondriasis has been seen in 3% of medical inpatients and in
around 5% of outpatients (Barsky 2001; Faravelli et al. 1997; Fink et al.
2004), and there is some debate regarding whether factors such as low
education level, low socioeconomic status, and old age increase these rates
(El-Gabalawy et al. 2013; Rief et al. 2001). Comorbid psychiatric disorders
are common, especially major depression, panic disorder, generalized
anxiety disorder, personality disorders, and obsessive-compulsive disorder
(Escobar et al. 1998; Fallon et al. 2012; Fink et al. 2004; Simon et al. 2001).

Conversion Disorder
Conversion disorder, also labeled functional neurological symptom disorder
in DSM-5 (Table 13–3), is characterized by one or more symptoms of
altered voluntary motor or sensory function, which do not appear
compatible with recognized neurological or medical conditions. The
symptoms cause significant distress and/or impairment in important areas of
functioning, and may involve weakness or paralysis, abnormal movements
(e.g., tremor), swallowing or speech symptoms, pseudoseizures, or sensory
loss. As with other somatic symptoms, however, the presence of true
medical comorbidity can cloud the picture. Some researchers have argued
that conversion disorder is actually a form of a dissociative disorder (Brown
et al. 2007). Previous DSM nomenclature for conversion symptoms was
rooted in psychodynamic theory and assumed the presence of a
psychological conflict that seemed to be prompting the symptom.

TABLE 13–2. DSM-5 criteria for illness anxiety disorder

A. Preoccupation with having or acquiring a serious illness.
B. Somatic symptoms are not present or, if present, are only mild in
intensity. If another medical condition is present or there is a high risk
for developing a medical condition (e.g., strong family history is
present), the preoccupation is clearly excessive or disproportionate.
C. There is a high level of anxiety about health, and the individual is easily
alarmed about personal health status.
D. The individual performs excessive health-related behaviors (e.g.,
repeatedly checks his or her body for signs of illness) or exhibits
maladaptive avoidance (e.g., avoids doctor appointments and hospitals).
E. Illness preoccupation has been present for at least 6 months, but the
specific illness that is feared may change over that period of time.
F. The illness-related preoccupation is not better explained by another
mental disorder, such as somatic symptom disorder, panic disorder,
generalized anxiety disorder, body dysmorphic disorder, obsessive-
compulsive disorder, or delusional disorder, somatic type.
Specify whether:
Care-seeking type
Care-avoidant type
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the
full criteria set, including specifier descriptions and coding and reporting procedures.
Source. DSM-5 criteria for illness anxiety disorder reprinted from Diagnostic and Statistical Manual
of Mental Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, p. 315.
Used with permission. Copyright © 2013 American Psychiatric Association.

There are no clear prevalence figures for conversion disorder in older

individuals. Reported prevalence rates range from 1% to 4% in medical
populations (Rabinowitz and Laek 2005). Comorbid diagnoses include
substance abuse, chronic illness, head trauma, and previous conversion
symptoms. Psychogenic nonepileptic seizures (PNESs), sometimes referred
to as pseudoseizures, represent one type of conversion symptom. They are
characterized by behavioral spells that mimic various forms of seizures but
are not associated with electroencephalographic findings and have a
presumed psychological etiology (D’Alessio et al. 2006; Mari et al. 2006).
PNESs are more frequent in young women and are seen in 5%–20% of
outpatients with epilepsy, often in combination with an actual seizure
disorder (Chabolla et al. 1996); however, they have also been diagnosed in
individuals older than age 60 years (Behrouz et al. 2006).
Risk factors for conversion disorder include physical and sexual abuse,
depression, major life stress, personality disorder, and other neurological
illnesses (Jankovic et al. 2006;O’Sullivan et al. 2007; Roelofs et al. 2002;
Sar et al. 2004). Conversion disorder in late life may be even more likely to
be associated with an actual comorbid neurological disorder. The prognosis
is variable and depends on several factors, including the type of symptoms
and the degree of functional impairment and psychiatric comorbidity.
Recovery is variable but common (Jankovic et al. 2006;Ness 2007).
According to a review by Krem (2004), affected individuals with more
acute, quickly diagnosed conversion symptoms with minimal comorbidity
tend to do better over time compared with individuals who are older or have
symptoms of longer duration and more severe disability, especially seizures
and paralysis.

TABLE 13–3. DSM-5 criteria for conversion disorder (functional

neurological symptom disorder)
A. One or more symptoms of altered voluntary motor or sensory function.
B. Clinical findings provide evidence of incompatibility between the
symptom and recognized neurological or medical conditions.
C. The symptom or deficit is not better explained by another medical or
mental disorder.
D. The symptom or deficit causes clinically significant distress or
impairment in social, occupational, or other important areas of
functioning or warrants medical evaluation.
Specify symptom type:
With weakness or paralysis
 With abnormal movement
With swallowing symptoms
With speech symptom
With attacks or seizures
With anesthesia or sensory loss
With special sensory symptom
With mixed symptoms
Specify if:
Acute episode
Persistent
Specify if:
With psychological stressor
Without psychological stressor
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the
full criteria set, including specifier descriptions and coding and reporting procedures.
Source. DSM-5 criteria for conversion disorder (functional neurological symptom disorder) reprinted
from Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Washington, DC,
American Psychiatric Association, 2013, pp. 318–319. Used with permission. Copyright © 2013
American Psychiatric Association.

Etiology
The causes of somatic symptom and related disorders are usually
multifactorial and are often rooted in both early developmental experiences
and personality traits. For example, these disorders have been associated
with the experience of serious illness early in life (Stuart and Noyes 1999),
childhood abuse (Roelofs et al. 2002; Samelius et al. 2007; Waldinger et al.
2006), dissociative amnesia (Brown et al. 2005), significant psychological
stress (Hollifield et al. 1999; Ritsner et al. 2000), and the personality traits
of alexithymia and neuroticism (Bailey and Henry 2007; De Gucht 2003).
As noted throughout the chapter, somatic symptom and related disorders are
also highly associated with comorbid depression, anxiety and panic
disorders, substance abuse, and personality disorders, especially paranoid,
avoidant, and obsessive-compulsive personality disorders (Fallon et al.
2012; Noyes et al. 2001; Rabinowitz and Laek 2005; Sar et al. 2004).
Somatization may be more common in women and in older individuals,
although the prevalence of actual somatic symptom and related disorders
has not been associated with increased age, with the exception of
hypochondriasis. When present in late life, especially with late onset,
somatic symptom and related disorders may be associated with
neuropsychological impairment and/or comorbid neurological illness
(Sheehan and Banerjee 1999). Functional magnetic resonance imaging
scans have found distinctive patterns of increased cerebral activation in the
left inferior frontal lobe and in left limbic structures associated with
somatoform symptoms (Stone et al. 2007; Vuilleumier 2005). Specific
neuroimaging studies of patients with conversion symptoms have found
decreased activity in motor or somatosensory cortex, along with increased
activation in orbitofrontal and anterior cingulate cortex (Vuilleumier et al.
2001; Yazici and Kostakoglu 1998). Nonetheless, there is not yet sufficient
evidence to accurately identify any somatic symptom disorder using
neuroimaging (Browning et al. 2011). Overall factors associated with
somatic symptom and related disorders are summarized in Table 13–4.
Psychodynamic approaches suggest that somatic symptom and related
disorders result from unconscious conflict in which intolerable impulses or
affects are believed to be expressed through more tolerable somatic
symptoms or complaints. The classic example of this phenomenon is found
in conversion disorder, in which intolerable, unconscious impulses are
believed to be converted into motor or sensory dysfunction. Freud first
wrote about such a mechanism based on his studies of young women who
had what was then termed hysteria (Breuer and Freud 1893–1895/1955).
Specifically, psychodynamic theory suggests that excessive and intolerable
guilt or hostility is the psychological source of somatization—in particular,
hypochondriasis (Barsky and Klerman 1983). In such cases, physical
symptoms serve as a means of self-punishment for unacceptable
unconscious impulses. Anger directed toward caregivers is indirectly
expressed through distrust of and dissatisfaction with multiple physicians.
Some researchers have suggested that underlying and complicating this
psychodynamic rechannelization of anger or guilt is the trait of alexithymia,
in which an individual has a relative inability to identify and express
emotional states (Bailey and Henry 2007; Waller and Scheidt 2004). The
experiencing and reporting of bodily sensations thus substitute for
emotional expression. Although alexithymia has long been postulated to
play a role in both somatoform and psychosomatic illnesses, not all
empirical research has supported the correlation of alexithymia with
somatic complaints (Lundh and Simonsson-Sarnecki 2001).

TABLE 13–4. Factors associated with somatic symptom and related

disorders
Alexithymia
Childhood physical and/or sexual abuse
Chronic medical illness
Chronic pain
Dissociative amnesia
Female gender
Frontal lobe, anterior cingulate, and limbic dysfunction
Lower educational level
Low socioeconomic status
Neuroticism
Psychiatric illness
Anxiety disorders
Depressive disorders
Other somatoform disorder
Personality disorders
Substance abuse
Severe, persistent psychological stress

In late life, somatoform disorders may represent a dysfunctional attempt

to cope with accumulating physical and psychosocial losses, especially
when these losses are associated with functional disability, anxiety, and
depression. These include loss of or isolation from family, friends, and
caregivers; loss of beauty and strength; financial setbacks; loss of
independence; and loss of social role (e.g., as a result of retirement, the loss
of a spouse, or occupational disability). The psychological distress and
anxiety over such losses may be less threatening and more controllable
when it is shifted to somatic complaints or symptoms. In turn, a sick role
might be reinforced by increased social contacts and support. The presence
of comorbid medical problems and the use of multiple medications may
provide somatic symptoms around which psychological conflict can center.
In long-term care, older individuals are faced with many additional
overwhelming losses, and their own bodies often serve as the last bastion of
control. Somatic preoccupation thus serves as a means of coping with
stress, even though it is maladaptive and can result in excessive and
unnecessary disability. It may also serve to mobilize and control resources
and staff attention within the long-term-care environment.

Treatment
By definition, patients with somatic symptom and related disorders present
to clinicians with what appear to be legitimate somatic complaints. It is only
after repeated but fruitless workups, multiple and persistent complaints and
requests, and sometimes angry and inappropriate reactions to treatment that
clinicians begin to suspect a somatic symptom disorder. In some cases, the
manner of presentation and the symptom complex are more immediately
suggestive of a particular disorder. In any event, it is important for the
clinician to remember that the reported symptoms and complaints are quite
real and disturbing for the patient. Even after workups have indicated that
psychological factors are involved, it is never wise for a clinician to
challenge the patient or suggest that the symptoms are “all in your mind.”
The typical response to such a suggestion is for the patient to seek
additional opinions and medical tests, which in turn can perpetuate a cycle
of somatization in which underlying issues are never addressed.
Instead, the role of the clinician must be to foster a supportive,
consistent, and professional relationship with the affected individual. Such a
relationship will provide reassurance as well as protect the patient from
excessive and unnecessary medical visits and procedures. The clinician
should focus on responding to individual complaints, perhaps with periodic
but regularly scheduled appointments, and setting limits on workup and
treatment in a firm but empathic manner. This can be difficult to do when
patients become demanding and attempt to consume excessive clinic time,
but the clinician must endeavor to remain professional and to not
personalize the situation or feel as though he or she were failing the patient.
The clinician should focus on symptom reduction and rehabilitation and not
attempt to force the patient to gain insight into the potential psychological
nature of his or her symptoms.
It would obviously be hazardous for a clinician to diagnose a somatic
symptom disorder prematurely, because underlying organic pathology
might have eluded diagnosis. For example, multiple sclerosis, systemic
lupus erythematosus, and acute intermittent porphyria often have complex
presentations that elude initial diagnostic workup (Kellner 1987). Somatic
symptom and related disorders may coexist with actual disease states; for
example, many individuals with pseudoseizures also have a seizure disorder
(D’Alessio et al. 2006; Mari et al. 2006). Moene et al. (2000) found that
slightly more than 10% of patients who received an initial diagnosis of
conversion disorder actually had a true neurological disorder. At the same
time, it is important for the clinician to set limits on what he or she can offer
and to make appropriate referrals to specialists and/or mental health
clinicians.
In contrast to a primary care practitioner or a medical specialist, the
geriatric psychiatrist will play a more active role in addressing the disorder
itself rather than the actual physical complaints. Because many
presentations of somatic symptom and related disorders are chronic, the
goal of treatment is often to control symptoms rather than to cure the
patient. To facilitate this, the clinician must form a therapeutic alliance
through empathic listening and acknowledging of physical discomfort,
without trivializing the somatic complaints. An offer to review all available
medical records can sometimes be a tangible way of conveying one’s
seriousness to the patient. Educating the patient about various symptom
complexes and involving him or her in part of the decision making can be
empowering for the patient, especially a patient with chronic pain.
Individual therapy using a psychodynamic approach will focus on
helping the patient identify and then discuss psychological conflict and
associated emotions. Cognitive-behavioral therapy (CBT) will focus on
identifying distorted thought patterns and anxiety triggers and replacing
them with more realistic and adaptive strategies, as well as integrating
behavioral techniques to desensitize anxious reactions. There is an
impressive body of research supporting the efficacy of psychotherapy,
particularly CBT, for treating somatoform disorders (Kroenke 2007;
Thomson and Page 2007; Tyrer et al. 2014; Woolfolk et al. 2007).
Pharmacotherapy is a central component of treatment for somatic
symptom and related disorders. It can be targeted at a specific disorder or at
underlying anxiety and depression. Studies have documented successful
treatment of somatization disorder with either antidepressants or mood
stabilizers (García-Campayo and Sanz-Carrillo 2001). Hypochondriacal
symptoms were found to respond to a variety of antidepressant medications
—in particular, selective serotonin reuptake inhibitors—as well as to
anxiolytics (Barsky 2001; Fallon et al. 1996; Oosterbaan et al. 2001;
Somashekar et al. 2013). Antidepressants and/or anticonvulsants have long
been a mainstay of treatment for pain disorder (Eisenberg et al. 2007;
Fishbain et al. 1998; Karp and Weiner 2011; Kroenke 2007; Somashekar et
al. 2013).
The tendency of many psychiatrists to focus primarily on
pharmacotherapy can become a trap with somatic symptom and related
disorders, because the therapeutic relationship is such a key element. Given
the chronic nature of somatoform symptoms, it is unlikely that
pharmacotherapy will be a quick fix. When this narrow focus on treatment
with medications fails to result in rapid control of symptoms, the patient
may abandon the therapist for alternative treatment. Other patients may
welcome such a focus because it keeps them from having to face underlying
psychological issues. Instead, clinicians must be prepared for the long haul
and strike a balance between reasonable pharmacotherapy that targets
specific symptoms of anxiety or depression and a supportive alliance in
which the most appropriate therapy for the patient is used. If another
clinician serves as the therapist, frequent communication between
psychiatrist and therapist is necessary to coordinate treatment.
For the older patient with a somatic symptom disorder, the greatest
challenge is always trying to separate out actual medical disease from
somatic symptoms. The two are sometimes so intertwined that the line
between where one begins and the other ends cannot be reasonably
discerned without successful response of a discrete symptom to either a
medical or a psychiatric intervention. Moreover, many patients are quite
resistant to psychiatric care because they feel it delegitimizes their physical
suffering. Teamwork between internist and psychiatrist is key, allowing
both to identify the most important symptoms of concern to the patient, to
provide appropriate attention and workup, and to coordinate medical and
psychiatric interventions.

Key Points
• Somatic symptom and related disorders represent a heterogeneous group
of disorders characterized by prominent physical symptoms or
complaints that are associated with significant distress and impairment in
excess of what would be expected.
• The high degree of both medical and psychiatry comorbidity in late life
poses a unique diagnostic challenge for disorders with prominent
somatic symptoms.
• The main somatic symptom and related disorders seen in the elderly are
somatic symptom disorder, illness anxiety disorder, and conversion
disorder. Previous categories of pain disorder and undifferentiated
somatoform disorder are now subsumed within somatic symptom
disorder.
• Somatic symptom and related disorders are most commonly diagnosed
in younger individuals. Major risk factors include childhood abuse,
female gender, chronic illness or pain, lower education and
socioeconomic status, and comorbid anxiety, depression, personality
disorders, and substance abuse.
• Management of somatic symptom and related disorders requires a
consistent, empathic approach that focuses on symptomatic improvement
and rehabilitation, does not challenge the veracity of the patient’s
reports, and provides efficacious cognitive-behavioral therapy and
appropriate pharmacotherapy.

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Suggested Readings
El-Gabalawy R, Mackenzie CS, Thibodeau MA, et al: Health anxiety
disorders in older adults: conceptualizing complex conditions in late
life. Clin Psychol Rev 33(8):1096–1105, 2013
Kroenke K: Efficacy of treatment for somatoform disorders: a review of
randomized controlled trials. Psychosom Med 69(9): 881–888, 2007
Puri PR, Dimsdale JE: Health care utilization and poor reassurance:
potential predictors of somatoform disorders. Psychiatr Clin North Am
34(3):525–544, 2011
Rabinowitz T, Laek J: An approach to the patient with physical complaints
or irrational anxiety about an illness or their appearance, in The 10-
Minute Guide to Psychiatric Diagnosis and Treatment. Edited by Stern
TA. New York, Professional Publishing Group, Ltd, 2005, pp 225–238
Somashekar B, Jainer A, Wuntakal B: Psychopharmacotherapy of somatic
symptoms disorders. Int Rev Psychiatry 25(1):107–115, 2013
 CHAPTER 14

Sexuality and Aging

Marc E. Agronin, M.D.

People are living longer and healthier lives, and many expect sexuality to
continue to play an important role. As a result, sexual issues and disorders
are an important part of assessment and treatment by the geriatric
psychiatrist, in both outpatient and long-term-care settings. The idea of
sexuality in late life, once commonly regarded with denial, humor, or even
disgust, too often led clinicians to view sexual dysfunction as a normal and
untreatable part of aging. Such distorted attitudes have changed widely,
however, starting with the sexual and feminist revolutions in the 1960s and
1970s and buoyed by the widespread use of hormone replacement therapy
and then the advent of oral erectogenic agents for erectile dysfunction. This
widespread openness toward late-life sexuality coupled with reliable
treatments for sexual dysfunction has made sexuality a more common and
comfortable topic of conversation among aged individuals and their
clinicians, and can now ensure the persistence of enjoyable sexual function
in later years. In addition, the destigmatization of sexual dysfunction has no
doubt encouraged many older couples to seek treatment who otherwise
might have suffered in silence and shame.

Sexual Behaviors in Late Life

Several major studies over the past 25 years have shown that a majority of
middle-aged and older individuals continue to be sexually active, although
with modest decreases in activity, determined in part by gender and the
availability of partners. These studies have indicated that older men are
more sexually active than older women and that individuals with steady
partners are more active than single individuals. In general, sexual interest
and activity in late life depend on the previous level of sexual activity; the
availability, health, and sexual interest of the partner; and the individual’s
overall physical health (Lindau et al. 2007; Schick et al. 2010). Physical
health appears to be the most important factor for older men, whereas the
quality of the relationship is most influential for older women.
Early surveys of sexuality in late life by Marsiglio and Donnelly (1991)
and the National Council on the Aging (1998) both found that a majority of
individuals over age 60 remained sexually active (defined as having sexual
intercourse at least once a month), with men being more sexually active and
overall rates generally declining with increased age. These findings have
been supported by a series of studies of late-life sexuality conducted by
AARP (which changed its name from the American Association of Retired
Persons in 1999). In the original 1999 mail survey, researchers gathered
responses from 1,384 men and women ages 45 years and older (Jacoby
1999). The survey found that three-quarters of both men and women in the
sample remained sexually active. Eighty-four percent of men and 78% of
women ages 45–59 years had steady sexual partners, compared with 58% of
men and 21% of women older than age 75. In terms of frequency, 50% of
individuals ages 45–59 years reported having sex at least once a week,
compared with 30% of men and 24% of women ages 60–74 years. Of the
respondents, the majority of men without partners said they masturbated,
whereas more than 77% of women did not. The study also examined
attitudes toward specific aspects of sexuality; 60% of men and 35% of
women said that sexual activity was important to their overall quality of
life. Two-thirds of all respondents were extremely or somewhat satisfied
with sex. Attitudes toward partners were generally favorable, with a
majority of both genders describing their partners with terms that included
“best friend,” “kind and gentle,” and “physically attractive.” The study also
found several generational differences in attitudes toward sex. Individuals
older than age 60 were less likely than younger respondents to approve of
oral sex, masturbation, and sex between unmarried partners.
A 2004 update of the AARP late-life sexuality study surveyed 2,930 men
and women in the United States ages 45 years and older, and included
respondents with African American, Asian, and Hispanic ethnicity (AARP
2005). Of this group, approximately two-thirds were married or living with
a partner, and 5% identified themselves as gay or lesbian. Attitudes toward
sexuality were remarkably similar to those seen in the 1999 survey, with
only a few new findings. As before, the vast majority of individuals had
positive attitudes toward sex, and those with partners described themselves
as more satisfied, optimistic, and tolerant than those without partners.
African Americans and Hispanics were more likely to be extremely
satisfied with their partners. Those who engaged in physical exercise on a
regular basis had greater degrees of sexual satisfaction. An increasing
number of individuals were seeking information on sex from the Internet
and from health care providers. Compared with the 1999 survey, the 2004
survey found less opposition to sex between unmarried partners.
The 2004 AARP survey found no major changes in sexual behaviors,
with 86% of respondents continuing to be sexually active. Men were more
active than women, and rates of sexual activity declined with age. The
percentage of men seeking erectogenic medications doubled from 10% to
22%, with 68% of these respondents saying that the treatment helped. The
number of women undergoing hormone replacement therapy dropped by
50%, no doubt related to warnings about increased cancer risk. More
individuals reported engaging in masturbation and oral sex in 2004 than in
1999. Sixty percent of men and 50% of women reported engaging in
masturbation at least once in the 6 months prior to the survey.
AARP conducted another survey in 2009 using a probability sample of
1,670 individuals ages 45 years and older, which included 630 Hispanic
respondents (Fisher 2010). In contrast to previous surveys, the overall
percentage of individuals having sexual intercourse at least once a week
dropped about 10 points to 41% of those with a steady partner (and 28%
overall), and there were similar drops in levels of sexual satisfaction.
Approximately 50% of men and 26% of women ages 45–49 years reported
having sexual intercourse at least once a week, which dropped to 15% of
men and 5% of women ages 70 years and older. Levels of both sexual
activity and satisfaction were higher among individuals who were single
than among those who were married. Although all of these findings suggest
important changes from previous surveys, it is important to keep in mind
that the methodology of the 2009 survey was different, using telephone
versus mail surveys.
 The AARP study findings are consistent with those of several other
surveys. Lindau et al. (2007) interviewed a probability sample of 3,005
adults ages 57–85 in the United States and found that 73% of those ages
57–64 years were sexually active, declining to 53% of those ages 65–74 and
26% of those 75 and older. Rates of having sex at least two to three times
per month fell from 67.5% of men and 62.6% of women in the youngest
cohort, to 65.4% of both men and women in the middle cohort, and to
54.2% of men and 54.1% of women in the oldest cohort. Overall, men were
more sexually active than women across all age groups. Older individuals
with poorer health rankings were less sexually active and more prone to
sexual dysfunction. A large cross-national study of 27,000 older individuals
in 29 countries found that men had increased levels of sexual satisfaction,
regardless of the country, and that sexual satisfaction decreased with
increasing numbers of partners (Laumann et al. 2006).

Aging Gay and Lesbian Individuals

There are approximately 1–3 million gay and lesbian individuals over age
60 in the United States, and this number is expected to double in the next 30
years. The 2009 AARP survey found that 8% of male and 2% of female
respondents reported having same-sex relationships; 3% of men described
themselves as gay, less than 0.5% of women reported being lesbian, and 1%
of respondents described themselves as bisexual (Fisher 2010). A small but
growing literature indicates that older gay and lesbian individuals continue
to be sexuality active and to feel high levels of satisfaction with both their
lifestyle and their sex lives (Adelman 1990). In one study of 100 gay men
ages 40–77 years, 80% remained sexually active, with 34% reporting
having sex more than once a week and 69% reporting the same amount of
sexual enjoyment as when they were younger (Pope and Schulz 1990).
Kimmel (1977) earlier reported similar findings and suggested that gay men
might have a number of age-associated advantages, including being less
dependent on family and children and having large networks of supportive
friends.

Sexuality in Long-Term-Care Settings

Sexuality among residents in long-term-care settings is stigmatized not only
because the residents are elderly but also because they are no longer living
independently and often have multiple medical and psychiatric problems,
including cognitive impairment. As a result, both residents and staff tend to
view sexuality in a negative manner. In one study, for example, even though
the majority of long-term-care staff acknowledged the sexual needs of
residents, most did not think it was necessary for these individuals to be
sexually active (Mroczek et al. 2013; Saretsky 1987). Residents often feel
sexually unattractive and are pessimistic about whether sex would even be
possible or enjoyable (Kaas 1978;Wasow and Loeb 1979). Not surprisingly,
the rate of sexual activity is low in most nursing homes (Hajjar and Kamel
2004a; Mulligan and Palguta 1991). For many residents, however, the
desire for sexual relationships still exists. In a 1982 study involving 250
nursing home residents, White (1982) found that 91% had not been sexually
active in the last month and 17% wanted to be sexually active but lacked
privacy or a partner. Other common barriers to sexual activity among long-
term-care residents include loss of interest, chronic illness, sexual
dysfunction, and negative attitudes of staff (Hajjar and Kamel 2004a;
Richardson and Lazur 1995; Wasow and Loeb 1979).
When one or both members of a couple are living in a long-term-care
facility, staff must be aware of residents’ rights to sexual expression. Mental
health consultants can help remove barriers to sexual activity in long-term-
care settings in several ways. A key to accomplishing this goal is educating
staff about sexuality in late life so that stereotypes are dispelled. Such an
education provides staff with an understanding of residents’ rights to sexual
expression and the role of sexuality in helping residents meet needs for
intimacy and physical contact (Roach 2004; Spector et al. 1996). Also,
residents should be educated about sexuality in late life and about their
sexual rights. One way to facilitate these educational goals for residents and
staff in long-term-care settings is to develop and promote a policy on
sexuality.
To carry out such a policy, clinical staff in long-term-care facilities
should ensure that a sexual history is obtained during intake and routine
nursing, medical, and mental health evaluations. These evaluations can also
be used to assess residents’ concerns and capacities with respect to sexual
function and relationships. Long-term-care facilities must ensure adequate
privacy for couples wishing to be intimate and must facilitate conjugal or
home visits. To this end, facilities might provide private rooms for married
couples or individuals with other partners, when feasible. Privacy can be
increased with “Do Not Disturb” signs, locks on doors, and reminders to
staff and residents to knock before entering a resident’s room (Spector et al.
1996). Finally, facilities can provide beauty services such as hair styling and
manicures (Richardson and Lazur 1995).

The Sexual Response Cycle and Aging

The effects of aging on sexual function must be viewed against the
backdrop of normal adult sexual response. A four-stage model of the
normal sexual response cycle was developed by sex researchers William
Masters and Virginia Johnson (1966) from their pioneering work in human
sexuality. The four-stage cycle illustrates the physiological changes that
take place in the body during sexual activity. These four stages are
excitement or arousal, plateau, orgasm, and resolution. Kaplan (1974) and
others added a fifth stage, desire, to account for a psychological and
physiological component of sexuality that underlies sexual response
(Snarch 1991; Zilbergeld and Ellison 1980). In this later model, sexual
response is not a linear process but rather a waxing and waning pattern of
sexual arousal that may culminate in orgasm, depending on a host of
factors. All of these factors can be influenced by age-related changes in
sexual function.
The first stage of the five-stage model, desire, involves physical and
psychological urges to seek out and respond to sexual interaction. This
drive is centered in the limbic system of the brain, particularly in the
hypothalamus, and is stimulated in both sexes by testosterone. Desire is
intimately linked to the physiological process of sexual excitement or
arousal (the second stage); it is difficult for one to exist without the other.
In both men and women, sexual arousal can be triggered by thoughts and
fantasies or by direct physical stimulation. Autonomic nervous stimulation
leads to predictable physiological responses, including increased muscle
tone, increases in heart and respiratory rates, and increased blood flow to
the genitals (vasocongestion). In men, these responses result in penile
erection, whereas in women, they result in vaginal lubrication and swelling
of breast and genital tissues, especially the clitoris. The relatively brief
plateau stage is characterized by a sense of impending orgasm and is
followed by orgasm and then a refractory period of relaxation called
resolution. In both sexes, orgasm is characterized by euphoria associated
with rhythmic contractions of genital muscles. In men, orgasm is brief and
is accompanied by ejaculation. In women, orgasm tends to last longer and
there may be multiple successive occurrences.
Normal aging produces several changes in the sexual response cycle
(Table 14–1). In women, the most significant changes occur during
menopause, a 2- to 10-year period that usually ends in the early 50s. The
decline and eventual cessation of ovarian estrogen production during
menopause leads to important changes in sexual function, including atrophy
of urogenital tissue; a decrease in vaginal size; and diminished vaginal
lubrication, vasocongestion, and erotic sensitivity of nipple, clitoral, and
vulvar tissue (Wilson 2003). As a result, sexual desire may decrease, sexual
arousal may require more time, sexual intercourse may be more
uncomfortable because of reduced lubrication of vaginal and clitoral tissue,
and orgasms may be felt as less intense (Dennerstein et al. 2008). Up to
85% of menopausal women also experience symptoms such as hot flashes,
headaches and neck aches, mood changes, and excess fatigue. During
menopause, women also experience decreases in testosterone production
that may lead to diminished sensitivity of erogenous tissue and reduced
libido (Morley 2003; Nappi et al. 2006).
In most women, hormone replacement therapy largely reverses these
menopause-associated changes in sexual function. Estrogen is often
prescribed with the synthetic progesterone, called progestin, to replicate
previous hormone levels. It can be administered orally or via a slow-release
transdermal patch (Alexander et al. 2004). In addition, estrogen cream can
be applied directly to genital tissues to relieve irritation and enhance
lubrication (Minkin et al. 2014; Suckling et al. 2006). Unfortunately, overall
research findings have indicated a small but potentially unacceptable risk of
stroke and breast cancer associated with long-term oral hormone
replacement therapy, which therefore is not recommended (Lacey et al.
2002; Marjoribanks et al. 2012; Nelson et al. 2012; Rossouw et al. 2002).

TABLE 14–1. Normal age-related changes in sexual function

Men
Testosterone production modestly decreases, with unpredictable effect on
sexual function.
 Sperm count changes minimally, but amount of functional sperm and rate
of conception decrease.
There are no predictable changes in sexual desire (libido).
Increased tactile stimulation is needed for sexual arousal.
Erections take longer to achieve and are more difficult to sustain.
Penile rigidity decreases because of decreases in blood flow and smooth
muscle relaxation.
Sensation of urgency during plateau stage is diminished.
Ejaculation is less forceful, with decreased ejaculate volume.
Refractory period increases by hours to days.
Women
During menopause, estrogen production decreases and eventually stops.
Sexual desire (libido) may decrease due in part to decreased testosterone
levels.
Blood supply to pelvic region is reduced.
Vagina shortens and narrows. Vaginal mucosa is thinner and less
lubricated.
During arousal, vaginal lubrication and swelling occur more slowly and
are decreased.
Sexual arousal may take longer and may require increased stimulation.
During orgasm, strength and amount of vaginal contractions decrease.
Source. Agronin and Westheimer 2011; Westheimer and Lopater 2002.

Compared with women, the sexual changes in aging men occur more
gradually with a less predictable time frame (Morley 2003; Westheimer and
Lopater 2002). As men age, desire may involve less anticipatory physical
arousal, and sexual arousal and orgasm may take longer to achieve. Older
men require more physical stimulation to achieve erections, which tend to
be less frequent, less durable, and less reliable. The volume of ejaculate
during orgasm is decreased. In older men, the resolution or refractory stage
is much longer, lasting hours to days instead of minutes to hours as in
younger men. Testosterone levels in men decline 35% on average by age 80
years, although some men have more significant declines, with levels
dropping below 200 ng/dL, the level at which they are diagnosed with
hypogonadism (Morley 2003). Some researchers have suggested the
existence of a male menopause or andropause resulting from declining
testosterone levels and involving a symptom complex that includes
decreased libido and sexual function; diminished bone and muscle mass,
muscle power, and body hair; and decreased lean body mass (Haider et al.
2014; Heaton and Morales 2001; Morley and Perry 2003; Pines 2011).
Research has suggested, however, that these changes are quite variable, and
that testosterone replacement therapy has inconsistent results (Harman
2005).
In both sexes, the effects of physiological changes in sexual function are
mediated by a number of psychosocial factors. The more an individual
knows about what constitutes normal age-associated changes in sexual
function, the easier it may be for him or her to accept these changes. For
example, a man who does not understand the normal changes in erectile
function may misinterpret them and believe that he has a sexual problem.
Similarly, a woman may misinterpret vaginal dryness as an indication that
she does not want to have sex. Such overreactions to normal changes can
lead an individual to engage in less frequent or more limited sexual activity.
In addition, some older individuals may accept ageist stereotypes about
sexuality and view their behaviors as inappropriate or potentially harmful,
despite the individuals’ relatively normal sexual desire and capacity. Other
individuals may lose self-confidence and feel less sexy, especially as they
struggle to cope with age-associated changes in physical appearance,
strength, and endurance. Such attitudinal barriers may be more damaging to
sexuality than actual physiological changes.
The quality of an individual’s relationship with a partner is also
influential. Couples often have to adapt sexual technique and spend more
time on foreplay to preserve previous levels of sexual function and
enjoyment. Partners who are unable to work together may experience
difficulty with sex and perhaps even sexual dysfunction. On the other hand,
aging can bring new possibilities for sexuality in later life. Partners may
have more time to spend with each other once children have left home or
during retirement. For postmenopausal women, sex may be associated with
a reduced level of anxiety because of the impossibility of pregnancy.
Sexually Transmitted Diseases
None of the published surveys about late-life sexuality asked respondents
about sexually transmitted diseases (STDs), even though older people are
certainly at risk for contracting them. According to surveillance data from
the Centers for Disease Control and Prevention (2012), rates of STDs
including chlamydia, gonorrhea, and syphilis in individuals ages 65 years
and older were the lowest of any group and had not changed appreciably in
the previous 5 years. In a study from Washington State, the most common
STDs in older individuals were nongonococcal urethritis in men and genital
herpes in women—representing 1.3% of all reported cases of STDs (Xu et
al. 2001). With respect to HIV and AIDS, the largest increase in individuals
living with HIV infection from 2008 to 2010 was among individuals older
than 65 years, with a rate at the end of 2010 of 85.7 per 100,000 persons in
the United States. Although rates of new infections among the elderly have
been decreasing, rates of stage 3 AIDS and death have increased (Centers
for Disease Control and Prevention 2011). It should be noted that not all of
these cases are due to sexual transmission.
Despite these low prevalence rates for STDs, older individuals remain at
risk because they continue to be sexually active. Adding to this risk is the
fact that many older people never received the sex education provided to
today’s younger population. Thus, they may neglect safe-sex practices due
to lack of knowledge, the absence of pregnancy risk, and a false sense of
safety from knowing that STDs are more prevalent in younger people. One
survey of a representative sample of 1,670 individuals 45 years and older
found that less than 20% of men and women who were single and dating
reported using a condom or any other form of protection on a regular basis
during sexual intercourse (AARP 2010). Given these lapses in safe-sex
measures, education about sexuality, STDs, and safe-sex practices remains
critical throughout the entire adult life cycle.

Sexual Dysfunction in Late Life

Although the majority of older individuals continue to engage in sexual
activity, the prevalence of sexual dysfunction does increase with age
(Lindau et al. 2007; Mulligan et al. 2003). The DSM-5 (American
Psychiatric Association 2013) classification of sexual disorders is provided
in Table 14–2. Erectile disorder (ED) is the most common form of sexual
dysfunction in older men, affecting 20%–40% of men in their 60s and
50%–70% of men in their 70s and 80s (Feldman et al. 1994; Laumann and
Waite 2008; Lewis et al. 2004). In older women, the most common forms of
sexual dysfunction are DSM-IV-TR (American Psychiatric Association
2000) hypoactive sexual desire, female orgasmic disorder, and dyspareunia
(Bitzer et al. 2008; Lindau et al. 2007). The percentage of women with low
sexual desire increases from 10% of women younger than age 50 to nearly
50% of women in their late 60s and 70s (Lewis et al. 2004). One study
found that 44%–49% of women ages 57–85 years reported low desire,
35%–44% had difficulty with lubrication, and 34%–38% had anorgasmia
(Lindau et al. 2007). In the same study, 31%–44% of men reported ED, and
14% were taking medications for it.
Unfortunately, physicians often fail to ask older patients about sexual
function, perhaps due to their discomfort with the topic or acceptance of
ageist stereotypes. As a result, many older individuals endure treatable
forms of sexual dysfunction and are either too ashamed to inquire about
treatment or are ignorant or pessimistic about treatment. The geriatric
psychiatrist can play a vital role in providing support, education, and
treatment to such individuals.
Although medical and psychiatric problems and medication effects are
usually the main causes of sexual dysfunction in late life, numerous
psychological factors must be considered, including performance anxiety,
the presence of another sexual disorder in one or both partners, fears of self-
injury or death due to medical conditions (e.g., a history of myocardial
infarction, shortness of breath), sensitivity to loss of personal appearance or
control of bodily functions (e.g., incontinence), relationship problems, and
life stress. The first occurrence of psychogenic sexual dysfunction often
follows a stressful event such as the loss of a loved one, a divorce, a
financial or occupational strain, or a major health scare. Such major stresses
may break sexual patterns and lead to uncertainty about how to resume
sexual activity. As noted, the availability of partners is an acute issue for
women, who outnumber men by more than two to one by age 85 years.
Medical and psychiatric disorders that are the most common causes of
sexual dysfunction in geriatric patients are listed in Table 14–3. In both
sexes, major risk factors for sexual dysfunction include diabetes mellitus,
peripheral vascular disease, cancer, pulmonary disease, depression, stroke,
dementia, Parkinson’s disease, and substance abuse. These and other
medical disorders exert both primary and secondary effects on sexual
function. Examples of primary effects include impaired sexual arousal due
to diabetic neuropathy and impaired genital vasocongestion due to
peripheral vascular disease. Secondary effects such as fatigue, pain, and
physical disability due to medical illness can make individuals feel less
sexy and less confident in their sexual ability, which in turn can lead to
hypoactive desire. Medications can also cause sexual dysfunction and can
affect both men and women at any point in the sexual response cycle
(Crenshaw and Goldberg 1996; Goodwin and Agronin 1997; Ludwig and
Phillips 2014; Thomas 2003). The most common problematic medications
include antihypertensives such as β-blockers and diuretics, antiandrogens,
and many psychotropic medications (Nicolai et al. 2014; Segraves and
Balon 2014; Zajecka 2003). Some of the medications most commonly
associated with sexual dysfunction in late life are listed in Table 14–4.

TABLE 14–2. DSM-5 classification of sexual dysfunctions

The symptoms of each of these sexual disorders occur on almost all or all
occasions of sexual activity:
Female sexual interest/arousal disorder: Absent or reduced sexual
interest, thoughts or fantasies, initiated behaviors, excitement or
pleasure, or genital or nongenital sensations during sexual activity or in
response to sexual stimulation
Male hypoactive sexual desire disorder: Persistent or recurrent
deficiency in or absence of sexual thoughts, fantasies, or desire
Erectile disorder: Marked difficulty in attaining an erection during
sexual activity, or marked difficulty in maintaining an erection until the
completion of sexual activity, or marked decrease in erectile rigidity
Delayed ejaculation: Marked delay in ejaculation or marked
infrequency or absence of ejaculation
Female orgasmic disorder: Marked delay in, infrequency of, or absence
of orgasm, or markedly reduced intensity of orgasmic sensations
Premature (early) ejaculation: Persistent or recurrent pattern of
ejaculation during partnered sexual activity within approximately 1
minute following vaginal penetration
 Substance/medication-induced sexual dysfunction: Significant
disturbance in sexual function during substance intoxication or
withdrawal or after exposure to a medication
Genito-pelvic pain/penetration disorder: Persistent or recurrent
difficulties during intercourse with vaginal penetration, pelvic pain,
fear or anxiety about pain, or tensing and tightening of pelvic floor
muscles

Sexual dysfunction in late life is often comorbid with other psychiatric

disorders. Symptoms range from transient dysfunction, present only during
episodes of illness, to full-blown sexual disorders independent of the
primary psychiatric disorder. Major depression often features loss of libido
but may also be associated with inhibited arousal and ED. Symptomatic
anxiety as well as anxiety and panic disorders are frequently associated with
sexual dysfunction—in particular, sexual phobias and sexual aversion
(Kaplan 1987). Unfortunately, many of the antidepressants used to treat
mood or anxiety disorders can cause or exacerbate sexual dysfunction (see
Table 14–4). ED, delayed or inhibited orgasm, and/or a decrease in desire is
experienced by 10%–60% of men taking serotonin selective reuptake
inhibitors (SSRIs), venlafaxine, or tricyclic antidepressants (TCAs)
(Montejo et al. 2001; Segraves 1998). Lower rates of sexual dysfunction
have been associated with the antidepressants mirtazapine (25%),
bupropion (5%–15%) and nefazodone (8%) (Kavoussi et al. 1997; Montejo
et al. 2001; Reichenpfader et al. 2014).
Individuals with schizophrenia and other psychotic disorders often have
sexual problems. Psychotic individuals with negative symptoms—such as
social withdrawal or discomfort in the presence of others, apathy, and
blunted affect—may have relatively little interest in sexual relationships.
Psychotic patients with positive symptoms—such as delusions,
hallucinations, and bizarre thought patterns—may have difficulty relating to
others and interacting in sexually comfortable or appropriate ways. During
periods of symptom remission, however, sexual relationships can be more
appropriate. All antipsychotic medications can cause sexual dysfunction,
usually in proportion to the dose; higher rates of dysfunction occur with
prolactin-raising agents such as risperidone, haloperidol, olanzapine, and
clozapine (40%–60%) than with prolactin-sparing agents such as
quetiapine, aripiprazole, and ziprasidone (16%–27%) (Baggaley 2008;
Serretti and Chiesa 2011). Like antidepressant and anxiolytic medications,
antipsychotics can decrease libido, interfere with sexual arousal, and inhibit
erections, ejaculation, and orgasm (Baggaley 2008).

TABLE 14–3. Medical and psychiatric conditions commonly associated

with sexual dysfunction in late life
Anxiety disorders (generalized anxiety disorder, panic disorder);
obsessive-compulsive disorder
Arthritis and other degenerative joint diseases
Atherosclerosis (peripheral vascular disease, stroke)
Cancer (especially urologic and genital cancers and their treatments)
Cardiac disease (coronary artery disease, congestive heart failure,
myocardial infarction)
Chronic obstructive pulmonary disease
Chronic organ failure (renal, hepatic)
Neurocognitive disorder (e.g., due to Alzheimer’s disease or
cerebrovascular disease)
Diabetes mellitus
Major depressive disorder and other mood disorders
Multiple sclerosis
Parkinson’s disease
Prostate disease and prostate surgery
Schizophrenia and other chronic psychotic disorders
Substance abuse

Assessment
The assessment of sexual dysfunction in late life involves identifying the
specific problem and then obtaining a comprehensive medical, psychiatric,
and sexual history to determine potential causes. A comprehensive sexual
history involves asking an individual about prior sexual experiences,
current sexual functioning, and attitudes toward sexuality and toward any
current partner. With older couples, interviewers must be able to identify
relevant age-appropriate issues (Agronin 2014; Agronin and Westheimer
2011). It is important to balance the need to gather sexual history with the
responsibility to be sensitive to the fact that sexual data may be some of the
most personal information that a patient will ever divulge. Finally, accurate
assessment of sexual dysfunction in late life depends to a large degree on a
comfortable and productive doctor-patient relationship, one in which the
patient and his or her partner feel secure enough to disclose adequate
history and the physician asks the right questions and has sufficient testing
performed. Partner involvement is crucial to a successful outcome.
The medical workup for sexual dysfunction may involve a physical
examination, laboratory testing, and specialized diagnostic testing. The
focus of the physical examination is on genital and urological anatomy and
function, including underlying vascular and neurological function.
Laboratory testing typically involves examination of routine blood
chemistry (e.g., blood count, electrolyte levels, glucose levels, lipid profile),
testosterone and prolactin levels, thyroid function, and, in men, prostate-
specific antigen levels. Specialized diagnostic tests for ED may include
nocturnal penile tumescence and rigidity testing (to determine whether
natural erections occur during sleep) and penile duplex ultrasonography (to
assess blood flow in the penis). This workup is typically conducted by a
urologist.

TABLE 14–4. Medications associated with sexual dysfunction in late life

α-Adrenergic blockers (prazosin, phentolamine)
Antiandrogens (leuprolide, ketoconazole)
Antidepressants (MAOIs, TCAs, SSRIs, venlafaxine)
Antihistamines
Antihypertensives (thiazide diuretics, β-blockers, ACE inhibitors,
clonidine, spironolactone, calcium-channel blockers, reserpine)
Antipsychotics (conventional and atypical)
Benzodiazepines
Cancer chemotherapeutic agents
 Cardiac medications (e.g., digoxin, amiodarone)
Corticosteroids
Disopyramide
L-Dopa

Histamine subtype 2 (H2) receptor blockers

Mood stabilizers (lithium, valproic acid, carbamazepine)
Note. ACE = angiotensin-converting enzyme; MAOI = monoamine oxidase inhibitor; SSRI =
selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

Treatment
Preservation and enhancement of sexual activity in geriatric patients require
recognition of and sensitivity to the fact that many of these individuals want
and intend to continue having sex, despite changes in physical and sexual
function. Once an evaluation is complete, both partners should be educated
about normal and dysfunctional sexuality (Bitzer et al. 2008). This
information helps to reassure the affected individual that he or she is not the
only person with the particular problem, that the problem has specific
causes, and that it can be treated. In addition, clinicians can help patients
recognize sexuality as a form of physical and psychological intimacy and
not solely as sexual intercourse. This discussion will build trust between the
patient and the clinician, and will help the patient feel comfortable about
seeking follow-up and being open about emotional reactions to the problem.
Many treatments fail at this point, not because the treatments cannot work
but because the patient and the clinician never establish a solid working
relationship. Treatment can also fail when one partner refuses to cooperate
with treatment or when problems within the couple’s entire relationship
become insurmountable.
Unique challenges are faced by couples in which one or both partners
have a chronic medical illness or disability. These couples often need to
shift their focus from intercourse to foreplay and to adapt sexual practices
to account for physical limitations such as fatigue, loss of muscle strength,
and pain (Agronin and Westheimer 2011; Morley and Tariq 2003; Schover
and Jensen 1988). Education is key. Organizations such as the American
Cancer Society, the United Ostomy Associations of America, National
Jewish Health (on respiratory disorders), and others have developed helpful
Internet guides to maintaining sexual function despite specific medical
illnesses. Physicians should work to maximize both rehabilitative and
palliative treatments—for example, making use of analgesics for pain,
inhalers for shortness of breath, or physical therapy for joint immobility and
muscle weakness. In addition, appropriate treatment of depression, anxiety,
or psychosis can often lead to significant improvement in sexual function,
assuming that the medications used to treat these disorders do not
themselves cause problems. Some ways in which an older couple can
enhance sexual function and cope with disability are outlined in Table 14–5.

Medication Effects
When medication side effects impair sexual function, physicians can
consider several options (Goodwin and Agronin 1997; Labbate et al. 2003;
Zajecka 2003). The first step is to continue administering the medication
and wait for tolerance to develop; many side effects diminish or disappear
after several weeks. If no change occurs, dose reduction can be tried.
Simplifying the overall regimen might also be helpful, given that
combinations of medications can cause more sexual side effects than each
medication alone. For certain medications, such as antidepressants that have
short half-lives, a drug holiday in which administration of the medication is
temporarily stopped for a day or two (such as for a weekend) can result in
transient improvement in sexual function (Rothschild 1995). However,
there is a risk of recurrence of psychiatric symptoms during this holiday.
Ultimately, the clinician may have to consider replacing the medication
with an agent that has less potential for sexual side effects, such as
bupropion or mirtazapine (Clayton et al. 2014; Reichenpfader et al. 2014).
With regard to antipsychotic medications, more potent agents with fewer
anticholinergic side effects and prolactin-sparing agents may cause less
dysfunction (Baggaley 2008; Serretti and Chiesa 2011).
When sexual dysfunction is due to antidepressant medication, the
clinician can also consider using antidotes to reverse sexual side effects
(Taylor et al. 2013; Thomas 2003; Zajecka 2003). Antidotes include
yohimbine, amantadine, cyproheptadine (a note of caution: cyproheptadine
can also reverse the antidepressant effects of SSRIs), bethanechol,
methylphenidate, buspirone, bromocriptine (for antipsychotic-induced
sexual dysfunction), and the antidepressants bupropion, nefazodone,
mirtazapine, and trazodone. The oral erectogenic agents sildenafil, tadalafil,
and vardenafil have also been shown to reverse antidepressant-induced ED
(Berigan 2004; Fava et al. 2006;Segraves et al. 2007; Taylor et al. 2013).
Depending on the chosen antidote for sexual side effects, the patient can
take a dose anywhere from 30 to 60 minutes before anticipated sex and can
take increasing doses until success is achieved. If intermittent use of an
antidote does not work, a regularly scheduled daily dose should be
considered.

TABLE 14–5. Ten ways to enhance sexual function in late life

1. Cultivate a positive attitude toward sexuality in later life.
2. Maintain optimal health and fitness. Avoid use of tobacco and
excessive use of alcohol.
3. Maintain open and honest communication with your partner about
how your sexual responsiveness has changed over time.
4. Focus on foreplay as much as on intercourse. Be open-minded about
adapting sexual practices to your needs.
5. Maximize treatment of medical problems or disabilities that are
interfering with sexual function. Consult a physician about any
concerns regarding excess exertion during sex. To achieve adequate
stamina, use appropriate exercise to build up strength and self-
confidence.
6. Before sex, maximize treatment of symptoms that affect sex. For
pain, consider taking a warm shower or bath, having a relaxing
massage, or taking analgesics before sex. For shortness of breath,
adapt sexual activity to minimize exertion and use prescribed
inhalers ahead of time. Choose times of day for sex when pain is at a
minimum.
7. If you are a woman, consider the use of estrogen cream, which can
relieve vaginal dryness and improve vasocongestion in peri- or
postmenopausal women. Tender genital or breast tissue may require
more gentle stimulation, sometimes along with the use of an external
lubricant.
 8. Identify problematic medications and investigate alternative agents
or strategies.
9. Avoid unrealistic expectations that sex must be the same as when
you were younger.
10. Explore sexual positions that decrease exertion or account for
equipment such as oxygen tanks or ostomy bags. Suggested positions
for intercourse include lying side by side or sitting face-to-face.
Source. Agronin and Westheimer 2011; Bitzer et al. 2008; Goodwin and Agronin 1997.

If none of these strategies work, the clinician must consider the trade-off
between the benefits of the original medication and the sexual side effects.
For some individuals, stopping the medication poses too great a risk of
recurrent psychiatric symptoms, and adequate alternatives may not exist. In
this frustrating situation, patients must choose either to discontinue a
needed medication or to cope with persistent sexual dysfunction.

Sex Therapy
In some older couples, sexual dysfunction has clear psychological roots; for
example, sexual dysfunction often occurs in the context of a dysfunctional
relationship. Sex therapy is always best done conjointly, where both
partners participate because both are an integral part of the problem and
solution. Historically, a psychodynamic model was used in sex therapy to
uncover underlying unconscious conflicts, but that approach is now viewed
as less successful, and cognitive-behavioral techniques are used in current
treatment models (Brotto and Luria 2014; Kaplan 1983, 1974; Westheimer
and Lopater 2002). Brief supportive and educational counseling is a first
step in treatment and can help dispel distorted and uninformed attitudes
toward sexuality in general and toward a sexual problem in particular.
Counseling can also help an individual or couple change sexual practices to
resolve a problem. In other cases, more intensive couples therapy is needed
to resolve long-standing relationship issues before work on a sexual
problem can begin.
Sex therapy involves both cognitive and behavioral techniques, with an
overall goal of building an association between relaxed and sensual
physical intimacy and sexual relations. The same principles can be applied
across the life span, with several refinements in late life. Using cognitive
therapy techniques, the therapist attempts to change distorted cognitive
attitudes toward sexual activity into more practical attitudes. For example,
many men with ED find it difficult not to assume the role of a spectator
during sex—that is, not to watch themselves with their partners and be
preoccupied with the status of their erections. This spectator role can
increase anxiety and distract the man from concentrating on pleasurable
sensations, with the result that ED is reinforced (Masters and Johnson
1970). To counter this, the man is taught to shift his mental focus from his
erection to pleasurable aspects of the encounter (Kaplan 1974). ED may
also be perpetuated by cognitive distortions such as catastrophizing, in
which the man thinks that if he does not achieve an erection during sex, he
will be rejected not only by his partner but by all women. Another common
cognitive distortion is all-or-nothing thinking, in which the man thinks that
he must achieve an instant erection during sex or else the whole thing is
pointless. The problem with such unrealistic cognitive distortions is that
they often become self-fulfilling prophesies. The therapist helps the patient
to gain insight into the negative effects of such thoughts and then to practice
replacing them with more realistic and hopeful ones, sometimes even with
positive assertions or affirmations of success (Goodwin and Agronin 1997).
Behavioral techniques used during sex therapy begin with exercises
called sensate focus, in which a couple practices physical relaxation
techniques during nonpressured sensual touching. Sensate focus helps to
reduce performance anxiety and restore the natural flow of the sexual
response cycle. Once the partners are able to feel relaxed and physically
intimate together without sexual stimulation, they gradually progress to
genital stimulation and then intercourse. Several adjustments in these
exercises may be required for the older couple. For example, older patients
with physical problems that involve some degree of disability may express
concerns about being able to exert themselves adequately during sexual
activity. The therapist might recommend one of several positions that
minimize exertion, such as lying side by side or having one partner kneel on
pillows and support himself or herself on a low bed. Other suggestions
outlined in Table 14–5 might also apply. Such simple suggestions may
remove some of the most anxiety-provoking barriers for an older couple,
especially the common but unfounded belief that older persons lack the
stamina or dexterity for sexual activity.
 During sex therapy, the therapist continues to work with the couple on
their relationship and tries to identify and confront resistance that inevitably
arises during treatment. Such resistance to these seemingly innocuous
exercises often reveals key problems in the relationship that are either
causing the sexual dysfunction or impeding its treatment. Regardless of age,
many couples find that sexual interest and pleasure reemerge and sexual
function improves during sex therapy, allowing them to enjoy once again
such a fundamental component of their relationship.

Specific Sexual Disorders

The next four sections will examine in detail several of the more common
sexual dysfunctions seen in late life that the geriatric psychiatrist and other
clinicians might encounter.

Female Sexual Interest/Arousal Disorder

Female sexual interest/arousal disorder is a significant sexual problem for
women across the life span and involves multiple psychological and
physical factors (Brotto and Luria 2014). In some older women, loss of
libido results from a poor self-image—brought about by age-associated
losses of physical strength and beauty—and from changes in sexual
function due to cessation of estrogen production during menopause. An
older woman’s ability to see herself as a sexual being can be further eroded
by exposure to negative societal attitudes and negative images of sexuality
in late life. Unfortunately, many women internalize these distorted, ageist
beliefs. Treatment of low desire must begin with sex education and
counseling to counter those psychological barriers. Estrogen replacement
therapy may help improve sexual arousal and comfort, which in turn may
lead to increased desire.
The critical physiological cause of low desire in women, however,
appears to be the menopause-associated reduction in levels of free
testosterone. Testosterone replacement therapy has been beneficial in some
women with hypoactive sexual desire (Basson 1999; Buster et al. 2005;
Shifren et al. 2006), although side effects can include weight gain,
virilization (e.g., growth of facial and chest hair, lowering of the voice),
suppression of clotting factors, and even liver damage (Kingsberg et al.
2007).

Erectile Disorder
ED, the most common sexual dysfunction in older men, historically was
seen as a psychological problem. More recent data, however, indicate that
ED is primarily caused by a problem with erectile physiology in the
majority of cases (Ludwig and Phillips 2014; Tariq et al. 2003). There are,
however, important psychological components of ED in terms of both cause
and effect. Many men equate erections with masculinity, potency, and
vitality. As a result, ED in late life is often experienced by men as a
harbinger of physical and sexual decline. Performance anxiety, stress,
depression, and relationship problems can trigger or exacerbate ED. In turn,
ED is associated with feelings of anger, anxiety, powerlessness, shame, and
humiliation in front of one’s partner. Recurrent ED can lead to depression.
Treatment of ED in geriatric patients involves the same approaches as
those used in younger men and has been revolutionized with the advent of
oral erectogenic agents. For men with hypogonadism as the likely cause of
ED, testosterone replacement therapy—in the form of a pill, transdermal gel
or patch, intramuscular injection, or subcutaneous implant—may be helpful
(Howell and Shalet 2001; Jacob 2011; Morley 2003). This treatment should
be avoided in men with a history of prostate or bladder cancer or with
bladder outlet obstruction. Some men have ED as a result of vascular
damage and may benefit from microsurgical revascularization. Peyronie’s
disease, characterized by scarring-caused curvature of the penis during
erection, can also be treated, with resultant improvement in erectile
function.
For many years, the only viable treatments for chronic ED involved
either the use of a vacuum constriction device prior to intercourse or the
surgical placement of a penile prosthetic device (Dutta and Eid 1999; Sison
et al. 1997). Initial pharmacological approaches to ED involved either
penile intracavernosal injection or urethral suppositories using alprostadil, a
synthetic form of prostaglandin E1, which worked by increasing smooth
muscle relaxation and arterial dilatation in the penis (Althof 1995; Padma-
Nathan et al. 1997). All of these approaches have given way, however, to
the use of the oral erectogenic agents sildenafil, tadalafil, and vardenafil.
These agents improve erectile function in men with both organic and
psychogenic ED by serving as selective inhibitors of phosphodiesterase
type 5 (PDE5). Sildenafil and vardenafil can be taken 30 minutes to 4 hours
before anticipated sexual activity, and tadalafil can be taken up to 30 hours
prior. Erections do not occur spontaneously on taking these medications but
require adequate physical stimulation. The obvious advantages of PDE5
inhibitors are ease of use and success in up to 70%–80% of affected men
(Boolell et al. 1996; Porst et al. 2003a, 2003b). Potential side effects include
headache, skin flushing, dizziness, gastrointestinal discomfort, blurred
vision, and the potential for blood pressure decreases when combined with
nitrates (e.g., sublingual nitroglycerin, isosorbide). In addition, the PDE5
inhibitors should be used with caution in men with abnormal penile shape, a
history of orthostatic hypotension, severe renal or hepatic disease,
concomitant use of certain antiviral and antifungal medications, and
diseases that increase the risk of priapism, such as sickle cell anemia,
multiple myeloma, and leukemia. An extremely rare but potentially
devastating side effect of PDE5 inhibitors that has emerged is nonarteritic
anterior ischemic optic neuropathy, or NOIAN (the acronym for the French
name for the condition), characterized by the rapid onset of visual loss.
Although the exact role of PDE5 inhibitors in the pathogenesis of NOIAN
has not been fully established, any changes in visual acuity while taking a
PDE5 inhibitor require immediate assessment (Bella et al. 2006).

Female Orgasmic Disorder

Female orgasmic disorder is common in sexually active women of all ages
(Graham 2014). It is often comorbid with female sexual interest/arousal
disorder and involves many of the same attitudinal barriers to resolution.
Many older women who have experienced inhibited orgasm for years resist
seeking help, especially if they do not perceive it as a problem for
themselves or their relationships. Individual sex therapy involves relaxation
techniques that incorporate sensual self-stimulation and guided
masturbation to improve clitoral stimulation (Graham 2014; Heiman and
Lopiccolo 1976). Both testosterone supplementation and sildenafil have
been used with some success (Davis et al. 2008; Nurnberg et al. 2008).
When orgasm can be achieved, sensate focus exercises can help to
incorporate it into the couple’s sexual relations.
Premature (Early) Ejaculation
Premature ejaculation (PE) is the most common sexual dysfunction in
younger men, reported in 20%–38% of various samples, and may remain
relatively constant even in older ages (Laumann et al. 1999; Lindau et al.
2007; Porst et al. 2007; Westheimer and Lopater 2002). Ideally, treatment
involves psychotherapeutic techniques to slow down perception of sexual
stimulation, as well as couples therapy to teach sexual practices to improve
PE as well as to deal with its impact on the relationship (Althof 2014). For
example, one commonly used behavioral technique is having the partner
gently squeeze on the man’s penis before penetration to reduce sensation
and stall ejaculation (Althof 2014; Kaplan 1989). Topical anesthetic agents
are sometimes useful in reducing the sensations that lead to PE. For
persistent symptoms, daily use of an antidepressant medication can often
produce the side effect of delaying ejaculation without necessarily affecting
erectile function (Waldinger 2007). In addition, PDE5 inhibitors have also
been found to effectively treat PE, both alone and in combination with
SSRIs (Aversa et al. 2011; Wang et al. 2007).

Sexual Function and Dysfunction in Dementia

Sexuality continues to play an important role in the lives of many
individuals with dementia, often by providing a nonverbal means of
communication and intimacy. Depending on the degree of cognitive
impairment, however, the ability to initiate sexual activity and sustain
performance may be impaired. Agitation, disinhibition, and psychosis
associated with dementia may give rise to sexually aggressive or
inappropriate behaviors. Ethical issues also complicate sexuality associated
with dementia. For example, one partner may not be fully competent to
consent to sex, especially with another individual who has dementia
(Davies et al. 2010), or the nonaffected partner may seek to fulfill sexual
needs outside the relationship. It is important to understand these issues
when assessing and treating dementia patients and their caregivers.
Unfortunately, health care professionals often fail to inquire about such
issues, despite the frequency with which they affect couples (Agronin 2014;
Robinson and Davis 2013).
 Dementia affects sexuality in several ways. Sexual desire may remain
strong and even increase, especially if inhibitions are reduced by cognitive
impairment. As the dementia progresses, the cognitively intact partner may
become concerned about whether the affected individual is truly consenting
to sexual activity (Hanks 1992). The partner without dementia may also feel
frustrated with a partner who does not always recognize him or her or who
requests sex repeatedly because he or she cannot remember when they last
had sex (Davies et al. 1992; Redinbaugh et al. 1997). The cognitively intact
partner’s sexual desire may decrease because he or she views the dementia
and associated changes in behavior and personality as a sexual turnoff.
Partners may be further confused by conflicting feelings of love and fidelity
for their spouses with dementia, and by guilt over their desires for
extramarital intimacy.
It is not surprising, therefore, that there is an overall decrease in sexual
activity in affected couples. One study found that 46% of couples were
sexually active 3 years after the initial diagnosis of dementia, but the rate
dropped to 41% at the 5-year mark and 28% after 7 years (Eloniemi-
Sulkava et al. 2002). This decrease may also be attributed in part to sexual
dysfunction associated with dementia. For example, cognitive impairment
may reduce the capacity for paying attention during sex to maintain a focus
on physical and mental stimulation, as well as the ability to initiate and
perform components of lovemaking (Rosen et al. 2010). This impairment
may explain why men with Alzheimer’s disease have high rates of ED,
including more than 50% in one sample (Zeiss et al. 1990), and why
inhibited orgasm is common in women with dementia (Wright 1991).
Although the percentage of individuals with dementia who demonstrate
sexually aggressive or inappropriate behaviors is relatively small, these
conditions tend to generate a disproportionate amount of anxiety for
caregivers and to require a disproportionate amount of clinical attention
from long-term-care staff (Joller et al. 2013). The problematic behaviors
associated with dementia include inappropriate sexual comments or
demands, hypersexual behaviors (e.g., repeated requests for sexual
gratification, compulsive masturbation), disinhibition (e.g., exposing
oneself, disrobing, masturbating in public areas), and sexually aggressive
behaviors (e.g., attempts to grope, fondle, or force sex on another person).
In various studies, these behaviors were seen in 2%–7% of individuals with
Alzheimer’s disease (Burns et al. 1990; Guay 2008; Kumar et al. 1988),
although these rates may be higher in institutionalized populations (Hajjar
and Kamel 2004b; Mayers 1994). For example, one study found that 25%
of residents of a dementia unit engaged in sexually inappropriate behaviors
(Hashmi et al. 2000). Because frontal and temporal regions of the brain are
involved in behavioral control and inhibition, individuals with dementia
affecting these areas of the brain may be particularly vulnerable to
developing such inappropriate behaviors (Mendez and Shapira 2013; Raji et
al. 2000). Other factors associated with inappropriate or hyperactive sexual
behaviors include mania, psychosis, medication effects, alcohol or drug
abuse, stroke, and head trauma (Guay 2008; Hashmi et al. 2000; Wallace
and Safer 2009).
When assessing an individual who has allegedly demonstrated
problematic behaviors, it is critical to identify the context of the behaviors.
For example, public disrobing or touching of genitals in public may not be
due to sexual urges but may instead reflect underlying confusion, delirium,
motor restlessness, or stereotypy associated with dementia. However,
caregivers and long-term-care staff sometimes misinterpret innocuous
behaviors as evidence of sexual disinhibition (Hajjar and Kamel 2004b;
Redinbaugh et al. 1997). A good example would be the aphasic individual
with dementia who reaches out or grabs for attention while in his or her
wheelchair, inadvertently hitting someone in the waist or chest area. The
individual is simply reaching out for help, but the staff member who is
touched in the groin or breast area may wrongly view this act as an act of
sexual aggression. It is also important to recognize that even individuals
with severe dementia have legitimate needs for physical stimulation and
intimacy, and these persons may be reacting out of frustration and
confusion because they lack the ability to communicate their needs verbally.
The geriatric psychiatrist must be able to address these challenging
issues of sexuality in dementia. Regardless of the setting, individuals with
dementia have a right to engage in sexual relationships if they still have the
capacity to understand the nature of the relationship and provide reasonable
consent. If the cognitively intact partner is concerned about the competence
of his or her spouse to engage in sexual activity, a psychiatric or
psychological consultation may shed light on the affected individual’s
understanding of the relationship. Lichtenberg and Strzepek (1990)
proposed several questions to be answered in any interview to determine an
individual’s capacity to consent to a sexual relationship: Does the individual
know who is initiating sexual contact? Can the individual describe his or
her preferred degree of intimacy? Is the sexual activity consistent with the
individual’s previous beliefs and values? Can he or she say “no” to
unwanted activity? Does the individual understand that a sexual relationship
with someone other than his or her spouse may be temporary? Can the
individual describe how he or she would react if the sexual relationship
were to end? Responses to these questions will help determine the affected
individual’s awareness of the relationship, his or her ability to avoid
coercion and exploitation, and his or her awareness of the possible risks.
One main purpose of psychological or psychiatric intervention is to
provide education about sexuality to caregivers in the community and to
staff in long-term-care settings. Such education will improve interpretation
of and response to apparent inappropriate sexual behaviors. In addition,
educational programs for long-term-care staff may foster attitudes that are
more open-minded (White and Catania 1982).
Behavioral approaches for inappropriate sexual comments include
setting verbal limits and directing the individual to a different topic. Staff
and caregivers must be careful to avoid reinforcing inappropriate
comments, such as by laughing at off-color jokes or teasing patients in a
seductive manner in response to sexual comments. In the case of
inappropriate or aggressive sexual advances, staff may need to physically
remove the individual from the situation or keep him or her away from
vulnerable individuals. Sometimes restrictive clothing (e.g., pants without
zippers, pants with suspenders) can cut down on public displays of genitals,
although caution must be used so that the individual is not inadvertently
restrained. Because sexual advances may reflect unmet sexual needs,
existing partners can be asked to consider providing more physical and
perhaps sexual intimacy, the hope being that doing so will remove the drive
to engage in inappropriate behaviors.
When behavioral approaches are insufficient, psychiatric consultation is
needed to provide better control through pharmacotherapy. The choice of
medication will depend on the nature and severity of the behaviors and on
the presence of underlying psychopathology, if any (Tucker 2010). In
general, however, much of sexual aggression can be viewed as any other
form of agitation associated with dementia and can be treated accordingly.
Thus, a variety of psychotropic agents—in particular, the atypical
antipsychotics and antidepressants—may help treat both agitation and
sexual problems associated with dementia (Joller et al. 2013; Ozkan et al.
2008). Medications may also be used to treat specific underlying
psychopathology. For example, overactive libido can sometimes be reduced
through use of an antidepressant with sexual side effects, such as an SSRI
or a TCA (Raji et al. 2000; Segraves 1998). If the inappropriate sexual
behaviors are believed to reflect hypersexuality due to mania, use of an
antipsychotic or a mood stabilizer is indicated. Another pharmacological
strategy for decreasing libido and sexual aggression is use of hormone
therapy. Estrogen has been shown to reduce aggression in men with
dementia (Kyomen et al. 1999), a finding that may be applicable to sexually
aggressive behaviors. Medroxyprogesterone is a steroid hormone with
antiandrogenic activity that has been shown to reduce sexually aggressive
behaviors in individuals with dementia (Light and Holroyd 2006). Potential
side effects include weight gain, glucose intolerance, and liver dysfunction.

Key Points
• Because individuals are living longer, healthier lives, sexuality continues
to play an important role, facilitated by increasingly positive attitudes and
newer and more effective treatments for sexual dysfunction.
• Sexual surveys indicate that although a majority of individuals ages 65
years and older continue to be sexually active, there are declines in both
the rate and the frequency of sexual activity, particularly in older single
women.
• The main predictors of sexual activity in late life include previous sexual
behaviors; the availability, health, and interest of a partner; and the
individual’s overall physical health.
• Rates of sexual dysfunction increase with age, with erectile disorder being
the most common disorder in older men and sexual interest/arousal
disorder being the most common disorder in older women.
• Depending on its form, sexual dysfunction in late life can be treated with a
variety of approaches, including treatment of causative medical or
medication-related factors, psychoeducation, individual or couples
counseling, sex therapy, and the use of disorder-specific medications, such
as oral erectogenic agents for erectile dysfunction.
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 CHAPTER 15

Bereavement
Moria J. Smoski, Ph.D.
Stephanie T. Jenal, Ph.D.
Larry W. Thompson, Ph.D.

This work was supported in part by grant R01-AG01959 from the National Institute on Aging and
grants R01-MH36834 and R01-MH37196 from the National Institute of Mental Health. In addition,
author M.J.S. was supported by K23-MH087754.

As the baby boomer population ages, increasing numbers of

individuals are confronting late-life bereavement. This chapter examines the
current research on bereavement among the elderly and explores the
following salient areas: the demographics of bereavement, theoretical and
empirical perspectives on adjustment to the loss of a loved one, and
therapeutic considerations in the diagnosis and treatment of complicated
grief.

Late-Life Bereavement
The terms bereavement and grief reaction have been used to refer to any
number of losses. These losses include (but are not limited to) the death of a
spouse, an adult child, another family member, or a close personal friend;
divorce (Cain 1988); anticipatory grief associated with caregiving for a
severely impaired loved one (Bass et al. 1991); and a significant decline in
one’s own health, attractiveness, capabilities, opportunities, and so forth
(Kalish 1987). When used in its narrowest sense, however, bereavement
refers to the reaction or process that results after the death of someone
close. Indeed, the death of a spouse is generally accepted as the most
common and traumatic life event in late life (Jacobs and Ostfeld 1977).
In the United States, 40% of women and 13% of men older than 65 years
have lost a spouse (Federal Interagency Forum on Aging Related Statistics
2012). The mean duration of widowhood or widowerhood is approximately
14 years for women versus only 7 years for men (U.S. Census Bureau
2001). These data, plus the fact that widowers are more likely than widows
to remarry after losing their spouses, have often led to the interpretation that
bereavement is a women’s issue. Although elderly women may live without
a spouse longer than their male peers, they also have lower mortality rates.
For example, in the University of Southern California longitudinal study of
spousal bereavement, the first year after bereavement saw a mortality rate
of 12% in men but only about 1% in women (Gallagher-Thompson et al.
1993; Thompson et al. 1991). Thus, the loss of a spouse is an important
issue regardless of gender.

Theories About Adjustment to Permanent Losses

Numerous theoretical perspectives on the function and process of
bereavement have been developed over the years. We provide only a brief
review. More comprehensive reviews have been written by others
(Neimeyer et al. 2011; Osterweis et al. 1984, Stroebe and Schut 1999;
Stroebe et al. 2001a).
Early work emphasized that mourning was a process whereby the
bereaved gradually “surrendered” attachment to the lost loved one by
engaging in certain specific psychological and behavioral tasks that
occurred at appropriate time points during the bereavement (Freud
1917[1915]/1957; Lindemann 1944). This process was thought to be
necessary for individuals to develop constructive new attachments to other
people entering their lives. Failure to complete these tasks would result in
the development of a psychiatric disorder. Bowlby (1961) offered a
somewhat different interpretation of grief behaviors. He posited that any
involuntary separation, including bereavement, gives rise to many forms of
attachment behavior (such as separation anxiety and pining) that reflect the
person’s desire to reunite with the lost person. In his view, the function of
bereavement is not a surrendering of attachment but rather an attempt to
regain a sense of connection with the lost object of attachment. With time,
these behaviors were thought to dissipate through a series of stages,
including shock, protest, despair, and finally breakage of the bond and
adjustment to a new self.
Parkes (1972) and Horowitz (1976) have proposed models that involved
phases or stages of reaction to the death of a loved one. These models are
similar to Kübler-Ross’s (1969) seminal stage model of the reactions of
individuals facing a terminal illness. Shock and disbelief, combined with
emotional numbness and cognitive confusion, characterize the initial
period, with intense free-floating anxiety and sharp mood fluctuations. The
second phase generally begins as the numbness and anxiety start to
decrease. During this period, family and friends gradually become less
available and often convey the message that the bereaved person should be
getting over his or her grief and moving on with life, although the
individual is far from ready to do so. Specific symptoms such as frequent
crying, chronic sleep disturbance, blue mood, poor appetite, low energy,
feelings of fatigue, loss of interest in daily living, and problems with
attention and concentration are common. Even though these symptoms can
also be indicative of depression, most grieving individuals do not develop
major depression; the sadness that accompanies bereavement is specific to
the loss of the loved person, rather than the more global dejection that
characterizes major depression. This second phase is described as a time of
“yearning and protest,” during which the bereaved may actively or
implicitly search for the deceased (Parkes 1972). Even though these seeking
experiences may be startling to an outside observer (e.g., believing one has
seen or heard the lost loved one), they are common. In one study
approximately half of bereaved individuals reported seeing, hearing, or
sensing their deceased spouse within 13 months of their death, an
experience that is sometimes reported as positive or comforting (Carlsson
and Nilsson 2007). Although many bereaved individuals report a profound
sense of connection to and an ongoing presence of the deceased, others note
no such experiences and seem mystified by the idea of such a phenomenon.
Such polarity in bereavement experiences further complicates any attempts
to describe a “typical” bereavement scenario (Bonanno 2009).
The final phase of the stage model is often referred to as “identity
reconstruction” (Lopata 1996). During this period the bereaved person
gradually reinvests the psychic energy that had been completely focused on
the lost loved one into new relationships and activities. Lopata (1996)
estimated that identity reconstruction usually takes a year or more,
depending on what she refers to as the “centrality of roles” involved and the
complexity of new learning that must occur in developing a new sense of
self.
Although stage theories of adaptation have been widely accepted by
health care professionals, little empirical evidence exists to support these
theories. For example, although stage theories would predict an eventual
end stage at which grieving ceases, grief symptoms often do not abate in
elderly widows and widowers (Bierhals et al. 1995–1996). To expect that
grief will resolve or end is now considered erroneous by some theorists
(Stroebe et al. 2001a). Bereavement, as Rosenblatt (1996) contended, is a
dynamic process that may continue for a number of years and even for the
remainder of one’s life. Also, bereaved individuals do not proceed from one
clearly identifiable phase to another in an orderly fashion, a fact particularly
true of older adults. Maciejewski et al. (2007) provide one of the few
empirical attempts to test a stage theory: they examined Jacobs’s (1993)
stage theory, which posits that bereaved persons pass through stages of
disbelief, yearning, anger, depression, and acceptance. Results were mixed:
Across indicators, acceptance was the most frequent response given and
yearning the second most frequent response, at all time points across 2
years postloss. However, when the researchers examined the peak
frequency within each indicator, peaks occurred in the predicted order.
Disbelief was at its highest immediately after loss and declined over time;
yearning peaked at approximately 4 months postloss and then declined; all
other indicators peaked in the predicted order (Maciejewski et al. 2007).
Even though participants did not complete a stage before moving to a new
one, the stage model did provide potentially useful information regarding
the ebb and flow of a given characteristic of grief. Although the specific
process of moving through stages has not been supported, stage models
may provide a useful descriptive overview of many commonly recognized
facets of the bereavement process.
Another trend in bereavement theory has been to consider environmental
changes and role adaptation along with individual emotional and
psychological adjustments. Whereas earlier positions focused solely on
intrapsychic processes (e.g., Bowlby 1961), more recently theorists have
incorporated interpersonal and social processes into their models (e.g.,
Neimeyer 1998). Grieving is not only a process involving preoccupation
with the deceased individual, accepting the loss, trying to make sense of
what has happened, and so on; it also involves attempts to construct
meaning from the loss and reduce the chaos associated with such traumatic
events. As Stroebe and Schut (1999, 2010) address with their dual process
model, the bereaved oscillate between dealing with loss-oriented stressors
and restoration-oriented stressors. The former relate to the specific
components of the loss leading to emotional, behavioral, and cognitive
symptoms and how to deal with these; the latter pertain to how one must
interact constructively with social/environmental systems to maintain
adaptive functioning in social, vocational, and avocational activities. Grief-
related tasks usually have included confronting the loss, restructuring
thoughts and memories about the deceased individual, and emotionally
withdrawing from (but not forgetting) the deceased individual. Restoration
tasks include accepting the changed world, spending time away from
grieving, and developing new relationships and identities. In keeping with
T.S. Eliot’s contention that “humankind cannot bear very much reality,”
Stroebe and Schut (1999) argued that alternation or oscillation in dealing
with these two types of stressors is critical in the adjustment process.
Provided that they are not persistently implemented and are not the only
coping efforts employed, psychological mechanisms that allow the
individual to avoid or minimize the massive impact of the loss help the
bereaved adapt. Balance in dealing with the two types of stressors as a
result of oscillation thus precludes the preoccupation with one or the other
that may lead to prolonged and complicated bereavement. Limited
empirical support for this model is emerging, with individuals reporting
actively dealing with both loss-oriented stressors and restoration-oriented
stressors showing the best psychological outcomes (Bennett et al. 2010).

Course of Bereavement Symptoms and Clinical

Definitions
Several longitudinal studies had consistent findings regarding the course of
depressed mood, anxiety, well-being, and level of grief following a loss.
Grief is separable from depression and can include components of
nonacceptance of loss, emotional responses to the loss, and thoughts about
the loss (Futterman et al. 2010). Generally, significant differences between
bereaved and nonbereaved individuals are readily apparent during the first 6
months after the loss. However, at approximately 12 months postloss, levels
of reported distress by the bereaved are substantially reduced, and often the
difference between bereaved and nonbereaved control subjects may be
difficult to detect (Harlow et al. 1991; Thompson et al. 1991). Even though
considerable recovery has occurred and individuals are successfully
handling the tasks of daily living, many symptoms are still present (Harlow
et al. 1991; Thompson et al. 1984) and some sadness may persist (Bonanno
2009). As described by Zisook and DeVaul (1984), “In uncomplicated
bereavement, acute grief is gradually replaced by slow resolution” (p. 175).
Although a period of distress followed by gradual abatement may be the
most common course following a loss, it is not the only pattern. Several
prospective and retrospective studies have identified other common
patterns, including resilience, relief, and chronic grief. Individuals
identified as resilient demonstrate consistently low levels of depression or
negative affect across the postloss period. This pattern is perhaps
surprisingly common, with estimates of the percentage of bereaved
individuals following the resilient pattern ranging from 34% (Ott et al.
2007) to 46% (Bonanno et al. 2004). Resilient individuals did not differ
from common or chronic grief groups in either relationship quality or
interviewer ratings of interpersonal skill or warmth (Bonanno et al. 2004;
Ott et al. 2007), but they were more likely than the other groups to use
religious coping (Ott et al. 2007). Follow-up analyses demonstrated that the
resilient group reported the most comfort from positive memories of their
spouse and the least search for meaning in the death (Bonanno et al. 2004).
Identifying the characteristics of individuals following a resilient course is
an active area of current research (Coifman et al. 2007a, 2007b). Promising
in this regard is a Malaysian study of elderly widowed Muslim adults,
which discovered that personal religiosity (i.e., viewing religion as
important and engaging in private prayer) decreased the negative
psychological effects of losing a spouse (Momtaz et al. 2010).
Individuals who have witnessed a loved one’s steady decline, and in
many cases have functioned as caregivers for their dying loved one, often
manifest a relief pattern. Observing the illness transforms both the loved
partner and the relationship, and dealing with the preparatory grief
accompanying that transformation often leaves caregivers physically and
psychologically spent. Rather than being shaken by their loss, they may
discover a sense of freedom, both for the deceased person who has been
liberated from suffering and for themselves, as they have the opportunity to
recover the life they relinquished to attend to the needs of the significant
other (Bonanno 2009).
Chronic grief (also referred to as complicated bereavement, traumatic
grief, or prolonged grief disorder) occurs in 10%–15% of individuals
(Bonanno et al. 2002; Ott et al. 2007) and is characterized by unremitting
distress that lasts for an extended period following a loss. Differential
diagnostic criteria for normal and chronic grief, depression, and other stress
disorders remain controversial. For abnormal grief, Horowitz et al. (1997)
emphasized the importance of both intrusive symptoms and signs of
avoidance and failure to adapt. Intrusive symptoms include unbidden
memories, strong spells of severe emotion related to the lost relationship,
and distressingly strong yearnings for the deceased. Signs of avoidance and
poor adjustment are characterized by feelings of emptiness or of being very
much alone; avoidance of people, places, or activities that remind one of the
deceased individual; unusual levels of sleep disturbance; and loss of interest
and decreased engagement in social, occupational, or recreational activities.
Evidence of these signs and symptoms must be present for 14 months after
the loss. Prigerson et al. (1999) have described a similar bereavement
pattern, which they call “traumatic grief.” The primary symptoms include
yearning and searching for the deceased individual, loneliness, and intrusive
thoughts about the deceased individual. These are accompanied by
traumatic distress that includes purposelessness; numbness or detachment;
disbelief; feelings of meaninglessness; loss of a sense of trust, security, or
control; and excessive irritability, bitterness, or anger related to the death.
Prigerson et al. (1999) do not include symptoms of avoidance and require
that the symptoms be present only for a period of 2 months.
Diverse cultural norms further complicate the distinction between
adaptive and abnormal grieving practices. Although the Western
consciousness typically encourages bereaved individuals to move through
the grieving process in a timely manner by disengaging with the deceased
and returning to the business of living, more studies are demonstrating the
potentially positive effects of maintaining a meaningful connection with the
lost loved one. A qualitative analysis of “sense of presence experiences”
among 12 bereaved individuals revealed that continued bonds facilitated
meaning making during the grieving process (Steffen and Coyle 2011).
Chinese bereavement rituals both underscore this point and also provide a
distinctive perspective. In contrast to the Western focus on the emotional
experience of the grieving person, the Chinese focus on the behavior of the
bereaved and the importance of demonstrating proper respect and love for
the deceased by carrying out mourning rituals in an appropriate manner.
Conducting funeral observances correctly is viewed as a way of helping the
deceased complete the transition, both moving successfully into the land of
the dead and establishing a good afterlife. Sending clear messages of love
and support through meaningful rituals is a manifestation of the Chinese
belief in the importance of an ongoing connection with the deceased
(Bonanno 2009). Rather than dichotomously categorizing ongoing
attachment to a deceased loved one as optimal or maladaptive, current
research indicates a more complex picture in which variables such as
quality of the relationship with the deceased partner, personal religious
beliefs, and the cultural context surrounding the bereaved contribute to the
meaning of such a connection and its potential for good or harm (Bonanno
2009).
Although no consensus is yet apparent, the groundwork is being laid for
specific criteria to distinguish abnormal (i.e., complicated or traumatic)
from normal grief reactions. Continued research is needed to help refine
and solidify what cognitive, affective, and behavioral features characterize
these two forms. As data are accumulated, theories and therapies will
continue to be modified. For example, as noted earlier in this section, it is
becoming increasingly apparent that continued attachment often can be
comforting (Stroebe et al. 2010; Wortman and Silver 1987). Variations in
grief practices across cultures have also emphasized the impact that cultural
traditions and beliefs can have on bereavement practices and have widened
the scope of what can be defined as “normal” grief reactions. Thus, one
might wonder if it is necessary to minimize one’s attachment to a deceased
individual in order to resolve one’s grief, or if grief resolution itself should
be the goal. Other issues include what constitutes a reasonable time period
for a “normal” grief reaction and what constitute the indisputable signs of
abnormal bereavement patterns predictive of poor adjustment. Until such
time as these issues are resolved, clinicians are encouraged to exercise
sensitivity when eliciting the meaning the bereaved ascribes to events,
recognize the cultural norms relevant to the person’s experience, and use
currently available guidelines, as noted in this chapter, to help evaluate and
assist the individual patient.

DSM Definitions
The recently revised DSM-5 (American Psychiatric Association 2013)
provides a clear distinction between the feelings of loss and emptiness that
typically characterize bereavement and the persistent, depressed mood and
global inability to experience pleasure indicative of a major depressive
episode. The manual notes that the sadness accompanying grief tends to
come in waves, and when it abates, feelings of joy and the ability for humor
often manifest; in contrast, the “down” state of major depressive episode
offers no respite. According to DSM-IV (American Psychiatric Association
1994), bereavement within the first 2 months following a loss was a specific
rule-out for a major depressive episode (unless the episode was
characterized by “marked functional impairment, morbid preoccupation
with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor
retardation” [p. 355]). In contrast, DSM-5 acknowledges the potential
comorbidity of these conditions by eliminating this “bereavement
exclusion” and noting that bereaved individuals who meet the criteria for
major depressive episode will not be denied this diagnosis because of their
bereaved status (Pies 2013).

Adaptation to Late-Life Bereavement: Risk

Factors for Intensification of Grief
Grief has been characterized by many not only as a highly charged
emotional state but also as a significant risk factor for a wide range of
negative outcomes, including mortality and major physical and mental
health disturbances. In contrast, some clinicians and researchers have been
struck by the ability of many older adults to survive and cope quite well
overall with the profound losses of old age. In their 10-year follow-up study
of a national sample of bereaved men and women, McCrae and Costa
(1993) found that the great majority of individuals showed considerable
ability to adapt to this major life stress (although length of recovery seemed
to vary considerably), and this finding was echoed in the resilience
demonstrated by the majority of grieving individuals (Bonanno 2009).
Nevertheless, an attempt to identify elders at risk for negative outcomes
after spousal loss is an important mental health objective (for a thorough
review, see Sanders 1993 and Stroebe et al. 2001a). Variables often
associated with prolonged or complicated bereavement include 1) age and
gender of the survivor, 2) mode of death, 3) presence of significant
depression shortly after the death, 4) ability to accept the loss, 5)prior
relationship satisfaction, and 6) social support. Strength of religious
commitment and involvement, participation in culturally appropriate
mourning rituals, and redistribution of roles within the family after the
death may also affect the grief process to some degree.
Gender differences in bereavement are complex. Stroebe et al. (2001b)
concluded that “widowers are indeed at relatively higher risk [of death] than
widows, and, given that death is the most extreme consequence of
bereavement, much weight may be attached to this finding” (p. 69).
Bowling (1988–1989) followed up with 500 elderly widows and widowers
for 6 years after their loss and found that men age 75 years or older had
excessive mortality compared with men of the same age in the general
population. Gallagher-Thompson et al. (1993) found that widowers who
died within the first year of spousal bereavement had reported more often
than survivors that their wives were their main confidants and that they had
minimal involvement in activities with other persons after their wives’
deaths. The differential psychological impact of bereavement on men and
women also appears unbalanced. Several studies have found that
bereavement has a greater impact on depression scores in men than in
women (van Grootheest et al. 1999; Williams 2003), but it may be that the
elevated depression scores for men indicate that men begin to experience
greater depression before the loss of their wives and then this level of
comorbid depression is maintained in bereavement (Lee and DeMaris
2007). Women have been found to have less life satisfaction than men
following the loss of a spouse (Lichtenstein et al. 1996; Williams 2003), but
they may also experience more personal growth after the loss (Carr 2004).
Referring to their “dual process” model, Stroebe et al. (2001b) hypothesized
that women are more focused on psychological aspects of coping with the
loss, whereas men are more focused on restoring their life pattern without
the loved one. However, societal and structural demands may prompt
flexible coping in women who have followed more traditional gender roles
(e.g., in addition to loss-focused coping, women must adjust to new
financial and domestic circumstances), whereas less pressure exists for men
to engage with their nonpreferred coping focus. Further research is needed
to determine whether less flexibility in coping focus mediates the
relationship between gender and psychological outcomes.
Violent, stigmatized (as in the case of AIDS), or unexpected deaths
generally are associated with poorer adaptation (Farberow et al. 1987;
Osterweis et al. 1984; Parkes and Weiss 1983; van der Houwen et al. 2010;
Worden 2002), although comparisons of the impact of long-term illness
versus that of unexpected loss have been inconsistent (Burton et al. 2006;
Kitson 2000).
Clinically significant depression within the first 2 months postloss is a
significant risk factor for poor outcome over time. Lund et al. (1993) found
that intense negative emotions at 2 months postloss—such as a desire to die
and frequent crying—were associated with poor coping 2 years later.
Wortman and Silver (1989) reviewed a number of studies indicating that
depression confounds successful resolution of grief. Both preloss
depression and depression early in bereavement may play a significant role
in adjustment. In a prospective longitudinal study of the course of
bereavement outcomes, it appears that a higher proportion of individuals
with preloss depression remained depressed at 18 months postloss (43%)
than of those without preloss depression (21%; Bonanno et al. 2002). In
work investigating the relationship between depression and later
bereavement outcome, Gilewski et al. (1991) found that individuals with
self-reported depression in the moderate to severe range were at greatest
risk for all other psychopathological symptoms, such as increased anxiety,
hostility, and interpersonal sensitivity. This result occurred whether their
spouses had committed suicide or died of natural causes. However, subjects
whose spouses had committed suicide and who were moderately to severely
depressed at the outset had the highest mean score of any subgroup on the
depression measure that was used. Individuals in this group also maintained
higher mean levels of depression over time and were more likely to score
high on other distress measures. These data suggest that, again, the
interaction of one or more risk factors may contribute to the greatest
distress.
One important psychological factor in predicting poor clinical outcomes
is the ability of the bereaved spouse to accept his or her loss. Feelings of
acceptance following a loss can vary widely, from a sense that “it was time”
or of relief at the resolution of the deceased partner’s pain and suffering, to
a profound sense of unfairness and lack of resolution at the loss. Analyses
of the Texas Revised Inventory of Grief—Present (TRIG-Present; Zisook et
al. 1982), a well-supported and validated measure of grief symptoms,
identified nonacceptance as a key dimension of grief symptoms that
remains stable over time (Futterman et al. 2010). Importantly, heightened
nonacceptance, but not the other TRIG-Present factors of grief-related
thoughts or emotional response, predicted more intense grief 12 months
postloss (Holland et al. 2013). By including “marked difficulty accepting
the death” in the criteria for persistent complex bereavement disorder,
DSM-5 highlights its importance in the clinical picture of bereavement.
The association between preloss relationship characteristics and clinical
symptoms of bereavement is complex (Itzhar-Nabarro and Smoski 2012).
More positive ratings of relationship satisfaction were associated with more
severe depression initially, but this correspondence was lower at 30 months
postloss. Bonanno et al. (2002) found that a poor relationship quality rating
preloss was most strongly associated with a pattern either of preloss
depression followed by an improvement in symptoms postloss, or of
chronic depression beginning preloss and continuing throughout
bereavement. Follow-up analyses did find increased idealization of the
relationship in bereaved individuals, but the degree of idealization did not
differ based on level of adjustment (Bonanno et al. 2004). Relationship
dependency was associated with risk of chronic grief (Ott et al. 2007).
These studies indicate that relationship variables may interact with several
other variables, including general psychological health and a change in
perspective on the relationship over the course of the bereavement process.
The role of social support is less ambiguous overall. Since the
publication of Cobb’s (1976) seminal paper on its stress-buffering effects,
social support has been widely recognized as a moderator of many kinds of
life stress. Across bereavement types (spousal, parental, etc.) and ages,
social support is predictive of positive mood as well as the nature of grief
and depressive symptoms (van der Houwen et al. 2010). In a
comprehensive review of the role of social support in mitigating the effects
of late-life spousal bereavement, Dimond et al. (1987) found in their
longitudinal study that the total size of the reported support network at
baseline was positively correlated with perceived coping skills and life
satisfaction at later times of measurement. They also found that the quality
of the network was inversely related to later depression and was positively
correlated with later measures of life satisfaction. Finally, through a series
of multiple regression analyses, they found that several baseline social
network factors made independent contributions to the variance accounted
for in predicting depression at later times of measurement. This finding
suggests that social support mitigates severe negative reactions to the loss
of a spouse in older individuals.
On the basis of these data, it is apparent that several risk factors are
associated with a more difficult subsequent grief process in elderly
individuals. It is noteworthy, however, that the available research was
conducted using volunteer subjects who typically enjoyed higher
educational and socioeconomic levels than the average members of the
general population. Furthermore, the response rate in survey studies of
bereavement tends to be low (around 30%–40%), which clearly limits the
ability to generalize findings. Greater efforts should be made to engage
elderly persons who are economically disadvantaged, who are in poor
health, and who have low social support systems and low community
involvement. In addition, more studies are needed not only on the
interactive effect of several of these risk factors (particularly because they
may change over time in relative salience to the individual) but also on
whether intensity or the same risk factors apply to bereavement due to other
causes, such as divorce and death of a parent or an adult child. Clearly,
more research also is needed on risk factors among ethnically and culturally
diverse elders.

Interventions for Late-Life Bereavement

Clinical comments throughout the bereavement literature indicate that
treatment can be immensely helpful to some individuals. The extent to
which a treatment might be effective depends in large measure on the
intensity and pattern of symptoms present. In some situations it appears that
intervention beyond the usual family and community support is not called
for and may even be counterproductive. In other cases, however,
medication, psychotherapy, or a combination of both is indicated. Decisions
regarding treatment strategy are facilitated by knowing whether the
symptom pattern is consistent with what would be termed a “normal grief
reaction” for the particular cultural group with which the person is
identified, or whether the severity, type of symptoms present, and/or risk
factor profile appear to suggest a complicated course. In particular, it is
important to determine whether the symptom picture is consistent with the
diagnostic criteria for some other psychiatric disorder, such as depression or
posttraumatic stress disorder. This distinction is critical for making
appropriate intervention choices (Raphael et al. 2001). DSM-5 differentiates
persistent complex bereavement disorder (included in Section III as a
condition for further study) from the normal bereavement process. It is
important to distinguish between the two, because different interventions
are indicated.

Treatment of Complicated Bereavement (Persistent Complex

Bereavement Disorder)
A thorough assessment for any comorbid psychological condition should be
conducted before beginning treatment for bereavement. This is especially
important for conditions whose symptoms are similar to those of
bereavement, such as depression. Clinical levels of depression should be
treated with medication and/or psychotherapy before the focus of treatment
can effectively shift to bereavement (National Institutes of Health
Consensus Conference 1992; Parkes and Weiss 1983; Raphael et al. 2001;
Reynolds 1992). Addressing the issue of when to begin treatment of
depression after a loss, Reynolds (1992) stated, “Our clinical practice has
been to intervene as early as 2 months, and certainly by 4 months, in the
presence of clear syndromal major depression” (p. 50). Remission of
depression will enable the focus of treatment to return to the bereavement.
Careful attention to the grief process can often then determine whether
additional interventions are required. In particular, risk factors may become
an important focus for remediation. For example, considerable evidence
indicates that older widowers may not thrive if they do not have a
constructive support system. Isolation is a documented risk factor, and men
undergoing stress may not have the requisite skills to build or implement a
nourishing social network. It may become necessary to provide specific
assistance with this problem. Once accomplished, other interventions may
not be necessary.
 Other common complications that are particularly significant in older
bereaved persons (Rozenzweig et al. 1997) and that require treatment
include posttraumatic stress disorder, anxiety disorders (that may or may
not be related to the bereavement), and subsyndromal depression (Reynolds
et al. 1999). However, few empirical studies have focused on the efficacy of
specific psychotropic treatment programs during bereavement for these
conditions. Open-label trials of bupropion (Zisook et al. 2001), nortriptyline
(Pasternak et al. 1991), antidepressant treatment with either nortriptyline or
sertraline (Oakley et al. 2002), and paroxetine (Zygmont et al. 1998) for
bereavement-related major depression in older adults have shown promise.
A review of pharmacotherapy for complicated grief concluded that tricyclic
antidepressants (TCAs) appear to address only depressive symptoms,
whereas selective serotonin reuptake inhibitors (SSRIs) may have efficacy
for both depressive and grief symptoms (Bui et al. 2012). A combination of
medication and psychotherapy appears to be more effective than either
alone when attempting to reduce psychiatric symptoms that occur with
bereavement (Miller et al. 1997; Reynolds et al. 1999; Simon et al. 2008).
Some older individuals either cannot or will not use psychotropic
medications. Although data have suggested that “counseling” of various
kinds may not be particularly helpful for individuals undergoing a normal
grief reaction (see the following section), there is evidence that various
psychological treatments can have a positive effect in treating complicated
bereavement (Currier et al. 2008; Neimeyer 2000; Shear et al. 2005).
A growing number of psychological interventions have been developed
specifically to target symptoms of complicated grief. A meta-analysis found
a medium effect size favoring these targeted interventions, especially
interventions grounded in cognitive-behavioral therapy, as more effective
than other supportive therapies, interpersonal therapy, or waitlist control
conditions (Wittouck et al. 2011). Cognitive and cognitive-behavioral
therapies of various forms are effective in treating patients with complex
bereavement reactions (Currier et al. 2010). One such strategy focuses on
core constructs known to be disrupted during intense grief (Viney 1990). As
these disrupted constructs are identified through self-monitoring and
Socratic questioning during treatment sessions, the client learns methods of
reconstructing shattered beliefs about the self, the present surroundings, and
future events. A blend of cognitive and behavioral techniques (such as
challenging dysfunctional thoughts and teaching specific behavioral skills
for use in resolving interpersonal problems) has been applied successfully
with individual patients (for an example, see Florsheim and Gallagher-
Thompson 1990).
One treatment for complicated grief, known as complicated grief
therapy, integrates attachment theory via interpersonal therapy with
cognitive-behavioral therapy (Shear et al. 2005; Wetherell 2012). The
treatment for complicated grief includes a series of cognitive-behavioral
techniques such as imaginal exposure to the death scene; in vivo, graded
exposure to avoided death-related circumstances; mindful breathing;
positive and negative memories of the loved one; and writing goodbye
letters to the deceased person. Also integral to the treatment are homework
assignments involving listening to tapes of imaginal exposure. Following
the dual process model (discussed in earlier section “Theories About
Adjustment to Permanent Losses”), the treatment also involved
motivational enhancement and goal setting to facilitate restorative goals.
The results of this treatment were encouraging: complicated grief, anxiety,
and depressive symptoms were significantly reduced. In a randomized
controlled trial, individuals undergoing complicated grief treatment showed
a greater response than those undergoing interpersonal psychotherapy
(Shear et al. 2005).
One of the more common psychodynamic therapies used with
complicated bereavement is Horowitz’s (1976) time-limited psychodynamic
therapy. This 12-session phase-oriented strategy is designed to help
individuals work through emotional reactions to traumatic life events.
Careful attention is also paid to tailoring treatment to the patient’s particular
personality type. Abreaction, clarification, and interpretation of defenses
and affects are used to facilitate realistic appraisals of the implications of a
death and to explore the effect of the loss of a relationship on the bereaved
person’s self-concept. Empirical data demonstrating the effectiveness of this
treatment are available (Horowitz et al. 1981, 1984).
To assist practitioners in assessing the efficacy of their bereavement
treatment, Wilson (2011) developed the Assimilation of Problematic
Experiences Sequence model, which describes the psychosocial changes
exhibited by clients as they deal with a challenging experience such as
grief. The complete assimilation sequence includes eight developmental
levels, from 0 to 7, and describes an individual’s progression from being
warded off/dissociated from the experience, to developing a vague
awareness of the painful situation, to gaining understanding/insight, and
eventually moving to problem solution and ultimately to
integration/mastery.
Finally, several interventions have targeted caregivers in an attempt both
to reduce distress during caregiving and to prevent complications during
bereavement. A support intervention targeting Alzheimer’s caregivers
reduced depressive symptoms both preloss and postloss compared with
caregivers in the no-treatment control condition (Haley et al. 2008).
Another intervention for Alzheimer’s caregivers was found to reduce grief
symptoms, although its impact on depression symptoms was less clear
(Holland et al. 2009). Given that preloss psychopathology, including
depression, is a predictor of chronic grief, interventions for at-risk
populations such as caregivers have promise in altering the course of
symptoms postloss.

Treatment of Normal Grief Reactions

There is a long history of formal and informal interventions for normal grief
reactions, including self-help groups and individual and group counseling.
Most bereaved persons (particularly elders) do not seek professional
assistance for their grief. Self-help support groups for bereaved persons are
often used by those who find the experience too painful and the loneliness
overwhelming. Despite conceptual and anecdotal support for the
effectiveness of these programs, relatively little empirical support has been
found. Several reviews have examined the literature on counseling for
normal grief reactions and have concluded that, by and large, these
interventions neither reduce grief or depressive symptoms above and
beyond the effects of time nor facilitate better adjustment postintervention
(Currier et al. 2008; Jordan and Neimeyer 2003; Schut et al. 2001). In fact,
individuals experiencing uncomplicated bereavement may experience an
iatrogenic effect of treatment, appearing worse off at the end of the
treatment than if they had not participated (García et al. 2013; Neimeyer
2000). Bonanno’s research on the inherent resilience of an individual to
cope with, adjust to, and assimilate the loss of a loved one further
substantiates these findings (Bonanno 2009). World Health Organization
(WHO) guidelines now specifically recommend against the routine use of
structured psychological interventions in uncomplicated bereavement (Tol
et al. 2013).
Using medication to treat uncomplicated grief (other than for specific
symptoms such as insomnia) has also been questioned. Many clinicians feel
that medication, if used at all, should be minimal and brief. For example,
Raphael et al. (2001) argued that if depression is not evident, then
antidepressants should not be prescribed to reduce symptoms of grief. There
are concerns that medication may impede recovery by masking the full
experience of bereavement (Parkes 1972; Worden 2002) and that
prescribing medication pathologizes a natural human process. Other
clinicians believe that the provider should intervene sooner rather than later,
given the tendency of depressive symptoms to persist throughout the first
year of spousal bereavement (Reynolds 1992). Given that there is limited
empirical evidence indicating that one must go through a difficult grieving
process in order to resume one’s life effectively (Bonanno et al. 2002), it
has been argued (Wortman and Silver 1987) that pharmacological (and
other) treatments for pain and suffering should be available to those who
request them. The empirical literature is equivocal with regard to
effectiveness of medication use in uncomplicated grief. There is some
indication that antidepressants, including TCAs and SSRIs, are effective for
reducing symptoms that are also present in depression. A small randomized
controlled trial comparing benzodiazepine use to placebo noted no
significant differences between groups in bereavement symptoms, although
there was a trend for negative impact of benzodiazepine use on sleep
initiation and bad dreams (Warner et al. 2001). Also, recently released
WHO guidelines in management of stress and trauma-related disorders
specifically recommend against the use of benzodiazepines in the
management of bereavement (Tol et al. 2013). Psychotropic medication use
following bereavement is common; a study in the United Kingdom noted
that almost one in five individuals ages 60 years and older received a new
prescription for a psychotropic drug (most commonly an anxiolytic,
hypnotic, or antidepressant) in the year following bereavement (Shah et al.
2013). Further research is necessary to determine the optimum level of
pharmacological intervention (including none) both to ease suffering and to
allow the natural process of bereavement to take its course.
 Key Points
• Bereavement can refer to a person’s reactions to any set of significant
losses but typically refers to the loss of a loved one such as a spouse.
• Among persons ages 65 years and older, 40% of women and 13% of
men have experienced the loss of a spouse.
• The dual process model of bereavement focuses on the interplay of loss-
oriented stressors related to losing the presence of the loved one in a
person’s life (e.g., loneliness, loss of support) and restoration-oriented
stressors related to building a new life without the presence of the loved
one (e.g., taking on roles previously performed by the spouse, changing
one’s identity from one of wife to widow). Bereaved persons’ oscillation
of their focus between these two stressors is thought to promote healthy
adjustment.
• Culture can play a key role in the expected course of grief, and clinicians
should take culture into consideration when assessing or designing
interventions for complicated grief.
• Although many individuals demonstrate resilience to or recovery from
depressive symptoms within 18 months after the loss of a spouse,
symptoms of grief such as missing the deceased person and engaging in
fond remembrances of the lost loved one may continue indefinitely, even
in individuals who show minimal depressive symptoms.
• Postloss adjustment among bereaved individuals can vary widely.
Several risk factors are predictive of poor adjustment. These include
male gender; loss through a violent, stigmatized, or unexpected death;
the presence of significant depressive symptoms early in the loss; poor
coping skills and low self-esteem; and poor breadth and quality of social
support.
• Bereavement reactions can be categorized as normal or complicated.
Most people experience “normal” grief, which can include the
experience of sadness, loneliness, or longing for the deceased;
experiencing the “presence” of the deceased; and/or disruptions in sleep
and appetite. Although there is no single standard set of criteria for a
diagnosis of complicated grief, typical definitions include the following
 concerns: marked distress, prolonged duration of symptoms, and
avoidance of or failure to adapt to new life roles.
• Several empirically validated treatments are available for complicated
bereavement. In addition to standard cognitive-behavioral therapy,
complicated grief therapy is a promising intervention based on principles
used in the treatment of posttraumatic stress disorder.
• Normal bereavement typically resolves without the need for treatment
beyond targeted interventions for specific symptoms (e.g., disturbed
sleep). In fact, some common interventions for normal bereavement have
been found to lead to a worsening of symptoms and are not
recommended.

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 CHAPTER 16

Sleep and Circadian Rhythm Disorders

Andrew D. Krystal, M.D., M.S.
Mugdha E. Thakur, M.D.

The authors would like to thank Jack D. Edinger, Ph.D., and William K. Wohlgemuth, Ph.D., who
were coauthors on the previous edition of this chapter.

Sleep disorders are an important aspect of geriatric psychiatry. In the

United States, more than half of noninstitutionalized individuals older than
65 years report chronic sleep difficulties (Foley et al. 1995; National
Institutes of Health Consensus Development Conference Statement 1991;
Prinz et al. 1990). Sleep disturbances affect quality of life, increase the risk
of accidents and falls, and, perhaps most important, are among the leading
reasons for long-term-care placement (Pollak and Perlick 1991; Pollak et al.
1990; Sanford 1975). Working effectively with elderly individuals requires
expertise in the diagnosis and treatment of sleep disorders.
DSM-5 (American Psychiatric Association 2013) broadly includes 10
sleep-wake disorders: insomnia disorder, hypersomnolence disorder,
narcolepsy, breathing-related sleep disorders, circadian rhythm sleep-wake
disorders, non–rapid eye movement sleep arousal disorders, nightmare
disorder, rapid eye movement (REM) sleep behavior disorder, restless legs
syndrome (RLS), and substance/medication-induced sleep disorder. Patients
with these disorders may present with complaints of inadequate or
excessive sleep, or dissatisfaction with the timing or quality of sleep.
The majority of age-related sleep complaints appear to stem from an
increased incidence of disorders such as sleep apnea, periodic limb
movement disorder (PLMD), and medical and psychiatric disorders that
lead to secondary sleep-related symptoms (Bliwise 1993; Foley et al. 1995;
Gislason and Almqvist 1987; Prinz 1995; Prinz et al. 1990). However,
evidence shows that changes in sleep and the circadian rhythm occur even
in healthy elderly individuals without such disorders (Bliwise 1993; Foley
et al. 1995; Gislason and Almqvist 1987; Prinz 1995; Prinz et al. 1990).
Given that these changes are not necessarily associated with complaints of
sleep disturbance or diminished daytime function, sleep and circadian
rhythm disturbances may not be an inevitable consequence of aging. These
factors provide some challenges for clinical care. One of these challenges is
the need to use a different threshold for normality in elderly patients. Sleep
attributes that are considered abnormal in a younger individual may not be
associated with symptoms in an elderly person. Furthermore, clinical care
of the elderly population requires a heightened awareness of and expertise
in identifying underlying medical and psychiatric disorders.
Although these challenges can be formidable, they are not
insurmountable. In this chapter, we first review the changes in sleep and
circadian rhythm that occur in individuals without medical and psychiatric
disorders. We then review the disorders that can cause disturbances of sleep
and chronobiology and whose likelihood increases with age. Finally, we
discuss evaluation and treatment of elderly individuals with a sleep
complaint or suspected sleep-related dysfunction.

Influence of Aging on Sleep and Circadian

Functions
Since the 1970s, extensive research has shown that marked changes in sleep
and circadian rhythm accompany aging. Perhaps the most striking change in
sleep patterns in older adults is the frequent interruption of sleep by periods
of wakefulness (Ohayon et al. 2004). Older adults also have decreased total
sleep time, reduced sleep efficiency (time asleep as a percentage of time in
bed), decreased slow-wave and REM sleep, and increased stage 1 and 2
sleep. After researchers control for medical and psychiatric comorbidities, it
appears that the majority of these changes occur in early and middle
adulthood and that sleep in healthy individuals changes only modestly after
age 60 (Ohayon et al. 2004). As shown in Figure 16–1, nocturnal sleep time
steadily decreases across the life span, and nocturnal wake time increases
because of an increase in arousals.
The sleep-wake cycle appears to change significantly with age as well.
The amplitudes of both the sleep-wake cycle and the 24-hour body
temperature rhythm appear to decrease with aging (Bliwise 2000; Czeisler
et al. 1999). Aging is also associated with a tendency to fall asleep and
awaken earlier (Monk 2005). Additionally, compared with younger people,
older adults are more likely to be sleepy and nap during the day (Buysse et
al. 1992; Martin and Ancoli-Israel 2006). Multiple psychosocial changes
that accompany aging may alter or eliminate important zeitgebers (“time
markers”) for the circadian system and promote the onset of sleep
difficulties among older adults.

Disorders Associated With Sleep and Circadian

Rhythm Disturbances
A number of medical and psychiatric conditions are associated with sleep
difficulties, and these conditions occur more frequently with increasing age.
The long-standing view was that such medical and psychiatric conditions
caused disorders of sleep and circadian rhythm, which were best viewed as
symptoms (National Institutes of Health Consensus Conference 1984). This
point of view discouraged targeting treatment specifically to address the
associated sleep disorders. More recent data, however, suggest that in a
number of situations (the best examples are insomnia occurring with major
depressive disorder, generalized anxiety disorder, and chronic pain), the
relationship is more complex than previously believed, and in some cases
the causality appears to be bidirectional (Krystal 2006; National Institutes
of Health 2005). The emerging view is that sleep disorders occurring with
medical and psychiatric disorders have been undertreated, and the term
comorbid has been proposed to replace secondary as a means of describing
sleep disorders that occur with medical and psychiatric conditions (National
Institutes of Health 2005).
FIGURE 16–1. Sleep-stage distributions across age groups.
Note. REM=rapid eye movement.

Primary Sleep Disorders

Breathing-Related Sleep Disorders

Of the DSM-5 breathing-related sleep disorders, sleep apnea is the most
relevant to the practice of geriatric psychiatry. In patients with sleep apnea,
breathing ceases for periods of 10 seconds or more (Aldrich 2000), either
because no effort is made to breathe (central sleep apnea) or because the
oropharynx collapses during attempts to breathe (obstructive sleep apnea).
The predominant type of sleep apnea seen in elderly persons is obstructive
sleep apnea (Ancoli-Israel et al. 1987). A number of studies suggest that the
frequency of obstructive sleep apnea increases with age (Ancoli-Israel
1989; Ancoli-Israel et al. 1991; Dickel and Mosko 1990; Roehrs et al.
1983). Both apneas (complete cessation of respiration) and hypopneas
(partial decrease in respiration) result in hypoxemia and changes in
autonomic nervous system activity, leading to increases in systemic and
pulmonary arterial pressure and changes in cerebral blood flow. The
episodes are generally terminated by an arousal (brief awakening), which
results in fragmentation of sleep. These arousals are believed to be an
important contributor to the symptoms of excessive daytime sleepiness and
the cognitive difficulties seen in sleep apnea. Even though apnea generally
causes excessive sleepiness, mild to moderate apnea can be associated with
insomnia. Referral to a sleep disorders specialist is required for diagnosis
and treatment. The treatment of choice for obstructive sleep apnea is
continuous positive airway pressure (CPAP). This treatment involves
blowing air through the nose at night to increase pressure within the upper
airway, thereby preventing the collapse that leads to apnea. Some
individuals (particularly those with anatomical anomalies predisposing
them to apnea) are treated with upper airway surgery. Central sleep apnea is
relatively rare, a 4%–10% of patients with apnea (White 2000). This
disorder can be caused by a number of different pathophysiologies,
including any cause of waking alveolar hypoventilation, congestive heart
failure, neurological disorders, and nasal and upper airway obstruction.
Therapy should be targeted to the particular underlying process, although in
many cases no such problem can be identified, and CPAP is usually the first
treatment attempted (White 2000).

Periodic Limb Movement Disorder and Restless Legs

Syndrome
In PLMD, repetitive muscular contractions occur during sleep; these
contractions most commonly involve the legs and often cause sleep
disturbances. When these events occur infrequently, they are not considered
pathological because they tend not to be associated with any symptoms
(Roehrs et al. 1983). The frequency of these events is characterized in terms
of the number of movements associated with arousal that occur per hour of
sleep (the movement-arousal index). There is some debate about what
movement-arousal index is abnormal. Thresholds ranging from 5 to 15
movements per hour have been suggested (Ancoli-Israel et al. 1991; Dickel
and Mosko 1990). Some authors have suggested that a higher threshold for
abnormality should be applied to elderly individuals, who tend to be
symptom free at movement-arousal indices typically associated with
significant symptoms in younger individuals (Ancoli-Israel 1989). Perhaps
even more relevant for those working with older patients is that PLMD, like
sleep apnea, is more prevalent among elderly people (Roehrs et al. 1983).
Several studies indicate that clinically significant PLMD is seen in 30%–
45% of adults age 60 years or older, compared with 5%–6% of all adults
(Ancoli-Israel et al. 1991).
Individuals with PLMD may complain of leg kicks (most commonly
noticed by the bed partner), cold feet, excessive daytime sleepiness, and
insomnia (Ancoli-Israel 1989; Ancoli-Israel et al. 1991; Roehrs et al. 1983).
The insomnia may be characterized by difficulty falling asleep or staying
asleep (Ancoli-Israel 1989). Unfortunately, the presence of this disease is
difficult to predict reliably on the basis of the patient’s history (Ancoli-
Israel 1989; Dickel and Mosko 1990). Furthermore, a high level of
confidence in the diagnosis is needed before institution of treatment,
because treatment typically involves long-term use of medications that can
have significant side effects. Therefore, when a history is suggestive of
PLMD, standard practice is to make a referral for a polysomnogram for
definitive diagnosis (Ancoli-Israel 1989). Polysomnography is also
indicated when an individual has significant insomnia or hypersomnia that
does not respond to usual treatment. Such a patient may have significant
PLMD that was undetected when the patient’s history was obtained.
RLS is often associated with PLMD and is described as an
uncomfortable feeling in the lower extremities that creates an irresistible
urge to move. RLS has a circadian pattern with worsening of symptoms in
the evenings. Symptoms are also worse when the individual is at rest rather
than active. In fact, patients experience improvement in symptoms with
movement such as walking, rubbing, or stretching their legs. RLS occurs in
6% of the adult population and is present in up to 28% of patients older than
65 years (Clark 2001). Polysomnography is not needed for a diagnosis of
RLS, which is made through history taking.
When compared in the general population, RLS is almost twice as
prevalent in elderly women as in elderly men. RLS, as well as PLMD, has
been associated with anemia (O’Keeffe et al. 1994). In elderly patients,
ferritin levels lower than 45 µg/L have a positive correlation with an
increased risk of RLS, and such patients often benefit from administration
of supplemental iron (O’Keeffe et al. 1994). Also associated with PLMD
and RLS are diabetes mellitus, pregnancy (not relevant to the geriatric
population), iron deficiency anemia, and use of certain medications,
including antidepressants and antipsychotics (Bliwise et al. 1985). Workup
to exclude these conditions is typically carried out before initiating
medication treatment.
The same medications are effective for both RLS and PLMD. The
primary treatment for these conditions is dopaminergic agonists such as
ropinerole and pramipexole (Bliwise et al. 2005; Montplaisir et al. 1999).
Second-line treatment options include anticonvulsants (gabapentin) and
benzodiazepines (clonazepam). Opiates are typically reserved for patients
who do not respond to these other drugs. Because of the high prevalence of
PLMD and RLS in the elderly population, the geriatric psychiatrist should
be acquainted with the symptoms of these disorders. Effective treatment
often significantly improves the quality of life of affected individuals.

Neuropsychiatric Disorders

Bereavement-Related Depression
Psychological factors that most commonly affect sleep in elderly persons
are reactions to loss, such as loss of health or functional capacity, and
reactions to the death of a friend or loved one. Although grief is a normal
reaction to bereavement, it is often associated with substantial sleep
disturbance (American Psychiatric Association 2013). When bereavement-
related grief is associated with more frequent intrusive thoughts and
avoidance behaviors, there appears to be more sleep disturbance,
predominantly in the form of difficulty in falling asleep (Hall et al. 1997).
Bereavement and depression are closely linked, however. If symptoms are
severe or persistent, depression may be diagnosed in a bereaved person
after taking into consideration his or her psychiatric history and the cultural
norms for what may be normal grieving (American Psychiatric Association
2013). Antidepressant medication may be helpful. A short course of
sedative-hypnotic therapy may provide substantial symptomatic relief. If
this approach is taken, the medication should be tapered off when the other
symptoms of bereavement-related grief diminish. Because the clinician will
not know at the outset how long treatment will be needed, considerations
related to longer-term treatment pertain (see “Pharmacological Treatment”
later in this chapter). Although unlikely, it is possible for rebound insomnia
to occur after a relatively short course (3–4 weeks) of treatment. For this
reason, clinicians should warn patients of this possibility and wait at least
several days after discontinuing the medication to determine whether there
is persistent insomnia. If all symptoms of bereavement depression have
resolved except insomnia, cognitive-behavioral therapy for insomnia (CBT-
I) should be considered (see “Cognitive-Behavioral Treatment” later in this
chapter). Grief counseling should also be considered.

Major Depressive Disorder

Depression is frequently associated with sleep disruption in individuals
older than 60 years. Roughly 10%–15% of individuals older than age 65
experience clinically significant depressive symptoms (Hoch et al. 1989).
The most frequent complaints in affected individuals are experiencing a
decrease in total sleep time and waking earlier than desired. Daytime
sleepiness may also occur but is less common.
Major depressive disorder is the condition in which there is the strongest
evidence for a complex bidirectional relationship with sleep disturbance
(Krystal 2006). Although insomnia has long been viewed as a secondary
symptom of underlying depression, the results of a series of studies are
inconsistent with this point of view (National Institutes of Health
Consensus Conference 1984). The findings include evidence that those with
insomnia have an increased future risk of major depressive disorder, that
insomnia is an independent risk factor for suicide in depressed individuals,
that antidepressant treatment frequently does not result in resolution of
insomnia, and that this residual insomnia is associated with an increased
risk of depression relapse (Breslau et al. 1996; Fawcett et al. 1990;
Livingston et al. 1993; Reynolds et al. 1997).
The strongest evidence of the importance of depression is a study that
examined the administration of the insomnia agent eszopiclone along with
the antidepressant fluoxetine for initial therapy of depression (N=545) (Fava
et al. 2006; Krystal et al. 2007). Compared with subjects treated with
fluoxetine and placebo, those receiving fluoxetine and eszopiclone not only
slept significantly better but also experienced more rapid and greater
improvement in nonsleep aspects of depression. A similar placebo-
controlled study of extended-release zolpidem added to escitalopram
showed improved sleep parameters but no significant augmentation of the
antidepressant response of escitalopram (Fava et al. 2011). Another pilot
study with a similar design examined the effect of CBT-I (see “Cognitive-
Behavioral Treatment” later in this chapter) and found that compared with
subjects treated with escitalopram and a sham therapy, those treated with
escitalopram and CBT-I showed higher rates of remission of both insomnia
and depression (Manber et al. 2008). Even though studies of this type have
not been carried out in older adults, these data nonetheless make a strong
case for the importance of treating insomnia in those with depression. The
relative utility of sedating antidepressants versus the combination of
nonsedating antidepressants (e.g., selective serotonin reuptake inhibitors)
and insomnia agents has not been evaluated.

Neurocognitive Disorders

Alzheimer’s Disease
Individuals with Alzheimer’s disease (AD) have been found to experience
an increased number of arousals and awakenings, to take more daytime
naps, and to have a diminished amount of REM sleep and slow-wave sleep
(Prinz et al. 1982). Patients may develop circadian rhythm disturbances
leading to the decreased night-time sleep and increased daytime sleep
(Bliwise 2004). Patients with advanced dementia may have periods of
wakefulness and sleep during each hour of the 24-hour day. Moreover,
cholinesterase inhibitors, the primary treatment for AD, can cause vivid
dreaming and insomnia. Individuals with dementia also often experience
behavioral agitation, including wandering, vocalizations, and general
combativeness, which are thought to worsen in the evening (a phenomenon
called “sundowning”). However not all studies report this kind of temporal
specificity in agitation symptoms (Bliwise 2004). Nocturnal sleep
disruption is among the leading reasons that individuals with dementia
become institutionalized (Pollak and Perlick 1991; Pollak et al. 1990;
Sanford 1975).
Pharmacological and nonpharmacological treatment studies of sleep
disturbance in patients with AD have focused on global impairment of sleep
rather than on the construct of sundowning. Many aspects of good sleep
hygiene that are emphasized in the management of insomnia in the general
population can help patients with dementia who have sleep disturbance.
These include an activity/exercise program, avoidance of daytime naps, and
limiting evening beverages (including elimination of alcohol and coffee).
Morning light therapy and caregiver education may also be helpful (Bliwise
2000; McCurry et al. 2005). For patients who go to bed very early (e.g., 8
P.M.) and awaken in the very early hours of the morning (e.g., 3 A.M.),
exposure to light in the evening hours or exercise in the evening hours can
help postpone bedtime and consequently time of awakening. A recent
Cochrane review found no evidence that melatonin improved any major
sleep outcomes in patients with AD (McCleery et al. 2014). In a small 2-
week study, trazodone 50 mg at bedtime was found to improve nighttime
sleep without worsening daytime sleepiness (Camargos et al. 2014). There
are no placebo-controlled trials of either benzodiazepines or
nonbenzodiazepines in the treatment of sleep disturbance in AD.
Management of sundowning should include identification and treatment of
possible precipitants (e.g., pain, delirium, psychiatric diagnoses, sleep
disorders). If symptoms of agitation persist after addressing causes, then
these should be addressed with nonpharmacological (preferred) and
pharmacological approaches when needed (see Chapter 19, “Agitation in
Older Adults,” for details).

Parkinson’s Disease
Sleep complaints are noted in 60%–90% of individuals with Parkinson’s
disease (PD) (Trenkwalder 1998). The majority of PD patients with affected
sleep experience difficulty in initiating and maintaining sleep, daytime
fatigue and sleepiness, RLS, and an inability to turn over in bed. The last of
these features was rated as the most troublesome symptom of sleep
disturbance in a study by Lees et al. (1988). Another sleep problem seen in
patients with PD is REM sleep behavior disorder (RBD), in which the
patient acts out dreams because the paralysis that usually occurs during
REM sleep is absent (Clarenbach 2000). In fact, patients (typically men)
with the idiopathic form of RBD are at increased risk of developing a
parkinsonian disorder or dementia, usually linked to α-synuclein pathology,
the risk being 20%–40% after an average of 5 years follow-up (Postuma et
al. 2009; Schenck et al. 1996). Dopaminergic medications used to treat PD,
such as carbidopa/levodopa, may contribute to sleep initiation problems and
sleep difficulties in the first half of the night and may cause nightmares
(Trenkwalder 1998). Few studies are available to guide treatment of
insomnia in patients with PD. The preferred treatment for RBD is low-dose
clonazepam (0.5–1 mg at bedtime), in addition to addressing environmental
safety to prevent injury when dreams are acted out. Clonazepam is effective
in 90% of cases, with results seen in as little as 1 week and with only rare
occurrence of tolerance in older adults (Bloom et al. 2009). Results from a
pilot placebo-controlled trial suggest that doxepin (10 mg at bedtime) may
improve insomnia in patients with PD (Rios Romenets et al. 2013). A small
study comparing eszopiclone and placebo did not show improved total
sleep time (which was the primary outcome measure) with eszopiclone, but
eszopiclone did improve quality of sleep and some measures of sleep
maintenance (Menza et al. 2010). A small open-label trial of low-dose
quetiapine (mean dose of 32 mg given at bedtime) demonstrated benefit
with good tolerability (Juri et al. 2005). Finally, although there are no
studies of zolpidem for insomnia in PD, recent preliminary reports suggest
that subhypnotic doses of zolpidem may help reduce dyskinesias in patients
with PD (Chen et al. 2008; Růzicka et al. 2000).

Medical Conditions

Pain
Pain is a central feature of many medical conditions that occur with
increased frequency in elderly individuals; these conditions include
arthritis, neuropathies, angina, reflux esophagitis, and peptic ulcer disease
(Aldrich 2000). Disruption of sleep is frequently noted in persons with
significant pain (Pilowsky et al. 1985). Attempts to ameliorate the condition
causing the pain should be the first step. When these attempts fail, treatment
for the pain should be instituted. Often, combined behavioral and
pharmacological treatment is needed. Some evidence indicates that pain,
like depression, may have a bidirectional relationship with sleep
disturbance. Two studies have suggested that the treatment of insomnia
leads to improvement in pain. These studies involved the treatment of
individuals with fibromyalgia with CBT-I and treatment of individuals with
rheumatoid arthritis with the benzodiazepine triazolam (Edinger et al. 2005;
Walsh et al. 1996). These data speak to the importance of treating insomnia
in patients with chronic pain (see “Treatment of Insomnia” later in this
chapter). In another study, CBT-I was effective for older adults with
insomnia comorbid with osteoarthritis pain; however, pain severity was not
significantly impacted by the treatment (Vitiello et al. 2013).

Chronic Obstructive Pulmonary Disease

Individuals with chronic obstructive pulmonary disease (COPD) have been
found to have both subjective and objective evidence of disturbed sleep, but
the degree of sleep disruption is unrelated to hypoxemia (Douglas 2000).
Also, daytime sleepiness, which is seen in patients with sleep apnea, does
not appear to occur. Polysomnography is not routinely indicated for
individuals with COPD who have sleep difficulties (Connaughton et al.
1988), and the need for polysomnography in COPD patients should be
determined in the same way that the need in other patients is determined.
Sleep apnea appears to be no more common in individuals with COPD than
in the general population. Nocturnal oxygen may be needed in some
patients; however, individuals who tend to become most hypoxemic at night
are those who are most hypoxemic during the day (Connaughton et al.
1988). Oral theophyllines, which are frequently used in COPD treatment,
are adenosine-receptor antagonists and may have a sleep-disruptive effect
(Douglas 2000). Also, individuals with COPD should be instructed to avoid
alcohol, which can exacerbate hypoxemia and promote other complications.
Benzodiazepines should be used with caution because they may increase
inhibition of ventilatory or arousal responses and may worsen nocturnal
hypoxemia (Douglas 2000). In severe COPD, the benzodiazepines
triazolam and flunitrazepam but not the nonbenzodiazepine zolpidem were
found to adversely affect oxygenation (Murciano et al. 1993). However, in
patients with mild to moderate COPD, both zolpidem and triazolam
improved awakenings compared with placebo, and neither had an adverse
effect on respiration versus placebo (Steens et al. 1993). The melatonin
receptor agonist ramelteon has also been found to improve sleep without
adversely affecting respiration in patients with mild to moderate COPD
(Kryger et al. 2008).

Cerebrovascular Disease
The sleep pathology associated with cerebrovascular disease depends on
which areas of the brain are affected by the condition. Hypersomnia has
been associated with lesions of the cephalad portions of the ascending
reticular activating system, which includes the midbrain and paramedian
region of the thalamus (the thalamic lesions most commonly occur in the
dorsomedial nucleus, intralaminar nuclei, and centromedian nucleus)
(Bassetti and Chervin 2000). Large lesions of the cerebral hemispheres and
lesions of other regions such as the caudate and striatum have been less
commonly associated with hypersomnia. Insomnia directly related to
damage of specific areas of the brain is much less common than insomnia
caused by multifactorial complications of strokes or other medical or
psychiatric conditions associated with an individual’s cerebrovascular
disease (Bassetti and Chervin 2000). Therefore, treatment should be
directed toward these associated conditions.

Nocturia
The urge to urinate is an often-overlooked cause of awakenings in the
elderly population (Bliwise 2000). Surprisingly, it has been reported that
nocturia (excessive urination at night) is the most common explanation
given by elderly individuals for difficulty in maintaining sleep; 63%–72%
of elderly individuals cite nocturia as a reason for sleep maintenance
problems (Middelkoop et al. 1996). Furthermore, several studies have
documented the sleep disturbance caused by and daytime adverse effects of
nocturia (Bliwise 2000). The most common causes of nocturia are
conditions that increase in frequency with age: benign prostatic hypertrophy
in men and decreased urethral resistance due to decreased estrogen levels in
women (Bliwise 2000). Sleep apnea, which increases in prevalence in the
elderly population, can also lead to nocturia (Bliwise 2000). Thus, when
evaluating elderly individuals with complaints of sleep maintenance, the
clinician should assess for nocturia and the associated conditions that
increase the risk of nocturia. If detected, this disorder can generally be
treated effectively by addressing the underlying condition. Patients should
also be advised to restrict fluids in the evenings, to avoid alcohol, and to
ensure that diuretics are dosed in the mornings.

Menopause-Related Symptoms
Despite the enormous number of individuals with menopause-related sleep
difficulties, there is a striking lack of research in this area (Krystal et al.
1998). Although little is known, there appears to be clear evidence that
many women experience sleep disruption in association with vasomotor
symptoms (night sweats, hot flashes, decreased urethral resistance often
leading to nocturia) that are caused by decreased levels of circulating
estrogen and progesterone (Bliwise 2000; Krystal et al. 1998). Several
factors hinder elucidation of menopausal sleep disturbance. One is that
many disorders that cause insomnia increase in frequency with age and are
highly prevalent during the period in which women experience menopausal
changes. Another factor is that although hormone replacement therapy is
highly effective in ameliorating the vasomotor symptoms of menopause, the
subjective reports of sleep disturbance often do not change (Krystal et al.
1998). Although menopausal sleep disturbance is poorly understood, it has
been suggested that behavioral conditioning occurs, just as is often the case
with individuals who, having experienced insomnia during a period of high
stress, continue to have insomnia after the stress has resolved (Krystal et al.
1998).
Given these considerations, elderly women with insomnia should be
evaluated for underlying causes of sleep disturbance (e.g., medical and
psychiatric conditions, primary sleep disorders), and it should be
determined whether there is an association between changes in menstrual
periods, vasomotor symptoms, and insomnia symptoms. If an association
between insomnia and menopausal changes appears to exist, a trial of
hormone replacement therapy could be considered. If hormone therapy is
contraindicated, the antidepressants venlafaxine, paroxetine, and fluoxetine,
as well as gabapentin, have shown some efficacy in the management of
vasomotor symptoms with good tolerability (North American Menopause
Society 2004). If an insomnia complaint persists after amelioration of
vasomotor symptoms, other treatments such as pharmacological
management of insomnia or CBT-I should be considered (see “Treatment of
Insomnia” later in this chapter). Two studies have been carried out in
women with insomnia occurring in association with menopause (Dorsey et
al. 2004; Soares et al. 2006). These studies document the efficacy of
zolpidem 10 mg at bedtime and eszopiclone 3 mg at bedtime for improving
sleep difficulties that occur in association with hot flashes. Further studies
are needed to determine the efficacy of CBT-I and of other insomnia agents.

Loss of Hearing, Vision, and Mobility

Many elderly individuals experience decrements in hearing, vision, and
mobility (e.g., walking, driving). These changes are caused by a variety of
medical conditions that increase in frequency with age. Changes in these
vital functions can have a profound effect on sleep. Most frequently, this
effect stems from a loss of activities in which the affected individual can
engage; to pass the time, the person takes unplanned naps or tries to sleep
more than he or she is physiologically able to. The result is fragmentation
of sleep and loss of circadian rhythmicity. Affected individuals report
spending many frustrating hours awake in bed at night. Although this
problem should be easily solved by increasing activity and developing new
activity options, in practice, making these changes is difficult to achieve.

Evaluation of Individuals With Sleep-Related

Complaints
The first step in evaluating a patient with sleep-related complaints is a
comprehensive clinical evaluation. The patient should be carefully assessed
for sleep disorders and for underlying medical, psychiatric, and
environmental conditions. A physical examination should be performed if
the history suggests a need for it. Several laboratory tests are available to
the clinician, including overnight polysomnography and the Multiple Sleep
Latency Test (Buysse et al. 2006). Subjective sleep logs and actigraphy can
also be used. Each of these methods of assessment may be useful,
depending on the nature of the complaint.
Polysomnography is the primary laboratory test in sleep medicine. It
allows the determination of stages of sleep (wakefulness; stage I, II, III, and
IV sleep; and REM sleep) throughout the night, as well as the monitoring of
nocturnal breathing, movements, cardiac function, and brain function.
Polysomnography is primarily used to evaluate for sleep apnea, PLMD,
nocturnal seizures, and nocturnal medical or psychiatric events.
The Multiple Sleep Latency Test is a daytime test in which the patient
takes a series of four or five naps spaced 2 hours apart throughout the day.
This test provides a physiological assessment of daytime sleepiness.
A subjective sleep log can be useful, particularly in the assessment of
complaints of insomnia and circadian rhythm disturbances (Buysse et al.
2006). Each morning on awakening, for at least a week, the patient records
information about the previous night’s sleep. This information typically
includes the time to bed, time to onset of sleep, number of awakenings
during the night, length of awakenings, time of final awakening, rise time,
quality of the night’s sleep, and level of restedness. In addition, naps during
the previous day and the use of sleep aids are recorded.
Actigraphy is an objective assessment of activity throughout the day and
night (Morgenthaler et al. 2007). Patients wear an actigraph, which is much
like a wristwatch, 24 hours a day for several days. Data are typically
recorded in 1-minute epochs and stored in the actigraph’s memory. The
information is used to characterize the typical sleep-wake patterns and to
determine the amount of wakefulness during the sleep period.
The choice among these methods is determined by the presenting
complaint. For example, an individual complaining of excessive daytime
sleepiness and snoring at night usually requires overnight
polysomnography. Someone complaining of difficulty in staying asleep at
night requires a sleep log assessment. A person who complains of an
inability to fall asleep until 3 A.M. and difficulty in awakening before noon
may need actigraphy and a sleep log assessment.
To develop a diagnosis and a treatment plan, the clinician must combine
the results of laboratory tests with the information obtained during the
comprehensive evaluation. The treatment plan may include further testing,
consultation, or institution of a treatment regimen.

Treatment of Insomnia
Although changes in sleep appear to be a part of aging, insomnia is not an
inevitable consequence of aging. No treatment is needed to address the
changes in sleep that normally occur. However, when individuals
experience insomnia as defined in the chapter introduction, treatment
should be instituted, because untreated insomnia is associated with
significant morbidity and decreased quality of life (Breslau et al. 1996;
National Institutes of Health 2005; Ohayon 2002; Ozminkowski et al. 2007;
Weissman et al. 1997; Zammit et al. 1999). Treatment of insomnia in
elderly patients poses some particular challenges. In this section, we discuss
the two major types of treatment for insomnia: cognitive-behavioral
treatment and pharmacological treatment. In this discussion, we focus on
issues relevant to elderly patients.

Cognitive-Behavioral Treatment
Myriad lifestyle changes that accompany aging increase risks of insomnia
among older adults (Morgan 2000). With aging comes the increased
incidence of infirmities that lead to reduced activity levels and a general
flattening of the sleep-wake activity rhythm. Retirement leads to increased
vacant time and a loss of both routine and zeitgebers that regulate and
stabilize the sleep-wake cycle. Retirement coupled with loss of a spouse
may lead to dramatically reduced social contacts and increased boredom.
Many individuals attempt to reduce hours of daytime boredom by daytime
napping and by staying in bed longer during their nighttime sleep period.
Such practices often lead to increased nocturnal wake time. Dysfunctional
beliefs about sleep, such as “Everyone should try to get 8 hours a night” and
“Older adults can do little to improve their sleep,” may actually perpetuate
sleep difficulties over time (Means and Edinger 2002; Morin et al. 1993).
Nonpharmacological interventions that address these misconceptions and
the sleep-disruptive habits they sustain are often useful for combating
insomnia in older patients.
Currently, a range of behavioral interventions are available for treating
these patients, including relaxation therapies, cognitive therapies, and
treatments that target disruptive sleep habits. Among the more effective of
these interventions is stimulus control therapy, developed by Bootzin
(1972). This treatment is particularly useful for older individuals who have
fallen out of a normal sleep-wake routine and for those who compromise
their nighttime sleep by excessive daytime napping. Stimulus control
therapy addresses such problems by curtailing daytime napping and by
enforcing a consistent sleep-wake schedule. In addition, this treatment
enhances sleep-inducing qualities of the bedroom by eliminating sleep-
incompatible behaviors in bed. The patient with insomnia is instructed to go
to bed only when sleepy; establish a standard wake-up time; get out of bed
whenever he or she is awake for more than 15 or 20 minutes; avoid reading,
watching TV, eating, worrying, and engaging in other sleep-incompatible
behaviors in the bed and bedroom; and refrain from daytime napping. This
treatment has appeal because it is easily understood and usually can be
outlined in one visit. However, follow-up visits are usually needed to ensure
compliance and achieve optimal success.
Because older adults appear to have a reduced homeostatic sleep drive
(Dijk et al. 1997) as well as a propensity to spend excessive time in bed
(Carskadon et al. 1982), measures are often needed to reduce the amount of
time older patients with insomnia routinely allot for nocturnal sleep. Such a
reduction is the aim of sleep restriction therapy (Spielman et al. 1987;
Wohlgemuth and Edinger 2000). This treatment typically begins with the
patient maintaining a sleep log. After 2–3 weeks, the average total sleep
time (TST) is calculated. Subsequently, an initial time-in-bed (TIB)
prescription may be set either at the average TST or at a value equal to the
average TST plus an amount of time that is deemed to represent normal
nocturnal wakefulness (e.g., 30 minutes). However, unless evidence
suggests that the individual has an unusually low sleep requirement, the
initial TIB prescription is seldom set at less than 5 hours per night. The TIB
prescription is increased by 15- to 20-minute increments after weeks in
which the person with insomnia sleeps more than 85%–90% of the TIB, on
average, and continues to report daytime sleepiness. Conversely, TIB is
usually reduced by similar increments after weeks in which the individual
sleeps less than 80% of the time spent in bed, on average. Because TIB
adjustments are usually necessary, sleep restriction therapy typically entails
an initial visit, when treatment instructions are given, and follow-up visits,
when TIB prescriptions are altered.
Research suggests that stimulus-control and sleep-restriction therapies
are more effective than most other nonpharmacological interventions
(Morin et al. 1999, 2006; Murtagh and Greenwood 1995). Moreover, a
meta-analytic comparison suggests that behavioral therapies compare
favorably with hypnotic pharmacotherapies in terms of short-term treatment
effects and, unlike hypnotics, have enduring benefits and few side effects
(Smith et al. 2002). In recent years, the term cognitive-behavioral therapy
for insomnia (CBT-I) has been used to refer to a specific combination of
therapies for insomnia that include stimulus control, sleep restriction, and
cognitive strategies to alter dysfunctional sleep-related beliefs. Clinical
trials have generally suggested that this combination of therapies holds
particular promise for treatment of the sleep maintenance difficulties so
common in older age groups (Edinger et al. 2001, 2007; Morin et al. 1999).
Additionally, a study of a brief behavioral intervention focusing on only
behavioral elements of insomnia treatment was found to be robustly
effective (Buysse et al. 2011). Given such findings, behavioral interventions
should be included in treatment plans for older patients with insomnia,
particularly when improper sleep scheduling and other lifestyle factors
contribute to sleep complaints.

Pharmacological Treatment
It is well established that untreated insomnia is associated with significant
adverse effects (Gislason and Almqvist 1987; Krystal 2007; Zammit et al.
1999). Although a number of medications have been demonstrated to have
potent therapeutic effects on insomnia (Table 16–1), the utility of
pharmacotherapy for this purpose has remained controversial primarily
because of concerns about the risks of long-term treatment.
The long-standing view of the medication management of insomnia has
been that tolerance and withdrawal are inevitable with use for longer than
several weeks (National Institutes of Health Consensus Conference 1984).
As a result, treatment for longer periods was discouraged (National
Institutes of Health Consensus Conference 1984). It is important to note
that this view was not empirically based. It is important to note that this
view was not empirically based, given that it was much later that data from
placebo-controlled studies of the treatment of insomnia with these agents
for periods longer than 3 weeks became available. These studies examining
periods up to 1 year of nightly treatment demonstrate that tolerance and
withdrawal are not inevitably associated with longer therapy duration
(Ancoli-Israel et al. 2005; Krystal et al. 2003, 2008; Walsh et al. 2007).
They established the efficacy and safety of the nonbenzodiazepine
eszopiclone 3 mg at bedtime in adults younger than age 65 years in two 6-
month placebo-controlled studies, one of which had a subsequent 6-month
open-label extension phase (Krystal et al. 2003; Walsh et al. 2007). Another
nonbenzodiazepine, zolpidem (10 mg at bedtime), was dosed 3–7 nights per
week for 6 months in younger adults and was found to improve sleep
without evidence of significant adverse effects related to the duration of
therapy (Krystal et al. 2008). The melatonin receptor agonist ramelteon has
also been found to have sustained sleep onset efficacy and safety over 6
months of nightly treatment in a placebo-controlled trial in adults ages 18
years and older (Mayer et al. 2009). Most recently, a yearlong placebo-
controlled study of nightly treatment with the hypocretin/orexin receptor
antagonist suvorexant was carried out in adults at least 18 years of age and
was found to have sustained efficacy and good tolerability (Michelson et al.
2014). This medication has just been approved (August 2014) by the U.S.
Food and Drug Administration (FDA) for prescription treatment of
insomnia in the United States.

TABLE 16–1. Attributes of medications used to treat insomnia

Half-life (hours) Principal side effects
Benzodiazepines 2.9–74a Motor and cognitive
impairment
Zolpidem 2.6±1 Motor and cognitive
impairment
Zaleplon 1 Motor and cognitive
impairment
Eszopiclone 6 Motor and cognitive
impairment
Ramelteon 1 Dizziness, myalgia
Doxepin (low 10–50 Anticholinergic effects
dose)
Trazodone 11±5 Orthostatic hypotension,
priapism (rare)
Mirtazapine 20–40 Dry mouth, weight gain
Diphenhydramine 4±2 Anticholinergic effects,
motor impairment
Chloral hydrate 7±3 Alcohol interaction, gastric
irritation, motor and
cognitive impairment,
respiratory depression at
high doses
aBenzodiazepine half-lives: flurazepam=74±24; diazepam=43±13; quazepam=39; lorazepam=14±5;
estazolam=12±12; temazepam=11±6; triazolam=2.9±1.
Source. Adapted from Golden et al. 1998; Hobbs et al. 1996; Krystal 2009; Physicians’ Desk
Reference 2002; Potter et al. 1998.

Fewer double-blind, placebo-controlled studies of the pharmacological

treatment of insomnia have been carried out in adults older than 65 years
than in younger adults; this represents a mismatch between the research on
the pharmacological treatment of insomnia and clinical practice. Although
the number of studies carried out decreases with age, the use of
pharmacotherapy to treat insomnia in clinical practice increases in both
frequency and duration of treatment in older patients (Asplund 2000;
Ohayon et al. 1996). Studies of treatment for up to 2–12 weeks have
established the risk-benefit profile for eight agents available in the United
States for the treatment of insomnia. These are the benzodiazepines
flurazepam, triazolam, and temazepam; the nonbenzodiazepines
eszopiclone, zaleplon, and zolpidem; the melatonin agonist ramelteon; and
the tricyclic antidepressant doxepin (Krystal 2009; Krystal et al. 2010). The
relative shortage of placebo-controlled studies is a particular problem in the
older population with respect to adverse effects. The data on adverse effects
of insomnia medications in older adults that could be used to make
decisions regarding treatment in clinical practice are available for seven
agents (flurazepam, temazepam, zolpidem, zaleplon, eszopiclone,
ramelteon, and doxepin). Not surprisingly, daytime sedation and cognitive
effects have been reported with the benzodiazepines flurazepam and
temazepam, which have relatively longer half-lives than agents more
recently approved by the FDA for the treatment of insomnia. In one
relatively small study of temazepam in older adults, however, no significant
daytime adverse effects were noted (Morin et al. 1999). The other agents
studied—zolpidem (5 mg), zaleplon (5–10 mg), eszopiclone (2 mg),
ramelteon (8 mg), and doxepin (3 mg), dosed at bedtime—had largely
favorable adverse-effect profiles compared with placebo in older
individuals. The only study to examine long-term treatment (>12 weeks) in
older adults identified that in up to 1 year of nightly treatment with the
nonbenzodiazepine zaleplon 5–10 mg at bedtime in an open-label study,
there were no significant risks associated with long-term therapy or
significant discontinuation effects (Ancoli-Israel et al. 2005). The long-term
efficacy and safety of eszopiclone and zolpidem in older adults remain to be
established, as do the long-term efficacy and safety of other agents with the
exception of suvorexant, the hypocretin/orexin antagonist, for which a
subset of the patients in the year-long placebo-controlled study were adults
older than 65 years (Michelson et al. 2014).
Of the medications most frequently used to treat insomnia, the
nonbenzodiazepine hypnotic zaleplon and the melatonin receptor agonist
ramelteon have the shortest half-lives (approximately 1 hour), making them
well suited for treating problems falling asleep. Because of its short half-
life, zaleplon may also be useful in the middle of the night for individuals
who sometimes wake up at that time (Stone et al. 2002). Zolpidem, with a
half-life of approximately 2.5 hours, is another agent approved for the
treatment of difficulties falling asleep. An orally absorbed version of low-
dose zolpidem (trade name Intermezzo) has been demonstrated to reduce
the time to return to sleep in the middle of the night in placebo-controlled
trials in the general adult population without significant morning
impairment if taken 4 hours before getting out of bed (Roth et al. 2013).
Although the agent with the shortest half-life that effectively treats the
sleep difficulty should always be used in order to minimize risks,
individuals with difficulty staying asleep generally need longer-acting
agents. Of the agents available in the United States, eszopiclone (2 mg at
bedtime) and doxepin (3 mg at bedtime) are demonstrated to improve the
ability to stay asleep in older adults with insomnia (Krystal et al. 2010;
McCall et al. 2006). The doxepin study which lasted for 12 weeks is
particularly notable for its effect on sleep maintenance and early morning
awakenings given that these are the primary sleep complaints of elderly
people. Although other antidepressants are widely used to treat insomnia in
the United States (most notably trazodone, mirtazapine, and amitriptyline),
there has yet to be a study of any of these agents in older adults with
insomnia (Walsh 2004).
The primary adverse effects of the benzodiazepines and
nonbenzodiazepines are motor and cognitive impairment. Many older adults
may be particularly vulnerable to adverse outcomes because of these
effects. In terms of motor impairment, these agents might be expected to
increase the risks for falls in older adults. Although there is evidence for an
association of falls with benzodiazepines, nonbenzodiazepines, and
medications with anticholinergic and antiadrenergic effects (which include
antihistamines and antidepressants), there are also studies suggesting that
untreated insomnia increases the risks for falls (Allain et al. 2005; Avidan et
al. 2005; Brassington et al. 2000; Koski et al. 1998; Nebes et al. 2007;
Neutel et al. 2002; Suzuki et al. 1992). Further research will be needed to
provide guidance, when managing insomnia in clinical practice, as to how
to take into account the risks of falls caused by being awake at night versus
the risks of falls caused by medications.
In this regard, as with the treatment of any condition, decisions regarding
the treatment of insomnia should involve weighing the risks and benefits
associated with each of the available treatment options—that is, each of the
insomnia medications versus CBT-I versus no treatment. The available
studies of the pharmacological treatment represent the empirical basis for
making such decisions. Although these studies establish a favorable risk-
benefit profile for a number of agents over periods of treatment up to 2
weeks, more studies clearly are needed to provide a more effective guide
for the treatment of insomnia in older adults. Given the limited number of
studies in older adults, it is tempting to apply the results of studies carried
out in younger adults to the treatment of older insomnia patients. However,
this should be done with great caution given the greater vulnerability to
adverse effects of older adults and the likelihood that medication blood
levels will be higher and the effects will be longer lasting because of slower
drug metabolism in this population (Krystal 2009).
In summary, although CBT-I should always be considered for patients
with insomnia, medications may be needed in some cases. In general, it is
best to use agents with relatively short half-lives to minimize risks of
daytime impairment. However, some older adults require an agent that
addresses difficulty staying asleep. A number of medications have been
demonstrated to have a favorable risk-benefit profile for the treatment of
insomnia in older individuals and can be used in such cases. However, it is
important to be cognizant of the risks of treatment in this highly vulnerable
population. More studies of insomnia therapies in older adults—and, in
particular, of longer-term trials of treatment—are needed.

Conclusion
Management of sleep disorders in elderly patients is challenging. Although
sleep complaints are not an inevitable consequence of aging, elderly
persons are more prone to primary sleep disorders and medical and
psychiatric conditions that cause sleep difficulties. Therefore, evaluation of
a sleep complaint in an elderly individual should include a thorough workup
to determine whether primary sleep pathology and associated psychiatric
and medical disorders are present. Effective behavioral and medication
treatments exist for treating sleep and circadian rhythm disorders in elderly
patients, but these treatments have significant limitations. More research is
needed to develop and assess nonmedication therapies that are effective in
treating insomnia and normalizing the circadian rhythm. Particularly
promising areas include cognitive-behavioral approaches and exercise
programs.
In addition, research to improve medication treatment is needed. More
medications are needed that can help elderly individuals stay asleep without
causing next-day sedation. Furthermore, medications are needed that do not
cause motor or cognitive impairment or anticholinergic side effects and that
have been evaluated in trials of long-term treatment in older adults. Studies
of the efficacy and safety of antidepressants in the treatment of insomnia in
older adults are also needed.

Key Points
• More than one-half of noninstitutionalized individuals older than age 65
years report chronic sleep difficulties.
• Although disturbed sleep is not an inevitable consequence of aging,
elderly people are at increased risk of experiencing a number of sleep
disorders and are uniquely vulnerable to the consequences of these
disorders, which include insomnia, restless legs syndrome, sleep apnea,
and disorders of circadian rhythm.
• Effective behavioral and medication treatments exist for treating sleep
and circadian rhythm disorders in elderly patients, but more research is
needed to develop improved treatments and to establish the risk-benefit
profiles of some of the most commonly administered therapies.

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 CHAPTER 17

Substance-Related and Addictive

Disorders
Shahrzad Mavandadi, Ph.D.
David W. Oslin, M.D.

Alcohol and drug misuse are associated with a wide array of negative
physical and mental health outcomes that are exacerbated with advancing
age, such as functional and cognitive decline, compromised immune
function, and depression; however, relatively little work has examined the
correlates and consequences of substance use among older adults.
Accordingly, substance misuse in later life, which encompasses misuse of
alcohol and illicit, prescription, and over-the-counter drugs, has been called
an “invisible epidemic” (Widlitz and Marin 2002). Epidemiological work,
which has focused on younger populations, demonstrates that beginning in
the middle to late 20s, overall rates of alcohol and illicit drug use begin to
decline, with the majority of older adults reporting no substance use.
Nevertheless, changes in demographic and cohort trends suggest that
substance misuse in later life is a pressing public health matter and that
older adults represent a group in growing need of specialized substance
treatment programs and services (Gfroerer et al. 2003).
With the aging of the U.S. population and the resultant increase in the
proportion of adults living to advanced ages, a concomitant increase has
occurred in the number of older adults who misuse alcohol and drugs. Not
only are older adults the fastest growing segment of the U.S. population, but
in the next several decades the aging population will be composed primarily
of “baby boomers,” individuals born between the years 1946 and 1964. The
aging of the baby boom cohort poses unique challenges to providers; in
addition to reporting higher rates of illicit drug and alcohol use and
addiction than earlier cohorts, the baby boom cohort also is significantly
larger than previous cohorts (Han et al. 2009a).
The potential public health impact of these demographic trends is
highlighted by examining changes in rates of substance use and misuse in
the last several decades. For example, it has been estimated that from the
early 1990s until 2002, the prevalence of alcohol abuse or dependence
tripled to 3.1% among adults ages 65 years and older (Grant et al. 2004).
Heavy and binge drinking among adults older than 65 years also has
increased, with recent reports citing rates near 10.2% (Substance Abuse and
Mental Health Services Administration 2013) (Figure 17–1). Reports of
substance use among the baby boomers are notably higher; 29.3% of adults
ages 50–54 years were heavy or binge drinkers in 2012 (see Figure 17–1),
and rates of illicit drug use among those in this age group increased from
3.4% to 7.2% from 2002 to 2012 (Substance Abuse and Mental Health
Services Administration 2013) (Figure 17–2).
FIGURE 17–1. Current, binge, and heavy alcohol use across the life
span: 2012.
Source. Reprinted from Figure 3.1 (Current, binge, and heavy alcohol use among persons aged 12 or
older, by age: 2012) in Substance Abuse and Mental Health Services Administration: Results from
the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series
H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD, Substance Abuse and Mental Health
Services Administration, 2013. Available at:
http://www.samhsa.gov/data/NSDUH/2012SummNatFindDetTables/NationalFindings/NSDUHresult
s2012.htm#ch3.1.1. Accessed January 15, 2014.

In light of these epidemiological changes, it is projected that by the year

2020, the number of older adults requiring substance abuse treatment will
increase to 5.7 million, a significant departure from the estimated 2.8
million in need of treatment in 2002–2006 (Han et al. 2009b). Hence, to
meet the special needs of older adults experiencing problems with alcohol
and drugs, social services professionals and providers within primary and
specialty care settings, particularly specialty mental health care, must learn
to recognize signs and symptoms of substance misuse and gain a firm
understanding of available treatment options. Doing so will enhance efforts
directed toward reducing problematic use and foster improvements in
overall quality of life among older adults with substance use problems.

FIGURE 17–2. Past-month illicit drug use among adults ages 50 to 64

years: 2002–2012.
+Difference between this estimate and the 2012 estimate is statistically significant at the 0.05 level.
Source. Reprinted from Figure 2.10 (Past month illicit drug use among adults aged 50 to 64 years:
2002–2012) in Substance Abuse and Mental Health Services Administration: Results from the 2012
National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46,
HHS Publication No. (SMA) 13-4795. Rockville, MD, Substance Abuse and Mental Health Services
Administration, 2013. Available at:
http://www.samhsa.gov/data/NSDUH/2012SummNatFindDetTables/NationalFindings/NSDUHresult
s2012.htm#ch2.4. Accessed January 15, 2014.

Guidelines and Classification: A Spectrum of Use

Proper screening, diagnosis, and treatment of individuals with drug and/or
alcohol problems require an understanding of both drinking guidelines and
the full range of substance use behavior seen among older adults. Because
physiological factors render older adults more sensitive not only to alcohol
and illicit drugs but also to over-the-counter and prescription medications,
guidelines and recommendations for use of these substances by older adults
differ from those applied to younger adults. For example, lean body mass
and total water volume decrease relative to total fat volume in later life. As
a result, total body volume decreases, thereby increasing the serum
concentration, absorption, and distribution of alcohol and drugs in the body
(Moore et al. 2007). Age-related declines in the efficiency of metabolic
enzymes that target these substances as well as increases in central nervous
system sensitivity also contribute to an amplified response to drug and
alcohol use among older adults. Furthermore, interactions between alcohol
and over-the-counter or prescription medications, which are commonly
used by older adults for a variety of acute and chronic medical and
psychiatric conditions, may be especially harmful. Consuming alcohol in
combination with prescription or over-the-counter drugs may lead to
exaggerated or adverse therapeutic effects or, conversely, a blunting of the
effectiveness of some medications (Moore et al. 2007).
Taking these age-related factors into account, guidelines for alcohol use
are lower for older relative to younger adults. Recommendations set forth
by the National Institute on Alcohol Abuse and Alcoholism (2005) and the
Center for Substance Abuse Treatment (Blow 1998) on older adults state
that adults age 65 years or older should consume no more than one standard
drink per day or seven standard drinks per week (Table 17–1). Moreover,
older adults should not consume more than two standard drinks on any one
occasion (binge drinking). These drinking-limit recommendations are in
accord with data concerning the relationship between heavy consumption
and alcohol-related problems as well as evidence for the beneficial health
effects of low-risk drinking among older adults (Klatsky 2010; Moos et al.
2009; Plunk et al. 2014).
Recommendations regarding the appropriate prescription and use of
over-the-counter and prescription drugs must be considered on a case-by-
case basis, with special consideration given to the potential benefits versus
the potential risks of medication use for each patient. There are no accepted
safe limits for tobacco, marijuana, or other illicit drug use.
Although the guidelines and recommendations for substance use address
acceptable limits, it is important to recognize that there is still a great deal
of variability in the degree to which older adults use alcohol and drugs.
Understanding patterns of use can help inform the treatment and counseling
of older adults in numerous settings. Thus, to capture this variability, or
“spectrum of use,” a number of categories have been created. The following
categories and their definitions, which focus primarily on patterns of
alcohol use, reflect both the clinical experience and research findings of
addiction specialists (Blow 1998; National Institute on Alcohol Abuse and
Alcoholism 2005).
Abstainers is the term used to describe individuals who report drinking
no more than two drinks in the previous year. This is the most common
drinking pattern in later life; approximately 40%–70% of older adults report
abstinence, and abstinence rates increase further with advancing age
(Kirchner et al. 2007; Wu and Blazer 2014). Nevertheless, determining the
reasons for abstinence has important implications for subsequent treatment
and counseling of older adults who do not drink. For example, although
some individuals may have had lifelong patterns of abstinence, others may
not drink because of the onset or presence of acute or chronic illness.
Furthermore, some individuals may abstain from alcohol use because of a
previous history of alcohol problems or abuse. This latter group, in
particular, deserves special consideration and would benefit from preventive
monitoring and screening. Not only could new stressors cause relapse
among those with a history of problematic drinking or abuse, but past use
may make older adults more vulnerable to other mental health problems
such as psychiatric disorders or cognitive declines.

TABLE 17–1. Alcohol conversion chart

“1 standard drink”
Beverage type Quantity
Beer (˜5% alcohol) 12 oz
Wine (˜12% alcohol) 5 oz
Fortified wine (˜17% alcohol) 3 oz
Hard liquor (80-proof distilled spirits) (˜40% 1½
alcohol) oz (i.e., 1 shot)
Malt liquor (˜7% alcohol) 8 oz
Liqueur or aperitif (˜24% alcohol) 2–3 oz
Additional conversions
Beverage type/quantity No. of standard drinks
Beer
 1 six-pack of 16-oz cans/bottles 8
1 quart 3
1 liter (33.8 oz) 2.8
Wine (e.g., red, white, Chianti)
1 bottle (25 oz) 5
1 bottle (40 oz) 8
Fifth 6
1 magnum 12
½ gallon 16
Fortified wine (e.g., sherry, port; low-end wines [e.g., Night Train,
Thunderbird, “bum wine”])
Pint 7
Fifth 12
Hard liquor (e.g., bourbon, rum, gin, tequila, vodka)
Fifth 18
Pint 11
Quart 20
½ gallon 40
1 bottle (25 oz) 17
1 bottle (40 oz) 27
Malt liquor (e.g., King Cobra, Olde English)
12 oz 1½
40 oz 5
Source. Data modified from National Institute on Alcohol Abuse and Alcoholism: Tips For Cutting
Down On Drinking (NIH Publication No. 07-3769). Bethesda, MD, U.S. Department of Health and
Human Services, Public Health Services, National Institutes of Health, National Institute on Alcohol
Abuse and Alcoholism, reprinted September 2008. Available at:
http://pubs.niaaa.nih.gov/publications/Tips/tips.pdf. Accessed December 4, 2014.

Low-risk, social, or moderate drinkers include individuals who drink

within the recommended guidelines (i.e., drink no more than one drink per
day) and do not exhibit any alcohol-related problems. Older adults in this
group also observe caution and do not drink when driving a motor vehicle
or boat, or when using contraindicated medications.
 Low-risk medication/drug users are individuals who adhere to
physicians’ prescriptions. Nevertheless, it is important to evaluate the
number and types of medications being used by low-risk users, because
harmful medication interactions may still occur among this group.
At-risk or excessive substance users among older adults are those who
consume substances above recommended levels yet experience minimal or
no substance-related health, social, or emotional problems. At-risk
substance use in older individuals generally applies to the consumption of
alcohol or prescription and over-the-counter medications rather than illicit
drugs. Given the guidelines outlined earlier in this section, excessive
alcohol use can readily be defined as drinking more than one drink per day.
Determining a prespecified threshold beyond which drug use poses a risk is
more challenging; this is because of the high variability in appropriate
pharmacological treatment regimens and recommendations that result from
individuals having different medical circumstances and needs. However,
identifying older adults who are taking high doses of medication and have
also been taking medications for a period of time exceeding what would be
reasonable clinical practice would help target individuals who may be at
risk. For example, the prolonged or improper use of psychoactive
medications, such as benzodiazepines, presents a particularly high risk of
negative health outcomes and adverse drug reactions (Lader 2014).
Targeting and identifying older adults in this category is important;
although they currently may not be experiencing any substance use–related
problems, these individuals may have a high risk of developing alcohol- or
medication-related health problems should their substance use remain
consistent or increase over time. Preventive brief interventions for at-risk
users are valuable and effective, and abstinence or reductions in substance
use have been shown to improve quality of life for this group.
Substance use disorder describes a pattern in which alcohol or drug
consumption is at a level at which adverse medical, psychological, or social
consequences have occurred or are significantly likely to occur. Thus, this
category of use is not dependent on the quantity or frequency of use but
rather the extent to which substance use impairs physical and/or
psychosocial functioning. Previously classified as two separate disorders
(i.e., substance abuse and dependence) according to DSM-IV criteria
(American Psychiatric Association 1994), substance use disorder spans
multiple domains of functioning and falls along a continuum, with mild,
moderate, and severe subclassifications (Table 17–2; American Psychiatric
Association 2013). It is important to note, however, that criteria are based
mostly on research with young to middle-aged adults and have not been
sufficiently validated among older populations; therefore, the symptoms
and consequences set forth in DSM-5 may not be sensitive enough to
capture disorder in later life. For example, some of the standard symptoms
of substance use disorder listed in DSM-5, such as employment problems or
interpersonal difficulties, may not be as readily applied to older individuals,
given age-related factors such as retirement, widowhood, and resultant
changes in occupational and social roles and network composition. As a
result, the risks associated with this pattern of substance use may be
underestimated. Moreover, determining whether individuals meet
diagnostic criteria relies heavily on self-reported behavioral symptoms. This
is potentially problematic because self-report is susceptible to bias because
of memory impairments, lack of insight or knowledge regarding the adverse
effects of substance use, or unwillingness to admit symptoms. For instance,
benzodiazepine misuse may go unnoticed or unreported because older
adults may not link the consequences of medication use to health or social
problems. Notwithstanding these limitations in diagnostic criteria, because
older adults in this group are at a greater risk of negative consequences such
as falls, liver disease, pancreatitis, and harmful alcohol-medication
interactions, they represent a group that would greatly benefit from
screening, identification, and specialized treatment and services (Fink et al.
2002).

Epidemiology of Late-Life Substance Use

Alcohol
Even though alcohol misuse is often underreported and thus underestimated
in later life, epidemiological work suggests that alcohol problems are
common among older adults. For instance, the most recent National Survey
on Drug Use and Health found that 53.1% of adults ages 60–64 years
endorsed current alcohol use in the past month, 14.3% endorsed bingeing
behavior, and 4.3% endorsed heavy use (Substance Abuse and Mental
Health Services Administration 2013). Although rates of use were lower for
those age 65 years or older, they were nonetheless significant: 41.2% of
respondents reported past-month alcohol use, 8.2% bingeing, and 2.0%
heavy use (see Figure 17–1). With respect to alcohol use disorder,
epidemiological work has found that 4.1% of adults ages 65–75 years (8.1%
of men and 1.0% of women) reported a lifetime history of alcohol use
disorder, whereas 1.6% of adults ages 75 years and older reported a history
of alcohol use disorder (Gum et al. 2009).
Because substance misuse is more likely to be present in health care
settings, rates of alcohol problems are higher among clinical than among
community-based samples. For example, in their screening program of over
12,000 primary care patients, Barry et al. (1998) found that 5% of patients
screened positive for at-risk or problem drinking, as measured by alcohol
consumption, binge drinking, or the presence of alcohol-related problems.
Similarly, Callahan and Tierney (1995) found that 10.6% of their sample of
3,954 primary care patients ages 60 and older met criteria for problem
drinking. In a more recent study of older adults in primary care settings,
Kirchner et al. (2007) reported that of the 24,863 individuals screened,
21.5% drank within the recommended levels (1–7 drinks per week),
whereas 4.1% were at-risk drinkers (8–14 drinks per week), and 4.5% were
heavy (>14 drinks per week) or binge drinkers. Rates of abuse and
dependence appear to be particularly high among patients in mental health
clinics and nursing homes. In their study of 140 patients enrolled in a
geriatric mental health outpatient clinic, Holroyd and Duryee (1997) found
that 8.6% of patients met DSM-IV criteria for alcohol dependence.
Furthermore, Oslin et al. (1997b) found that 29% of male nursing home
residents had a lifetime diagnosis of alcohol abuse or dependence, with
10% of residents meeting criteria for abuse or dependence within 1 year of
admission to the home. Moreover, a census analysis of Department of
Veterans Affairs (VA) nursing home admissions data found that 29% and
15% of residents ages 57–64 and 65–72, respectively, had a diagnosis of an
alcohol use disorder (Lemke and Schaefer 2010).

TABLE 17–2. DSM-5 criteria for substance use disorder

A. A problematic pattern of substance use leading to clinically significant
impairment or distress, as manifested by at least two of the following,
occurring within a 12-month period:
 1. The substance is often taken in larger amounts or over a longer
period than was intended.
2. There is a persistent desire or unsuccessful efforts to cut down or
control the substance use.
3. A great deal of time is spent in activities necessary to obtain the
substance, use the substance, or recover from its effects.
4. Craving, or a strong desire or urge to use the substance.
5. Recurrent substance use resulting in a failure to fulfill major role
obligations at work, school, or home.
6. Continued substance use despite having persistent or recurrent social
or interpersonal problems caused or exacerbated by the effects of
the substance.
7. Important social, occupational, or recreational activities are given up
or reduced because of substance use.
8. Recurrent substance use in situations in which it is physically
hazardous.
9. Substance use is continued despite knowledge of having a persistent
or recurrent physical or psychological problem that is likely to have
been caused or exacerbated by the substance.
10. Tolerance, as defined by either of the following (note that tolerance
and withdrawal alone are not sufficient for a diagnosis of a mild
disorder):
a. A need for markedly increased amounts of the substance to
achieve intoxication or desired effect.
b. A markedly diminished effect with continued use of the same
amount of the substance.
11. Withdrawal, as manifested by either of the following:
a. The characteristic withdrawal syndrome for the substance (refer
to Criteria A and B of the criteria set for alcohol or other specific
substance withdrawal).
b. Substance (or closely related substance, such as benzodiazepine
with alcohol) is taken to relieve or avoid withdrawal symptoms.
Specify current severity:
 Mild
Moderate
Severe
Specify if (see DSM-5 text on specific disorders for definitions of course
specifiers):
In early remission
In sustained remission
On maintenance therapy
In a controlled environment
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the
full criteria set, including specifier descriptions and coding and reporting procedures.

Source. DSM-5 criteria reprinted from Diagnostic and Statistical Manual of Mental Disorders, 5th
Edition. Washington, DC, American Psychiatric Association, 2013. Used with permission. Copyright
© 2013 American Psychiatric Association.

Prescription and Over-the-Counter Medications

The use of pharmaceutical drugs is prevalent in older adulthood, and the
risk of misusing prescription and over-the-counter medications, which
include substances such as sedatives/hypnotics, narcotic and nonnarcotic
analgesics, diet aids, and decongestants, also increases with age. According
to a review of the scant literature on this topic, up to 11% of older women
misuse prescription drugs, and it is projected that 2.7 million adults will be
using prescription drugs for nonmedical purposes by the year 2020
(Simoni-Wastila and Yang 2006). A large proportion of medications
prescribed to older adults include psychoactive, mood-altering drugs.
Psychotherapeutic medications, in particular, are subject to improper use
and can lead to negative health consequences, when used either alone or in
combination with other drugs and alcohol. For example, among adults ages
50 years and older, 9.4% of nonmedical opioid users have been shown to
meet criteria for prescription opioid disorder in the previous year (Blazer
and Wu 2009b). Moreover, the use of benzodiazepines—one of the most
commonly prescribed medications in the United States—increases with age
and tends to be chronic in later life. Incidentally, benzodiazepines also tend
to be one of the most inappropriately prescribed psychotherapeutic
medications among older adults (Maust et al. 2014).
 Examination of pharmaceutical data supports the notion that older adults
are more likely than younger people to take multiple medications (Bushardt
et al. 2008; Golden et al. 1999). In fact, it has been estimated that the
average older patient takes 5.3 prescription medications each day (Golden
et al. 1999). For instance, in one study of prescription medication use
among adults age 65 years and older, 29.4% were prescribed six or more
concurrent drugs, 15.7% were prescribed one or more potentially
inappropriate drugs, and 9.3% met criteria for both (Bushardt et al. 2008).
Over-the-counter drug use also is quite common; in one study, 87% of older
adults reported regular use of over-the-counter medications, and 5.7% were
taking five or more over-the-counter medications concurrently (Stoehr et al.
1997). Polypharmacy, or the concomitant use of multiple drugs, may have
negative consequences in cases in which complex medication regimens are
not carefully and appropriately adhered to by patients or monitored by
physicians (Hajjar et al. 2007). Thus, clinicians should be cautious when
prescribing or recommending a treatment, take both risks and benefits into
account when determining a treatment plan, and clearly communicate
guidelines for appropriate use to patients. Clinicians also should carefully
consider discontinuing medications that do not prove effective. For
example, medications often are continued from one care setting to another
without clear justification for use as older adults are navigated through the
health care system.

Illicit Drugs
Unlike alcohol and prescription or over-the-counter medication use, illicit
drug use among older adults is rare. Based on data from the Epidemiologic
Catchment Area study, analyses in the early 1990s estimated that the
lifetime prevalence rate of drug abuse and dependence was 0.12% for older
men and 0.06% for older women, whereas the lifetime history of illicit drug
use was 2.88% for men and 0.66% for women (Anthony and Helzer 1991).
More recent work, however, suggests that illicit substance use is more
common among older adults than previous estimates suggest. For example,
examination of national trends of drug use among adults ages 50–59 years
revealed that 9.4% of adults used an illicit or non-medical drug in the
previous year (Han et al. 2009a). The rate of illicit substance use (mainly
heroin and cocaine) was reported to be 45% among adults ages 55 years and
older admitted to substance abuse treatment facilities (Lofwall et al. 2008).
Finally, according to the most recent National Survey on Drug Use and
Health, the percentage of adults ages 55–59 years using illicit drugs in the
past month increased from 1.9% in 2002 to 6.6% in 2012 (Substance Abuse
and Mental Health Services Administration 2013). Although 6.6% may not
appear to be a significant proportion of older adults, it is important to keep
in mind that the baby boomers were among the only age groups that showed
notable increases in illicit substance use during the designated time period
(see Figure 17–2). Thus, rates of illicit substance use and abuse among
older adults will likely continue to rise in the next several decades because
of the aging of the baby boom cohort.

Correlates and Consequences of Substance Use

Problems

Correlates and Risk Factors of Substance Abuse

Several studies have sought to identify factors that are related to increased
vulnerability to substance misuse and the maintenance of problematic
substance use patterns in later life. Factors such as gender, medical
comorbidity, history of past use, and social and family environment are all
correlated with problematic substance use. Longitudinal work, for instance,
suggests that older men tend to drink greater quantities of alcohol than older
women and are more likely to have alcohol-related problems (Moore et al.
2005). Older men also are more likely to have had a longer history of
problem drinking (Gomberg 2003). The relationship between certain risk
factors and alcohol abuse also may vary across genders; among alcohol
abusers, women are more likely than their male counterparts to have been
married to a problem drinker, to report negative life events and ongoing
difficulties with a spouse and other family members, and to have a history
of depression (Gomberg 2003; Lemke et al. 2008). Furthermore, increases
in free time coupled with a reduction in role obligations may have an
impact on problem drinking in older women (Wilsnack and Wilsnack
1995). For both men and women, age-related losses in social, physical, and
occupational/role domains, such as widowhood, the death of family and
friends, reduced physical function, and retirement, help contribute to the
adoption or maintenance of abusive drinking patterns in later life (Dawson
et al. 2005a; Lemke et al. 2008). Finally, longitudinal work has
demonstrated that additional social context and life history factors, such as
friends’ approval of drinking and a history of heavy drinking or alcohol
problems, also are related to a higher likelihood of late-life drinking
problems (Moos et al. 2004).
With respect to prescription and over-the-counter drugs, factors such as
declining physical health and physiological changes that accompany the
aging process increase exposure and reactivity to medications and thus the
potential for misuse of these substances in later life. Women, though less
likely than men to use and abuse alcohol, are more likely than men to use
and misuse psychoactive medications (Simoni-Wastila and Yang 2006),
particularly if they are divorced or widowed, have lower socioeconomic
status (e.g., education and income), or have been diagnosed with a mood
disorder such as depression or anxiety (Closser and Blow 1993). Comorbid
psychiatric diagnoses, in general, increase the risk for prescription drug use
disorder, regardless of gender (Simoni-Wastila and Yang 2006). When
considering the full range of factors associated with drug misuse, the
clinician needs to recognize factors such as inappropriate prescribing
practices and insufficient monitoring of drug reactions and patient
adherence by health care providers (Maust et al. 2014).

Consequences of Substance Use

Although the literature presented thus far has alluded to the adverse effects
of problematic substance use, there is some evidence to suggest that low-
risk or moderate alcohol consumption may have a positive impact on
physical health and mental well-being. For example, low-risk or moderate
alcohol consumption is associated with a reduced risk of cardiovascular
disease in both men and women and also a reduced risk of cardiovascular
disease–related disability (Abramson et al. 2001; Bryson et al. 2006).
Furthermore, researchers in one study of older adults without
cardiovascular disease found that alcohol consumption was related to
lipoprotein subclass distribution (Mukamal et al. 2007a). Specifically,
results indicated that moderate alcohol use was associated with fewer small
low-density lipoprotein (LDL) particles and a greater number of large- and
medium-sized high-density lipoprotein (HDL) particles.
 Studies also have demonstrated that moderate alcohol consumption may
protect against type 2 diabetes mellitus and functional decline and may also
affect additional indicators of well-being. In their prospective study of
4,655 older adults with no diabetes at baseline, Djoussé et al. (2007) found
that regardless of the type of beverage consumed, light to moderate alcohol
consumption was associated with a lower incidence of diabetes
approximately 6.3 years later. With respect to functional decline, findings
from cross-sectional work suggest that among older men, low to moderate
alcohol consumption is associated with lower odds of reporting physical
limitations when compared with abstinence or heavy use (Cawthon et al.
2007). Finally, light to moderate alcohol use has beneficial effects on
subjective well-being for both men and women (Lang et al. 2007); it
improves self-esteem, reduces stress, and provides relaxation, particularly
in social situations (Peele and Brodsky 2000).
Although the literature cited previously does suggest that low to
moderate use of alcohol can lead to various health benefits among older
adults, it is important to recognize that there is no evidence to support the
notion that recommending that nondrinkers initiate drinking will translate
into reduced health risks. Moreover, there is no evidence to suggest that an
individual with a medical condition, such as cardiovascular disease, will
benefit from continued drinking or the initiation of drinking. In fact,
abstinence should still be recommended for individuals who are taking
certain medications, those who have been diagnosed with certain acute or
chronic conditions (e.g., diabetes and cardiovascular disease), and those
who present with a history of alcohol or drug abuse, because substance use
is detrimental in these cases.
Drinking that exceeds levels of low-risk or moderate use should be
carefully monitored and targeted for intervention, given the mounting
evidence of the risks of drinking above these recommendations (Oslin
2000). Even moderate alcohol use can lead to adverse health outcomes. For
example, whereas moderate alcohol consumption decreases the risk of
strokes caused by blocked blood vessels, it increases the risk of having a
stroke caused by bleeding or hemorrhaging. Similarly, although there is a
graded positive correlation between moderate alcohol use and bone mineral
density at the hip, moderate use has a U-shaped relationship with risk of hip
fracture (Mukamal et al. 2007b). Low to moderate consumption of alcohol
also has been demonstrated to impair one’s ability to drive and may
increase the risk of accidents and fatal injuries due to falls, motor vehicle
crashes, and suicides (Sorock et al. 2006). Depression, memory problems,
liver disease, cardiovascular disease, cognitive changes, and sleep problems
also have been linked to moderate alcohol use, whereas alcohol dependence
is associated with an increased probability of morbidity and mortality from
disease-specific disorders such as acute pancreatitis, alcohol-induced
cirrhosis, or alcohol-related cardiomyopathy (Rehm et al. 2003, 2009).
When assessing and treating older adults, clinicians not only need to take
the above factors into account but also need to consider the potential
interaction between alcohol and both prescribed and over-the-counter
medications, especially psychoactive medications such as benzodiazepines,
barbiturates, and antidepressants. As mentioned previously, alcohol use
represents one of the leading risk factors for the occurrence of adverse drug
reactions and is known to interfere with the metabolism of medications such
as digoxin and warfarin (Mallet et al. 2007; Onder et al. 2002; Weathermon
and Crabb 1999). Certain medications may themselves have a wide array of
negative consequences on health if not used and prescribed carefully. For
example, benzodiazepines are associated with an increased risk of falls and
fractures, impaired driving, disruptions in sleep cycles, and, among the frail
elderly, excessive disability (Charlson et al. 2009; Madhusoodanan and
Bogunovic 2004). Likewise, diphenhydramine has been linked to cognitive
deficits in healthy older adults, which may translate into excessive cognitive
deficits in patients with dementing illnesses (Katz et al. 1998; Tannenbaum
et al. 2012). Vulnerability to these adverse consequences is increased when
the medication is used for a longer duration than intended or warranted, or
when the medication is improperly prescribed by giving an excessive dose
or prescribing the medication for the wrong indication.
Finally, mental health providers should be well versed in the impact of
moderate alcohol consumption on other mental health disorders. In a study
of over 2,000 elderly patients, Oslin et al. (2000) demonstrated that
reducing moderate alcohol use (defined as 1–7 drinks per week) while
treating a depressive disorder enhanced treatment outcomes. Results further
indicated that the greater the alcohol consumption, the larger the negative
effect on the treatment of depression. Although data are sparse, there is
speculation that moderate alcohol use also may have a negative impact on
the prognosis and course of dementing illnesses such as Alzheimer’s
disease. Moreover, alcohol use may elicit the onset of, or exacerbate
preexisting, personality changes or behavioral disturbances in patients with
dementia.

Screening and Diagnosis of Substance Use

Problems

Potential Barriers to Screening and Diagnosis

As outlined previously, alcohol and drug problems are common in later life.
However, substance misuse remains largely underrecognized and
undertreated among older adults. It has been suggested that adults ages 60
years and older be screened for alcohol and prescription drug use as part of
their routine mental and physical health care (Blow 1998; Wu and Blazer
2014). Routine screening would enable the identification not only of those
older adults who have problematic substance use but also of those who are
at risk of misusing drugs and alcohol. Furthermore, proper screening helps
determine whether additional assessment is needed. Nonetheless, various
factors may interfere with screening and diagnostic processes.
At the provider level, the common misconception that older substance
users have a lifelong history of problem use may make it difficult for
clinicians to identify individuals who either have or are at high risk of
developing late-onset conditions. Although this assumption is more likely
to hold for patterns of illicit drug use, up to one-third of older adults seeking
treatment for alcohol problems have developed these problems in later life.
Furthermore, insufficient knowledge regarding symptoms or the potential
health impact of at-risk or problematic drinking may inhibit screening
efforts. Diagnostic criteria and symptoms for alcohol and prescription drug
misuse are not easily applied to older adults and are often confounded with
symptoms of comorbid medical illnesses, further complicating the
screening and diagnostic process for providers (Table 17–3). Additionally,
the use of multiple diagnostic terms can lead to confusion regarding who
should be screened, how screening should proceed, and which problems or
patterns of use should be treated. A general lack of appreciation of the
benefits of reduced substance use in the absence of disorder, and the belief
that there are few accessible and effective treatments for substance use, can
also significantly lower a clinician’s motivation to screen for or to recognize
at-risk or problem drinking. Assuming a clinician does have a desire to
assess patients for at-risk or problematic use, the self-report nature of
screening instruments may interfere with accurate and appropriate decision
making because of various biases related to self-report measures.
Furthermore, the lack of screening instruments that assess both alcohol and
drug misuse and that are validated with older adults further compounds the
problems associated with recognizing substance use in later life (Dowling et
al. 2008).
At the patient level, confusion as to what constitutes a substance use
problem and who might benefit from an intervention also affects patients’
behavior with regard to seeking assessment. Like providers, older adults
may perceive physical symptoms (e.g., fatigue, sleep problems, anxiety,
confusion) as normative or attribute them to other medical illnesses. Also,
older individuals and their families may not feel that the substance use is
problematic, due either to denial or to lack of knowledge regarding
recommendations and guidelines for acceptable drinking and
prescription/over-the-counter drug use levels. In addition to these factors,
age- and substance-related declines in memory may contribute to
underreporting of past and current alcohol or drug use. Despite these
potential issues, research suggests that retrospective self-report is as reliable
as a prospective diet record in identifying patterns of alcohol use (Leigh
2000; Werch 1989).

TABLE 17–3. Common signs and symptoms of potential substance

misuse and abuse in older adults
Anxiety
Blackouts, dizziness
Depression, mood swings
Disorientation
Falls, bruises, and burns
Family problems
Financial problems
Headaches
Idiopathic seizures
Incontinence
Increased tolerance to alcohol or medications
Legal difficulties
Memory loss
New difficulties in decision making
Poor hygiene
Poor nutrition
Sleep problems
Social isolation
Source. Adapted from Barry KL, Blow FC, Oslin DW: “Substance Abuse in Older Adults: Review
and Recommendations for Education and Practice in Medical Settings.” Substance Abuse 23:105–
131, 2002.

Assessing the Frequency and Quantity of Use

Notwithstanding the barriers mentioned in the previous section, successful
screening techniques have been designed and implemented. Techniques
used to assess the quantity and frequency of alcohol and drug use fall into
three categories: prospective monitoring and recording of alcohol and drug
use, retrospective accounts of daily use over some defined period of time
(i.e., the timeline followback [TLFB] method), and questions regarding
average consumption practices. The prospective monitoring (diary) method
is considered to be the gold standard because it elicits the greatest number
of reports of consumption and is highly associated with sales data for
alcoholic beverages among younger adults (Lemmens et al. 1992; Tucker et
al. 2007). However, proper completion of this type of measure is time-
consuming and requires multiple visits, and therefore this method is
impractical for screenings or brief assessments.
The TLFB method represents the most commonly used technique in
treatment studies for addiction and has become the technique of choice for
such studies. Among older adults, 7-day TLFB assessments are highly
correlated with reports from prospective diaries. Nevertheless, certain
difficulties arise with the use of this method. First, the specific week of
measurement under assessment may not be representative of the person’s
usual drinking behavior. Second, although the TLFB closely matches
prospective diary reports for nondrinkers or daily drinkers, it
underestimates consumption for less frequent users of alcohol (Lemmens et
al. 1992). The TLFB also takes longer to administer than do assessments
evaluating the average frequency and quantity of use, and because of the
varying individual definitions of a “standard” drink, it is more effective and
accurate when administered by an interviewer than when self-administered.
 Finally, although general questions about the average, rather than daily,
quantity and frequency of use over a specified time period are least likely to
match prospective diary reports and may underestimate the frequency of
moderate drinking, asking questions is the method of choice among many
clinicians due to ease of administration. Likewise, the “brown bag”
approach, in which patients are asked to bring to an appointment all
prescribed and over-the-counter medications they are currently taking, is a
useful and convenient aid for determining medication use and misuse.
Although reports of the quantity and frequency of use can be independently
used to screen and identify at-risk patients, this information must be
combined with other measures when the clinician is attempting to detect
problem drinking or substance use disorder.

Standardized Screening Instruments

Brief, low-cost, convenient, standardized assessments that can be used to
screen not only for frequency and quantity of alcohol use but also for
drinking consequences and alcohol/medication interactions are essential to
the success of efforts targeted toward prevention and early intervention for
older adults at risk. As described earlier in “Potential Barriers to Screening
and Diagnosis,” screening should be a component of routine mental and
physical health care and should be updated annually, before the older adult
begins taking any new medications, or in response to problems that may be
alcohol or medication related. Standardized screening questions can be
administered by various methods, including verbal interview and paper-
and-pencil or computerized questionnaire. All three methods have
demonstrated equivalent reliability and validity (Barry and Fleming 1990;
Berks and McCormick 2008; Conigliaro et al. 2000).
To complement questions assessing the quantity and frequency of use, as
discussed in the previous section, the Alcohol Use Disorders Identification
Test (AUDIT) and the CAGE often are used to screen for at-risk substance
use or misuse among older adults. The AUDIT and its abbreviated version,
the AUDIT-C (Figure 17–3), are simple screening measures that capture the
frequency of drinking and bingeing in the past year (Bush et al. 1998;
Dawson et al. 2005b; Rubinsky et al. 2013). The AUDIT-C is scored on a
scale of 0–12, with a score of 0 indicating no alcohol use during the
preceding year. For older adults, a score of 3 or more reflects a positive
screen and suggests the need for further evaluation. Generally, the higher
the AUDIT-C score, the more likely it is that the individual’s drinking is
affecting his or her health and safety and is indicative of an alcohol use
disorder (Bush et al. 1998; Rubinsky et al. 2013).
The CAGE questionnaire (Mayfield et al. 1974) is the most widely used
alcohol screening test in clinical practice. Four items regarding alcohol use
are designed to assess whether patients have 1) felt that they should Cut
down on their drinking, 2) felt Annoyed that people criticized their
drinking, 3) felt Guilty about their drinking, and 4) had a drink upon
waking in the morning to get rid of a hangover—an Eye-opener. A
modified version of the CAGE questionnaire asks only about recent
problems, and the threshold is often reduced to one positive response as an
indicator of problems in older adults. This modified version of the CAGE
has demonstrated high specificity for detecting alcohol abuse but relatively
low sensitivity for alcohol use disorder (Buchsbaum et al. 1992; Moore et
al. 2002).
FIGURE 17–3. Alcohol Use Disorders Identification Test–C (AUDIT–C)
alcohol screening.
Source. Adapted from Bush K, Kivlahan DR, McDonell MB, et al.: “The AUDIT Alcohol
Consumption Questions (AUDIT-C): An Effective Brief Screening Test for Problem Drinking.”
Archives of Internal Medicine 158:1789–1795, 1998. Copyright © 1998, American Medical
Association. All rights reserved. Adapted with permission.

As this last point suggests, it important to recognize that the utility of the
questionnaires may vary as a function of the category of drinking (e.g., at-
risk drinking, alcohol use disorder) that is being assessed. In one
comparison of the relative sensitivity and specificity of self-administered
versions of the CAGE and AUDIT, Bradley et al. (1998) demonstrated that
an augmented version of the CAGE (i.e., a measure including the CAGE
items, the first two items of the AUDIT, and the question “Have you ever
had a drinking problem?”) performed better than the traditional CAGE and
AUDIT when screening for active substance use. However, the AUDIT was
superior to both versions of the CAGE in identifying heavy drinkers.
Finally, although both the augmented CAGE and the AUDIT were effective
in identifying both heavy drinkers and those actively abusing or dependent
on alcohol, the AUDIT performed better. In sum, these results suggest that
the selection of screening instruments used in clinical practice should be
driven by the goals of screening. For example, when screening for both
heavy drinking and alcohol use disorder, clinicians might consider using the
AUDIT or AUDIT-C as opposed to the CAGE (Aertgeerts et al. 2001;
Rubinsky et al. 2013).
Following administration of a screening instrument such as the AUDIT
or CAGE, clinicians can ask follow-up questions about consequences,
health risks, and social/family issues related to substance use. In accordance
with DSM-5 criteria, to assess severity of alcohol use disorder, the clinician
should ask questions about alcohol-related problems, a history of failed
attempts to stop or to cut back, and withdrawal symptoms (e.g., anxiety,
tremors, sleep disturbance). The use of a substance abuse assessment
instrument such as DSM-5 criteria can assist clinicians and researchers by
providing a structured approach to assessment as well as a checklist of
items that can be evaluated across older adults. Furthermore, such
assessments can inform clinicians’ decision making and help determine
whether specialized alcohol treatment might be needed.
Although the screening assessments described in this section focus on
alcohol use, there are also screening instruments for drug consumption,
including a modified version of the CAGE (Hinkin et al. 2001) and the
Drug and Alcohol Problem Assessment for Primary Care (DAPA-PC;
Nemes et al. 2004). Although further work is needed to determine the
validity of these instruments, initial findings are positive.

Use of Biological Markers for Screening

Although biological markers of alcohol and drug use have proved to be less
accepted in clinical practice than in research, they can be useful. Laboratory
values that can indicate recent use or abuse include levels of blood alcohol
or of acetate, which is a metabolite of alcohol (Topic and Djukic 2013).
Markers of chronic alcohol use include γ-glutamyl transferase, mean
corpuscular volume, HDL level, and carbohydrate-deficient transferrin
(Hock et al. 2005; Oslin et al. 1998b). Additionally, urine drug screens are
useful as both screening tools and confirmation of self-report when
assessing prescription/over-the-counter medication and illicit drug abuse.
The majority of drugs of abuse will remain detectable in a urine drug screen
for 4 or more days, with some still detectable after several weeks.

Treatments for Substance Use Problems

Although there are numerous treatment options for substance use in later
life, as discussed in the subsections that follow, little formal research has
been conducted to compare the relative efficacy of these various approaches
among older adults. Nevertheless, results from naturalistic studies are
promising: older adults who engage in treatment not only have comparable
or significantly better outcomes than their younger counterparts (Lemke and
Moos 2003b; Oslin et al. 2005; Satre et al. 2003, 2004a) but also are more
likely to complete treatment than are younger patients (Oslin et al. 2002;
Satre et al. 2004a). Moreover, brief interventions and therapies have been
shown to reduce drinking levels among older at-risk drinkers (Jonas et al.
2012). Therefore, despite popular belief, older adults are quite receptive and
responsive to treatment, especially in programs that offer age-appropriate
care and have providers who are knowledgeable about aging issues.

Brief Interventions and Therapies

Low-intensity brief interventions or brief therapies are cost-effective and
practical techniques that can be used in the initial treatment of at-risk and
problem drinkers in a variety of clinical settings (Jonas et al. 2012;
O’Donnell et al. 2014). Brief interventions are time limited and
nonconfrontational in their approach. Given that these interventions are
based on concepts and techniques from the behavioral self-control
literature, one of the hallmarks of brief interventions is to encourage
individuals to change their behavior through motivational interviewing
(Miller and Rollnick 1991).
Randomized clinical trials of brief interventions for alcohol problems
among older populations reveal that older adults can be engaged in brief
intervention protocols and find the protocols acceptable. Results also point
to a greater reduction in alcohol consumption among at-risk drinkers
receiving interventions than among control groups. The best evidence
emerges from randomized trials of brief (10- to 15-minute) multicomponent
interventions that include physician/behavioral specialist counseling visits
and follow-up telephone calls from clinic staff that involve advice,
education, and the creation of contracts (Jonas et al. 2012). For example, in
one randomized clinical study of at-risk drinkers, older primary care
patients randomly assigned to a brief intervention arm were less likely to
evidence at-risk and heavy drinking at 3-month follow-up and had lower
rates of alcohol use at 12-month follow-up relative to those in the control
group (Moore et al. 2011). Likewise, meta-analytic reviews suggest that
older primary care patients randomized to brief interventions evidence
reductions in alcohol consumption at follow-up (Jonas et al. 2012).
Although the majority of trials have been conducted in primary care
settings, brief interventions for older adults are likely to be effective in
mental health care settings as well. Thus, geriatric mental health providers
are encouraged to gain familiarity with brief intervention therapy both as a
primary treatment tool and, if needed, as a way to motivate patients for
more formal addiction treatment.

Psychosocial Treatments
The literature regarding the efficacy of psychological therapies specifically
for the treatment of substance use disorder in older adulthood is sparse. In
one study of older veterans with substance abuse problems, Schonfeld et al.
(2000) found that individuals who completed 16 weeks of a group
intervention for relapse prevention were more likely than noncompleters to
abstain at 6-month follow-up. Using cognitive-behavioral and self-
management approaches, the group sessions included modules on coping
with factors such as social problems, loneliness, depression, and anxiety
and on dealing with high-risk situations for relapse. In a more recent
treatment study, participants ages 50 years and older who completed an 18-
session program that also incorporated both cognitive-behavioral and self-
management approaches evidenced significant improvement in their social
functioning, decreased use of nonmedical prescription drugs and alcohol,
and reduced binge drinking at 6-month follow-up (Outlaw et al. 2012).

Twelve-Step Programs
A large proportion of community-based and residential treatment programs
incorporate the traditional 12-step peer support model of recovery and
rehabilitation. Originally developed by Alcoholics Anonymous (AA) and
later adapted by groups such as Narcotics Anonymous, the 12-step model
involves group support and encouragement to help members achieve and
maintain sobriety. Participants share their experiences with one another and
follow the 12 steps, which include admitting to one’s addiction, recognizing
the influence of a greater power as a source of strength, and acknowledging
and atoning for past mistakes (Alcoholics Anonymous 2004).
Although self-help groups have been associated with positive outcomes
for many individuals, findings regarding rates of group engagement and
outcomes among older individuals remain mixed. In their matched
comparison of older versus younger and middle-aged adults who
participated in age-integrated residential treatment, Lemke and Moos
(2003a) found that older patients engaged in 12-step programs as frequently
as their younger and middle-aged counterparts when assessed at follow-up.
Results also indicated that more involvement in self-help groups
posttreatment was associated with better outcomes across all three age
groups.
Similarly, an investigation of patients who had completed an outpatient
treatment program for chemical dependency yielded no age group
differences in AA affiliation 5 years posttreatment (Satre et al. 2004a).
Upon examination of a subset of participants in the sample who reported
attending 12-step meetings in the prior year, no age group differences in the
actual number of meetings attended emerged as significant. However,
despite the fact that rates of attendance appeared to be comparable across
age groups, the depth of involvement differed; older adults were less likely
than middle-aged adults to self-identify as being a 12-step group member
and were less likely than younger and middle-aged adults to report calling a
fellow group member for help. Comparable results were observed in
examining 1-month postdischarge outcomes among alcohol-dependent
patients admitted to a 12-step residential rehabilitation program (Oslin et al.
2005). Although rates of postdischarge abstinence and AA attendance did
not differ across middle-aged and older adults, older adults were
significantly less likely to contact a sponsor. Furthermore, older adults were
less likely than middle-aged adults to engage in formal aftercare (31.2% vs.
56.4%).
 Taken together, these findings highlight the importance of more careful
examination of factors that may be related to 12-step program attendance,
degree of engagement, and outcomes among older adults. These factors
include, but are not limited to, perceived stigma, level of comfort regarding
disclosure of personal information in group settings, degree to which age-
relevant issues are addressed during group meetings, and logistic barriers
such as lack of transportation and health problems that may preclude older
adults from attending group sessions and engaging with sponsors (Oslin et
al. 2005; Satre et al. 2004a).

Pharmacotherapy
Until relatively recently, the long-term treatment of older alcohol-dependent
adults did not involve the use of pharmacological agents. Although
disulfiram was originally the only medication approved for the treatment of
alcohol dependence, it was seldom used in older patients because of the
potential for adverse effects. In 1995, the opioid antagonist naltrexone
became the first pharmacological agent approved by the U.S. Food and
Drug Administration in over 50 years for use in the treatment of alcohol
dependence. Approval of the drug was based on findings from clinical trials
that showed that naltrexone was safe and effective in preventing relapse and
reducing alcohol cravings (O’Malley et al. 1992; Volpicelli et al. 1992).
Although these original clinical trials used samples of middle-aged adults,
naltrexone also has been shown to be effective among older adults. For
example, results from a double-blind, placebo-controlled, randomized trial
demonstrated that among older veterans ages 50–70 years, half as many
naltrexone-treated subjects relapsed to significant drinking when compared
with those treated with placebo (Oslin et al. 1997a).
Acamprosate has emerged as another promising agent in the treatment of
alcohol dependence (Maisel et al. 2013; Rösner et al. 2008). Although the
exact action of acamprosate is still unclear, it is believed to reduce
glutamate response (Kennedy et al. 2010). The clinical evidence favoring
acamprosate is impressive. Sass et al. (1996), for example, found that 43%
of alcohol-dependent subjects treated with acamprosate were abstinent at
the conclusion of their 48-week randomized, placebo-controlled trial
compared with 21% in the placebo group. Similar findings for the favorable
association between acamprosate treatment and abstinence have been
observed in other randomized trials (Baltieri and De Andrade 2004).
Moreover, meta-analytic work supports the notion that although
acamprosate might be considered more effective in promoting and
sustaining abstinence, naltrexone may be more effective in reducing heavy
drinking and craving (Maisel et al. 2013). Unfortunately, no studies of the
efficacy or safety of acamprosate among older patients have been conducted
to date.

Detoxification and Withdrawal

In individuals who stop consuming substances or drastically cut down on
their consumption after heavy use, withdrawal symptoms are likely to
occur. During hospitalization, a patient may be particularly vulnerable to
alcohol or benzodiazepine withdrawal if the clinical team is unaware of the
patient’s problems with these substances. In light of the potential for life-
threatening complications, clinicians caring for patients who abuse
substances, particularly in settings in which withdrawal management or
treatment is available, need to have a fundamental understanding of
withdrawal symptoms and be able to provide detoxification management.
Clinicians also should be aware of the anticipated time course of various
symptoms.
Alcohol withdrawal symptoms can range from unnoticeable and mild to
severe and life-threatening. The classic set of symptoms associated with
alcohol withdrawal includes autonomic hyperactivity (increased pulse rate,
increased blood pressure, and increased temperature), restlessness,
disturbed sleep, anxiety, nausea, and tremor. Severe withdrawal is marked
by auditory, visual, or tactile hallucinations; delirium; seizures; and coma.
Adverse functional and cognitive complications are particularly more likely
to occur among older patients. Commonly abused prescription drugs and
illicit agents, such as benzodiazepines, opioids, and cocaine, cause distinct
withdrawal symptoms that are also potentially life-threatening. It is
important to recognize that among older individuals the duration of
withdrawal symptoms is longer, and withdrawal has the potential to
complicate other medical and psychiatric illnesses. Nonetheless, there is no
evidence to suggest that older patients are more prone to alcohol withdrawal
or require longer treatment for withdrawal symptoms (Brower et al. 1994).
Moderators and Correlates of Treatment Response and
Adherence
Some evidence suggests that certain factors may have an impact on the
degree of treatment response and adherence among older adults receiving
treatment. For example, age-specific treatment, or age matching, has been
shown to improve treatment completion and to result in higher rates of
attendance at group meetings when compared with mixed-age treatments.
In one study, male veterans with alcohol problems were randomly assigned
after detoxification to either age-specific treatment—which emphasized
peer support, promotion of self-esteem, and time-limited goal setting—or
standard mixed-age treatment. Outcomes at 6 months and 1 year showed
that patients in the elder-specific program were 2.9 times more likely at 6
months and 2.1 times more likely at 1 year to report abstinence compared
with patients in the mixed-age group (Kashner et al. 1992).
The type of treatment setting also may affect rates of adherence. In a
study comparing engagement outcomes among older primary care patients
referred to specialty mental health providers versus those referred to an
integrated care model using a brief intervention, 60.4% of at-risk drinkers
attended at least one visit in the integrated care model (Bartels et al. 2004).
In contrast, only 33% of patients attended at least one visit to a specialty
provider. It is important to note that these differences emerged in spite of
efforts to address barriers to accessing specialty care, such as copayments
and insurance claims, and to ensure appointments within 2 weeks of
patients being identified with at-risk drinking.
Finally, certain patient-level characteristics may differentially predict
treatment outcomes. For example, women may have more favorable
treatment outcomes than men. Satre et al. (2004b) demonstrated that 6
months after treatment at a private outpatient chemical dependency
program, older women with alcohol dependency were significantly more
likely than their male counterparts to report abstinence from alcohol and
drugs during the prior 30 days (79.3% vs. 54.0%, P=0.02). Similarly,
among patients who were not abstinent, men reported a mean of 4 heavy
drinking days over the prior 30 days, whereas none of the women reported
heavy drinking. Gender differences in outcomes appear to persist up to 7
years after alcohol and drug treatment; at 7-year follow-up, 76.0% of
women versus 54.2% of men reported abstinence in the prior 30 days (Satre
et al. 2007). In addition to gender, variables associated with older age that
may be related to more favorable treatment outcomes include longer
retention in treatment and absence of individuals in the patient’s close social
networks (e.g., family and friends) who encourage alcohol or drug use
(Satre et al. 2004b, 2007).

Medical and Psychiatric Comorbidity

The co-occurrence of problematic substance use and other medical and
psychiatric conditions deserves special attention because such comorbidity
may affect the course, treatment, and prognosis of both conditions.
Although epidemiological studies have clearly demonstrated that
comorbidity between substance use and other psychiatric symptoms is
common in younger populations, less is known about comorbidity between
substance use and psychiatric illness in late life. Nevertheless, a few studies
have demonstrated that concurrent substance use disorder is common
among older adults who have mental health problems. For example, in their
study of data from the National Epidemiologic Survey on Alcohol and
Related Conditions, Sacco et al. (2009) found that among high-risk alcohol
users (who were categorized based on their pattern of alcohol use and on
meeting criteria for alcohol abuse and dependence) ages 60 years and older,
24.9%, 8.8%, and 5.9% met criteria for major depression, anxiety disorder,
and antisocial personality disorder, respectively. In a nationally
representative sample of adults ages 50 years and older, Blazer and Wu
(2009a) found an association between a major depressive episode and
greater odds of marijuana and cocaine use in the past year. Not surprisingly,
rates of comorbidity are significantly higher among clinical samples of
treatment-seeking older substance users (Wu and Blazer 2014).
Comorbid depressive and alcohol symptoms not only are common in late
life but also may have a reciprocal effect on one another. Individuals with
comorbid depression and alcoholism have a more complicated clinical
course of depression, marked by an increased risk of suicide and more
social dysfunction, than individuals with alcoholism alone (Conwell 1991;
Waern 2003). In the same vein, substance use disorder has been associated
with an increased incidence of developing a new psychiatric disorder. For
example, in a longitudinal analysis of adults ages 60 and older with an
alcohol use disorder, 4% developed a new major depressive disorder and
2% a new generalized anxiety disorder over the span of 3 years, whereas
6.7% of those with a drug use disorder developed major depressive disorder
(Chou et al. 2011).
Co-occurrence of alcohol use and dementing illnesses such as
Alzheimer’s disease is also a complex issue (Ridley et al. 2013). Although
Wernicke-Korsakoff syndrome is well defined and is often caused by
alcohol dependence, alcohol-related dementia (ARD) may be difficult to
differentiate from Alzheimer’s disease because of a lack of well-specified
diagnostic criteria. As a result, clinical diagnostic criteria for ARD have
been proposed and validated in at least one trial examining a method for
distinguishing ARD, including Wernicke-Korsakoff syndrome, from other
types of dementia (Oslin and Cary 2003; Oslin et al. 1998a). Despite these
diagnostic issues, it is generally agreed that alcohol abuse contributes to
cognitive deficits in later life. In one of the first community-based studies to
include alcohol survey data, the Epidemiologic Catchment Area study
found that the prevalence of a lifetime history of alcohol abuse or
dependence was 1.5 times greater among individuals with mild and severe
cognitive impairment than among those with no cognitive impairment
(George et al. 1991). Similarly, among older individuals seeking alcohol
treatment, 23% had dementia associated with alcohol dependence
(Finlayson et al. 1988). Finally, patients with ARD who become abstinent
do not show a progression in cognitive impairment comparable to that
found in Alzheimer’s disease (Oslin and Cary 2003).
Sleep disorders and disturbances also frequently co-occur with excessive
alcohol use. It is well established that alcohol causes changes in sleep
patterns, such as decreased sleep latency, decreased stage 4 sleep, and
precipitation or aggravation of sleep apnea (National Institute on Alcohol
Abuse and Alcoholism 1998; Wagman et al. 1977). Age-related changes in
sleep patterns also occur with advancing age and include an increase in
rapid eye movement (REM) episodes, a decrease in REM length and stage 3
and 4 sleep, and an increase in awakenings. Age-associated changes in
sleep can be exacerbated by factors such as alcohol use and depression. For
instance, in their study of younger subjects, Moeller et al. (1993)
demonstrated that alcohol and depression had additive effects on sleep
disturbances when occurring together. Furthermore, Wagman et al. (1977)
demonstrated that abstinent alcoholic individuals experienced poor sleep
due to insomnia, frequent awakenings, and REM fragmentation.
Nevertheless, upon drinking alcohol, sleep periodicity normalized and REM
sleep was temporarily suppressed, suggesting that alcohol use could be used
to self-medicate for sleep disturbances.

Future Directions
Substance misuse among older adults represents a pressing public health
issue, both now and for years to come. In light of changes in demographic
and cohort trends, recent years have seen an increase in the number of older
individuals who misuse or abuse alcohol and drugs. Moreover, there is a
growing awareness that older adults often engage in at-risk or problem
substance use. Nevertheless, individuals in need of treatment or at risk for
future problems often go unidentified and untreated. Therefore, research
and clinical efforts aimed at improving screening efforts and identifying
system-, provider-, and patient-level factors that may interfere with
screening and referral processes for older adults at risk are warranted. In
this vein, a better understanding among clinicians and patients of
recommended drinking levels and the risks associated with moderate to
heavy alcohol consumption is needed, particularly in light of the high
prevalence of co-occurring medical and psychiatric problems in this age
group. Clinicians also should ensure that screening becomes a part of
routine practice when caring for their older patients.
Furthermore, because both provider recommendations and patient
engagement are influenced, in part, by the availability of effective
treatment, better dissemination of information regarding currently available
and efficacious treatments for at-risk use and substance use disorder is
needed. It is important to note, however, that treatment studies in addiction
have traditionally excluded patients older than age 65, resulting in a gap in
knowledge regarding treatment outcomes and an understanding of the
neurobiology of addiction in older individuals. Thus, research endeavors
should continue to focus on developing more effective treatments for
substance misuse in later life, taking into consideration and empirically
assessing the various factors (e.g., patient-, treatment-, and system-related
factors) that may moderate treatment engagement and outcomes. Along
these lines, more formal research that focuses on the relative efficacy of
various treatment modalities, specifically among older adults, is needed.
Finally, given that these issues are particularly relevant to older adults,
future work may benefit from examining nutrition, vitamin
supplementation, and comorbid medical and psychiatric illness, both as foci
for treatment and as aspects of health that may be complicated by substance
use.

Key Points
• Although demographic and cohort trends suggest that rates of substance
misuse among older adults are increasing, the misuse of alcohol and/or
drugs among this group remains largely underrecognized and
undertreated. Accordingly, substance misuse in later life has been
referred to as an “invisible epidemic.”
• Proper screening, diagnosis, and treatment of older adults with drug
and/or alcohol problems require an understanding of both age-specific
guidelines and the full range of substance use behavior seen among older
adults.
• In light of physiological changes that accompany aging, it is
recommended that adults ages 65 and older should consume no more
than an average of 1 standard drink per day.
• The use of multiple pharmaceutical drugs is prevalent in older
adulthood, and thus the risk of misusing prescription and over-the-
counter medications increases with age. Psychotherapeutic medications,
in particular, should be closely monitored, because they are subject to
improper use and can lead to negative health outcomes and interactions
when used alone or in combination with other drugs and alcohol.
• Factors such as medical comorbidity, history of past use, gender, and
social and family environment are related to increased late-life
vulnerability to substance misuse and the maintenance of problematic
substance use patterns.
• Diagnostic criteria and symptoms for alcohol and drug misuse are not
easily applied to older adults, because they are often confounded with
symptoms of comorbid medical illnesses. Thus, when diagnosing and
 treating older adults, it is important that providers be able to distinguish
between symptoms of substance misuse and those stemming from
comorbid conditions.
• Routine screening allows for the identification not only of older adults
with substance use disorder, but also of those who are at risk of misusing
drugs and alcohol. Proper screening also helps determine needs for
additional assessment and/or intervention. Standardized brief, low-cost
assessments exist that can be used to assess the quantity and frequency
of alcohol and drug use in clinical practice.
• A variety of treatments for substance misuse, such as brief interventions,
psychotherapy, 12-step programs, and pharmacotherapy, have been
shown to be effective among older adults.
• Special attention should be paid to co-occurrence of problematic
substance use and other medical and psychiatric conditions (e.g.,
depression, dementia, sleep disturbance) because such comorbidity may
affect the course, treatment, and prognosis of both conditions.

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 CHAPTER 18

Personality Disorders
Thomas E. Oxman, M.D.

Compared with many other psychiatric disorders, personality disorders

are relatively difficult and time intensive to diagnose and treat. In elderly
persons, personality problems are confounded by a variety of additional
issues, both negative and positive. The natural history of personality in later
life is affected by the combination of increasing medical-neuropsychiatric
comorbidity with ongoing normal psychosocial development.
As a person ages, the likelihood of multiple chronic diseases increases.
The existence of comorbidity results in more functional impairment and
requires adaptation (Marengoni et al. 2011). It can become more difficult to
ascertain the primary cause of increased impairment and to determine
where best to focus therapeutic interventions. The risk of neurocognitive
disorders also increases dramatically in later life. A common feature of
dementias is a change in personality or an exacerbation of preexisting
characteristics. Without longitudinal history it can be difficult to know
whether such presentations are manifestations of a personality disorder, a
neurocognitive disorder, or both.
It is not uncommon for geriatric psychiatrists to comment that problems
related to personality disorders are less frequently a focus in their patients
compared with the patients of their general psychiatry colleagues.
Prevalence studies tend to support this observation. If these prevalence
studies are valid, there are several explanations as to why at least some
personality disorders might fade with age. One that deserves attention is
that of maturation, described in adult development theory and research.
 Although general research in personality disorders has increased, there is
a relative dearth of such studies with respect to elderly persons (Agronin
and Maletta 2000). This lack is particularly clear in the area of treatment.
Substantial evidence shows the negative effect of personality disorders on
the outcome of depressive disorders in elderly persons. In contrast to
research on personality disorders, there has been a dramatic increase in
research on the relationship of personality traits in the elderly to cognitive
dysfunction, morbidity, and mortality (Oldham and Skodol 2013). Although
certain personality traits are significantly related to poor outcomes,
evidence on the benefits of treatment for personality traits or disorders in
elderly persons remains limited. There is even less evidence on treatment
and outcomes in nursing homes and general hospitals, the settings in which
the geriatric psychiatrist is most likely to be called on to diagnose and treat
personality disorders and traits.

Definitions
Personality refers to an individual’s “enduring patterns of perceiving,
relating to, and thinking about the environment and oneself” (American
Psychiatric Association 2013, p. 826). Personality consists of both
temperament (i.e., genetic dispositions) and character (i.e., qualities
developed through interaction with the environment) (Robinson 2005). For
a patient to be diagnosed with a personality disorder, DSM-5 requires that
the individual have an enduring pattern of experience and behavior that is
noticeably different from cultural expectations, as manifested in two or
more of the following domains: cognition, affectivity, interpersonal
functioning, and impulse control. The pattern must have developed by early
adulthood and must be intractable and relatively stable across the lifespan.
A personality disorder influences a wide range of both social and personal
situations. As is the case with all DSM-5 disorders, a personality disorder
results in significant distress or functional impairment. Finally, the enduring
pattern must not be a manifestation of another mental disorder, a medical
disorder, or use of a substance.
In treating elderly persons, ruling out manifestations of other disorders is
particularly important because of the high prevalence of chronic medical
disorders. When a change in personality occurs because of the comorbidity
of another mental disorder, a medical disorder, or use of a substance, the
DSM-5 diagnosis of personality change due to another medical condition is
the appropriate diagnosis. However, dementias are also increasingly
prevalent with age and are often associated with changes in personality. A
change in personality is often the chief complaint when an older individual
is brought by caregivers for a specialist evaluation (Duchek et al. 2007).
These changes may be totally unrelated to premorbid personality, as occurs
in frontal lobe dementias (Rabinovici and Miller 2010), or may be marked
exaggerations of preexisting traits, as occurs in Alzheimer’s disease (Archer
et al. 2007). Because of the progressive pervasiveness of neurocognitive
disorders, the DSM-5 diagnosis of personality change due to another
medical condition does not apply. Although these issues are important in
differential diagnosis, for the purposes of this chapter the discussion of
personality disorder is focused more closely on conditions that meet DSM-5
personality disorder criteria.
After making a global assessment of the presence or absence of a general
personality disorder based on the key features listed previously, the next
step is to identify a specific personality disorder or a personality cluster.
Since 1980, DSM has categorized three different personality disorder
clusters (Table 18–1): Cluster A—odd, eccentric (including paranoid,
schizoid, and schizotypal personality disorders); Cluster B—dramatic,
emotional, erratic (including antisocial, borderline, histrionic, and
narcissistic personality disorders); and Cluster C—anxious, fearful
(including avoidant, dependent, and obsessive-compulsive personality
disorders). The number of specific disorders has varied slightly over the
past 20 years. Likewise, over the length of a lifespan often reaching 75–85
years, both personality and a personality disorder are likely to change
somewhat; therefore, attention to identification of a cluster is particularly
helpful. Because older patients with personality disorders commonly show
symptoms of more than one personality disorder, diagnosis of a specific
disorder is likely to be more difficult than in younger adults; in these cases,
patients should be diagnosed with other specified personality disorder or
unspecified personality disorder.

Prevalence, Criteria, and Controversies

The prevalence of personality disorders in the general population is less
accurately known than that of other mental disorders but is estimated at
9%–15% for all ages, with a high prevalence of other comorbid mental
disorders (Grant et al. 2004; Lenzenweger et al. 2007). The prevalence of
personality disorders in psychiatric settings is usually two to three times
higher than that in the community (Schuster et al. 2013).
The prevalence of personality disorders in the general population of
older persons (3%–13%) is lower by about half than in younger persons
(Agronin and Maletta 2000; Schuster et al. 2013). As in the general
population, the prevalence in selected outpatient or inpatient samples of
older persons is much higher than in community settings (Agronin and
Maletta 2000; Ames and Molinari 1994). In part, the lower prevalence of
personality disorders in the elderly appears to be due to a decline in severity
over the years, especially of Cluster B disorders (Hunt 2007; Tracie Shea et
al. 2009; Tyrer and Seiverwright 1988). Zanarini et al. (2007) reported the
results of a 10-year follow-up study of 362 patients with personality
disorders diagnosed at an inpatient admission. Twelve of 24 symptoms
followed showed patterns of sharp decline, reported by less than 15% of
patients who reported them at baseline. Symptoms related to impulsivity
(such as self-mutilation and suicide attempts) and entitlement resolved
relatively quickly. Mood symptoms such as anger, loneliness, and emptiness
were more stable. In a subsequent 16-year follow-up, Zanarini et al. (2013)
found a corresponding improvement to more mature, adaptive defense
mechanisms in patients with borderline personality disorder.
The association of personality disorders with depressive disorders in the
elderly population is probably the single most reported psychiatric
comorbidity. This association of personality disorders and depressive
disorders is an important relationship because the presence of a personality
disorder in the context of a depressive disorder complicates differential
diagnosis and treatment planning (Lynch et al. 2007). For depressive
disorders, the worst outcomes occur among patients with comorbid
personality disorders (Abrams et al. 2001; Morse and Lynch 2004). This
comorbidity is associated with a longer time to response and greater
nonresponse to treatment. Expectations about treatment outcomes with
antidepressants, electroconvulsive therapy, or hospitalization are thus
lowered, and decisions about the need for psychotherapy are increased. The
relationship between personality disorder and depression may be
etiological; that is, personality disorders predispose to the occurrence of
affective dysregulation and depressive disorders (Galione and Oltmanns
2013).
The reports of lower prevalence of personality disorders in older
individuals have raised substantial controversy. There is some concern that
the criteria for personality disorders may not be equally valid across the
lifespan (Balsis et al. 2007) and therefore falsely lower the prevalence in the
elderly population. One suggested response is to modify the criteria for
personality disorders in later life (Agronin and Maletta 2000).

TABLE 18–1. Personality disorders and related aspects of aging

Cluster and types Characteristics Developmental needs Related aspects of
aging

A. Odd, eccentric
Paranoid Perception that people Trust, acceptance Forced intimate contact
are dangerous; from physical
vigilance, dependence highlights
suspiciousness the disorder.
Schizoid Isolation, autonomy Reciprocity, intimacy The disorder is
relatively persistent.
Schizotypal Bizarre behavior Trust, social skills, Individuals without the
abstract thinking disorder who
experience theft and
ageism, leading to
appropriate
suspiciousness, may
be misdiagnosed.

B. Dramatic, erratic
Antisocial Exploitiveness, taking Empathy Elderly individuals are
advantage of others more law abiding, and
antisocial personality
is less common in
older prisoners.
Borderline Sensitivity to rejection, Reflection, Prevalence and/or
feelings of systematization severity of the
abandonment disorder declines.
Histrionic Expressiveness, Self-esteem beyond With older age there is
exhibitionism attractiveness, less energy and less
reflection opportunity for
promiscuity,
 shoplifting, and
impulse expression.
Narcissistic Self-aggrandizement, Group identification, Increased losses, such as
perceived specialness, ability to share retirement and
competitiveness bereavement,
aggravate regulation
of self-esteem.

C. Anxious, fearful
Avoidant Vulnerability, inhibition Self-assertion, This disorder is
expressiveness associated with poor
outcome in major
depression.
Dependent Helplessness, attachment Mobility, self-reliance Individuals without the
disorder who have
fewer social
opportunities and
more medical illnesses
may be subject to
overdiagnosis.
Obsessive- Perfectionism, Playfulness, spontaneity The disorder is
responsibility, relatively persistent.
compulsive systematization

Another suggested response is to adopt a dimensional approach (Oldham

and Skodol 2013). Personality researchers frequently use dimensional
concepts relating to personality traits, rather than the categorical language
of disorders (Widiger and Mullins-Sweatt 2009). From this perspective, the
categorical diagnostic approach is problematic because of co-occurring
disorders, heterogeneity within diagnoses, and the limited evidence base.
There has been a relative explosion of aging-related research linking
personality traits to a variety of outcomes, including depression (Hayward
et al. 2013), cognitive function (Kuzma et al. 2011), dementia (Dar-Nimrod
et al. 2012; Low et al. 2013), telomere length (van Ockenburg et al. 2014),
health and physical functioning (Roberts et al. 2009), and mortality (Iwasa
et al. 2008). The most frequent model of personality traits is the five-factor
model consisting of neuroticism, extraversion, openness, agreeableness, and
conscientiousness (Digman 1990). In general, higher levels of neuroticism
(having more anxiety, depression, and vulnerability to stress) are associated
with poorer outcomes, whereas higher levels of extraversion (being more
outgoing and sociable) and conscientiousness (being better organized and
having more self-discipline and willpower) are associated with better
outcomes. In nonclinical samples younger persons are somewhat higher on
traits of extraversion, neuroticism, and openness, whereas older persons are
higher on agreeableness and conscientiousness, with most of the change
occurring in young adulthood rather than later life (Roberts et al. 2006).
Perhaps most important with respect to geriatrics is that longitudinal studies
of twins show that childhood personality change is primarily due to
genetics, whereas the majority of personality change in adulthood is
environmental, including change caused by experience and by disease
(Roberts et al. 2006).
The developers of DSM-5 revisited a dimensional versus a categorical
approach but ultimately remained with the DSM-IV categorical model
(Oldham and Skodol 2013). Although a dimensional approach may improve
description and identification, it is less clear how the approach would be
used in treatment, other than to revert to a categorical approach that uses
cutoff scores on the dimensional scales. The dimensional approach included
for further study in Appendix B of DSM-IV (American Psychiatric
Association 1994, 2000) involved a “Defensive Functioning Scale” for
defense mechanisms (Vaillant 1994). In this approach, defense mechanisms
were categorized into seven levels ranging from high adaptive (e.g.,
altruism) to defensive dysregulation (e.g., delusional projection). This
approach has been replaced with the “Alternative DSM-5 Model for
Personality Disorders,” based on the five-factor model, which is located in
Section III of DSM-5 (Widiger and Mullins-Sweatt 2009). This DSM-5
approach is proposed as a truly alternative model for clinical use, if
preferred, rather than as a proposed axis for further study.
Rather than different criteria being needed for the elderly population, it
is possible that the criteria are relevant but that prevalence is reduced by
mortality, particularly if there is comorbid substance abuse (Vaillant 2012).
It is also possible that at least some disorders, particularly those in Cluster
B, do improve with age (Tyrer and Seiverwright 1988; Zanarini et al. 2007).
For example, older substance abusers show lower levels of crime and drug
use compared with when they were younger (Hanlon et al. 1990), older
homicide offenders are far less likely to have personality disorders than
younger offenders are (Putkonen et al. 2010), and in general the elderly are
more law abiding, with far fewer arrests (Harlow 1998). Therefore, it is not
inconsistent for older patients with personality disorders to exhibit fewer
“high-energy” diagnostic criteria (e.g., lawbreaking, identity disturbance,
promiscuity). Do these findings mean that a maturational change has
occurred or merely that the symptom displays are more subtle because of
physical and institutional restrictions (Hillman et al. 1997)? Although
arguments for modified criteria may ultimately be valid, equal theory and
evidence from adult development research at least support the current
criteria and the resulting epidemiological findings.

Adult Development
Erikson’s concept of epigenesis is important in understanding how
personality disorders might improve with age. Erikson was a strong
proponent of the interaction of the psychosocial environment with
development across the lifespan. Erikson’s stage theory of late-life
development (Erikson et al. 1986) proposed that the major developmental
task of older age is to look back and seek meaning across the lifespan,
rather than looking forward as in previous developmental modes that are
now in decline. The goal of this task, as discussed by Erikson, is to maintain
more integrity than despair about one’s life. In this process, as at previous
life stages, each earlier life stage conflict must be reconciled and integrated
with the current stage, allowing resolution of earlier conflicts. Individuals
with personality disorders might be expected to have greater difficulty in
accomplishing this resolution than other individuals. However, this
resolution is not an all-or-nothing phenomenon. The achievement of even
some resolution may contribute to the mellowing of a personality disorder.
As Vaillant (2012) has pointed out through his extended involvement with
longitudinal research, “If you follow lives long enough, they change as do
the factors that affect healthy adjustment” (p. 52).
Vaillant and others (e.g., Diehl et al. 1996) have provided empirical
verification for Erikson’s life-stage concepts through longitudinal study of
the maturation of defenses across the lifespan (Vaillant 2012). Defenses are
involuntary mental mechanisms for regulating the realities that persons are
powerless to change. Vaillant and others (Haan 1977) have described a
hierarchy of defenses from immature and maladaptive to mature and
adaptive. Mature defenses include humor, altruism, sublimation,
anticipation, and suppression. Mature and adaptive defenses synthesize and
attenuate conflicts rather than distorting or denying them. Across several
longitudinal studies that included privileged persons (Vaillant 2012), gifted
persons (Terman 1925), and persons from the core inner cities (Glueck and
Glueck 1968), Vaillant established that mature defenses were more
consistently identified primarily in Erikson’s later developmental stages
(Vaillant 1993) and that the development of these defenses was independent
of education and social privilege (Vaillant 1993, 2012). Similarly, others
have identified a socioemotional selectiveness for optimizing positive
emotional meaningfulness with age (Charles and Carstensen 2010) and
improved coping skills with aging (Ryff 1999).
Events with psychological and social impact can reveal previously
submerged difficulty. For example, the death of a spouse may unmask
dependency problems. Retirement or bereavement may lead to narcissistic
problems such as poor regulation of self-esteem and faulty adaptation to
loss. However, experience—something that the elderly have more of than
any other age group—may attenuate the impact of such later-life events,
even for older persons with personality disorders (Birditt and Fingerman
2005; Ryff 1999). For example, to cope effectively with stress, individuals
must learn to recognize the difference between situations that can and
cannot be changed and then must match the right coping skill with the right
situation. Emotion-focused coping is used when a situation cannot be
changed; problem-focused coping is used when a situation can be changed.
It is only through repeated experience that these skills develop (Ryff 1999).
Although stressful situations certainly exacerbate the symptoms of
personality disorders, Neugarten (1970) pointed out how the meaning of
stressful situations changes over time. People expect to experience the death
of loved ones and anticipate their own declining health as they age and have
time to mentally rehearse how they will respond to these “on-time” losses.
When these losses occur “off time”—at earlier stages of life—the stress is
usually experienced as much greater. The improvement in coping skills with
aging is also accompanied by socioemotional selectivity—that is, the
tendency of elderly persons to remember more pleasant events and positive
emotions in favor of unpleasant ones (Charles and Carstensen 2010;
Erikson et al. 1986; Nashiro et al. 2012; Vaillant 2012).
Consideration of this line of evidence should not minimize the impact of
personality disorders or the need for some management of them in later life.
Even if the prevalence of personality disorders truly does decline, there are
still some elderly persons with continuing disorders that cause impairment
to themselves and their environment. Consideration of adult development
helps us understand how some persons with personality disorders may
improve and to understand that this improvement is consistent with the
epidemiological findings of reduced psychopathology in later life. Equally
important, adult developmental theory helps the clinician consider the
positive aspects of development, even in individuals with severe
psychopathology (Erikson et al. 1986; Ryff 1999). Some people who
experienced a terrible childhood and young adulthood can still find
enjoyment at the end of life. Waiting 50 or more years for relative happiness
is a long time, so assisting in positive adaptation can certainly be
worthwhile (Vaillant 2012). Until the debate on the validity of the
epidemiological findings versus the criteria used to make those findings is
more definitively settled, perhaps designations of personality disorder “in
remission” or “in partial remission” would be a more appropriate and
parsimonious way of addressing diagnoses of personality disorder in the
elderly population.

Evaluation
Because personality disorders typically have a lifelong pattern, diagnosis
generally requires greater historical and collateral information than for
many other disorders. Complete understanding of the causes of signs and
symptoms in geriatric psychiatry is a difficult accomplishment. The
interplay of multiple etiological factors is the rule rather than the exception.
The Structured Clinical Interview for DSM-IV Personality Disorders
(SCID-II; First et al. 1997) and the Personality Disorders Examination
(PDE; Loranger 1988) are semistructured interviews for personality
disorders that can be used to guide a diagnostic interview and increase
reliability. Historical information, from medical records and from persons
who have known a patient over a long period, is still an essential
component of an accurate and valid diagnosis. The interview requires a
longitudinal inquiry about various life stages to establish the historical
presence of a personality disorder, even if not all current criteria are met.
Several ancillary self-report instruments are available for initial screening
purposes. However, the results of these self-reports have a low concordance
with the results of interview methods (Perry 1992), and their use is best
established and tolerated in younger populations, not among elderly
persons, in whom acquired brain disease is an increasing issue.
General personality inventories, as opposed to personality disorder
instruments, are more valid and reliable dimensional assessment tools that
have also been used with elderly patients. Originally derived through
empirical lexical research into natural language trait descriptions, a
significant body of research has repeatedly identified five broad domains of
personality (Digman 1990). The NEO Personality Inventory—Revised
(NEO PI-R; Costa and McCrae 1992), which uses a neuroticism (e.g.,
worrying vs. calm), extraversion (e.g., joiner vs. loner), openness (e.g.,
preference for variety vs. routine), agreeableness (e.g., trusting vs.
suspicious), and conscientiousness (e.g., hardworking vs. lazy) five-factor
model with 30 facets, is the most commonly used and researched
personality inventory (Widiger and Mullins-Sweatt 2009). The NEO PI-R
has also proved useful as a screening tool for personality disorders (Miller
et al. 2005). The NEO PI-R has been validated in a geriatric population and
appears valid for screening of paranoid, borderline, histrionic, avoidant, and
dependent personality disorders (Van den Broeck et al. 2013). However, the
NEO PI-R has more than 200 items, and copyright fee issues make it
unwieldy for routine clinical use. Although DSM-5 did not make the
recommended paradigm shift to a dimensional model of personality
disorders (Oldham and Skodol 2013; Widiger and Mullins-Sweatt 2009),
Section III of DSM-5 provided an “Alternative DSM-5 Model for
Personality Disorders,” including a five-factor personality trait model with
personality disorders understood as maladaptive variants of five domains
and 25 facets. The five broad trait domains in DSM-5 are negative
affectivity versus emotional stability, detachment versus extraversion,
antagonism versus agreeableness, disinhibition versus conscientiousness,
and psychoticism versus lucidity. The Personality Inventory for DSM-5
(PID-5; Krueger et al. 2012), an instrument derived from this model, is an
“emerging measure” available for free at the American Psychiatric
Association Web site (www.psychiatry.org/practice/dsm/dsm5/online-
assessment-measures). For most clinicians, patients, and families, the full-
length 220-item instrument is probably too cumbersome for routine use;
therefore, brief forms are also available. Notably for geriatric psychiatry,
the PID-5 does not sufficiently focus on the positive dimensions of adult
development, which should be accorded equal importance with negative
dimensions when personality is being evaluated.
Geriatric psychiatrists are familiar with the phenomenon that acquired
brain disease in later life appears to strengthen undesirable personality traits
that were present, although less intense and conspicuous, in earlier adult
life. However, if signs and symptoms of personality disorder were not
present before the onset of a neurocognitive illness or brain injury, it is
rational to assume that such illnesses play a causative role in the personality
change. A reasonable approach to a diagnosis in geriatrics, as always,
includes these elements: 1) careful and detailed review of the medical and
psychosocial history; 2) mental status and physical examinations, with
special attention to the neurological examination; and 3) a screening
laboratory examination—including, in some cases, brain imaging, an
electroencephalogram, and neuropsychological tests.
In many instances, family members are better able than older patients to
provide the historical information that provides the best clues about the
patient. Whenever possible, their help should be sought concerning the
older patient in whom personality disorder is suspected. Viewing the patient
within the family context usually gives added depth of understanding to the
clinical perspective.
Syndromes based on frontal lobe pathology that result in loss of normal
executive function present some of the most difficult diagnostic challenges,
especially if the onset of symptoms is subtle, the rate of progression is slow,
and the main attributes of the premorbid personality are obscure.
Individuals with frontal or frontotemporal lobe disease may show good
preservation of memory function. They are, however, prone to trouble with
“mechanistic planning, verbal reasoning, or problem solving” and “obeying
the rules of interpersonal social behaviour, the experience of reward and
punishment, and the interpretation of complex emotions” (Grafman and
Litvan 1999, p. 1921; Passant et al. 2005).
These difficulties are similar to some of the problems experienced by
many people with borderline, narcissistic, histrionic, paranoid, and
antisocial personality disorders. A question of interest is whether a person
can develop a later-life personality disorder de novo, without the presence
of underlying brain disease or substance abuse. The answer is not
definitively known, but the occurrence is probably rare and such a diagnosis
is not allowed in DSM-5, which requires onset of personality disorder by
early adulthood. Also of relevance, signs and symptoms of personality
disorders can be quite evident in early adult life, then be diminished or
quiescent in mid-adult life, and then reemerge under the stress of social
losses or physical illness in later life (Rosowsky and Gurian 1992).
Additionally, the manifestations of personality disorders may vary in
different parts of the life cycle. For example, in persons with borderline
personality disorder, phenomena such as splitting, intense and unstable
interpersonal relationships, impaired affective regulation, and extreme
difficulty with control and regulation of anger often persist throughout the
life cycle. Problems such as severe impulsivity, risky behavior, and self-
mutilation tend to diminish with advancing age (Zanarini et al. 2007).
However, other self-injurious behaviors may take their place. These include
self-starvation, abuse of medications, and noncompliance with medical
treatment (Rosowsky and Gurian 1992). These behaviors may occur for
other reasons, but their presence should at least alert the clinician to the
possibility of borderline personality disorder. Notably, late-onset obsessive-
compulsive symptoms or traits are particularly likely to have a basis in
brain disease.

Treatment Issues
The broad focus of personality disorder treatment is on reducing symptoms,
improving social functioning, and changing responses to the environment
(Robinson 2005). Off-label use of psychotropic agents is sometimes
valuable for symptom reduction, whereas psychotherapy and caregiver
education are helpful for addressing environmental response. All of these
possibilities should be considered for their contribution to improved
function of older persons.

Psychotherapy
In contrast to the unconscious maturation of defenses, the conscious
alteration of personality is unusual. Although individuals are sometimes
able to change patterns of behavior, attitudes, ways of thinking, and ways of
feeling, changing the fundamental personality structure is extremely
difficult. At the same time, it is possible and important to try to help
patients avoid behavior that significantly harms themselves or others.
Validating feelings and empathizing with distress, without necessarily
agreeing to the proportionality of the response, is a first step in the
therapeutic relationship (Hunt 2007). Helping patients recognize and alter
erroneous or distorted thinking is thus also important and possible.
Cognitive-behavioral therapy, and its variant Dialectical Behavior Therapy
(Lynch et al. 2007), or insight-oriented psychotherapy may significantly
help older individuals who are functioning at higher levels and who are not
otherwise seriously ill or incapacitated (Beck et al. 2004; Clarkin et al.
2007; Hunt 2007). For patients in psychiatric hospitals and for residents of
group homes or nursing homes, intensive psychotherapy with a goal of
changing lifelong maladaptive personality features is neither an available
nor an indicated treatment modality. However, for such individuals,
supportive and consistent psychotherapeutic contact can be of great benefit
(Hunt 2007).
As noted, psychotherapy of any type, either by itself or in combination
with pharmacotherapy, with a goal of a global revision of maladaptive
aspects of personality in later life, is unlikely to succeed. Individualized
treatment targeting specific symptoms that discomfort, threaten, or
endanger patients or their family or caregivers—for example, behavioral
management to minimize harm from impaired social judgment—is far more
realistic and more likely to realize success. However, it is still important not
to be rigid or negative about the psychotherapeutic potential of older
individuals. It is illness, not merely age, that limits or impairs the plasticity
of the personality and the potential for self-change. Older patients are often
impressive in their resilience, courage, open-mindedness, and willingness to
try new ways of thinking and behaving—and those showing these
characteristics include some individuals whose adaptation to life in earlier
years was far from optimal (Vaillant 2012). This observation is in keeping
with Erikson’s view of progressive development throughout life.
Psychoanalytically oriented psychotherapy, cognitive-behavioral therapy,
interpersonal therapy, dialectical behavior therapy, and other forms of
psychotherapy all have their adherents and proponents (De Leo et al. 1999).
All are probably helpful to certain individuals. The principal features of
successful psychotherapy for geriatric patients are a structure with
consistency, availability, empathic and respectful listening, flexibility, and
open-mindedness on the part of the psychotherapist. These features are
probably more important than a particular theoretical orientation (Clarkin et
al. 2007).
Therapists who are not yet old themselves have a difficult challenge.
They have no direct experience with or memory of being old (Rosowsky
1999). Some geriatric psychiatrists may be two full generations younger
than their patients. Extraordinary empathy is required of these clinicians,
but also of most practicing geriatric psychiatrists, who are usually caring for
persons older than themselves.

Pharmacotherapy
A diagnosis of personality disorder should not preclude pharmacological
treatment of concomitant psychiatric disorders, such as affective illness or
psychosis, as well as specific symptoms that may respond to psychotropic
medications. Successful treatment of affective or psychotic symptoms may
show that the symptoms were the result of these eminently treatable
diseases rather than entrenched maladaptive personality traits. Personality
disorder, depressive illness, and acquired brain disease share overlapping
symptom constellations: symptoms such as irritability, hostility, and
uncooperativeness can derive from all three. Even the most perspicacious
diagnostician may not be able to tease out a clear etiological diagnosis for
these difficult behavioral symptoms. In such cases, an empirical treatment
trial with antidepressant medicine is indicated. Preliminary evidence
suggests that selective serotonin reuptake inhibitors (SSRIs) (Knutson et al.
1998; Tang et al. 2009) and second-generation antipsychotics (Black et al.
2014) may alter aspects of personality separate from specific symptoms.
Individuals with other symptoms—such as anger outbursts, apathy, and
impaired social judgment—may also benefit from pharmacotherapy
(Hollander et al. 2003). Pharmacological treatment should be a systematic
trial guided by three principles. First, a medication should be selected for an
identified target symptom area (e.g., affect, impulsivity, aggression,
anxiety) (Table 18–2). Second, such trials should include a repeatable
assessment strategy (e.g., global rating, self-report, or caregiver report
targeted to the symptom area). Third, trials should have a specified duration
at the end of which a decision is made whether or not to continue the
medication. SSRIs and other newer antidepressant drugs, anticonvulsants,
and atypical antipsychotic drugs, used alone or in combinations, may be
useful in systematic trials for specified symptoms. The evidence is limited
or mixed for geriatric patients, and caution is indicated, especially because
of the side effects of antipsychotics (Maglione et al. 2011).

Caregiver Education
Education of caregivers is an important function of geriatric psychiatrists.
Family members may be having great difficulty in dealing with unfamiliar
negative, disinhibited, or inappropriate behavior. If an underlying medical
or neurological etiology can be discerned, caregivers can be reassured about
the cause of the otherwise inexplicable changes in their relationship with
their loved one. This reassurance helps reduce guilt, anxiety, and
uncertainty in the family of the afflicted person.

TABLE 18–2. Symptom areas and pharmacotherapy classes in

personality disorders
Symptom area and types Pharmacotherapy class
Cognition/perception
Loose associations, thought Antipsychotics
blocking
Overvalued ideas, delusions
Hallucinations, depersonalization
Affect/mood
Harm/avoidance SSRIs

Depression, lability Mood stabilizers

Anger Benzodiazepines

Anxiety
Behavior
Impulsivity Mood stabilizers

Aggression TCAs, MAOIs

Novelty seeking Antipsychotics

Reward/dependence
Note. MAOI=monoamine oxidase inhibitor; SSRI=selective serotonin reuptake inhibitor; TCA =
tricyclic antidepressant.
 Primary caregivers in nursing homes, who are usually overworked and
underpaid, may not realize that much of the unpleasant behavior of patients
that they encounter in their work is not under full volitional control.
Uncooperativeness or angry outbursts may have the appearance of simple
willfulness or intentionally oppositional behavior. Patients with long-
standing personality disorders (as well as those with dementia, stroke, or
other types of brain injury) typically have significant deficits in volitional
capacity. Understanding this point does not necessarily make the care of
these patients easier, but it does provide a perspective on behavior that is
otherwise difficult to comprehend and tolerate. However, at times it may be
necessary for the psychiatrist to evaluate the competence of a patient with
personality disorder and consider proposing guardianship (Little and Little
2010).

Conclusion
Understanding of the causes of disordered personality development is far
from adequate. Diagnosis, and especially treatment, of personality disorders
in elderly patients is difficult. Understanding the differentiation between
lifelong development and acquired neuropsychiatric illness is an important
diagnostic challenge. Geriatric psychiatrists usually try to manage
personality disorder symptoms and ameliorate their harmful effects rather
than attempt to cure the underlying disorder. Behavioral management,
psychotherapy, pharmacotherapy, and caregiver support are the tools that
must be judiciously used.

Key Points
• The natural history of personality in later life is influenced by the
combination of increasing medical-neuropsychiatric comorbidity and
ongoing normal psychosocial maturation.
• Longitudinal history is necessary for determining whether presumed
personality problems in later life are a manifestation of a personality
disorder, a neurocognitive disorder, or both.
 • The prevalence of personality disorders in older persons is generally
lower than that in younger persons in the general population.
• Positive adaptation in late-life development can mediate the severity and
presentation of personality disorders.
• Substantial evidence shows the negative effect of personality disorders
on the outcome of depressive disorders in elderly persons.
• It is possible and important to use psychotherapeutic and caregiver
interventions to try to help older patients with personality disorders
avoid behavior that significantly harms themselves or others.
• Systematic pharmacological treatment should include a target symptom
area, an assessment strategy for that symptom area, and a specified
duration of treatment.

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Suggested Readings
Erikson EH, Erikson JM, Kivnick HQ: Vital Involvement in Old Age. New
York, WW Norton, 1986
Oldham JM, Skodol AE: Personality and personality disorders, and the
passage of time. Am J Geriatr Psychiatry 21:709–712, 2013
Oltmanns TF, Balsis S: Personality disorders in later life: questions about
the measurement, course, and impact of disorders. Annu Rev Clin
Psychol 7:321–349, 2011
Terracciano A, Iacono D, O’Brien RJ, et al: Personality and resilience to
Alzheimer’s disease neuropathology: a prospective autopsy study.
Neurobiol Aging 34:1045–1050, 2013
Vaillant GE: Triumphs of Experience: The Men of the Harvard Grant Study.
Cambridge, MA, Harvard University Press, 2012
van Ockenburg SL, de Jonge P, van der Harst P, et al: Does neuroticism
make you old? Prospective associations between neuroticism and
leukocyte telomere length. Psychol Med 44(4):723–729, 2014
 CHAPTER 19

Agitation in Older Adults

Mugdha E. Thakur, M.D.
Lisa P. Gwyther, M.S.W., L.C.S.W.

We would like to thank W. Goforth, M.D., who was a co-author on the previous edition of this
chapter.

Agitation in older adults is associated with a variety of diagnoses,

including mood disorders, psychotic disorders, neurocognitive disorders,
and substance use disorders. While “agitation” is not a diagnostic category,
it is overwhelmingly one of the most common referral questions in geriatric
psychiatry. The geriatric psychiatrist is frequently called upon to guide the
management of agitation seen in the context of major neurocognitive
disorders, particularly of the moderate to severe variety. Delirium,
particularly hyperactive delirium, is another frequent referral question
where geriatric psychiatrists are called upon to help with managing
agitation. Agitation, which is characterized by disruptive motor or vocal
activity, is very distressing to patients and greatly affects their quality of
life. It frequently interferes with delivery of care in medical and nursing
homes settings, causes frustration for family members, and often limits the
capacity for home care. In this chapter we focus on the diagnostic workup
of agitation as well as the pharmacological and nonpharmacological
management of agitation in the context of delirium and neurocognitive
disorders. We use the term neurocognitive disorder (DSM-5; American
Psychiatric Association 2013) interchangeably with the term dementia
throughout this chapter.
Diagnostic Approach to Patients With New-Onset
Agitation
Behavioral manifestations of major neurocognitive disorder are common
(Lyketsos et al. 2000) and represent major predictors of caregiver
depression, burden, and stress across cultures (Chen et al. 2000; Gallicchio
et al. 2002; Gitlin et al. 2012; Shankar et al. 2014; Teri 1997). Anxiety and
agitation, the most commonly cited psychiatric manifestations of major
neurocognitive disorder, can be as disruptive and painful for the patient as
they are for family caregivers. Disruptive or resistive behaviors resulting
from anxiety and agitation increase the risk of harm to the affected
individual and others (Chow and MacLean 2001; Tractenberg et al. 2001),
and caregivers frequently become frightened, upset, or simply exhausted by
the demands of caring for a family member with agitation. Agitation is also
commonly seen in hyperactive delirium, and patients with neurocognitive
disorders are at an increased risk for delirium, making delirium a likely
cause of agitation in neurocognitive disorders.
A careful psychiatric evaluation and history are key components of the
initial approach to the individual who is presenting with agitation. It is
important to determine whether the onset of agitation is acute, subacute, or
chronic. A sudden onset of disruptive behavior typically suggests a medical
etiology, whereas a slower, insidious onset of agitation may represent a
distress response to a change in caregiver, routine, or environment in a
patient who is losing capacity to express him- or herself. Agitation may also
be seen without obvious precipitants in the course of gradual progression of
neurocognitive disorder in an elderly individual. In addition to identifying
the type of onset, it is important to delineate the actual features of the
behavior. The term agitation may be used to describe behaviors ranging
from increased verbal complaining, at one end of the spectrum, to
significant aggression, at the other, depending on the care setting and the
informant. Therefore, it is very important to determine what the label
actually signifies in a given patient. This may alert the clinician to possible
etiologies such as pain/discomfort or suspiciousness.
A laboratory workup is usually required in cases of sudden onset of
agitation to rule out medical contributors. Blood chemistry, a complete
blood count, and urinalysis and urine culture should be obtained. If
respiratory symptoms are present, a chest X ray may be needed. A
computed tomography or magnetic resonance imaging brain scan may be
indicated, especially if focal neurological findings are present or there is a
sudden change in mental status. Because agitation is often associated with
sensory impairment, particularly visual and auditory deficits, audiometric
and visual testing may identify potential areas for further intervention.
Potential medical causes of agitation are shown in Table 19–1. In patients
with neurocognitive disorders, causes of agitation can also include
constipation, fatigue, dehydration, a full bladder, caffeine, incontinence,
sensory loss, immobility, depression, aphasia and delusions, hallucinations,
and misidentifications.
If an agitated patient is paranoid, part of the task of the clinician is to
determine whether the individual’s mistrustful and suspicious demeanor
may be warranted. Older adults with major neurocognitive disorders are at
high risk of abuse or neglect; therefore, exploring with family members or
relevant others a patient’s accusation of harm or neglect is often part of the
assessment. If after such exploration the clinician is not convinced that the
accusations are wholly explained by a delusion, a social services agency or
department should be requested to investigate further.

TABLE 19–1. Common medical causes of agitation in elderly persons

Medication
Drug-drug interaction
Accidental misuse
Central nervous system toxic side effect
Systemic disturbance (e.g., medication-induced electrolyte imbalance)
Urinary tract infection
Poor nutrition, decreased oral intake of food and fluid
Respiratory infection
Recent stroke
Occult head trauma if patient fell recently
Pain
Constipation
Alcohol or substance withdrawal
Chronic obstructive pulmonary disease
Approaches to Management of Agitation
Treatment of agitation can be broadly divided into nonpharmacological and
pharmacological approaches. Current recommendations emphasize
instituting measures to prevent agitation in delirium (Inouye et al. 2006)
and reserving pharmacological treatment for situations that compromise
safety. Similarly, in neurocognitive disorders, the preferred approach to
management is nonpharmacological, with pharmacological approaches used
as second-line. In this section we first discuss nonpharmacological
approaches to preventing and managing agitation in individual patients with
neurocognitive disorders. We then discuss the pharmacological
interventions available to clinicians and the specific situations in which
their use may be appropriate.

Nonpharmacological Approaches
Current person-centered dementia care assumes that most resistive
behaviors in dementia are responses to unmet needs or to environmental or
interpersonal triggers. Nonpharmacological strategies are recommended as
first-line approaches for agitation in dementia. These approaches can be
taught effectively to family and nonprofessional caregivers (Belle et al.
2006; Cohen-Mansfield et al. 2007; Doody et al. 2001; Hepburn et al. 2007;
Logsdon et al. 2007; Teri et al. 2005). These strategies focus on changing
the patient’s activities, routines, and/or human, physical, and social
environments to provide reassurance, appropriate stimulation and cues, and
security. As the individual with dementia becomes less adaptable to change,
the human and physical environment must adapt to him or her. Behavioral
approaches generally include person-specific problem solving, enriched
cues, adapted work or expressive activities, exercise, communication
strategies, and caregiver skills training.

Key Messages for Families About Agitation in Dementia

Families of persons with dementia should be told directly that anxiety,
suspiciousness, and restless agitation are common symptoms of brain
disorders, even in the context of excellent, well-intentioned family care. At
the same time, it is helpful to suggest that disruptive behaviors do not occur
in a vacuum. Agitation has a person-specific situational context and
meaning that may often, but not always, be understood. Agitated or even
aggressive behavior is often beyond a dementia patient’s control or
intentionality. In fact, he or she may not be aware of agitation or a change in
behavior.
Frequent or escalating agitation requires a prompt and multimodal
response. Ignoring agitated or disruptive behaviors will not make them go
away. Persons with dementia are most likely to be angry at what they
perceive as an intolerable situation that no longer makes sense. For this
reason it is wise for families not to take attacks or accusations personally.
Families should also be reminded that persons with dementia are more
likely to take out their frustration on those closest to them while appearing
gracious and appropriate with strangers.
Families should be told that individuals with dementia generally cannot
“try harder.” A corollary is that reasoning, arguing, coaxing, pleading,
extracting promises, confronting, or punishing agitated persons may only
escalate the distressing behavior. Families respond effectively if they
understand that agitated people with dementia are likely to be scared and
overwhelmed by disorientation and that they may forget appropriate public
or private behavior. Agitation is frequently accompanied by a loss of
impulse control and a decrease in frustration tolerance that can result in
uncharacteristic cursing, insensitivity, tactlessness, or sexually inappropriate
behavior. Although people with dementia may seem insensitive to others’
feelings, they are extremely sensitive to and will respond negatively to
patronizing, angry, tense, rushed, or demanding verbal or nonverbal
communication from family members.
Agitated individuals with dementia generally respond well to calm,
dignified, familiar settings with predictable routines and to requests tailored
to their retained noncognitive capacities, remaining strengths, and energy
levels. Although patients with Alzheimer’s disease may appear to do less as
a result of apathy, they can become fatigued from just trying to make sense
of what is going on around them. Late-day fatigue or wearing out may
explain some agitated behavior associated with “sundowning” (patients’
becoming more confused, agitated, or psychotic in the late afternoon or
early evening) and extremely exaggerated reactions to minor incidents.
Furthermore, patients with mild to moderate Alzheimer’s disease may resist
activities they perceive as too difficult or too demeaning in order to limit
embarrassment or failure.

Questions to Guide Problem Solving for Agitation in Dementia

Consideration of the following nine questions can help pinpoint and resolve
caregivers’ problems with a patient’s agitated behavior:

1. Which agitated, anxious, or resistive behaviors are most disruptive to

family life at this stage of dementia and in the current family context?
2. Describe the behavior, including its frequency, intensity, duration, and
timing. Is it harmful or does it cause distress to the person with dementia
or to others? Can the family change expectations or increase tolerance
for this change in the person as they knew him or her?
3. Is there any pattern, trigger, or time of day that sets off the behavior (e.g.,
a move, travel, hospitalization, request to do a complex task)?
4. Does anything happen afterward that makes the behavior worse (e.g.,
caregiver anger, abandonment, patient failure)?
5. Is the person uncomfortable (e.g., due to pain, hunger, thirst,
constipation, full bladder, fatigue, infection, cold, fear, misperceived
threats, difficult communication)?
6. Is the person looking for something familiar from the past (e.g.,
rummaging in drawers, searching for a toilet or an old employer)?
7. Will a change in environment help (e.g., reduction of number of people,
confusion, stimuli, noise)?
8. Can the caregiver use familiar phrases to calm or reassure the person
(e.g., “I’ll get right on it”; “Ain’t that the truth?”; “Even the Lord rested
on Sundays”)?
9. Can routines be changed or adapted to prevent future occurrences of the
behavior (e.g., exercising early in the day, bathing less frequently,
avoiding rush-hour shopping)?

Common Strategies to Reduce Agitation

Nonpharmacological strategies to reduce agitation begin with assessment of
retained abilities, patient preferences, and available family or staff
resources. Reducing triggers by treating medical or physical problems,
especially undiagnosed pain or delirium, and providing reassurance and
redirection may help as well.
Nonpharmacological strategies for reducing agitation in patients with
dementia usually involve redirection of the individual’s attention away from
triggering events or contexts or distraction with offers of pleasant events
specific to the person (e.g., going for ice cream or a ride, listening to
personalized calming or engaging music, exercise routines, watching old
videotapes). Other strategies include breaking down complex tasks into
one-step guided directions, simplifying instructions, guided choices when
decision making is overwhelming, and allowing adequate rest or passive
observation between stimulating activities. Environmental strategies include
using labels, cues, or pictures; hazard-proofing the environment to reduce
dangers of exploration or egress; removing guns or hazardous power tools
or kitchen equipment; and using lighting or security objects to reduce
nighttime confusion or daytime fear or uncertainty.

Communication Begins With Understanding

Families begin to communicate effectively when they can understand the
experience and perspectives of people with dementia. With the current
focus on early diagnosis and treatment of Alzheimer’s disease, more
individuals with insight who have new diagnoses of Alzheimer’s disease are
willing to provide direction. The following excerpts from a Canadian
support group of individuals living with early-stage dementias can offer
guidance to family caregivers:

Please don’t correct me. Remember, my feelings are intact and I get hurt easily. Try to ignore
offhand remarks that I wouldn’t have made in the past. If you focus on my mistakes, it just
makes me feel worse. I may say something that is real to me but not factual to you. It is not a
lie. Don’t argue—it won’t solve anything. (Snyder 2001, p. 2)

When a person with dementia is agitated, he or she may be thinking along

the following lines (Gwyther 2000, p. 998):

How dare you question me? I have always taken care of myself.

I make sense—you and events don’t.

Your reality and reasoning wear me out.

I am only protecting what is mine from those people—things keep disappearing.

 Can’t you see this is not a good time? I’m overwhelmed and scared.

Communication Strategies to Reduce Agitation

The following are suggestions for trying to communicate with an agitated
person with dementia: Get the person’s attention. Take time to support the
person’s dignity. Make sure vision and hearing are adequate or “tuned up.”
Make eye contact; using a clear adult tone, call the person by a preferred or
recognizable name that serves as a reminder or that props up the person’s
identity or social roles (e.g., “Good morning, Coach”); approach slowly
from the side or front or crouch down at his or her level; and offer your
hand, palm up. Listen, but do not feel compelled to talk constantly. Words
are not as important as a calm tone, pleasant expression, and nondistracting
environment (turn off the TV or turn down the radio). Use familiar words
and speak in a normal tone and tempo, but give the person time to process
and respond. Repeat your words exactly, if necessary. If you are unsure of
the person’s meaning, ask questions (e.g., “Am I getting closer to what you
want?”). Be patient—you may need to repeat yourself to reassure him or
her.
If frustration mounts, take a deep breath and suggest a better time to talk
or another topic. Avoid expressions that may be ambiguous or vague, such
as “Don’t go there,” “NOT,” or “bottom line.” Use concrete subjects,
names, and references. Avoid pronouns. Do not test or ask the person if he
or she remembers you. Use positive statements such as “It’s time for lunch
—let’s go” rather than “Do you want to go now?” Alternatively, offer
guided choices; for example, show two shirts and ask, “Would you like to
wear the red shirt or blue shirt to lunch?” Explain what happens next, but
wait until just before it will happen. Demonstrate or model so the person
can follow your lead. Use appropriate, respectful humor or his or her
favorite phrases (“See ya later, alligator”). It is always appropriate to make
fun of yourself, especially if you forget. Smile, nod, gesture, or use singing,
music, rhymes, or photos when words fail.

Summary of Nonpharmacological Approaches

Families often want brief, concrete suggestions for dealing with agitation.
The following format may be helpful (Alzheimer’s Association 2014a,
2014b; Gwyther 2001):
 DO—slow down, soothe the person, or structure the situation. Join the person in your sincere
wish to solve the problem. Respond to his or her emotions (“You seem frustrated or sad” or “This
must be hard for you”). Encourage and reinforce positive adaptations that work for the person (“I
depend on my husband for brute strength in carrying those grocery bags”). Be extra gracious and
polite. Back off and ask permission. Repeatedly reassure. Use visual and verbal cues; reduce
glare and/or add light. Offer guided choices between two options. Avoid complex multistep
directions or ambiguity. Distract with a favorite snack, or ask for help with raking or another
adult repetitive task. Increase time spent in pleasant activities such as sitting in a porch glider at
sunset. Offer a security or tactilely appealing object, rest, or privacy after an upset. Limit caffeine
and alcohol. Use comforting rituals such as holding hands during grace, an afternoon tea break,
checking the bird feeder, or a hand massage or manicure. Do for the person what he or she can no
longer comfortably do alone. Join the person in modified favorite activities—social, creative,
exercise, or sports. Remove the person from confusing, frustrating, or scary experiences such as
TV shows that the person believes are happening to him or her.
DO NOT—raise your voice, take offense, corner, crowd, restrain, rush, criticize, ignore,
confront, argue, reason, shame, blame, demand, lecture, condescend, moralize, force, explain,
teach, show alarm, or make a sudden move out of the person’s view.
SAY—May I help you? Do you have time to help me? Let’s take a break now—we have
earned it. You’re safe here. I will get right on it. Everything is under control. I apologize (even if
you didn’t do it). I’m sorry you are upset. I know it’s hard. We’re in this together. I will make
sure those men can’t get in here. Do what you can and I’ll finish up. We’re doing fine now.

Pharmacological/Medical Approaches
There are times when agitation warrants pharmacological intervention, and
the risks of persistent agitation versus the risks and benefits of treating the
agitation must be weighed carefully. Most clinicians view agitation as a
condition manifested by excessive verbal and/or motor behavior. It is
distinguished from aggression, which can also be verbal (e.g., cursing,
threats) or physical (e.g., hitting, kicking, shoving objects or people, biting,
scratching). Agitation can escalate to aggression, so it is vital for the
clinician to intervene early in approaching agitated patients. However, it is
imperative to determine the cause of agitation so that interventions can then
be directed at both treating the underlying cause and managing the agitation
itself, given that uncontrolled agitation has been demonstrated to have
multiple deleterious effects on patient and family safety and welfare.
Agitation most commonly occurs in the context of delirium or dementia,
and often these conditions coexist in frail elderly patients. These conditions
are discussed in depth in the next two subsections of the chapter. Agitation
can also be a feature of late-life depression, and although treatment of the
underlying depression should also treat the agitation, the full effect of
antidepressant medications may not be apparent for several weeks.
However, acute, severe, or escalating agitation may require medication such
as the newer atypical neuroleptics for adequate control. Benzodiazepines
should generally be avoided in an agitated patient because of their high
potential for worsening delirium as well as potentially disinhibiting the
patient further; however, they may be appropriately used in cases of alcohol
or benzodiazepine withdrawal, or when the agitation can be assumed to be
the result of severe anxiety rather than delirium or the nonspecific agitation
that can accompany dementia.

Agitation in the Context of Delirium

Delirium is a common disorder, with an estimated prevalence of 15%–50%
among hospitalized elderly patients (Inouye et al. 2007; Levkoff et al.
1991). Management of delirium is focused on primary prevention,
identifying and treating the underlying causes, minimizing psychoactive
medications, reorientation, safe and early mobilization, and normalization
of the sleep-wake cycle (Inouye et al. 2006). However, the severely agitated
delirious patient may require immediate attention if the behavior interferes
with workup or ongoing medical care, or puts the patient or care providers
at risk of physical harm.
Although the efficacy of antipsychotic agents in the acute management
of agitation is not supported by substantial evidence (Flaherty et al. 2011),
these agents remain the treatment of choice for lack of effective
alternatives. The exception is delirium secondary to alcohol or
benzodiazepine withdrawal delirium, in which case benzodiazepines
become the treatment of choice. Haloperidol has been studied as a
prophylactic agent for the prevention of delirium in older hospitalized
patients after hip surgery (Kalisvaart et al. 2005). In this randomized
placebo-controlled study, low-dose haloperidol did not reduce the incidence
of delirium but did reduce the duration and severity of the episodes,
suggesting its effectiveness for symptomatic management. Haloperidol
should be initiated at 0.5–1 mg orally or intramuscularly, and doses should
be repeated judiciously as needed. Although haloperidol typically does not
cause hypotension or significant sedation, it may produce extrapyramidal
symptoms at higher doses and should be avoided in patients with
parkinsonism. Intravenous haloperidol, although associated with
significantly fewer extrapyramidal side effects, is associated with
prolongation of the QT interval, calling for added precaution for use of the
medication. In patients with delirium who also have dementia, the use of
antipsychotics should be carefully considered in view of the black box
warning for increased all-cause mortality for patients treated with these
agents.
Oral administration of atypical antipsychotics at low doses is frequent in
practice; risperidone, olanzapine, and quetiapine may have comparable
efficacy and tolerability to low-dose haloperidol (Lonergan et al. 2007;
Maneeton et al. 2013). The use of ziprasidone or aripiprazole in delirium
currently is limited to case reports or retrospective chart reviews (Alao et al.
2005; Boettger et al. 2011; Leso and Schwartz 2002).
Treatment of alcohol or benzodiazepine withdrawal delirium depends
primarily on administration of sufficient doses of benzodiazepines to arrest
the withdrawal process; identification of this form of delirium is important
because of the high morbidity and mortality associated with it if it is not
treated appropriately. Similarly, delirium secondary to hepatic
encephalopathy has its own treatment pathway and relies primarily on the
administration of either lactulose or nonabsorbable antibiotics (rifaximin).

Agitation in the Context of Dementia

Agitation is a frequent behavioral symptom in dementia, with 24% of
caregivers in one survey reporting agitation and/or aggression (Lyketsos et
al. 2000). Agitation in dementia occurs most often in response to unmet
needs and inability to tolerate stressful unfamiliar human and physical
environments, depression, unrecognized delirium, or pain (Kales et al.
2014). A person with dementia may become agitated throughout the day,
intermittently through the day, or at specific times of day. One-fourth of
inpatients with Alzheimer’s disease were found on nursing evaluation to
exhibit sundowning behavior (Little et al. 1995). Behaviors associated with
agitation in patients who have dementia include aggression, combativeness,
disinhibition, wandering, and hyperactivity.
As with all behavioral problems, the first step in treatment is to identify
potential precipitants. The specific behavior must be clearly described, and
its timing, duration, intensity, and impact on the patient’s routine and care
need to be considered. Evaluation should include assessment for common
systemic causes (e.g., pain, infection, dehydration, constipation, other
illnesses) as well as changes in medication. Patients should also be
evaluated for depression and psychotic symptoms. Psychological factors,
such as loneliness or lack of privacy in institutional care, should be
considered. Environmental factors, such as overstimulation or lack of
stimulation, or change in surroundings also need to be considered and
addressed. Identified potential precipitants must be addressed before
consideration of treatment. In long-term-care facilities, interprofessional
teams must be involved in assessment and ongoing care of patients with
agitation.

Pharmacological Treatment
Currently, no treatments have been approved by the U.S. Food and Drug
Administration (FDA) for the management of agitation in dementia.
Moreover, nonpharmacological treatments are considered first line in the
management of these patients. Given the potential risks and limited efficacy
associated with most medications that have been studied for this indication,
pharmacological treatments are reserved for the following situations: 1) to
alleviate persistent distress, to maintain function, or to allow delivery of
needed care when nonpharmacological treatments have been tried and have
failed and 2) if the situation is serious enough to warrant urgent
pharmacological intervention (i.e., the patient is a danger to self or others).
Several medication classes have been studied for management of agitation
in dementia and are reviewed here.

Antipsychotics. Haloperidol, risperidone, aripiprazole, olanzapine, and

possibly quetiapine are the only antipsychotic agents that have shown
efficacy in placebo-controlled trials of agitation in dementia. In general,
atypical antipsychotics are the class that has been best studied; a systematic
review of all available placebo-controlled trials of atypical antipsychotics
suggests that risperidone and aripiprazole are more effective than
olanzapine, and quetiapine may be only marginally effective in addressing
dementia-related behaviors (Maglione et al. 2011). The overall
effectiveness of these agents is modest, with an effect size of 0.16
(Schneider et al. 2006). Haloperidol has comparable efficacy to atypical
antipsychotics. Atypical antipsychotics have been found to increase the risk
of somnolence, urinary tract infection or incontinence, extrapyramidal
symptoms or abnormal gait, and worsening of cognition (Schneider et al.
2006). Perhaps the biggest concern regarding the use of antipsychotics
stems from data regarding increased mortality. In 2004, the FDA conducted
a meta-analysis of 17 placebo-controlled trials of atypical antipsychotics
and found an increased risk of all-cause mortality of 4.5% in the drug group
versus 2.6% in the placebo group over a mean trial duration of 10 weeks; as
a result, all atypical antipsychotics received a black box warning for use in
patients with dementia. Jeste et al. (2008) calculated the number needed to
treat and number needed to harm and concluded that for every 9–25
agitated patients with dementia treated with an atypical antipsychotic, there
would be one death. Of the six large cohort studies comparing the mortality
risk of typical antipsychotics and atypical antipsychotics, four found a
higher risk of mortality with typical antipsychotics, and two found no
difference (Maglione et al. 2011). The FDA expanded the black box
warning to include typical antipsychotics in 2008. Whether there are
individual differences in mortality risks for different antipsychotics is not
known. Kales et al. (2012) conducted a retrospective cohort study using
data from the U.S. Department of Veterans Affairs for dementia patients
ages 65 and older who began outpatient treatment with an antipsychotic
(risperidone, olanzapine, quetiapine, or haloperidol) or valproic acid and its
derivatives (as a nonantipsychotic comparison). The total sample included
33,604 patients, and individual drug groups were compared for 180-day
mortality rates. Risperidone was used as a reference; haloperidol was found
to have the highest mortality risk, followed by risperidone, olanzapine, and
valproic acid, which were similar, and quetiapine had the lowest mortality
risk. Although this study had limitations because of its retrospective
pharmacoepidemiological design, the authors did try to account for
confounders such as site of care (haloperidol may have been prescribed in
medical settings, suggesting greater medical comorbidity and therefore
greater mortality) as well as dosage (quetiapine may have been dosed
inadequately). However, even after controlling for these confounders, the
above findings held true. Lower mortality associated with quetiapine in this
study should be correlated with the systematic review by Maglione et al.
(2011), which showed that quetiapine has marginal efficacy at best.

Mood stabilizers. Carbamazepine and valproic acid have been studied in

placebo-controlled trials for agitation in dementia. In a double-blind study
of nursing home patients, Tariot et al. (1998) found that compared with the
placebo group, patients taking carbamazepine showed significant
improvement in agitation and aggression. The drug was well tolerated. The
modal dose of carbamazepine was 300 mg/day, achieving a mean serum
level of 5.3 μg/mL. Another smaller study of outpatients treated with
carbamazepine 400 mg/day versus placebo suggests similar efficacy, but
with a trend toward worsening hallucinations (Olin et al. 2001). Patients
receiving carbamazepine should be monitored for hyponatremia,
agranulocytosis, and the possibility of drug interactions because of hepatic
cytochrome P450 enzyme induction by carbamazepine. Although valproic
acid is used quite widely in clinical practice in management of agitation,
double-blind placebo-controlled trials did not support its efficacy and in fact
revealed high rates of adverse events for valproic acid compared with
placebo (Lonegan and Luxenberg 2009; Tariot et al. 2001, 2005) In the
study by Tariot et al. (2001), 54% of the treated patients dropped out
compared with 29% of control patients. Of all treated patients, 22%
dropped out because of adverse effects, and the study had to be
discontinued prematurely. Moreover, in a retrospective study comparing
mortality rates of atypical antipsychotics and valproic acid in dementia
patients (Kales et al. 2012), valproic acid was found to have mortality rates
comparable to those of risperidone, underscoring the point that although
antipsychotic risks in dementia are well known, other agents are less well
studied and often are used based on the assumption of their safety rather
than certainty of their safety.

Antidepressants. Citalopram has been shown to be efficacious in double-

blind placebo-controlled trials for treating agitation in dementia (Pollock et
al. 2002; Porsteinsson et al. 2014). In the study by Porsteinsson et al.
(2014), citalopram’s effect was similar to what has been shown for
antipsychotics in dementia. Citalopram was associated with increased risk
of QT prolongation, as well as slight worsening of cognition, as seen in
previous antipsychotic trials. Lyketsos et al. (2003) found sertraline to be
effective in the treatment of depression among patients with dementia;
however, there was no significant benefit of sertraline on neuropsychiatric
symptoms. The authors did report that in subgroup analyses of full
responders versus nonresponders (in terms of depression symptoms), full
responders had significantly greater improvement on nonmood items of the
Neuropsychiatric Inventory (NPI). A placebo-controlled study of trazodone,
haloperidol, and behavior management techniques did not find a difference
between placebo and any of the treatment groups (Teri et al. 2000). In
another very small study, trazodone was found to be efficacious for treating
agitation in patients with frontotemporal dementia (Lebert et al. 2004).

Cholinesterase inhibitors and memantine. The Cholinesterase Inhibitor

and Atypical Neuroleptic in the Management of Agitation in Alzheimer’s
Disease (CALM-AD) study (Howard et al. 2007) was a placebo-controlled
trial of donepezil 10 mg/day for treatment of agitation in Alzheimer’s
disease. Unfortunately, donepezil was no better than placebo in this 12-
week study. Rodda et al. (2009) conducted a systematic review of
randomized, placebo-controlled trials of donepezil, rivastigmine, and
galantamine to examine their efficacy in the treatment of behavioral and
psychological symptoms of Alzheimer’s disease. Fourteen studies were
included (nine with donepezil), and median treatment duration was 24
weeks. Most studies used the NPI as a behavioral outcome measure, and
generally NPI scores at baseline were low. Four studies were designed
specifically to assess behavioral outcomes, whereas in the majority of
studies behavioral outcomes were only secondary measures. Three studies
found statistically significant, albeit modest, differences in the change of
NPI total score between drug and placebo. Perhaps the strongest evidence
for use of cholinesterase inhibitors to target agitation was in individuals
with Lewy body dementia. McKeith et al. (2000) demonstrated that
rivastigmine 12 mg/day is superior to placebo in addressing behavioral
symptoms in patients with Lewy body dementia. Patients treated with
rivastigmine were significantly less apathetic and anxious, and had fewer
delusions and hallucinations than control subjects. This finding is
particularly exciting given the neuroleptic sensitivity of patients with Lewy
body pathology. In our experience, this is the patient group in whom
cholinesterase inhibitors can make a significant impact in improving quality
of life by addressing agitation and visual hallucinations. A prospective
double-blind, placebo-controlled trial of memantine in moderate to severe
Alzheimer’s dementia failed to show its efficacy for improving agitation
(Fox et al. 2012). However, a pooled retrospective analysis of three trials of
memantine in patients who had moderate to severe Alzheimer’s disease
with agitation, aggression, or psychotic symptoms at baseline suggests
efficacy and tolerability of memantine at 12 and 24 weeks (Wilcock et al.
2008).

Other medications. Propranolol augmentation (mean dose of 106

mg/day) was found to be superior to placebo for treating agitation in
patients with Alzheimer’s disease who were maintained on stable doses of
their baseline psychotropics (Peskind et al. 2005). Unfortunately, the gains
were lost at 6-month follow-up. The α-blocker prazosin (mean dose of 6
mg/day for 8 weeks) has also been found to be efficacious in a small
placebo-controlled study for treatment of agitation in dementia (Wang et al.
2009). Individuals with orthostasis or with systolic blood pressures of less
than 110 were excluded from this study, which nevertheless had a dropout
rate of 50%. Both propranolol and prazosin should be titrated very
gradually in carefully selected patients, who should then be monitored for
orthostasis and falls. Most recently, Husebo et al. (2011) demonstrated, in a
cluster randomization study of nursing home patients with moderate to
severe dementia, that implementation of a pain management protocol for 8
weeks was better than treatment as usual at targeting agitation (which,
rather than pain, was the primary outcome measure in the study). Patients
received acetaminophen, buprenorphine patch (for those who could not take
medication orally), morphine (when acetaminophen had failed), or
pregabalin (for neuropathic pain). Seventy percent of patients in the study
took only scheduled acetaminophen, and effect size of the intervention was
comparable to that seen in atypical antipsychotic trials. Thus, a systematic
approach to the management of pain can significantly reduce agitation in
dementia. Transdermal estrogen has been found to be no better than placebo
for treatment of aggression in dementia, with in fact a rebound increase in
agitation on removal of estrogen patches at the end of the 8-week study
period (Hall et al. 2005). Finally, there are no placebo-controlled trials of
benzodiazepines for agitation in dementia, and there are no trials of
medication combinations versus individual medications.
In summary, antipsychotics are the class of medicines that are best
studied for agitation in dementia, perhaps with the best evidence for
(modest) efficacy and also evidence for harm, including an increased
mortality risk. Other agents that have shown benefit in double-blind,
randomized, placebo-controlled trials include citalopram, carbamazepine,
propranolol, prazosin, and pain medication. Table 19–2 lists the different
medication classes that can be used to treat agitation in dementia. Informed
consent of the patient or a legal representative must be obtained following
discussion of potential risks (including the black box warning in case of
antipsychotics) and benefits.
Because all efficacious treatments of agitation in dementia have inherent
risks, the need for continued pharmacological treatment of agitation should
be regularly reassessed. Devanand et al. (2012) carried out a well-designed
study of antipsychotic discontinuation in patients with Alzheimer’s disease
and psychosis or agitation. One hundred eighty patients received open-label
treatment with risperidone for 16 weeks. Responders were then randomized
to continuation of risperidone or transition to placebo. At 16 weeks, 60% in
the placebo group had relapsed versus 33% in the risperidone group. In
contrast, the Dementia Antipsychotic Withdrawal Trial in Alzheimer’s
Disease (DART-AD) study (Ballard et al. 2008) did not show detrimental
effects of stopping antipsychotic treatment when compared with placebo.
There was some evidence to suggest that patients with higher baseline
scores of agitation are more likely to benefit from continued treatment. This
study also showed a significantly increased risk of mortality for patients
who were allocated to continue antipsychotic treatment compared with
those allocated to placebo (Ballard et al. 2009). Together, these findings
suggest that although there is a risk of reemergence of agitation after
stopping antipsychotic medications, particularly in those patients with
higher baseline scores of agitation, there may be increased mortality from
long-term antipsychotic use. Given the paucity of long-term data for most
psychotropics, it is judicious to attempt dose reduction after several weeks
and discontinuation of medication if appropriate. If symptoms reemerge,
careful consideration and documentation of risks and benefits of ongoing
psychopharmacological treatment are necessary.
TABLE 19–2. Medication classes showing efficacy in double-blind,
randomized, placebo-controlled trials in addressing
agitation and aggression in patients with dementia and
suggested daily dosages (subject to tolerability)
Medication class Suggested daily dosage (mg/day)
Antipsychotics Risperidone (0.5–2 mg)
Aripiprazole (2–10 mg)
Olanzapine (2.5–10 mg)
 Quetiapine (50–200 mg)
Haloperidol (0.5–2 mg)
Antidepressant Citalopram (20 mg)
Anticonvulsant Carbamazepine (300–400 mg)
β-Blocker Propranolol (100 mg)
α-Blocker Prazosin (6 mg)

Conclusion
Geriatric psychiatrists are frequently called upon to guide the management
of agitation in elderly persons in different settings. It is important to
understand and address underlying contributors to agitation, whether they
be medical, psychological, or environmental. Instituting measures to
prevent agitation is critical, as is educating caregivers about
nonpharmacological approaches for managing agitation. Unfortunately,
most pharmacological options for treating agitation are associated with
risks. More research is needed to address what nonpharmacological
interventions are best suited to which patients and in what situations. Safer
pharmacological options are also needed to manage agitation so as to
improve the quality of life of our older patients.

Key Points
• Agitation is a common and disabling condition in elderly people.
• The causes of agitation include a wide differential that must be evaluated
and corrected prior to consideration of treatment.
• Nonpharmacological approaches are the preferred treatment for agitation
in older adults.
• When the patient does not respond to nonpharmacological approaches or
if symptoms are severe, pharmacological approaches may be warranted.
• If pharmacological means are used, ongoing risk-benefit analyses should
guide treatment; the lowest possible dosages should be used for the
shortest possible times.
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Suggested Readings
Jeste DV, Blazer D, Casey D, et al: ACNP White Paper: update on use of
antipsychotic drugs in elderly persons with dementia.
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Nassisi D, Korc B, Hahn S, et al: The evaluation and management of the
acutely agitated elderly patient. Mt Sinai J Med 73:976–984, 2006
Roger KS: A literature review of palliative care, end of life, and dementia.
Palliat Support Care 4:295–303, 2006
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adults with dementia: an evaluative review. Int Psychogeriatr 18:195–
225, 2006
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neuropsychiatric symptoms in cognitively impaired nursing home
patients. J Geriatr Psychiatry Neurol 20:41–49, 2007

Suggested Resources for Direct Care or Family

Caregivers
Bathing Without a Battle: Creating a Better Bathing Experience for
Persons with Alzheimer’s Disease and Related Dementias
(http://bathingwithoutabattle.unc.edu; accessed March 2014)
—This website provides a variety of options of bathing techniques for
patients with dementia. It also provides educational credits for nursing
home nurses and assistants.
Improving Antipsychotic Appropriateness in Dementia Patients (IA-
ADAPT) (http://www.healthcare.uiowa.edu/igec/iaadapt/ (accessed
March 2014). Iowa Geriatric Education Center, The University of Iowa
—This website provides educational resources for interprofessional
teams involved in caring for patients with dementia.
Hand in Hand: A Training Series for Nursing Homes Toolkit
(http://www.cms-handinhandtoolkit.info; accessed March 2014).
Baltimore, MD, Centers for Medicare & Medicaid Services
—This website provides education for nursing home personnel.
The 36-Hour Day, 5th Edition: The 36-Hour Day: A Family Guide to
Caring for People Who Have Alzheimer Disease, Related
Dementias, and Memory Loss, by Nancy Mace and Peter Rabins,
Johns Hopkins Press, 2011
—This is an excellent reference book that provides psychoeducation
and resources for families of patients with dementia.
About Alzheimer’s Disease: Caregiving, Alzheimer’s Disease Education
and Referral Center
(http://www.nia.nih.gov/alzheimers/topics/caregiving; accessed June
11, 2014). Bethesda, MD, National Institute on Aging
—This website offers family members helpful “tip sheets” for a variety
of topics, including challenging behaviors, everyday care,
communication, relationships, safety, and caregiver health.
 PART IV

Treatment of Psychiatric Disorders in Late

Life
 CHAPTER 20

Psychopharmacology
Benoit H. Mulsant, M.D.
Bruce G. Pollock, M.D., Ph.D.

Pharmacological intervention in late life requires special care. Older

patients are more susceptible to drug-induced adverse events. Most
concerning, several psychotropic medications have been associated during
the past decade with serious adverse events, including increased mortality
risk. Older persons are also more likely to experience adverse effects,
including cardiac effects such as prolonged QTc, arrhythmias, and sudden
death; peripheral and central anticholinergic effects such as constipation,
urinary retention, delirium, and cognitive dysfunction; antihistaminergic
effects such as sedation; and antiadrenergic effects such as postural
hypotension that not only interfere with basic activities but also lead to falls
and fractures. In addition, older patients might develop adverse effects such
as hyponatremia, bleeding, and altered bone metabolism. Increased
susceptibility to these various adverse effects in elders may be a result of the
pharmacokinetic and pharmacodynamic changes associated with aging, such
as diminished glomerular filtration, changes in the density and activity of
target receptors, reduced liver size and hepatic blood flow, and decreased
cardiac output (Pollock et al. 2009; Uchida et al. 2009) (Table 20–1).
Illnesses that affect many elderly persons (e.g., diabetes) further diminish
the processing and removal of medications from the body. In addition,
polypharmacy and the associated risk of drug interactions add another level
of complexity to pharmacological treatment in older patients. Poor
adherence to treatment regimens—which can be a result of impaired
cognition, confusing drug regimens, or lack of motivation or insight
associated with the psychiatric disorder being treated—is a significant
obstacle to effective and safe pharmacological treatment. Finally,
psychotropic medications are not as extensively studied in elders as in
younger individuals or in patients without comorbid medical illness
(Mulsant 2014; Pollock et al. 2009). New methodologies such as population
pharmacokinetics can help to address the lack of information about dosage
and drug-drug interactions (Jin et al. 2010). Nonetheless, even with currently
available knowledge, medications cause considerable morbidity in elders. In
a study by Laroche et al. (2007), 66% of the admissions to an acute geriatric
medical unit were preceded by the prescription of at least one inappropriate
medication; even among patients taking appropriate medications, the
prevalence of adverse drug reactions was 16%.
Despite these challenges, psychiatric disorders can be treated successfully
in late life with psychotropic drugs. In this chapter, we summarize relevant
geriatric data published as of November 2014 on the efficacy, tolerability,
and safety of the major psychotropic drugs.

Antidepressant Medications

Selective Serotonin Reuptake Inhibitors

Six selective serotonin reuptake inhibitors (SSRIs) are available in the
United States: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine,
and sertraline. They are approved by the U.S. Food and Drug Administration
(FDA) for the treatment of major depressive disorder (all except
fluvoxamine) and several anxiety disorders (generalized anxiety disorder:
escitalopram, paroxetine; obsessive-compulsive disorder: fluoxetine,
fluvoxamine, paroxetine, sertraline; panic disorder: fluoxetine, paroxetine,
sertraline; posttraumatic stress disorder: paroxetine, sertraline; and social
anxiety disorder: paroxetine, sertraline in adults). In older adults, SSRIs
remain first-line antidepressants (Sonnenberg et al. 2008) because of their
broad spectrum of action, high efficacy (Mukai and Tampi 2009; Pinquart et
al. 2006; Tedeschini et al. 2011), ease of use, good tolerability, and relative
safety (Mulsant et al. 2014). More than 40 randomized controlled trials
(RCTs) of SSRIs involving more than 6,000 geriatric patients with
depression have been published (Table 20–2). However, as with most drugs,
few clinical trials of SSRIs have been conducted under “real-life” geriatric
situations (e.g., in long-term-care facilities) or in very old patients. Overall,
published trials support the efficacy and tolerability of SSRIs in older
patients with major depression (Tedeschini et al. 2011). These patients are at
high risk for relapse and recurrence, and maintenance therapy with
escitalopram or paroxetine has been shown to be effective in their prevention
(Gorwood et al. 2007; Reynolds et al. 2006). Many open studies and some
small controlled trials in special populations also have concluded that SSRIs
are reasonably efficacious, safe, and well tolerated in older patients with
mild cognitive impairment (Devanand et al. 2003; Reynolds et al. 2011),
minor depression (Lavretsky et al. 2010; Rocca et al. 2005), schizophrenia
(Kasckow et al. 2001), cardiovascular disease (Glassman et al. 2002;
Serebruany et al. 2003), cerebrovascular disease (Y. Chen et al. 2007;
Murray et al. 2005; Rampello et al. 2004; Rasmussen et al. 2003; Robinson
et al. 2000, 2008), Parkinson’s disease (Barone et al. 2006; Devos et al.
2008), or other medical conditions (Arranz and Ros 1997; Evans et al. 1997;
Goodnick and Hernandez 2000; Karp et al. 2005; Lotrich et al. 2007;
Trappler and Cohen 1998), as well as in family dementia caregivers with
minor or major depression (Lavretsky et al. 2010).
Two published placebo-controlled trials of citalopram (Lenze et al. 2005)
and escitalopram (Lenze et al. 2009) support the efficacy of SSRIs in older
patients with generalized anxiety disorder. The use of SSRIs to treat other
anxiety disorders is based on small open trials (Flint 2005; Lenze et al. 2002;
Sheikh et al. 2004b; Wylie et al. 2000) or extrapolation from studies in
younger adults.

TABLE 20–1. Physiological changes in elderly persons associated with

altered pharmacokinetics
Organ system Change Pharmacokinetic consequence

Circulatory system Decreased concentration of plasma Increased or decreased free

albumin and increased α1-acid concentration of drugs in plasma
glycoprotein
Gastrointestinal tract Decreased intestinal and splanchnic Decreased rate of drug absorption
blood flow
Kidney Decreased glomerular filtration rate Decreased renal clearance of active
metabolites
Liver Decreased liver size; decreased Decreased hepatic clearance
hepatic blood flow; variable effects
on cytochrome P450 isozyme
activity
Muscle Decreased lean body mass and Altered volume of distribution of
increased adipose tissue lipid-soluble drugs, leading to
increased elimination half-life
Source. Adapted from Pollock BG: “Psychotropic Drugs and the Aging Patient.” Geriatrics 53 (suppl
1): S20–S24, 1998. Used with permission.

Several published studies, including three RCTs, suggest that citalopram

may be efficacious in the treatment of behavioral disturbances associated
with dementia, including not only agitation and disinhibition but also
delusions and hallucinations (Nyth and Gottfries 1990; Nyth et al. 1992;
Pollock et al. 1997, 2002, 2007; Porsteinsson et al. 2014). However, all these
studies used citalopram doses above the maximum of 20 mg/day
recommended by the FDA in older patients (U.S. Food and Drug
Administration 2012). In the most recent and largest placebo-controlled trial,
older patients with dementia randomized to citalopram up to 30 mg/day had
longer QTc and more cognitive impairment than those randomized to
placebo (Porsteinsson et al. 2014). The evidence supporting the use of other
SSRIs in the treatment of noncognitive symptoms associated with dementia
is much weaker: there is only one small (N = 40) published positive
randomized trial supporting the use of escitalopram in the treatment of
behavioral and psychotic symptoms (Barak et al. 2011). Some open studies
and small single-site controlled trials also supported the use of SSRIs for the
treatment of depression associated with Alzheimer’s dementia (Katona et al.
1998; Lyketsos et al. 2003; Nyth and Gottfries 1990; Nyth et al. 1992;
Olafsson et al. 1992; Petracca et al. 2001; Taragano et al. 1997). However, a
larger multicenter trial failed to confirm these results; in this study, sertraline
was not more efficacious and was less well tolerated than placebo for the
treatment of depression in Alzheimer’s disease (Rosenberg et al. 2010;
Weintraub et al. 2010). Another multicenter study also showed no
differences in the efficacy of sertraline, mirtazapine, or placebo in treating
depression in patients with Alzheimer’s disease, but the tolerability of either
drug was worse than placebo (Banerjee et al. 2011). In a double-blind
placebo-controlled discontinuation study in 128 patients with dementia and
neuropsychiatric symptoms (but no depressive disorder), discontinuation of
an SSRI that had been prescribed for at least 3 months was associated with a
worsening of depressive symptoms compared with continuing the SSRI
(Bergh et al. 2012).
TABLE 20–2. Summary of published randomized controlled trials of
selective serotonin reuptake inhibitors for the acute
treatment of geriatric depression
Medication No. of published Dosages studied (mg/day) Comments
trials (cumulative
no. of older
participants)
Citalopram 7a (1,343) 10–40 Citalopram was more
efficacious than placebo in
one of two trials and as
efficacious as amitriptyline
and venlafaxine. It was
better tolerated than
nortriptyline but associated
with a lower remission rate.
Several trials included
patients with stroke and
dementia.
Escitalopram 2b (781) 10–20 In one failed trial,
escitalopram and fluoxetine
were well tolerated but not
superior to placebo. In
another trial, escitalopram
did not differ from placebo.
Fluoxetine 13c (2,092) 10–80 Fluoxetine was more
efficacious than placebo in
two of five trials and as
efficacious as amitriptyline,
doxepin, escitalopram,
paroxetine, sertraline,
trimipramine, and
venlafaxine. In patients with
dysthymic disorder,
fluoxetine was marginally
superior to placebo. In
patients with dementia of
the Alzheimer’s type,
fluoxetine did not differ
from placebo.
Fluvoxamine 4d (278) 50–200 Fluvoxamine was more
efficacious than placebo and
as efficacious as dothiepin,
imipramine, mianserin, and
sertraline.
Paroxetine 9e (1,474) 10–60 Paroxetine was more
efficacious than placebo and
as efficacious as
amitriptyline, bupropion,
 clomipramine, doxepin,
fluoxetine, and imipramine.
Paroxetine was less
efficacious than venlafaxine
in older patients (n=30) who
had previously failed to
respond to two other
antidepressants.
Mirtazapine was marginally
superior to paroxetine. In
very old long-term-care
patients with minor
depression, paroxetine was
not more efficacious but
was more cognitively toxic
than placebo. One trial
included patients with
dementia.
Sertraline 11f (1,948) 50–200 Sertraline was more
efficacious than placebo and
as efficacious as
amitriptyline, fluoxetine,
fluvoxamine, imipramine,
nortriptyline, and
venlafaxine. Sertraline was
better tolerated than
imipramine and
venlafaxine. Greater
cognitive improvement
occurred with sertraline
than with nortriptyline or
fluoxetine. Some trials
included long-term-care
patients. In one small
single-site trial, sertraline
was more efficacious than
placebo for the treatment of
depression associated with
Alzheimer’s dementia.
However, this finding was
not replicated in a larger
multicenter trial.
aAllard et al. 2004; Andersen et al. 1994; Kyle et al. 1998; Navarro et al. 2001; Nyth and Gottfries
1990; Nyth et al. 1992; Roose et al. 2004b; Rosenberg et al. 2007.
bBose et al. 2008; Kasper et al. 2005.
cAltamura et al. 1989; Devanand et al. 2003; Doraiswamy et al. 2001; Evans et al. 1997; Feighner and
Cohn 1985; Finkel et al. 1999; Kasper et al. 2005; Petracca et al. 2001; Schatzberg and Roose 2006;
Schöne and Ludwig 1993; Taragano et al. 1997; Tollefson et al. 1995; Wehmeier et al. 2005.
dPhanjoo et al. 1991; Rahman et al. 1991; Rossini et al. 2005; Wakelin 1986.
eBurrows et al. 2002; Dunner et al. 1992; Geretsegger et al. 1995; Guillibert et al. 1989; Katona et al.
1998; Mazeh et al. 2007; Mulsant et al. 2001b; Rapaport et al. 2003; Schatzberg et al. 2002; Schöne
and Ludwig 1993.
fBondareff et al. 2000; Cohn et al. 1990; Doraiswamy et al. 2003; Finkel et al. 1999; O.V. Forlenza et
al. 2001; Lyketsos et al. 2003; Newhouse et al. 2000; Oslin et al. 2000, 2003; Rosenberg et al. 2010;
Rossini et al. 2005; Schneider et al. 2003; Sheikh et al. 2004a; Weintraub et al. 2010.

Available data from head-to-head randomized comparisons indicate that

all SSRIs currently available have similar efficacy and tolerability in the
treatment of depression (Gartlehner et al. 2011) (see Table 20–2).
Nevertheless, in older patients, experts now favor the use of escitalopram or
sertraline over citalopram, fluvoxamine, fluoxetine, or paroxetine (Mulsant
et al. 2014) because of favorable pharmacokinetic profiles (Table 20–3) and
lower potential for clinically significant drug interactions (Table 20–4) or for
other adverse effects. Notably, a warning has been issued by the FDA
against the use of dosages of citalopram above 40 mg/day in any person and
above 20 mg/day in people older than age 60 years because of a risk of
prolonged QTc and torsades de pointes (Castro et al. 2013; U.S. Food and
Drug Administration 2012; Wenzel-Seifert et al. 2011).
Some data also suggest that citalopram and sertraline may be more
beneficial in terms of cognitive improvement (Burrows et al. 2002;
Doraiswamy et al. 2003; Furlan et al. 2001; Jorge et al. 2010; Newhouse et
al. 2000; Savaskan et al. 2008). However, more recent data suggest that
citalopram—like other SSRIs—may have deleterious cognitive effects in
some older patients (Culang et al. 2009) or in patients with dementia
(Porsteinsson et al. 2014), and executive dysfunction is associated with a
lower or slower improvement from citalopram, escitalopram, or other SSRIs
(Manning et al. 2013; Sneed et al. 2010).
In older patients, SSRI starting dosages (see Table 20–3) are typically
half the minimal efficacious dosage in younger adults, and the dosage is
usually doubled after 1 week. All of the SSRIs can be administered in a
single daily dose except fluvoxamine, which should be given in two divided
doses. Even though frail older patients typically tolerate these drugs
relatively well (Oslin et al. 2000), some patients experience some
gastrointestinal distress (e.g., nausea) during the first few days of treatment.
Significant hyponatremia resulting from the syndrome of inappropriate
antidiuretic hormone secretion (SIADH) is a potentially dangerous adverse
effect that is observed almost exclusively in elderly individuals and typically
during the first couple of weeks of treatment (Coupland et al. 2011; Fabian
et al. 2004).
SSRIs, as well as other serotonergic drugs, may directly affect platelet
activation (Pollock et al. 2000), and they are associated with an increase in
the risk of cerebral, gastrointestinal, or postsurgical bleeding (Auerbach et
al. 2013; Hung et al. 2013; Looper 2007; Löppönen et al. 2014; Mortensen et
al. 2013; Shin et al. 2014; Wang et al. 2014). They act synergistically with
other medications that increase the risk of bleeding, such as nonsteroidal
anti-inflammatory drugs (NSAIDs), low-dose aspirin, or warfarin. Thus,
SSRIs should be used cautiously in older patients taking these medications,
and the prophylactic use of acid-suppressing agents should be considered in
some high-risk patients (de Abajo and García-Rodríguez 2008; Yuan et al.
2006).
SSRIs also can be associated with bradycardia and should be started with
caution in patients with low heart rates (e.g., patients taking β-blockers).
SSRIs rarely cause extrapyramidal symptoms (Mamo et al. 2000), and they
are well tolerated by most patients with Parkinson’s disease (P. Chen et al.
2007). The risk of falls and hip fracture does not differ among different
classes of antidepressants (Liu et al. 1998), but there is concern that chronic
use of SSRIs and other serotonergic drugs may contribute to the risk of
fractures through their direct effects on bone metabolism (Diem et al. 2007;
Garfield et al. 2014; Richards et al. 2007; Shea et al. 2013).

TABLE 20–3. Pharmacokinetic properties of second-generation

antidepressants
Medication Half-life Proportionality Risk of Efficacious dosage range in
(days), of dosage to uncomfortable elderly (mg/day)a
including plasma discontinuation
active concentration symptoms
metabolites
Selective serotonin reuptake inhibitors
Citalopram 1–3 Linear Low 20b
across
therapeutic
range
Escitalopram 1–2 Linear Low 10–
across 20
 therapeutic
range
Fluoxetine 7–10 Nonlinear Very low 20–
at higher 40
dosages
Fluvoxamine 0.5–1 Nonlinear Moderate 50–
at higher 300
dosages
Paroxetine 1 Nonlinear Moderate 20–
at higher 40
dosages
Sertraline 1–3 Linear Low 50–
across 200
therapeutic
range
Serotonin-norepinephrine reuptake inhibitors
Desvenlafaxine 0.5 Linear up to High 50
600 mg/day
Duloxetine 0.5 Linear Moderate 60–
across 120
therapeutic
range
Levomilnacipran 0.5 Linear Moderate 40–
across 120
therapeutic
range
Venlafaxine XR 0.2 Linear High 75–
across 300
therapeutic
range
Other second-generation antidepressants
Bupropion 1 Linear Very low 150–
across 400
therapeutic (SR)
range 150–
 450
(XL)
Mirtazapine 1–2 Linear Moderate 15–
across 45
therapeutic
range
Trazodone 5–9 Linear Low 50–
across 600
therapeutic (see
range text)
Vilazodone 1 Linear Moderate 20–
across 40
therapeutic
range
Vortioxetine 2–3 Linear Low 5–
across 20
therapeutic
range
Note. SR=sustained release; XL=extended release; XR=extended release.
aStarting dosage is typically half of the lowest efficacious dosage; all the selective serotonin reuptake
inhibitors can be administered in single daily doses except fluvoxamine, which should be given in two
divided doses.
bIn August 2011, the U.S. Food and Drug Administration issued a drug safety communication updated
in March 2012, stating the following: “20 mg per day is the maximum recommended dose for patients
with hepatic impairment, who are greater than 60 years of age, who are CYP 2C19 poor metabolizers,
or who are taking concomitant cimetidine (Tagamet), because these factors lead to increased blood
levels of citalopram, increasing the risk of QT interval prolongation and Torsade de Pointes”
(http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm).

TABLE 20–4. Second-generation antidepressants’ inhibition of

cytochrome P450 (CYP) and potential for causing or being
involved in significant drug-drug interactions
Potential for causing or
being involved in
clinically significant
drug-drug interactions
Medication CYP1A2 CYP2C9 CYP2D6 CYP3A4 Causing Being
and involved
2C19
Selective serotonin reuptake inhibitors
Citalopram + 0 + 0 Low Low
(2C19
inhibitors)
Escitalopram + 0 + 0 Low Low
(2C19
inhibitors)
Fluoxetine + ++ +++ ++ High High
Fluvoxamine +++ +++ + ++ High High
Paroxetine + + +++ + Moderate Moderate
Sertraline + + + + Low Low
Serotonin-norepinephrine reuptake inhibitors
Desvenlafaxine 0 0 0 0 Minimal Minimal
Duloxetine 0 0 + + Low Low (1A2
and 2D6
inhibitors)
Levomilnacipran, 0 0 0 0 Low Low
milnacipran
Venlafaxine 0 0 0 0 Low Low (2D6
inhibitors)
Other second-generation antidepressants
Bupropion 0 0 ++ 0 Low Moderate
(2B6
inhibitors)
Nefazodone 0 + 0 +++ High High
Trazodone 0 0 0 0 Low Moderate
(3A4
inhibitors
and
inducers)
Vilazodone 0 0 0 0 Low Low (3A4
inducers
and
inhibitors)
 Vortioxetine 0 0 0 0 Low Low (2D6
inhibitors
and 3A4
inducers)
Note. 0=minimal or no inhibition; +=mild inhibition; ++=moderate inhibition; +++=strong inhibition.

A large pharmacoepidemiological study in patients age 66 years or older

found that SSRIs, compared with non-SSRI antidepressants, are associated
with a greater risk for suicide during the first month of therapy (Juurlink et
al. 2006). However, the absolute risk was low, which suggests that there may
be a vulnerable subgroup at risk for an idiosyncratic response. By contrast, a
very large meta-analysis and controlled data available to the FDA indicated
a substantial reduction in the risk for suicidal ideation in older patients
taking SSRIs compared with those taking placebo (Barbui et al. 2009;
Friedman and Leon 2007; Nelson et al. 2007).

Serotonin-Norepinephrine Reuptake Inhibitors

As of November 2014, the FDA has approved four serotonin-norepinephrine
reuptake inhibitors (SNRIs) for the treatment of major depressive disorder in
adults: desvenlafaxine, duloxetine, levomilnacipran, and venlafaxine.
Duloxetine and venlafaxine have also been approved for the treatment of
generalized anxiety disorder, duloxetine for diabetic peripheral neuropathic
pain and fibromyalgia, and venlafaxine XR (extended release) for panic
disorder and social anxiety disorder. A fifth SNRI, milnacipran, is indicated
solely for the treatment of fibromyalgia. Because of their favorable side-
effect profile in younger individuals and their dual mechanism of action
(Chalon et al. 2003; Harvey et al. 2000), SNRIs are the preferred alternatives
to SSRIs in both younger and older patients (Alexopoulos et al. 2001;
Cooper et al. 2011; Mulsant et al. 2014). Some early meta-analyses
suggested that venlafaxine may be associated with a higher rate of remission
than SSRIs (e.g., Shelton et al. 2005; Smith et al. 2002; Stahl et al. 2002;
Thase et al. 2001, 2005a); however, a number of more recent meta-analyses
and head-to-head trials have contradicted these results or challenged their
clinical significance in both younger patients (Bradley and Lenox-Smith
2013; Cipriani et al. 2009, 2012; Gartlehner et al. 2011; Hansen et al. 2005;
Lam et al. 2010; Papakostas et al. 2007; Rush et al. 2006b, 2008; Schueler et
al. 2011; Thaler et al. 2012; Vis et al. 2005) and older patients (Mukai and
Tampi 2009; Nelson et al. 2008; Rajji et al. 2008). Also, the risk-benefit
ratio of SNRIs may differ in younger and older patients and may change the
relative desirability of these medications in the treatment of older patients.
The efficacy, tolerability, and relative safety of SNRIs in the treatment of
late-life depression are supported by 11 published controlled trials involving
about 1,700 older patients (9 trials with venlafaxine and 2 with duloxetine;
Table 20–5). Two additional analyses of geriatric data pooled from
randomized placebo-controlled trials conducted in mixed-age adults support
the efficacy of desvenlafaxine and duloxetine for late-life depression
(Kornstein et al. 2010a; Nelson et al. 2005). In a series of randomized
comparisons of desvenlafaxine with escitalopram or placebo in
perimenopausal and postmenopausal women ages 40–70 years with major
depressive disorder, desvenlafaxine and escitalopram had similar efficacy
and tolerability (Kornstein et al. 2010b; Soares et al. 2010) and
desvenlafaxine was more efficacious than placebo (Clayton et al. 2013;
Kornstein et al. 2014). Additional data from open-label studies and case
series support the efficacy of SNRIs in older individuals, including those
with atypical depression (Roose et al. 2004a), treatment-resistant depression
(Mazeh et al. 2007; Whyte et al. 2004), dysthymic disorder (Devanand et al.
2004), poststroke depression (Dahmen et al. 1999), generalized anxiety
disorder (Katz et al. 2002), chronic pain syndromes (Grothe et al. 2004),
stress urinary incontinence (Mariappan et al. 2005), or pain symptoms
associated with geriatric depression (Karp et al. 2010; Raskin et al. 2007;
Wohlreich et al. 2009).
To our knowledge, the only published data on the use of levomilnacipran
or milnacipran in geriatric patients come from one small (N = 92)
randomized placebo-controlled trial of milnacipran for the prevention of
poststroke depression (Tsai et al. 2011). Results suggest that milnacipran
was well tolerated and was more efficacious than placebo in preventing
poststroke depression. In a post hoc pooled analysis of five placebo-
controlled RCTs of levomilnacipran in patients with major depressive
disorder, the 106 patients who were 60 years of age and older experienced a
remission rate that was comparable to the remission rate of midlife patients
(Montgomery et al. 2008).
SNRIs do not significantly inhibit any of the major cytochrome P450
(CYP) isoenzymes and thus are unlikely to cause clinically significant drug-
drug interactions (Oganesian et al. 2009; Spina et al. 2012) (see Table 20–4).
However, venlafaxine and duloxetine are metabolized by CYP2D6, and their
concentration can increase markedly in genetically poor metabolizers or in
patients who are taking drugs that inhibit this isoenzyme (Whyte et al. 2006).
The concentration of duloxetine also can be increased by drugs that inhibit
CYP1A2. Dose adjustments of SNRIs are not recommended on the basis of
age, but SNRIs should be used with caution in older patients with renal or
liver disease (Dolder et al. 2010).
SNRIs inhibit the reuptake of serotonin. Thus, they share the side-effect
profile of SSRIs, including not only nausea, diarrhea, headaches, and
excessive sweating but also sexual dysfunction (Montejo et al. 2001),
SIADH and hyponatremia (Kirby et al. 2002), bleeding (de Abajo and
García-Rodríguez 2008; Löppönen et al. 2014), serotonin syndrome (McCue
and Joseph 2001; Perry 2000), changes in bone metabolism (Garfield et al.
2014; Shea et al. 2013), and discontinuation symptoms (Montgomery et al.
2009). SNRIs are also associated with adverse effects that can be linked to
their action on the adrenergic system, including dry mouth, constipation,
urinary retention, increased ocular pressure, cardiovascular problems, and
transient agitation (Aragona and Inghilleri 1998; Benazzi 1997; Dolder et al.
2010). These adverse effects appear to be dose dependent (Clayton et al.
2009; Liebowitz and Tourian 2010; Thase 1998) and are usually self-
limiting. However, the cardiovascular effects of SNRIs are of special
concern in the elderly. SNRIs can cause not only some increase in blood
pressure (Clayton et al. 2009; Thase 1998; Thase et al. 2005c; Zimmer et al.
1997) but also clinically significant orthostatic hypotension, syncope,
electrocardiographic changes, arrhythmia, acute ischemia, and death in
overdose (Clayton et al. 2009; Davidson et al. 2005; Johnson et al. 2006;
Lessard et al. 1999; Reznik et al. 1999). At present, it is not known whether
the cardiovascular risks of most of the various SNRIs differ; however, the
bulk of the available data implicates venlafaxine as more of a problem for
patients. In the United Kingdom, the National Institute for Clinical
Excellence has recommended that venlafaxine should not be prescribed to
patients with preexisting heart disease, that an electrocardiogram should be
obtained at baseline, and that blood pressure and cardiac functions should be
monitored in those patients taking higher doses (National Collaborating
Centre for Mental Health 2004). Overall, some data in adult patients suggest
that SNRIs may be less well tolerated than escitalopram and sertraline
(Cipriani et al. 2009), and a randomized trial conducted under double-blind
conditions in older nursing home residents found that venlafaxine was less
well tolerated than sertraline, without evidence for an increase in efficacy
(Oslin et al. 2003). In a large observational study, venlafaxine was associated
with a higher risk of fracture, stroke, or all-cause mortality than other
commonly prescribed antidepressants (Coupland et al. 2011); however, in
the absence of randomization, one cannot rule out that this association was
due to confounding factors that could not be controlled for.

TABLE 20–5. Summary of published randomized controlled trials of

second-generation antidepressants other than selective
serotonin reuptake inhibitors for the acute treatment of
geriatric depression
Medication No. of published trials Dosages Comments
(cumulative no. of older studied
participants) (mg/day)
Serotonin-norepinephrine reuptake inhibitors
Desvenlafaxine 0NA No published
geriatric
randomized
trial as of
November
2014.
Duloxetine 2b (681) 20–60 Duloxetine was
more
efficacious and
as well
tolerated as
placebo in one
trial (in this
trial, duloxetine
also showed
efficacy on pain
and cognitive
measures). In a
second trial,
duloxetine was
more
efficacious than
placebo on
secondary
measures but
not on the
primary
efficacy
measure and
 duloxetine was
less well
tolerated.
Levomilnacipran, 0NA No published
geriatric
milnacipran randomized
trial as of
November
2014.
Venlafaxine 9d (1,032) 50– Venlafaxine did
not differ from
300 placebo in one
trial.
Venlafaxine
was as
efficacious as
citalopram,
clomipramine,
dothiepin,
fluoxetine,
nortriptyline,
and sertraline
and was more
efficacious than
paroxetine (in
30 older
patients who
had previously
failed to
respond to two
other
antidepressants)
and trazodone.
It was less well
tolerated than
placebo,
fluoxetine, and
sertraline;
tolerated as
well as
citalopram and
dothiepin; and
better tolerated
than
clomipramine,
nortriptyline,
and trazodone.
Other second-generation antidepressants
Bupropion 2a (163) 100– Bupropion was as
efficacious as
 450 imipramine and
paroxetine.
Mirtazapine 2c (370) 15– Mirtazapine was
as efficacious
45 as low-dose
(total daily
dose=30–90
mg)
amitriptyline
and marginally
superior to
paroxetine.
Vilazodone 0 NA No published
geriatric
randomized
trial as of
November
2014.
Vortioxetine 0 NA No published
geriatric
randomized
trial as of
November
2014.
Note. NA=not applicable.
aBranconnier et al. 1983; Doraiswamy et al. 2001; Weihs et al. 2000.
bRaskin et al. 2007; Wohlreich et al. 2009; Oakes et al. 2013; Robinson et al. 2014.
cHøyberg et al. 1996; Schatzberg et al. 2002.
dAllard et al. 2004; Gastó et al. 2003; Kok et al. 2007; Mahapatra and Hackett 1997; Mazeh et al.
2007; Oslin et al. 2003; Schatzberg and Roose 2006; Smeraldi et al. 1998; Trick et al. 2004.

In conclusion, it seems prudent not to use SNRIs as first-line agents in

older patients but to reserve SNRIs for those whose symptoms do not
respond to one or two SSRIs (Alexopoulos et al. 2001; Mulsant et al. 2001a,
2014) or those who present with depression and chronic pain (Karp et al.
2010; Raskin et al. 2007; Wohlreich et al. 2009). This recommendation is
congruent with the results from small geriatric studies (Cooper et al. 2011;
Karp et al. 2008; Mazeh et al. 2007; Whyte et al. 2004) and with the results
from the Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) study (Rush et al. 2006a, 2006b, 2008). In this large study,
mixed-age patients who had failed to respond to a first-line SSRI had similar
outcomes when the next treatment step was to augment the SSRI with
sustained-release bupropion or buspirone, switch to another SSRI, or switch
to an agent from another class (i.e., bupropion or venlafaxine XR). The
following steps included using a combination of venlafaxine XR and
mirtazapine with outcomes similar to those associated with switching to the
monoamine oxidase inhibitor (MAOI) tranylcypromine (Rush et al. 2006a,
2006b, 2008). One should be cautious when combining venlafaxine and
mirtazapine in older patients with cardiovascular disease given the recent
warning that mirtazapine can cause prolongation of QT and torsades de
pointes, in particular when it is combined with other drugs that can also
prolong the QT interval (Health Canada Advisory 2014).

Other Second-Generation Antidepressants

Only limited controlled data support the efficacy and safety of bupropion,
nefazodone, or mirtazapine in older populations, and to our knowledge, as of
November 2014, there are no published data on the use of vilazodone or
vortioxetine in geriatric patients (see Table 20–5). Because of their usually
favorable side-effect profiles and their different mechanisms of action,
bupropion and mirtazapine are often used as monotherapy in older
individuals who cannot tolerate SSRIs or SNRIs, or as monotherapy or in
combination in older individuals who do not respond to SSRIs or SNRIs
(Alexopoulos et al. 2001; Buchanan et al. 2006; Mulsant et al. 2001b, 2014).

Bupropion
Published data supporting the safety and efficacy of bupropion in geriatric
depression are limited to small controlled trials (see Table 20–5) and one
small open study (Steffens et al. 2001). Expert consensus favors the use of
bupropion—alone or as an augmentation agent—in older depressed patients
whose symptoms have not responded to SSRIs or who cannot tolerate them
(Alexopoulos et al. 2001; Buchanan et al. 2006; Mulsant et al. 2001a, 2014).
In particular, bupropion can be helpful for patients who complain of nausea,
diarrhea, unbearable fatigue, or sexual dysfunction during SSRI treatment
(Nieuwstraten and Dolovich 2001; Thase et al. 2005b). Although
augmentation with bupropion has been reported to be helpful in patients who
were partial responders to SSRIs or venlafaxine (Bodkin et al. 1997; Spier
1998), the safety of this combination in older patients has not been
established (Joo et al. 2002). Controlled data on the use of bupropion in
individuals with heart disease (Kiev et al. 1994; Roose et al. 1991), in
smokers (Tashkin et al. 2001), and in persons with neuropathic pain
(Semenchuk et al. 2001) confirm clinical experience that bupropion is
relatively well tolerated by medically ill patients. Bupropion is
contraindicated in patients who have or are at risk for seizure disorders (e.g.,
poststroke patients). However, the sustained-release preparation of
bupropion appears to be associated with a very low incidence of seizure,
comparable to that of other antidepressants (Dunner et al. 1998). Bupropion
also has been associated with the onset of psychosis in case reports (Howard
and Warnock 1999), and the prudent action is to avoid this medication in
psychotic patients or in agitated patients at risk for the development of
psychotic symptoms. The propensity of bupropion to induce psychosis in at-
risk patients has been attributed to its action on dopaminergic
neurotransmission (Howard and Warnock 1999). The same mechanism has
been hypothesized to underlie the association of bupropion with gait
disturbance and falls in some patients (Joo et al. 2002; Szuba and Leuchter
1992).
Bupropion is a moderate inhibitor of CYP2D6 (Kotlyar et al. 2005) (see
Table 20–4). It appears to be metabolized by CYP2B6 (Hesse et al. 2004),
and adverse effects of bupropion such as seizures or gait disturbance may be
more likely in individuals who take drugs that inhibit CYP2B6, such as
fluoxetine or paroxetine (Joo et al. 2002).

Mirtazapine
The antidepressant activity of mirtazapine has been attributed to its blockade
of α2 autoreceptors, resulting in a direct enhancement of noradrenergic
neurotransmission and an increase in the synaptic levels of serotonin (5-
hydroxytryptamine [5-HT]), indirectly enhancing neurotransmission
mediated by serotonin type 1A (5-HT1A) receptors. In addition, like the
antinausea drugs granisetron and ondansetron, mirtazapine inhibits 5-HT2
and 5-HT3 receptors. Thus, mirtazapine could be particularly helpful for
individuals who do not tolerate SSRIs because of sexual dysfunction
(Gelenberg et al. 2000; Montejo et al. 2001), tremor (Pact and Giduz 1999),
or severe nausea (Pedersen and Klysner 1997). In one case series,
mirtazapine was used successfully to treat depression in 19 mixed-age
oncology patients who were receiving chemotherapy (Thompson 2000). It
also has been combined with SSRIs (Pedersen and Klysner 1997); however,
these combinations should be used cautiously because they have been
associated with a serotonin syndrome in an older patient (Benazzi 1998).
The STAR*D study found that a combination of mirtazapine and venlafaxine
XR had modest efficacy in patients with treatment-resistant depression,
comparable to the efficacy of the MAOI tranylcypromine (Rush et al.
2006a); however, only a few STAR*D participants were elderly, and the
safety of this combination has not been established in older patients.
No published placebo-controlled trials and only two comparator-
controlled trials of mirtazapine in geriatric depression have been done (see
Table 20–5). Consistent with this paucity of controlled data, experts favor
the use of mirtazapine as a third-line drug in older depressed patients who
cannot tolerate or whose symptoms have not responded to SSRIs or
venlafaxine (Alexopoulos et al. 2001). Mirtazapine also has been used to
treat depression in frail nursing home patients (Roose et al. 2003) and in
older patients with dementia (Raji and Brady 2001), but there are concerns
about its effect on cognition. It has been shown to impair driving
performance in two placebo- and active comparator–controlled trials in
healthy volunteers (Ridout et al. 2003; Wingen et al. 2005) and to cause
delirium in older patients with organic brain syndromes (Bailer et al. 2000).
This deleterious effect on cognition is possibly a result of mirtazapine’s
antihistaminergic and sedative effects. Other adverse effects of mirtazapine
include weight gain with lipid increase (Nicholas et al. 2003), hyponatremia
(Cheah et al. 2008), and, very rarely, neutropenia or even agranulocytosis
(Hutchison 2001). In a large observational study in older primary care
patients treated for depression, mirtazapine was associated with a higher risk
of stroke and mortality than other commonly prescribed antidepressants
(Coupland et al. 2011); however, in the absence of randomization, one
cannot rule out that this association was due to confounding factors that
could not be controlled for. In March 2014, Merck Canada issued a warning
endorsed by Health Canada that mirtazapine can cause QT prolongation and
torsades de pointes in association with overdose or when other risk factors
for QT prolongation are present (e.g., in patients with cardiovascular disease
or when combined with other medications that can cause QT prolongation)
(Health Canada Advisory 2014).

Trazodone
Trazodone is indicated for the treatment of major depressive disorder, but it
is now almost exclusively used off-label as a hypnotic or a sedative agent
(Bossini et al. 2012) due to its sedative effect associated with antagonism of
the 5-HT2A receptor and, to a lesser extent, the 5-HT2B, 5HT1A, and α1
receptors. To minimize adverse effects, doses should be kept low (e.g., 50–
150 mg at bedtime) when trazodone is used as a hypnotic agent. Some
evidence going back to the early 1990s indicates that trazodone at low to
moderate doses (50–300 mg/day) has an efficacy comparable to that of
haloperidol in the treatment of agitation or aggression in patients with
dementia (Henry et al. 2011; Houlihan et al. 1994; Sultzer et al. 1997; Teri et
al. 2000). In a unique small (N=30) RCT, trazodone (50 mg given at 10
P.M.) was well tolerated, and it was more efficacious than placebo in the
treatment of sleep disturbances of patients with Alzheimer’s disease
(Camargos et al. 2014).
At doses typically used to treat depression (300–600 mg/day), trazodone
antagonism of α1-adrenergic receptors may cause dry mouth, orthostatic
hypotension (with syncope), QT prolongation or arrhythmias, and priapism
(which is rare in older adults). Like other psychotropic medications,
trazodone has been associated with hyponatremia and it can be involved in a
serotonergic syndrome, in particular when combined with SSRIs or SNRIs
or other medications that also affect the serotonergic system. In a large
observational study in older primary care patients treated for depression,
trazodone was associated with the highest risk of all-cause mortality among
11 commonly prescribed antidepressants (Coupland et al. 2011); however, in
the absence of randomization, one cannot rule out that this association was
due to confounding factors that could not be controlled for. Trazodone is
mostly metabolized by CYP3A4. Therefore, its dose should be reduced
when it is coprescribed with medications that inhibit this liver enzyme (see
Table 20–4), and drinking a large quantity of grapefruit juice should be
discouraged in patients taking trazodone.

Nefazodone
Given the absence of any controlled trials of nefazodone in treating geriatric
depression, mediocre outcomes in an open study (Saiz-Ruiz et al. 2002),
potentially problematic drug-drug interactions caused by its strong inhibition
of CYP3A4 (see Table 20–4), and reports that the incidence of hepatic
toxicity or even liver failure is 10- to 30-fold higher with nefazodone than
with other antidepressants (Carvajal García-Pando et al. 2002), nefazodone
should not be used in older patients.

Vilazodone and Vortioxetine

Vilazodone is a newer antidepressant that acts as both a serotonin reuptake
inhibitor and a partial agonist at the 5-HT1A receptor, with negligible
noradrenergic or dopaminergic effects. In clinical trials in adults, the most
common adverse effects were diarrhea, nausea, and headache. Vortioxetine
is the newest antidepressant available in the United States. It has a complex
multimodal mechanism but predominantly seems to be a serotonin reuptake
inhibitor (Berhan and Barker 2014). In clinical trials in adults, its most
common adverse effects were nausea, constipation, and vomiting. The full
prescribing information for vortioxetine (Physicians’ Desk Reference 2014)
does not recommend dosage adjustments in older people and reports that in a
study of 300 cognitively intact adults ages 64–88 with recurrent major
depressive disorder, patients randomized to vortioxetine 5 mg/day
experienced a greater reduction in depressive symptoms than those
randomized to placebo. However, as of November 2014, given the absence
of published randomized clinical trials or open studies of vilazodone or
vortioxetine in geriatric patients, it is prudent to avoid their use in older
patients (Mulsant et al. 2014; Schiff et al. 2011).

Tricyclic Antidepressants and Monoamine Oxidase Inhibitors

Tricyclic antidepressants (TCAs) and MAOIs have become third- and
fourth-line drugs in the treatment of late-life depression because they are less
well tolerated than SSRIs, they have a narrow therapeutic range, and their
use requires special precautions (Mulsant et al. 2001a; Rajji et al. 2008; von
Wolff et al. 2013; Wilson and Mottram 2004). The tertiary-amine TCAs—
amitriptyline, clomipramine, doxepin, and imipramine—can cause
significant orthostatic hypotension and anticholinergic effects, including
cognitive impairment, and they should be avoided in elderly persons
(American Geriatrics Society 2012 Beers Criteria Update Expert Panel 2012;
Beers 1997). The secondary amines desipramine and nortriptyline are
preferred in older patients (Mulsant et al. 2014). They have a lower
propensity to cause orthostasis and falls, in addition to having linear
pharmacokinetics and more modest anticholinergic effects (Chew et al.
2008). Their relatively narrow therapeutic index (i.e., the plasma level range
separating efficacy and toxicity) necessitates monitoring of plasma levels
and electrocardiograms in older patients. A single dose is given at bedtime;
5–7 days after initiation of desipramine at 50 mg or nortriptyline at 25 mg,
plasma levels should be measured and dosages adjusted linearly, with
targeted plasma levels of 200–400 ng/mL for desipramine and 50–150
ng/mL for nortriptyline. These narrow ranges ensure efficacy while
decreasing risks of cardiac toxicity and other side effects. Like the tertiary-
amine TCAs, desipramine and nortriptyline are type 1 antiarrhythmics: they
have quinidine-like effects on cardiac conduction and should not be used in
patients who have or are at risk for cardiac conduction defects (Roose et al.
1991). Most anticholinergic side effects of desipramine or nortriptyline (e.g.,
dry mouth, constipation) resolve with time or usually can be mitigated with
symptomatic treatment (Rosen et al. 1993). TCAs have been associated with
cognitive worsening compared with placebo (Reifler et al. 1989) and with
less cognitive improvement than occurs with sertraline (Bondareff et al.
2000; Doraiswamy et al. 2003) or other SSRIs.
Even though MAOIs have been found to be efficacious in older depressed
patients (Georgotas et al. 1986), and they may have a special role in patients
with atypical or treatment-resistant depression, these medications are now
rarely used in older patients (Shulman et al. 2009). This is in large part
because they can cause significant hypotension or life-threatening
hypertensive or serotonergic crises as a result of dietary or drug interactions.
When MAOIs are used in older individuals whose symptoms have typically
failed to respond to SSRIs, SNRIs, and TCAs, phenelzine is preferred to
tranylcypromine because it has been more extensively studied in older
patients (Georgotas et al. 1986). A typical starting dosage would be 15
mg/day, with a target dosage of 45–90 mg/day in three divided doses.
Patients need to follow dietary restrictions (Shulman and Walker 2001) and
to inform any health care providers (including pharmacists) that they are
taking an MAOI. Another option is the selegiline transdermal patch, which
was developed to deliver selegiline blood concentrations sufficient to inhibit
monoamine oxidase A and B (MAO A and MAO B) in the brain without
inhibiting MAO A in the gastrointestinal tract, thereby reducing the risk of
hypertensive crisis (Nandagopal and DelBello 2009). No geriatric data are
available, but dietary restrictions are not needed at the 6-mg/24-hour dosage;
however, they are recommended with higher dosages (Robinson and
Amsterdam 2008), and potentially lethal drug interactions remain a concern.

Psychostimulants
Even though some clinicians prescribe psychostimulants for the treatment of
late-life mood disorders, this practice has minimal empirical support. A few
small double-blind trials suggested that methylphenidate is generally well
tolerated and modestly efficacious for medically burdened depressed elders
(Satel and Nelson 1989; Wallace et al. 1995). Methylphenidate also has been
used for the treatment of apathy and anergia associated with late-life
depression or dementia (Herrmann et al. 2008). A small study suggested that
methylphenidate can be used in older depressed patients to augment SSRIs,
which inhibit dopamine release and may contribute to apathy and fatigue
(Lavretsky et al. 2006). The wakefulness-promoting agent modafinil and its
R-enantiomer armodafinil appear to induce a calm alertness through
nondopaminergic mechanisms. These agents have been used to target apathy
and fatigue in patients taking SSRIs (Dunlop et al. 2007; Fava et al. 2007;
Goss et al. 2013) and as adjunctive treatment for negative symptoms of
schizophrenia (Lindenmayer et al. 2013), but there are almost no published
geriatric data for these drugs (Darwish et al. 2011; Varanese et al. 2013).
Caution is advised regarding the possible exacerbation by methylphenidate
and other psychostimulants of anxiety, psychosis, anorexia, or hypertension
and potential interactions with warfarin. Experience with other dopaminergic
medications, such as pergolide, piribedil, pramipexole, and ropinirole, in
elderly patients has been limited, but there have been several encouraging
controlled trials in patients with Parkinson’s disease and depression (Aiken
2007; Barone et al. 2006, 2010; Rektorová et al. 2003) and in elderly
patients with cognitive impairment (Nagaraja and Jayashree 2001).

Antipsychotic Medications
In older adults, as in other age groups, atypical antipsychotics are now being
prescribed as first-line drugs for the treatment of psychotic symptoms of any
etiology. Studies support the efficacy of these agents in the treatment of late-
life schizophrenia and late-onset psychoses (Scott et al. 2011; Suzuki et al.
2011) and in the treatment of behavioral and psychological symptoms of
dementia (Maher et al. 2011; Maher and Theodore 2012). However, use of
these agents in patients with dementia is being questioned (Ballard and
Corbett 2010; Mulsant 2014; Salzman et al. 2008). In 2005, two highly
publicized reports and an FDA warning indicated a nearly twofold increase
in the rate of deaths in older patients with behavioral and psychological
symptoms of dementia treated with atypical antipsychotics when compared
with placebo (Kuehn 2005; Schneider et al. 2005). These reports have led to
a reexamination of the safety of both conventional and atypical
antipsychotics in older patients. Over the past decade, a series of studies
have emphasized their association with mortality (Ballard et al. 2009;
Langballe et al. 2014; Ray et al. 2009; Wang et al. 2005), stroke (Gill et al.
2005; Herrmann et al. 2004), severe hyperglycemia in patients with diabetes
(Lipscombe et al. 2009), fractures (Liperoti et al. 2007), and venous
thromboembolism (Kleijer et al. 2010). The relative safety of atypical
compared with conventional antipsychotics remains unclear: atypical
antipsychotics appears to be associated with lower mortality than typical
antipsychotics (Langballe et al. 2014; Schneider et al. 2005) and they may
cause fewer falls (Hien et al. 2005; Landi et al. 2005) and fewer
extrapyramidal symptoms (Lee et al. 2004; Meagher et al. 2013; Rochon et
al. 2005; van Iersel et al. 2005); however, they may cause more
cerebrovascular events (Percudani et al. 2005), venous thromboembolism
(Liperoti et al. 2005), and pancreatitis (Koller et al. 2003). Given the
increased recognition of the risks associated with the use of antipsychotics in
older patients, clinicians need to consider their potential risks and benefits
for each individual patient (Gauthier et al. 2010; Rabins and Lyketsos 2005).
Antipsychotics should be prescribed only to patients who have failed to
respond to nonpharmacological interventions or alternative medications
(Ballard and Corbett 2010; Mulsant 2014; Sink et al. 2005). When
antipsychotics are prescribed to older patients, the minimal effective dose
should be used for the shortest possible duration (Tsuboi et al. 2011). Their
long-term use is justified when they are used to treat schizophrenia, bipolar
disorder, and possibly major depressive disorder with psychotic features;
discontinuation should be attempted in stable patients with other disorders.
Although antipsychotics can be discontinued safely in most older patients
with dementia, their discontinuation can be associated with poor outcomes,
in particular in older patients who had presented with more severe agitation
or psychosis (Declercq et al. 2013).

Risperidone
Of the atypical antipsychotics currently available in the United States,
risperidone has the most published geriatric data for a variety of conditions
(Schneider et al. 2005, 2006a; Sink et al. 2005; Suzuki et al. 2011). The
efficacy and tolerability of risperidone in the treatment of behavioral and
psychological symptoms of dementia have been reported in several
randomized placebo-controlled trials (e.g., Brodaty et al. 2003; De Deyn et
al. 1999, 2005b; Katz et al. 1999; Schneider et al. 2006a, 2006b; Sink et al.
2005); in randomized comparisons with haloperidol (Chan et al. 2001; De
Deyn et al. 1999; Suh et al. 2004), promazine and olanzapine (Gareri et al.
2004), and olanzapine (Fontaine et al. 2003; Mulsant et al. 2004); and in
many uncontrolled studies or large case series. The efficacy of risperidone in
the treatment of agitation or psychosis is further supported by a placebo-
controlled trial showing that individuals with Alzheimer’s disease whose
agitation or psychosis had responded acutely to risperidone experienced an
increased risk of relapse when they were switched to placebo after 4 months
(hazard ratio 1:9) or 8 months (hazard ratio 4:9) compared with those who
remained on risperidone (Devanand et al. 2012). Taken together, these data
support risperidone as a first choice among antipsychotics for the treatment
of patients with dementia and distressing psychosis or severe agitation.
However, the substantial risks associated with the use of risperidone and
other atypical antipsychotics in these patients—including increased mortality
(number needed to harm=87) and stroke (number needed to harm=53)
(Maher and Theodore 2012; Maher et al. 2011)—should lead to caution.
The efficacy and tolerability of risperidone in the treatment of late-life
schizophrenia are supported by one randomized comparison with olanzapine
(Harvey et al. 2003; Jeste et al. 2003) and one randomized open-label study
of crossover from conventional antipsychotics to risperidone or olanzapine
(Ritchie et al. 2003, 2006). The parallel study showed similar efficacy
between olanzapine and risperidone but more weight gain and less cognitive
improvement with olanzapine. In the crossover study, patients switched to
olanzapine were more likely to complete the switching process and to show
an improvement in psychological quality of life. The results from these two
controlled trials are supported by a large body of uncontrolled data in older
patients with schizophrenia and other psychotic disorders (e.g., Davidson et
al. 2000; Madhusoodanan et al. 1999). In addition, an analysis of 57 patients
with schizophrenia ages 65 years and older who participated in randomized
studies of the long-acting injectable (“depot”) risperidone (Risperdal Consta)
found that it was well tolerated and produced significant symptomatic
improvements (Lasser et al. 2004).
One randomized comparison with haloperidol (Han and Kim 2004) and
some uncontrolled data (e.g., Mittal et al. 2004; Parellada et al. 2004)
support the efficacy and tolerability of risperidone in the treatment of
delirium (Wang et al. 2013). In another RCT, a significantly lower incidence
of delirium was observed in patients given a single 1-mg dose of risperidone
just after cardiac surgery than in those given placebo (Prakanrattana and
Prapaitrakool 2007; Zhang et al. 2013). However, there have been several
case reports of delirium induced by risperidone. One small randomized
comparison with clozapine (N=10) (Ellis et al. 2000) and several open trials
of low-dose risperidone in the treatment of Parkinson’s disease and drug-
induced psychosis or Lewy body dementia have had inconsistent results,
with clear worsening of parkinsonian symptoms in some studies (e.g., Culo
et al. 2010; Ellis et al. 2000; Leopold 2000). Thus, risperidone should be
used with great caution in the treatment of these disorders (Parkinson Study
Group 1999).
As with other atypical antipsychotics, the efficacy and tolerability of
risperidone in younger patients with bipolar disorder (and possibly other
mood disorders) (Andreescu et al. 2006) are well established. However,
given the risks associated with antipsychotics, experts continue to favor the
use of mood stabilizers as first-line agents for older patients with bipolar
disorder, except in the presence of severe mania or mania with psychosis, in
which case they favor combining risperidone, olanzapine, or quetiapine with
a mood stabilizer (Sajatovic et al. 2005b, 2013; Young et al. 2004).
Commonly reported side effects of risperidone include orthostatic
hypotension (on initiation of treatment) and extrapyramidal symptoms that
are dose dependent (Katz et al. 1999). At a given dosage, concentrations of
risperidone (and possibly its active metabolite paliperidone or 9-
hydroxyrisperidone) seem to increase with age (Aichhorn et al. 2005).
Therefore, typical dosages should be between 0.5 and 2 mg/day for older
patients with dementia and lower than 4 mg/day for older patients without
dementia. Of all the atypical antipsychotics, risperidone appears to be the
most likely to be associated with hyperprolactinemia (Kinon et al. 2003).
Risperidone causes only moderate electroencephalographic abnormalities
(Centorrino et al. 2002), and it is rarely associated with cognitive
impairment, probably because of its low affinity for muscarinic receptors
(Chew et al. 2006; Harvey et al. 2003; Mulsant et al. 2004). Like other
antipsychotics, risperidone can cause weight gain, diabetes, or dyslipidemia.
It is more likely to do so than are aripiprazole and ziprasidone but less likely
than are clozapine, olanzapine, and quetiapine (American Diabetes
Association et al. 2004; Feldman et al. 2004; Zheng et al. 2009).

Paliperidone
Paliperidone is the active 9-hydroxy metabolite of risperidone, and therefore
some of its pharmacological action, efficacy, and side effects are similar to
those of risperidone. Its once-daily extended-release formulation takes 24
hours to reach a maximum concentration, and its clearance is not affected by
hepatic impairment or CYP2D6 metabolism but is affected by renal
function. It is the only medication indicated for the treatment of
schizoaffective disorder in the United States. Its efficacy and tolerability in
the treatment of older patients with psychosis is supported by data from 125
subjects ages 65 years and older who participated in three 6-week
registration trials that led to the medication’s approval by the FDA for the
treatment of schizophrenia (e.g., Davidson et al. 2007; Kane et al. 2007).
Otherwise, limited available data support the efficacy and safety of
paliperidone in the treatment of older patients with schizophrenia
(Madhusoodanan and Zaveri 2010): in a 6-week randomized placebo-
controlled trial followed by a 24-week open-label extension, 114 patients
ages 65 years and older (mean age of 70) received paliperidone 3–12 mg/day
or placebo. Discontinuation due to adverse events and weight gain were
similar in the two groups. Half of the patients treated with paliperidone
experienced prolactin elevation, but it was not related to any adverse event.
Changes in efficacy measures were similar in the two groups (Tzimos et al.
2008). Paliperidone has not yet been systematically studied in older patients
with bipolar disorder or dementia, and doses remain speculative for these
populations. The availability of a long-acting injectable form of paliperidone
that requires only monthly injections is an attractive option for patients who
require a long-acting injectable antipsychotic (González-Rodríguez et al.
2014; Rado and Janicak 2012), but its more widespread use is impeded by a
paucity of geriatric data.

Olanzapine
Next to risperidone, olanzapine has the most published geriatric data. Its
efficacy and tolerability in the treatment of behavioral and psychological
symptoms of dementia have been reported in several randomized placebo-
controlled trials (e.g., Clark et al. 2001; De Deyn et al. 2004; Schneider et al.
2006b; Street et al. 2000) and in randomized comparisons with haloperidol
(Verhey et al. 2006), promazine or risperidone (Gareri et al. 2004), and
risperidone (Fontaine et al. 2003; Mulsant et al. 2004). However, a meta-
analysis of published and nonpublished placebo-controlled trials of
olanzapine in the treatment of behavioral and psychological symptoms of
dementia concluded that “olanzapine was not associated with efficacy
overall” (Schneider et al. 2006a, p. 205). More recently, a 2011 review
published by the U.S. Agency for Healthcare Research and Quality focusing
on data available since 2006 concluded that—like aripiprazole and
risperidone—olanzapine is associated with statistically significant small
benefits for older patients with behavioral disturbances associated with
dementia (Maher and Theodore 2012; Maher et al. 2011).
The efficacy and tolerability of olanzapine in the treatment of late-life
schizophrenia have been confirmed in two randomized comparisons with
haloperidol (Barak et al. 2002; Kennedy et al. 2003) and two randomized
comparisons with risperidone (Harvey et al. 2003; Jeste et al. 2003; Ritchie
et al. 2003, 2006). In one RCT in patients with delirium, olanzapine and
haloperidol were found to have comparable efficacy (Skrobik et al. 2004). In
another RCT, a significantly lower incidence of delirium was observed in
patients given 5 mg of olanzapine just before and just after joint replacement
surgery compared with patients given placebo; however, when delirium
occurred, it was longer and more severe in patients who had received
olanzapine (Larsen et al. 2010; Zhang et al. 2013). Caution is needed when
using olanzapine in patients with delirium because some controlled trials
have reported some cognitive worsening in patients with dementia while
taking olanzapine (Kennedy et al. 2005; Mulsant et al. 2004), and several
case reports of delirium induced by olanzapine have been published.
Similarly, the need for caution when olanzapine is used to treat psychosis in
patients with Parkinson’s disease or Lewy body dementia is reinforced by
two comparative trials (Breier et al. 2002; Goetz et al. 2000) and several
open trials or case series (e.g., Marsh et al. 2001; Molho and Factor 1999;
Parkinson Study Group 1999; Walker et al. 1999) that have reported a
significant worsening of motor symptoms in these patients.
The evidence supporting the efficacy and safety of olanzapine in younger
patients with bipolar disorder and other mood disorders (Andreescu et al.
2006; Shelton et al. 2001; Thase 2002) is strong. One large published trial in
which more than half of the randomized patients were age 65 years and older
supports the efficacy and tolerability of olanzapine in the treatment of major
depressive disorder with psychotic features (Meyers et al. 2009). Otherwise,
there is a paucity of data relevant to older individuals with mood disorders
(Sajatovic et al. 2005a, 2005b; Young et al. 2004). Similarly, very few
geriatric data are available on the rapidly dissolving or the intramuscular
preparations of olanzapine (Belgamwar and Fenton 2005).
On review of all evidence available in 2004, a consensus conference
concluded that among the atypical antipsychotics, clozapine and olanzapine
were associated with the highest risk for diabetes and caused the greatest
weight gain and dyslipidemia (American Diabetes Association et al. 2004).
Limited geriatric data show a similar higher risk of metabolic problems in
older patients (Feldman et al. 2004; Micca et al. 2006; Zheng et al. 2009).
Other common side effects include sedation and gait disturbance.
Extrapyramidal symptoms appear to be dose dependent and are rare at the
lower dosages typically used in older patients (5–10 mg/day). Olanzapine
also has been associated with electroencephalographic abnormalities
(Centorrino et al. 2002), and its strong blocking of the muscarinic receptor
(Chew et al. 2005, 2006; Mulsant et al. 2003) (Table 20–6) may explain why
it has been associated with the following: constipation in a large series of
long-term-care patients (Martin et al. 2003); an inverted dose-response
relationship, with lower efficacy in older agitated or psychotic patients with
dementia randomized to 15 mg/day than in those randomized to 5 mg/day,
suggesting that higher doses may be toxic in these patients (Street et al.
2000); a differential cognitive effect from risperidone in randomized trials
involving older patients with schizophrenia (Harvey et al. 2003) or dementia
(Mulsant et al. 2004); worsening of cognition in a large placebo-controlled
trial in older nonagitated, nonpsychotic patients with Alzheimer’s disease
(Kennedy et al. 2005); and frank delirium in some clinical cases. Individuals
who are older, female, or nonsmokers or who are taking a drug that inhibits
CYP1A2 (e.g., fluvoxamine or ciprofloxacin) have higher concentrations of
olanzapine and may be at higher risk for adverse effects (Gex-Fabry et al.
2003). Because of olanzapine’s adverse-effect profile, experts do not
recommend it as a first-line antipsychotic in older patients at special risk for
anticholinergic or metabolic adverse effects (Bell et al. 2010).

Quetiapine
Results of several randomized placebo-controlled trials of quetiapine in
older patients with behavioral and psychological symptoms of dementia are
inconclusive (Cheung and Stapelberg 2011; Schneider et al. 2006a). For
instance, in a large trial of 333 institutionalized participants, quetiapine 200
mg/day (but not 100 mg/day) differed from placebo on global impressions
and positive symptom ratings but not on the important primary outcome
measures of agitation and psychosis (Zhong et al. 2007).

TABLE 20–6. Receptor blockade of atypical antipsychotics

D2 5-HT2 M1 α1
Aripiprazole * ++ 0 +
Asenapine +++ +++ 0 +++
Clozapine + ++ +++ +
Iloperidone +++ ++++ 0 ++++
Lurasidone +++ ++ 0 ++
Olanzapine ++ +++ ++ +
Paliperidone +++ +++ 0 ++
Quetiapine + ++ + +
Risperidone +++ ++++ 0 +++
Ziprasidone ++ ++ 0 +
Note. Receptor types: α1=α-adrenergic type 1; D2=dopamine type 2; 5-HT2=5-hydroxytryptamine
(serotonin) type 2; M1=muscarinic type 1.
0=none; +=minimal; ++=intermediate; +++=high; ++++=very high.
*High-affinity partial agonist.

Several uncontrolled or unblinded studies suggest that quetiapine may

have a role in the treatment of older patients with primary psychotic
disorders (e.g., Madhusoodanan et al. 2000; Tariot et al. 2000; Yang et al.
2005). Similarly, two small RCTs (Devlin et al. 2010, 2011; Tahir et al.
2010) and several other small studies (e.g., Kim et al. 2003; Pae et al. 2004;
Sasaki et al. 2003) suggest that quetiapine may be effective for the treatment
of delirium.
Because of its low propensity to cause extrapyramidal symptoms,
quetiapine is often used as a first-line antipsychotic in older patients with
Parkinson’s disease, dementia with Lewy bodies, or tardive dyskinesia
(Fernandez et al. 2002; Poewe 2005); however, quetiapine was not found to
be efficacious in these patients in two double-blind trials (Kurlan et al. 2007;
Rabey et al. 2007).
Quetiapine also has FDA approval for the treatment of acute mania and
depression associated with bipolar disorder in adults and as adjunctive
therapy to antidepressants for the treatment of major depressive disorder in
adults. Relevant published data from geriatric patients with bipolar disorder
are limited (Carta et al. 2007; Tadger et al. 2011). By contrast, in one
geriatric randomized placebo-controlled trial of a flexible dose (50–300
mg/day) of quetiapine in 338 older patients with major depression, remission
and response rates were remarkably high (56% and 64%, respectively) and
significantly higher than those with placebo (23% and 30%, respectively).
Adverse events observed in more than 10% of the patients randomized to
quetiapine included somnolence, headache, dry mouth, and dizziness (Katila
et al. 2013).
There have been several case reports of SIADH and serotonin syndrome
in older patients treated with quetiapine (e.g., Atalay et al. 2007; Kohen et al.
2007). Like other antipsychotics, quetiapine can also cause somnolence or
dizziness (Jaskiw et al. 2004; Katila et al. 2013; Yang et al. 2005), but the
incidence of these adverse effects can be minimized by a slower dose
titration. The risk for weight gain, diabetes, or dyslipidemia associated with
quetiapine appears similar to the risk associated with the use of risperidone
but lower than the risk associated with the use of clozapine or olanzapine
(American Diabetes Association et al. 2004; Feldman et al. 2004).

Clozapine
Clozapine is still considered the drug of choice for younger patients with
treatment-refractory schizophrenia, and one small case series suggested that
it can be similarly helpful in older patients for the treatment of primary
psychotic disorders refractory to other treatments (Sajatovic et al. 1997). An
RCT comparing clozapine and chlorpromazine in older patients with
schizophrenia (Howanitz et al. 1999) and one large case series (Barak et al.
1999) also supported the use of clozapine in moderate dosages (i.e.,
approximately 50–200 mg/day) in older patients with primary psychotic
disorders. The strongest published geriatric studies of clozapine are focused
on the treatment of drug-induced psychosis in patients with Parkinson’s
disease (Ellis et al. 2000; Goetz et al. 2000; Parkinson Study Group 1999).
The results of these studies suggest that clozapine at low dosages (12.5–50
mg/day) could be the preferred treatment for this condition (Parkinson Study
Group 1999). However, the use of clozapine in older individuals is severely
limited because of its significant hematological, anticholinergic (including
severe constipation and ileus associated with fatalities), neurological (e.g.,
seizures), cognitive, metabolic, and cardiac adverse effects (Alvir et al.
1993; Bishara and Taylor 2014; Centorrino et al. 2002; Chew et al. 2006;
Hibbard et al. 2009; O’Connor et al. 2010; Rajji et al. 2010).

Aripiprazole
Aripiprazole has partial dopamine type 2 (D2) receptor agonist properties
(i.e., in high dopaminergic states it acts as an antagonist, and in low
dopaminergic states it acts as an agonist). This may explain why it is
unlikely to cause extrapyramidal side effects or prolactin elevation
(associated with osteoporosis), even at high D2 receptor occupancy (Mamo
et al. 2007). It has only moderate affinity to the adrenergic α1 receptor and
histamine H1 receptor and negligible affinity to the muscarinic receptor
(Chew et al. 2006). As a result, orthostatic hypotension and
antihistaminergic and anticholinergic adverse effects are less likely to occur
than with other atypical agents. However, akathisia may be a common side
effect in older patients (Coley et al. 2009; Sheffrin et al. 2009). Several
randomized placebo-controlled trials of aripiprazole in older patients with
behavioral and psychological symptoms of dementia have been published
(De Deyn et al. 2005a; Mintzer et al. 2007; Streim et al. 2008). Recent
expert opinions (De Deyn et al. 2013; Herrmann et al. 2013b) are congruent
with a meta-analysis of these trials that concluded that “efficacy on rating
scales was observed by meta-analysis for aripiprazole” (Schneider et al.
2006a, p. 191) and with a 2011 review published by the U.S. Agency for
Healthcare Research and Quality that reached a similar conclusion (Maher
and Theodore 2012; Maher et al. 2011).
 Aripiprazole is approved by the FDA for the treatment of manic or mixed
episodes associated with bipolar disorder and as an adjunctive treatment for
major depressive disorder. Lenze, Mulsant, Reynolds, and their collaborators
have completed a large federally funded randomized placebo-controlled trial
of aripiprazole augmentation of venlafaxine XR in older patients with major
depression who did not respond to venlafaxine XR monotherapy (300
mg/day). As of November 2014, the results of this study had not yet been
published. However, two small prospective open studies (Sajatovic et al.
2008; Sheffrin et al. 2009) and analyses of pooled geriatric data (Steffens et
al. 2011; Suppes et al. 2008) support the efficacy and tolerability of
aripiprazole augmentation in older patients with major depression that does
not respond fully to an antidepressant.

Ziprasidone
On the basis of ziprasidone’s lower effect on glucose, lipids, and weight
(American Diabetes Association et al. 2004) and its lack of affinity for the
muscarinic receptor (Chew et al. 2006) (see Table 20–6) and thus its low
potential to cause cognitive impairment, ziprasidone is an attractive
medication for older patients with psychosis. However, geriatric data on oral
ziprasidone remain limited (Berkowitz 2003; Wilner et al. 2000). Three
published studies on the use of intramuscular ziprasidone found no adverse
cardiovascular or electrocardiographic changes in a small number of older
patients (Greco et al. 2005; Kohen et al. 2005; Rais et al. 2010). However,
after thioridazine, ziprasidone remains the antipsychotic that is most likely to
be associated with QT prolongation (Wenzel-Seifert et al. 2011). Thus, in the
absence of systematic geriatric studies, ziprasidone should be used with
caution in older patients and should be avoided in patients with cardiac
disease or in those who take other drugs associated with QT prolongation.

Newer Atypical Antipsychotics

In recent years, three other atypical antipsychotics have been approved by
the FDA for use in schizophrenia: asenapine, iloperidone, and lurasidone.
Except for two case series of 11 and 15 older patients with bipolar disorder
treated with asenapine (Baruch et al. 2013; Sajatovic et al. 2014), there is an
almost total absence of published geriatric data for these three medications
(Guay 2011; Rado and Janicak 2012). Coupled with their lack of clear
advantages over other atypical antipsychotics and some potential
disadvantages (Guay 2011), this absence of data precludes making any
recommendations for the use of these three newer antipsychotics in older
patients (Schiff et al. 2011).

Mood Stabilizers
As a class, mood stabilizers are high-risk medications for older patients.
There is a paucity of controlled studies and an abundance of concerns
regarding the drugs’ potential toxicity, problematic side effects, and drug
interactions. Beyond their approved indications, anticonvulsants are also
used in the management of agitation accompanying dementia. Currently, no
consensus exists as to which drug should be preferred as a first-line mood
stabilizer in older individuals with bipolar disorder or secondary mania
(Sajatovic et al. 2005b; Shulman 2010; Young et al. 2004). However, the
neuroprotective properties of lithium (Foland et al. 2008; Germaná et al.
2010; Hajek et al. 2012a, 2012b; Macritchie et al. 2010) and the favorable
cognitive effects of lamotrigine (Gualtieri and Johnson 2006) make them
attractive agents for older patients with bipolar disorder (D’Souza et al.
2011; Sajatovic et al. 2013).

Lithium
Lithium continues to be used in older patients for the treatment of bipolar
disorder (D’Souza et al. 2011; Shulman 2010) or, less commonly, as an
augmentation agent in treatment-resistant depression (Cooper et al. 2011;
Flint and Rifat 2001; Ross 2008) and for the prevention of depressive relapse
following electroconvulsive therapy (Sackeim et al. 2001). Several
publications have described the design and the characteristics of the
participants in the first RCT of the pharmacotherapy of manic or mixed
episodes in older patients with bipolar disorder (Al Jurdi et al. 2012; Beyer
et al. 2014; Young et al. 2010). Although the results of this randomized
comparison of the efficacy and tolerability of divalproex and lithium have
been reported at several scientific meetings, they have not yet been
published. Available data from open and controlled trials suggest that
lithium is efficacious in the acute treatment and prophylaxis of mania in
older patients (D’Souza et al. 2011; Sajatovic et al. 2005a; Shulman 2010);
however, age-related reductions in renal clearance and decreased total body
water significantly affect the pharmacokinetics of lithium in older patients,
increasing the risk of toxicity (D’Souza et al. 2011). Medical comorbidities
common in late life—such as impaired renal function, hyponatremia,
dehydration, and heart failure—further exacerbate the risk of toxicity
(D’Souza et al. 2011; Sajatovic et al. 2006, 2013). Thiazide diuretics,
angiotensin-converting enzyme inhibitors, and NSAIDs may precipitate
toxicity by further diminishing the renal clearance of lithium. Lithium
toxicity can produce persistent central nervous system impairment or be
fatal: it is a medical emergency that requires careful correction of fluid and
electrolyte imbalances and that may require administration of mannitol (or
even hemodialysis) to increase lithium excretion.
Older patients require lower lithium dosages than do younger patients to
produce similar serum lithium levels, and their lithium levels, electrolytes,
and thyroid-stimulating hormone should be monitored regularly (D’Souza et
al. 2011; Rej et al. 2014a). Also, older persons are more sensitive to
neurological side effects of lithium and experience them at lower lithium
levels. This sensitivity may be a consequence of increased permeability of
the blood-brain barrier and subtle changes in sodium-lithium
countertransport, resulting in a higher ratio of brain-to-serum concentration
in older patients than in younger patients (Forester et al. 2009).
Neurotoxicity may manifest as coarse tremor, slurred speech, ataxia,
hyperreflexia, and muscle fasciculations. In vitro, lithium has moderate
anticholinergic activity (Chew et al. 2008). This may explain why cognitive
impairment has been observed with levels well below 1 mEq/L and why
frank delirium has been reported with levels as low as 1.5 mEq/L (Sproule et
al. 2000). Consequently, treatment in older patients may require lithium
levels to be kept as low as 0.4–0.8 mEq/L. In addition, despite the absence of
definite evidence, concerns about the association between long-term use of
lithium and renal disease and the possible causal role of lithium in this
association remain (Rej et al. 2014b). Despite its potential toxicity, lithium
remains an important drug in the treatment of bipolar disorder and treatment-
resistant depression in late life because of its potential effect on suicidality
(Müller-Oerlinghausen and Lewitzka 2010) and its potential neuroprotective
properties (Foland et al. 2008; Germaná et al. 2010; Hajek et al. 2012a,
2012b; Macritchie et al. 2010).
Anticonvulsants
Anticonvulsants are used as alternatives to lithium in the treatment of bipolar
disorder (Young et al. 2004) and as third-line alternatives to antipsychotics
and SSRIs for the management of agitation associated with dementia
(Herrmann et al. 2013b). There may be a subgroup of patients with bipolar
disorder with dysphoria or rapid cycling who respond poorly to lithium but
do well with anticonvulsants (Post et al. 1998).

Divalproex
Divalproex, a compound of sodium valproate and valproic acid in an enteric-
coated form, is a broad-spectrum anticonvulsant approved by the FDA for
the treatment of acute manic or mixed episodes associated with bipolar
disorder, with or without psychotic features. It also may be efficacious in the
treatment of bipolar depression (Bond et al. 2010). Small case series have
suggested that divalproex is relatively well tolerated by older patients with
bipolar disorder (Kando et al. 1996; Noaghiul et al. 1998). Nonetheless, it
should not be used in patients with dementia because of six negative
placebo-controlled trials showing that compared with placebo, divalproex is
not more effective but is more toxic—including potential neurotoxicity and
cognitive toxicity—in older patients with dementia and agitation (Herrmann
et al. 2013b; Sink et al. 2005; Tariot et al. 2005, 2011). Sedation, nausea,
weight gain, and hand tremors are common dose-related side effects.
Reversible thrombocytopenia can occur in up to half of the elderly patients
taking divalproex and may ensue at lower total drug levels than in younger
patients (Fenn et al. 2006). Other dose-related adverse effects include
reversible elevations in liver enzymes and transient elevations in blood
ammonia levels. However, liver failure and pancreatitis are rare. Divalproex
has other metabolic effects of concern to aging patients, such as increases in
bone turnover and reductions of serum folates, with concomitant elevations
in plasma homocysteine concentrations (Sato et al. 2001; Schwaninger et al.
1999).
The pharmacokinetics of valproate vary according to formulation, and
valproic acid, divalproex sodium, and its extended-release (ER) preparation
are not interchangeable. Valproate is metabolized principally by
mitochondrial β-oxidation and secondarily by the cytochrome P450 system;
typical half-lives are in the range of 5–16 hours and are not affected by aging
alone. Concomitant administration of valproate will increase concentrations
of carbamazepine, diazepam, lamotrigine, phenobarbital, and primidone.
Conversely, concurrent administration of carbamazepine, lamotrigine,
phenytoin, and topiramate may decrease levels of valproate. Fluoxetine and
erythromycin may potentiate the effects of valproate. Changes in protein
binding as a result of drug interactions are no longer considered clinically
important beyond causing the misinterpretation of total (i.e., free and bound)
drug levels (Benet and Hoener 2002). Because valproate binding to plasma
proteins is generally reduced in the elderly, use of free drug levels correlates
better with adverse effects (Fenn et al. 2006).

Lamotrigine
Lamotrigine is approved by the FDA for the maintenance treatment of
bipolar I disorder to prevent mood episodes (depressive, manic, or mixed
episodes) and it is considered a first-line agent for the treatment of bipolar
depression in adults (Fenn et al. 2006). Pooled geriatric data from two
randomized placebo-controlled trials support the efficacy of lamotrigine in
preventing bipolar depression in older patients (Sajatovic et al. 2005a, 2007).
Open studies and case reports suggest a role for lamotrigine in the treatment
of bipolar depression (Sajatovic et al. 2011), and possibly bipolar mania and
dementia-related agitation as well (Sajatovic et al. 2007).
In contrast with many other mood stabilizers and antidepressants,
lamotrigine does not seem to be associated with weight gain or to cause
significant drug interactions. It is also less likely than other mood stabilizers
to be associated with cognitive impairment (Gualtieri and Johnson 2006).
Typically, lamotrigine is well tolerated, but somnolence and rashes have
been observed in older patients. Rashes are the most common reason for
discontinuation, but their incidence is less frequent with lamotrigine than
with carbamazepine (Fenn et al. 2006). Severe rashes, including Stevens-
Johnson syndrome or toxic epidermal necrolysis, have been observed in
about 0.3% of adult patients (Messenheimer 1998). At the first sign of rash
or other evidence of hypersensitivity (e.g., fever, lymphadenopathy),
lamotrigine should be discontinued, and the patient should be evaluated. The
incidence of rashes can be reduced by using a low initial dose and a slow
titration.
Because valproate increases lamotrigine concentration, the initial and
target doses need to be halved in patients who are receiving divalproex and
the titration of lamotrigine needs to be slowed down. Conversely,
carbamazepine approximately halves lamotrigine concentrations, and the
initial lamotrigine dose needs to be doubled in patients who are receiving
carbamazepine.

Carbamazepine and Oxcarbazepine

The extended-release formulation of carbamazepine is approved by the FDA
for the acute treatment of manic and mixed episodes associated with bipolar
disorder. In a placebo-controlled trial in 51 nursing home patients,
carbamazepine also was shown to be efficacious in treating agitation and
aggression associated with dementia (Tariot et al. 1998). Common side
effects in older patients include sedation, nausea, dizziness, rash, ataxia,
neutropenia, and hyponatremia. Older patients are also at risk for
agranulocytosis, aplastic anemia, hepatitis, and problematic drug interactions
(Fenn et al. 2006). Carbamazepine is primarily eliminated by CYP3A4, and
its clearance is reduced with aging. Its interactions with other drugs are
protean: carbamazepine concentrations are increased to potential toxicity by
CYP3A4 inhibitors such as macrolide antibiotics, antifungals, and certain
antidepressants (see antidepressants that inhibit CYP3A4 in Table 20–4).
CYP3A4 inducers—such as phenobarbital, phenytoin, and carbamazepine
itself—lower the concentration of carbamazepine and the concentrations of
many drugs metabolized by this isoenzyme, including lamotrigine,
valproate, some antidepressants, and antipsychotics (Fenn et al. 2006).
Oxcarbazepine, the 10-keto analogue of carbamazepine, is a less potent
CYP3A4 inducer and less likely to be involved in drug interactions.
Although oxcarbazepine has been studied in a small number of younger
patients with bipolar disorder, there is a paucity of data pertaining to older
psychiatric patients (Sommer et al. 2007). Therefore, its use cannot be
recommended in older patients.

Gabapentin and Pregabalin

Although gabapentin has been used in bipolar disorder, trials have not borne
out its effectiveness, and only small case series or case reports of its use in
dementia are available (Sommer et al. 2007). Nonetheless, it has a generally
favorable side-effect profile and modest anxiolytic and analgesic effects,
particularly for neuropathic pain. Gabapentin does not bind to plasma
proteins and is not metabolized, being eliminated by renal excretion. In
patients with renal impairment, neurological adverse effects such as ataxia,
involuntary movements, disorganized thinking, excitation, and extreme
sedation have been noted. Even in the absence of renal dysfunction, elderly
patients may be prone to excessive sedation. Therefore, in the elderly, initial
dosages of 100 mg twice daily are more prudent than the 900 mg/day
recommended as a starting dosage for younger patients with epilepsy.
Pregabalin is a structural congener of gabapentin. It has an improved
pharmacokinetic profile and it is approved by the FDA not only for the
treatment of epilepsy (as adjunctive therapy for adult patients with partial-
onset seizures) but also for neuropathic pain associated with diabetic
peripheral neuropathy and spinal cord injury, postherpetic neuralgia, and
fibromyalgia. Some published pooled geriatric data from 11 placebo-
controlled trials show that pregabalin 150–600 mg/day is associated with
clinically meaningful pain relief in older patients with painful diabetic
neuropathy or postherpetic neuralgia (Semel et al. 2010). In these studies
pregabalin’s main adverse effects are dizziness, somnolence, and peripheral
edema, and they are dose related. In addition, a placebo-controlled trial
(Montgomery et al. 2008) and some open data (Karaiskos et al. 2013)
support the off-label use of 150–600 mg/day of pregabalin in older patients
with generalized anxiety disorder.

Topiramate
Early reports of the efficacy of topiramate in younger patients with bipolar
disorder have not been confirmed by subsequent studies (Sommer et al.
2007). In younger patients, topiramate is one of the few psychotropic
medications that have been associated with weight loss. However, it also has
been associated with cognitive impairment that can be severe enough to
interfere with functioning (Gualtieri and Johnson 2006). Additionally,
because of the paucity of data pertaining to use of topiramate in older
psychiatric patients (Sommer et al. 2007), its use cannot be recommended in
these patients.

Anxiolytics and Sedative-Hypnotics

The SSRIs and SNRIs have displaced benzodiazepines as first-line
pharmacotherapy for anxiety in late life, whereas benzodiazepine receptor
agonist hypnotics (i.e., eszopiclone, zaleplon, zolpidem) and the
intermediate half-life benzodiazepine lorazepam have become the most
commonly used hypnotics.

Benzodiazepines and Benzodiazepine Receptor Agonists

In older patients, detrimental effects of benzodiazepines and benzodiazepine
receptor agonists frequently outweigh any short-term symptomatic relief that
they may provide and they should be avoided (American Geriatrics Society
2012 Beers Criteria Update Expert Panel 2012). Even single small doses of
diazepam, nitrazepam, and temazepam cause significant impairment in
memory and psychomotor performance in older subjects (Nikaido et al.
1990; Pomara et al. 1989). Even benzodiazepines with shorter half-lives
increase the risk of falls and hip fractures in frail elderly patients (Ray et al.
2000). More recently, benzodiazepines have also been linked to adverse
respiratory outcomes in older patients with chronic obstructive pulmonary
disease (Vozoris et al. 2014) and to an increased risk for Alzheimer’s
dementia (Billioti de Gage et al. 2014). Although benzodiazepine receptor
agonists are perceived as being safer, they also have been associated with
falls and hip fractures (Wang et al. 2001) or cognitive impairment and traffic
accidents (Glass et al. 2005; Gustavsen et al. 2008; Leufkens et al. 2009).
Finally, both benzodiazepines and benzodiazepine receptor agonists are
associated with a significantly increased risk of mortality in older patients
(Kripke et al. 2012; Weich et al. 2014).
Nevertheless, benzodiazepines may be used for the prevention of alcohol
withdrawal or as a temporary adjunctive treatment for anxiety- or
depression-related sleep disturbance when the primary pharmacotherapy is
an antidepressant. Relative contraindications include heavy snoring (because
it suggests sleep apnea), dementia (because such patients are at increased
risk for daytime confusion, impairment in activities of daily living, and
daytime sleepiness), and the use of other sedating medications or alcohol.
Benzodiazepines with long half-lives (chlorazepate, chlordiazepoxide,
clonazepam, diazepam, flurazepam, halazepam, and quazepam) are probably
associated with more adverse effects and therefore should be avoided
(Ballokova et al. 2014; Fick et al. 2003; Hemmelgarn et al. 1997). Also,
several drugs with shorter half-lives (i.e., alprazolam, triazolam, midazolam,
eszopiclone, zaleplon, and zolpidem) undergo phase 1 hepatic metabolism
by CYP3A4 that is subject to specific interactions and age-associated decline
(Freudenreich and Menza 2000; Greenblatt et al. 1991). Sedatives with very
short half-lives also may increase the likelihood that confused elderly
patients will awake in the middle of the night to stagger off to the bathroom.
Lorazepam and oxazepam do not undergo phase 1 hepatic metabolism, have
no active metabolites, have acceptable half-lives that do not increase with
age, and are not subject to drug interactions. Lorazepam is available in
appropriately small doses (0.5-mg pills) and is well absorbed
intramuscularly. It is preferred for inducing sleep because oxazepam has a
relatively slow and erratic absorption.

Buspirone
The anxiolytic buspirone, a partial 5-HT1A agonist, is rarely used.
Nevertheless, it may be beneficial for some patients with generalized anxiety
disorder or as an augmentation agent in treatment-resistant depression (Flint
2005; Trivedi et al. 2006). It appears to be well tolerated by elderly patients
without the sedation or addiction liability of the benzodiazepines (Steinberg
1994). Therefore, it may be helpful for some older patients who are prone to
falls, confusion, or chronic lung disease. Nonetheless, buspirone may take
several weeks to exert an anxiolytic effect, has no cross-tolerance with
benzodiazepines, and may cause dizziness, headache, or nervousness (Strand
et al. 1990). It is of limited use for panic or obsessive-compulsive disorders.
The pharmacokinetics of buspirone are not affected by age or gender, but
coadministration with verapamil, diltiazem, erythromycin, or itraconazole
will substantially increase buspirone concentrations, and its combination
with serotonergic medications may result in the serotonin syndrome
(Mahmood and Sahajwalla 1999).
Cognitive Enhancers

Cholinesterase Inhibitors
In addition to memantine (discussed in the next subsection), four
cholinesterase inhibitors have received FDA approval for the symptomatic
improvement of Alzheimer’s disease. Table 20–7 describes three of these
drugs: donepezil, galantamine, and rivastigmine. The fourth, tacrine, is no
longer recommended because of its potential hepatotoxic effects.
Cholinesterase inhibitors produce modest improvements in cognition and
function in patients with Alzheimer’s disease (Hansen et al. 2008;
Herrmann et al. 2013b), including those with severe Alzheimer’s disease
(Herrmann et al. 2013b; Howard et al. 2012; Winblad et al. 2006).
Therefore, a trial with a cholinesterase inhibitor is recommended in most
patients with Alzheimer’s disease; in the absence of convincing evidence
that one of the three cholinesterase inhibitors is more effective than the
others, the selection of a specific drug is based on its pharmacokinetic and
adverse effects profile (see Table 20–7) (Herrmann et al. 2013b).
Cholinesterase inhibitors have modest benefit of uncertain clinical
significance in vascular dementia (Kavirajan and Schneider 2007). They
may also have a role in the management of other cognitive disorders, such
as Lewy body dementia (Gustavsson et al. 2009; Rolinski et al. 2012),
dementia with Parkinson’s disease (Herrmann et al. 2013b: Rolinski et al.
2012), frontotemporal dementia (Herrmann et al. 2013b), mild cognitive
impairment (Diniz et al. 2009; Doody et al. 2009), and cognitive
impairment associated with late-life depression (Reynolds et al. 2011).
Available data are not consistent, however, and there is no agreement on the
role of cholinesterase inhibitors in the treatment or prevention of behavioral
or psychological symptoms associated with dementia (Freund-Levi et al.
2014; Gauthier et al. 2010; Herrmann et al. 2013b; Howard et al. 2007;
Lockhart et al. 2011; Rodda et al. 2009; Sink et al. 2005).
No evidence suggests that cholinesterase inhibitors alter the underlying
neuropathology of Alzheimer’s disease or its eventual progression. Indeed,
a rapid symptomatic deterioration may occur when cholinesterase inhibitors
are discontinued (Scarpini et al. 2011). In patients with diminished
cognitive reserve, even small anticholinergic effects can substantially
impair cognition (Mulsant et al. 2003; Nebes et al. 2005). Drugs with potent
anticholinergic effects directly antagonize cholinesterase inhibitors (Chew
et al. 2008; Modi et al. 2009). Thus, it is imperative that unnecessary
anticholinergic medications be discontinued before initiating a
cholinesterase inhibitor (Lu and Tune 2003; Modi et al. 2009).
The main adverse effects of cholinesterase inhibitors are concentration
dependent and result from their central and peripheral cholinergic actions.
Nausea, diarrhea, weight loss, bradycardia, syncope, and nightmares are
associated with all of the cholinesterase inhibitors and may lead to their
discontinuation (see Table 20–7; Gill et al. 2009; Hernandez et al. 2009;
Park-Wyllie et al. 2009); gastrointestinal adverse effects may be less
frequent with donepezil (Mayeux 2010). However, despite theoretical
concerns, the use of cholinesterase inhibitors appears to be safe in patients
with chronic airway disorders (Thacker and Schneeweiss 2006). Finally, in
a placebo-controlled study in older patients with a major depressive
disorder receiving maintenance antidepressant pharmacotherapy, donepezil
was associated with a higher rate of recurrence of depression than placebo
(Reynolds et al. 2011). With these adverse effects in mind, clinicians should
be aware of the drugs’ specific pathways of elimination and potential
pharmacokinetic drug interactions with CYP2D6 or CYP3A4 inhibitors and
with CYP3A4 inducers when prescribing donepezil and galantamine
(Pilotto et al. 2009; Seritan 2008). Rivastigmine is affected by renal
function, and FDA warnings have emphasized the need for careful dose
titration (and retitration if restarting) to prevent severe vomiting (Birks et al.
2009).

TABLE 20–7. Cholinesterase inhibitors

Clearance Dosing Significant Pharmacodynamics
adverse effects
Donepezil Half-life=70–80 5–10 mg/day in Mild nausea, Reversible
hours; CYP3A4, one dose; start at diarrhea, acetylcholinesterase
CYP2D6 5 mg at bedtime bradycardia inhibition
Galantamine, Half-life=7 hours; 8–24 mg/day Moderate nausea, Reversible
galantamine ER CYP2D6, divided into two vomiting, acetylcholinesterase
CYP3A4 doses; start at 8 diarrhea, inhibition; nicotinic
mg/day twice anorexia, tremor, modulation may
daily insomnia increase
 acetylcholine
release
Rivastigmine, Half-life=1.25 6–12 mg/day Severe nausea, Pseudoirreversible
rivastigmine hours; renal divided into two vomiting, acetylcholinesterase
patch doses; start at anorexia, weight inhibition; also
1.5 mg twice loss, sweating, butylcholinesterase
daily. For patch, dizziness inhibition
start at 4.6
mg/day and
increase after 4
weeks to 9.5
mg/day. Retitrate
if drug is
stopped.
Note. CYP=cytochrome P450; ER=extended release.

NMDA Receptor Antagonist

Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has
FDA approval for the treatment of moderate to severe Alzheimer’s disease.
As an uncompetitive antagonist with moderate affinity for NMDA
receptors, memantine may attenuate neurotoxicity without interfering with
glutamate’s normal physiological actions. In placebo-controlled clinical
trials in patients with moderate to severe Alzheimer’s disease, memantine
was associated with modest delay in deterioration of cognition and
activities of daily living, when administered alone (Reisberg et al. 2003) or
in combination with donepezil (Tariot et al. 2004). However, in a study of
patients with moderate or severe Alzheimer’s disease, memantine and
donepezil were found to have similar efficacy with respect to cognitive
outcomes and activities of daily living. Furthermore, there were no
significant benefits of the combination of donepezil and memantine over
donepezil alone (Howard et al. 2012). Thus, combining a cholinesterase
inhibitor and memantine is not recommended (Herrmann et al. 2013b). As
with data on the cholinesterase inhibitors, data on memantine are not
consistent and thus there is no agreement on the role of memantine in the
treatment or prevention of behavioral or psychological symptoms
associated with dementia (Gauthier et al. 2008; Herrmann et al. 2011,
2013a, 2013b; Lockhart et al. 2011; Rive et al. 2013; Wilcock et al. 2008).
However, memantine may have a role in the treatment of Parkinson’s
disease dementia and Lewy body dementia (Aarsland et al. 2009; Emre et
al. 2010; Matsunaga et al. 2013).
 Memantine is well tolerated, although it may cause confusion in some
patients (Kavirajan 2009). It does not appear to be implicated in drug-drug
interactions, but it is excreted by the kidneys, and its dosage needs to be
reduced in patients with significant impairment in renal function.

Conclusion
Substantial evidence now exists to guide the use of psychotropic
medications in older persons. Most available data pertain to: the use of
SSRI or SNRI antidepressants in the treatment of major depressive
disorders; the use of atypical antipsychotics in the treatment of behavioral
and psychological symptoms of dementia; and the use of cognitive
enhancers in the treatment of cognitive impairment due to Alzheimer’s
disease. Existing data support the short-term and long-term efficacy and the
relative safety of SSRI and SNRI antidepressants in the treatment of most
older individuals with a major depressive disorder or an anxiety disorder. In
contrast, the risks associated with the use of antipsychotics outweigh their
potential benefits in many older persons presenting with behavioral and
psychological symptoms of dementia. Cognitive enhancers appear
relatively safe in older individuals with dementia but their efficacy is
modest. Pharmacoepidemiological data show that benzodiazepines continue
to be prescribed to a larger number of older individuals despite their
toxicity. Empirical data to guide the use of mood stabilizers or
antipsychotics in older persons with bipolar disorder or schizophrenia are
lacking. Similarly, better data are needed to inform the selection,
sequencing, and combination psychotropic medications in older persons
whose symptoms do not respond to first-line pharmacological interventions.

Key Points
• Substantial evidence supports the short-term and long-term efficacy and
the relative safety of SSRI and SNRI antidepressants in the treatment of
most older persons with a major depressive disorder or an anxiety
disorder.
 • In contrast, the risks associated with the use of antipsychotics outweigh
their potential benefits in many older persons presenting with behavioral
and psychological symptoms of dementia.
• Cognitive enhancers appear relatively safe in older persons with
dementia but their efficacy is modest.
• Pharmacoepidemiological data show that benzodiazepines continue to be
prescribed to many older persons despite their toxicity.
• Empirical data to guide the use of mood stabilizers or antipsychotics in
older persons with bipolar disorder or schizophrenia are lacking.
• Similarly, better data are needed to inform the selection, sequencing, and
combination of psychotropic medications in older persons whose
symptoms do not respond to first-line pharmacological interventions.

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dementia: a randomized, double-blind, placebo-controlled study. Curr
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Zimmer B, Kant R, Zeiler D, et al: Antidepressant efficacy and
cardiovascular safety of venlafaxine in young vs old patients with
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Suggested Readings

Antidepressant Medications
Mulsant BH, Blumberger DM, Ismail Z, et al: A systematic approach to the
pharmacotherapy of geriatric major depression. Clin Geriatr Med
30(3):517–534, 2014

Antipsychotic Medications
Maher AR, Maglione M, Bagley S, et al: Efficacy and comparative
effectiveness of atypical antipsychotic medications for off-label uses in
adults: a systematic review and meta-analysis. JAMA 306(12): 1359–
1369, 2011 21954480
Meagher DJ, McLoughlin L, Leonard M, et al: What do we really know
about the treatment of delirium with antipsychotics? Ten key issues for
delirium pharmacotherapy. Am J Geriatr Psychiatry 21(12): 1223–
1238, 2013 2356742
Suzuki T, Remington G, Uchida H, et al: Management of schizophrenia in
late life with antipsychotic medications: a qualitative review. Drugs
Aging 28(12):961–980, 2011 22117095

Mood Stabilizers
Sajatovic M, Forester BP, Gildengers A, Mulsant BH: Aging changes and
medical complexity in late-life bipolar disorder: emerging research
 findings that may help advance care. Neuropsychiatry 3(6): 621–633,
2013 24999372

Anxiolytics and Sedative-Hypnotics

American Geriatrics Society 2012 Beers Criteria Update Expert Panel:
American Geriatrics Society updated Beers Criteria for potentially
inappropriate medication use in older adults. J Am Geriatr Soc 60(4):
616–631, 2012 22376048

Cognitive Enhancers
Herrmann N, Lanctôt KL, Hogan DB: Pharmacological recommendations
for the symptomatic treatment of dementia: the Canadian Consensus
Conference on the Diagnosis and Treatment of Dementia 2012.
Alzheimers Res Ther 8 (suppl 1): S5, 2013 24565367
 CHAPTER 21

Electroconvulsive Therapy and Other

Forms of Brain Stimulation
Richard D. Weiner, M.D., Ph.D.
Mustafa M. Husain, M.B.

Electroconvulsive therapy (ECT) involves the electrical induction of

a series of seizures as a treatment for mental disorders, most notably major
depression. This chapter covers the history of ECT; indications for its use;
risks; the evaluation of patients for ECT; ECT technique; and management
of patients after completion of the ECT course, including the use of ECT to
prevent relapse (maintenance ECT). Because brain stimulation has become
a rapidly evolving area in geropsychiatric practice, a section is also
included to cover newer treatment modalities. The chapter ends with a brief
discussion of what can be expected in the future of brain stimulation
therapies. Throughout the chapter, a particular focus is placed on the use of
ECT and other related treatments in elderly patients.

History
In 1935, the Hungarian neuropsychiatrist Ladislas Meduna chemically
induced seizures in a small series of patients with schizophrenia (Shorter
and Healy 2007). His rationale for doing so was based on the hypothesis
(later shown to be incorrect) that individuals with epilepsy had a reduced
incidence of schizophrenia. Having achieved some partial success in
therapeutic outcome, Meduna’s new pharmacoconvulsive therapy was
greeted with great acclaim as a means to manage what had been an
otherwise untreatable illness. When this treatment modality spread to Italy
shortly thereafter, another neuropsychiatrist, Ugo Cerletti, was impressed by
the efficacy of this new treatment but was also frustrated by its technical
complexity (Shorter and Healy 2007). From his work as an experimental
epileptologist, Cerletti was aware of an electrical model of seizure induction
that had been used in animal research and that offered the opportunity for
more efficient and less complex treatment than pharmacoconvulsive
therapy. After further experimentation, Cerletti and his assistant Lucio Bini
were successful in using electrical seizure induction to treat one of their
patients with schizophrenia, and ECT rapidly replaced pharmacoconvulsive
therapy throughout the world.
Although ECT was first used in the treatment of schizophrenia,
clinicians soon realized that its highest therapeutic potency was in treating
mood disorders. The peak in ECT utilization was from the early 1940s
through the mid-1950s, at which point the first effective antipsychotic and
antidepressant medications came into clinical use. Although these new
psychopharmacological agents obviated the need for ECT in many
individuals, trials comparing the antidepressant efficacy of ECT and these
medications indicate that ECT remains the most rapid and effective means
to induce remission (Husain et al. 2004; UK ECT Review Group 2003).
In the early days of ECT, there was considerable fear concerning the use
of ECT in older adults, largely because of the medical comorbidity that is
common in this age group. The cardiovascular physiology of ECT was not
yet well understood, and more recent procedural innovations—such as
oxygenation, muscular relaxation, general anesthesia, and physiological
monitoring—had not yet been instituted. Instead, ECT during that early
period was accomplished in a distinctly nonmedical setting, often in
psychiatrists’ offices, without the presence of other medical staff or medical
support resources.
As ECT methodology became more refined, practitioners became more
willing to use it with previously underserved populations, including older
adults. In Texas, which has mandatory reporting of ECT use, 19% of ECT
treatment courses were administered to individuals age 65 years or older
between September 1, 2012, and August 31, 2013 (Texas Department of
State Health Services 2014).
Indications for ECT

Diagnostic Indications
The most common diagnostic indication for ECT is major depression
(American Psychiatric Association 2001). A significant body of literature
not only supports the efficacy of ECT for major depression but suggests that
ECT is the most rapid and effective treatment for this condition (Husain et
al. 2004). This literature includes a series of randomized, double-blind,
placebo-controlled studies in which the placebo control was “sham ECT,”
whereby subjects received all aspects of a usual clinical ECT treatment
except the electrical stimulus (Brandon 1986). Evidence from meta-
analytical studies also suggests greater efficacy of ECT than of
antidepressant medication (Janicak et al. 1985; UK ECT Review Group
2003). Although this type of analysis has not been carried out comparing
ECT with newer antidepressant medications, there are some data supporting
an advantage for ECT compared with selective serotonin reuptake inhibitors
(Folkerts et al. 1997).
Regarding subtypes of depression, ECT appears to be effective in
treating both melancholic and severe nonmelancholic depression (Sackeim
and Rush 1995), as well as bipolar and unipolar major depression (Weiner
and Krystal 2001). In addition, ECT may be particularly effective in
treating psychotic major depression (Petrides et al. 2001; Sobin et al. 1996).
Although ECT is used more frequently for major depression than for
other illnesses and the vast majority of ECT research studies have focused
on this condition, evidence suggests that ECT has efficacy in treating a
number of other mental disorders. Two reviews of the efficacy of ECT in
the treatment of bipolar disorder, including mania, mixed states, and
depressive episodes, have reported substantial efficacy (Dierckx et al. 2012;
Versiani et al. 2011). In this regard, ECT has been reported to achieve a
response rate as high as 80%, to have efficacy equal to that of lithium, and
to have a significant advantage over lithium in patients who have not
responded to lithium or antipsychotic medication. The relative efficacy of
ECT compared with anticonvulsant antimanic agents has not yet been
studied, and no systematic studies exist to indicate the utility of ECT in
individuals with rapid-cycling bipolar disorder.
 Another disorder for which ECT has efficacy is schizophrenia. Although
ECT was first employed as a treatment for this condition, the superior
response to ECT of patients with mood disorders was soon evident.
Following the development of antipsychotic medications in the late 1950s,
the use of ECT as a treatment for schizophrenia gradually declined.
Regardless, a number of studies have suggested that antipsychotic
medications and ECT have comparable efficacy (Pompili et al. 2013). In
addition, evidence suggests that for treatment of acute psychotic episodes,
the combination of antipsychotic medications and ECT may have greater
efficacy than either ECT or medications alone (Chanpattana et al. 2010;
Klapheke 1993). The combination of clozapine and ECT appears to be
particularly potent, even in patients whose psychotic ideation has been
nonresponsive to clozapine alone (Kho et al. 2004). However, no evidence
indicates that ECT has efficacy for the treatment of deficit or “negative”
symptoms of schizophrenia.
The presence of affective symptoms appears to increase the likelihood of
response to ECT in individuals with schizophrenia (Pompili et al. 2013). In
this regard, case reports and case series suggest that individuals with
schizoaffective disorder may respond better to ECT than do patients with
schizophrenia (American Psychiatric Association 2001). Catatonia, which
can be associated with both schizophrenia and mood disorders, is highly
responsive to ECT (Krystal and Coffey 1997), even when this condition is
associated with medical conditions such as systemic lupus erythematosus,
uremia, hepatic encephalopathy, porphyria, and hyperparathyroidism
(Fricchione et al. 1990; Rummans and Bassingthwaighte 1991).
Some evidence suggests that ECT may also be a useful treatment for
Parkinson’s disease when medication management fails or is not tolerated
(Fregni et al. 2005). However, it should also be noted that patients with
Parkinson’s disease may be at increased risk for developing cognitive side
effects and delirium with ECT (Figiel et al. 1991). In addition, the benefits
gained with ECT in regard to Parkinson’s symptoms and signs are transient,
necessitating the use of maintenance ECT in such cases (Wengel et al.
1998).

Response to ECT in Older Adults

Several prospective studies suggest that ECT is a highly effective acute
treatment for major depression in elderly individuals (Kamat et al. 2003;
Kerner and Prudic 2014; O’Connor et al. 2001; Riva-Posse et al. 2013; Tew
et al. 1999; van der Wurff et al. 2003; Wesson et al. 1997). Furthermore,
there is evidence that ECT has a significant longitudinal impact on the
course of major depression in older adults, in terms of both efficacy and
long-term morbidity and mortality rates (Philibert et al. 1995). There is
consensus among the larger studies that elderly patients show at least
equivalent improvement to middle-aged patients and greater improvement
than those who are younger. For example, a large study by the Consortium
for Research in ECT (CORE), involving 253 patients split into three age
groups (≥65 years, 46–64 years, and ≤45 years), found that whereas
remission rates for the older two groups were equivalent (90% for both), a
lower proportion of younger patients (70%) remitted (O’Connor et al.
2001). A more recent European study has reported similar finding
(Birkenhäger et al. 2010).

Continuation or Maintenance ECT

Although ECT is a highly effective treatment for a number of
neuropsychiatric conditions, it is not a cure in the sense that it does not
ensure that future episodes will not occur (Weiner and Krystal 2001; Weiner
et al. 2000). Also, evidence indicates that the relapse rate of major
depressive disorder may be particularly high for older adults (Huuhka et al.
2004). As a result, it is important to institute some form of continuation or
maintenance therapy (American Psychiatric Association 2001). This point
is underscored by the findings from a study by Sackeim et al. (2001a), in
which roughly 80% of patients successfully treated with ECT for major
depression relapsed within 6 months. Most commonly, continuation or
maintenance pharmacotherapy is instituted after a successful course of ECT.
Nevertheless, prophylactic pharmacotherapy is not universally effective,
and roughly 50%–60% of depressed individuals will relapse within a year
of the end of the ECT course when treated with typical continuation or
maintenance pharmacotherapy (Sackeim et al. 1990, 2001a). The relapse
rate appears to be even higher among individuals whose depression was
resistant to medication before the ECT course (Sackeim et al. 1990). One
study suggests that rather than single-agent therapy, more aggressive
pharmacotherapy—specifically the combination of nortriptyline and lithium
—is associated with a decrease in the relapse rate to roughly 40% within 6
months after ECT (Sackeim et al. 2001a).
An alternative to continuation or maintenance pharmacotherapy is
continuation or maintenance ECT. Although a number of case series and
retrospective reports have suggested the efficacy of continuation or
maintenance ECT, not until the past decade has a randomized controlled
trial of maintenance ECT versus maintenance pharmacotherapy been
carried out; Kellner et al. (2006) reported similar 6-month outcomes for
patients treated with maintenance bilateral ECT and for patients treated
with a combination of lithium and nortriptyline maintenance
pharmacotherapy. After a successful course of ECT, pharmacotherapy is
usually instituted unless at least one of the following conditions exists: 1)
prophylactic pharmacotherapy has failed in the past, 2) the patient is
intolerant of medications, 3) the patient has a medical illness that
contraindicates medication management, or 4) the patient has a preference
for prophylactic ECT (American Psychiatric Association 2001).
Although not much has been written about the use of maintenance ECT
in elderly patients, a review of the topic concluded that it is probably as
effective as maintenance pharmacotherapy in the management of
individuals who have responded to ECT treatment of acute major
depressive episodes (van Schaik et al. 2012).

Deciding to Recommend an Index ECT Course

In general, the decision about whether to recommend ECT for a given
patient should rest on a careful assessment of risks and benefits. Even
though ample evidence suggests that ECT is a highly effective treatment for
a number of neuropsychiatric disorders, it is generally not used as a first-
line treatment. However, first-line treatment with ECT should be considered
when there is an urgent need for response in a patient with major depression
or mania (American Psychiatric Association 2001; Quitkin et al. 1996).
This situation typically occurs when the presenting condition threatens the
patient’s life because of suicidality, malnutrition, dehydration, or inability to
comply with treatment of a critical medical problem. In addition, the first-
line use of ECT should be considered when, because of circumstances such
as medical illness, ECT is deemed to be safer than pharmacotherapy
(American Psychiatric Association 2001; Weiner et al. 2000). ECT should
also be considered on a primary basis when a patient has an informed
preference for ECT or when there has been a preferential response to ECT
in prior episodes (American Psychiatric Association 2001).
The secondary use of ECT is generally undertaken because of either
medication intolerance or a lack of response to pharmacotherapy (American
Psychiatric Association 2001). Unfortunately, there is no currently accepted
definition for medication failure. Operationally, when making this decision,
practitioners generally take into account the number of medications tried,
the duration of treatment, the dose administered, symptom severity,
tolerance of pharmacotherapy, the expected risks associated with ECT, and
patient preference (American Psychiatric Association 2001). In support of
the use of ECT following medication failure are several studies indicating
that a significant number of individuals respond to ECT after one or more
failed trials of medication (Avery and Lubrano 1979; Paul et al. 1981;
Prudic et al. 1996).

Risks of ECT and Its Use in Patients With

Neurological and Medical Disorders
Because the decision about whether to pursue a course of ECT should
involve an evaluation of both the expected risks and benefits of ECT, it is
important to be able to carry out an assessment of the likelihood of potential
adverse sequelae for each patient.

Mortality
Although it is difficult to establish an accurate mortality rate associated
with any medical procedure, it has been estimated that the overall mortality
rate for ECT is roughly 2 deaths per 100,000 treatments (Shiwach et al.
2001). A more recent study from the Veterans Administration patient
population found no mortalities in 73,440 treatments administered from
1999 to 2010 (Watts et al. 2011). This relatively low mortality rate appears
to be comparable to the rate associated with minor surgery and has been
considered to be less than that associated with pharmacotherapy with
tricyclic antidepressants (Sackeim 1998). Furthermore, some studies have
suggested that depressed inpatients who receive ECT have a lower
mortality rate after discharge than individuals who receive other types of
treatment (Philibert et al. 1995). It is important to understand, however, that
the likelihood of ECT-related death in high-risk populations—most
commonly in older adults—can be substantially higher than that mentioned
above. Still, even in such situations, the risk of undertaking ECT may be
lower than the risk of not doing it.

Cognitive Side Effects

The most important side effect with ECT is cognitive dysfunction, which
remains a key factor limiting the use of this treatment modality (American
Psychiatric Association 2001). The most common cognitive side effects are
anterograde amnesia (difficulty retaining new information) and retrograde
amnesia (difficulty recalling information learned in the past). Both
anterograde and retrograde memory side effects tend to most strongly affect
information encountered during the period of time closest to the ECT
treatment course. Anterograde amnesia typically resolves within a few
weeks after the treatment course, whereas retrograde amnesia tends to
resolve more slowly (Weiner et al. 1986). Despite objective evidence that
memory performance transiently decreases after ECT, some patients
indicate that their memory function improves, likely a result of the lifting of
depressive symptoms (American Psychiatric Association 2001; Weiner et
al. 1986). This finding appears to be present in older adults as well as in
younger individuals, particularly in individuals in whom the severity of
depression-related cognitive deficits presents as a pseudodementia
(Bosboom and Deijen 2006). A review of ECT effects on cognitive
functioning in elderly patients reported limited data but no evidence that
such deficits are substantially greater than those of younger individuals
(Tielkes et al. 2008).
Both the degree and the duration of objective and subjective memory
side effects of ECT vary substantially among individuals who receive ECT.
A number of research studies have identified factors that can affect
objective memory side effects of ECT (American Psychiatric Association
2001). Compared with unilateral placement of stimulus electrodes, bilateral
placement has repeatedly been shown to increase the risk of amnesia,
including in elderly populations (O’Connor et al. 2010; Stoppe et al. 2006).
In addition, greater risk is associated with higher stimulus intensity
(compared with the seizure threshold), larger numbers of ECT treatments,
higher dosages of barbiturate anesthetic, and less time between treatments.
Furthermore, some patients—including those taking lithium and
medications with anticholinergic properties, as well as those having
preexisting cerebral disease—appear to be at increased risk of cognitive
side effects (American Psychiatric Association 2001). Individuals with
diseases affecting the basal ganglia and subcortical white matter may be at
particular risk (Figiel et al. 1990).

Other Risks With ECT

It is important to identify individuals at risk for medical complications with
ECT and to be aware of the modifications in ECT technique that may
minimize risks. Elderly patients referred for ECT frequently have
preexisting medical illnesses (Christopher 2003; Weiner and Krystal 2001).
Although some illnesses appear to increase the risks of ECT (Zielinski et al.
1993), no illness should be considered an absolute contraindication to use
of ECT, given that risk is relative rather than absolute (Weiner and Krystal
2001; Weiner et al. 2000). The decision about whether to pursue a course of
ECT should always involve a careful weighing of the risks and benefits of
carrying out ECT versus those of not using it. Conditions for which
evidence suggests increased risks with ECT are discussed in the following
subsections, as are modifications in ECT technique that may decrease these
risks, as well as the specific issue of adverse effects of ECT in older adults.

Central Nervous System Disorders

The primary central nervous system (CNS) risks of ECT stem from the
increase in intracranial and intravascular pressure that can occur with ECT
seizures (Krystal and Coffey 1997). Despite these increases in pressure, the
CNS complication rate is generally quite low. A number of CNS disorders
leave individuals more vulnerable to increases in pressure than in the
general ECT population. For example, patients with any space-occupying
CNS lesions such as tumors, subdural hematomas, intracranial arachnoid
cysts, or normal pressure hydrocephalus have been considered to be at
increased risk for noncardiogenic pulmonary edema, cerebral edema, brain
hemorrhage, and cerebral herniation (Krystal and Coffey 1997). Although
space-occupying cerebral lesions were once considered an absolute
contraindication to ECT, a number of reports describe successful ECT in
individuals with these lesions. Patients with small lesions but no edema or
pretreatment elevation of intracranial pressure can usually be safely treated
with ECT (Krystal and Coffey 1997). For the remainder of patients with
space-occupying CNS lesions, the risks may be diminished (although not
removed) by pretreating with an antihypertensive agent, osmotic diuretics,
and steroids, and by employing hyperventilation during treatment.
The increase in intravascular pressure that occurs with ECT theoretically
might be expected to lead to an increased risk of intracranial hemorrhage;
however, such events are extremely rare (Krystal and Coffey 1997).
Nonetheless, individuals with recent strokes, arteriovenous malformations,
and aneurysms are considered to be at increased risk (Krystal and Coffey
1997). In two case series involving a total of 34 patients who received ECT
while recovering from strokes, no occurrences of hemorrhages or
worsening of any stroke-associated deficits were reported (Currier et al.
1992; Murray et al. 1986). Nevertheless, the American Psychiatric
Association (2001) recommends waiting as long as possible after a stroke
before administering ECT. The use of antihypertensive agents should be
considered to diminish the rise in intravascular pressure in patients with a
history of hemorrhagic stroke; however, such prophylaxis may be
counterproductive in individuals who have suffered cerebral ischemic
events (American Psychiatric Association 2001).
Other adverse CNS conditions that can be associated with ECT include
prolonged seizures (lasting longer than 3 minutes) and status epilepticus (a
single seizure lasting at least 30 minutes, or more than one seizure in which
consciousness is not regained during the interictal period) (American
Psychiatric Association 2001). Prolonged seizures can lead to increased
cognitive side effects, which can be minimized by rapidly administering
antiepileptic drugs to terminate such events. It appears that the risk of both
prolonged seizures and status epilepticus may be increased by some
medications (including theophylline and lithium), as well as by medical
conditions that lower the seizure threshold (such as hyponatremia)
(American Psychiatric Association 2001).
As noted earlier in the section “Cognitive Side Effects,” patients with
preexisting cerebral disease may be particularly likely to experience
problems with ECT-related amnesia. At times, even frank delirium may
occur. These risks, which appear to be most prominent in individuals with
dementia or with basal ganglia disease, can be minimized by decreasing the
frequency of treatments and using unilateral electrode placement. However,
the coexistence of ECT-responsive disorders with known or possible
dementia should not be a deterrent to the use of ECT, particularly because at
least a portion of cognitive dysfunction in such individuals may represent
pseudodementia, which might resolve with ECT. Also, there has been
growing interest recently in the use of ECT to manage extreme agitation or
aggression in patients with dementia (Acharya et al. 2014), although such
use is controversial.

Cardiovascular Disorders
Fluctuations in pulse and blood pressure that occur during ECT treatments
may be associated with cardiovascular complications (Weiner et al. 2000).
Immediately after the stimulus, there is an increase in parasympathetic tone,
which can lead to a sudden but transient decrease in heart rate, not
uncommonly presenting as a brief period of asystole. The subsequent
induced seizure, however, is associated with a sympathetic surge that
markedly increases both blood pressure and heart rate. This sympathetic
surge is then followed by a relative increase in parasympathetic tone as the
induced seizure ends.
Despite these autonomic fluctuations, cardiovascular complications from
ECT rarely occur in patients without preexisting cardiovascular risk factors
(Takada et al. 2005; Weiner et al. 2000). The risk is increased in patients
with recent myocardial infarction, uncompensated congestive heart failure,
severe valvular disease, unstable aneurysm, unstable angina or active
cardiac ischemia, uncontrolled hypertension, high-grade atrioventricular
block, symptomatic ventricular arrhythmia, and supraventricular arrhythmia
with uncontrolled ventricular rate (American Psychiatric Association 2001;
Applegate 1997). For patients with these conditions, a consultation with a
cardiologist is recommended to help with the risk-benefit analysis and for
treatment modifications that may decrease risks. It has been proposed that
an assessment of functional cardiac status (such as a stress test) should be
considered in 1) men younger than age 60 and women under age 70 with
definite angina, 2) men older than age 60 and women over age 70 with
probable angina, 3) all patients with angina and two risk factors for
myocardial infarction, and 4) those with clinically significant extracardiac
vascular disease (Applegate 1997). A finding of good functional status
indicates that the risk is low; otherwise, further cardiac evaluation is
indicated.
Individuals with coronary artery disease are at risk for ischemia during
both the periods of relative parasympathetic tone and the periods of
increased sympathetic system tone (Christopher 2003; Weiner et al. 2000).
When parasympathetic tone is increased, there is a risk of ischemia due to
hypoperfusion, whereas when sympathetic activity rises, the increased
cardiac workload can lead to complications. The risks of complications due
to these factors can be decreased pharmacologically. Anticholinergic
medications such as atropine can be used to decrease the occurrence and
severity of bradycardia, β-adrenergic blockers can be used to decrease
cardiac workload, and nitrates or calcium channel blockers may be used to
decrease the risks of ischemia (Weiner et al. 2000). Typically, patients who
are receiving medications for the treatment of coronary artery disease at the
time of referral for ECT are maintained on those medications throughout
the ECT course, including administration before ECT on treatment days
(Applegate 1997). Changes to the medication regimen or the addition of
other medications to decrease the risks of complications should generally be
considered in conjunction with a cardiology consultant.
Patients with pathologies associated with low cardiac output such as
heart failure or those with severe valvular disease are at particular risk
during the sympathetic surge because of the increase in afterload and
decreased diastolic filling time (Stern et al. 1997). Such patients should not
be administered large volumes of fluid (Rayburn 1997). A number of
medications have been suggested as means to decrease risks in these
situations, including β-adrenergic blockers, α-adrenergic blockers, nitrites,
digitalis, and anticholinergic agents; however, the use of such agents is
controversial (Weiner et al. 2000). No single regimen appears to be optimal
for all patients with these diseases, and the treatment plan should be
individualized on the basis of risk-benefit considerations.
Arrhythmias may increase the risks of ECT (Takada et al. 2005).
Bradyarrhythmias are typically best managed with atropine to prevent
exacerbation during increases in parasympathetic tone. Because of the
anticonvulsant effects of lidocaine, ventricular ectopy should be treated
with other agents before the ECT treatment (Hood and Mecca 1983). There
is a risk that individuals with atrial fibrillation may experience spontaneous
cardioversion with ECT that can lead to an embolic event (Petrides and
Fink 1996). For this reason, consideration should be given to
echocardiography (to rule out a mural thrombus) and the use of
anticoagulants (Weiner et al. 2000).

Endocrinological Disorders
Several endocrinological disorders require special consideration before
ECT. The most commonly encountered is diabetes mellitus. Patients with
diabetes are more likely than other ECT patients to have problems
stemming from the need to fast from midnight until the time of the ECT
treatment. Insulin doses may need to be adjusted, and pretreatment
intravenous glucose administration can be considered if indicated (Weiner
et al. 2000).
In patients with hyperthyroidism and pheochromocytoma, β-adrenergic
blockers are typically administered to prevent triggering of a thyroid storm
or hypertensive crisis, which can be elicited by the sympathetic surge
(Weiner et al. 2000). In cases of pheochromocytoma, α-adrenergic and
tyrosine hydroxylase blockers may be needed.

Metabolic Disorders
The metabolic problems that are of primary concern are hyperkalemia and
hypokalemia, both of which may lead to cardiac arrhythmias. The former is
of particular concern because of the transient rise in serum potassium
caused by succinylcholine and the muscle activity that may occur during the
induced seizures (Christopher 2003; Weiner et al. 2000). In individuals with
hyperkalemia, prolonged paralysis and associated apnea induced by
succinylcholine may be seen. Although it is best to correct these conditions
before administering ECT, in cases where correction is not possible, the use
of paralytic agents other than succinylcholine should be considered.

Hematological Disorders
Thrombophlebitis carries with it the risk of embolism with ECT, a risk that
is generally easily avoided with the use of anticoagulant medications. The
use of warfarin has been recommended, with a goal of achieving an
international normalized ratio (prothrombin time normalized to the
laboratory control value) between 1.5 and 2.5 (Petrides and Fink 1996).

Pulmonary Disorders
Patients with asthma or chronic obstructive pulmonary disease have an
increased risk of posttreatment bronchospasm, which should be mitigated
by the use of bronchodilators (Weiner et al. 2000). Theophylline should be
avoided if possible, or the dose should be kept to a minimum because of an
increased risk of prolonged seizures.

Gastrointestinal Disorders
Patients with gastroesophageal reflux are commonly encountered in the
practice of ECT. Complications of aspiration may be diminished with the
use of a pretreatment histamine type 2 antagonist the night before and the
morning of treatment (Weiner et al. 2000). To increase gastric emptying,
pretreatment metoclopramide may be considered, and sodium citrate may
also be used to neutralize the acidity of stomach contents. Although it has
not been reported, fecal impaction has been mentioned as a risk factor for
intestinal rupture with ECT (Weiner et al. 2000). Consequently, in patients
referred for ECT, it is important to address constipation, which is
particularly common in the elderly population.

Genitourinary Disorders
Urinary retention could, in theory, lead to bladder rupture with ECT. As a
result, it has been recommended that patients void before ECT, and urinary
catheterization should be considered in those with significant obstruction or
difficulty urinating (Weiner et al. 2000).

Musculoskeletal Disorders
Musculoskeletal conditions, such as osteoporosis, unstable fractures, and
loose or damaged teeth, are common in older adults and carry an increased
risk of complications with ECT. Patients with osteoporosis or with recent or
unstable fractures are at risk for bone damage during the induced
convulsion, and should be considered high fall risks. The contraction of the
jaw muscles that leads to teeth clenching cannot be diminished with the use
of paralytic agents because it occurs by direct electrical stimulation of the
muscle tissue and not via neuromuscular transmission. Therefore, the use of
a mouth guard is always necessary. However, those with loose or damaged
teeth may require customized devices, dental treatment, or tooth extraction
before ECT.

Adverse Effects in Older Adults

Advanced age itself does not appear to increase the medical risks of ECT.
As a group, however, older individuals have a higher frequency of
comorbid medical and neurological conditions that increase the risks of
treatment, as outlined in the preceding subsections (Kujala et al. 2002;
Nuttall et al. 2004; Takada et al. 2005; Tomac et al. 1997). Interestingly,
although early studies have reported that older adults in general tend to
have greater and more prolonged cognitive impairment with ECT
(American Psychiatric Association 2001; Sackeim et al. 2007), such
increased risk has more recently been questioned (Tielkes et al. 2008;
Verwijk et al. 2014). Still, particularly for those with preexisting cognitive
impairment, modifications of treatment technique should be considered to
minimize cognitive side effects.
The greater frequency of comorbid medical and neurological disease in
elderly persons also increases the risks associated with pharmacological
management of their neuropsychiatric conditions. In some cases, these risks
can make pharmacological management extremely difficult and may lead to
a referral for ECT. In this regard, Manly et al. (2000) compared the
frequency of side effects associated with ECT and pharmacotherapy in a
group of depressed patients older than 75 years who were matched for age,
sex, and diagnosis. These researchers reported that ECT resulted in fewer
side effects (particularly cardiovascular and gastrointestinal) and greater
efficacy than pharmacological management. This study underscores that
ECT is a relatively safe treatment for older adults and that in many cases it
may be both the safest and most effective option.

Pre-ECT Evaluation

Basic Components of the Evaluation

Each pre-ECT evaluation should be carried out by an individual clinically
privileged to administer ECT in conjunction with an anesthesia provider.
This evaluation should include 1) a thorough psychiatric history and
examination, including history of response to ECT and other treatments; 2)
a medical history and examination, with special attention paid to
cardiovascular, respiratory, neurological, and musculoskeletal systems; 3) a
history of dental problems and examination for loose or missing teeth; and
4) a history of personal and family experiences with anesthesia (American
Psychiatric Association 2001; Tess and Smetana 2009). Laboratory tests are
generally performed, although there is no agreed-on routine set of tests to
carry out in each case. The most commonly administered pre-ECT
screening battery of tests includes a complete blood count, serum chemistry
(including sodium and potassium), and electrocardiogram (American
Psychiatric Association 2001). A chest radiograph is indicated in patients
with cardiovascular or pulmonary disease or with a history of smoking
(American Psychiatric Association 2001; Weiner et al. 2000).
The decision about whether to pursue testing of cerebral function and
structure (e.g., electroencephalographic [EEG], neuroradiological, and/or
neuropsychological assessment) should be made on an individual basis,
guided by the patient’s history and examination. Spinal radiographs should
be considered in individuals with known or suspected spinal disease.
Further testing or consultation should be considered when the nature or
extent of a problem is uncertain, when the risks of ECT in the setting of the
existing medical disease are unclear, or when there is uncertainty about how
to modify ECT technique to decrease risks. In every case, the pre-ECT
assessment should include an evaluation of the risks of cognitive
impairment based on the considerations described in the earlier section
“Cognitive Side Effects” as well as the information obtained by history,
examination, and testing. This evaluation should play a key role in
recommendations about treatment technique in terms of electrode
placement, treatment frequency, dosing, and medications to be avoided.

Decision About Whether to Administer ECT

The decision about whether to recommend ECT should be based on a
careful assessment of risks and benefits of ECT versus alternative
treatments, the data obtained in the evaluation, and information presented in
the available literature. The starting point for this decision should be the
psychiatric diagnosis. ECT should be seriously considered only when the
patient has a condition for which there is evidence of ECT efficacy
(American Psychiatric Association 2001). For individuals with an ECT-
responsive disease, a number of factors should be considered in developing
a recommendation about ECT. These factors include the severity of the
illness, the degree of refractoriness to other treatments, an assessment of the
risks of ECT, and the patient’s preference.
In conditions such as major depression, for which ECT is the most
effective treatment known, the greater the severity of illness, the stronger
the indication for ECT (Weiner and Krystal 2001). When psychosis is
present or when there is a high degree of lethality because of suicidality,
dehydration or malnutrition, or the patient’s inability to cooperate with
necessary medical treatment, ECT is frequently the treatment of choice.
Unfortunately, no proven guidelines exist for how to define treatment
refractoriness in terms of medication dosage or duration or number of failed
trials. Consequently, the choice of when to refer a patient for ECT on the
basis of medication resistance or intolerance is generally based on factors
such as symptom severity, morbidity of the episode, and patient preference
as much as it is on the characteristics of prior medication trials.
The assessment of risks based on the evaluation is an important part of
deciding whether to pursue ECT. The greater the perceived risk, the
stronger the indication for ECT must be for a recommendation to be made.
When the risks of ECT are assessed to be significantly life-threatening,
ECT should be pursued only if the illness is so lethal that the risks of not
pursuing ECT are determined to be greater. As noted earlier in “Other Risks
With ECT,” however, risk is a relative index.

Informed Consent
The collaborative aspect of decision making has been formalized as the
legal doctrine of informed consent (American Psychiatric Association
2001). No patient with the capacity to give voluntary consent should be
treated with ECT without his or her written, informed consent. Although
there is no clear consensus about how to determine capacity to give consent,
this capacity has generally been interpreted as evidence that the patient can
understand information about the procedure and can act responsibly on the
basis of this information (American Psychiatric Association 2001). The
process of determining competency, the process for giving ECT
involuntarily in cases of emergency, and the specific procedures regarding
informed consent should be carried out as specified by applicable state
statutes. Because of the increased likelihood of cognitive dysfunction in
older adults, capacity to consent is of particular concern (Rabheru 2001).
At a minimum, written consent should be obtained before the initial
course of ECT, before a treatment course involving an unusually large
number of treatments, and before initiating continuation or maintenance
ECT (American Psychiatric Association 2001). To adequately convey the
risks and benefits, the consent form should include the following
information: 1) a description of treatment alternatives; 2) a detailed
description of how, when, and where ECT will be carried out; 3) a
discussion of options regarding electrode placement; 4) the typical range of
number of treatments; 5) a statement that there is no guarantee that the
treatment will be successful; 6) a statement that continuation or
maintenance treatment of some kind will be necessary; 7) a discussion of
the possible risks, including death, cardiac dysfunction, confusion, and
memory impairment; 8) a statement that the consent also applies to
emergency treatment that may be clinically necessary at times when the
patient is unconscious; 9) a listing of patient requirements during the ECT
course, such as taking nothing by mouth after midnight before treatment;
10) a statement that there has been an opportunity to ask questions and an
indication of who can be contacted with further questions; and 11) a
statement that consent is voluntary and can be withdrawn at any time
(American Psychiatric Association 2001).
Informed consent involves more than just signing a consent form; it
requires a consent discussion with the patient or surrogate (and, if possible,
a significant other). The consent discussion should include any significant
differences in likelihood of benefit or extent of risk from that depicted in
the consent form, and mention of such discussion should be briefly
documented in the patient’s medical record.

Management of Medications
Each pre-ECT assessment should include an evaluation of the patient’s
medications and recommendations about how medications should be taken
before and during the ECT course. Medications that are needed to decrease
medical risks should be continued, but their dosing and timing of
administration may need to be changed (American Psychiatric Association
2001). Similarly, orders should be written specifying dosage and timing of
any medications that are to be added to decrease risks based on the pre-ECT
evaluation. Other nonpsychotropic medications should be withheld until
after the treatment on ECT days or—in the case of those that interfere with
or increase the risks of ECT—should be discontinued.
Regarding the use of psychotropic medications during the ECT course,
there are considerable differences of opinion and great variation in practice.
The only situation in which compelling evidence exists for a potentiating
effect of psychotropic medication on ECT is the use of antipsychotic agents
in individuals with schizophrenia (and inferentially in those with psychotic
depression) (American Psychiatric Association 2001). The literature
regarding the benefits of antidepressant medication as a means to augment
the ECT response is unclear, although it does not appear that such a
combination is associated with significantly increased risk. The primary
reasons that have been given for the use of antidepressant medication
augmentation are that it is difficult at times to accomplish drug withdrawal
before instituting ECT, that there is a desire to decrease the risk of early
relapse after ECT, and that “there is nothing to lose.”
When possible, antidepressant medications should be chosen that have
relatively fewer effects on cardiac function. The following psychotropic
medications are among those that are best avoided or maintained at the
lowest possible levels: 1) lithium—it may increase the risks for delirium or
prolonged seizures; 2) benzodiazepines—their anticonvulsant properties
may decrease efficacy (but can be reversed with flumazenil at the time of
ECT) (Krystal et al. 1998); and 3) antiepileptic drugs—their anticonvulsant
properties may decrease efficacy, but they may be needed in those with
epilepsy or with very brittle bipolar disorder (in which case the medication
should be withheld the night before and the morning of treatment if
possible).

ECT Technique

Inpatient Versus Outpatient Administration

Although ECT has traditionally been an inpatient treatment modality, a shift
has occurred over time—much like the one that has occurred in the realm of
surgical procedures—to offer it on an outpatient basis (American
Psychiatric Association 2001). At present, inpatient ECT is reserved for
situations in which 1) the patient’s psychiatric illness itself requires an
inpatient level of care or 2) such a level is required to ensure that ECT can
be safely administered (e.g., for patients with high medical risk factors and
no support system). These situations are particularly likely to occur with
older adults. Even when inpatient treatments are initially required,
consideration should be given to switching to an outpatient mode when it is
clinically feasible.

Anesthetic Considerations
ECT is a procedure involving general anesthesia. Airway management, the
administration of medications necessary for anesthesia, and the handling of
medical emergencies during and immediately following the ECT procedure
are the responsibility of the anesthesia provider (American Psychiatric
Association 2001). Appropriate medical backup should be present,
particularly for high-risk cases.
The patient is ventilated by mask with 100% oxygen throughout the
procedure, beginning at least a few minutes before anesthesia induction and
lasting until a satisfactory level of spontaneous respiration is maintained
during the postictal period. General anesthesia is usually provided by
intravenous methohexital, typically 1 mg/kg (American Psychiatric
Association 2001; Ding and White 2002; Saito 2005). Because seizure
threshold (the amount of electricity necessary to induce a seizure) appears
to increase with age, and stimulus output of ECT devices is limited by the
U.S. Food and Drug Administration (FDA), difficulties in seizure induction
can be experienced with older adults, particularly late in an index ECT
course. In such situations, methohexital dosage can be slightly diminished
by concurrent usage of a short-acting sedative narcotic such as remifentanil,
or the anesthetic itself can be switched to one with less anticonvulsant
properties (e.g., etomidate or ketamine).
After loss of consciousness, the muscle relaxant succinylcholine is
administered intravenously, again with a typical dosage of 1 mg/kg
(American Psychiatric Association 2001). When the patient’s muscles are
relaxed (ascertainable by disappearance of relaxant-induced fasciculations
and loss of deep tendon reflexes or twitch response to a peripheral nerve
stimulator), the electrical stimulus can be delivered.
An anticholinergic medication, such as glycopyrrolate or atropine, may
be administered before anesthesia to minimize the risk of stimulus-related
asystole and the occurrence of postictal oral secretions. However, most
practitioners use such agents selectively because they potentiate seizure-
related tachycardia. When seizure-related hypertension and tachycardia are
severe or when prophylaxis is indicated on the basis of preexisting
cardiovascular disease, β-blocking medications (e.g., labetalol) are often
used to minimize these effects. Again, it is best to use such agents
selectively. When necessary, postictal agitation or delirium can be managed
with the use of intravenous midazolam (1 mg), haloperidol (2–5 mg), or the
α2 agonist dexmedetomidine (10–40 mcg), as well as by providing
reassurance and maintaining a quiet, low-light environment for the postictal
recovery process. Dexmedetomidine is interesting in that if it is
administered preictally, it will blunt the sympathetically mediated rise in
heart rate and blood pressure during the induced seizure (Aydogan et al.
2013).
With older adults, it is important to recognize that lower doses of
medications may be indicated because of altered metabolism or tolerance.
In addition, time to effect may be longer in older adults. On the other hand,
under some circumstances, higher doses may be necessary (e.g., more
relaxant agent may be needed for an individual with osteoporosis).

Physiological Monitoring
During ECT, as with any procedure utilizing general anesthesia, vital signs
and pulse oximetry are monitored throughout the procedure and during the
immediate postictal period until stabilization occurs. After spontaneous
respiration resumes and vital signs and oxygen saturation are trending
toward baseline, the patient is moved to a postanesthesia care unit or area
(previously referred to as a recovery room), where monitoring of vital signs
and oxygenation continues.
Both the motor and EEG representations of seizure activity are
monitored during ECT. To allow monitoring of the motor response in a
patient whose muscles are relaxed, a blood pressure cuff is placed around
the ankle and inflated to approximately 200 mm Hg just before
administration of the muscle relaxant. This action prevents muscle activity
distal to the cuff from being suppressed during the seizure. Ictal EEG
recordings are made, using recording leads placed on the head, in
conjunction with amplification and display capabilities built into the ECT
device. It is recommended that two EEG channels be recorded so that
seizure activity from both the left and the right cerebral hemispheres can be
monitored. Such recording can be accomplished by placing one pair of
recording electrodes over the left prefrontal and left mastoid areas and the
other pair over the homologous areas on the right.

Stimulus Electrode Placement

There are three major types of stimulus electrode placement: bitemporal,
bifrontal, and unilateral nondominant (the right side for the great majority
of individuals). Bitemporal ECT involves placement of both stimulus
electrodes over the frontotemporal regions, with the center of each electrode
approximately 1 inch above the midpoint of a line transecting the external
canthus of the eye and the tragus of the ear. Bifrontal electrode placement
involves locating the center of the stimulus electrodes approximately 5 cm
superior to each external canthus. The preferred type of unilateral
nondominant placement involves location of one electrode over the right
frontotemporal area (as described for bitemporal ECT) and the other over
the right centroparietal area, just to the right of the vertex of the scalp, a
point defined by the intersection of lines between the inion and nasion and
between the tragi of both ears.
There is significant controversy over the choice of stimulus electrode
placement (American Psychiatric Association 2001). Although unilateral
ECT appears to be effective in many patients as long as stimulus intensity is
sufficient (see “Stimulus Dosing” below), some patients may preferentially
respond to bitemporal ECT. On the other hand, ECT-associated amnesia is
greater with bitemporal ECT. A reasonable trade-off is to use unilateral
ECT initially, unless an urgent response is necessary or the patient has
indicated a preference for or has shown a past preferential response to
bitemporal ECT. With bifrontal electrode placement, the newest of the three
techniques (Bailine et al. 2000), data are mixed, with some studies
suggesting that both efficacy and cognitive effects of bifrontal ECT may be
less than with bitemporal ECT and perhaps slightly greater than with
unilateral ECT, but a large multicenter trial did not show an advantage for
bifrontal ECT (Kellner et al. 2010).
The choice of stimulus electrode placement is particularly challenging in
older adults, for whom an urgent need for a rapid response is often present,
yet in whom adverse cognitive effects are of concern, especially in those
who have preexisting cerebral impairment. One study reported that high-
dose unilateral ECT was as effective as bitemporal ECT in older adults
(Stoppe et al. 2006), although the placement controversy is still not
resolved.

Stimulus Dosing
All contemporary ECT devices used in the United States utilize a
bidirectional, constant-current, brief-pulse stimulus waveform. This
waveform is more efficient than the older sine-wave stimulus for inducing
seizures and allows ECT to be administered with fewer adverse cognitive
effects (Weiner et al. 1986). More recently, these devices have also
incorporated the use of the ultrabrief pulse stimulus, defined as a pulse
duration of less than 0.5 milliseconds, which is a more efficient way to
induce seizures (Loo et al. 2007) and is associated with less memory
impairment, although it may also be associated with a slightly more delayed
antidepressant effect (Sackeim et al. 2008). Regardless of stimulus
waveform type, however, the paradigm for the choice of stimulus dose
intensity dosing remains as controversial as the choice of electrode
placement. The disagreement centers on whether to dose with respect to an
empirically determined seizure threshold estimate obtained at the first
treatment (dose-titration technique) or to use a formula based on factors
such as age, gender, and electrode placement to make this decision
(formula-based technique) (American Psychiatric Association 2001).
Coffey et al. (1995) found that the dose-titration technique is better in
that it offers a more precise means to determine the patient’s seizure
threshold (which can vary manyfold) and thereby allows the practitioner to
more effectively control stimulus intensity. In practice, seizure threshold is
estimated at the first treatment by incrementally increasing the dose from a
low level until a seizure is induced.
 Regardless of the dosing paradigm, compelling evidence suggests that
stimulus intensity for unilateral brief pulse ECT should be somewhere
between 2.5 and 8 times seizure threshold (in terms of electrical charge),
with the range reflecting uncertainty as to the minimum dose necessary to
optimize therapeutic outcome (McCall et al. 2000). In this regard, it is
important to note that increasing stimulus intensity also increases the
severity of ECT-associated memory impairment, although to a lesser degree
than a switch to bilateral ECT. Stimulus intensity is less of an issue with
bilateral brief pulse ECT, in which a stimulus 1.5 times seizure threshold
appears to be sufficient. However, stimulus intensity is of most concern
with ultrabrief pulse ECT, certainly for unilateral electrode placement but
likely also for bitemporal and bifrontal placement (Sackeim et al. 2008).
Although evidence-based guidance in this regard is presently limited, it is
recommended for ultrabrief pulse stimuli that a stimulus intensity 6–8 times
seizure threshold be used for unilateral ECT and 4–6 times seizure
threshold for bitemporal treatments.
As alluded to above (see “Anesthetic Considerations”), seizure threshold
is a function of age, with substantially higher thresholds being present in
older adults. This higher threshold leaves older adults at greater risk for
being unable to receive a stimulus of sufficient intensity, because the
maximum output of ECT devices used in the United States is limited by
FDA regulations (Krystal et al. 2000a). The risk that the threshold will
exceed the maximum available stimulus intensity is greatest late in the
treatment course, because seizure threshold rises to a varying extent with
the number of treatments.

Determination of Seizure Adequacy

ECT-induced seizures are identical to spontaneous grand mal seizures
except that with ECT the motor response is attenuated pharmacologically.
The EEG recording during ECT (ictal electroencephalogram) manifests the
typical EEG features of a grand mal seizure, with irregular polyspike
activity marking the tonic portion of the seizure and repetitive polyspike
and slow-wave discharges during the clonic component. During the
immediate postictal period, a relative suppression (i.e., flattening) of EEG
activity can typically be seen (Weiner et al. 1991).
 Compelling evidence indicates that not all seizures are equally potent
from a therapeutic perspective. With unilateral ECT, barely suprathreshold
seizures—despite having identical durations as seizures from more
moderately suprathreshold stimuli—are only minimally therapeutic
(Sackeim et al. 1993). Based on findings that seizures with higher stimulus
intensity exhibit attributes such as higher amplitude, greater regularity in
shape, and greater postictal EEG suppression (Krystal et al. 1995) and that
such features are associated with therapeutic response to ECT, a growing
interest has developed in the possibility that electroencephalographically
based stimulus dosing may one day be feasible. This type of innovation
would be particularly attractive because it would allow practitioners a
means to tailor the stimulus intensity to the minimum therapeutic dose for
each individual and control for the variable rise in seizure threshold that
occurs over the ECT course (Krystal et al. 2000b). ECT device
manufacturers in the United States have incorporated “seizure quality”
features into their devices, although their utility for routine clinical usage
remains to be established (see American Psychiatric Association 2001;
Rasmussen et al. 2007). This utility is particularly questionable for
ultrabrief pulse ECT, where seizures appear less intense than with brief
pulse ECT and where postictal EEG suppression is less apparent (qualities
that also may make determination of seizure endpoint more challenging).
Regardless of stimulus waveform, seizure quality determinations can be
more difficult with elderly patients, possibly because of the effects of age-
related neuronal loss on the intensity of ictal hypersynchrony.

Frequency and Number of ECT Treatments

In the United States, ECT is typically administered three times a week, with
an index course usually lasting between 6 and 12 treatments, although more
or fewer are sometimes necessary. The frequency of ECT may be reduced
to twice a week or even once a week if amnesia or confusion becomes a
major problem (American Psychiatric Association 2001), something that is
not infrequently indicated with elderly patients. The decision about when to
end the index ECT course depends on treatment outcome. In general, the
index ECT course is considered complete when a therapeutic plateau has
occurred—that is, when the patient has reached a maximum level of
response. If no substantial improvement occurs by the sixth treatment,
consideration should be given to making changes in the ECT technique,
such as increasing stimulus intensity, changing stimulus waveform,
switching stimulus electrode placement, or discontinuing any medications
with anticonvulsant properties. If no response occurs after 12 ECT
treatments, alternative treatment modalities should be considered. At the
present time, these modalities would generally involve combination
pharmacotherapy using multiple agents of different classes.

Maintenance Therapy
The conditions for which ECT is used are typically recurrent. The risk of
relapse, particularly during the first 6 months, is extremely high (Tew et al.
2007), necessitating an aggressive program of maintenance treatment to
minimize the likelihood of relapse. This maintenance treatment may be
pharmacological or in the form of continued ECT (at a greatly lowered
frequency).

Pharmacological Maintenance Therapy

Pharmacological maintenance treatment is usually attempted after the initial
index ECT course unless the patient indicates a strong preference for
maintenance ECT. With major depression, evidence suggests that a
combination of antidepressant and mood stabilizer may be more effective in
maintaining remission than an antidepressant drug alone (Sackeim et al.
2001a). Unfortunately, medication resistance during the index episode may
diminish the likelihood of a sustained prophylactic effect (Sackeim et al.
1990). Maintenance pharmacotherapy following ECT treatment of mania or
schizophrenia has not been well studied. In the absence of applicable data,
an aggressive regimen of different drug classes should be considered.

Maintenance ECT
The high relapse rate following ECT, even with pharmacological
maintenance therapy, has created renewed interest in the practice of
maintenance ECT. After a flurry of largely positive case-series reports
(Rabheru and Persad 1997), a randomized trial of maintenance ECT versus
pharmacotherapy in patients treated for major depression was carried out,
with results indicating that the efficacy of maintenance ECT over a 6-month
period was comparable to that obtained by combination pharmacotherapy
with both lithium and nortriptyline (Kellner et al. 2006).
Although there are no established guidelines for a maintenance ECT
regimen, practitioners typically start with weekly treatments for 2–4 weeks,
followed by another 1–2 months of biweekly treatments, followed by 3-
week and then 4-week intervals. After 12 months, treatments are either
stopped or continued at an even lower frequency. Although many
maintenance ECT patients do well with such a regimen, others appear to
require more frequent treatments or even supplementation with
psychotropic medications. Others eventually relapse, leading to another
index ECT course or a switch to alternative treatment modalities. On the
basis of data from a multicenter trial of maintenance ECT versus
maintenance pharmacotherapy, Lisanby et al. (2008) suggested use of a
symptom-based approach to maintenance ECT for patients who have
responded well to an index course of ECT for major depression. With this
approach, the patient is administered four weekly treatments followed by
close monitoring for at least 6 months; recurrence of depressive
symptomatology is followed by one or two ECT treatments during the
following week. A further multicenter trial incorporating this technique is
currently under way.

TABLE 21–1. Advantages and disadvantages of noninvasive versus

invasive forms of clinical brain stimulation
Type Treatment Advantages Disadvantages
Noninvasive Transcranial Minimal risk Daily treatments
magnetic No significant Compliance issues
stimulation neurocognitive Depth of stimulation
(TMS) adverse events needed in the
Transcranial direct elderly
current
stimulation
(tDCS)
Invasive Vagus nerve Continuous Implantation, with
stimulation stimulation associated
(VNS) treatment complications
 Deep brain Replacement of
stimulation device every few
(DBS) years

In terms of cognitive effects, maintenance ECT is significantly better

tolerated than index ECT treatments, particularly if the interval between
treatments is kept large. A review of cognitive effects of maintenance ECT
in elderly patients suggests that this group is not at particularly increased
risk in this regard (Tielkes et al. 2008); however, some patients requiring
frequent maintenance ECT do have cumulative difficulties with amnesia,
and these should be taken into account in treatment planning. Given the
general good tolerance of maintenance ECT, there is no maximum lifetime
number of ECT treatments.

Other Brain Stimulation Therapies

In recent years, major research initiatives have been undertaken to study
and further develop alternative approaches to the use of other brain
stimulation techniques for treating depression. The majority of these trials
have been conducted in the general adult population, and thus these
approaches have not been tested exhaustively in elderly patients despite
their potential for successfully treating late-life depression. Nevertheless,
there are promising results from research on the development of
transcranial magnetic stimulation (TMS), transcranial direct current
stimulation (tDCS), vagus nerve stimulation (VNS), and deep brain
stimulation (DBS) in adult populations, which can be applied in geriatric
patients as well (Table 21–1).

Transcranial Magnetic Stimulation

TMS involves the noninvasive use of rapidly alternating magnetic fields to
stimulate areas of the brain related to mood regulation. Electric current is
run through a figure 8–shaped electrical coil, producing a magnetic field
that passes through the scalp and skull to excite targeted areas of the brain.
The technology continues to evolve, allowing increasing precision in the
administration of specific frequencies and the fine-tuning of other stimulus
parameters. A few variations of TMS configuration have arisen, including
repetitive TMS (rTMS) which involves rapid pulsing of the magnetic
stimulation and has been found to be efficacious in the treatment of
depression. rTMS is the most widely studied form of TMS to date and was
approved by the FDA in 2008 for treatment of mild to moderate depression
in patients who have failed to respond to or cannot tolerate antidepressant
medications. One of the limitations of rTMS in geriatric patients is its
restricted ability to stimulate deeper structures that have been affected by
cortical atrophy. Nahas et al. (2004) increased TMS intensity when treating
elderly patients (mean age 61.2 ± 7.3) to between 103% and 141% of motor
threshold (average intensity=114%) in an attempt to overcome this
limitation. They observed positive results but did not find a statistically
significant correlation between improvement in depression and stimulus
intensity in this population. More research into this approach is needed.
In a review of small clinical trials comparing rTMS with ECT in the
treatment of major depression, Berlim et al. (2013) reported significantly
higher efficacy with ECT. This finding is compatible with the lower effect
size that is present with rTMS use in this patient population. Furthermore,
although there is considerable diagnostic and severity overlap between
subjects in rTMS and ECT trials in major depression, rTMS trials typically
exclude subjects with psychotic or severe suicidal ideation.
A second TMS variation, deep TMS (dTMS), was approved by the FDA
in 2013 and may address some of the deeper structure limitations because it
uses an H-shaped coil to generate a magnetic force capable of reaching
deeper into the brain. Evaluation of its efficacy in geriatric populations is in
the early stage.
TMS has demonstrated a strong safety record accompanied by minimal
side effects, which is important in the treatment of elderly subjects. Studies
have consistently shown that TMS is relatively well tolerated by patients,
with only 4.5% of patients terminating early due to side effects (O’Reardon
et al. 2007). The procedure has resulted in only mild adverse events, the
most common of which are headaches, muscle twitches, and pain at the
stimulation site (George et al. 2010; O’Reardon et al. 2007). All of these
can be minimized by adjusting the stimulation parameters. Also important
for geriatric patients is the fact that no significant adverse cognitive side
effects were noted in these trials. A more serious risk is posed by the
increased potential for seizure induction; to date there have been 13
documented cases of seizure related to TMS. Of note, many of these
instances involved neurologically compromised patients or treatment
parameters that fell outside the recommended standards (Wani et al. 2013).

Transcranial Direct Current Stimulation

tDCS is a noninvasive brain stimulation therapy that has grown from its
initial development as a research technique to encompass clinical
application as well. It uses weak levels of direct current (usually ranging
from 1 to 2.5 mA) to stimulate cortical neuronal activity. Administration
involves placing two electrodes at targeted cortical areas (dorsolateral
prefrontal cortex) on the patient’s head, such that the electric current
passing between them flows through the underlying cortical tissue, inducing
neuronal excitation.
Because it is in the early phases of development, tDCS has not yet been
tested specifically in the geriatric population. Several factors, such as the
length and frequency of treatment, lead placement, and patient
characteristics, influence treatment outcomes (Brunoni et al. 2012). tDCS is
attractive as a brain stimulation treatment due to its demonstrated minimal
risk of serious adverse events. Minor adverse events commonly reported by
patients include burning, tingling, and itching sensations at the site of
stimulation during treatment, but these can be managed effectively through
the use of anesthetic ointments as part of the treatment procedure. Thus,
tDCS, should it prove efficacious in the treatment of major depression,
could serve as a promising, simpler, and lower-risk noninvasive treatment
that can serve as a viable alternative with minimal side effects in the
treatment of late-life depression.

Vagus Nerve Stimulation

VNS was the first FDA-approved invasive treatment to be developed for
depression. The vagus nerve is thought to affect depression through its
relationship with areas of the brain associated with mood regulation (Wani
et al. 2013). The use of neuroimaging technology has produced
documentation that the VNS alters activity in mood-related cortical regions
of the brain in research carried out on depressed patients (Daban et al.
2008).
 VNS involves the implantation of an electrical pulse generator in the
patient’s chest to provide intermittent electrical stimulation to the left vagus
nerve. An external programming device is used to activate and adjust
stimulus dosing. The most commonly reported side effects are voice
alteration and increased cough (Sackeim et al. 2001b), and these often
resolve as the patient develops tolerance for the stimulation. Physicians can
also choose to alter the stimulation levels to promote tolerance and reduce
side effects. However, the surgical procedures involved in VNS may lead to
complications and serious adverse events.
Due to its invasive nature, VNS is approved in the United States only for
use as an adjunctive long-term treatment for chronic or recurrent treatment-
resistant depression in adults; however, efficacy in this population has been
limited, with low effect size and evidence of efficacy only after several
months. Still, research continues in an effort to improve and refine
stimulation parameters and clinical application (Rodez et al. 2009; Wani et
al. 2013).

Deep Brain Stimulation

DBS is an investigational approach to treating severe depression that
continues to be evaluated, although the FDA approved use of DBS for
Parkinson’s disease in 2002. Many patients being treated for Parkinson’s
disease with DBS implants reported concomitant improvement in mood
symptoms (Kuehn 2007), and this finding generated interest in DBS as an
approach to treating severe depression. Today, due to the invasive nature of
the treatment, DBS is reserved for individuals with severe treatment-
resistant depression. Although DBS continues to be used in elderly patients
with Parkinson’s disease, there are ongoing controlled trials of DBS for
chronic refractory depression.
DBS involves surgical implantation of electrodes in a targeted area of the
brain (e.g., Brodmann area 25). These electrodes are attached to a
neurostimulator that is implanted in the patient’s chest wall, and electrical
impulses are generated on a constant basis. The frequency and intensity of
these impulses can be controlled with a small handheld programming
device. Other regions of the brain have also been targeted in patients with
treatment-resistant depression, including the ventral striatum and the
nucleus accumbens (Schlaepfer et al. 2008, 2014).
 In spite of the invasive nature of DBS, an important strength is that it has
not been shown to affect cognitive functioning (Mayberg et al. 2005). Still,
there are risks associated with the surgical procedure, including infection,
bleeding in the brain, and seizures. Additionally, irritability, headaches, and
pain at the generator site have been reported (Lozano et al. 2008). Further
research is attempting to identify other cortical regions for stimulation and
establish techniques and procedures that minimize such side effects
(Schlaepfer et al. 2014).

Future of ECT and Other Brain Stimulation

Therapies
The use of ECT has persisted for 70 years, despite the development of
many alternative treatment options. Its continued viability, however,
depends not only on innovations in alternative treatments but also on the
continued optimization of ECT in terms of both efficacy and adverse
effects. As noted above in the section “ECT Technique,” research is under
way to improve on the available options for both stimulus electrode
placement and electrical stimulus parameters. Other work is being done to
enable practitioners to better predict which patients might be ECT
responders.
Future alternatives to ECT include not only new psychopharmacological
agents but also new types of brain stimulation therapies, such as TMS,
tDCS, VNS, and DBS. Although these innovative alternative brain
stimulation techniques are still in their early phases of development and
limited data are available to support their present use in the geriatric
population, they are promising due to the absence of the neurocognitive and
systemic side effects that are associated with both ECT and
pharmacological treatments. Future studies are needed to explore the
efficacy of treating severe treatment-resistant depression in elderly patients
with these interventions. In the meantime, a clear role remains for ECT in
the treatment of a variety of disorders, most notably major depression, for
which older individuals are at a particularly high risk.

Key Points
 • ECT is the most rapid and effective treatment for major depressive
episodes in older adults.
• Major risks of ECT are largely a function of medical comorbidity.
• An index ECT treatment course can be ended once a therapeutic plateau
has been reached.
• The risk for relapse after an acute course of ECT is high, and aggressive
maintenance treatment is needed.
• Other brain stimulation therapies for the treatment of depression include
transcranial magnetic stimulation, transcranial direct current stimulation,
vagus nerve stimulation, and deep brain stimulation.
• Most of the brain stimulation therapies have been studied primarily in
the general adult population, and data to support their efficacy in older
adults are limited.
• Future clinical trials are needed to test the benefit of these therapies in
the geriatric population.

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Suggested Readings
Abrams R: Electroconvulsive Therapy, 4th Edition. New York, Oxford
University Press, 2002
American Psychiatric Association: The Practice of ECT: Recommendations
for Treatment, Training, and Privileging. Washington, DC, American
Psychiatric Press, 2001
Dukakis K, Tye L: Shock: The Healing Power of Electroconvulsive
Therapy. New York, Avery, 2006
Endler NS: Holiday of Darkness, Revised. Toronto, ON, Wall & Davis,
1990
Fink M: Electroconvulsive Therapy: A Guide for Professionals and Their
Patients, 2nd Edition. New York, Oxford University Press, 2010
Higgins ES, George MS: Brain Stimulation Therapies for Clinicians.
Washington, DC, American Psychiatric Publishing, 2009
Mankad MV, Beyer JL, Weiner RD, et al: Clinical Manual of
Electroconvulsive Therapy. Washington, DC, American Psychiatric
Publishing, 2010
Manning M: Undercurrents: A Life Beneath the Surface. San Francisco,
CA, Harper Collins, 1995
Reti IM: Brain Stimulation: Methodologies and Interventions. New York,
Wiley, 2015
Shorter E, Healy D: Shock Therapy: A History of Electroconvulsive
Treatment in Mental Illness. New Brunswick, NJ, Rutgers University
Press, 2007
 CHAPTER 22

Nutrition and Physical Activity

Kathryn Porter Starr, Ph.D., R.D.
Connie Watkins Bales, Ph.D., R.D.
Martha E. Payne, Ph.D., R.D., M.P.H.

Health Promotion in Older Adults

The attainment of 65 years or more of living carries with it all the positive
attributes—such as apparent resistance to early mortality—and negative
consequences—including the effects of a lifetime of environmental
exposures and health insults—of being an older adult. However, the quality
and quantity of life from age 65 years onward remain very responsive to the
impact of lifestyle factors, particularly the type of dietary and physical
activity patterns maintained. In fact, with the onslaught of age-related
decrements in physical function and the concomitant onset of the chronic
diseases of aging, it could be argued that this period in the life cycle offers
one of the most important opportunities for lifestyle interventions to make a
difference in health-related quality of life (Wellman 2007). This chapter
provides a detailed discussion of the complex interactions of diet and
physical activity with mental health and treatments for mental health
disorders. In addition, this chapter provides a thorough discussion of
assessment techniques and clinical guidelines for both nutrition and
physical activity in older adults.
As during all stages of the life cycle, good nutrition and healthy patterns
of physical activity are basic requirements for optimal health in later life.
Essential nutrients are required to support the structural and metabolic
functions of the body, the components of which are constantly being turned
over and replenished, even in mature individuals. For example, essential
amino acids are the required building blocks for protein synthesis (for both
structural and functional proteins), whereas vitamins and minerals are
required as cofactors for a host of essential enzymes in metabolic pathways.
Of particular relevance to mental health and cognitive function are select
nutrients (see next section, “Mental Health, Nutritional Status, and Physical
Activity”) that are essential for nervous system function because of their
roles in membrane health, myelin production, and neurotransmitter
synthesis, as well as their participation in key enzymatic reactions. The
commonly quoted caveat to “use it or lose it” aptly applies to physical
activity; maintaining an active lifestyle preserves muscle mass and muscle
strength, as well as bone mineral density, and has been linked with
improved mood, sleep patterns, and quality of life.
In addition to maintaining essential life-sustaining functions, judiciously
applied diet and exercise regimens can help prevent or at least delay the
onset of many age-related chronic diseases and thus play a critical health-
preserving role for high-risk individuals. Many of the leading causes of
illness and death in the second half of life, including cardiovascular disease,
stroke, diabetes mellitus, osteoporosis, certain cancers, anxiety, and
depression, are amenable to modification with diet and/or physical activity
intervention strategies. Beyond these disease prevention effects, healthy diet
and activity patterns also contribute to functional status and overall well-
being. For example, reducing the risk of falls and associated injuries is a
key benefit of physical activity. While healthy diet patterns and physical
activity play important roles in promoting optimal mental health, it is also
true that mental/cognitive parameters can have considerable impact on
nutritional status and physical activity patterns (Vreeland 2007). As
illustrated in Figure 22–1, determinants of the quality of life during aging
include physical and mental health, along with both diet and physical
activity. These interactions are explored in more detail in the following
sections.

Mental Health, Nutritional Status, and Physical

Activity: A Complex Interplay
Effect of Diet and Physical Activity on Mental Health and
Cognitive Well-Being
Although the specific etiological mechanisms have not been fully
delineated, it is well recognized that mental function can be adversely
affected by poor dietary choices. As shown in Figure 22–1, the
interrelationships among diet and physical activity, mental health, and
physical health are critical determinants of health and quality of life among
older adults. A problem in any one component can lead to deterioration in
other components and in overall health. For example, as shown in Figure
22–2, excess kilocalorie intake may lead to obesity and related physical
impairments, which, in turn, may promote depression.
The role of nutrition in the structure and function of the central nervous
system is well substantiated, and effects are manifested throughout the life
course. Many of the studies examining nutritional interventions to preserve
cognitive function focus on the important role of inflammation and
oxidative stress in normal aging of the brain. One line of research targets
antioxidants that, when consumed from dietary sources, could help slow
typical age-related changes in the brain. It is proposed that dietary
components such as the polyphenolic compounds found in foods (e.g.,
blueberries, red wine, tea) have favorable effects on signal transduction,
neural communications, memory, and attention (Cimrová et al. 2011; Lau et
al. 2007). Studies of supplementation with these and other compounds are
actively under way. Although discussion of preventive nutrition to benefit
brain function is beyond the scope of this chapter, the clinical practitioner
should be aware of the popularity of this topic and the possibility that their
patients may be “self-medicating” with foods or supplements that claim to
enhance cognitive function.
FIGURE 22–1. Determinants of quality of life in the elderly.
FIGURE 22–2. Example of a vicious cycle in relation to obesity.

When patients present with mental difficulties for the first time, the
clinician needs to consider a diverse laundry list of possible nutritional
concerns. Although the effects of nutritional deficits might be transitory, the
symptoms can be disabling and are likely to obscure any other underlying
mechanisms of impairment. Chronic inadequate food intake is a concern
and can lead to weakness, fatigue, and other vague symptoms due to
negative energy balance. Certain vitamin deficiencies can have cognitive
components, as we address in the later subsection “Vitamins.” Dehydration
is an important contributor to delirium and confusion in older adults, who
are known to have a diminished thirst response compared with younger
adults (Luckey and Parsa 2003). Lack of compliance with therapeutic
dietary restrictions and instructions can also contribute to poor mental
status. For example, when diabetic control is poor, the acute cognitive
effects of both hyperglycemia and hypoglycemia can be marked. Poor
glycemic control can also contribute to poor cognitive outcomes in the long
term (Ravona-Springer et al. 2012; West et al. 2014). Gregg et al. (2000)
used repeated clinical neuropsychological testing to evaluate the
relationship of diabetes and disease duration to cognitive function in a large
population-based study of older women and found an increased risk of
cognitive decline in individuals with diabetes mellitus.

Role of Nutrition in the Etiology of Dementia

The possibility that the lifelong intake of key nutrients or sustained dietary
patterns might fundamentally modify the development of major dementias
like Alzheimer’s disease and vascular dementia is the subject of intense
study. If altering a modifiable factor such as diet could preclude the onset of
devastating conditions such as dementia and depression, this would, of
course, be of incredible public health significance. Nutrients and dietary
constituents of interest in this regard have included alcohol and fish, various
types of fats, and vitamins related to homocysteine metabolism. Although
no definitive recommendations can be made based on current findings,
some of the most recently available related evidence is presented in this
section.

Alcohol
Although there are distinct disadvantages to advocating regular alcohol
consumption for adults of any age, there is a considerable amount of
evidence linking modest to moderate alcohol intake (no more than one daily
drink for women and two daily drinks for men) with benefits related to
preservation of cognitive function. A longitudinal study of 5,033 older men
and women assessed cognitive performance over 7 years and associated
light to moderate wine consumption with beneficial effects on cognitive
performance compared with low or no alcohol intake (Arntzen et al. 2010).
Weyerer et al. (2011) found that light to moderate alcohol consumption was
associated with significant reduction in the incidence of dementia and
Alzheimer’s disease in 3,202 men and women ages 75 years and older.
Furthermore, in a meta-analysis of 74 studies of older adults, Neafsey and
Collins (2011) found that compared with abstinence, moderate alcohol
consumption reduced risk of overall dementia by 23%, Alzheimer’s disease
by 27%, and vascular dementia by 34%. Despite these benefits, the
protective effect of moderate alcohol intake was diminished in individuals
with the allele producing the ε4 type of apolipoprotein E (APOE*E4)
(Panza et al. 2012).
It remains to be determined whether alcohol has direct benefits to
cognition or whether alcohol use is associated with other factors (e.g.,
physiological, cultural) that promote these benefits; however, a number of
potential mechanisms linking alcohol consumption and cognitive
consumption have been proposed. Moderate alcohol intake has been found
to reduce brain infarcts and white matter lesions and to reduce vascular risk
by increasing prostacyclin concentrations, reducing generation of
thromboxane A2, inhibiting platelet function, and increasing high-density
lipoprotein cholesterol levels (Frisardi et al. 2010; Panza et al. 2012).
Additionally, polyphenols in wine provide antioxidant effects that may be
protective for cognitive decline.

Type of Fat and Intake of Fish

The type of fat consumed may be an important determinant of cognitive
health. Dietary fats are divided into four general categories: saturated, trans-
unsaturated, monounsaturated, and polyunsaturated, with the latter
subdivided into omega-6 and omega-3 fats. Saturated and trans-unsaturated
fats are likely detrimental to cognitive as well as overall health, whereas
monounsaturated and polyunsaturated (especially omega-3) fats are
associated with a reduced risk of cognitive decline and dementia (Solfrizzi
et al. 2006). Adherence to the Mediterranean diet, characterized by high
intake of monounsaturated and omega-3 fats, moderate ethanol
consumption, and low intake of saturated fats, has been associated with a
reduced risk for cognitive decline (Scarmeas et al. 2006). In contrast, a
Western-style diet, characterized by high intake of high-fat (saturated) dairy
products as well as meats, potatoes, and processed foods, is associated with
greater cognitive decline (Parrott et al. 2013).
Because certain fish are the primary food sources of omega-3 fatty acids,
several studies have evaluated associations between fish intake and
cognitive health. A study of subjects of all ages (>15 years; N=4,644) in
New Zealand linked good mental health with the consumption of fish
(Silvers and Scott 2002). Morris et al. (2005) studied dietary intake of fish
and omega-3 fatty acids in relation to cognitive decline in a prospective
cohort study of adults age 65 years or older. Although fish consumption was
linked with slower rates of cognitive decline in this study, the relationship
seemed to be associated with fats (saturated, polyunsaturated, trans-
unsaturated) other than the omega-3 fatty acid component of the diet. This
finding is consistent with results from other studies that have failed to
detect a beneficial effect of fish oil supplementation on cognition (van de
Rest et al. 2008) and demonstrates the complex interplay of nutrients in the
diet.

Vitamins
Epidemiological studies, including longitudinal observations, have been
conducted to examine the relationships between vitamin intake and incident
dementia. The most commonly studied vitamins are folate and vitamin B12,
the deficiencies of which have been linked with symptoms of dementia in
older adults (Clarke 2007). Two longitudinal studies of adults older than age
65 years who were dementia free at baseline looked at predictors of incident
dementia over 2–6 years. Intakes of folate at baseline (assessed by a food
frequency questionnaire) and serum folate levels were associated with a
decreased risk of dementia, including Alzheimer’s disease, independent of
other risk factors (Kim et al. 2008a; Luchsinger et al. 2007). However,
Cochrane reviews for folate (Malouf and Grimley Evans 2008) and for
vitamin B12 (Malouf and Areosa Sastre 2003) have not supported a
cognitive benefit for these nutrients, and there are other such findings in the
literature (Eussen et al. 2006; Paulionis et al. 2005). The inconsistencies
across the folate literature may relate to the relatively more beneficial
influence of naturally occurring folate than of supplemental folic acid, and
to the correlation of folate-rich foods with other beneficial foods such as
fruits and vegetables. Regarding vitamin B12, the varied findings may
indicate that only deficient states promote dementia.
A study by Przybelski and Binkley (2007) suggested that vitamin D has
a role in cognitive function. Other studies have linked low plasma
antioxidant levels with cognitive impairment (N=589 elderly subjects)
(Akbaraly et al. 2007) and brain white matter hyperintense lesions (N=355
subjects ages 45–75 years) (Schmidt et al. 1996). It is likely that other
nutrients will also emerge as candidates for promoting optimal cognitive
status. Already, some investigators have tried interventions using nutritional
supplements to enhance cognitive function in the elderly, with limited
success (Wouters-Wesseling et al. 2005). This lack of success is consistent
with general lack of support for nutritional supplements for promoting
health in a healthy population, and the need for a food-based approach for
prevention of dementia. It is therefore not surprising that dietary patterns
have been shown to influence risk of cognitive decline. The available
scientific evidence supports a Mediterranean dietary pattern for the
prevention of late-life cognitive decline and dementia (Lourida et al. 2013),
rather than a focus on promoting single nutrients.

Nutrition and Late-Life Depression

Another important concern is the potential role of diet in the etiology of
depression. Diet may exert an influence on depression risk by promoting
physical illnesses that lead to depression, by causing brain changes or other
intermediate conditions that are favorable to the development of depression,
or potentially by directly promoting depression (Figure 22–3).
Depression in older adults is inextricably linked to vascular diseases,
including heart disease, diabetes, and stroke. Vascular disease and
depression promote one another. Key nutrients are known to be critical
factors in determining vascular disease risk and may thus lead indirectly to
late-life depression, as shown in Figure 22–3. Vascular promoters include
saturated fat, trans-unsaturated fat, cholesterol, high-fat dairy products,
meats, and excess total energy (kcals), all of which are common
components of a Western-style diet. Preventive dietary factors for vascular
diseases include monounsaturated fat, polyunsaturated fats (including
omega-3 fatty acids), fiber, folate, ethanol (in moderation), fish, fruits, and
vegetables, which are the primary components of a Mediterranean diet as
well as other healthy diets. In addition, obesity has been shown to increase
risk of depression in older adults (Almeida et al. 2009; Roberts et al. 2003).
A number of nutrients, including the B vitamins and omega-3 fatty acids,
have been linked to depression. Of the B vitamins, pyridoxine (B6),
cobalamin (B12), and folate (B9) are essential for serotonin production and
myelin formation and have been implicated in depression. Pyridoxine
deficiency is common in older adults, and low levels of pyridoxine have
been correlated with depression (Bell et al. 1991; Stewart et al. 1984;
Tolonen et al. 1988). However, studies of these factors have not
demonstrated that low pyridoxine levels or pyridoxine deficiency causes
depression.
Cobalamin deficiency, also common in older adults, is mostly
attributable to insufficiency of intrinsic factor, which is necessary for
gastrointestinal absorption of B12 (Andrès et al. 2004). Although prolonged
B12 deficiency has been shown to cause irreversible neurological damage,
its relationship to depression is less clear. Although cross-sectional
population studies have associated depression with low B12 (Penninx et al.
2000; Tiemeier et al. 2002), longitudinal studies have failed to find such an
association (Eussen et al. 2002; Sachdev et al. 2005).
Folate has been studied extensively in relation to depression, and its
importance may relate to neuronal function (serotonin or myelin
production) or vascular function (including homocysteine metabolism).
Some clinical and cross-sectional epidemiological studies have shown that
individuals with depression have poorer folate status than nondepressed
individuals (Ghadirian et al. 1980; Hunter et al. 1967; Ramos et al. 2004;
Sachdev et al. 2005), whereas many studies have failed to demonstrate any
relationship (Bjelland et al. 2003; Eussen et al. 2002; Gariepy et al. 2009;
Lindeman et al. 2000a; Penninx et al. 2000; Tiemeier et al. 2002).
Longitudinal studies have established that incident depression is associated
with lower baseline levels of serum folate in older adults (Kim et al. 2008b)
as well as with lower baseline dietary intake of folate in middle-aged men
(Tolmunen et al. 2004). The effect of folate on depression may be
influenced by the form of folate consumed (naturally occurring folate vs.
folic acid from fortification or dietary supplements) (Payne et al. 2009),
may vary by genetic profile, and may be related to treatment response (see
later section “Diet and Physical Activity as Psychiatric Treatment”).
There is evidence that omega-3 fatty acid metabolism may be altered
with depression, but the findings of dietary studies have been conflicting
(Adams et al. 1996; Maes et al. 1999). Population studies have shown that
fish consumption may be protective for depression, associating higher fish
consumption with a decreased risk of depression (Hibbeln 1998; Tanskanen
et al. 2001). However, a fish and fish oil supplementation trial conducted in
the United Kingdom did not confirm a beneficial effect on depression (Ness
et al. 2003). Likewise, a large epidemiological study (N=29,133 men ages
50–69 years) did not confirm any beneficial effects of dietary omega-3 fatty
acids on mood. In fact, in this study higher intakes of omega-3 fatty acids
were reported by subjects with anxiety or depressed mood (Hakkarainen et
al. 2004a, 2004b). It may be either that some component of fish other than
omega-3 fatty acids is responsible for epidemiological studies that link fish
intake with beneficial effects on mental health or that individuals who
consume fish also have other healthy factors in their diets.

FIGURE 22–3. A dietary mechanism for late-life depression.

Diet may promote (or prevent) depression by influencing one’s risk of vascular diseases, including
atherosclerosis and diabetes. These vascular diseases are known to promote late-life depression. In
addition, diet may directly promote (or prevent) depression by altering neuronal health or
neurotransmitter levels. Potential moderators of both pathways include ischemic brain lesions and
inflammation. CRP=C-reactive protein.
 The inconsistent findings regarding depression risk and individual
nutrients or foods have led some researchers to focus on dietary patterns.
This is a reasonable approach because nutrients and foods vary together in
the diet. The Mediterranean diet has received the most attention, and studies
have yielded promising results; greater adherence to this dietary pattern has
been found to decrease incident risk of depression (Sánchez-Villegas et al.
2009; Skarupski et al. 2013). A meta-analysis examined the role of the
Mediterranean diet in preventing mental and cognitive disorders
(Psaltopoulou et al. 2013). Higher adherence to a Mediterranean diet was
found to reduce risk not only for depression (relative risk [RR]=0.68; 95%
confidence interval [CI]=0.54–0.86), but also for stroke (RR=0.71; 95%
CI=0.57–0.89) and cognitive impairment (RR=0.60; 95% CI= 0.43–0.83).

Physical Activity as a Determinant of Cognitive Status and

Mood
Physical activity has been associated with numerous cognitive benefits,
including delayed onset of dementia (Larson et al. 2006), higher Mini-
Mental State Examination scores (Almeida et al. 2006), and increased brain
volumes (Colcombe et al. 2006). Also encouraging are reports linking
greater aerobic fitness with white matter integrity in certain regions of the
brain (Marks et al. 2007). A Cochrane review on the impact of aerobic
exercise on cognition in adults ages 55 years and older found positive
association on cognitive speed and auditory and visual attention (Angevaren
et al. 2008). Furthermore, in a meta-analysis of 15 prospective studies of
healthy older adults, low to moderate physical activity was associated with
a 35% reduced risk of cognitive decline compared with sedentary
individuals (hazard ratio [HR]=0.65; 95% CI=0.57–0.75) (Sofi et al. 2011).
Mental health is also associated with physical activity. Hamer et al.
(2014) followed older adults for 8 years and found that those who were
significantly less likely to report depressive symptoms participated either in
moderate activity (odds ratio [OR]=0.67; 95% CI=0.53–0.85) or in vigorous
activity (OR=0.51; 95% CI=0.39–0.67); however, only those who
participated in vigorous activity had reduced risk for cognitive impairment
(OR=0.64; 95% CI=0.48–0.85). Reported mental well-being is higher in
older adults with good mobility status (Lampinen et al. 2006). Acree et al.
(2006) measured health-related quality of life in older adults (mean age=70)
and categorized them by physical activity level. The researchers concluded
that older adults who were regular participants in physical activity of at
least moderate intensity for greater than 1 hour per week had higher health-
related quality of life than those who were less active. In contrast, older
men living in neighborhoods where walkability was lower were more likely
to be depressed than those living in environments that were more supportive
of physical activity (Berke et al. 2007).
Even when cognitive deficits are already present, as in patients with
depression or dementia, a carefully tailored program of physical activity can
be beneficial. In a randomized controlled trial (RCT) involving 134 patients
with mild to severe Alzheimer’s disease, a simple exercise intervention
resulted in a slower decline in the ability to perform activities of daily living
(Rolland et al. 2007). Additionally, a meta-analysis of seven RCT exercise
interventions for older adults with depression found that mixed exercise
(combination of strength and endurance exercise training) was associated
with a reduction in depression severity compared with the control condition
of no exercise (standardized mean difference=–0.34; 95% CI=–0.52 to –
0.17) (Bridle et al. 2012). The reduction in depression that results from
exercise is similar to that from taking antidepressants (Taylor et al. 2011) or
undergoing psychotherapy (Cuijpers et al. 2010).

Indirect Effects of Lifestyle Factors on Mental Health

When diet and physical activity behaviors precipitate medical illnesses,
there also may be deterioration in mental health (see Figure 22–1) and in
factors that are known to affect brain health. For example, heart disease is
known to promote late-life depression; individuals are three times more
likely to develop depression after an acute myocardial infarction (Thombs
et al. 2006). Physical inactivity and certain dietary components known to
promote heart disease may, in turn, promote late-life depression. It is known
that depression is associated with reduced adherence to taking medication
and medical treatments, increased health care utilization and health care
cost, and overall reduced quality of life (Fiske et al. 2009). Therefore,
promoting preventive factors for cardiovascular disease may similarly
prevent late-life depression.
In summary, all indications are that physical activity positively
influences both physical and mental health. Despite the considerable study
that has been done, many questions remain about the specific interplay of
nutrition and physical activity.

Impact of Mental Health Status on Diet and

Physical Fitness
Mental disorders and other causes of cognitive decline can have profound
direct effects on nutritional status and physical activity level. This impact
may be especially important in older adults, who are likely to be accruing
age-related decrements in both the mental and physical domains over time.
As shown in Figure 22–1, the interrelationships between diet and physical
activity, mental health, and physical health are critical determinants of
health and quality of life among older adults. A problem in any one
component can lead to deterioration in other components and in overall
health.

Mood Disorders
Mood disorders, including major depression and bipolar illness, and
situational conditions, such as bereavement and living alone, can
significantly affect health behaviors, including diet and physical activity.
Depression among older adults is often characterized by reduced appetite
and weight loss (Kolasa et al. 1995; Morley 1996; Pirlich and Lochs 2001;
Reife 1995). In fact, many geriatricians consider depression to be the most
common cause of poor food intake and nutritional frailty among elderly
individuals (Morley 2001). The loneliness and loss experienced by many
elderly individuals affect both mood and dietary status, contributing to the
anorexia and malnutrition of aging (Ferry et al. 2005). Locher et al. (2005)
conducted in-depth interviews with isolated elderly individuals and reported
that when eating alone, they consumed on average 114 fewer calories per
meal than when someone joined them at mealtime. In a French survey of
150 adults ages 80 years and older who lived alone, Ferry et al. (2005)
documented high rates of undernutrition. In these situations, inadequate
nutrient intakes may lead to muscle loss, an increased risk of bone fractures,
and nursing home admission (Christensen and Somers 1994).
 Although depression can interfere with food intake by affecting general
interest in daily activities, there are also possible physiological mechanisms
whereby depression could lead to decreased appetite and weight loss. One
potential explanation is that corticotrophin-releasing factor (CRF), a potent
anorectic agent known to be elevated in depressed individuals, may depress
appetite (Morley 1996). Some have blamed antidepressants for the weight
loss associated with depression; however, this relationship was observed
long before the advent of psychotropic medications. In addition, only a
subset of antidepressants is known to cause weight loss.
Patients who suffer from atypical depression may experience weight gain
as a result of increased appetite and inactivity. Obesity may develop or be
exacerbated in this situation. In addition to changes in quantity of food
consumed by individuals with depression, food quality may decline.
Carbohydrate-rich foods lacking in micronutrients (i.e., food of low nutrient
density) may be preferred by depressed individuals (Wurtman and Wurtman
1996). Elderly individuals with depression have higher intakes of saturated
fat and cholesterol than do those without depression (Payne et al. 2006). A
lack of energy may curtail healthy eating in depressed people; for example,
they may choose to eat fast food rather than spend the time preparing
healthier meals at home.
With regard to physical activity, the loss of energy and motivation that
may accompany depression naturally makes efforts to exercise extremely
difficult. At the other end of the spectrum, some people with depression,
bipolar disorder, or other mood disorders experience agitation, an increase
in energy, or excessive activity.

Stroke, Dementia, and Other Brain Diseases

Neurological and psychiatric conditions lead directly and indirectly to
cognitive and behavioral difficulties that can greatly impair one’s ability to
consume a healthy diet and to be physically active. The most obvious of
these is stroke, the aftereffects of which can hinder cognitive processes as
well as motor skills and other functions. Stroke patients may experience
problems chewing or swallowing food as well as cognitive changes that
impair their ability to plan meals, shop for food, prepare meals, and make
healthy food choices. Malnutrition at the time of hospital admission for
stroke is common in older patients and contributes to poor outcomes,
including increased length of stay, incidence and complications of
dysphagia, and likelihood of subsequent need for enteral feeding
(Martineau et al. 2005). Depending on its extent and location, paralysis may
limit mobility and can cause physical difficulties with food preparation or
consumption. Although eventual recovery of some body functions and
activities following stroke is common, nutritional status can deteriorate in
the 4–10 weeks this recovery can require (Kwakkel et al. 2006). In addition,
some stroke patients do not fully recover their ability to eat but remain at
high nutritional risk for months (Carlsson et al. 2004). In a study of patients
admitted to a geriatric rehabilitation unit following ischemic stroke, 35%
were malnourished at 1 week poststroke and 22% remained malnourished at
6 months (Brynningsen et al. 2007). Evidence-based guidelines for nutrition
support in patients following acute stroke have been developed and linked
with improvements in some patient outcomes (Perry and McLaren 2003).
Cognitive deficits, such as those resulting from Alzheimer’s disease,
vascular disease, and other causes, may also lead to changes in dietary
behavior. Patients with Alzheimer’s disease tend to lose weight early in the
disease process (White et al. 1996), leading to serious consequences,
including increased mortality (White et al. 1998). Early weight loss may be
the result of inadequate access to food and the inability to prepare food.
Appetite alterations (due to taste and/or smell alterations) and anorexia (due
to the effect of inflammatory mediators such as the cytokines) may also
play a role. In patients with late-stage dementia, sustaining sufficient oral
intake is extremely challenging, and tube feedings may be initiated.
Unfortunately, the survival rates are poor and not improved by the tube
feeding in most cases (Mitchell et al. 2003). Careful hand feeding may be a
more desirable alternative for many patients with advanced dementia
(Aselage et al. 2015).
In addition to stroke and dementia, ischemic and other forms of damage
may occur in the brain, particularly in elderly individuals. As with stroke,
the brain regions affected likely determine the symptoms, which can
include changes in appetite, psychomotor changes, and cognitive
impairment. Cognitive impairment may also occur with bipolar disorder,
schizophrenia, delirium, and a variety of other disorders. As with stroke,
cognitive impairment can lead to weight loss or malnutrition by hindering
meal planning, food choices, and food purchasing and preparation. In
severe cases individuals may forget to eat or how to eat.
 Stroke, dementia, and other cognitive problems are likely to impact
physical activity in addition to nutritional status. Although many of
individuals impaired by these conditions have the ability to be active at
some level, for safety reasons they need to be carefully supervised, and they
may have difficulty following instructions about proper performance and
safety aspects of the exercise.

Alcoholism
Alcoholism is a condition with considerable impact on both mental and
physical health because it occurs at the intersection of nutritional imbalance
and mental disorders. People with alcoholism often consume inadequate
amounts of vitamins and minerals and may have an insufficient intake of
protein. Not only does ethanol displace healthier dietary components, but
behavioral manifestations of alcoholism may hinder consumption of a
nutritionally adequate diet. In addition, alcoholic individuals may develop
deficiencies of certain nutrients (e.g., folate and other B vitamins) due to
malabsorption (Halsted et al. 2002). Chronic alcohol misuse can lead to
severe vitamin depletion and the development of Wernicke-Korsakoff
syndrome in susceptible individuals (Thomson 2000).
In a study assessing the prevalence of alcohol consumption in older
adults, Wilson et al. (2014) found that 14.5% of older individuals consumed
more than the National Institute on Alcohol Abuse and Alcoholism’s
recommended limit. However, when health status was taken into account
using the Alcohol-Related Problems Survey, 53.3% (95% CI=0.50–0.57) of
older adult drinkers were categorized as having harmful or hazardous
alcohol consumption (Wilson et al. 2014). Alcohol can enhance or negate
medication effects and lead to adverse drug events, impaired psychomotor
function, and sedation in older adults; therefore, it is important that
clinicians also assess heath status while investigating alcohol consumption
(Moore et al. 2007; Wilson et al. 2014).

Interaction of Treatments With Nutrition and

Physical Activity
Nutritional status can affect and be affected by mental health treatments,
particularly pharmacological ones. The most obvious concern is for drug-
nutrient interactions. Other issues are weight changes caused by drug
treatment and side effects that affect dietary habits. Diet and physical
activity have also been used as treatments for mental illness. Finally,
nutritional status can influence treatment outcomes.

Drug-Nutrient Interactions
Use of medications, including polypharmacy, is higher among elderly
individuals than among younger adults. This greater use, combined with the
physiological changes of aging, contributes to drug-related problems
including drug-nutrient interactions (Knight-Klimas and Boullata 2004).
The poor nutritional state that is common in elderly individuals can
exacerbate drug-nutrient interactions. A serious example of such an
interaction is a hypertensive crisis resulting from consumption of tyramine-
containing foods during monoamine oxidase inhibitor (MAOI) therapy
(McCabe 1986). Although addressing the list of possible drug-nutrient
interactions that may occur with psychotropic medications is beyond the
scope of this chapter, a general approach is recommended: Clinicians
should 1) consider the patient’s nutritional status (including malnutrition,
nutrient deficiencies, and body weight) and current diet (including intake of
vitamin, mineral, and herbal dietary supplements), 2) evaluate the potential
for known drug-nutrient interactions for the medication being considered
(which can be obtained from a drug-nutrient interaction reference book or a
pharmacist), and 3) discontinue the offending agent and/or institute
appropriate dietary modifications.

Other Treatment Concerns

In addition to drug-nutrient interactions, side effects from medications can
lead to changes in diet and nutritional status. For example, tricyclic
antidepressants (TCAs) and conventional antipsychotics often lead to
weight gain, whereas some selective-serotonin reuptake inhibitors (SSRIs)
cause weight loss. Side effects such as dry mouth or nausea may affect the
quality or quantity of food intake. The potential nutritional consequences of
psychotropic medications should be considered before and throughout
treatment.
Diet and Physical Activity as Psychiatric Treatment
Dietary manipulation and physical activity regimens have been used to treat
mental disorders. For example, aerobic exercise has been shown to be as
effective as antidepressants in treating major depression in elderly
individuals (Blumenthal et al. 1999; Hamer et al. 2014). Omega-3 fatty
acids have been used successfully in patients with bipolar disorder
(Balanzá-Martínez et al. 2011; Osher et al. 2005) and schizophrenia
(Marano et al. 2013). Nutritional status may also affect treatment outcomes
of these disorders. For example, baseline folate status has been positively
associated with response to SSRIs in elderly patients with depression
(Alpert et al. 2003). L-Methylfolate has been used successfully as an
adjunctive therapy for SSRI-resistant depression (Papakostas et al. 2012).
Finally, it should be noted that some individuals who have mental health
problems take dietary supplements, including vitamins, minerals, and herbal
supplements, as a means of treating their condition. For example, St. John’s
wort (Hypericum perforatum) shows some antidepressant properties
(Kasper et al. 2006) but has not been studied sufficiently in elderly
populations. In addition to safety concerns about a minority of herbal
supplements, dietary supplement users are at risk for consuming specific
nutrients in amounts far exceeding those that would be attainable through
diet.

Achieving Optimal Nutrition and Physical Fitness

in Later Life

Nutritional Issues and Wellness Barriers for Older Adults

Aging brings an array of potential barriers to optimal nutrition. These
include physiological and metabolic changes that can alter the nutritional
adequacy of the diet consumed and, in some cases, the requirements for
micronutrients. Age-associated decrements in energy requirements (see
later subsection “Energy-Yielding Nutrients and Alcohol”) lead to reduced
food intake and thus a decrease in nutrient consumption. As appetites
diminish, overall diet quality may also suffer as less well-liked foods (e.g.,
vegetables) may be eliminated in favor of comfort foods that are high in fat
and low in micronutrients (Chernoff 2005). Results of the National Health
and Nutrition Examination Survey show that average dietary intakes of
older adults were generally lower than recommended for potassium,
magnesium, calcium, and vitamins D and E (Moshfegh et al. 2009). In most
cases, nutrient intakes were higher in persons ages 60–69 years than in
those ages 70 years and older. Medical comorbidities and a host of other
factors, including economic, geographic, and psychosocial concerns, can
also affect dietary behaviors and thus nutritional status (Bales and Johnson
2012). The complications of chronic illness and the side effects of
medications and other medical interventions for chronic conditions (e.g.,
special diets, surgery, chemotherapy) decrease the likelihood of achieving
nutritional adequacy on a regular basis. The introduction of therapeutic
diets for these conditions also increases the likelihood of poor nutritional
status (Niedert 2005). In addition, environmental, social, financial, and
functional barriers can compound nutritional risk.
The first step in addressing dietary inadequacies is to recognize the
potential barriers to behavior change that inevitably present themselves.
Environmental and social factors strongly influence dietary intake and
ultimate nutritional adequacy (Locher et al. 2005). Limited social contact
(e.g., eating meals alone) impacts dietary intake, as does inadequate
assistance with shopping and preparing food. Institutionalization (e.g., in a
hospital, assisted living, or nursing home) is almost always linked with
increased nutritional risk. Fixed-income limitations put some elders in the
position of choosing between other essential expenses, such as prescription
medications, and money to be spent on nutritious foods.

Primer on Nutritional Assessment

Nutritional screening and assessment are part of the standard of care for all
older adults (Bauer et al. 2010). Early identification of risk factors and signs
of impending problems relating to food intake is important both in the
community setting and in long-term care settings so that appropriate
interventions can be optimally effective. Nutritional screening tools are
used to identify individuals who are at increased risk for being
undernourished or malnourished. The Mini-Nutritional Assessment Short-
Form (MNA-SF; Kaiser et al. 2009) and the DETERMINE Checklist
(Barrocas et al. 1995) are nutrition screening instruments recommended for
use with older adults. When nutritional risk is identified, a full assessment
is then warranted. A thorough nutritional assessment usually combines
elements of all three of the major components of nutritional assessment:
clinical, dietary, and biochemical.
Clinical nutritional deficiencies that can be identified in a physical
examination include skin changes, fatigue, weakness, changes in ability to
taste or smell, and gastrointestinal complaints (poor appetite, oral problems,
nausea, vomiting, diarrhea, constipation); however, the single most
important clinical measure of undernutrition in older adults is that of current
body weight and any recent changes. According to the Long-Term Care
Minimum Data Set (Blaum et al. 1995), a weight loss of 5% of usual body
weight in 30 days or of 10% in 180 days is a trigger for activating clinical
assessment protocols. Unintentional recent weight loss is associated with
increased mortality (Newman et al. 2001).
Conventionally accepted methods of dietary assessment include diet
histories, 24-hour recall interviews, food records, and abbreviated food
frequency questionnaires. These tools are often difficult to implement
because of time and effort burdens, the patient’s cognitive and/or memory
limitations, or the lack of a proxy source when the patient is unable to give
a firsthand account of foods eaten. Assessment approaches that rely solely
on memory (e.g., 24-hour recall) may be less accurate than information
enriched by an ongoing record or checklist that can be completed as soon as
a meal is eaten.
Another approach to nutritional assessment makes use of an instrument
such as the Mini Nutritional Assessment (MNA) or the Subjective Global
Assessment (SGA). The MNA (Figure 22–4) is a validated tool (with a
predictive value for detecting undernutrition of 97%) that incorporates
several domains, including functional status, lifestyle, diet, self-perception
of health, and anthropometric indices (Donini et al. 2003). The SGA
assesses nutritional status based on the patient’s history and physical
examination and is used to derive a clinical grade of that status (Detsky et
al. 1994; Sacks et al. 2000). However, neither of these indices addresses the
potential that being overweight could be masking the existence of
micronutrient deficiencies.
Although there are inherent limitations in blood markers of nutritional
status, the most commonly used biochemical assessment is for one or more
markers of protein status. Serum albumin, the most commonly measured
parameter, declines slightly with age (0.8 g/L/decade after age 60 years) and
is influenced by a host of pathological changes that are frequent in older
adults, including chronic inflammation, advanced liver disease, heart
failure, and nephrotic syndrome. Additionally, albumin is unlikely to be
responsive to protein repletion in a timely manner (Omran and Morley
2000). Therefore, serum albumin is not recommended as a sole marker of
nutritional status (Sullivan et al. 2002). Prealbumin is a transport protein for
thyroxine with a half-life of 2 days. Prealbumin levels usually show daily
improvements with good nutritional repletion. Blood tests for levels of
individual micronutrients are rarely done because they are expensive,
difficult to obtain (not routinely performed in most clinical laboratories),
and not always indicative of actual nutrient status.
FIGURE 22–4. Mini Nutritional Assessment (MNA®).

References. (1) Vellas B, Villars H, Abellan G, et al: Overview of the MNA—its history and
challenges. J Nutr Health Aging 10(6):456–463, 2006; (2) Rubenstein LZ, Harker JO, Salvà A, et al:
Screening for undernutrition in geriatric practice: developing the short-form mini-nutritional
assessment (MNA-SF). J Gerontol A Biol Sci Med Sci 56(6):M366–M372, 2001; (3) Guigoz Y: The
Mini Nutritional Assessment (MNA) review of the literature—What does it tell us? J Nutr Health
Aging 10(6):466–485, 2006; (4) Kaiser MJ, Bauer JM, Ramsch C, et al: Validation of the Mini
Nutritional Assessment short-form (MNA-SF): a practical tool for identification of nutritional status.
J Nutr Health Aging 13(9):782–788, 2009.
MNA® is a registered trademark of Société des Produits Nestlé, S.A., Vevey, Switzerland.
© Nestlé, 1994, Revision 2009. N67200 12/99 10M. For more information: www.mna-elderly.com.
General Nutrition Recommendations

Dietary Reference Intakes

Although calorie needs decline with age (see next subsection, “Energy-
Yielding Nutrients and Alcohol”), the requirements for most other nutrients
do not, making dietary nutrient density important at a time in life when
individuals may have trouble reaching the requirements. The Institute of
Medicine’s dietary requirements are expressed as Dietary Reference Intakes
(DRIs), including Recommended Daily Allowances (RDAs) or Adequate
Intakes (AIs) as appropriate, for all recognized essential nutrients, including
macronutrients, vitamins, and minerals (Table 22–1) (Institute of Medicine
1997, 1998, 2000, 2005, 2010). In previously released versions of these
recommendations, the oldest age category was 51 years and older, but the
most recently released recommendations are for people older than 70 years.
These recommendations are most helpful in terms of guiding nutritional
assessment and supplementation with regard to the micronutrients (vitamins
and minerals). More specific guidelines are needed to individualize
recommendations for energy and macronutrient intakes.

Energy-Yielding Nutrients and Alcohol

The DRI recommendations for macronutrients are given in Table 22–1. The
Institute of Medicine (2005) has also published formulas for calculating
total daily energy expenditures (TDEEs) based on gender, age (in years),
weight (in kilograms), height (in meters), and physical activity level
(PA=1.00 assumes that physical activity level is sedentary). These
equations, developed for use in normal and overweight individuals ages 19
years and older, are as follows:

Men:
TDEE=864–(9.72×age)+
[PA×(14.2×weight+503×height)]

Women:
TDEE=387–(7.31×age)+
[PA×(10.9×weight+660.7×height)]
 Energy requirements decline with age because of reductions in metabolic
rate, loss of lean body mass, and a diminution of energy expenditure for
physical activity. A progressive reduction in TDEE occurs with age,
assumed to be about 7 and 10 kcal per year for adult women and men,
respectively. Although food and calorie (energy) intakes also decrease with
age, before age 60 years there is rarely a detrimental effect, because the
reduced energy intake is more than offset by the aforementioned
decrements in requirements. In fact, being overweight and having excess
adiposity pose serious health risks in middle and early old age and persist as
late-life concerns for some individuals (Porter Starr et al. 2014; Villareal et
al. 2005). Typically, however, energy deficits and poor nutrient intakes are
the most likely nutritional concerns in late life. As people age from their
20s through their 80s, mean energy intakes are reduced by up to 1,200 kcal
in men and up to 800 kcal in women, according to the Third National
Health and Nutrition Examination Survey (Wakimoto and Block 2001). It is
well recognized that inadequate energy intakes and low body mass indices
(BMIs) are linked with frailty in elderly individuals (Markson 1997). Poor
food intake also jeopardizes the adequacy of micronutrients; food choices
may be poor when appetites falter.

TABLE 22–1. Dietary reference intakes for adults ages 51 years and
older
Men Women
Nutrient 51–70 years >70 years 51–70 years >70 years
Proteina (g) 56 56 46 46
Carbohydrate 130 130 130 130
(g)
Fiber (total)b 30 30 21 21
(g)
Fatc (g)
Linoleic 14 14 11 11
acidb
α-Linolenic 1.6 1.6 1.1 1.1
acidb

Vitamin A 900 900 700 700

 (μg retinal
activity
equivalents)
Vitamin D 600 800 600 800
(IU)
Vitamin E 15 15 15 15
(mg)
Vitamin Ka 120 120 90 90
(μg)
Vitamin C 90 90 75 75
(mg)
Thiamin (mg) 1.2 1.2 1.1 1.1
Riboflavin 1.3 1.3 1.1 1.1
(mg)
Niacin (mg) 16 16 14 14
Folacin (μg) 400 400 400 400
Vitamin B6 1.7 1.7 1.5 1.5
(mg)
Vitamin B12 2.4 2.4 2.4 2.4
(μg)
Calcium (mg) 1,000 1,200 1,200 1,200
Magnesium 420 420 320 320
(mg)
Iron (mg) 8 8 8 8
Zinc (mg) 11 11 8 8
Copper (μg) 900 900 900 900
Chromium1 30 30 20 20
(μg)
Selenium (μg) 55 55 55 55
a0.80 g/kg/day.
bThere is no Dietary Reference Intake for total fat because of insufficient

data. AIs are given in this table for essential fatty acids.
cAdequate Intakes (AIs) represent the recommended average daily intake

level based on observed or experimentally determined approximations. AIs

are used when there is insufficient information to determine a
Recommended Dietary Allowance.

Source. Institute of Medicine 1997, 1998, 2000, 2005, 2010.

The current RDA for protein (4 kcal/g) is 0.80 g/kg/day and is the same
for adults of all ages. Protein intakes decrease with age; however, even
though most people’s protein intake usually exceeds the RDA, there are
indications that older adults may need more dietary protein than do younger
adults to support good health, promote recovery from illness, and maintain
functionality (Bauer et al. 2013). Protein insufficiency can be a particular
concern in some high-risk individuals, especially when experiencing the
stress of medical illness and when institutionalization occurs.
Fat is another macronutrient that provides energy and is in fact the major
fuel source for the body (providing 9 kcal/g). In addition, fat is needed for
the absorption of fat-soluble vitamins and other dietary components. As
discussed earlier in “Type of Fat and Intake of Fish,” dietary fats are
divided into four general categories: saturated, trans-unsaturated,
monounsaturated, and polyunsaturated, with the latter subdivided into
omega-6 and omega-3 fats. Only certain fatty acids must be consumed from
the diet (essential fatty acids)—namely, two of the long-chain
polyunsaturated fatty acids: linolenic (an omega-3) and linoleic (an omega-
6). Saturated fatty acids, monounsaturated fatty acids, and cholesterol can
be synthesized by the body. Trans fats are not needed by the body and are,
in fact, detrimental to health. Older adults consume substantially less than
the RDA of fat, as well as of cholesterol. The percentage of calories coming
from fat in the diet declines and reaches its lowest value in the oldest age
groups (Wakimoto and Block 2001).
Carbohydrates are categorized into starches and sugars
(monosaccharides and disaccharides) and are also an important energy
source for the body (providing 4 kcal/g). A minimum amount of
carbohydrate (130 g for adults) must be consumed daily to meet needs that
cannot be met by another fuel source (such as fat). Glucose is the only fuel
source used by erythrocytes and is the preferred energy source for the brain,
which accounts for 20% of the body’s resting metabolic rate (Siegel 1999).
In the absence of sufficient dietary carbohydrate, liver glycogen and
skeletal muscle are broken down to generate glucose.
 In recent years, the popularity of low-carbohydrate diets for weight loss
(Yancy et al. 2004) and findings regarding the benefits of protein for satiety
have renewed interest in manipulations of macronutrient proportions in the
diet. In fact, a number of different distributions of macronutrients (e.g.,
Mediterranean diet pattern, vegetarian diet) other than the more traditional
low-fat diet can be used to achieve a healthy dietary pattern (Malik and Hu
2007).
Although alcohol does yield calories (7 kcal/g), recommendations about
alcohol for older adults are difficult to reconcile based on the available
scientific evidence. On the one hand, the intake of moderate amounts of
alcohol by older adults is linked with decreased risk of cardiovascular
disease (thought to be caused by decreased inflammation and increased
high-density lipoprotein levels) (Mukamal et al. 2006), risk of ischemic
stroke (except in APOE*E4-positive individuals) (Mukamal et al. 2005),
bone density of the hip (Mukamal et al. 2007), and even dementia
(Mukamal et al. 2003). On the other hand, the issue of alcohol misuse and
abuse among the elderly is a concern, particularly when any kind of
cognitive impairment is present. Therefore, it is difficult to apply these
research findings given the inadvisability of promoting ethanol
consumption in the elderly because of concerns about falls and alcohol
abuse (see earlier section “Alcoholism”). However, if a patient already
consumes light to moderate amounts of alcohol on a regular basis and is not
having problems, it may be acceptable for this level of consumption to
continue and it may be beneficial to suggest consumption of red wine, the
alcoholic beverage that contains the highest levels of beneficial
phytochemical compounds.

Water and Fiber

Although improving the intakes of dietary fiber will likely reduce the risk
of age-related chronic diseases such as diabetes and cancer, recommended
dietary fiber intakes (20–30 g/day) are almost never met by adults of any
age (Clemens et al. 2012). The importance of hydration is well recognized
in geriatrics. Although most typically the concern is about dehydration
because the thirst response is diminished in elderly individuals (Kayser-
Jones 2006), there are also potential negative effects of excessive water
consumption, including dilutional hyponatremia (water intoxication) and
increased nocturia (Morley 2000). The recommendation for healthy older
adults is about six glasses (1.5 L) of fluid per day (Lindeman et al. 2000b),
except during stressful situations when more is needed because of fluid loss
(e.g., severely hot weather, heavy exertion).

Use of Nutritional Supplements

Micronutrient (vitamin and mineral) supplements have two important and
distinct applications for older adults. The first, repletion of a confirmed
clinical or subclinical deficiency, is an important and well-accepted
therapeutic application. The second is more controversial. Many older
supplement users choose to take them in an effort to preserve health and/or
to prevent disease. Supplement use is higher among older adults than the
general population, is more common among women than men, and is linked
to strong health-seeking behaviors (Buhr and Bales 2009; Rock 2007). The
most commonly used supplement is a multivitamin-mineral preparation.
Although there is limited scientific support for the health-related efficacy
for long-term use of this type of supplement, a recent report from the
Physicians’ Health Study II did link multivitamin supplement use with
reductions in cancer risk in older men (Gaziano et al. 2012).
Certain individual micronutrients are also taken for health promotion
reasons. Antioxidant nutrients are commonly taken as supplements and
have been studied extensively because epidemiological studies linked them
with health benefits. However, the findings regarding vitamins A, C, and E
and β-carotene in the prevention of cardiovascular disease and/or cancer
have been largely disappointing and do not support the use of supplements
of these nutrients (Buhr and Bales 2009). Some evidence indicates potential
benefits of antioxidant supplements for delaying progression of age-related
macular degeneration (Age-Related Eye Disease Study Research Group
2001) and of selenium for cancer prevention (Bardia et al. 2008), although
further research is needed. Similarly, despite the demonstrated ability of the
B vitamins folate, B12, and B6 to lower homocysteine levels, and
epidemiological evidence linking homocysteine with negative health
outcomes, evidence from large RCTs has shown that these vitamins have
little benefit (Buhr and Bales 2010).
Moreover, there is concern that folic acid supplements might enhance the
growth of existing undiagnosed cancers and/or increase the risk of
cardiovascular disease (Ebbing et al. 2009; Miller et al. 2010). In contrast,
strong evidence supports the benefits of supplements of calcium and
vitamin D for reducing the risk of fractures (both nutrients together) and
falls (vitamin D). Dietary calcium intakes are universally low in adults of
all ages, which is a concern given the evidence for beneficial effects of
supplemental calcium, either with or without concomitant vitamin D, on
bone health and fracture risk. Therefore, dietary sources of calcium need to
be emphasized, with the goal of minimizing the supplemental dose needed
to meet the recommended intake, thereby enhancing compliance and
reducing the likelihood of side effects. In addition to the possibility of
inducing constipation, calcium supplementation has been linked with an
increased risk of myocardial infarction (Li et al. 2012) and of all-cause and
cardiovascular death (Michaëlsson et al. 2013). Also well recognized are
the cardiovascular health benefits of modest increases in consumption of
fatty fish or fish oil supplements (Mozaffarian and Rimm 2006).

General Physical Activity Recommendations

Benefits of Exercise
Physical activity is essential for optimal health throughout the life cycle,
providing protection against a diverse array of diseases and disorders linked
with aging, including cardiovascular disease, thromboembolic stroke,
diabetes mellitus, osteoporosis, certain cancers, anxiety, and depression
(Chodzko-Zajko et al. 2009; Nelson et al. 2007). Prevention of the risk of
falls and associated injuries is another key benefit. Physical activity
preserves muscle mass and strength as well as bone mineral density and has
been linked with improved mood and sleep patterns.
Initiating a fitness program to increase activity levels in a sedentary
individual requires an exercise assessment and subsequent individualization
of the exercise prescription to avoid injuries to the musculoskeletal or
cardiovascular system. Physical limitations must be identified, specific
exercises selected, and exertion ranges established. The American College
of Sports Medicine (2013) provides detailed guidance for fitness
assessments and exercise prescriptions. Additionally, the U.S. National
Institute on Aging has established Go4Life (http://go4life.nia.nih.gov), an
exercise and physical activity campaign targeted toward increasing exercise
in older adults. Ongoing reassessment will allow the program to be
upgraded in response to progress by the participant. It should be stressed
that even for individuals with physical limitations or chronic health
conditions, some level of physical activity is almost always beneficial.

Recommendations for Physical Activity and Exercise in Older

Adults
In 2008, the U.S. Department of Health and Human Services (DHHS)
released the Physical Activity Guidelines for Americans, which included
specific guidelines for older adults. These recommendations were
developed by a committee comprised of experts from the fields of public
health, behavior science, epidemiology, exercise science, medicine, and
gerontology, and further built on the previously released recommendations
for older adults from the American College of Sports Medicine (ACSM)
and the American Heart Association (AHA) (Nelson et al. 2007). Both sets
of recommendations (DHHS and ACSM/AHA) contain advice on the types
and amount of physical activity that will benefit the health of older adults,
including the following:

• Aerobic activities. Older adults should do at least 150 minutes of

moderate-intensity or 75 minutes of vigorous-intensity physical activity
per week, with aerobic activity lasting longer than 10 minutes. Moderate-
intensity aerobic activity is best described as producing noticeable
increases in heart rate and breathing and reaching a level of 5 or 6 on a
10-point scale, where sitting is 0 and maximal effort is a 10. Vigorous-
intensity aerobic activity is a level 7 or 8 on a 10-point scale. To promote
and maintain health, older adults should be physically active throughout
the entire week. When older adults are physically unable to complete 150
minutes of moderate-intensity physical activity, they should be as
physically active as their condition permits.
• Muscle-strengthening activities. Older adults will also benefit from
resistance weight training that will maintain or enhance muscular strength,
and should do muscle-strengthening activities twice a week. Exercises
should focus on all major muscle groups and be repeated 8–12 times to
enhance muscle strength. The benefits of prescribed and supervised
 resistance training include enhancement of muscular strength and
endurance, functional capacity, independence, and quality of life
(Williams et al. 2007). The American Geriatrics Society Panel on
Exercise and Osteoarthritis (2001) published specific guidelines for
resistance training in the elderly (1 RM=one repetition maximum [a
measure of intensity]):

Low: 40% 1 RM; 10–15 repetitions

Moderate: 40%–60% 1 RM;
8–10 repetitions
High: >60% 1 RM; 6–8 repetitions

• Balance activities. Many older adults are at risk of falls, and to reduce the
ensuing risk of injury, these adults should participate in activity that
focuses on maintaining or improving balance. The important components
of balance training are exercises that challenge balance (i.e., backward
walking, sideways walking) and lower-body strength exercises (i.e., chair
stands). T’ai Chi exercises are also a great way to increase balance and
reduce the risk of falls.
• Activities to increase flexibility. Flexibility is important in everyday
physical activity, and older adults should spend at least 10 minutes, 2 days
each week, on exercises that will maintain or increase flexibility.
• Developing and implementing an activity plan. Older adults seeking to
reach the recommended levels of physical activity should implement a
plan of gradual increase in exercise over time. It is acceptable to spend
time with activity that is lower than the recommended amount as long as
there is a stepwise increase toward sufficiency. Each recommended type
of activity, as well as how, when, and where such exercise should occur,
must be addressed in the plan, and older adults should self-monitor and
reevaluate their individual activity plans as physical ability and health
status vary.

Special Caveats for Older Adults

Older adults are capable of reaching high levels of physical activity,
although it may be difficult for some to do so. Physical activity should
therefore be promoted in particular ways so as to encourage adults in
reaching their potential. Although achieving the recommended level of
exercise is ideal, adults who participate in less activity still benefit in terms
of health, and this should be emphasized to those who cannot reach the
recommended goal. Similarly, engaging in moderate activity at
recommended levels is more important than working toward vigorous
activity, because the latter increases the risk of injury, reduces adherence to
the exercise plan, and may not provide much added benefit (Franklin et al.
2000; Powell et al. 2011). Vigorous activity may be difficult to reach due to
age-related loss of fitness, chronic diseases, or functional limitations, and
should not be emphasized in promoting physical activity of older adults. To
reach a level of moderate activity, older adults should take care to increase
exercise over time so as to reduce risk of injury due to overuse and allow
for attainment of intermediate goals. Experience, fitness, and self-
confidence are all necessary for reaching the recommended level of
physical activity and may be acquired through spending a period of time at
one step. Part of an exercise regimen should focus on muscle-strengthening
activity, which plays a strong role in preventing loss of muscle mass and
bone (Chodzko-Zajko et al. 2009; Nelson et al. 2007). Given that only
21.7% of older adults currently meet the muscle-strengthening guidelines,
the importance of muscle-strengthening activities should be promoted when
recommending types of exercise (Centers for Disease Control and
Prevention 2013).

Minimizing Risk During Exercise

Almost all older adults can and should be physically active on a regular
basis. Although there are always concerns about safety, the majority of
older persons experience few problems if they receive appropriate guidance
in planning their activity program. However, heart disease, osteoporosis,
and musculoskeletal injuries may increase the risk of adverse events and
therefore should be managed appropriately (Concannon et al. 2012;
Hootman et al. 2002). Cardiac arrest is a rare event, and exercise
incorporated into leisure-time activity has been shown to reduce the risk of
sudden death (Franklin 2014). The risk of musculoskeletal injuries can be
kept to a minimum by appropriate supervision and guidance for use of
warm-up routines and suitable equipment. Alternatives such as T’ai Chi and
pool exercises with motion against water resistance can often be safety
employed (Hartman et al. 2000). In individuals with osteoporosis, fractures
due to falls or unsafe movements are a concern. Fractures are exceedingly
painful and necessitate cessation of exercise until healing is complete.
Specialized instructions for exercise programs in patients with osteoporosis
have been developed (Bonner et al. 2003; National Osteoporosis
Foundation 2013).

Conclusion
Diet and physical activity are important determinants of both physical and
mental health. Although the specific mechanisms by which these lifestyle
parameters affect mental function are not fully understood, there is no
question that healthy dietary intakes and a physically active lifestyle
promote and help sustain optimal cognitive function. The guidelines
presented in this chapter can benefit all patients and should be a part of the
regular care plan. To assist patients in setting and achieving realistic
behavioral goals, the physician should partner with other professionals,
including registered dietitians, speech-language pathologists, dentists,
pharmacists, physical and occupational therapists, and other specialists, to
individualize diet and physical activity prescriptions.

Key Points
• Nutrition and physical activity are important determinants of overall
health and also play an important role in key elements of mental health
and cognitive status.
• Although a number of lifestyle factors have been implicated in the
etiology of mental disorders, the available scientific evidence does not
support a recommendation of specific nutrients or foods for the prevention
of dementia. However, adherence to a Mediterranean dietary pattern may
promote mental and brain health.
• Because late-life depression is known to promote vascular disease,
depressed individuals should be encouraged to consume a diet that will
reduce their vascular risk.
• Regular physical activity appears to benefit cognitive health and is
therapeutic for depression and dementia in terms of function and quality
of life.
• Mental disorders that can negatively affect nutritional and physical fitness
status include depression, dementia, and other mental illnesses; treatments
for these conditions may also impact nutrition and activity patterns.
• Older adults should consume a varied diet that includes high-quality
protein, fruits, and vegetables, and provides the recommended amounts of
all essential nutrients and meets but does not exceed energy requirements.

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 CHAPTER 23

Individual and Group Psychotherapy

Moria J. Smoski, Ph.D.
Patricia A. Areán, Ph.D.

Psychotherapy has been shown to be an effective treatment for a

number of mental disorders seen in older adults. As a treatment modality it
can be particularly useful for older adult psychiatric patients who cannot or
will not tolerate medication or who are dealing with stressful conditions,
interpersonal difficulties, limited levels of social support, or recurrent
episodes of a disorder. However, it has been estimated that only 10% of
older adults in need of psychiatric services actually receive professional
care, and there has been minimal utilization of mental health services in this
age group (Lebowitz et al. 1997; Weissman et al. 1981). African American
older adults seek out professional mental health care about one-half as often
as their white counterparts, instead turning to informal support networks as
a means of coping (Conner et al. 2010). Older adults report a longer delay
in initiation of mental health treatment than do younger cohort groups
(Wang et al. 2005).
Although many practitioners assume that older adults have negative
attitudes toward psychotherapy, research on attitudes toward treatment in
elderly samples is not conclusive. Contrary to clinical lore, growing
descriptive research suggests that older adults may prefer counseling over
medication treatment (Connor et al. 2010; Gum et al. 2006). Older adults
have also been shown to report a greater number of positive attitudes
toward mental health professionals and to be less concerned than younger
adults about stigma attached to seeking treatment for depression (Rokke
and Scogin 1995). However, older adults prefer that mental health treatment
be provided in a primary care context rather than through specialty clinics;
favor therapists who understood their existential and spiritual concerns and
values; and, as result of their unique sociohistorical context, often feel more
comfortable receiving care from practitioners who share the same race,
ethnicity, and religion (Bartels et al. 2004; Chen et al. 2006; Gum et al.
2010; Hinrichsen 2006; Snodgrass 2009). Whenever possible, patient
preferences or biases regarding treatment should be considered before
referral for psychotherapy.
As discussed in more detail in the later sections on specific disorders,
older adults will respond to many of the therapeutic interventions used with
younger populations with very little in the way of modification to treatment.
Although highly effective treatments that were originally developed through
use with younger adult populations—such as cognitive-behavioral therapy
(CBT) for mood and anxiety disorders and dialectical behavior therapy
(DBT) for personality disorder—have been successfully modified for older
adult populations, the adaptations are related more to issues regarding
cognitive, functional, and sensory impairments than to actual patient age.
For older adults with cognitive impairments, the pace of therapy should be
slower, and the inclusion of significant others in therapy is advisable. For
patients with vision impairments, any written materials should be in larger
font sizes, or the use of audio recordings of sessions can facilitate treatment.
Accounting for unique cohort-based differences (e.g., sociohistorical
environment, norms and commonly held beliefs, role expectations, illness
beliefs, culture) and age-specific stressors (e.g., chronic illness and
disability, loss of loved ones and therefore sources of support, caregiving
responsibilities) is also advisable. Inhome mental health services may be a
valuable option for patients who lack reliable transportation and/or have a
medical or physical disability. Alternatively, telephone and Internet-based
interventions may also help older adults overcome common treatment
barriers (Alexander at al. 2010). Thorough pretreatment assessment and
modifications specific to the individual’s strengths and deficits can help to
circumvent age-related pitfalls in psychological treatment (Knight and Poon
2008; Snodgrass 2009; Yang et al. 2009). It is important for therapists to
keep in mind, however, that many older adults, particularly those between
the ages of 65 and 80 years, are high functioning. They may not need these
age-specific modifications. Therapists should get to know each patient first
before making assumptions about what the patient can or cannot do.
 In this chapter we review the theoretical and empirical evidence for
psychotherapy in older adults, giving consideration to both individual and
group-based therapies. The material is organized by type of disorder and,
for each disorder, by type of therapy. When possible, we evaluate the
evidence with respect to quality of data, generalizability, and long-term
effects of treatment.

Depressive Disorders

Individual Cognitive-Behavioral Therapies

Traditional CBT, particularly CBT for older adults, focuses on three main
problematic behaviors: negativity bias, affect regulation, and behavioral
activation/motivation. Therapy sessions are constructed first to ascertain the
prominent area of focus and then to teach patients a series of remedial skills
to address those areas. In the first week or two of therapy, patients are asked
to keep track of their activities, moods, perceptions of daily events, and
work and social interactions, particularly noting when they are feeling any
kind of negative emotion. After this assessment phase, the patient and
therapist work toward behavioral goals depending on the results of the
assessment. If it is deemed that the patient has a strong negativity bias (i.e.,
is attending only to negative or threatening social and environmental cues,
or is overly interpreting situations to be negative and threatening), the work
will focus on helping the patient reorient his or her attention toward a
balanced appraisal of life events. If the assessment reveals that the patient
suffers from low motivation and limited social and physical activities, then
the main focus of CBT is on behavioral activation activities and on
strategies to increase motivation (Serfaty et al. 2009). In the literature on
depression in older adults, CBT has been the most frequently studied
psychotherapy (Gould et al. 2012; Karlin et al. 2015). However, when
compared with other types of active therapy, there is no real difference in
treatment outcomes (Peng et al. 2009). Nevertheless, older people tend to
have better outcomes with CBT than younger cohorts, potentially due to
better attendance at therapy sessions (Walker and Clarke 2001).

Group-Based Cognitive-Behavioral Psychotherapies

Although group-based CBT does exist, very little research has been done on
the effectiveness of this mode of delivery. Group-based CBT has been
effective for older adults with cognitive disabilities (McLaughlin and
McFarland 2011) and is effective as an augmentation therapy for people
taking antidepressant medications (Wilkinson et al. 2009). In the general
adult population, group CBT was found to be as effective as individual
CBT but 1.5 times less expensive to deliver (Bland 2010; Brown et al.
2011).

Individual Problem-Solving Therapy

Problem-solving therapy (PST) is a learning-based behavioral intervention
that helps patients focus on solving problems that they feel are contributing
to their depression (Areán et al. 1993). According to PST theory, depression
is a function of patients’ inability to solve important problems in their lives,
either because the problems are particularly challenging or because the
patients have never had the opportunity to learn effective coping skills
(Nezu and Perri 1989). In PST, patients are taught a seven-step method for
solving any kind of problem. Common problems of focus involve social
engagement, relationships, motivation, coping with loss, and disease
management. PST takes between 4 and 10 sessions. Although the main goal
of treatment is to teach patients to become better problem solvers, the
patient chooses the problems to work on and develops and selects the
solution.
PST is effective for a variety of older adult populations, including low-
income elderly (Areán et al. 2010a) and those with comorbid cognitive
impairments (Kiosses et al. 2011) or vision impairment (Rovner et al.
2007). This therapy is effective by telephone and video conference (Choi et
al. 2013). PST is also effective across service settings (Rovner et al. 2007)
and can be learned and implemented by a variety of community providers
(e.g., social workers, case managers) (Kiosses et al. 2010; Tasman and
Rovner 2004; Unützer et al. 2001). In a meta-analysis, PST was found to be
as effective as other interventions for treating depression in adults; however,
there was far less dropping out from PST than from interventions such as
CBT and interpersonal therapy (Cuijpers et al. 2007).

Group Problem-Solving Therapy

Very little data exist on the effectiveness of group-based PST, although
manuals do exist. In a study comparing group-based PST to group-based
life review therapy in older adults with major depression, both treatments
were effective in reducing symptoms; however, PST resulted in a far greater
number of people recovered from depression (Areán et al. 1993). In a study
comparing collaborative care to usual care for depression in older adults
seen in primary care, patients who had responded favorably to PST were
offered PST maintenance groups, but very few people elected to participate
in the group treatment, preferring to be seen individually for follow-up
(Areán et al. 2008).

Interpersonal Psychotherapy
Interpersonal psychotherapy (IPT) focuses on four common psychosocial
problems related to depression: loss and grief, interpersonal disputes and
conflicts, role transitions, and interpersonal skill deficits. IPT consists of an
assessment phase, treatment phase, maintenance, and relapse prevention
phase (Miller 2008). IPT for older adults is very similar to IPT for younger
adult populations. The initial assessment phase of IPT consists of collecting
an interpersonal inventory that helps the therapist and patient identify the
primary focus of treatment. Once the focus is identified, two important
techniques are used to help the patient move past the problem:
communication analysis and differentiating content affect and process affect
(Stuart and Noyes 2006). Communication analysis involves asking the
client to describe the last time he or she encountered the interpersonal
problem and discussing the specific details of that problem (e.g., what was
actually said in the encounter and how the client felt). After the causes of
the interpersonal problem are identified, the patient develops new
communication skills to express his or her needs and affect. These skills are
strengthened through in-session role-play and between-session practice of
these new communication skills. During this process, the therapist works
with the patient to identify feelings while discussing the incident in therapy
(process affect) and the feelings the client experiences outside of the
therapy session (content affect).
IPT in the general adult population is a very effective treatment;
however, the research on IPT in older adults is mixed, owing to a relatively
small data base and the fact that larger trials addressed prevention of
recurrence of depression in those at high risk for recurrence (Areán and
Cook 2002). IPT has been found to be very promising as an acute treatment
in older adults with depression (Miller et al. 2001, 2003; Reynolds et al.
1999). However, as a prevention intervention, the results are not as positive
(Carreira et al. 2008; Reynolds et al. 2010). The majority of studies on IPT
for late-life depression have been done in academic medicine; there has
only been one of primary care–based treatment for older adults (Post et al.
2008), and the specific effects of IPT have not been published (Bruce et al.
2004).

Other Psychotherapeutic Techniques

A number of other psychotherapeutic techniques for older adults have less
empirical support but warrant mentioning: self-guided therapies (e.g.,
bibliotherapy and Internet-based therapies) and life review. Self-guided
treatments are those in which patients have access to the therapy in the form
of a book or Web site and are instructed to follow the instructions. Self-
guided therapy has been proven effective in treating depression (Cuijpers et
al. 2008). A study by Naylor et al. (2010) compared a physician-delivered
behavioral prescription to read Feeling Good versus usual care for
depression in a primary care setting. Dysfunctional attitudes and depressive
symptoms were similarly reduced in both treatment groups, and perceived
life satisfaction and enjoyment increased. Bibliotherapy might be a viable
alternative for patients who cannot afford the cost of medication, who
respond partially or not at all to medication, who are reluctant to engage in
tertiary psychiatric or psychological care, or who suffer from adverse side
effects (Bowman et al. 1995; Scogin et al. 1989; van’t Hof et al. 2011).
Life review and reminiscence psychotherapies are based on the patient’s
reexperiencing of personal memories and significant life experiences. These
interventions have been empirically supported as effective therapies in the
treatment of late-life depression, with reminiscence therapy showing
comparable reductions in depressive symptoms as CBT in a meta-analysis
performed by Pinquart et al. (2007). Reminiscence therapy is often
administered in a group setting with the goal of improving one’s self-esteem
and sense of social cohesiveness. Recent research suggests that this is an
acceptable and viable intervention for late-life depression (Preschl et al.
2012; Serrano Selva et al. 2012).
Anxiety Disorders

Individual Cognitive-Behavioral Therapies

Anxiety disorders are among the most prominent mental disorders of late
life, with generalized anxiety disorder (GAD) being the most commonly
diagnosed (Blazer et al. 1991). Wolitzky-Taylor et al. (2010) have written a
comprehensive review of anxiety disorders in older adults. Anxiety
disorders in late life have been associated with significant distress,
increased morbidity and health-related activity limitations, memory deficits,
and significant reductions in health-related quality of life. Although
pharmacotherapy for late-life anxiety is quite effective, unwanted side
effects can limit the utility of pharmacotherapy (Stanley et al. 2009;
Wetherell et al. 2013).
Research on evidence-based treatments for late-life anxiety is still in its
infancy; however, CBT appears to be the best form of psychotherapy to
manage the diagnostic and treatment issues that exist in older populations
with anxiety (Ayers et al. 2007; Stanley and Novy 2000; Stanley et al. 1996,
2004; Wetherell et al. 2003). CBT for anxiety disorders focuses on
modifying anxious responses to inappropriately feared stimuli. Therapy
includes repeated exposure to feared stimuli to facilitate habituation and to
provide corrective learning about the actual level of danger or threat from
feared stimuli (Foa and Kozak 1986; Moscovitch et al. 2009). These
approaches include behavioral techniques such as imaginal and in-vivo
exposures and cognitive approaches that focus on modifying beliefs about
potential threats. Cognitive modifications may include reducing the
perceived danger of physical symptoms of anxiety in panic disorder (e.g.,
recognizing that heart rate increases do not indicate a threat of heart attack)
or decreasing the overestimation of negative evaluation from others in
social phobia (Deacon and Abramowitz 2004). CBT has been found to be
effective for a range of anxiety symptoms (Barrowclough et al. 2001), with
comparable effectiveness to medication management (Gorenstein et al.
2005) and additional benefit to the use of CBT as augmentation to
medications (Wetherell et al. 2013). Findings from a meta-analysis (Covin
et al. 2008) support the conclusion that CBT for GAD is highly effective in
reducing pathological worry, which is the cardinal symptom of GAD.
 In one example of a randomized trial of GAD treatment, Stanley et al.
(2003a) compared the efficacy of CBT with that of a minimal contact
condition. The researchers’ treatment protocol included education training,
relaxation training, cognitive restructuring, and exposure to anxiety-
provoking stimuli. CBT participants reported a significant within-group
improvement in the severity of GAD symptoms at the end of intervention
and at 12-month follow-up. These findings suggest that CBT not only may
provide effective immediate therapy but also may promote long-term gains
in the management of GAD. Several other randomized trials have also
supported the use of CBT for the treatment of GAD (Mohlman et al. 2003;
Stanley et al. 1996, 2003b; Wetherell et al. 2003), including in primary care
settings (Stanley et al. 2009). Using CBT as augmentation of medication
management for anxiety disorders in older adults may be especially
effective in reducing worry, and CBT is associated with reduced relapse
following discontinuation compared with discontinuation of a selective
serotonin reuptake inhibitor (SSRI) (Wetherell et al. 2013). Adapting CBT
to use in primary care facilities will provide treatment where older
individuals are most likely to look for it and facilitates collaboration
between CBT therapists and prescription providers. This integration may
also be a cost-effective treatment option, as has been the case in primary
care psychotherapy for depression.
Although CBT has strong promise for treating GAD in older adults,
further empirical research must be conducted to verify its efficacy in this
population and to determine mediators and moderators of treatment
response. For example, it appears that CBT is not effective in older adults
who have consistently low executive function abilities but is effective in
individuals whose executive functioning improves along with their
psychological symptoms (Mohlman and Gorman 2005). In addition, and in
contrast to younger adult populations, older individuals with more severe
anxiety at baseline as well as psychiatric comorbidities showed the greatest
benefit from treatment (Wetherell et al. 2005). Although older adults do
benefit from CBT, they do not appear to benefit to the same extent as
younger adults (Wolitzky-Taylor et al. 2010). A greater understanding of
the mechanisms and predictors of treatment response will help further
refine CBT as an effective treatment for late-life anxiety disorders.
Acceptance and commitment therapy (ACT) is among the newer
interventions with roots in CBT that show promise for treatment of late-life
anxiety. ACT focuses on increasing cognitive flexibility, decreasing
experiential avoidance, and increasing engagement with values-based
actions. Rather than targeting the frequency or intensity of anxious
symptoms, ACT aims to increase the patient’s acceptance of those
experiences through learning to mindfully observe them rather than
attempting to push them away or inadvertently fueling them through
perseverative thinking (Luoma et al. 2007). A preliminary trial that
demonstrated the feasibility of using ACT in older adults with anxiety
disorders resulted in a lower dropout rate than conventional CBT (Wetherell
et al. 2011). Further investigation is necessary to determine whether ACT
may represent an improvement over CBT in the treatment of late-life
anxiety.

Relaxation Training
Relaxation training may be one of the most frequently used treatments for
anxiety in older adults. Work by DeBerry (1981–1982, 1982; DeBerry et al.
1989) showed that progressive muscle relaxation and meditation relaxation
techniques reduced anxiety symptoms more effectively than treatment
control conditions in older adults. Scogin et al. (1992) assessed the use of
progressive muscle relaxation and imaginal relaxation. General symptom
improvements were maintained at 1-month follow-up, and gains in
treatment responders were maintained at a 1-year follow-up assessment
(Rickard et al. 1994). Relaxation training has some advantages for treating
mild anxiety in older adults. The strategies can be taught in brief individual
or group sessions. Theoretically, the strategies can be delivered during a
regular visit to a primary care physician. As with many behavioral
strategies, relaxation training has the advantage of masquerading as skills
training for patients who might avoid traditional psychotherapy. Also,
patients with cognitive deficits, who may have difficulty with more
cognitive-based strategies, may benefit from purely behavioral strategies.
One caveat is that relaxation training may be counterproductive when used
in combination with exposure-based treatments, because intentional
relaxation during exposures may provide temporary relief but interfere with
long-term learning to tolerate anxiety (Abramowitz 2013).
Substance-Related Disorders
With the baby boom generation entering late life, a rise is expected in the
number of older adults who use alcohol and illicit substances because of the
higher rates of substance use in that age cohort. Since 2002 the rate of illicit
drug use more than doubled (from 1.9% to 4.1%) among adults ages 55–59
years (Substance Abuse and Mental Health Services Administration 2011).
Sadly, there has been very little focus on the development of treatments
specifically for older adults, despite the fact that a number of studies
indicate that substance use disorder treatment needs to be age specific for
the treatment to be acceptable to older adults (Schonfeld et al. 2000; Satre
et al. 2003, 2004).

Cognitive-Behavioral Treatment
Although some previous comprehensive cognitive-behavioral interventions
have shown promise for treating substance abuse in older adults, they are
also plagued with high dropout rates (Schonfeld et al. 2000). Schonfeld et
al. (2010) assessed the effectiveness of the Florida Brief Intervention and
Treatment for Elders (BRITE) project—a low-cost approach for older
adults at risk for illicit and nonillicit substance abuse and misuse.
Prescription medication misuse and alcohol abuse were most prevalent in
the sample. The treatment protocol involved a brief home-based
intervention of one to five sessions that included motivational interviewing,
education about relevant substances and consequences of substance use and
misuse, reasons to quit drinking, and medication management. Following
graduation from the brief intervention, participants completed a 16-session
cognitive-behavioral treatment. The BRITE approach resulted in a
significant reduction of depression and suicide risk, as well as alcohol and
prescription medication misuse (Schonfeld et al. 2010).

Screening, Brief Intervention, and Referral to Treatment

(SBIRT)
Brief interventions in primary care have received increasing attention for
the treatment of alcohol use in older adults. Because primary care
physicians are most likely to identify overuse of alcohol in their patients,
this setting is a natural area for which to develop treatment protocols. Brief
counseling by the treating physician has been found to be significantly more
effective in reducing alcohol misuse in older adults than providing a general
health booklet (Fleming et al. 1999). The screening, brief intervention, and
referral to treatment (SBIRT) model was developed primarily to assist
primary care clinicians in detecting and managing this illness (Babor et al.
2007). This model provides patients with an initial brief screening to
determine extent of substance use, and patients who screen positive are
treated in one of two settings. Some are treated within primary care with a
brief motivational intervention focusing on increasing patient awareness
about substance use and the pros and cons of that use to help motivate the
patients to make changes in their substance use. Those requiring a higher
level of care are referred to specialty substance abuse treatment outside of
the primary are setting (Young et al. 2012). To date, there have been no
studies investigating the effectiveness of this model specifically for older
adults (Barry et al. 2002). One study did find, however, that primary care–
based brief treatment for alcohol misuse in older adults was as effective as
specialty referral to treatment (Oslin et al. 2006).
Previous editions of this book have indicated that there is insufficient
research on the management of substance abuse in older populations. This
research continues to be scarce.

Personality Disorders

Cognitive-Behavioral Therapies
Personality disorders are enduring patterns of inner experience (e.g.,
cognition, affect, impulse control) and behavior (e.g., interpersonal
difficulties) that have an onset in adolescence or early adulthood, are stable
over time, deviate considerably from normal cultural expectations, and
cause distress or impairment in functioning. Meta-analyses have concluded
that the prevalence rate for personality disorders in older adults is between
10% and 20% (Abrams 1996; Abrams and Horowitz 1999), essentially
analogous to the 13% prevalence rate for younger age groups (Torgersen et
al. 2001). Overall, the emotionally constricted/risk-averse disorders in
Clusters A (paranoid and schizoid personality disorders) and C (obsessive-
compulsive, avoidant, and dependent personality disorders) are the most
commonly diagnosed in late life (Abrams 1996; Abrams and Horowitz
1999; Kenan et al. 2000; Morse and Lynch 2004), and there are also high
rates of diagnosis of personality disorder not otherwise specified (mapping
to the categories of other specified personality disorder or unspecified
personality disorder in DSM-5 [American Psychiatric Association 2013])
compared with individual personality disorder diagnoses (Abrams 1996;
Abrams and Horowitz 1999; Kenan et al. 2000). In addition, personality
disorder rates are even higher (approximately 30%) among depressed older
adult samples (Abrams 1996; Thompson et al. 1988).
Personality psychopathology has generally been associated with poorer
response to treatment among older adults, whether treated with
antidepressants or psychotherapy (Abrams et al. 1994; Lynch et al. 2007;
Thompson et al. 1988; Zweig 2008; but see Gum et al. 2007; also see
Gradman et al. 1999for a review). Depressed older adult patients with
comorbid personality disorder are four times more likely to experience
maintenance or reemergence of depressive symptoms than are those without
personality disorder diagnoses (Morse and Lynch 2004). Despite this, and
despite calls for greater attention to the development and improvement of
interventions for personality disorders in late life (e.g., Videler et al. 2012),
there are few controlled studies of the treatment of personality disorders in
older adults.
The only published randomized clinical trial specifically targeting
personality disorders in older adults was conducted by Lynch et al. (2007).
The study focused on providing standard DBT using both group and
individual sessions following Linehan’s (1993) manual. Participants were
depressed older adults who presented with at least one comorbid personality
disorder and who failed an 8-week SSRI trial. Compared with patients in a
medication-only condition, participants who received DBT plus medication
management reached the level of remission more quickly and showed
improvements in interpersonal sensitivity and aggression (Lynch et al.
2007). Adaptations of standard DBT focusing on the most common older
adult personality disorders (e.g., paranoid personality disorder, obsessive-
compulsive personality disorder) are in development, with treatment targets
that include reducing rigidity, cognitive inflexibility, emotional constriction,
and risk aversion (Lynch and Cheavens 2008).
 Despite the promising nature of these findings, the bulk of empirical
evidence suggests that the presence of a personality disorder in an older
adult seriously compromises treatment. In addition, rates of personality
disorders among older adults may be only slightly lower than those in
younger age groups, and subsyndromal personality disorders may be more
prevalent in older populations relative to younger ones (Abrams and
Bromberg 2006). It appears that psychotherapy interventions likely will be
enhanced when they target the unique behavioral, cognitive, and
interpersonal dynamics associated with older-adult personality disorders.

Psychotherapy With Individuals Who Have

Cognitive Impairments
One frequent consideration for providers and referring physicians is the
degree to which an older adult with impairments in memory or executive
function can engage with and benefit from individual and/or group
psychotherapy. Cognitive difficulties in late life occur on a spectrum,
ranging from a lack of any impairment, to age-related cognitive decline, to
specific deficits and/or mild cognitive impairment, to more frank dementia.
At some point along this spectrum, patients become less able to perform
and capitalize on cognitive and behavioral changes without significant
support from caregivers and environmental modifications. The challenge
for providers is to assess the appropriateness of a given intervention and
make modifications as necessary to maximize benefits.
Psychotherapies, especially cognitive-behavioral therapies, are thought
to rely on executive functioning and memory skills (Hariri et al. 2000;
Mohlman 2008; Mohlman and Gorman 2005). Cognitive reappraisal
requires patients to attend to their thoughts, hold them in working memory,
generate alternative thoughts, and implement those alternative thoughts.
Implementing behavioral changes requires memory for the new behavior to
implement it, planning, and sustained attention to new behaviors. Because
psychotherapy requires executive and memory skills, it is hypothesized to
be less effective for individuals with cognitive impairments. Empirical
studies are mixed, with some finding reduced effectiveness in patients with
cognitive impairments (Mohlman and Gorman 2005) and others finding no
correlation between cognitive screening measures (e.g., the Mini-Mental
State Examination; Folstein et al. 1975) and treatment outcome in older
adults (Marquett et al. 2013; Wetherell et al. 2005), especially if cognitive
performance improves with treatment. However, given that individuals with
cognitive impairments also have a reduced response to pharmacotherapy
(Manning et al. 2013; Pimontel et al. 2012), the presence of cognitive
impairments does not necessarily disqualify a patient from consideration for
psychotherapy. Several successful modifications of standard psychotherapy
interventions for depression and anxiety have been developed for patients
with comorbid cognitive impairments, including IPT (Miller and Reynolds
2007), CBT (Mohlman 2008), and PST (Areán et al. 2010b). In addition,
CBT interventions have shown promise for reducing depression and anxiety
in neurological conditions, including Parkinson’s disease (Armento et al.
2012) and multiple sclerosis (Moss-Morris et al. 2013).
Several modifications to therapy may be used to better accommodate and
target cognitive impairments. One common modification is the
incorporation of a caregiver in the therapy process. Caregivers can assist
with the generation of treatment targets, help in implementing changes
outside of therapy (e.g., assisting with behavioral experiments as part of
cognitive therapy or helping to work past barriers to behavioral activation
goals), and provide reminders and reinforcement for therapy content for
patients with memory impairments. In addition to helping patients
maximize insight and change from therapy, the caregivers themselves can
benefit from recognizing their own changing roles as caregivers, learning
realistic expectations for their loved ones’ abilities, and maximizing their
effectiveness in assisting their loved one. In cognitive-behavioral
approaches, a modification strategy for individuals with milder impairments
is to target cognitive change (e.g., challenge their beliefs about being a
“burden,” generate realistic assessments about fall risks in those with fear
of falling). For individuals with more moderate to severe impairment, the
focus shifts to behavioral changes and adaptations to the environment (e.g.,
reinforcing positive reminiscence over expressions of dysphoria, facilitating
engagement with valued and/or pleasant activities) (Teri and Gallagher-
Thompson 1991). Finally, training programs that target remediation of
executive dysfunction have been administered along with standard CBT,
with benefits to both cognitive function and worry reduction in patients
with GAD (Mohlman 2008). These programs include audiotape-workbook
or computer-based trainings that target speed of processing, attention, and
cognitive flexibility processes in in-session and at-home exercises (Anguera
et al. 2013; Mohlman 2008). With these modifications, psychotherapy can
lead to significant improvements in mood and behavioral symptoms.
Even within the context of mild to moderate dementia, there are
psychosocial interventions that can benefit patients’ mood and behavior.
Because the dementia as a whole is not expected to abate, treatment targets
global quality of life, affective states, disruptive behavioral symptoms,
functional impairment, and prevention of self-harm. Most psychosocial
interventions for dementia are based on behavioral strategies and may target
caregivers as well as or in lieu of the patients themselves. Teri et al. (2005)
and Livingston et al. (2005) provide overviews of current empirically
supported treatment approaches.
One example of a psychosocial intervention for dementia is cognitive
stimulation therapy (CST). Derived from reality-orientation therapy, which
aims to continuously reorient patients’ attention to the present situation and
surroundings by frequent reminders of who they are and where they are,
CST focuses on improving information processing abilities. Treatment can
take place in formal groups and/or through training of professional or lay
caregivers to administer intervention activities during the course of day-to-
day activities. Several randomized controlled studies have found improved
performance in patients receiving CST, whether as a stand-alone
intervention (Hayslip et al. 2009; Quayhagen et al. 1995; Spector et al.
2001, 2003) or as an augmentation of cholinesterase inhibitor medication
(Onder et al. 2005). Cognitive abilities were generally preserved and/or
improved in the treatment groups relative to control subjects (Onder et al.
2005; Spector et al. 2003). Relative improvements in mood (Spector et al.
2001) and behavior (Quayhagen et al. 1995) were observed, but not all
studies showed improvements in these areas (e.g., Onder et al. 2005;
Quayhagen et al. 2000; Spector et al. 2003). Overall, CST appears to be a
promising approach to preserving cognitive function in older adults with
dementia, but further study is necessary to determine its influence on mood
and/or problem behaviors.
Other treatments with growing empirical support are based on the
progressively lowered stress threshold (PLST) theory (Hall and Buckwalter
1987). According to this perspective, the disease processes underlying
dementia progressively lower the patient’s ability to cope with stressors
such as fatigue, change in routine, or physical illness. Treatment consists of
educating and training caregivers in managing the patient’s environment to
minimize such stressors. PLST-based training is effective in reducing
problem behaviors (Gerdner et al. 2002; Huang et al. 2003) and caregiver
distress over patient behavior problems (Gerdner et al. 2002). Although
further research is necessary to match the empirical validation of behavioral
therapies for problem behaviors in dementia, the PLST approach shows
great promise.

Conclusion
It is evident that psychotherapy offers significant promise for the treatment
of psychopathology in elderly persons and at times may be the treatment of
choice in terms of both efficacy and patient preference. We encourage
practitioners to select treatments that have been tested with randomized
clinical trials rather than basing their choices on theoretical preference or
ease of application. The use of treatments without this type of empirical
support can slow or reduce recovery.
Future research should continue to examine the beneficial effects of
strategies combining medication and psychotherapy. In addition, research
examining the mechanisms of change and issues associated with treatment
response by disorder and type of therapy remain to be more fully
developed. Finally, continued research is needed to focus on populations
with treatment-resistant illnesses such as personality disorders, substance
dependence, and comorbid disorders.

Key Points
• Psychotherapy is a good option for treating mental disorders in older
adults who have trouble tolerating medications, who prefer
psychotherapy over medication treatment, or who have conditions for
which psychotherapy is the most effective treatment.
• Modifications of traditional therapies may be necessary to compensate
for age-related problems with vision, hearing, mobility, and cognition.
• Effective treatments for depression include several different individual
and group cognitive-behavioral therapies, interpersonal psychotherapy,
 and short-term psychodynamic therapy.
• The most common anxiety disorder among older adults is generalized
anxiety disorder. Behavioral treatments such as relaxation training and
cognitive-behavioral therapy are the most effective treatments for this
disorder.
• Patients with personality pathology have poorer response to treatment of
other comorbid conditions such as depression and anxiety. Few
treatments targeting personality disorder in older adults have been tested.
One promising and empirically validated treatment is a modification of
dialectical behavior therapy for older adults.
• Although cognitive impairments may limit the effectiveness of
psychotherapy, modifications such as the inclusion of a caregiver in the
therapy process or adjunctive cognitive remediation techniques can
improve outcomes.

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We gratefully acknowledge the contributions of Thomas R. Lynch, Ph.D.,
and Dawn E. Epstein to previous editions of this chapter. Moria J. Smoski’s
effort toward this chapter was supported by grant K23 MH087754 from the
National Institute of Mental Health (NIMH). Patricia A. Areán’s effort
toward this chapter was supported by grant K24 MH074717 from NIMH.
 CHAPTER 24

Working With Families of Older Adults

Lisa P. Gwyther, M.S.W., L.C.S.W.
Diane E. Meglin, M.S.W., L.C.S.W., D.C.S.W.

No single model exists for working with families of older adults.

Clinicians need to provide both patients and families with person- and
family-centered assessment and treatment, taking into account issues of
context, diversity, and heterogeneity. Despite the need for family-specific
treatment, there are patterns of family issues that consistently emerge based
on trajectories of psychiatric illness. Perhaps the most specific guidance in
the literature comes from meta-analyses and reviews of clinical research on
families of older adults with progressive degenerative dementias (Adelman
et al. 2014; Gallagher-Thompson and Coon 2007; Gillick 2013; Pinquart
and Sörensen 2006b; Reinhard et al. 2012; Weimer and Sager 2009).
Over the course of an older adult’s degenerative dementia, families will
confront depression, delusions, agitation, behavioral changes, and other
psychiatric symptoms in their cognitively impaired relative (Gitlin et al.
2012; Lyketsos et al. 2000; Olin et al. 2002; Tractenberg et al. 2002). The
burden on the family can be great, information can be insufficient, and
doubt can be overwhelming (Gwyther 2000). Families who are caring for
older members with dementia need reminders from psychiatrists to focus on
maintaining family quality of life as well as quality of care within the
constraints imposed by psychiatric, functional, and behavioral changes
(Hughes et al. 1999).
In this chapter, we take a chronological approach to working with
families over the course of the dementia of an older adult. Dementias are
the focus because of ample evidence that dementia is more disruptive of
family life and more likely to result in negative mental health outcomes for
family caregivers (especially females) (Pinquart and Sörensen 2006a).
Compared with family caregivers of older adults with normal cognition,
family caregivers of older adults with Alzheimer’s disease spend more
hours per week providing care, with measurable negative impacts on
caregivers’ mental health, personal and family time (Langa et al. 2001), and
family relationships (Gwyther 2005). Psychiatrists working with families of
persons with dementia should expect to treat vulnerable primary family
caregivers as well as families in conflict (Rabins et al. 2006). Alzheimer’s
disease has forced long-term-care services, policy, and treatment to move
from a narrow focus on aging to a more dynamic family focus that is more
inclusive of the person with dementia (Batsch and Mittelman 2012).

Family Care for Older Adults With Dementia

Half of family caregivers live with the older adult over a disease course of
3–20 years. Despite the high rates of shared residence, evidence suggests
that 30% of older adults with moderate to severe dementia live alone, often
with extensive supervision and assistance from local and long-distance
family caregivers (Tierney et al. 2004). Certain trends have emerged from
studies of family care in dementia. A shift is occurring away from the direct
provision of care by families toward more long-distance care or family care
coordination. Dementia care may necessitate that people move to be closer
to one another, and moves and daily proximity may increase stress as well.
An increasing number of adult children have become primary caregivers,
and many of them are still working part or full time. Although employment
might lead to burdensome role overload, some caregivers experience
unanticipated benefits from continuing to work. Dementia care frequently
precipitates the family’s first experience with seeking help from agencies
and other family members. Increasing evidence shows that the lack of an
available and affordable long-term-care system is pushing the limits of
family capacity and solidarity (Hurd et al. 2013).
Family care is universally preferred, as a result of strong family values
that cross cultural and ethnic lines; however, exclusive reliance on family
care has well-documented personal and social costs. Family caregivers may
become overwhelmed, exhausted, depressed, or anxious. Many family
caregivers report loss of pleasure, motivation, friends, activities, privacy,
intimacy, or identity. Gradual and sometimes sudden loss of the person as
he or she once was can precipitate significant ambiguous loss or
disenfranchised grief in family members.
Despite the apparent investment of families in care for older adults, some
families never comprehend minimal safety risks associated with dementia
care. Elder mistreatment—whether abuse or passive or active neglect—may
be associated with exceeding these family limits (Fulmer et al. 2005).
Families may feel powerless and overwhelmed when they cannot
predictably control the symptoms and course of dementia. The psychiatrist
working with the family has several tasks: assessment of tolerance limits,
education, treatment of psychiatric consequences of caregiver burden, and
management of family expectations of the disease course and of
themselves.
Despite assumptions about a single primary family caregiver, often a
change in primary caregiver occurs when a spouse or partner dies or
cognitively declines or when siblings pass a cognitively impaired parent
among themselves in a futile attempt to equalize responsibility.
Increasing dependency, loss, and grief are realities for families caring for
a loved one with Alzheimer’s disease, but not all family outcomes are
negative or burdensome (Tschanz et al. 2013). Although depression and
anxiety are the most frequently reported psychiatric symptoms among
caregivers of Alzheimer’s disease patients, some families express pride in
their care as a legacy of their commitment to family values. Recent studies
report both health benefits and decrements from assuming family care
(Roth et al. 2013).
The following reminders about family care may prove useful to
clinicians and families:

1. Family care is an adaptive challenge: the family is not necessarily the

problem, nor is the family necessarily the obstacle to effective care. Few
incentives (financial, religious, or counseling) will make an unwilling
family assume care. The reverse is equally true: few disincentives will
keep a determined spouse, partner, or child from honoring his or her
commitment.
 2. The family rarely has one voice. Different perceptions and expectations
of close and distant family members frequently precipitate family
conflict. There is no perfectly fair and equal division of family care
responsibility. Families can expect a permanent imbalance in the normal
give and take of family relationships while working toward a more
equitable sharing of responsibility.
3. Few families have the luxury of only one person needing care at a time.
4. Manipulation by dependent elders is much less common than are real
unmet dependency needs. More underutilization of services and
underreporting of burden occur than overutilization and overreporting.
5. There is no one right way or ideal place to offer family care. Many
families are forced to choose between equally unacceptable options.
Successful family caregivers gather information, take direct action when
possible, and often reframe things that they cannot change in more
positive terms (e.g., “It could be worse—at least she is still with me”).
6. Successful family caregivers are flexible in adjusting expectations of
themselves, the older adult, other family members, and professionals as
they work to fit the needs and capacities of all. Coping with family care
is facilitated by a sense of humor, a strong faith or value system,
creativity, practical problem-solving skills, and emotional support from
other family members or friends.
7. Families caring for older adults with dementia must define and negotiate
complex situations, perform physically intimate tasks, manage emotions
and communication, modify expectations, and capitalize on the older
adult’s preserved capacities.
8. A family caregiver’s awareness of an available service, need for the
service, or knowledge of how to access the service does not necessarily
lead to the appropriate or timely use of that service.
9. There is no perfect control in a family care situation. Families are better
off if they work on their reactions to stress or lack of control.
10. Denial is a common defense of family caregivers. Some people need to
deny the inevitable outcome (e.g., loss of a beloved spouse or partner,
eventual placement of a parent in a nursing home) to provide hopeful,
consistent daily care.
11. A primary caregiver at home is efficient and preferred. Primary
caregivers, however, need breaks, respite, backup people, and services to
 supplement their personalized care. Even in ideal situations, contingency
plans are necessary (Derence 2005; Lund et al. 2009).

Goals in Working With Families of Older Adults

Clinical goals with families of older adults will vary depending on the
presenting problems and family resources. Common goals, however, are to
normalize variability, address safety issues, mobilize secondary family
social support, facilitate appropriate decision making at care transitions
(particularly with requests for antipsychotics or sedatives to treat the
dementia patient’s agitation, aggression, or sleep disturbance), and help
family members to accept help or let go of direct care as necessary. In
essence, the family is forced to adapt to a new state of normal in their
family life, often with resistance from the member with dementia. Well-
timed psychiatric help can assist family members and elders in accepting
new realities, promote appropriate decision making, and facilitate smooth
care transitions.
Other goals in working with family caregivers include treating their own
mood, substance-related, or anxiety disorders and providing individual and
family treatment around issues of grief, loss, or conflict in family
relationships that limit the effectiveness of care. In general, family
treatment should enhance the effectiveness of family care and coping, the
self-efficacy of caregivers (Semiatin and O’Connor 2012), and the family’s
satisfaction with their preferred levels of involvement.
Psychiatrists working with family caregivers over time will monitor the
quality of family care; the mental health, capacity, and vulnerability of
caregivers; and the impact of the demands of care on family relationships
(Sun et al. 2013). Psychiatrists should be alert to anxiety, self-neglect,
suicidal ideation, depression, or anger in caregivers, as well as abuse,
exploitation, or neglect of patients. These indications should prompt
immediate recommendations for treatment, respite, or relinquishment of
caregiving responsibilities. Exigent negative caregiver outcomes on which
to focus therapy include decrements in mental health, social participation,
and personal or family time, as well as loss of privacy.
Interdisciplinary Partnerships
Focused treatment with families of older adults holds great potential for
positive outcomes, particularly in the context of an interprofessional
partnership or team (Bass et al. 2013; Fortinsky et al. 2014). Research
suggests that social workers’ individual and family counseling with spouse
caregivers can mobilize and sustain community and secondary family
support, reduce and prevent further primary caregiver depression, preserve
caregiver self-reported health, change negative appraisals of behavioral
symptoms, and even delay nursing home placement by over a year
compared with a control group (Mittelman et al. 1996, 2004, 2007).
Psychiatrists may work collaboratively with social workers or nurses
who can help provide timely or sustained assistance during the particularly
vulnerable times of care transitions (Boustani et al. 2011). The psychiatrist’s
role is to assess and treat a family caregiver’s psychiatric illness and to treat
the cognitively impaired patient’s psychiatric symptoms. Over time, the
social worker or nurse may provide care management and monitor family
capacity and tolerance while educating the family about common symptoms
and care transitions (Callahan et al. 2012).
Some families will initially resist referrals to a social worker but may
become more amenable if the social worker is described as an expert
consumer guide or family consultant. At care transition times, a family
consultant can provide assessment, intervention, and resource information.
The family consultant can help families learn how to become their own care
managers and increase their level of independence in handling the requisite
tasks. The consultant may serve as a teacher, coach, advocate, counselor,
cheerleader, or support person who can provide energy and a fresh
perspective to promote family resilience.
Referrals to well-developed and validated psychoeducational group
treatment programs have demonstrated equally positive results (Hepburn et
al. 2007; Livingston et al. 2013). Participation in peer counseling or support
groups can have positive outcomes for active caregiver participants
(Pillemer and Suitor 1996). One particularly helpful resource is the
Rosalynn Carter Institute for Caregiving (www.rosalynncarter.org), which
offers an Evidence-Based Caregiver Intervention Resource Center and
detailed information on interventions and training that have been found to
positively affect caregiver outcomes. Another is Maslow’s (2012) review of
more than 40 evidence-based family interventions.
Another way to monitor goals in the psychiatric treatment of families of
older adults is to base treatment on known precipitants of the breakdown of
family care. Major precipitants of placement include both patient and
caregiver factors (Yaffe et al. 2002). One of the patient factors that strongly
predicts placement is disruptive psychiatric and behavioral symptoms.
Changes in behavior and personality are also major causes of caregiver
burden and depression. To the extent that psychiatric consultation is
available to the older adult for treatment of psychiatric symptoms, and to
the extent that the family can be taught nonpharmacological approaches
(see Chapter 19, “Agitation in Older Adults”), the health of the family and
caregivers and effective home care for the older adult can be preserved.
Other predictors of family care breakdown are unresolved family
conflicts or mood disorders, substance abuse, or anxiety disorders of the
primary caregiver. Treating depression in a family caregiver generally has a
positive impact on the mood, function, and behavior of the older adult with
cognitive impairment (Teri et al. 1997), and vice versa.

The Family as Information Seeker

Families are more likely than older adults with dementia to initiate and seek
psychiatric care throughout the course of the illness. The stigma of
psychiatric illness often delays psychiatric diagnosis (Werner et al. 2012),
and ethnic and cultural beliefs that equate cognitive decline with normal
aging can produce the same result. Psychiatrists must remind families that a
specific diagnosis suggests treatment options. Stigma is best addressed by
correcting misconceptions or lack of information. An unconvinced family
can be told that Alzheimer’s disease is a brain disorder that can and does
happen to anyone. The brain becomes the vulnerable organ in dementia, and
psychiatric symptoms are brain symptoms just as angina is a symptom of a
heart disorder. When damaged, both organs require special diagnosis and
care.
Many family caregivers do not seek a diagnosis until psychiatric
symptoms (e.g., suspiciousness) emerge or personality changes (e.g.,
uncharacteristic irritability) disrupt family life. Unfortunately, the patient is
most likely to resist an evaluation once these symptoms have emerged.
Psychiatrists typically are reluctant to speak with family members without
the consent of the patient. An evaluation can be facilitated if the psychiatrist
agrees to see the patient about a less threatening symptom, such as
headaches, loss of interest, or low energy.

Diagnostic Office Visits

Although the patient is entitled to time alone with the psychiatrist initially,
later time alone with family informants is invaluable to the psychiatrist as
he or she assesses the effects of functional loss and other family stressors.
Most family caregivers prefer to talk privately with the psychiatrist to avoid
confronting the older adult about his or her symptoms and declining
condition. It may be helpful to have two family members accompany the
patient for an evaluation. One family member can distract or sit with the
older adult while another speaks privately with the psychiatrist.

Initial Communication With Older Adults and

Their Families
Initially, communication with patients and their family members will likely
be in response to the common emotional reactions to learning that there is a
diagnosis of degenerative dementia. One husband described the physician’s
diagnostic disclosure of his wife’s early-stage Alzheimer’s as emotionally
more devastating than being shot down in Vietnam. Elders and family
members may also express doubt about the diagnosis. Rather than confront
their doubt or denial, the clinician might suggest to them that they behave
as if the diagnosis of Alzheimer’s disease had been confirmed while
awaiting confirmation based on symptoms or progression of the disease.
Asking directly about common early changes, such as difficulty handling
money, problems managing medications, or increased irritability, may
highlight expectable mental status changes while offering a preview of
psychiatric expertise. Sometimes, explaining the symptoms of apathy and
loss of executive function can help families understand why their efforts to
get the elder to try harder at tasks are likely to prove frustrating and futile.
 Initial family sessions often elicit fear from family caregivers about their
interdependent future or risks of heritability. Frustration is another common
theme that emerges in early family treatment. Family caregivers frequently
express frustration with the elder’s obsessive need for repetition and
reassurance. Clinicians can help families cope by offering information to
clear up misconceptions about the presumed intentionality of the elder’s
resistance. Additionally, the elder’s confabulations are typical and
predictable attempts to fill in gaps for a failing memory. Encouraging the
family to get angry at the disease rather than at professionals, the services,
or each other can be extremely helpful. Families should be reminded that
conflict among their members will only limit needed help (Coon et al.
2003). It is important for the family to understand that the elder’s realistic
dependency does not imply weakness of character or lack of will. Families
of patients with early or mild dementia should be encouraged to take
advantage of education and support programs offered by Alzheimer’s
Disease Centers and the Alzheimer’s Association (Logsdon et al. 2010).
These groups provide vital information and a community for both patient
and family when they may be most reluctant to share the diagnosis with
family and friends. These programs, along with online and written
materials, help both the patient and the family care partner to reduce the
risks associated with early isolation, reduced social engagement, and lack of
meaningful activity.
Fatigue and exhaustion are also common issues. Encouraging rest,
respite, exercise, and energy economies can be helpful for family members.
Another common theme in family work is the guilt that family members
feel about losing patience or missing early opportunities to recognize
distress in a relative. They appreciate reminders from clinicians that
everyone experiences regret based on unique but certain limits. Most well-
intentioned families seeking psychiatric treatment have done what seemed
best, given limited information at the time. They can be reminded that it
would have been worse if they had done nothing.
Families overwhelmed by guilt benefit from specific reminders to expect
and accept negative feelings and resentment, to forgive themselves when
efforts go awry, to establish time and energy priorities based on current
quality of life preferences, to set limits, to say “no” and mean it, and to act
from love or a values commitment. If helps for them to be reminded that
regret is inevitable, but often unexpected resilience can help family
members pick themselves up and learn from personal experience and from
the experience of others in a support group.
After the psychiatric evaluation, key themes should be highlighted and
repeated in writing for absent family members. Older spouses in first
marriages are generally more comfortable facing threatening health
information together, and one spouse may be put off by attempts to separate
him or her from the impaired spouse. Providing the same information to
both spouses at the same time helps older couples preserve their couple
identity and accept the psychiatric recommendations as a mutual and shared
adaptive challenge.

Family Expectations of Psychiatrists

Vulnerable family caregivers may seek a private place and time, undivided
professional attention, and the comfort of initial familiar, polite small talk.
Families want psychiatrists to listen without rushing to implied
understanding or suggestions. Families of older adults expect to be asked
what they have tried in coping with their relative’s impairment. Even more,
these families appreciate the psychiatrist’s asking about what else is going
on in their lives.
Wandering and getting lost are common symptoms of dementia.
Caregivers may expect expert advice and immediate cures for these
disruptive symptoms, and they often seek explanations about why
medications do not “treat” wandering as well as environmental,
communication, and activity strategies do. They need specific referrals to
the Medic Alert + Alzheimer’s Association Safe Return program
(www.alz.org/care/dementia-medic-alert-safe-return.asp). They also need
help in accepting respite to cope with the toll of prolonged hypervigilance
required to protect from wandering.
Families of older adults want psychiatrists to tailor information and
education relevant to their immediate, pressing concerns. For example, a
family concerned about the combative behavior of an older adult may be
helped by a psychiatrist who responds, “First, let’s get the guns out of the
house” (Lynch et al. 2008).
When depleted primary caregivers are confronting the range of
behavioral symptoms of an older adult with Alzheimer’s disease, they may
look to the psychiatrist to lend positivity, optimism, a proactive attitude,
perspective, and objectivity. They may want acknowledgment of their
contributions to the older adult’s quality of life and forgiveness for what
they were unable to accomplish despite their best intentions. The
psychiatrist must be careful with well-intentioned attempts to commend
families for doing “a great job.” A family caregiver might be quick to point
out, “I am not performing a job—I am her husband, and I promised to take
care of her in sickness and in health.”
Families also appreciate preventive self-care reminders from
psychiatrists, but vague suggestions that caregivers need to take care of
themselves often frustrate overwhelmed families that have few resources.
Family members need help translating principles of respite and meaningful
use of respite time in ways that are congruent with their personal values and
cultural expectations. Specific examples may help. For example, some
family members respond to statements such as “Family care without respite
is like expecting your car to run on empty—it doesn’t” or “Even the Lord
rested on Sundays.” Respite options can be presented as opportunities to
“recharge your battery” (Gitlin et al. 2006).
Also, increasing evidence shows that encouraging physical activity
(King and Brassington 1997; Teri et al. 2003) and actively assessing and
treating sleep disorders in older adults and their family caregivers are
associated with positive care and family outcomes (McCurry et al. 2005,
2011).
Families look to psychiatrists for support in making certain decisions and
may ask for help in mobilizing other family members. Expertise in family
communication and family systems theory is particularly helpful and
relevant at these junctures (Eisdorfer et al. 2003). Family caregivers expect
psychiatrists to let them express feelings even when these feelings are
judged to be unacceptable. They may want help managing anger toward the
older adult, other family members, service providers, or God. These
families appreciate psychiatrists who create new choices by reframing the
problem or situation. For example, a family caregiver may seek permission
from the psychiatrist to be less than perfect or a “good-enough-for-now”
family caregiver. At such times, a psychiatrist’s use of humor and
compassion can produce dramatic relief.
Assessing the Family of an Older Adult
A targeted assessment of the family of an older adult may result in referrals
to Alzheimer’s Association services, private or public geriatric care
management, family or peer counseling, home help, day programs, assisted
living, or nursing home care. Cultural values, expectations, and health
beliefs will influence how and when families decide to pursue referrals, as
well as their receptivity to family treatment by psychiatrists. Pinquart and
Sörensen (2005) investigated the ethnic differences in stressors, resources,
and psychological outcomes of family caregiving. They suggested that
more specific theories are needed to explain some of the differential effects
of minority groups of caregivers. In addition to ethnic minorities, other
groups that deserve clinical and research attention are older adults, partners,
and families with issues of sexual and gender diversity. In many regions of
the country, gay, lesbian, bisexual, and transgender (LGBT) communities
still do not have legal protections or fully sanctioned empowerment to make
care decisions for their partners or families. Some helpful resources are the
National Resource Center on LGBT Aging (www.lgbtagingcenter.org), the
Family Caregiver Alliance’s LGBT Caring Community Online Support
Group (www.caregiver.org/lgbt-caring-community-online-support-group),
and Services and Advocacy for Gay, Lesbian, Bisexual and Transgender
Elders (www.sageusa.org).
One of the most useful ways to elicit a picture of family functioning is to
ask the family to describe a typical day. Clues about how much time the
patient is left alone and about potential safety risks come from such open-
ended questions. The psychiatrist should probe further if the caregiver hints
about increased use of alcohol or psychoactive medications in response to
stress. Older husband caregivers may be particularly at risk of increased
alcohol use in response to care demands.
The psychiatrist should encourage or support positive activities such as
regular exercise, social stimulation, and secondary family support. A person
caring for his or her partner may be frustrated by the other’s loss of interest
in cooking. A suggestion to try regular meals at a familiar restaurant may
conserve the couple’s energy and better meet their nutritional and social
needs.
 Asking questions about a typical day may elicit family anger at the
patient’s apathy and social withdrawal or reveal a family’s lack of
awareness of safety issues. The family may complain that the older adult
with cognitive impairment is becoming more irritable or jealous of
grandchildren. Probing further may reveal that this grandparent is still
providing child care despite significant declines in his or her judgment or
capabilities.
It is important to assess the home and neighborhood environment.
People with dementia are easy targets for exploitation by telephone and
mail fraud and from people who come to the door. High-crime
neighborhoods pose additional risks. An older adult who spends time at the
corner store buying alcohol and cigarettes may be especially vulnerable.
The psychiatrist should ask specifically about the primary caregiver’s
health. The psychiatrist should be alert to offhand comments such as “I’m
fine as long as he can drive me to chemotherapy.” The caregiver should be
asked about his or her own sleep and how it is affected by the sleep pattern
of the adult receiving care. Many family caregivers report being frustrated,
overwhelmed, edgy, or exhausted but will deny having depression, anxiety,
or psychiatric symptoms. Although psychiatrists are well advised to
respond promptly to poorly controlled rage or suicidal or violent threats,
skillful probing may be required to elicit other symptoms.
A review of family relationships may elicit new or historical family
conflicts that can complicate care. For example, a distant, estranged sibling
might insist that the family caregiver is exaggerating symptoms in an
attempt to take control. A written explanation from the psychiatrist about
actual dependency and level-of-care needs can help clarify the situation,
corroborate the caregiver’s experiences, and give credence to what is truly
needed.
Another key to effective family assessment is to ask about other family
commitments. For example, a daughter backing up her mother’s care of her
father may be distracted by anxiety about her own husband’s failing
business or a child’s drug addiction. Cultural expectations must be carefully
assessed along with each family member’s subjective perceptions of
financial resources. When paid or formal services are needed, family
decision making is often related to subjective perceptions of future financial
adequacy rather than the objective cost or affordability of services. Some
family members may be saving for a rainy day, whereas others may value
preserving their inheritance above meeting the elder’s current care needs.
It is wise to assess family strengths, skills, and goals. For example, some
families may cope well with providing care for incontinence or end-of-life
care but be unable to tolerate the disruptive behaviors or sleep patterns of
moderate dementia. Families that have coped with chronic mental illness or
substance abuse in other family members may have well-developed coping
strategies or support systems (such as Alcoholics Anonymous) that can help
them adapt to care for their impaired elder.
Finally, assessment should include some review of the family’s
experience with previous and current help from family members or paid
services. Some key issues include the adequacy, quality, cost, and
dependability of the help. For example, if a previous home care worker
stole from them or failed to show up, the family would be less likely to
accept another home care referral. Previous family conflict over elder care
is likely to limit the family’s willingness to ask for help. If a family believes
that the help they give each other is adequate, dependable, or sufficient,
they often are unwilling to consider formal services because they do not
perceive a need.

Selecting Interventions for Families of Older

Adults
Families of persons with dementia need a continuing source of reliable
information. Referrals to the Alzheimer’s Association (www.alz.org) and
the Alzheimer’s Disease Education and Referral Center of the National
Institute on Aging (www.nia.nih.gov/alzheimers) help meet this need.
Multidomain interventions have been shown to enhance positive
caregiver outcomes (Belle et al. 2006). The most effective of these
interventions for family caregivers emphasize problem-solving and/or
active participatory skill-building strategies for behavior change over purely
didactic educational approaches. Effective multidimensional approaches are
flexible and tailored to individual risk factors. They are timed to key
transition points or stressors in care trajectories and are offered in sufficient
dosages or amounts of assistance over time to ensure sustained outcomes.
Combining individual and family counseling, family education, support
group participation, and care management is associated with decreased
caregiver burden and depression. This also results in decreases in the elder’s
disruptive symptoms and increases in caregiver satisfaction, subjective
well-being, and self-efficacy. Psychoeducational and psychotherapeutic
interventions produce the most consistent short-term effects on all outcome
measures (Burgio et al. 2003). For example, a multimodal approach for
treating an elder’s agitation could include treatment of depression in the
elder or in the family caregiver with pharmacological and
nonpharmacological strategies; participation by the family caregiver in
psychoeducational, skills training, or caregiver support groups; and
participation by the elder and the family caregiver in structured exercise
programs.
Nonpharmacological approaches to the treatment of depression in elder
care family dyads could be based on increasing the frequency of
individually selected pleasant events (Teri et al. 1997). Once the elder and
caregiver have identified which activities are the most enjoyable, the goal
becomes one of increasing the frequency and duration of these activities. In
a dyadic intervention study, Whitlatch et al. (2006) found that individuals
with early-stage dementia and their family caregivers were able to
participate in and benefit from a structured intervention that focused on care
planning for future needs.
Referrals to support groups should be balanced, and participation should
not be oversold. Benefits of participation in support groups are derived
from experiential similarity, consumer information, coping and survivor
models, expressive or advocacy outlets, and (for some participants) the
creation of substitute family or social outlets. Participants may know more
about Alzheimer’s disease and services but may not necessarily use that
information. Also, participants may feel less isolated and misunderstood
than nonparticipants. Clinical experience in working with families over
time suggests that for some families, support groups provide a low-cost,
readily available venue to share difficult feelings such as anger, regret, and
frustration. Support groups can be a safe place to express disappointment in
services, professionals, or other family members. Well-facilitated support
groups help families recognize that they are not failures and to receive
immediate practical help unavailable elsewhere. Increasingly, online
discussion or e-mail groups or chats are serving a similar purpose. There
are, however, few evidence-based studies documenting the benefits of
caregiver support group participation.
One support group does not fit all. Black individuals frequently do not
feel the need to talk about family business among strangers but may
respond to a church-based group on family care. In an open mutual help
group with revolving membership, not all participants will be dealing with
the same care issues. The exclusive focus on Alzheimer’s disease as just
one aspect of family life may not meet certain families’ needs. Some
families cannot get to meetings regularly, and some groups are not
consistently available. These factors limit the benefits of such a minimalist
intervention. The benefits of participation can be enhanced by encouraging
families to shop around for a group that best meets their needs and
reminding them that they may be able to obtain comparable social support
from groups to which they already belong, such as a church, synagogue,
employee, or retiree organization.
Information available online is useful for seeking resources at care
transition points as well. For example, if placement becomes an issue,
information about quality care and finding nursing homes and assisted
living facilities is available online from Centers for Medicare and Medicaid
Services (www.medicare.gov/Publications/Pubs/pdf/02174.pdf) and the
National Consumer Voice for Quality Long-Term Care
(www.theconsumervoice.org). State ombudsman offices also offer online
information about local facilities. Online discussion boards and Alzheimer’s
disease–focused discussion groups can be helpful as well.

Educational Strategies With Families of Older

Adults
Many families are too overwhelmed at a first psychiatric consultation or
diagnostic evaluation to absorb information or instructions. Teachable
moments with family members come at crisis points with specific
psychiatric symptoms, such as when an older individual with dementia
makes accusations of family theft or spousal infidelity or when the patient
insists that his or her spouse or partner is an imposter. A medicine metaphor
is appropriate: the timing and “dosing” of information may enhance
effective use of that information in adapting care over time. Some families
may have read or heard inaccurate or partially correct information about
symptoms that can be easily corrected. Some may have heard myths that all
elderly persons with dementia are aggressive. Some families have been
overwhelmed by too much questionably credible information online. Just
like medication management in geriatrics, the maxim “start low and go
slow” applies equally well to family education about dementia.
Overwhelming families with too many treatment suggestions or referrals is
just as likely to lead to poor compliance as is changing multiple medication
regimens all at once. Finally, information should be presented in hopeful
terms, such as “Treating your depression should have positive effects on
your partner’s mood as well” or “Many families surprise themselves with
their resilience.”
The presentation of information in a timed and dosed manner also offers
opportunities for repetition of key themes. The key messages for family
caregivers listed in Table 24–1 can be presented at intervals and in “doses”
that are based on the frequency of contact with the family, the family’s need
to know, and the family’s capacity to understand.
TABLE 24–1. Key messages for family caregivers
1. Be willing to listen to the older adult, but understand that you cannot fix
or do everything he or she may want or need. Know that it will not
necessarily get easier, but things will change, and the experience will
change you forever.
2. You are living with a situation you did not create, and your choices are
limited by circumstances beyond your control. Seek options that are
good enough for now.
3. You can only do what seems best at the time. Identify what you can and
will tolerate, then set limits and call in reinforcements. Doubts are
inevitable.
4. Find someone with whom you can be brutally honest, express those
doubts and negative feelings, and move on.
5. Solving problems is much easier than living with the solutions. It is
tempting for distant relatives to second-guess or criticize. Hope for the
best but plan for the worst.
6. It is not always possible to compare how one person handles things with
how another relative would handle them if the positions were reversed.
 7. The older adult is not unhappy or upset because of what you have done.
He or she is living with unwanted dependency. Sick people often take
out their frustration on close family members.
8. Considering what is best for your family involves compromise among
competing needs, loyalties, and commitments. Everyone may get some
of what he or she needs. Think twice before giving up that job, club, or
church group. Make realistic commitments, and avoid making promises
that include the words always, never, or forever.
9. Find ways to let your older relative give to or help you. He or she needs
to feel purposeful, appreciated, and loved.
10. Take time to celebrate small victories when things go well.

Responding to Families Over the Course of

Progressive Impairment
Over the course of a patient’s dementia, family caregivers become not only
information seekers but also care managers, consumer advocates, surrogate
decision makers, and health care providers. It is difficult to negotiate these
complex roles, but it is even more difficult if the family caregiver is
burdened by role overload. Assessing caregiver vulnerability can be
facilitated by asking family members to self-assess their pressure points or
signs of increasing caregiver overload (U.S. Department of Veterans Affairs
2014).
Clinical red flags may signal imminent danger resulting from the
caregiver’s precarious health. Unsubtle hints may be a caregiver’s
comments such as “after my last stroke,” “before he totaled the car,” or
“sometimes I feel like just letting him wander away.” Pursuing these
threads with standard clinical protocols is certainly warranted.
Other issues surface when working with families of moderately impaired
older adults. Isolation of the caregiver and patient is common as friends
drop off in response to disruptive behavioral symptoms or the need for
constant supervision of the older adult. Families need to be reminded that
being vulnerable does not make older people grateful or lovable and that
cabin fever among cohabitating elders and family caregivers can be a real
threat to mental health and safety. Families are especially sensitive to elders
who confuse or mistake family identities or suggest that family members
are impostors. Making suggestions that family caregivers say something
like “I’ll try to do it like your mother would” may help them understand and
respond to accusations of this type.
Family members need to be warned not to give up cherished activities—
social engagement has positive mental health effects at any age.
Maintenance of a strong religious faith or community has also been shown
to have positive effects on elders and family caregivers. Expressive outlets
such as sports, the arts, or advocacy can help families cope with frustration
and anger. Prayer, meditation, exercise, massage, and yoga, in combination
with active treatment of depression or anxiety, are all worthy treatment
recommendations. An older person’s participation at an adult day center can
be presented to the family as a source of social stimulation for the elder and
a stress-reduction strategy for the family caregiver (Zarit et al. 2014).

Helping Families Assess Capacity of Older Adults

Many families turn to psychiatrists to assess the judgment and decision-
making capacity of older adults, whether the concerns are related to
handling money, making health decisions, living alone, or driving. Money-
handling and health care decisions should be addressed soon after diagnosis
to ensure time for patients to select a surrogate. Often families seek
psychiatric consultation when family conflict surfaces over the patient’s
selection of a surrogate or the surrogate’s handling of the older adult’s
funds. Questions about whether the patient had sufficient capacity at the
time he or she wrote a will or assigned power of attorney can become
adversarial and unrelated to family treatment.
Effective work with families regarding capacity should be done early
with a preventive focus. It is wise for one family member to make sure bills
are paid. This can be done with different levels of the patient’s involvement,
from making decisions about which bills to pay to signing checks or
establishing payeeship.

Assessment of and Limitations on Driving

The clinician can encourage the family to assess driving capacity based on
observations of the patient’s current driving and provide the family with
reminders that dementia affects judgment, reaction time, and problem
solving. Psychiatric assessment of the patient or a more intensive driving
evaluation from a trained occupational therapist, along with current
observations from the family, will provide direction on when the patient’s
driving should be limited. Unfortunately, by the time there is evidence of a
decline in driving abilities, many patients cannot adequately report or judge
their safety on the road. Anonymous reports to the Department of Motor
Vehicles may or may not lead to required testing or removal of the patient’s
license, but the absence of a license, taking of the keys, or even dismantling
the car rarely stops a determined older adult with dementia.
Driving is one area in which the family must be encouraged and
prepared to assess the patient’s capacity over time. The signs of decline in
driving skills listed in Table 24–2 may help guide family observations and
reports to the psychiatrist.

TABLE 24–2. Signs of decline in driving skills

Incorrect signaling
Trouble navigating turns
Moving into the wrong lane
Getting confused about exits
Parking in inappropriate places
Driving at inappropriate speeds
Delayed responses to unexpected situations
Failure to anticipate dangerous situations
Scrapes or dents on car, garage, or mailbox
Becoming lost in familiar places
Arriving unusually late from a short-distance drive
Receiving moving violations or warnings about near misses
Confusing the brake and the accelerator
Stopping in traffic for no apparent reason

Psychiatrists may suggest a range of successful ways to limit driving,

such as the following:
• A prescriptive reminder to stop driving can be tempered with a qualifier
such as “until we determine your diagnosis or treatment.” Families
appreciate a physician’s willingness to be the source of such unwelcome
news. However, patients have been known to keep driving, making
comments such as “That doctor doesn’t know anything.” Families also
report that patients are unlikely to “forget” those responsible for taking
their keys, and patients may continue to blame family members for loss of
driving independence.
• Shaving the patient’s keys, substituting an incorrect key, removing a
distributor cap, or otherwise disabling a car can sometimes reduce the
need to confront the patient with lost skills. However, patients have been
known to fix the car, replace the keys, or even buy a new car while the old
one was “in the shop.”
• The car could be sold, given to a grandchild who needs it for school or
work, moved to an undisclosed location, or put up on blocks. One family
of a taxi driver put the taxi on blocks in the backyard to help the patient
remember that it was “broken.”
• The family can also arrange for solutions that limit the need for driving—
delivery services, senior vans, or offers of regular rides to church or for
visits. Some families find that a taxi charge account or a privately hired
driver or helpful younger family member to drive and escort the patient
works best.

Addressing Questions of Capacity to Live Alone

Families may go to extremes to keep an older adult with dementia in a
familiar environment, allowing values of autonomy and choice to
temporarily trump safety. The psychiatrist, in addition to performing a
psychiatric assessment of the patient’s cognition, judgment, functional
impairment, and decision-making capacity, can suggest that the family
consider the following questions:

• Can the family member with dementia use the telephone to call for help
from a family member or to call 911? Will the person respond
inappropriately to telemarketers or to mail or e-mail scams? Have
mysterious packages or bills for unusual items begun appearing? Does the
person make repetitive calls every few minutes to the police or to the same
 family member at work or at home? Are any suspicious new friends
accompanying the patient to the bank?
• Can the family member with dementia get to the store or to his or her
regular activities? Does the patient overbuy or underbuy certain items?
• Can the individual handle money and pay bills or, if not, is he or she
willing to let others do this for him or her or have bills forwarded or paid
online?
• Can the patient take medicine appropriately, on time, and in correct doses?
Does he or she self-medicate or risk overdoses of unnecessary
medications?
• Is the family member bathing, changing clothes, and dressing
appropriately for the weather?
• Is the person leaving the house after dark or traveling in dangerous areas
alone? Does the patient let strangers in or buy from or contribute to
questionable causes based on visits to his or her home?
• Is the person having problems positioning his or her body to use a toilet,
or is he or she urinating in wastebaskets or outdoors?
• Is the patient falling or getting lost by wandering outside a safe area?
• Are there significant changes in the family member’s appetite, weight,
sleep, appearance, or eating habits?
• Is discreet surveillance by neighbors, friends, or family readily available?

The last question regarding discreet surveillance is paramount. Persons

with moderate dementia may live alone successfully if they have regular
contact with, surveillance by, or checking from neighbors or family
members. Environmental demand varies considerably and must be assessed
along with patient variables.

Families and Institutionalization of the Older Adult

Family stress does not stop at the door of the nursing home. Indeed, ample
evidence shows that families experience great burden, disruption, and
conflict in the time immediately before and after placing their family
member in assisted living or a nursing home (Gaugler et al. 2009). Family
members may seek psychiatric services to deal with guilt and grief, and
often with their anger toward the nursing facility, the lack of affordable care
options, and each other. Many families are disappointed by the lack of
medical or psychiatric treatment available to residents of assisted living or
nursing homes. Families should be encouraged to work with the facility and
the nursing home ombudsman while dealing with their affective, anxiety,
and grief symptoms.

Conclusion
Clinical work with families of older adults is about helping them adapt to
change, uncertainty, variability, and loss. Much of psychiatric treatment of
families helps them modify expectations for new dependency while
learning to forgive themselves and others for inevitable doubts and
mistakes. Interprofessional partnerships and teamwork with the Alzheimer’s
Association, with health care or primary care coordination or care transition
(medical home) initiatives, or with nurses or social workers offer the most
effective and efficient models for psychiatric services to families of older
adults. There is often as much need for “timed and dosed” patient and
family education as there is need for treatment of psychotic, depressive,
anxious, or other psychiatric symptoms or syndromes of the elder or family
members. Families expect psychiatrists to provide active treatment and
monitoring of psychiatric symptoms, reassurance, interpretation of
information, and referrals. In addition, it is always helpful to acknowledge
losses and contributions to care by individual family members, to encourage
caregiver self-care, to offer authoritative absolution for inevitable mistakes,
and to offer decisional support, especially in regard to transitions in care,
including a move to palliative or hospice care.

Key Points
• Psychiatric treatment of families helps them modify expectations for
their family member’s progressive cognitive decline and learn to forgive
themselves and others for inevitable doubts and mistakes.
• Interprofessional consultation, partnerships, and teamwork with the
Alzheimer’s Association and with health, aging, and social services offer
 the most effective and efficient models for psychiatric services to
families of older adults.
• Psychiatrists should provide active treatment and monitoring of family
caregivers’ psychiatric symptoms, outline reasonable expectations, and
offer families information about outcomes of treatment.
• It is helpful to acknowledge family caregivers’ losses and their
contributions to care. It is also important to encourage their own self-
care and to offer them expert decisional support during transitions in
care.

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Oxford University Press, 2006
 CHAPTER 25

Clinical Psychiatry in the Nursing Home

Joel E. Streim, M.D.
Nursing homes provide long-term care for elderly patients with chronic illness and
disability as well as rehabilitation and convalescent care for those recovering from acute illness.
As documented in previous reviews (Streim and Katz 2009), clinical studies have consistently
provided evidence that the diagnosis, management, and treatment of mental disorders are
important components of nursing home care. The delivery of mental health services in nursing
homes continues to be shaped by several factors, including growing scientific knowledge,
availability of new treatments, evolving federal regulations, measurement-based care, public
dissemination of quality measures, and changes in the medical marketplace. This chapter reviews
historical trends and current information on the psychiatric problems that are common in the
nursing home, discusses current trends affecting clinical care, and presents a conceptual model for
the organization of mental health services in the nursing home setting.

Nursing Home Populations

The National Nursing Home Survey (NNHS) was first conducted in 1973–1974 and repeated in
1977, 1985, 1995, 1997, 1999, and most recently 2004 (National Center for Health Statistics
2004). According to the 2004 NNHS, 4% of Americans ages 65 years and older—1.5 million
people—resided in 16,100 long-term-care facilities (Jones et al. 2009). Compared with 1995
survey data from the National Center for Health Statistics (Dey 1997), this percentage actually
represents a 0.11% decline in the proportion of adults older than 65 years residing in nursing
homes, although the proportion of residents in the oldest age groups has been continuously
increasing. Between 1977 and 1999, the proportion of nursing home residents ages 65–84 years
decreased from 52.2% to 43.8%, whereas the proportion of residents ages 85 and older increased
from 34.8% to 46.5% (Decker 2005). Not surprisingly, with the increasing age of residents in
nursing homes, there was a decline in the proportion of residents who were independent in the
performance of basic activities of daily living (ADLs). For example, 30% of residents in 1977
could dress without assistance, compared with only 13% in 1999. In that same period, the
proportion of residents who were completely independent in bathing declined from 13% to 5.6%
(Decker 2005). These trends suggest that despite the increased availability of long-term-care
services at home and in assisted living facilities since the 1990s, nursing homes have continued to
be utilized to care for the oldest and most frail elderly.
These trends were also influenced by the availability of Medicare reimbursement for the first
100 days of nursing home care following discharge after a stay of at least 72 hours in an acute care
facility. Since the late 1980s, this provision has led to nursing home admission for subacute
rehabilitation of hospitalized patients who are too disabled to return home immediately after
hospital discharge. A Rand Corporation study of post–hospital care for Medicare beneficiaries
found that post–acute use of formal care in skilled nursing facilities increases with age (Steiner
and Neu 1993).
Persons living in nursing homes in the past two decades have tended to be very disabled: 96%
of residents required assistance with bathing, 86% with dressing, 57% with toileting, and 45%
with feeding. Thirty percent had ambulatory dysfunction, and 24% required assistance getting in
and out of bed. The proportion needing help with three or more ADLs was 83.3%, and only 8%
were independent in all ADLs (Krauss and Altman 1998; Rhoades and Krauss 1999). Among
residents ages 65 and older, 27% had visual impairment and 23% had hearing impairment.
Approximately half of nursing home residents had some incontinence of both bladder and bowel.
These statistics show that, in general, nursing home residents are characterized by old age and
high levels of disability (National Center for Health Statistics 2004).

Prevalence of Psychiatric Disorders

Over the past three decades, the prevalence of psychiatric disorders among residents of U.S.
nursing homes has been found to be uniformly high. Epidemiological studies conducted between
1986 and 1993, based on psychiatric interviews using DSM-III (American Psychiatric Association
1980) or DSM-III-R (American Psychiatric Association 1987) diagnostic criteria, reported
prevalences of psychiatric disorders between 80% and 94% (Chandler and Chandler 1988;
Parmelee et al. 1989; Rovner et al. 1986, 1990a; Tariot et al. 1993). In one study, case
ascertainment by review of selected medical records revealed a 68% prevalence of psychiatric
diagnosis (Linkins et al. 2006), suggesting that chart documentation of mental disorders by
nursing home clinicians may underestimate the actual rates of mental disorders. Although there
have been no interview-based epidemiological studies in nursing homes published since 1993,
subsequent prevalence data from the Medical Expenditures Panel Survey (MEPS) revealed that
70%–80% of residents had cognitive impairment and 20% had a diagnosis of a depressive
disorder (Krauss and Altman 1998). Although the MEPS data were not derived from clinical
interviews, they indicate prevalence rates of dementia and depression that were greater than the
prevalence rates found in nursing home studies a decade earlier.
Prevalence estimates since the 1990s have been based on standardized data collection utilizing
the Minimum Data Set, version 2.0 (MDS 2.0), as mandated by the Centers for Medicare and
Medicaid Services (2006). Fullerton et al. (2009) ascertained that more than half a million people
with mental illnesses (excluding dementia) resided in U.S. nursing homes on any given day,
exceeding the number in all other health care institutions combined. Using MDS data from 2005,
Grabowski et al. (2009) determined that 27.4% of the 1.2 million new U.S. nursing home
admissions that year had schizophrenia, bipolar disorder, depression, or anxiety. These
investigators found that by 2005, the number of individuals admitted with mental illness exceeded
by 50% the number admitted with dementia only. Most of this shift was explained by a sharp
increase in the proportion of individuals admitted with depression, as well as expanding options
for individuals with dementia to receive care at home or in assisted living facilities. However,
dementia (with or without comorbid mental illnesses) remains a common condition among
nursing home residents, accounting for 36.5% of new admissions in 2004. A review of
epidemiological studies and the 2004 NNHS calculated that among nursing home residents, the
median prevalence of dementia was 58%; behavioral and psychological symptoms of dementia,
78%; major depression, 10%; and depressive symptoms, 29% (Seitz et al. 2010). Considered
together, these prevalence data, whether based on clinical interviews, chart review, or MDS data,
strongly suggest that nursing homes are de facto neuropsychiatric institutions, although they were
not originally intended for this purpose. The challenge of providing short- and long-term-care
services in nursing homes is therefore complicated by the extensive psychiatric comorbidity found
in this setting (Reichman and Conn 2010).

Cognitive Disorders and Behavioral Disturbances

In the last quarter of the twentieth century, the most common psychiatric disorder in nursing
homes was dementia, with prevalence rates of 50%–75% (Chandler and Chandler 1988; Katz et
al. 1989; Parmelee et al. 1989; Rovner et al. 1986, 1990a; Tariot et al. 1993; Teeter et al. 1976).
Alzheimer’s disease (DSM-III-R primary degenerative dementia) accounted for about 50%–60%
of cases of dementia, and vascular dementia accounted for about 25%–30% (Barnes and Raskind
1981; Rovner et al. 1986, 1990a). Other causes of dementia were reported with lower prevalence
and greater variability between sites. More recently, a study of 714 residents in three private
nursing facilities found a 7.7% prevalence rate of Parkinson’s disease and a 3.7% prevalence rate
of Parkinson disease dementia (Hoegh et al. 2013). The prevalence rates of dementia with Lewy
bodies and frontotemporal dementia have not been specifically ascertained in nursing home
populations.
Delirium is common in nursing homes and occurs primarily in patients made more vulnerable
by a dementing illness. Available studies indicated that approximately 6%–7% of residents were
delirious at the time of evaluation (Barnes and Raskind 1981; Rovner et al. 1986, 1990a).
However, this figure probably underestimates the number of patients who have cognitive
impairment associated with reversible toxic or metabolic factors. In one study, investigators found
that nearly 25% of impaired residents had potentially reversible conditions (Sabin et al. 1982);
another study found that 6%–12% of residential care patients with dementia actually improved in
cognitive performance over the course of 1 year (Katz et al. 1991). A large study of residents with
severe cognitive impairment found improvement at 6-month follow-up in 14% of the sample,
associated with the following baseline findings: higher function, antidepressant medication use,
and falls (Buttar et al. 2003). In the nursing home, as in other settings, a common reversible cause
of cognitive impairment may be cognitive toxicity from drugs used to treat medical or psychiatric
disorders. However, there is evidence that long-acting opioids, previously thought to have adverse
effects on cognitive function, may actually lead to improvements in functional status and social
engagement without decrements in cognitive status or increases in the rate of delirium among
nursing home residents who are treated for nonmalignant chronic pain (Won et al. 2006). For
residents admitted to the nursing home for post–acute care rehabilitation, unresolved delirium is
associated with poor functional recovery (Kiely et al. 2006). Severity of cognitive impairment and
depressive symptoms at the time of initial assessment has been found to predict the trajectory and
course of delirium in nursing home residents (von Gunten et al. 2013).
The clinical features of dementing disorders include treatable behavioral and psychological
symptoms of dementia—such as hallucinations, delusions, depression, anxiety, and agitation—that
can contribute to disability. Combined 1-year prevalence of psychosis, agitation, and depression
has been estimated between 76% and 82% (Ballard et al. 2001), and 2-year prevalence of
neuropsychiatric symptoms was found to be 96.6% among residents with dementia (Wetzels et al.
2010). Among nursing home populations, psychotic symptoms have been reported in
approximately 25%–50% of residents with a primary dementing illness (Berrios and Brook 1985;
Chandler and Chandler 1988; Rovner et al. 1986, 1990a; Teeter et al. 1976). Clinically significant
depression is seen in approximately 25% of patients with dementia. Dementia complicated by
mixed agitation and depression accounts for more than one-third of complicated dementia in
nursing home populations and is associated with multiple psychiatric and medical needs,
psychotropic drug use, and hospital admissions (Bartels et al. 2003).
MEPS data revealed that 30% of residents exhibit behavioral problems, including verbal abuse
by 11.8%, physical abuse by 9.1%, socially inappropriate behavior by 14.5%, resistance to care by
12.5%, and wandering by 9.4% (Krauss and Altman 1998). In the nursing homes operated by the
Department of Veterans Affairs (VA) health care system, approximately 70% of residents with
dementia have been found to exhibit some type of challenging behavior (McCarthy et al. 2004). A
more recent prospective cohort study of nursing home residents with dementia found a point
prevalence of agitation or aggression ranging from 20.5% to 29.1%, with a 2-year cumulative
prevalence of 53.8%; a point prevalence of irritability ranging from 21.4% to 28.2%, with a 2-year
cumulative prevalence of 58.1%; and a point prevalence of aberrant motor behavior fluctuating
between 18.8% and 26.5%, with a cumulative prevalence of 50.4% (Wetzels et al. 2010).
Disturbances of behavior, in addition to impaired ability to perform ADLs, have been identified as
the most common reasons that patients with dementia are admitted to nursing homes (Steele et al.
1990), and disruptive behaviors frequently complicate care after admission (Cohen-Mansfield et
al. 1989; Teeter et al. 1976; Zimmer et al. 1984). Most psychiatric consultations in long-term-care
settings are for the evaluation and treatment of behavioral disturbances such as pacing and
wandering, verbal abusiveness, disruptive shouting, physical aggression, destructive acts, and
resistance to necessary care (Fenton et al. 2004; Loebel et al. 1991). Behavioral disturbances occur
most frequently in patients with dementia, often in those with psychotic symptoms—an
association that remains even after controlling for level of cognitive impairment (Rovner et al.
1990b). Agitation and hyperactivity are also commonly associated with depression (Heeren et al.
2003; Volicer et al. 2012), as are delirium, sensory deprivation or overload, occult physical illness,
pain, constipation, urinary retention, and adverse drug effects (including akathisia due to
neuroleptics) (Cohen-Mansfield and Billig 1986). Depressive symptoms are associated with
disruptive vocalizations in nursing home residents, even after controlling for gender, age, and
cognitive status (Dwyer and Byrne 2000). In a study comparing verbal and physical non-
aggressive agitation, verbal agitation was correlated with female gender, depressed affect, poor
performance of ADLs, and impaired social functioning (Cohen-Mansfield and Libin 2005).
In addition to agitation, symptoms such as apathy, inactivity, and withdrawal occur among
nursing home residents with and without a diagnosis of depression. Apathy has been found to
increase over time, with a 2-year cumulative incidence of 42.1% (Wetzels et al. 2010). Although
these symptoms are less disturbing to staff and less frequently lead to psychiatric consultation
(Fenton et al. 2004), they can be disabling and may be associated with decreases in socialization
and self-care.

Depression
Among community-dwelling elders in the United States and Europe, depression increases the risk
of nursing home admission (Ahmed et al. 2007; Harris and Cooper 2006; Onder et al. 2007), and
this association remains after controlling for age, physical illness, and functional status (Harris
2007). Among nursing homes residents, depressive disorders represent the second most common
psychiatric diagnosis, after dementia. Most studies in U.S. nursing homes show depression
prevalence rates of 15%–50%, depending on the population studied and instruments used, and on
whether major depression or depressive symptoms are being reported (Baker and Miller 1991;
Chandler and Chandler 1988; Hyer and Blazer 1982; Katz et al. 1989; Kaup et al. 2007; Lesher
1986; Levin et al. 2007; McCusker et al. 2014; Parmelee et al. 1989; Rovner et al. 1986, 1990a,
1991; Tariot et al. 1993; Teeter et al. 1976). Studies from other countries have shown similar rates
(Ames 1990, 1991; Ames et al. 1988; Barca et al. 2010; Chahine et al. 2007; Harrison et al. 1990;
Horiguchi and Inami 1991; Jongenelis et al. 2004; Mann et al. 1984; Rozzini et al. 1996; Snowdon
1986; Snowdon and Donnelly 1986; Spagnoli et al. 1986; Trichard et al. 1982). Approximately
6%–10% of all nursing home residents, and 20%–25% of those who are cognitively intact, meet
criteria for a diagnosis of major depression; the latter figure is an order of magnitude greater than
rates among community-dwelling elderly persons (Blazer and Williams 1980; Kramer et al. 1985).
The prevalence of less severe but clinically significant (e.g., minor or subsyndromal)
depression among residents in long-term-care settings is even higher. In one study, Parmelee et al.
(1992) reported that the 1-year incidence of major depression was 9.4% and that patients with
preexisting minor depression were at increased risk; the incidence of minor depression among
those who were euthymic at baseline was 7.4%. Similarly, McCusker et al. (2014) found that
baseline depression score was an independent risk factor for incident depression. These data show
that minor or subsyndromal depression in nursing home residents appears to be a risk factor for
major depression and might represent an opportunity for preventive treatment in this population.
Depression among nursing home residents tends to be persistent. Although there may be
moderate decreases in self-rated depression in the initial 2 weeks to 6 months after nursing home
admission (Engle and Graney 1993; Smalbrugge et al. 2006), Ames et al. (1988) found that only
17% of patients with diagnosable depressive disorders had recovered after an average of 3.6 years
of follow-up. Smalbrugge et al. (2006) found persistence of symptoms in two-thirds of residents at
6-month follow-up, although rates were significantly higher among those with more severe
symptoms at baseline.
Evidence for morbidity associated with depression comes from studies that showed an increase
in pain complaints among residents with depression (McCusker et al. 2014; Parmelee et al. 1991),
an association between depression and biochemical markers of subnutrition (Katz et al. 1993), and
independent associations of delirium and diabetes with depression (McCusker et al. 2014).
Depression in nursing home residents, both with and without dementia, is associated with
disability (Kaup et al. 2007). Among individuals admitted to nursing homes for post–acute care
rehabilitation, those with depression have poorer functional outcomes (Webber et al. 2005). In
addition to its association with morbidity and disability, depression in nursing home populations
has been found to be associated with an increase in mortality rate, with effect sizes ranging from
1.6 to 3 (Ashby et al. 1991; Katz et al. 1989; Parmelee et al. 1992; Rovner et al. 1991; Sutcliffe et
al. 2007). Whereas Rovner et al. (1991) reported that the increased mortality rate remained
apparent after controlling for the patients’ medical diagnoses and level of disability, Parmelee et
al. (1992) found that the effect could be attributed to the interrelationships among depression,
disability, and physical illness.
In addition to the medical comorbidity, disability, and mortality that characterize major
depression among nursing home residents, there is evidence for heterogeneity in these patients
that may reflect the existence of clinically relevant subtypes of depression. A treatment study by
Katz et al. (1990) demonstrated that measures of self-care deficits and serum levels of albumin
were highly intercorrelated and that both predicted a lack of response to treatment with
nortriptyline. Therefore, although this study demonstrated that major depression is a specific,
treatable disorder—even in long-term-care patients with medical comorbidity—there is also
evidence in this setting for a treatment-relevant subtype of depression characterized by high levels
of disability and low levels of serum albumin. This latter condition may be related to the
syndrome of frailty that is well described in the geriatric medical literature (Malmstrom et al.
2014). As described later in this chapter (see “Pharmacotherapy”), evidence also indicates that
depression among nursing home residents with dementia may differ from depression among
residents who are depressed and cognitively intact. Several studies of nursing home residents have
demonstrated poorer response to treatment with noradrenergic and serotonergic antidepressant
drugs in very old residents with comorbid cognitive impairment or dementia (Magai et al. 2000;
Oslin et al. 2000; Rosen et al. 2000; Streim et al. 2000; Trappler and Cohen 1996, 1998). These
findings provide evidence for another treatment-relevant subtype of depression, although this
condition may not be specific to the nursing home setting. Similarly poor antidepressant treatment
responses have been amply demonstrated in very old outpatients whose depressive symptoms are
associated with vascular risk factors and executive dysfunction (Sneed et al. 2007, 2008).

Progress in Treatment of Psychiatric Disorders in the Nursing

Home
An appreciation of the unique characteristics of nursing home populations—particularly the
extremes of old age and the high prevalence rates of cognitive impairment, psychiatric and
medical comorbidity, and disability—has led to increased recognition that results of efficacy
studies conducted in general adult outpatient populations may not be readily generalizable to
nursing home residents. This recognition points to the need for treatment studies conducted
specifically with nursing home patients. Although the number of randomized controlled studies is
limited, there is a growing body of literature on treatment outcomes in the nursing home.

Nonpharmacological Management of Behavioral Disturbances

Since 1990, numerous studies have been published describing nonpharmacological interventions
for behavioral disturbances associated with dementia in the nursing home setting. Few of these are
randomized controlled trials. Comprehensive reviews of these studies have been written by
Cohen-Mansfield (2001), Olazarán et al. (2010), Teri et al. (2002), Snowden et al. (2003), and
Livingston et al. (2005).
Several nonpharmacological interventions have been shown to be effective, although only
behavior management therapies (Cohen-Mansfield et al. 2012; Karlin et al. 2014), specific types
of caregiver and residential care staff education (Deudon et al. 2009), and possibly sensory and
cognitive stimulation appear to have lasting effectiveness (Livingston et al. 2005). Although
effective interventions have been developed, implementation has been limited by many barriers,
including lack of specialized staff training and inadequate reimbursement for this type of care
(Cody et al. 2002; Lawrence et al. 2012). One promising approach combined enhanced activities,
guidelines for the use of psychotropic medication, and educational rounds for nursing home staff
(Rovner et al. 1996). In a randomized clinical trial, this approach was shown to reduce the
prevalence of problem behaviors and the use of antipsychotic drugs and physical restraints.
Individualized consultation for staff nurses about the management of patients with dementia was
also shown to diminish the use of physical restraints (Evans et al. 1997). Reductions in agitation
were observed in a study of a daytime physical activity intervention combined with a nighttime
program to decrease noise and sleep-disruptive nursing care practices (Alessi et al. 1999). A few
multisensory stimulation methods have shown promising results, although randomized controlled
trials are still needed. Namaste Care, a program developed for nursing home residents with
advanced dementia, emphasizes the calming effects of touch as well as sound, smell, and taste
(Simard and Volicer 2010; Fullarton and Volicer 2013). Snoezelen rooms provide stimulation to
meet patients’ multisensory needs (Berg et al. 2010; van Weert et al. 2005). Bright light therapy
has been shown to increase observed nocturnal sleep time but not to improve agitated behavior in
nursing home residents with dementia (Lyketsos et al. 1999). Although some studies have claimed
that aromatherapy with lavender oil is effective in reducing agitated behaviors, results have not
been consistently replicated when controlling for non-olfactory aspects of treatment in residents
with severe dementia (Snow et al. 2004). Music therapy has been shown to reduce agitation, but a
comparison to general recreational activities showed no additional beneficial effects of music
(Vink et al. 2013). Humor therapy was found to significantly reduce agitation but not depression
(Low et al. 2013).
Individualized activities matched to skills and interests of residents with dementia have also
been shown to reduce agitation and negative affect (Kolanowski et al. 2005). A randomized
placebo-controlled trial of nonpharmacological individualized interventions to address unmet
needs demonstrated significant declines in total, physical non-aggressive, and verbal agitation
(Cohen-Mansfield et al. 2012).
The largest intervention trial of nonpharmacological interventions to date has been conducted
in the VA Community Living Centers, which are residential nursing facilities that include the
provision of dementia care for veterans (Karlin et al. 2014). Program elements included a
psychologist serving as the primary interventionist and behavioral coordinator, working closely
with facility staff to develop and implement a behavioral intervention plan to address challenging
behaviors associated with dementia. The multicomponent psychosocial approach was based on a
model developed by Teri et al. (2005) for training direct care workers in assisted living residences.
This program, when adapted to the VA Community Living Center setting, achieved a 35%
reduction in the frequency and 46% reduction in the severity of challenging dementia-related
behaviors. Although not specific to the nursing home setting, recommendations of a
multidisciplinary expert panel on nonpharmacological management of neuropsychiatric symptoms
of dementia were recently published by Kales et al. (2014).

Psychotherapy
Evidence for the efficacy of psychotherapy in other settings suggests that it may be of value for
treating mental disorders of aging in patients whose cognitive abilities allow them to participate.
However, a search of the PsycINFO, PubMed, and Cochrane databases for the terms
psychotherapy and nursing homes from 1987 to the time of writing this chapter identified only a
limited number of controlled studies of the effectiveness of specific psychotherapeutic modalities,
individual or group, for nursing home residents (Table 25–1). Bharucha et al. (2006) identified and
reviewed 18 controlled studies of “talk” psychotherapy for depression and psychological well-
being in nursing home populations, and found that a majority showed at least short-term benefits
on measures of mood, hopelessness, perceived control, self-esteem, or other psychological
variables. However, the authors noted that interpretation of the findings of many of these studies
was limited by small sample sizes, variable study entry criteria, short duration of trials,
heterogeneous outcome assessment methods, and lack of detail on intervention methods.
Controlled research on psychotherapeutic interventions has included studies of task-oriented
versus insight-oriented therapy (Moran and Gatz 1987); reality orientation (Baines et al. 1987);
reminiscence groups (Baines et al. 1987; Chao et al. 2006; Goldwasser et al. 1987; Haslam et al.
2010; McMurdo and Rennie 1993; Orten et al. 1989; Politis et al. 2004; Rattenbury and Stones
1989; Youssef 1990); exercise, activity, and progressive relaxation groups (Bensink et al. 1992;
McMurdo and Rennie 1993); supportive group psychotherapy (Goldwasser et al. 1987;
Szczepanska-Gieracha et al. 2014; Williams-Barnard and Lindell 1992); validation therapy (Tondi
et al. 2007; Toseland et al. 1997); cognitive or cognitive-behavioral group therapies (Abraham et
al. 1992; Zerhusen et al. 1991); focused visual imagery therapy (Abraham et al. 1997); and a
psychosocial activity intervention (Beck et al. 2002). Except in the investigations by Abraham et
al. (1992, 1997), patients were not selected on the basis of specific psychiatric symptoms or
syndromes but rather on the basis of age, cognitive status, or mobility.
Some of these studies reported improvements on measures of communication, behavior,
cognitive performance, mood, social withdrawal, physical function, somatic preoccupation, self-
esteem, perceived locus of control, quality of life, and life satisfaction. Case reports and
demonstration projects by experienced clinicians also documented the value of psychotherapy for
treating depressed nursing home residents (Leszcz et al. 1985; Ollech 2006; Sadavoy 1991).
Overall, there is a paucity of research on the outcomes of well-described psychotherapies among
nursing home residents who have well-characterized psychiatric disorders. Nevertheless, the
available evidence from nursing home research, considered together with outcomes of
psychotherapy for older adults in other clinical settings, suggests that psychotherapy should be
regarded as an important component of mental health treatment for the more cognitively intact
nursing home residents with depression.

Pharmacotherapy
Pharmacological treatments are commonly used in nursing homes for dementia and its associated
psychological and behavioral symptoms, and for depression. More comprehensive reviews of the
evidence for pharmacological treatment of neuropsychiatric symptoms of dementia specifically in
the nursing home setting are provided by Bharani and Snowden (2005) and Seitz et al. (2013).
Randomized, placebo-controlled clinical trials of psychotropic drugs conducted specifically in
nursing home populations are summarized in Table 25–2. Some of the earlier studies provided
evidence for the efficacy of antipsychotic drugs in managing agitation and related symptoms in
nursing home residents with dementia, but the effect sizes were often modest, and high placebo
response rates were common (Barnes et al. 1982; Schneider et al. 1990; Sunderland and Silver
1988). Subsequently, several multicenter, randomized, double-blind, placebo-controlled clinical
trials demonstrated efficacy of some of the atypical antipsychotic agents for the treatment of
psychotic symptoms and agitated behavior in nursing home residents with dementia. These
include published studies of risperidone (Brodaty et al. 2003; Katz et al. 1999), olanzapine
(Meehan et al. 2002; Street et al. 2000), quetiapine (Zhong et al. 2007), and aripiprazole (Mintzer
et al. 2007, Rappaport et al. 2009). Secondary analyses of data from the nursing home trials of
risperidone showed that the medication had antipsychotic effects and also had independent effects
on aggression or agitation. Other studies of atypical antipsychotic drugs in nursing home residents
with dementia failed to show statistically significant benefits on the a priori designated primary
outcome measures related to psychosis or behavioral disturbances (De Deyn et al. 1999, 2005;
Mintzer et al. 2006; Streim et al. 2008), although some of these studies found possible benefits on
secondary behavioral measures. Widespread interest in studying atypical antipsychotics for
treatment of elderly nursing home residents was partly attributable to the expectation that these
agents would be better tolerated than conventional antipsychotics in this population. For example,
early follow-up studies had suggested that risperidone may cause less tardive dyskinesia than do
typical antipsychotic agents (Jeste et al. 2000).

TABLE 25–1. Randomized controlled studies of the outcomes of psychotherapeutic

interventions in elderly nursing home residents
Study Type of Sample Outcome Results and comments
intervention measures
Moran and Task-oriented N=59; mean Self-reported Task group improved on
 Gatz 1987 group vs. insight- age 76.3 psychosocial all measures except trust.
oriented group years; competence in Task group had
vs. waiting-room conversant, 1) sense of significant increase in
control group mobile control, 2) trust, life satisfaction
3) active compared with insight
coping, 4) and control groups.
striving for Insight group improved
social approval; on sense of control and
life satisfaction trust.
Baines et al. Reality orientation N=15; mean Cognitive Only the group that
1987 vs. reminiscence age 81.5 function; life received reality
therapy vs. no- years; satisfaction; orientation first and then
therapy control moderate communication; reminiscence therapy
group (crossover to severe behavior; staff showed sustained
design) cognitively knowledge of improvement in
impaired residents communication and
behavior and
nonsustained
improvement in function
(information/orientation).
No improvement was
found in other groups.
Intervention was
associated with improved
staff knowledge of
residents.
Goldwasser Reminiscence N=27; Depression; Reminiscence group
et al. 1987 group therapy vs. dementia cognitive showed nonsustained
supportive group (MMSE: function; improvement in self-
therapy vs. no- range 1– behavioral/ADL reported depression on
treatment control 22; mean function BDI. Neither
group 10.4) intervention showed
significant effects on
cognitive or behavioral
function.
Orten et al. Reminiscence N=56; mean Social behavior; Significant improvement
1989 group vs. control age 82.6 ADL function; for one of three
group years; agitation; experimental groups; no
moderately somatic improvement when all
confused complaining; groups were analyzed
attitude together. Investigators
suggest that therapist
skills are an important
variable.
Rattenbury Reminiscence N=24; mean Psychological Both intervention groups
and Stones group vs. current ages of well-being improved on happiness-
1989 topics discussion groups 83– (happiness- depression scale. No
 group vs. no 87 years; depression improvement on other
group judged by scale); activity measures, including
nursing level; functional mood scale. Positive
home staff level; mood correlation between
not to be happiness scores and
cognitively increased verbal activity
impaired level between week 1
and week 4.
Youssef 1990 Group N=60, all Depression Young-old group had
reminiscence women; significant improvement
counseling for young-old in depression scores on
young-old ages 65–74 BDI. Old-old group
subjects vs. years; old- showed improvement
group old ages only on social
reminiscence ≥75 years withdrawal and somatic
counseling for preoccupation items but
old-old subjects not on total BDI scores.
vs. control group Control condition was
not described.
Ames 1990 Psychogeriatric N=93; mean Depression; ADL No difference between
team age 82.3 performance intervention and control
recommendations years groups. Only 27 of 81
vs. routine recommended
clinical care interventions were
actually implemented
(e.g., medication
changes, referral for
mental health services).
Role of psychogeriatric
services in management
of the facilities and
medical care of the
residents was not clearly
defined.
Zerhusen et Group cognitive N=60; mean Depression; Cognitive therapy group
al. 1991 therapy vs. music age 77 performance had 30% improvement in
group (control) years ratings of group self-rated depression
vs. routine leaders scores on BDI; no
clinical care significant improvement
(control) in control subjects.
Group gains did not vary
with group leader
ratings.
Williams- Group therapy with N=73; age Self-concept Self-concept improved in
Barnard high nurse ≥65 years 68.4% of residents in
and Lindell prizing vs. group high-prizing group,
1992 therapy with low 29.4% of residents in
 nurse prizing vs. low-prizing groups, and
control group (3 10.8% of residents in
meetings for control group. Self-
control vs. 16 concept declined in 40%
meetings for of low-prizing group and
experimental 5.3% of high-prizing
groups) group.
Bensink et PR group vs. N=28; age Locus of control; Only PR group showed
al. 1992 activity group ≥65 years; self-esteem increase in perceived
(control) mean age internal locus of control.
77 years; Both PR and activity
MMSE groups showed
score ≥20 improvement in self-
esteem, with greater
effect in PR group.
Abraham et CB group therapy N=76; mean Cognitive No effects of group
al. 1992 vs. FVI group age 84 function; therapy on geriatric
therapy vs. years; depression; depression, hopelessness,
control groups (3 depressed hopelessness; or life satisfaction. Both
meetings for and mildly life satisfaction CB and FVI groups
control vs. 16 to showed improved
meetings for moderately cognitive function on
experimental cognitively modified MMSE, with
groups) impaired greater gains in FVI
participants. No
significant cognitive
change in ED control
groups.
McMurdo Exercise sessions N=49; mean Physical function; Physical function
and Rennie vs. reminiscence age 81 ADL improved in exercise
1993 groups years performance; group and declined in
depression; life reminiscence group.
satisfaction; Self-reported depression
cognitive (BDI scores) declined in
function both groups; exercise
group showed
significantly greater
improvement than
reminiscence group.
Abraham et CB group therapy N=76; mean Depression Secondary analyses. Both
al. 1997 vs. FVI group age 84 factors; CB and FVI reduced
therapy vs. years; cognitive depressive symptoms
control groups depressed factors over 24 weeks.
and mildly
to
moderately
 cognitively
impaired
Toseland et VT group vs. N=88; mean Behavioral VT group had less physical
al. 1997 social contact age 87 disturbances; and verbal aggression
group (control) years; depression; use and less depression than
vs. usual care dementia of physical social contact or usual
group (control) restraints; use care group. VT not
of psychotropic effective in reducing
medication physical restraints or
psychotropic drug use.
Social contact and usual
care groups had great
reductions in
nonaggressive behavioral
problems.
Beck et al. ADL group vs. N=127; Positive and Significantly more positive
2002 psychosocial mean age negative affect; affect in treatment
activity 83 years; frequency of groups; no decrease in
intervention vs. MMSE disruptive negative affect and no
both vs. placebo mean score behaviors change in disruptive
vs. no 10; with behaviors.
intervention disruptive
behaviors
Politis et al. Reminiscence- N=37; Apathy; quality Significant reduction in
2004 based activity dementia of life; activity NPI apathy scores in
intervention vs. level both groups, but no
“time and difference between
attention” one- groups; greater within-
on-one meetings group improvement on
with activities quality-of-life measure
therapist for control group only.
(control)
Chao et al. Reminiscence N=24 Depression; self- Significant improvement
2006 group therapy vs. esteem; life on self-esteem measure;
usual care satisfaction no significant effects on
(matched depression or life
controls) satisfaction.
Haslam et al. Individual vs. N=73; age Memory Group reminiscence
2010 group range 58– performance; enhanced memory; social
reminiscence vs. 93 years; well-being activity control condition
social activity cognitively enhanced well-being
(control); weekly intact and
for 6 weeks demented;
MMSE
mean score
16.6
 Graessel et Cognitive (and N=98; mean Cognitive Cognitive function and
al. 2011 motor) age 85.1 function; ADL ADL performance were
stimulation group years; performance; stable in treatment group
vs. usual care dementia mean MMSE at 12-month follow-up;
group (control) score=14.6 control group declined
on both measures
Note. ADL=activities of daily living; BDI=Beck Depression Inventory (A. T. Beck et al. 1961); CB=cognitive-behavioral;
ED=education-discussion; FVI=focused visual imagery; MMSE=Mini-Mental State Examination (Folstein et al. 1975);
NPI=Neuropsychiatric Inventory (Wood et al. 2000); PR=progressive relaxation; VT=validation therapy.

These controlled clinical trials have examined only the acute effects of treatment, typically for
6–12 weeks of treatment, and little is known about the effectiveness of treatment for longer
periods. However, there is evidence to suggest that the need for and benefit from antipsychotic
drug treatment changes over the course of months in nursing home patients with dementia. Several
double-blind, placebo-controlled studies of antipsychotic drug discontinuation demonstrated that
the majority of patients who had been receiving longer-term treatment could be withdrawn from
these agents without reemergence of psychosis or agitated behaviors (Bridges-Parlet et al. 1997;
Cohen-Mansfield et al. 1999; Ruths et al. 2004). These data are consistent with findings from
older discontinuation studies (Barton and Hurst 1966; Risse et al. 1987). Therefore, it is important
to periodically reevaluate the need for continuing antipsychotic drug treatment.
Since 2003, analyses of safety data from randomized controlled studies of atypical
antipsychotic drugs in elderly patients with dementia, including the aforementioned nursing home
studies, have revealed significantly increased risks of cerebrovascular adverse events and
mortality in this population. Although elevated risks were not found in every study, pooled
analyses showed that the rate of cerebrovascular adverse events (including stroke and transient
ischemic attacks) is greater than with placebo (U.S. Food and Drug Administration 2003). Most of
the affected individuals had known cerebrovascular risk factors prior to starting drug treatment.
These findings led to regulatory warnings in the United States, Canada, and the United Kingdom
regarding the safety of these drugs in elderly patients with dementia.
The U.S. Food and Drug Administration (FDA) also warns that elderly patients with dementia-
related psychosis who are treated with atypical antipsychotics have a risk of death of about 1.7
times greater than those treated with placebo (4.5% vs. 2.6%) and provides a reminder that
atypical antipsychotics do not have FDA approval for the treatment of patients with dementia-
related psychosis (U.S. Food and Drug Administration 2005). Consistent with this FDA warning,
a meta-analysis by Schneider et al. (2005), which examined results of 15 randomized controlled
trials, many of which were conducted using nursing home patients, found that the risk of mortality
was 3.5% for elderly patients treated with atypical antipsychotics versus 2.3% for patients treated
with placebo. Although no placebo-controlled trials of ziprasidone or clozapine are known to have
been conducted in elderly patients with dementia, it is reasonable to view the increased mortality
as a class effect. Wang et al. (2005) found a significantly higher adjusted risk of death for elderly
patients taking conventional antipsychotics compared with those taking atypical antipsychotic
medications, regardless of whether the patients had dementia or resided in a nursing home. The
authors suggested that conventional antipsychotic medications are at least as likely as atypical
agents to increase the risk of death in older adults. Subsequent comparisons with community-
dwelling populations revealed higher mortality rates among nursing home residents with dementia
who were newly started on antipsychotic drugs (Gill et al. 2007; Rochon et al. 2008).
TABLE 25–2. Randomized, placebo-controlled studies of the efficacy of psychotropic
medications in elderly nursing home residents
Study Medication and dosage Sample Efficacy measures Results and comments
(mg/day)
Beber 1965 Oxazepam (10–80) vs. N=100; mean age 79 Anxiety and Improvement in all
placebo years; nonpsychotic
with chronic brain
tension; parameters was
syndrome (n=28), depression, significantly
mixed lethargy, greater in
anxiety/depression
(n=26), anxiety autonomic oxazepam-treated
(n=43), or depression reactions; group than in
(n=3) irritability, placebo-treated
insomnia, group; 44 subjects
agitation, received
phobic concomitant
reactions treatment with
other drugs,
including
neuroleptics,
antidepressants,
hypnotics,
antiparkinsonian
agents, and
analgesics.
Barnes et al. Thioridazine N=53; mean age BPRS; SCAG; Total scores and
1982 (mean 62.5) vs. 83 years; NOSIE; CGI global ratings
loxapine (mean dementia and showed modest
10.5) vs. three or more efficacy with
placebo behavioral thioridazine and
symptoms loxapine, but
were not
statistically better
than placebo; high
placebo response
rate; significant
improvement in
anxiety,
excitement,
emotional lability,
and
uncooperativeness
in active
treatment groups,
but no significant
differences in
overall efficacy
between
thioridazine and
 loxapine;
significant
improvement on
BPRS and SCAG
only in subjects
with high-severity
baseline scores.
Stotsky 1984 Thioridazine N=237 nursing Modified Ham- Thioridazine was
(10–200) vs. home patients; A; modified well tolerated,
diazepam (20– mean age 80 NOSIE; with few side
40) vs. placebo years; all global effects.
nonpsychotic evaluations Thioridazine-
with cognitive treated group
impairment, improved
emotional significantly more
lability, ADL than placebo
dysfunction group on all Ham-
and agitation, A items (74% vs.
anxiety, 42%) and global
depressed evaluations.
mood, or sleep Thioridazine-
disturbance treated group
(also studied improved
were 273 significantly more
patients on than diazepam
geriatric wards group on NOSIE
of state and global
hospitals) ratings. Insomnia
responded better
to diazepam, but
there was more
overall
improvement on
Ham-A rating
with thioridazine.
Dehlin et al. Alaproclate N=40; mean age Intellectual No difference in
1985 (400) 82 years; function; efficacy was
(serotonin primary motor found between
reuptake degenerative, function alaproclate and
inhibitor) vs. multi-infarct, (ADL); placebo. Severity
placebo or mixed emotional of dementia
dementia; not function ranged from mild
selected on (including to severe.
basis of depressive Behavioral
affective or symptoms); problems were
behavioral clinical global not described.
symptoms evaluation
Katz et al. Nortriptyline N=30 residents Ham-D*; Significant
1990 (mean 65.25) of nursing Geriatric improvement
vs. placebo home or Depression occurred in
congregate Scale; CGI patients treated
housing; mean with nortriptyline
age 84 years; compared with
major placebo on Ham-
depression D and CGI but
(Ham-D scores not on Geriatric
≥ 18) Depression Scale.
Location (in
nursing home vs.
congregate
housing) was not
significantly
related to
response. Trend
toward decreased
nortriptyline
response in
nursing home was
related to higher
levels of disability
and lower serum
albumin in
nursing home
patients.
Nyth and Citalopram (10– N=98; mean age GBS; CGI; Compared with
Gottfries 30; mean 25) 77.6 years; MADRS control subjects,
1990 vs. placebo primary Alzheimer’s
degenerative disease patients in
(Alzheimer’s citalopram group
disease) or had significant
multi-infarct reduction in
dementia irritability and
(vascular depressed mood
dementia) on GBS. From
baseline to week
4, Alzheimer’s
disease patients in
citalopram group
improved
significantly on
MADRS and on
GBS emotional
blunting,
confusion,
irritability,
 anxiety, fear-
panic, depressed
mood, and
restlessness. No
treatment benefits
were found in
vascular dementia
patients. Placebo
group worsened
on CGI. Few
adverse effects
occurred, with no
drug-placebo
differences.
Finkel et al. Thiothixene N=33; mean age CMAI; MMSE; Thiothixene-treated
1995 (0.25–18; 85 years; GDS; ADLs group had
mean 4.6) vs. dementia with significantly
placebo agitated or greater reduction
aggressive in agitation than
behavior placebo group
after 11 weeks of
treatment and 6
weeks after
crossover from
placebo; no
between-group
differences were
seen on MMSE,
GDS, and ADLs.
Tariot et al. Carbamazepine N=51; dementia BPRS; CGI; Carbamazepine-
1998 (modal dose with agitation agitation; treated group had
300; mean aggression; significantly
serum level 5.3 cognition; greater
μg/mL) vs. functional improvement on
placebo status; staff BPRS compared
time with placebo
group at 6 weeks.
Global
improvement
occurred in 77%
of patients taking
carbamazepine
and in 22% of
those taking
placebo.
Secondary
analyses showed
 that improvement
was attributable to
decreased
agitation and
aggression.
Nurses reported
perception of
decreased time
required to
manage agitation
in carbamazepine
group.
Significantly
more adverse
events were seen
with
carbamazepine
(59%) than with
placebo (29%).
De Deyn et al. Risperidone N=344; BEHAVE-AD*; No significant
1999 (0.5–4; mean Alzheimer’s, CMAI; CGI; difference in
1.1) vs. vascular, and MMSE response rates
haloperidol mixed were seen on
(0.5–4; mean dementia BEHAVE-AD
1.2) vs. (MMSE mean between
placebo; 12 score 8.7) risperidone and
weeks placebo,
BEHAVE-AD
total and
aggression
subscale and
CMAI aggression
item scores were
lower and CGI
was significantly
greater with
risperidone than
with placebo; post
hoc analysis
showed
significantly
greater reduction
in BEHAVE-AD
aggression scores
with risperidone
than with
haloperidol.
Somnolence was
 greater with
risperidone
(12.2%) than with
placebo (4.4%).
Extrapyramidal
symptoms were
significantly
greater with
haloperidol (22%)
than with
risperidone (15%)
or placebo (11%).
Slight but
significant decline
was seen in
MMSE scores in
haloperidol group.
Response defined
as ≥ 30%
reduction in
BEHAVE-AD
score
Katz et al. Risperidone N=625; mean BEHAVE-AD*; Significantly
1999 (0.5–2) vs. age 82.7 years; CMAI; CGI; greater reductions
placebo; 12 psychotic and MMSE; occurred in
weeks behavioral FAST; PSMS BEHAVE-AD
symptoms and total scores and in
Alzheimer’s Aggressiveness
disease, and Psychosis
vascular subscale scores
dementia, or with risperidone 1
mixed mg and 2 mg than
Alzheimer’s with placebo.
disease and Response rates
vascular were significantly
dementia greater with
(MMSE mean risperidone 1 mg
score 6.6) (45%) and 2 mg
(50%) than with
placebo (33%).
More
extrapyramidal
symptoms and
somnolence were
seen with 2 mg
than with 1 mg of
risperidone.
 Optimal dosage
for nursing home
patients with
severe dementia
appears to be 1
mg.
Response defined
as ≥ 50%
reduction in
BEHAVE-AD
score
Magai et al. Sertraline vs. N=31; all women Depression; Both groups were
2000 placebo with late-stage facial affect improved at 8
Alzheimer’s weeks; sertraline
disease and had no significant
depression benefits over
placebo. “Knit-
brow” facial
response
approached
significance for
treatment × time
effect.
Street et al. Olanzapine (5, N=206; mean NPI-NH core* Olanzapine 5 mg
2000 10, 15) vs. age 83.8 years; and total and 10 mg
placebo; 6 Alzheimer’s (including produced
weeks disease with Occupational significant
psychotic Disruptiveness improvement in
and/or scores); summary
behavioral BPRS; MMSE measures of
symptoms agitation,
(MMSE mean aggression, and
score 6.9) psychosis.
Olanzapine 5 mg
significantly
reduced
disruptive effects
on caregivers
compared with
placebo.
Olanzapine was
associated with
somnolence and
gait disturbance
but not with
increased
extrapyramidal
 symptoms, central
anticholinergic
effects, or
cognitive
impairment
compared with
placebo; 18% of
placebo group and
44% of
olanzapine group
dropouts were due
to adverse events.
Olin et al. Carbamazepine N=21; BPRS*; CGI-C; Both groups
2001 (mean 388) vs. Alzheimer’s Ham-D improved on CGI-
placebo; 6 dementia C (56% on
weeks (MMSE mean carbamazepine,
score 6.0) 58% on placebo),
but no significant
differences were
seen on BPRS,
CGI, or Ham-D.
Adverse events
were mild and
similar in drug
and placebo.
Porsteinsson Divalproex N=56; mean age BPRS*; OAS; Divalproex group
et al. 2001 (mean 826; 85 years; BRSD; showed
mean serum probable or CMAI; CGI-C significant
level 45.4 possible improvement on
μg/mL) vs. Alzheimer’s BPRS at 6 weeks
placebo; 6 disease, compared with
weeks vascular placebo only in a
dementia, or secondary
mixed analysis after
dementia with adjustment for
agitation several
(MMSE mean covariates; 68%
score 6.8) of divalproex
group and 52% of
placebo group had
reduced agitation
on CGI (NS).
Significantly
more side effects
(generally mild)
were reported in
divalproex than in
 placebo group
(68% vs. 33%),
but sedation was
39% with
divalproex vs.
11% with
placebo.
Tariot et al. Donepezil (5– N=208; mean NPI-NH; CDR- Both groups
2001a 10) vs. placebo age 85.7 years; SB; MMSE; improved on NPI-
probable or PSMS NH, with no
possible significant
Alzheimer’s difference
disease or between
Alzheimer’s donepezil and
disease with placebo.
cerebrovascular Significantly
disease greater
(MMSE mean improvement was
score 14.4) seen with
donepezil than
with placebo on
CDR-SB at week
24 and on MMSE
at weeks 8, 16,
and 20, but not on
PSMS.
Improvement was
not influenced by
advanced age. No
difference in
adverse events
was found for
drug vs. placebo.
Tariot et al. Divalproex N=172; BRMS*; BPRS; Study was
2001b (mean 1,000) Alzheimer’s CMAI; CGI-C discontinued early
vs. placebo; 6 disease, due to
weeks vascular or significantly
mixed greater rate of
dementia with adverse events
symptoms of with divalproex,
mania (MMSE especially
mean score somnolence.
7.4)
Burrows et al. Paroxetine (10– N=24; age 80 CSD; Ham-D No significant
2002 30) vs. placebo years and benefit was found
older; with paroxetine
for treatment of
 nonmajor nonmajor
depression depression.
Meehan et al. Olanzapine (2.5– N=204; recruited PANSS-EC*, Significantly
2002 5 IM single from nursing ACES greater mean
dose) vs. home and reduction in
lorazepam vs. hospital sites; PANSS-EC scores
placebo; 24 Alzheimer’s, was seen 2 hours
hours vascular, and postdose for
mixed olanzapine 2.5
Alzheimer’s- and 5 mg vs.
vascular placebo; no
dementia difference was
(MMSE mean found between
score 11.8) olanzapine and
lorazepam;
adverse events
were not
significantly
different across
groups.
Brodaty et al. Risperidone N=345; mean CMAI Compared with
2003 (0.5–2; mean age 83 years; aggression*; placebo group,
0.95) vs. Alzheimer’s, CMAI non- risperidone group
placebo; 12 vascular, or aggression had significant
weeks mixed subscales; improvement on
dementia, with BEHAVE- CMAI total
aggressive AD; CGI-S; aggression and
behavior CGI-C nonaggressive
(MMSE mean agitation scores,
score 5.5) on BEHAVE-AD
total scores and
psychosis
subscale, and on
CGI severity and
change scores.
Risperidone
group had more
somnolence, falls,
urinary tract
infections, and
cerebrovascular
adverse events,
but no drug-
placebo difference
was found in
extrapyramidal
side effects.
De Deyn et al. Olanzapine (1, N=652; NPI-NH No significant
2005 2.5, 5, or 7.5) Alzheimer’s psychosis difference was
vs. placebo; 10 dementia with subscale*; seen between any
weeks psychosis CGI-C*; NPI dose of
(MMSE mean total, olanzapine and
score 13.7) individual placebo on
item, and primary
occupational outcomes. More
disruptiveness weight gain
scores occurred with
olanzapine, but no
difference was
found in
anticholinergic or
extrapyramidal
adverse effects or
dropout rates due
to adverse effects.
Tariot et al. Divalproex (800) N=153; probable BPRS agitation The trial was
2005 vs. placebo; 6 or possible factor*; BPRS completed by
weeks Alzheimer’s total, CGI-C, 72% of enrolled
disease with CMAI subjects. No
agitation significant drug-
placebo
differences were
found on primary
or secondary
outcome
measures.
Mintzer et al. Risperidone (1 N=473; BEHAVE-AD Both groups
2006 or 1.5; mean Alzheimer’s psychosis improved, with no
1.03) vs. dementia with subscale*; significant
placebo; 8 psychosis CGI-C* differences on
weeks (MMSE mean primary outcome
score 12.4) measures.
Subgroup analysis
showed patients
with MMSE < 10
had significantly
greater
improvement on
CGI-C with
risperidone. No
difference in
discontinuation
rates for
risperidone and
 placebo groups
were found, but
risperidone group
had higher rates
of somnolence
(16.2% vs. 4.6%)
and death (3.8%
and 2.5%).
Winblad et al. Donepezil (10) N=248; severe SIB*; ADCS- Significant
2006 vs. placebo; 26 Alzheimer’s ADL severe*; improvement in
weeks disease MMSE; NPI; SIB scores and
(MMSE score CGI-I less decline in
range 1–10) ADL function
were seen in
donepezil group
at 6 months. CGI-
I significant for
donepezil in
completer
analysis only. No
significant
behavioral
benefits were
seen. Rates of
adverse events
were comparable
in drug and
placebo groups,
but more patients
in donepezil
group
discontinued
treatment because
of adverse events.
Mintzer et al. Aripiprazole (2, N=487; mean NPI-NH Aripiprazole 10 mg
2007 5, or 10 fixed age 82.5 years; psychosis group had
dose) vs. Alzheimer’s subscale*; significantly
placebo; 10 dementia with NPI-NH total; greater
weeks psychosis CGI-S; CGI-I; improvement than
(MMSE mean BPRS placebo group on
score 12.4) psychosis, NPI-NH
core and total psychosis scores
score; CMAI; and response
response rates, BPRS core
defined as ≥ and total scores,
50% decrease and CMAI scores.
in NPI score Aripiprazole 5 mg
 group showed
significantly
greater
improvement only
on BPRS and
CMAI.
Aripiprazole 2 mg
was not
efficacious. There
was a dose-
dependent
occurrence of
cerebrovascular
adverse events in
the aripiprazole
groups. Death
rates in the
placebo, 2, 5, and
10 mg groups
were 3%, 3%,
2%, and 7%,
respectively,
although the
differences were
not statistically
significant.
Zhong et al. Quetiapine (100 N=333; PANSS-EC*; No significant
2007 or 200) vs. Alzheimer’s CGI-C; NPI- differences were
placebo; 10 and mixed NH; CMAI found between
weeks dementia quetiapine and
placebo by LOCF
analysis of
PANSS-EC, NPI-
NH, or CMAI
scores at
endpoint.
However,
quetiapine 200
mg (but not 100
mg) was
significantly
better than
placebo on CGI-C
scores and CGI-C
response rates
using both LOCF
and observed case
(OC) analyses and
 on PANSS-EC
using OC
analysis. No
differences were
seen in incidence
of postural
hypotension, falls,
and
cerebrovascular
adverse events.
There were more
deaths with
quetiapine,
although rates
were not
statistically
different from
those with
placebo.
Response defined
as ≥ 40%
reduction in
PANSS-EC, or
much or very
much improved
on CGI-C
Streim et al. Aripiprazole (2, N=256; mean NPI-NH No significant
2008 5, 10, or 15 age 83 years; psychosis difference was
flexible dose Alzheimer’s subscale*; found between
titration) vs. dementia with CGI-S*; NPI- aripiprazole and
placebo; 10 psychosis NH total; placebo on NPI-
weeks (MMSE mean BPRS NH psychosis or
score 13.6) psychosis, CGI-S at
core, and total endpoint.
scores; CMAI; However,
CSDD; NPI significantly
caregiver greater
distress; improvement
ADCS ADL occurred in the
scores; CGI-I aripiprazole group
on secondary
outcomes: NPI
and BPRS total
scores, CMAI,
CGI-I, CSDD.
More somnolence
was seen with
 aripiprazole
(14%) than with
placebo (4%);
other adverse
effects were
similar for
aripiprazole and
placebo, with low
rate of
extrapyramidal
side effects in
both groups.
Response defined
as ≥ 50%
decrease in NPI
scores
Rappaport et Aripiprazole (5– N=129; mean PANSS-EC; Greater
al. 2009 15 IM) vs. age 80 years; ACES improvements
placebo (IM); Alzheimer’s, were seen on
24 hours vascular, mixed PANSS-EC scores
dementia with with aripiprazole
agitation 10 and 15 mg
(MMSE mean than with placebo;
score 13.3) double the
incidence of
adverse events
were seen with
aripiprazole
(50%–60%) than
with placebo
(32%).
Sommer et al. Oxcarbazepine N=103; mean NPI-NH No significant
2009 (300–900) vs. age 83.5 years; agitation and between-group
placebo; 8 Alzheimer’s, aggression differences were
weeks vascular, or subscores; found on any
mixed NPI caregiver outcome
dementia with burden scale; measures.
agitation and BARS
aggression
Note. ACES=Agitation-Calmness Evaluation Scale (Copyright ©1998, Eli Lilly & Company; all rights reserved); ADCS-
ADL=Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (Galasko et al. 1997); ADL=activities of daily
living; BARS=Brief Agitation Rating Scale (Finkel et al. 1993); BEHAVE-AD=Behavioral Pathology in Alzheimer’s Disease
(Reisberg et al. 1996); BPRS=Brief Psychiatric Rating Scale (Overall and Gorham 1962); BRMS=Bech-Rafaelsen Mania Scale
(Bech et al. 1979); BRSD=Behavior Rating Scale for Dementia (by the Consortium to Establish a Registry for Dementia [Mack et
al. 1999]); CDR-SB=Clinical Dementia Rating (Nursing Home Version)–Sum of the Boxes (Hughes et al. 2000); CGI=Clinical
Global Impression Scale (Guy 1976); CGI-C=Clinical Global Impression of Change (Guy 1976; Schneider et al. 1997); CGI-
I=Clinical Global Impression of Improvement (Guy 1976); CGI-S=Clinical Global Impression of Severity (Guy 1976);
CMAI=Cohen-Mansfield Agitation Inventory (Cohen-Mansfield et al. 1989); CSDD=Cornell Scale for Depression in Dementia
(Alexopoulos et al. 1988); FAST=Functional Assessment Staging (Reisberg 1988); GBS=Gottfries-Brane-Steen Geriatric Rating
Scale (Gottfries et al. 1982); GDS=Global Deterioration Scale (Reisberg et al. 1988); Geriatric Depression Scale (Yesavage et al.
1982); Ham-A=Hamilton Anxiety Scale (Hamilton 1959); Ham-D=Hamilton Rating Scale for Depression (Hamilton 1960);
IM=intramuscular; LOCF=last observation carried forward; MADRS=Montgomery-Åsberg Depression Rating Scale (Montgomery
and Åsberg 1979); MMSE=Mini-Mental State Examination (Folstein et al. 1975); NOSIE=Nurses’ Observation Scale for Inpatient
Evaluation (Honigfeld et al. 1966); NPI-NH=Neuropsychiatric Inventory–Nursing Home Version (Wood et al. 2000);
NS=nonsignificant; OAS=Overt Aggression Scale (Yudofsky et al. 1986); PANSS-EC=Positive and Negative Symptom Scale–
Excited Component (Kay et al. 1987); PSMS=Physical Self-Maintenance Scale (Lawton and Brody 1969); SCAG=Sandoz Clinical
Assessment–Geriatric (Shader et al. 1974); SIB=self-injurious behavior.

*Primary outcome measure.

In light of the concerns about risks of antipsychotic drugs in elderly nursing home residents
with dementia, experts in the field have suggested that nonpharmacological approaches should be
considered first when treating noncognitive behavioral symptoms (Blazer 2013). For those nursing
home patients whose behavioral symptoms do not respond to nonpharmacological interventions,
the decision to use an atypical antipsychotic should be based on a careful assessment of each
individual’s risk-benefit profile.
Six randomized clinical trials evaluated the efficacy of mood-stabilizing anticonvulsant drugs
for the treatment of agitation and aggression in nursing home residents. The first was a study of
carbamazepine that showed it to be effective for agitation and aggression but not for psychotic
symptoms such as delusions and hallucinations (Tariot et al. 1998). In this study, nursing reports
indicated that less staff time was required for patient care in the group treated with carbamazepine.
Another trial of carbamazepine found high rates of improvements in both drug- and placebo-
treated patients, with nonsignificant between-group differences (Olin et al. 2001). A subsequent
study of oxcarbazepine failed to show efficacy for treatment of agitation and aggression (Sommer
et al. 2009). Several placebo-controlled studies evaluated divalproex with few encouraging results;
one trial was discontinued before completion because of adverse effects among the drug treatment
group. Overall, these studies failed to provide evidence for efficacy in reducing agitated behavior
(Porsteinsson et al. 2001; Tariot et al. 2001b, 2005). It is noteworthy that the tolerability of
divalproex was limited by somnolence, weakness, and diminished oral intake in this population of
elderly nursing home subjects with dementia.
Acetylcholinesterase inhibitors have been shown to delay the decline in cognitive function in
patients with mild to severe Alzheimer’s disease. Although few studies have been conducted
specifically in nursing home samples, the 2004 NNHS found that of the 49.1% of survey
participants with dementia, 30% were receiving cholinesterase inhibitors (Seitz et al. 2009). One
randomized clinical trial of donepezil in nursing home residents showed effects on cognitive
performance that were comparable with those observed in less impaired outpatients (Tariot et al.
2001a). A subsequent study demonstrated that donepezil improves cognition and preserves
function in Alzheimer’s disease patients with severe dementia who are residing in nursing homes
(Winblad et al. 2006). These studies also examined the effects of donepezil on behavioral
disturbances, as a secondary outcome measure, and did not find significant benefits. Ballard et al.
(2005) compared the effects of quetiapine, rivastigmine, and placebo on agitation and cognition in
nursing home patients with dementia and found that neither drug is effective for the treatment of
agitation and that quetiapine is associated with significantly greater cognitive decline. One study
by Tariot et al. (2004) reported significant improvement on Neuropsychiatric Inventory scores in
patients for whom memantine rather than placebo was added to stable doses of donepezil, but
memantine has not yet been studied prospectively in the nursing home setting. Survival analyses
in an observational study suggest that the addition of memantine to a cholinesterase inhibitor may
delay the time to nursing home placement (Lopez et al. 2009).
There have been only five randomized controlled clinical trials evaluating the effects of
antidepressants in nursing home residents. The first study found no differences in intellectual,
emotional, or functional status in residents with dementia who were treated with alaproclate
(Dehlin et al. 1985). The second study, which was also placebo controlled, showed a positive
response to nortriptyline for treatment of major depression in a long-term-care population with
high levels of medical comorbidity (Katz et al. 1990). In the third study, patients were randomized
to receive regular or low-dose nortriptyline, and significant plasma level–response relationships
were demonstrated in cognitively intact patients (Streim et al. 2000). These findings confirmed the
validity of the diagnosis of depression in nursing home residents in the context of significant
medical comorbidity and disability. However, in patients with dementia, the plasma level–
response relationship was significantly different, suggesting that the depression occurring in
dementia might be a treatment-relevant subtype of depression or a distinct disorder. The fourth, a
controlled antidepressant trial in nursing home residents with late-stage Alzheimer’s disease,
showed no significant benefits of sertraline over placebo (Magai et al. 2000). In the fifth, a
randomized placebo-controlled trial of paroxetine in very old residents with non-major depression,
no significant benefit was found for drug over placebo (Burrows et al. 2002).
Available open-label studies of the efficacy of selective serotonin reuptake inhibitors (SSRIs)
in nursing home residents with depression have had mixed results, some consistent with the
findings of Magai et al. (2000), suggesting that SSRIs may be less effective for depression in
patients with dementia than in those who are cognitively intact (Oslin et al. 2000; Rosen et al.
2000; Trappler and Cohen 1996, 1998). Findings from nonrandomized open-label antidepressant
trials in depressed nursing home residents are summarized in a review by Boyce et al. (2012).
Although the SSRIs might be expected to be well tolerated by frail elderly nursing home
patients because of their side-effect profiles, there is evidence that these drugs can cause serious
adverse events in this population. Thapa et al. (1998) demonstrated that the use of SSRIs was
associated with a nearly twofold increase in the risk of falls among nursing home residents,
comparable with the risk found with tricyclic antidepressant drugs. Investigators in the United
Kingdom reported that antidepressant use was associated with better physical functioning but also
with greater frequency of falls among residential care patients (Arthur et al. 2002). A randomized,
double-blind comparison trial found that venlafaxine was less well tolerated than sertraline in frail
nursing home patients without conferring more treatment benefits, as might be expected from an
agent with mixed serotonergic and noradrenergic effects (Oslin et al. 2003).

History of Deficient Mental Health Care as an Impetus for

Nursing Home Reform
Although psychiatric disorders are extraordinarily common among nursing home residents and
efficacious treatments exist, psychiatric services are often not adequate in these settings.
Historically, nursing home design, staffing, programs, services, and funding have not evolved to
meet the needs of patients with mental disorders (Reichman and Conn 2010; Streim and Katz
1994). In the 1980s, it was estimated that as many as two-thirds of nursing home residents with
psychiatric disorders were misdiagnosed (German et al. 1986; Sabin et al. 1982) and that as little
as 5% of nursing home residents’ needs for mental health services were being met (Burns and
Taube 1990). This mismatch of psychiatric needs and available treatment led not only to neglect
but also to inappropriate treatment; psychiatric problems were often mismanaged by using
physical or chemical restraints.

Physical Restraints
The 1977 NNHS showed that 25% of 1.3 million U.S. nursing home residents were restrained by
geriatric chairs, cuffs, belts, or similar devices, primarily in an attempt to control behavioral
symptoms (National Center for Health Statistics 1979). Other early surveys demonstrated rates of
restraint as high as 85%. Patient factors predicting the use of restraints, in addition to agitation and
behavior problems, include age, cognitive impairment, risk of injuries to self (e.g., from falls) or
others (e.g., from combative behavior), physical frailty, the presence of monitoring or treatment
devices, and the need to promote body alignment. Institutional and systemic factors associated
with restraint use include pressure to avoid litigation, staff attitudes, insufficient staffing, and the
availability of restraint devices. Potential adverse effects include an increased risk of falls and
other injuries (Capezuti et al. 1996) as well as functional decline, skin breakdown, physiological
effects of immobilization stress, disorganized behavior, and demoralization. Although mechanical
restraints have frequently been used in attempts to control agitation, they do not in fact decrease
behavioral disturbances (Werner et al. 1989), and cross-national studies indicated that nursing
home residents can be managed without such measures (Cape 1983; Evans and Strumpf 1989;
Innes and Turman 1983).

Misuse of Psychotropic Drugs

Concerns about inadequate and inappropriate care have also focused on the overuse of
psychotropic drugs in nursing home residents, especially the misuse of these drugs as chemical
restraints to control patient behaviors. Studies in the 1970s and 1980s reported that approximately
50% of residents had orders for psychotropic medications, with 20%–40% being given
antipsychotic drugs, 10%–40% given anxiolytics or hypnotics, and 5%–10% given antidepressants
(Avorn et al. 1989; Beers et al. 1988; Buck 1988; Burns et al. 1988; Cohen-Mansfield 1986;
Custer et al. 1984; DeLeo et al. 1989; Ray et al. 1980; Teeter et al. 1976; Zimmer et al. 1984).
Psychotropic drugs were frequently prescribed without adequate regard for the residents’
psychiatric diagnosis or medical status. In one study, Zimmer et al. (1984) reported that only 15%
of residents being given psychotropic drugs had received a psychiatric consultation. Other studies
reported that 21% of patients without a psychiatric diagnosis were receiving psychotropic
medication (Burns et al. 1988), that physicians’—as opposed to patients’—characteristics
predicted drug dosages (Ray et al. 1980), and that psychotropic drugs were often prescribed in the
absence of any documentation of the patient’s mental status in the clinical record (Avorn et al.
1989).
The greatest concerns about inappropriate overprescribing of medications originally related to
the misuse of antipsychotic drugs as chemical restraints to control resident behaviors. In light of
subsequent concerns about balancing safety and efficacy of antipsychotic drugs in managing
psychosis and agitation in nursing home residents with dementia, it is now apparent that patients
with nonpsychotic behavioral problems may be more appropriately managed with other
medications, behavioral treatments, interpersonal approaches, or environmental interventions.
Moreover, it is important to note that whereas all the evidence for the efficacy of antipsychotic
medications comes from short-term studies, these medications are frequently prescribed for long-
term treatment. In this context, concerns about overuse of antipsychotic medications were
supported by findings from drug discontinuation studies (see “Pharmacotherapy” above). One
classic double-blind study of antipsychotic withdrawal showed that only 16% of patients who had
been receiving medications on a chronic basis exhibited significant deterioration when the drugs
were withdrawn (Barton and Hurst 1966). A subsequent small-scale withdrawal study in patients
who had been receiving antipsychotic drugs for several months showed that 22% experienced
increased agitation on withdrawal, indicating benefit from continued treatment, but that 22% were
unchanged and 55% actually showed improvement (Risse et al. 1987).

Inadequate Treatment of Depression

Although the focus of public concern and regulatory scrutiny in the 1970s and 1980s was on
overprescription of antipsychotic medications in patients with dementia, undertreatment of other
psychiatric conditions in the nursing home has also been a serious problem. In a report that did
much to stimulate nursing home reform, the Institute of Medicine Committee on Nursing Home
Regulation (1986) highlighted problems both in the overuse of antipsychotic drugs and in the
underuse of antidepressants for treatment of affective disorders. Similarly, in reviewing
epidemiological studies on the use of psychotropic medications in nursing homes, Murphy (1989)
noted that antidepressants were the one class of drugs that appeared to be underused and that, as a
result, major depression in this setting often remained untreated during the 1970s and 1980s.
Before 1990, fewer than 15% of residents with a known diagnosis of depression were receiving
antidepressant medication (Heston et al. 1992).

Federal Regulations and Psychiatric Care in the Nursing Home

The misuse of physical and chemical restraints was a rallying point for advocacy groups that
urged the federal government to institute a process of nursing home reform. In addition, the U.S.
General Accounting Office was concerned that states were admitting patients with chronic and
severe psychiatric problems to Medicaid-certified nursing homes not because patients needed this
type of care but because admission would shift a substantial portion of the costs of patients’ care
from the state to the federal government. Apparently in response to both sets of concerns,
Congress enacted the Nursing Home Reform Act as part of the Omnibus Budget Reconciliation
Act of 1987(OBRA-87, P.L. 100-203). This legislation provided for government regulation of the
operation of nursing facilities and of the care that they provide (Elon and Pawlson 1992). This
legislation directed the Health Care Financing Administration—reorganized and renamed in 2001
as the Centers for Medicare and Medicaid Services (CMS)—to issue regulations (Health Care
Financing Administration 1991) that operationalize the laws and to develop guidelines (Centers
for Medicare and Medicaid Services 2014) that assist federal and state surveyors in interpreting
the regulations and determining whether nursing facilities are in compliance. The regulations and
survey process were implemented in 1990. Mental health screening, assessment, care planning,
and treatment are addressed under sections of the regulations that pertain to resident assessment,
resident rights and facility practices, and quality of care (Health Care Financing Administration
1991, 1992a, 1992b).
The regulations include provisions for preadmission screening and annual resident review that
require assessment of each resident before admission to any nursing facility that receives federal
funds (Health Care Financing Administration 1992a). When an initial first-stage screening reveals
that a serious mental disorder (other than dementia) might be present, a second-stage assessment
that includes a psychiatric evaluation must be made to ascertain whether the patient has a mental
disorder, to make a specific psychiatric diagnosis, and to determine whether there is a need for
acute psychiatric care that precludes adequate or appropriate treatment in a nursing home. Patients
found to have dementia on the initial screen are exempt from the preadmission psychiatric
evaluation. Thus, preadmission screening is intended 1) to prevent inappropriate admission to
nursing homes of patients who do not have dementia but who have severe psychiatric disorders
and 2) to help ensure that patients with disabilities due to treatable psychiatric disorders are not
placed in long-term-care facilities before they receive the benefits of adequate psychiatric
treatment.
For eligible patients who are admitted to a nursing home, an annual reassessment must be made
to determine whether nursing home care remains appropriate. Regulations requiring
comprehensive assessment for all residents (Health Care Financing Administration 1991) have led
to development of a uniform Resident Assessment Instrument, which includes the Minimum Data
Set (MDS) (Centers for Medicare and Medicaid Services 2013; Morris et al. 1990). An updated
version of the MDS, Version 3.0, was implemented in 2010 (Centers for Medicare and Medicaid
Services 2006; Saliba et al. 2012). Members of an interdisciplinary health care team must
administer this instrument on at least a quarterly basis and report results to CMS (Health Care
Financing Administration 1992c). Areas of assessment relevant to mental health include hearing,
speech, and vision; cognitive patterns; mood; behavior; functional status; health conditions;
swallowing and nutritional status; medications; special treatments and procedures (including
rehabilitative, respite, and hospice care); and restraints. Responses on the MDS may indicate
changes in a patient’s clinical status that warrant further evaluation and possible need for changes
in the care plan. Changes in a resident’s status may trigger requests for psychiatric consultation.
Regulations related to resident rights and facility practices restrict the use of physical restraints
and antipsychotic drugs when they are “administered for purposes of discipline or convenience
and not required to treat the resident’s medical symptoms” (Health Care Financing Administration
1991, p. 48,875). Regulations related to quality of care further require that residents not receive
“unnecessary drugs” and that antipsychotic medications not be given “unless these are necessary
to treat a specific condition as diagnosed and documented in the clinical record” (p. 48,910). An
unnecessary drug is defined as any drug used 1) in excessive dose (including duplicate therapy),
2) for excessive duration, 3) without adequate monitoring, 4) without adequate indications for its
use, 5) in the presence of adverse consequences that indicate that it should be reduced or
discontinued, or 6) for any combination of the first five reasons (Health Care Financing
Administration 1991). The surveyor guidelines based on these regulations further limit the use of
antipsychotic medications, antianxiety agents, sedative-hypnotics, and related medications
(Centers for Medicare and Medicaid Services 2014). For each of these classes, the guidelines
specify a list of acceptable indications, upper limits for daily dosages, requirements for monitoring
treatment and adverse effects, and time frames for attempting dosage reductions and
discontinuation. These guidelines are periodically updated to reflect new clinical knowledge and
the availability of new drugs approved by the FDA, with a recent revision posted to the CMS Web
site in 2014 (Centers for Medicare and Medicaid Services 2014).
To minimize concerns about federal interference with medical practice, the current guidelines
include qualifying statements that recognize cases in which strict adherence to prescribing limits
or gradual dosage reduction or discontinuation is “clinically contraindicated.” Although the focus
is on limiting the use of psychotropic drugs, the guidelines acknowledge that appropriate medical
treatment can entail continuing treatment with psychotropic medications. Thus, the physician’s
options for treating nursing home residents need not be unduly restricted by the regulations if the
clinical rationale—explaining that the benefits of treatment (in terms of symptom relief, improved
health status, or improved function) outweigh the risks—is clearly documented in the medical
record. Although the facility, not the physician, is accountable for compliance with the
regulations, the physician’s clinical reasoning and judgment play a critical role in the process of
ensuring quality care.
In addition to addressing the use of psychotropic drugs, the interpretive guidelines also outline
conditions for the use of physical restraints. According to the guidelines, restraints are not
permitted unless there is documentation that their use is necessary to enable the resident to achieve
or maintain the highest practicable level of function. Physical or occupational therapists should be
consulted and should provide documentation if restraints are deemed necessary to enhance body
positioning or improve mobility.
Although much of the emphasis of the federal regulations is on eliminating inappropriate
treatment, requirements also call for the provision of necessary and appropriate care for residents
with mental health problems. Under the provisions designed to ensure quality of care, federal
regulations define a need for geriatric psychiatry services in nursing homes, requiring that “the
facility must ensure that a resident who displays mental or psychosocial adjustment difficulties
receives appropriate services to correct the assessed problem” (Health Care Financing
Administration 1991, p. 48,896).
In 1999, twelve years after the nursing home reform amendments were passed into law by
Congress, the Health Care Financing Administration developed quality indicators derived from
resident assessment data (Nursing Home Quality Indicators Development Group 1999) to provide
surveyors with benchmarks for measuring and comparing the quality of care provided by
individual nursing homes. In 2002, CMS expanded these efforts by introducing the Nursing Home
Quality Initiative, which derives quality measures from regularly reported MDS data and posts
these on the Medicare.gov Web site in a program called Nursing Home Compare (Medicare.gov
2014a). This publicly accessible Web site enables health care consumers to compare the quality of
care delivered by individual facilities in the same region or across the nation. At the time this book
chapter was written, five short-stay quality measures and 13 long-stay quality measures were
posted. Quality measures that are directly or may be indirectly relevant to mental health of nursing
home residents are listed in Table 25–3. These measures include the percentage of residents
experiencing moderate to severe pain, falls with injuries, depressive symptoms, weight loss,
increased need for help with ADLs, physical restraint, and receipt of antipsychotic medication.
In 2007, CMS also began a national rollout of the Quality Indicator Survey, which was
designed to make the nursing home survey process more resident centered, comprehensive, and
consistent (Lin and Kramer 2013). Whenever a state survey finds that a percentile threshold has
been exceeded in any of these areas, it can result in a citation of deficiency for a nursing home.
The facility is then required to develop and submit a plan of correction for approval by the state
licensing agency. This system represents an advance in monitoring quality of care and promoting
cultural change in U.S. nursing homes, although the limits of risk adjustment for some of the
quality indicators has been questioned, and the results of quality surveys may be difficult to
interpret. Nevertheless, the aforementioned Nursing Home Quality Initiative is widely considered
to represent a major step forward in measurement-based care and public access to quality data.

Changing Patterns of Psychiatric Care

Since the passage of the Nursing Home Reform Act in 1987, and the implementation of the
resultant regulations in 1990, there have been significant changes in nursing home care, including
mental health care. Some of these changes may be attributed to the process of conducting surveys
and enforcing federal regulations. However, several other factors appear to have contributed,
including the dissemination of information about regulatory requirements, availability and
marketing of new medications, advances in scientific knowledge from nursing home research, and
cumulative effects of professional education regarding patient safety and good clinical practice.
Public reporting of quality measures and increasing consumer awareness are also likely to be
playing a role.
TABLE 25–3. Centers for Medicare and Medicaid Services Nursing Home Quality Measures
with relevance to mental health of residents
Short-stay quality measures
Percentage of residents who self-report moderate to severe pain
Percentage of short-stay residents who newly received an antipsychotic medication
Long-stay quality measures
Percentage of residents experiencing one or more falls with major injury
Percentage of residents who self-report moderate to severe pain
Percentage of residents who were physically restrained
Percentage of residents whose need for help with activities of daily living has increased
Percentage of residents who lose too much weight
Percentage of residents who have depressive symptoms
Percentage of long-stay residents who received an antipsychotic medication
Source. Medicare.gov 2014a.

Shifts in Antipsychotic Medication Use

Studies of the effect of federal regulations in the early years after implementation showed a
substantial decline in the use of antipsychotic drugs (Shorr et al. 1994) and physical restraints
(Hawes et al. 1997) and increases in antidepressant use (Lantz et al. 1996). Between 1991 and
1997, a 52.2% decrease (from 33.7% to 16.1%) in the use of antipsychotic medications was
reported (Hughes et al. 2000). One study reported that greater reductions in antipsychotic use
during this period were found in nursing facilities with an emphasis on psychosocial care, a less
severe case mix, and a higher nurse-to-resident ratio (Svarstad et al. 2001). Soon after the
regulations were introduced, several investigators developed educational programs for physicians,
nurses, and aides to teach practice principles consistent with federal guidelines. Studies evaluating
these educational interventions demonstrated reductions of 23%–72% in the use of antipsychotic
drugs (Avorn et al. 1992; Meador et al. 1997; Ray et al. 1993; Rovner et al. 1992; Schnelle et al.
1992). In the study showing the most substantial reductions, the frequency of behavior problems
was not found to increase (Ray et al. 1993). Studies of the appropriateness of antipsychotic use
examining documentation of CMS-approved diagnostic indications and appropriate target
symptoms, and dosing within the recommended limits in the surveyor guidelines, suggested
relatively high rates of compliance with the federal regulations (Llorente et al. 1998; Siegler et al.
1997).
Although the changes found by the studies were generally interpreted as an indication of
improvement in care, the studies did not examine health care outcomes or effects on residents’
quality of life (Snowden and Roy-Byrne 1998) and did not address concerns that reductions in
medication use might have an adverse effect on patients who required antipsychotic treatment,
such as those with a diagnosis of chronic schizophrenia or mood disorder with psychosis. A
retrospective study in a single nursing facility, which described attempts to discontinue or lower
the dosage of antipsychotic drugs in 75% of subjects studied, found that residents with appropriate
indications for antipsychotic use according to the federal regulations were significantly less likely
to have their antipsychotic agents stopped (Semla et al. 1994). Nevertheless, for 20% of residents
whose antipsychotic was discontinued or reduced in dosage, the agent was subsequently resumed
or its dosage was increased. This result, which is consistent with reports from earlier
discontinuation studies, suggests that the finding of a reduction in overall rates of antipsychotic
use may reflect a beneficial trend for a majority of patients, but this result cannot be interpreted as
an indication of across-the-board improvement in the quality of residents’ care (Lantz et al. 1996).
In contrast to the declining rates of antipsychotic use in the early 1990s, Online Survey
Certification and Reporting (OSCAR) data showed a reversal in this trend from 1995 to 1999,
with the national rate for antipsychotic drug use in nursing homes increasing from 16% to 19.4%
during that period (American Society of Consultant Pharmacists 2000). Despite this increase, a
survey conducted by the Office of the Inspector General of the Department of Health and Human
Services, using data from the year 2000, found that psychotropic drugs were appropriately
prescribed in 85% of 485 cases reviewed (Office of Inspector General 2001c).
However, the findings of the Office of the Inspector General are contradicted by a large
retrospective analysis of Medicare databases merged to MDS assessments from the same time
period (Briesacher et al. 2005). In this analysis, 27.6% of all Medicare beneficiaries in nursing
homes received antipsychotic medications between 2000 and 2001; of the treated patients, only
41.8% received antipsychotic therapy within federal prescribing guidelines. A cross-sectional
analysis of the 2004 NNHS similarly identified that 26% of nursing home residents in the survey
received antipsychotic medication, and 40% of these cases were without appropriate indications
for antipsychotic use (Stevenson et al. 2010).
The increased rates of antipsychotic medication use, coupled with the safety concerns related to
the risk of cerebrovascular adverse events and mortality, have prompted a closer look at
alternatives to antipsychotic drug treatment of behavioral disturbances in nursing home residents
with dementia. A study by Fossey et al. (2006), conducted in the wake of the safety findings
described earlier in this chapter (see “Pharmacotherapy”), examined 12-month outcomes of an
intervention that provided training and support to nursing home staff in psychosocial approaches
for managing agitated behavior associated with dementia. The rate of antipsychotic medication
use was 19.1% lower in the intervention homes, with no significant differences in the level of
agitated or disruptive behavior between intervention and control facilities. Thus, it appears that a
significant proportion of residents may be managed with less risk without a concomitant increase
in behavioral problems.
Over the past decade, CMS has also contracted with the Quality Improvement Organizations
(QIOs, which are private, not-for-profit entities formerly called Peer Review Organizations) in all
50 states, the District of Columbia, Puerto Rico, and the U.S. Virgin Islands to promote
population-based quality improvement in nursing home care (Rollow et al. 2006; Stevenson and
Mor 2009). In 2012, CMS launched a National Partnership to Improve Dementia Care, which uses
a multidimensional approach to reduce the inappropriate use of antipsychotic drugs in these
settings (Medicare.gov 2014b). As a component of this partnership, the scope of work for QIOs
currently involves extensive dementia care training for nursing home staff, supported by training
materials that focus on nonpharmacological management of dementia-related behaviors. Data
from this period, reported on the Nursing Home Compare Web site, reveal a 9% decline in the
national rate of antipsychotic use from 23.9% at the end of 2011 to 21.7% at the beginning of
2013. State-level data for this period show reductions ranging from 2.3% to 23.3%.

Increase in Antidepressant Drug Use

Despite the decline in use of antipsychotic drugs in the early 1990s, the overall use of
psychotherapeutic medications in U.S. nursing homes actually increased, from 21.7% in 1991 to
46.1% in 1997 (Health Care Financing Administration 1998). This increase was partly attributable
to a rise in the use of antidepressants from 12.6% to 24.9% (a 97.6% increase) during that period.
During the same period in the United Kingdom, rates of antidepressant use also increased by 72%,
from 11% in 1990 to 18.9% in 1997 (Arthur et al. 2002). From the mid-1990s to the mid-2000s,
the prevalence of antidepressant medication use in the United States more than doubled again. A
study of 12 Pennsylvania nursing homes found that 47.6% of residents were taking
antidepressants (Datto et al. 2002). OSCAR data showed that this was part of a national trend,
with more than 12,000 U.S. nursing homes reporting an increase in antidepressant prescribing:
from 21.9% in 1996, to 35.5% in 2001, to 47.5% in 2006 (American Society of Consultant
Pharmacists 2000; Hanlon et al. 2010). The 2004 NNHS found that the overall prevalence of
antidepressant use among elderly nursing home residents was 46.2%, with half of users age 85
years or older (Karkare et al. 2011). The most prescribed class of antidepressants was SSRIs
(31.1%), followed by serotonin modulators (4.7%), serotonin-norepinephrine reuptake inhibitors
(2.8%), tricyclic antidepressants (2.3%), and monoamine oxidase inhibitors (0.01%).
Considered together, these data represent an extraordinary change in the pattern of drug use in a
population that traditionally received inadequate pharmacotherapy for depression. The dramatic
increase in antidepressant prescriptions is probably due in part to the wide availability of newer
antidepressants that are perceived to be safer and better tolerated among elderly nursing home
residents with medical and psychiatric comorbidity. Education of primary care physicians about
the morbidity, disability, mortality, and costs associated with untreated depression may also have
played a role, as well as aggressive marketing by pharmaceutical companies. With current
antidepressant drug use rates that appear comparable to or greater than the estimated prevalence of
depression among nursing home residents, it is possible that a significant proportion of
antidepressant prescriptions are intended for indications other than depression, such as sleep, pain,
anxiety, or agitation. Research is needed to determine whether the reported changes in prescribing
have had a positive effect on the mental health of nursing home residents with depression.

Decline in Physical Restraint Use

Although the early effects of federal nursing home regulations on trends in psychotropic drug use
during the 1990s were difficult to discern (Lantz et al. 1996), the effect of the federal regulations
on restraints appeared to be uniformly positive, with several studies showing significant
reductions in the use of physical restraints (Castle et al. 1997). One study found restraint use rates
of 37.4% in 1990 (before OBRA-87 implementation in October 1990) and 28.1% in 1993 (after
introduction of the standardized Resident Assessment Instrument required by OBRA-87) (Hawes
et al. 1997). Siegler et al. (1997) found that restraint use could be significantly reduced without a
resultant increase in antipsychotic or benzodiazepine use. There is no published evidence of an
increase in fall-related injuries associated with lower rates of physical restraint use.

Special Care Units

Encouraged by consumer demand to better meet the needs of nursing home residents with
dementia, 10% of U.S. nursing homes had established special care units (SCUs) by 1991. A
decade later, it was estimated that 22% of nursing homes had designated SCUs for patients with
dementia. In the 2004 NNHS, 23.8% of facilities reported having special programs for the
management of behavior problems, although not all of these were provided exclusively on a
dedicated SCU (National Center for Health Statistics 2004). In an effort to characterize the
population served by these units, Holmes et al. (1990) reported that SCU patients had more severe
cognitive, behavioral, and functional deficits than non-SCU patients with dementia who lived in
the same nursing home. More than 90% of residents in SCUs have behavior problems (Wagner et
al. 1995).
Research on the effectiveness of SCUs is difficult to interpret and generalize because of the
heterogeneity of these facilities (Office of Technology Assessment 1992; Ohta and Ohta 1988),
lack of adjustment for differences between comparator groups, and the absence of any randomized
controlled trials (Lai et al. 2009). Some studies indicate that the facilities, services, and programs
offered by SCUs may not be significantly better than those available on conventional nursing
home units. A study of Minnesota nursing homes described unit and facility characteristics, noting
that the designation of SCU was not associated with more services or more individualized
dementia care than were units without the designation; however, the study found that some
dementia-specific features were less likely to be found in regular units of nursing homes that had
designated SCUs (Grant et al. 1995).
A case-control study of 625 patients in 31 SCUs and 32 traditional units found that residence in
an SCU was associated with reduced use of physical restraints but not with less use of so-called
pharmacological restraints (Sloane et al. 1991). A subsequent study that included data on more
than 1,100 residents in 48 SCUs reported that the use of physical restraints was not different and
that the likelihood of psychotropic medication use was actually greater for patients on SCUs than
for their counterparts on traditional units (Phillips et al. 2000). A study of 430 patients with
dementia residing in Alzheimer SCUs and traditional nursing facilities in Italy found lower odds
of physical restraint use and higher rates of withdrawal from antipsychotics in the SCU group,
with no differences in falls, hospitalization rates, or mortality (Nobili et al. 2008). Although
Saxton et al. (1998) reported evidence suggesting that mobility may be maintained for longer
periods of time among residents of SCUs, Phillips et al. (1997) found that the rate of decline in
ADL function is not significantly slower for SCU residents. Studies showing benefits of SCUs for
behavioral disturbances are limited, although one randomized clinical trial reported a reduced
frequency of catastrophic reactions (Swanson et al. 1993)—sudden agitated behavior in response
to overwhelming external stimuli—as a positive outcome for residence on a dementia SCU. Some
studies have demonstrated psychological benefits not only for SCU patients (Lawton et al. 1998)
but also for caregivers (Kutner et al. 1999; Wells and Jorm 1987), with evidence of increased
family involvement (Hansen et al. 1988; Sloane et al. 1998).
Studies have also examined the extent to which agitation is associated with aspects of the
treatment environment in SCUs. Independent correlates of low agitation levels in these units
included low rates of physical restraint use, a high proportion of residents in bed during the day,
small unit size, fewer comorbid conditions, low levels of functional dependency, and favorable
scores on measures of physical environment and unit activities. Despite the efforts of these
investigators, knowledge about the essential elements of treatment in SCUs remains insufficient,
and evidence for the effectiveness of these units has not been adequately demonstrated (Lai et al.
2009).

Subacute Care in Nursing Homes

Since 1983, when the Medicare Prospective Payment System established reimbursement for acute
care hospitals on the basis of diagnosis-related groups rather than number of inpatient days,
hospitals have had a strong incentive to limit lengths of stay by discharging patients earlier. In the
1990s, Medicare reimbursement rates for the first 100 days of nursing home care, computed
according to the Resource Utilization Groups system, were substantially higher for short-stay
patients who received rehabilitation services than for long-term-care patients. Thus, nursing
homes had an incentive to admit a higher proportion of short-stay patients with subacute
rehabilitation needs. This combination of financial incentives for early hospital discharge to
nursing homes serving as step-down facilities that provide subacute medical treatment,
convalescent care, and rehabilitation services resulted in significant increases in Medicare costs
for subacute care patients in the nursing home setting. Alarm about the increase in spending
occurring in the late 1990s prompted changes in Medicare reimbursement that resulted in dramatic
reductions in payments to nursing homes from the late 1990s onward.
In general, short-stay nursing home residents—patients who, after relatively brief stays in
nursing homes, are discharged to the community or die—differ from long-term-care patients in
that they are younger; more likely to be admitted directly from an acute care hospital; less likely to
have irreversible cognitive impairment, incontinence, or ambulatory dysfunction; and more likely
to have a primary diagnosis of hip fracture, stroke, or cancer. The objectives of mental health care
for short-stay patients are related not so much to managing behavior problems associated with
dementia as to helping patients cope with disease and disability, to searching for delirium and
reversible causes of cognitive impairment, and to treating disorders such as depression and anxiety
that can be impediments to rehabilitation and recovery. A high prevalence of potentially treatable
neuropsychiatric symptoms—including depression in 33%, nighttime disturbances in 19%,
anxiety in 15%, and irritability and disinhibition in 12%—was found in poststroke patients who
could not be successfully discharged from the nursing home where they received subacute
rehabilitative care (Buijck et al. 2012). In short, the objectives of mental health care for these
patients are similar to goals of traditional consultation-liaison psychiatry in the general hospital.
As the opportunities for psychiatric intervention follow these patients from the acute care hospital
into the nursing homes, the services required may need to be more frequent or intensive than those
usually available to long-term-care residents. A study by Lenze et al. (2012) demonstrated benefits
of applying motivational and behavioral skills for physical and occupational therapists to improve
patient engagement, therapy intensity, and functional outcomes for older adults in postacute
rehabilitation. For subacute care patients in nursing homes, an investment in psychiatric care can
lead to improved participation in rehabilitation efforts, with more efficient recovery and return to
independent functioning and a higher likelihood of successful discharge to the community.

Adequacy of Mental Health Care

The high prevalence of psychiatric problems and the federal mandate to ensure quality of care
define a need for geriatric mental health services in nursing homes (Smith et al. 1990). Although
the OBRA-87 regulations are having the intended impact (Snowden and Roy-Byrne 1998) and
have resulted in measurable improvements in several aspects of patient care, concurrent
improvements in access to mental health care, receipt of appropriate care, or improved mental
health outcomes have not been seen. Medicare claims data from 1992, two years after
implementation of the Nursing Home Reform Act of 1987, indicated that only 26% of all nursing
home residents and 36% of residents with a mental illness received psychiatric services (Smyer et
al. 1994). Although Medicare payments for psychiatric services in nursing facilities increased in
the mid-1990s, expenditures declined from $221 million in 1996 to $194 million in 1999 (Office
of Inspector General 2001a). Evidence since then shows continued low levels of mental health
treatment in nursing homes (Reichman and Conn 2010; Shea et al. 2000).
Historically, part of the problem has been attributable to poor case identification. Borson et al.
(1997) found that the required preadmission assessment is inadequate for identifying nursing
home applicants who require mental health services. Some of this lack of identification is because
patients with dementia are exempt from initial psychiatric evaluation; therefore, a large number of
patients with behavioral and psychological symptoms of dementia are not identified. Although
88% of patients in the sample in this study were appropriately placed on the basis of their personal
and nursing care needs, 55% had unmet mental health needs. As described earlier in this chapter
(see “Prevalence of Psychiatric Disorders”), individuals with serious mental illness constitute an
increasing proportion of admissions to nursing homes for subacute care (Fullerton et al. 2009),
and despite a relatively low level of skilled nursing care needs, they are more likely to become
long-stay residents (Aschbrenner et al. 2011b). Aschbrenner et al. 2011a) have suggested that a
substantial number of adults with serious mental illness residing in nursing homes may have the
functional capacity to live in less restrictive environments.
Also, for nearly two decades, there were concerns that the required periodic assessments using
the MDS Version 2.0 after admission did not provide adequate detection of depression (Brown et
al. 2002; McCurren 2002; Office of Inspector General 2001b; Schnelle et al. 2001; Snowden
2004). McCurren (2002) found poor correlation between the MDS 2.0 mood disturbance items
and the Geriatric Depression Scale, a well-validated screening instrument for depression in older
individuals. In examining the data from 1,492 nursing homes across five states, Brown et al.
(2002) found that 11% of residents were identified on the MDS as depressed, half the rate that was
expected on the basis of epidemiological studies that used direct clinical assessments.
Ruckdeschel et al. (2004) subsequently showed evidence to support the use of a self-report
approach to detection of depression by the MDS. This led to the eventual testing, validation, and
adoption of the 9-item depression scale of the Patient Health Questionnaire (PHQ-9) as the
standardized measure of mood that is currently embedded in MDS 3.0 (Saliba et al. 2012). This
newer version of the MDS was shown to perform better than MDS 2.0 and better than the
Geriatric Depression Scale for detection of clinical depression among nursing home residents. It is
hoped that improved measurement of depression will lead to improved rates of treatment and
remission. However, in the study by Brown et al. (2002), of the 11% of residents identified by
MDS as depressed, only 55% received antidepressant therapy. Thus, expected improvements in
detection of mental disorders will not, by themselves, necessarily lead to improved rates of
treatment.
Limited access to care appears to be a significant part of the problem. In a survey of nursing
homes across six states conducted by Reichman et al. (1998), 47.6% of 899 respondents indicated
that the frequency of on-site psychiatric consultation was inadequate. The 2004 NNHS similarly
reported that only 40.4% of nursing homes had mental health services available at the facility, and
only 48.5% had formal contracts for psychology or psychiatry services (National Center for
Health Statistics 2004). Directors of nursing judged 38% of nursing home residents as needing a
psychiatric evaluation, but more than one-fourth of rural facilities and more than one-fifth of small
facilities reported that no psychiatric consultant was available to them. Meeting the demand for
mental health treatment may also be more difficult for nursing facilities that are part of a chain or
that contain Medicaid beds (Castle and Shea 1997). Thus, evidence indicates that the federal
requirement that patients receive services to “attain or maintain the highest practicable physical,
mental, and psychosocial well-being” (Health Care Financing Administration 1991, p. 48910) has
not remedied the problem of access to mental health services in U.S. nursing homes (Colenda et
al. 1999; Grabowski et al. 2010). Despite this evidence for the continuing lack of available
services, the Office of Inspector General reported in 2001 that 27% of mental health services
provided in nursing homes and paid for by Medicare were “medically unnecessary” (Office of
Inspector General 2001a). It is important to recognize, however, that many of the services
identified as resulting in “inappropriate” payments were specifically for excessive psychological
testing and group psychotherapy for patients with severe cognitive impairment who were
determined by reviewers to be incapable of benefiting from these specific procedures. This survey
by the Office of Inspector General did not examine the adequacy of appropriate, medically
necessary psychiatric care.
Evidence shows that even among patients whose mental disorders are recognized and for
whom treatment is initiated, treatment is often inadequate. The report by Brown et al. (2002)
indicated that of nursing home residents known to be depressed and receiving antidepressants,
32% were taking dosages lower than the manufacturers’ recommended minimum effective dosage
for treating depression. In a survey of 12 nursing homes, Datto et al. (2002) found that 47% of
patients were taking antidepressants but that nearly half of these patients were still depressed.
Although a small proportion of these residents may have been in the early stages of treatment,
before a treatment response could reasonably be expected, it appears likely that many residents did
not receive proper follow-up care with required dosage adjustments or changes in therapy for
those who were not responsive to initial treatment. This finding points to a need for improved
adherence to practice guidelines for follow-up care to achieve remission of depression symptoms.
A more comprehensive treatment of this subject is available in the consensus recommendations
for improving the quality of mental health care in nursing homes (American Geriatrics Society
and American Association for Geriatric Psychiatry 2003).

Mental Health Care in Nursing Homes: A Model for Service

Delivery
The high prevalence of psychiatric disorders in nursing homes argues for the importance of
establishing systems that incorporate mental health into the basic services provided (Borson et al.
1987). In addition, the following factors attest to the importance of the professional components of
care: 1) the complex nature of the psychiatric disorders exhibited by nursing home residents, 2)
the need to evaluate medical as well as social and environmental factors as causes of mental health
problems, 3) the potential benefits of specific treatments, and 4) the need for careful monitoring to
assess treatment responses and prevent serious adverse effects of medications. Thus, clinical needs
demand that mental health services in nursing homes have two distinct but interacting systems:
one that is intrinsic to the facility and is contextual, and another that is professional and is
concerned primarily with the delivery of specific treatments.
It has been suggested that mental health training should be provided to facility staff to develop
basic skills in assessment and clinical management that can help staff handle problems that occur
when specific professional services are lacking. However, it is important to recognize that the
intrinsic and the professional systems cannot readily replace each other and that adequate care
requires both. Although there is a real need for staff training, a realistic goal is to develop staff
skills that complement rather than replace the activities of mental health professionals. This two-
system model has obvious implications with respect to the financing of mental health services in
nursing homes: it demonstrates the need to fund mental health care both as a necessary part of the
per diem costs of nursing home care and as a reimbursable professional service.
Although the intrinsic and the professional systems for mental health services are distinct, they
must interact: geriatric psychiatrists and psychologists and geropsychiatric nurse practitioners can
play important intrinsic roles as administrative and staff consultants, in-service educators,
moderators of case conferences, participants in interdisciplinary team meetings, and contributors
in other activities familiar to the consultation-liaison psychiatrist. Facility staff must be effective
in recognizing problems, facilitating referral, supporting treatment, and monitoring outcome to
enable the professional system to function optimally.
Intrinsic System
The intrinsic system of mental health care in nursing homes can be conceptualized as including a
wide range of components: design of the environment; implementation of psychosocial programs;
formulation of institutional policies and procedures for assessment, care delivery, monitoring, and
quality improvement; and optimization of the ways in which staff and residents interact. The
importance of the intrinsic system is recognized in nursing home regulations that require training
of nursing aides; in the nursing staff assessments required for completion of the MDS; and in
OBRA-87 requirements that nursing homes provide assessments, treatment planning, and services
to attain or maintain the highest practicable level of mental and physical well-being for each
resident. Because psychiatric disorders are common in nursing homes, nurses and aides should be
knowledgeable about the nature of the cognitive and functional deficits associated with dementia
and the manifestations of delirium and depression. Staff members should understand how to
modify their approach to working with residents when cognitive impairment or communication
deficits interfere with care. Staff should also know how to apply basic principles of behavioral
psychology to identify the causes of agitation and related behavioral symptoms in patients with
dementia as well as how to plan environmental and behavioral interventions.
A number of approaches to providing such staff training have been developed. Evaluation
studies have demonstrated that improved mental health care through staff training is an attainable
goal and have identified barriers that must be overcome (Smyer et al. 1992). As mental health care
is incorporated into the basic fabric of the nursing home, it must include provisions for patients
with variable degrees of cognitive impairment and depression in both the extent of residents’
autonomy, staff supervision and assistance, and the design of activities.
The concept that key components of mental health services should be intrinsic to the nursing
home is perhaps most evident in the design of SCUs for patients with dementia. Nonetheless, the
need for these services applies to all patients, not only to those with cognitive impairment.
Moreover, the potential benefits of such services are not limited to their effects on residents with
diagnosed disorders; there is also the potential for prevention. For example, the availability of
opportunities for pleasurable events and activities can have positive effects on mood and behavior
in residents with and without a diagnosis of depression. In addition, evidence indicates that
contextual interventions designed to encourage a sense of empowerment in residents can have
positive effects on both mental and physical health.
Knowledge of the benefits of encouraging autonomy is derived from the classic study by
Langer and Rodin (1976), who evaluated a controlled intervention designed to increase nursing
home residents’ sense of control over day-to-day events. Residents were randomly assigned to
either a treatment group in which staff gave the message that residents were expected to be
responsible for making decisions for themselves or a control condition in which the message
conveyed was that the staff was responsible for residents’ care. Both immediately after the
intervention and at 18-month follow-up, the treatment groups exhibited benefits in mood,
alertness, and active participation. The effects of control-enhancing interventions have been
confirmed in a number of other studies (e.g., Banziger and Roush 1983; Schulz 1976; Thomasma
et al. 1990) and have been discussed in terms of “learned helplessness” models (Avorn and Langer
1982).
Benefits of interventions designed to enhance the predictability of the environment have also
been confirmed (Krantz and Schulz 1980). In summary, these studies demonstrate that the social
environment within which care is provided can have a significant effect on nursing home
residents; environmental design should be viewed as a component of mental health care.
Professional System
The intrinsic system for mental health services as just described is necessary but not sufficient to
meet the needs of nursing home residents. In addition, the services of mental health professionals
are important in evaluating the interactions between medical and mental health problems, in
establishing psychiatric diagnoses, and in planning and administering specific treatments for
mental disorders. This component of the professional system must encompass medically oriented
psychiatric care, including psychopharmacological treatment. A position statement by the major
provider groups in this field (American Association for Geriatric Psychiatry et al. 1992)
acknowledged the history of misuse of psychotropic drugs in nursing homes, but the statement
emphasized that psychopharmacological treatment of diagnosed mental disorders is an important
part of the medical and mental health care of nursing home residents. The complexity of
psychopharmacological treatment in frail nursing home residents with medical comorbidity
requires that the skills of psychiatrists knowledgeable in geriatrics be an integral part of the
professional system.
The professional system should include care with a psychosocial as well as a biomedical focus.
For example, psychiatrists, psychologists, and psychiatric nurse practitioners and advanced
practice nurses with specific expertise in behavioral treatment may be successful in evaluating the
antecedents and causes of behavioral and psychological symptoms of dementia and in developing
environmental and behavioral interventions, even when efforts by the facility’s nursing staff have
proven ineffective (Teri et al. 2002). As described in the section “Psychotherapy” earlier in this
chapter, psychotherapy may be of value for residents whose cognitive abilities allow them to
participate. Further research is needed to determine how existing treatments should be modified
and how they can be administered to optimize their effectiveness in the nursing home. Despite the
need for more research, psychotherapy for the more cognitively intact nursing home residents with
depression should be considered an important treatment among the professional mental health
services made available to nursing home residents.
Integration of the professional and intrinsic components of mental health care in the nursing
home is required because of the inherent interdependence of these systems. To conduct valid
assessments and make diagnoses, mental health professionals must rely on nursing home staff to
report their shift-by-shift observations of residents’ behavior and other clinical signs. Mental
health professionals must also depend on nursing home staff to implement and monitor the
treatments they prescribe. Conversely, to succeed in providing appropriate mental health care to
nursing home residents, staff members in the intrinsic system must have access to ongoing
consultation from, and must receive direct support from, mental health professionals who are
knowledgeable in geriatrics.

Conclusion
The high prevalence of mental health problems among nursing home residents underscores the
importance of psychiatric care in nursing homes. Psychiatry in U.S. nursing homes has evolved
substantially over several decades, with changes driven by a combination of factors, including
scientific knowledge, availability of new treatments, evolving federal regulations, measurement-
based care, public dissemination of quality measures, and recognition of the need for integrated
approaches to the delivery of mental health services.
 Key Points
• According to the 2004 National Nursing Home Survey, 4% of Americans ages 65 years and
older—1.5 million people—resided in 16,100 long-term-care facilities.
• Epidemiological studies have consistently shown that 80%–94% of nursing home residents
have diagnosable psychiatric disorders. These prevalence data suggest that nursing homes are
de facto neuropsychiatric institutions, although they were not originally intended for this
purpose.
• Since the implementation of federal nursing home regulations in the early 1990s, the rate of
antipsychotic medication use has declined, and the use of antidepressants has increased.
However, approximately half of nursing home residents who are receiving antidepressant
medications continue to have symptoms of depression.
• Since 2003, analyses of safety data from randomized controlled studies of atypical
antipsychotic drugs in elderly patients with dementia, including nursing home studies, have
revealed significantly increased risks of cerebrovascular adverse events and mortality in this
population. This finding had led to initiatives by the Centers for Medicare and Medicaid to
improve the quality of dementia care in nursing homes, including the goal of reducing
antipsychotic drug use.
• Although mechanical restraints have frequently been used in attempts to control agitation, they
do not decrease behavioral disturbances, and cross-national studies have indicated that it is
possible to manage nursing home residents more safely without such measures.
• The social environment within which care is provided can have a significant effect on nursing
home residents; environmental design should be viewed as a component of mental health care.

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 Index
Page numbers printed in boldface type refer to tables or figures.

AA. See Alzheimer’s Association

AA (Alcoholics Anonymous), 476–477, 678
AAGP (American Association for Geriatric Psychiatry), 178, 213
AARP study of late-life sexuality, 390–391
A β. See Amyloid β protein
ABCA7 gene, in Alzheimer’s disease, 190, 191
Abnormal Involuntary Movement Scale (AIMS), 101
Absorption of drugs, 44
Abstract thinking
assessment of, 98, 185
in delirium, 159
in dementia, 46, 185
in schizotypal personality disorder, 494
Acamprosate, for alcohol dependence, 477
Acceptance and commitment therapy (ACT), 654–655
Access to mental health care, 34
in nursing homes, 728, 729, 733
options for psychotherapy, 650
ACE inhibitors. See Angiotensin-converting enzyme inhibitors
Acetaminophen, 112, 518
Acetylcholine, 216–217
in Alzheimer’s disease, 196
cholinesterase inhibitors and, 216
in delirium, 163, 164
in Parkinson’s disease dementia, 203, 204
Acetylcholinesterase inhibitors. See Cholinesterase inhibitors
ACT (acceptance and commitment therapy), 654–655
Actigraphy, 445, 447
Active listening, 264
Activities of daily living (ADLs) performance
assessment of, 52, 91, 101, 104
bereavement and, 418
 dementia and, 46, 180, 186, 215, 557
cholinesterase inhibitors for, 216, 220, 233
memantine for, 216, 559–560
physical activity for, 624
supportive care for, 231, 232
depression and, 247, 253
falls and, 47
instrumental (See Instrumental activities of daily living
performance)
by nursing home residents, 690, 692, 722, 723
behavioral problems and, 692, 693
in special care units, 726
studies of pharmacotherapy for, 698–702, 705–706, 712, 714
sarcopenia and, 42
Acute stress disorder, 339, 352
AD. See Alzheimer’s disease
ADH (antidiuretic hormone), 38
ADHD (attention-deficit/hyperactivity disorder), 75, 78
Adjustment disorder with depressed mood, 244, 244, 261–262
ADLs. See Activities of daily living performance
Adoption studies, 61
Adrenal androgens, 38
Adrenal medulla, 39
α-Adrenergic blockers
for agitation in dementia, 517, 518, 519
for benign prostatic hypertrophy, 49
for electroconvulsive therapy, 596, 597
in posttraumatic stress disorder, 361
sexual dysfunction induced by, 399
β-Adrenergic blockers
for agitation in dementia, 517, 518, 519
bradycardia induced by, 114, 532
depression induced by, 93
for electroconvulsive therapy, 596, 597, 602
sexual dysfunction induced by, 397, 399
Adult day care, 231, 681
Adult development, 496–497, 503
Adverse drug effects. See also specific drugs and classes
polypharmacy and, 50
Aerobic activities, 637. See also Physical activity
for depression, 628
effects on cognition, 210, 215, 624
Affect
assessment of, 95, 100, 103, 129
in bereavement, 419
blunted, 313, 397
definition of, 95
depressed, 249, 251, 260, 693
effect of geriatric assessment on, 52
as focus of cognitive-behavioral therapy, 650
as focus of interpersonal psychotherapy, 652
in frontotemporal lobar degeneration, 204
in generalized anxiety disorder, 355, 357
negative, 100, 313, 337, 355, 357, 419, 696, 701
of nursing home residents, 693, 696, 701
in personality disorders, 656
positive, 100, 251, 701
Age at onset, 21
of Alzheimer’s disease
amyloid β and, 198
apolipoprotein E ε4 allele and, 120, 189, 192
disease progression and, 192
early-onset, 68, 70
psychosis and, 315
of anxiety disorders, 335, 337, 339
of bipolar disorder, 249, 289–291, 294, 299
of delusional disorder, 314
of depression, 254, 258, 260
of frontotemporal lobar degeneration, 140, 206
of Huntington’s disease, 137
of Parkinson’s disease, 74
of schizophrenia, 15, 309–313, 314, 323
Age effects
on Alzheimer’s disease prevalence, 11
 on cognitive function, 46
on energy requirements, 632
on mental health service use, 24
on pharmacokinetics and pharmacodynamics, 44–45, 53–54, 212
on sexuality, 389–408
on sleep and circadian functions, 436, 437
on suicide mortality, 20, 21
Age-related macular degeneration, 35, 45
AGED (Amsterdam Groningen Elderly Depression) Study, 19
Agency for Healthcare Research and Quality, 548, 551
Aggression
agitation and, 508, 509, 513
delirium and, 160
dementia and, 72, 514, 517
depression and, 246
electroconvulsive therapy for, 596
genetic factors and, 195
family tolerance of, 95
among nursing home residents, 692, 693
management of, 701, 703, 706–709, 715, 716
personality disorders and, 501, 502
management of, 657
pharmacotherapy for, 407, 501, 518, 519
antipsychotics, 321, 703, 706–709
carbamazepine, 516, 555, 707, 716
in nursing homes, 703, 706–709, 715, 716
oxcarbazepine, 715, 716
trazodone, 542
posttraumatic stress disorder and, 354
sexual, 405–406
management of, 407
working with families of patients with, 672, 680
Aging
anxiety and, 337–339
chronic disease and, 45
life expectancy and, 4, 33–34, 53
normal, neuropsychology of, 132–133, 144
 physiological changes of, 34, 35–44
of population, 3–4, 25, 26, 33, 53, 177
wisdom and, 257–258, 272
Aging, Demographics, and Memory Study, 10, 12
Agitation, 7, 91, 95–96, 507–519
Alzheimer’s disease and, 47, 193, 194, 195, 315, 324
citalopram for, 227
sleep disorders and, 441
sundowning, 193, 195, 441, 510, 514
vs. anxiety, 96, 97
delirium and, 160, 169, 170, 171, 507, 508, 513–514
dementia and, 359, 377, 441, 507–508, 514–515
nonpharmacological management of, 509–513
sexual aggression and, 405, 407
depression and, 258, 259
electroconvulsive therapy for, 267
diagnostic approach to, 507–508
disorders associated with, 507
drug-induced
bupropion, 265
serotonin-norpeinephrine reuptake inhibitors, 537
effects on caregivers, 507–508
electroconvulsive therapy–induced, 602–603
key points related to, 519
mania and, 258
medical causes of, 508, 509
melancholia and, 259
mild cognitive impairment and, 182
among nursing home residents, 692, 693, 695
paranoia and, 508
schizophrenia and, 52
Agitation treatment, 324, 509–519
in delirium, 513–514
in dementia, 514–515
nonpharmacological, 223, 509–513
common strategies, 511
communication strategies, 512
 developing understanding, 511
electroconvulsive therapy, 267
family psychoeducation, 509–510
questions to guide problem solving, 510–511
summary of, 512–513
pharmacotherapy, 515–518, 519
antidepressants, 227, 516–517
antipsychotics, 47, 226, 268, 321, 323, 407, 513, 515–516,
518
benzodiazepines, 518
cholinesterase inhibitors, 517
for electroconvulsive therapy, 268
for inappropriate sexual behaviors, 407
memantine, 517
mood stabilizers, 516
for pain management, 518
prazosin, 517
propranolol, 517
transdermal estrogen, 518
Agnosia, 135, 180, 193, 223
Agoraphobia, 341–342
clinical features of, 339
diagnosis in older adults, 336
in DSM-5, 344
prevalence of, 16, 17
Agranulocytosis, drug-induced
carbamazepine, 297, 516, 555
clozapine, 108, 319
mirtazapine, 108, 542
Agreeableness, 495, 498
AGTR1 gene, in depression, 252
AIDS. See Human immunodeficiency virus infection
AIMS (Abnormal Involuntary Movement Scale), 101
Airway management, for electroconvulsive therapy, 602
Akathisia, 551,693
Akinesia, 74, 142
Akinetic mutism, 209
Alaproclate, use in nursing homes, 705, 715
Albumin plasma level, 44, 167, 529, 630, 694
Alcohol-related disorders
correlates and risk factors for, 468
diagnosis and screening for, 471–475
assessing frequency and quantity of use, 472–473
timeline followback method, 472
biological markers, 475
potential barriers to, 471–472
signs and symptoms, 472
standardized instruments for, 471, 473–475, 474
epidemiology and prevalence of, 8–9, 11, 13, 14, 15, 16–17, 18,
459–460, 460, 465–467
in treatment settings, 465, 467
impact on diet and physical activity, 627
treatment of, 460–461, 475–479
brief interventions and therapies, 475–476
for detoxification and withdrawal, 478
factors affecting response and adherence to, 479
pharmacotherapy, 477–478
psychosocial treatments, 476
psychotherapy, 655–656
twelve-step programs, 476–477
Alcohol-Related Problems Survey, 627
Alcohol use
abstaining from, 462
beverage conversion chart for, 463
binge drinking, 11, 26, 460, 462, 465, 476
cognitive effects of, 470
dementia and, 189, 620, 634
drug interactions with, 462, 470
chloral hydrate, 448
warfarin, 93
history taking for, 93
medical conditions and, 469–470
cardiovascular disease, 469, 470, 634
chronic obstructive pulmonary disease, 443
 psychiatric comorbidity with, 479–481
Alzheimer’s disease, 189, 471, 480
depression, 254, 470, 480
sleep disorders, 480–481
recommended limits for, 462, 627, 634–635
serum level and, 112
spectrum of, 462–464
withdrawal from, 112, 478
benzodiazepines for, 513–514
Alcohol Use Disorder and Associated Disabilities Interview Schedule
—DSM-IV Version, 9
Alcohol Use Disorders Identification Test (AUDIT), 473–475
AUDIT-C, 473, 474, 474
Alcoholics Anonymous (AA), 476–477, 678
Aldosterone, 38, 39, 44
Alexithymia, 379, 380–381
Alprazolam, 557
Alprostadil penile intercavernosal injections, 404
ALS (amyotrophic lateral sclerosis), 113, 141, 205
Altruism, 495, 496
Alzheimer’s Association (AA), 177
guidelines for diagnosis of Alzheimer’s disease, 46, 113
interprofessional partnerships with, 684
proposed criteria for mild cognitive impairment, 183, 184
Safe Return program, 675
support for families, 231, 232, 512–513, 675, 676, 678
Alzheimer’s disease (AD), 180, 189–199, 190, 193
alcohol intake and, 189, 620
amyloid cascade hypothesis of, 191, 196–198, 197, 198, 233
biomarkers for, 70, 113, 127, 128, 184, 188, 199, 207, 214–215
amyloid β protein, 69, 70, 112, 119, 122, 128, 196–199, 197,
198
tau proteins, 71, 112, 119, 122, 128, 196, 197, 198, 203, 316
comorbidity with
alcohol use, 189, 471, 480
depression, 47, 193, 228–229, 246
normal-pressure hydrocephalus, 206–207
 sexual dysfunction, 405
vascular neurocognitive disorder, 199, 200, 215
definition of, 178, 179
diagnosis and evaluation of, 113, 128
amyloid PET imaging, 119, 188
cerebrospinal fluid analysis, 112–113, 128
criteria for, 46, 113
electroencephalography, 119–120
FDG-PET imaging, 118, 196
genetic testing, 70, 71–72, 81, 120, 188
imaging studies, 118, 128, 195–196
dietary factors and, 111
differentiation from frontotemporal lobar degeneration, 118, 206
in DSM-5, 180
family caregivers for patients with, 230
functional impairment in, 190, 192–193, 194, 195, 316
pharmacotherapy effects on, 213, 217, 219
genetics of, 61, 64, 66, 68–72, 189–192, 191
amyloid β (Aβ) protein, 69, 70, 122
amyloid precursor protein (APP)
mutations, 68–70, 189
apolipoprotein E ε4 allele, 22, 66, 70–72, 120, 189, 192, 195,
196, 620
candidate gene studies, 71
cholinesterase inhibitor response and, 72
early-onset Alzheimer’s disease, 68–70, 189
environmental factors and, 22
genome-wide association studies, 66, 71, 72, 190–192
late-onset Alzheimer’s disease, 70–72, 189–191
neuropsychiatric symptoms, 72, 195
presenilin 1 and presenilin 2 mutations, 68–70, 189, 198
impact on diet and physical fitness, 626–627
incidence of, 68, 177
memory impairment in, 46, 134, 135, 139, 139, 193
mortality from, 177, 192
natural history of, 192
neuropathology of, 70, 134, 178–179, 189, 195–199, 197, 198
 in asymptomatic persons, 178–179, 215
cholinesterase inhibitors and, 558
in Down syndrome, 69
effect on pain perception, 377
Lewy body neurocognitive disorder and, 202
Parkinson’s disease and, 200, 203, 203
with psychosis, 316
vascular dementia and, 199, 200, 215
neuropsychiatric symptoms of, 72, 193–195
agitation, 47, 193, 194, 195, 227, 315, 324
apathy, 193, 194, 195
clusters of, 193–194
depression, 47, 193, 194
genetic factors and, 195
sleep disturbances, 193, 194–195, 440–441
sundowning, 193, 195, 441, 510, 514
neuropsychological assessment in, 128, 129, 132, 134, 135, 139,
144, 315–316
among nursing home residents, 691
pain in, 377
prevalence of, 12, 18, 46, 127, 177, 189
prevention trials for, 214–215
prodromal, 134
psychosis of, 72, 193, 195, 315–316, 316, 321–322, 324, 517
rate of cognitive and functional decline in, 192–193
residential care for, 4
risk factors for, 189
terminal stage of, 193
traumatic brain injury and, 22
treatment of, 7, 46–47, 210–233
adult day care, 231, 681
for cognitive symptoms, 47, 193, 216–220, 218, 558–560,
559
disease-modifying therapies, 193, 213–215, 233
family care, 670–684 (See also Family)
for neuropsychiatric symptoms, 221–230, 233
for psychosis, 321–322
 supportive care, 211–212, 230–233, 232
Alzheimer’s Disease Assessment Scale, Cognitive Subscale, 47, 130
Alzheimer’s Disease Centers, 675
Alzheimer’s Disease International, 177
Alzheimer’s Disease Neuroimaging Initiative, 113, 118
Amantadine, 204, 400
American Academy of Neurology, 109, 113, 118, 186
American Association for Geriatric Psychiatry (AAGP), 178, 213
American Cancer Society, 400
American College of Sports Medicine, 636–637
American Diabetes Association, 319
American Geriatrics Society, 50
Beers Criteria for Potentially Inappropriate Medication Use in
Older Adults, 50, 165, 168
American Heart Association, 637
American Psychiatric Association, 298
Personality Inventory for DSM-5, 498–499
Amiodarone, 110, 399
Amitriptyline, 543
cardiovascular effects of, 115
efficacy compared with other antidepressants, 530–531, 539
for insomnia, 450
AmpliChipR CYP450 test, 121
AMPS (Assessment of Motor and Processing Skills), 186
AMSTEL (Amsterdam Study of the Elderly), 338
Amsterdam Groningen Elderly Depression (AGED) Study, 19
Amsterdam Study of the Elderly (AMSTEL), 338
Amyloid β (Aβ) protein
Alzheimer’s disease and, 69, 70, 112, 119, 122, 128, 196–199,
197, 198, 203, 203
therapies targeting, 213, 214
cerebrospinal fluid analysis of, 112–113
in cognitively normal persons, 178
Lewy body neurocognitive disorder and, 200
normal-pressure hydrocephalus and, 207
Amyloid cascade hypothesis of Alzheimer’s disease, 191, 196–198,
197, 198, 233
Amyloid PET imaging, 99, 116, 118–119, 188, 196
Amyloid precursor protein (APP)
Alzheimer’s disease and, 68–70, 189, 191, 196, 198
cerebrospinal fluid analysis for, 113
testing for mutations of, 70
Amyotrophic lateral sclerosis (ALS), 113, 141, 205
Androgens, 38, 40. See also Testosterone
Andropause, 394
Anemia, 46, 346, 439
aplastic, carbamazepine-induced, 555
laboratory testing for, 108, 262
testosterone deficiency and, 40
vitamin B12 deficiency and, 111
Anesthesia, for electroconvulsive therapy, 602–603
Angiotensin, 39, 44
Angiotensin-converting enzyme (ACE) inhibitors, 44, 399
interaction with lithium, 295, 553
Anorexia. See Appetite changes
Anorgasmia, 396
Anti-Amyloid Treatment for Asymptomatic AD Trial, 214
Antibiotics, 44, 45. See also specific drugs
interaction with carbamazepine, 555
Anticholinergic agents
before electroconvulsive therapy, 268, 596, 597, 602
interaction with cholinesterase inhibitors, 558
for Parkinson’s disease, 204
Anticholinergic effects of drugs, 45, 49, 228, 451, 527
antipsychotics, 165, 318, 319, 322, 400, 549, 551, 709, 711
anxiety, 339
delirium, 45, 161, 163, 165–166, 168, 170, 212
diphenhydramine, 448
falls, 450
lithium, 553
tricyclic antidepressants, 448, 543–544
Anticipation, 496
Anticoagulants, 215. See also Warfarin
for electroconvulsive therapy, 597, 598
Anticonvulsants. See also specific drugs
for bipolar disorder, 295–298, 554–556
electroconvulsive therapy and, 595, 601
Antidepressants, 528–544, 560. See also specific drugs and classes
adverse effects of
delirium, 165
falls, 227, 228, 536
mania, 298
sexual dysfunction, 397, 399, 400, 407
for anxiety disorders, 360, 361, 363
for bereavement
complicated, 425
normal grief, 427
in dementia
for depression, 228–229
for neuropsychiatric symptoms, 227
for depression, 264–266, 266, 528–544, 530–531, 538–539
in bipolar disorder, 298
in dementia, 228–229
duration of therapy with, 248
efficacy of, 247
maintenance treatment after electroconvulsive therapy, 592,
606
Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) study of, 540, 541–542
dosing of, 265, 266, 533–534
drug interactions with
alcohol, 470
cytochrome P450 enzyme inhibition and, 535
for dysthymia, 530, 537
for electroconvulsive therapy augmentation, 601
for inappropriate sexual behaviors, 407
pharmacokinetics of, 533–534
for posttraumatic stress disorder, 361
for premature ejaculation, 405
for somatic symptom and related disorders, 382
for symptoms of personality disorders, 501, 502
 use in nursing homes, 705, 706, 708, 710, 717, 718, 725, 729, 733
utilization by older adults, 25
for vasomotor menopausal symptoms, 444
Antidepressants, tricyclic (TCAs), 543–544. See also specific drugs
adverse effects of, 228, 543–544
cardiovascular effects, 113–114, 114, 228, 265, 544
mania, 298
sexual dysfunction, 397, 399, 407
for bereavement
complicated, 425
normal grief, 427
for depression, 265, 543–544
dosing of, 265, 266, 544
electroconvulsive therapy and, 267
overdose of, 113
for symptoms of personality disorders, 502
therapeutic plasma levels of, 112, 265, 544
Antidiuretic hormone (ADH), 38
Antiglucocorticoid therapy, for anxiety disorders, 361
Antihistamines, 165, 166, 399
Antihypertensive agents. See also specific drugs
Alzheimer’s disease and, 193
before electroconvulsive therapy, 595
sexual dysfunction induced by, 397, 399
Antioxidants, 618, 635
cognitive decline and, 189, 213, 620, 621
Antipsychotic Discontinuation in AD trial, 226
Antipsychotics. See also specific drugs
adverse effects of, 318
anticholinergic effects, 165, 318, 319, 322, 400, 549, 551,
709, 711
cardiovascular effects, 114, 114, 318, 514
delirium, 165, 166, 318, 319, 322, 400, 549, 551, 709, 711
extrapyramidal symptoms, 322, 514, 515, 545
hyperprolactinemia, 117, 317, 398, 400, 547, 548, 551
mortality risk, 716
neuroleptic malignant syndrome, 226, 318
 neuroleptic sensitivity in Lewy body neurocognitive
disorder, 136, 190, 201, 226–227, 322, 517
in patients with dementia-related psychosis, 225–226
sexual dysfunction, 398, 399, 400
tardive dyskinesia, 101, 313, 314, 317, 318, 321, 323, 324,
550, 703
for delirium, 168, 170, 513–514
dosing of, 318, 319–320
electrocardiogram effects of, 114, 114
electroconvulsive therapy and, 267, 268, 601
for neuropsychiatric symptoms in dementia, 225–226
agitation, 47, 226, 268, 321, 323, 407, 513, 515–516, 519
monitoring and discontinuation of, 518
for personality disorders, 501, 502
for schizophrenia, 318
use in Lewy body neurocognitive disorder, 136, 190, 201, 226–
227, 322, 517
use in nursing homes, 697, 703, 704–714, 716, 721, 723–725, 733
use in Parkinson’s disease dementia, 227
Antipsychotics: atypical, 545–552. See also specific drugs
adverse effects of, 319, 324, 515, 560
extrapyramidal symptoms, 321, 322, 515, 545, 547, 549,
551, 707–709, 711, 714
laboratory monitoring for, 109, 319
metabolic effects, 109, 299, 317, 319, 545, 546
pancreatitis, 109
sexual dysfunction, 398, 399
stroke and mortality risk in elderly dementia patients, 225–
226, 299, 317, 319, 322, 324, 514, 515–516, 545, 546, 703,
716
tardive dyskinesia, 317, 318, 321, 324
aripiprazole, 551–552
asenapine, 552
for bipolar disorder, 298–299
clozapine, 551
for delirium, 168, 170, 514, 547
for delusional disorder, 320
 discontinuation of, 546
dosing of, 319–320
duration of use of, 546
for generalized anxiety disorder, 361
iloperidone, 552
for inappropriate sexual behaviors, 407
lurasidone, 552
for neuropsychiatric symptoms in dementia, 225–226
agitation, 47, 226, 321, 514, 515–516, 519
monitoring and discontinuation of, 518
olanzapine, 548–549
paliperidone, 547–548
for personality disorders, 501
prescribing guidelines for, 545–546
for psychosis in Alzheimer’s disease, 316, 321–322
quetiapine, 549–551
receptor blockade of, 550
risperidone, 546–547
for schizophrenia, 316, 318–319, 546–547
use in Lewy body disorders, 322, 547
use in nursing homes, 697, 703, 707–714, 716
for very-late-onset schizophrenia-like psychosis, 320
ziprasidone, 552
Antisense oligonucleotides (ASOs), 74
Antisocial personality disorder, 102, 480, 492, 494, 499
Anxiety, 7. See also Fear; Worry
vs. agitation, 96, 97
assessment of, 129
instruments for, 131, 359, 360
delirium and, 159, 170
dementia and, 181, 182, 223
drug-induced, 339
hyperthyroidism and, 111
impact on communication, 102
Lewy body neurocognitive disorder and, 228
limbic encephalopathy and, 209
mild cognitive impairment and, 182, 184
 among nursing home residents, 692
Parkinson’s disease and, 204
prevalence of, 11, 13, 26
prion disease and, 208
during psychiatric interview, 91, 92
social factors and, 23
Anxiety disorders, 333–349. See also specific disorders
age at onset of, 335, 337, 339
clinical course of, 359
comorbidity with alcohol abuse, 480
bipolar disorder, 286
dementia, 358–359
depression, 7, 245, 254, 346, 348, 349, 355–357
medical conditions, 354–355, 356
sexual dysfunction, 397
detection of, 361–362
in DSM-5, 334, 335
recommendations of Anxiety
Disorders Advisory Committee to the Lifespan
Disorders Work Group, 334, 336, 355
due to another medical condition, 355, 356
epidemiology of, 334–335, 338
generalized anxiety disorder, 336, 340, 346–349, 347
key points related to, 363
neuropsychology and neurobiology of, 357–358
panic disorder, 336, 340, 342–346, 345
phobias, 336, 338, 340, 341–342, 342–344
prevalence of, 8, 9, 15, 16–17, 18, 26, 334, 338
in treatment settings, 18, 19
risk factors for, 339
shared and distinct clinical features of, 339–341, 340
treatment of, 333, 359–363
clinical management, 361–363, 362
in the future, 361
patients’ views of, 362
pharmacotherapy, 360–361
benzodiazepines, 360, 363
 selective serotonin reuptake inhibitors, 333, 360, 361,
363, 528–529
psychotherapy, 333, 359–360, 363, 653–655, 660
Anxiolytics, 556–558
benzodiazepines, 360, 363, 556–557
for bereavement, 427
buspirone, 557–558
delirium induced by, 165
electroconvulsive therapy and, 267
for somatic symptom and related disorders, 382
utilization by older adults, 25
Apathy
delirium and, 159
dementia and, 181, 193, 194, 195, 510
pharmacotherapy for, 223, 227, 229
depression and, 143
discussing with family, 674, 677
frontotemporal lobar degeneration and, 136, 140, 204, 206
mild neurocognitive disorder and, 182
among nursing home residents, 693, 701
Parkinson’s disease and, 142, 204
pharmacotherapy for
in dementia, 223, 227, 229
in personality disorders, 501
psychostimulants, 266, 544–545
prion disease and, 208
progressive supranuclear palsy and, 205
selective serotonin reuptake inhibitor–induced, 227, 545
sexual dysfunction and, 397
vascular neurocognitive disorder and, 190, 200
Apathy in Dementia Methylphenidate Trial, 229
Aphasia, 101, 180, 224, 406
agitation and, 508
Alzheimer’s disease and, 135, 193
normal-pressure hydrocephalus and, 216
primary progressive, 73, 140–141, 188, 190, 204–205
prion disorders and, 208
Apolipoprotein E (APOE), 120
delirium and, 164
ε4 allele
Alzheimer’s disease and, 22, 66, 70–72, 120.189, 191, 192,
194, 195, 196, 620
cholinesterase inhibitor response and, 72
depression and, 251
genetic testing for, 71–72, 120
mild cognitive impairment and, 184, 211
frontotemporal lobar degeneration and, 73
genotyping of, 188
melatonin levels and, 194
APP. See Amyloid precursor protein
Appearance of patient, 95
Appetite changes, 7, 14, 91
Alzheimer’s disease and, 627
depression and, 100, 244, 252, 625–626
drug-induced
cholinesterase inhibitors, 218, 559
psychostimulants, 545
grief and, 416, 428
nutritional status and, 625, 629, 630
Apraxia, 180, 223
Alzheimer’s disease and, 134, 135, 193
corticobasal syndrome and, 205
Lewy body neurocognitive disorder and, 136
Aripiprazole, 551–552
adverse effects of, 319, 398, 551
for augmentation of venlafaxine in depression, 552
for delirium, 514
in hyperprolactinemia, 117
for mania, 298, 552
for neuropsychiatric symptoms in dementia, 551
agitation, 515, 519
receptor blockade of, 550, 551
use in nursing homes, 697, 713, 714
for very-late-onset schizophrenia-like psychosis, 320
Aromatherapy, 222, 696
Arrhythmias, 115
anxiety and, 354
drug-induced, 527
antipsychotics, 114
serotonin-norepinephrine reuptake inhibitors, 537
trazodone, 542
tricyclic antidepressants, 228, 544
due to potassium imbalance, 109
electroconvulsive therapy and, 268, 596, 597
Arthritis, 45, 54, 253, 295, 376, 398, 442
AS3MT gene, 78
Asenapine, 552
for mania, 298–299, 552
receptor blockade of, 550
ASOs (antisense oligonucleotides), 74
Aspirin, 45
drug interactions with
selective serotonin reuptake inhibitors, 532
valproate, 296
Assessment
of family, 93–95, 676–678
geriatric, 51–53, 54
laboratory testing, 107–123
neuropsychological, 97, 99, 127–145
nutritional, 629–630, 631
psychiatric interview, 89–104
rating scales for, 98–101
of suicidality, 97, 262
Assessment instruments, 6, 98–101
Abnormal Involuntary Movement Scale (AIMS), 101
Alcohol Use Disorder and Associated Disabilities Interview
Schedule—DSM-IV Version, 9
Alcohol Use Disorders Identification Test (AUDIT), 473–475
AUDIT-C, 473, 474, 474
Alzheimer’s Disease Assessment Scale, Cognitive Subscale, 47,
130
for anxiety, 359, 360
Assessment of Motor and Processing Skills (AMPS), 186
Beck Anxiety Inventory, 131
Beck Depression Inventory (BDI), 131, 698–700
Benton Facial Recognition Test, 131
Benton Visual Retention Test, 137
Boston Naming Test, 40
Brief Visuospatial Memory Test—Revised, 130, 135
Buschke Selective Reminding Test, 130, 135
CAGE questionnaire, 473–474, 475
California Verbal Learning Test, 2nd Edition (CVLT-II), 130,
135–138
Center for Epidemiological Studies Depression Scale (CES-D), 6,
100, 243, 250, 251, 260, 263
Clinical Dementia Rating, 135
Clock Drawing test, 99, 136, 185
Color Trail Making Test, 130
Composite International Diagnostic Interview (CIDI), 6, 9, 102
Confusion Assessment Method (CAM), 98–99, 156, 159, 171
for delirium, 156–158, 159
Delirium Observation Screening Scale, 156
Delirium Rating Scale, 156
for depression, 6, 52, 99–100, 243
DETERMINE Checklist, 630
Diagnostic Interview Schedule (DIS), 6, 8
Diagnostic Interview Schedule for DSM-IV (DIS-IV), 102
Drug and Alcohol Problem Assessment for Primary Care (DAPA-
PC), 475
Epworth Sleepiness Scale, 229
Family Confusion Assessment Method, 158
Finger Oscillation test, 131
Frontal Assessment Battery, 131, 136, 185
general assessment scales, 100–101
Geriatric Depression Scale (GDS), 6, 18, 52, 100, 131, 243, 262,
263, 706, 729
Geriatric Mental State Schedule, 100–101
Global Assessment of Functioning (GAF) Scale, 289
Grooved Pegboard test, 131
Hopkins Verbal Learning Test—Revised, 130, 135
Judgment of Line Orientation Test, 131, 137, 138
Mattis Dementia Rating Scale, 129
Memorial Delirium Assessment Scale, 157
Mental Alternation Test, 185
Mini-Cog, 160
Mini-Mental State Examination (MMSE), 6, 52, 97, 99, 130, 185,
246, 263, 287–288, 624, 658
Mini Nutritional Assessment (MNA), 630, 631
Mini-Nutritional Assessment Short-Form (MNA-SF), 630
Minnesota Multiphasic Personality Inventory—2, 131
Modified Mini-Mental State (3MS), 185
Montgomery-Åsberg Rating Scale for Depression, 100
Montreal Cognitive Assessment (MoCA), 99, 130, 160, 185
Mood Disorder Questionnaire, 285
Multilingual Naming Test, 40
Multiple Sleep Latency Test, 445
NEECHAM Confusion Scale, 156
NEO Personality Inventory—Revised (NEO PI-R), 498
for neurocognitive disorders, 98–99
Neuropsychiatric Inventory, 193, 195, 717
Neuropsychiatric Inventory—Clinician rating scale (NPI-C), 186
Neuropsychological Assessment Battery, 129
Nursing Delirium Screening Checklist, 156
for nutritional status, 630, 631
Older Americans Resources and Services (OARS)
Multidimensional Functional Assessment Questionnaire, 101, 244
Patient Health Questionnaire, 6
Patient Health Questionnaire (PHQ-9), 729
for personality disorders, 498–499
Personality Inventory for DSM-5, 498–499
Personality Inventory for DSM-5 (PID-5), 498–499
Present State Exam, 100
Problem Related to Living Alone, 244
Psychiatric Status Schedule, 100
Resident Assessment Instrument, 720
 Rey Auditory Verbal Learning Test, 130, 135
Rey-Osterrieth figure, 136
Schedule for Affective Disorders and Schizophrenia, 261
Short Category Test, 130, 136
Short Portable Mental Status Questionnaire, 160
Stroop Color and Word Test, 130, 136
Structured Clinical Interview for DSM-IV (SCID), 101–102
Structured Clinical Interview for DSM-IV Personality Disorders
(SCID-II), 498
structured diagnostic interviews, 101–102, 104
Subjective Global Assessment (SGA), 630
for substance use problems, 471, 473–475, 474
Symbol Digit Modalities Test, 130
Texas Revised Inventory of Grief—Present (TRIG-Present), 423
Trail Making Test, 130, 133, 135–137
use for case identification, 6
Wechsler Adult Intelligence Scale, 4th Edition (WAIS-IV), 130,
133, 135–138
Digit Span Backward subtest, 135–137
Digit Span subtest, 135
Wechsler Memory Scale, 4th Edition (WMS-IV), 130, 135
Wisconsin Card Sorting Test, 130, 136, 137
World Health Organization Disability Assessment Schedule 2.0
(WHODAS 2.0), 100
World Mental Health (WMH) Survey Version of the Composite
International Diagnostic Interview, 6, 102
Assessment of Motor and Processing Skills (AMPS), 186
Assimilation of Problematic Experiences Sequence model, 426
Assisted living facilities, 212, 629, 676, 679, 684, 690, 691, 696
Asthma, electroconvulsive therapy in, 598
Ataxia. See also Gait disturbances
celiac disease and, 210
dementia and, 182
drug-induced
carbamazepine, 295, 555
gabapentin, 556
lithium, 295, 553
 genes for, 74
prion diseases and, 208
Atrial fibrillation, 189, 192, 199, 597
Atrial natriuretic peptide, 44
Atropine, for electroconvulsive therapy, 596, 597, 602
Attachment theory, bereavement and, 416, 425
Attention
age-related changes in, 46
deficits of
bipolar disorder and, 291
delirium and, 158, 160
grief and, 416
Lewy body neurocognitive disorder and, 201
normal-pressure hydrocephalus and, 206
tests of, 130
Attention-deficit/hyperactivity disorder (ADHD), 75, 78
AUDIT (Alcohol Use Disorders Identification Test), 473–475
AUDIT-C, 473, 474, 474
Australian Imaging Biomarkers and Lifestyle Flagship Study of Aging,
215
Australian National Mental Health and Well-Being Survey, 17, 334,
338
Autism spectrum disorder, 75–76, 77, 78
Autonomic arousal, 340, 341
Autonomic dysfunction
during alcohol withdrawal, 478
in Lewy body neurocognitive disorder, 201, 202
Avoidance behaviors
agoraphobia and, 336, 343, 344
anxiety and, 334, 339, 340, 341, 357
bereavement and, 419, 428, 439
fear of falling and, 352
generalized anxiety disorder and, 336
panic disorder and, 343, 344, 345
posttraumatic stress disorder and, 335, 337, 352, 353
social anxiety disorder and, 343
specific phobia and, 336, 341, 342
Avoidant personality disorder, 260, 314, 492, 494, 498, 657

B lymphocytes, 43
Baby boomers, 3, 33, 415, 459
substance-related disorders among, 459, 460, 468, 655
suicide among, 20
Balance problems, 51
assessment of, 52
falls due to, 47, 48, 637
in Lewy body neurocognitive disorder, 202
medication-related, 47
nonpharmacological interventions for, 224
exercise, 637
Balint’s syndrome, 138
Baltimore Longitudinal Study of Aging, 34
Bapineuzumab, 213
Barbiturates, 112, 267, 470, 594
before electroconvulsive therapy, 268–269
Baroreceptor reflex, 34
BDI (Beck Depression Inventory), 131, 698–700
Beck Anxiety Inventory, 131
Beck Depression Inventory (BDI), 131, 698–700
Beers Criteria for Potentially Inappropriate Medication Use in Older
Adults, 50, 165, 168
Behavior therapy. See also Cognitive-behavioral therapy
brief interventions for substance-related disorders, 476
for depression, 264
dialectical behavior therapy, for personality disorders, 500–501,
650
for inappropriate sexual behaviors, 407
for insomnia, 446
in psychosis of Alzheimer’s disease, 316
Behavioral disturbances. See also Aggression; Agitation; Paranoia;
Psychosis/psychotic symptoms
agitation, 507–519
in Alzheimer’s disease, 47
genetic contributions to, 72
 sundowning, 193, 195, 441, 510, 514
in bipolar disorder, 284
in dementia, 180–182, 181
management of, 221–230, 233
family tolerance of, 95, 670, 678
in frontotemporal lobar degeneration, 73, 140, 204, 206
sexual inappropriateness or aggression, 405–406
Benign prostatic hypertrophy, 45, 49, 443
Benton Facial Recognition Test, 131
Benton Visual Retention Test, 137
Benzodiazepine receptor agonists, 168, 441, 443, 448, 448–449, 450,
556–557. See also specific drugs
Benzodiazepines, 556–557, 560, 561. See also specific drugs
adverse effects of, 360, 470, 556–557
cognitive and motor effects, 448, 450, 557
delirium, 162, 166. 168, 212
fall and fracture risk, 360, 450, 470, 556
sexual dysfunction, 399
for agitation in dementia, 518
for anxiety disorders, 360, 363
for benzodiazepine or alcohol withdrawal, 513–514, 557
drug interactions with, 557
alcohol, 470
electroconvulsive therapy and, 267, 601
elimination half-lives of, 448, 449, 556, 557
flumazenil reversal of, 601
for grief reactions, 427
misuse of prescribed drugs, 465
for sleep disorders, 448, 449, 557
in Alzheimer’s disease, 439
restless legs syndrome and periodic limb movement disorder,
439
for symptoms of personality disorders, 502
urine toxicology testing for, 112
use in chronic obstructive pulmonary disease, 443, 557
withdrawal from, 478
Bereavement, 415–428. See also Grief reaction
 adaptation to, 421–424, 428
acceptance of loss, 422–423
gender differences in, 421–422
preloss relationship and, 423
social support and, 423
after violent, stigmatized, or unexpected death, 422
complicated, 418, 419, 421, 424–426, 428
course of symptoms in, 418–420
cultural differences in responses to, 420, 428
definition of, 415
depression and, 255, 256, 416, 419, 421, 422, 426
sleep disturbances in, 416, 439–440
DSM-5 definitions related to, 420–421
persistent complex bereavement disorder, 424
dual-process model of, 418, 422, 426, 428
interventions for, 424–427, 428
normal grief reactions, 426–427
persistent complex bereavement disorder, 424–426
key points related to, 427–428
losses associated with, 415
normal vs. abnormal reactions to, 419–420, 428
personality disorders and, 497
resilience and, 418–419, 428
spousal, prevalence of, 415, 417
stage model of, 416–417
theories about adjustment to permanent losses, 416–418
Berlin Aging Group, 257
Beta-blockers. See β-Adrenergic blockers
Bethanechol, 400
Bibliotherapy, 653
BIN1 gene, in Alzheimer’s disease, 71, 190, 191
Binge drinking, 11, 26, 460, 462, 465, 476
Binswanger’s disease, 139, 141
Biomarkers, 14, 23, 99
for alcohol and drug use, 475
for Alzheimer’s disease, 70, 113, 127, 128, 184, 188, 199, 207,
214
 therapies targeting, 214, 215
for depression, 262
for frontotemporal lobar degeneration, 141
for nutritional status, 630
for prion diseases, 216
Bipolar and related disorders, 244, 283–300. See also Mania
age at onset of, 249, 289–291, 294, 299
biological basis of, 291
bipolar I disorder, 283–284
bipolar II disorder, 284
clinical course and prognosis for, 249, 288–289
comorbidity with, 286–288
anxiety disorders, 286
dementia, 286, 287–288
medical conditions, 287
personality disorders, 287
posttraumatic stress disorder, 286
psychotic depression, 259
substance-related disorders, 286–287
cyclothymic disorder, 284
depressive episodes in, 285, 298, 299, 554, 555
diagnosis of, 258, 283–284
in DSM-5, 283–284
due to another medical condition, 283, 284
epidemiology of, 284–286
functional impairment in, 288, 289, 291
genetics of, 61, 75
overlap with schizophrenia and depression, 75
imaging studies in, 292–294
magnetic resonance imaging, 292–294
poststroke, 292
volumetric findings, 292
key points related to, 299–300
mortality and, 288, 299
among nursing home residents, 245
other specified or unspecified, 283, 284
prevalence of, 245, 284–286, 299
 gender and, 286
in treatment settings, 285–286
with psychosis, 291
substance/medication-induced, 283, 284
suicidality and, 289
Bipolar disorder treatment, 294–299
effect of age of first manic episode on, 249
electroconvulsive therapy, 249, 299, 591, 593
key points related to, 299–300
omega-3 fatty acids, 628
pharmacotherapy, 249
antidepressants, 298
antipsychotics, 298–299, 547
carbamazepine, 295, 296–297, 555
for depressive episodes, 298, 299, 554, 555
gabapentin, 556
lamotrigine, 295, 297–298, 554–555
lithium, 295, 300, 553–554
oxcarbazepine, 295, 555
pregabalin, 556
topiramate, 556
valproate, 295, 296, 554
Systematic Treatment Enhancement Program for Bipolar
Disorder, 289, 298
Bisexuality, 109, 391, 677
Bisphosphonates, 42
Bladder outlet obstruction, 49, 403
Bleeding, drug-related, 527
selective serotonin reuptake inhibitors, 532
serotonin-norepinephrine reuptake inhibitors, 537
Blood glucose testing, 108, 109
Blood pressure. See also Hypertension; Hypotension
changes with aging, 36, 53
electroconvulsive therapy effects on, 268, 596, 597, 602, 603
Blood urea nitrogen, 108
“Blues,” 91
BMI (body mass index), 52, 632
Body dysmorphic disorder, 373
Body mass index (BMI), 52, 632
Bone changes with aging, 39, 40, 42, 51. See also Osteoporosis
Bone metabolism, drug effects on
selective serotonin reuptake inhibitors, 536
serotonin-norepinephrine reuptake inhibitors, 537
valproate, 554
Borderline personality disorder, 492, 493, 494, 498, 499–500
Boston Naming Test, 40
Bradycardia
drug-induced
antipsychotics, 115
β-blockers, 114
cholinesterase inhibitors, 218, 558, 559
selective serotonin reuptake inhibitors, 532
electroconvulsive therapy and, 596, 597
Bradykinesia, 137, 142, 205
Bradyphrenia, 137, 142
Brain biopsy, 187
Brain imaging. See Imaging studies
Brain stimulation therapies, 589–611
deep brain stimulation, 607, 609–610
electroconvulsive therapy, 266–270, 589–607
future of, 610
key points related to, 610–611
transcranial direct current stimulation, 607, 608–609
transcranial magnetic stimulation, 270, 607, 607–608
vagus nerve stimulation, 607, 609
Breathing changes with aging, 36–37
Breathing-related sleep disorders, 435, 437–438
Brief dynamic therapy, for depression, 264
Brief Intervention and Treatment for Elders (BRITE) project, 655–656
Brief interventions for substance-related disorders, 475–476, 655–656
Brief Visuospatial Memory Test—Revised, 130, 135
Bright light therapy, 222, 441, 696
Briquet’s syndrome, 375
BRITE (Florida Brief Intervention and Treatment for Elders) project,
655–656
Bromocriptine, 400
Bronchospasm, electroconvulsive therapy-induced, 598
Browning, Robert, 33, 34
Buprenorphine patch, 518
Bupropion, 540–541
adverse effects of, 265, 397, 541
psychosis, 541
seizures, 541
for antidepressant-induced sexual dysfunction, 400
in bereavement, 425
cytochrome P450 enzyme inhibition and drug interactions with,
535, 541
for depression, 265, 539, 540–541
augmentation therapy, 541
compared with paroxetine, 530
in dementia, 228
dosing of, 265, 266, 534, 539
pharmacokinetics of, 534
Buschke Selective Reminding Test, 130, 135
Buspirone, 400, 557–558

C9orf72 gene, in frontotemporal lobar degeneration, 73, 74

C677T gene, in depression, 252
Cache County Memory Study, 139, 192, 193, 194, 195
CACNA1C gene, in schizophrenia, 78
CACNB2 gene, in schizophrenia, 78, 79
CAGE questionnaire, 473–474, 475
Calcium, 39
bone density and, 42
dietary intake of, 39, 42, 629, 633, 636
plasma level of, 109
delirium and, 164
supplementation of, 42, 636
Calcium channel blockers, 45, 93, 297, 399, 596
Calculation tests, 98
California Verbal Learning Test, 2nd Edition (CVLT-II), 130, 135–138
CALM-AD (Cholinesterase Inhibitor and Atypical Neuroleptic in the
Management of Agitation in Alzheimer’s Disease) study, 517
CAM (Confusion Assessment Method), 98–99, 156–158, 159, 171
Canadian Study of Health and Aging, 10
Cancer, 45, 54
dementia and, 207, 209
depression and, 250, 259, 260–261
diet, exercise and, 618, 635, 636
postmenopausal hormone replacement therapy and, 390, 393
sexual dysfunction and, 396, 398, 403
urinary incontinence and, 48, 49
Cancer chemotherapy, 399, 541, 629, 677
Cancer genomics, 66
Carbamazepine, 555
adverse effects of, 121, 297, 555
hematological effects, 297, 516, 555
sexual dysfunction, 399
for agitation in dementia, 516, 519, 555
for bipolar disorder, 249, 295, 296–297, 555
dosing of, 297, 516
drug interactions with, 297
cytochrome P450 enzyme induction and, 516, 555
lamotrigine, 555
valproate, 296, 554
laboratory testing before initiation of, 297
HLA-B*1502 allele test, 121, 297
pharmacokinetics of, 297, 555
therapeutic plasma level of, 516
use in nursing homes, 707, 709, 716
Carbidopa/levodopa, 442
Carbohydrate intake, 626, 633, 634
Cardiac output, 35–36, 527, 597
Cardiovascular disease, 45, 54. See also Hypertension; Myocardial
infarction
alcohol use and, 469, 470, 634
calcium supplementation and, 636
 depression and, 247, 253, 260, 261, 625
electroconvulsive therapy in, 267
estrogen and, 40, 41
falls and, 48
fish intake and, 636
minimizing risk of exercise in, 638
sexual dysfunction induced by medications for, 399
use of electroconvulsive therapy in, 270, 596–597
use of medications in
bupropion, 541
tricyclic antidepressants, 114
venlafaxine, 540
ziprasidone, 552
Cardiovascular Health Study Cognition Study, 10
Cardiovascular system
changes with aging, 35–36, 53, 529
drug effects on, 537
antipsychotics, 114, 114, 318, 514
clozapine, 551
ziprasidone, 114, 552
cholinesterase inhibitors, 218
citalopram, 114–115, 227, 516, 529, 532
lithium, 114, 114
mirtazapine, 540, 542
serotonin-norepinephrine reuptake inhibitors, 537, 540
trazodone, 542
tricyclic antidepressants, 113–114, 114, 228, 265, 544
electroconvulsive therapy effects on, 268, 596
Caregivers. See also Family
burden on, 180, 182, 206, 669–670
burnout of, 231
coping strategies of, 193, 659, 671, 672, 674, 675, 678, 681
of dementia patients, 230, 670–672
with agitation, 507–508
nonpharmacological strategies for, 509–513
depression among, 256
 education and support for management of neuropsychiatric
symptoms, 223, 225
effect on rate of decline, 193
grief intervention for, 426
neuropsychiatric symptoms encountered by, 669
quality of life of, 669
supportive care for, 230–233, 232
education about personality disorders, 501–502
guilt feelings of, 675
monitoring quality of care provided by, 672
referral to resources for, 673
respite for, 94, 232, 233, 672, 675, 676
Rosalynn Carter Institute for Caregiving, 673
self-efficacy of, 672, 678
social isolation of, 675, 679, 680–681
support groups for, 673, 675, 678, 679
tolerance of behavioral problems by, 95, 670, 678
β-Carotene, 635
Cartilage changes with aging, 42
Case identification, 4, 5–8
accuracy of, 7
based on DSM-5 diagnostic categories, 5–6
based on severity of impairment, 6–7
definition of, 5
“fuzzy sets,” 7
goal of, 5
historical trends and methods for, 20
reliability and validity of, 7–8
use of diagnostic instruments for, 6
CASS4 gene, in Alzheimer’s disease, 190, 191
Cataracts, 35, 45
Catatonia
electroconvulsive therapy for, 591
mania and, 258
Catechol O-methyltransferase inhibitors, 204
Category tests, 98, 130
CATIE (Clinical Antipsychotic Trial of International Effectiveness),
318
Alzheimer’s Disease study, 226, 321
CBC (complete blood count), 108
CBT. See Cognitive-behavioral therapy
CBT-I (cognitive-behavioral therapy for insomnia), 440, 442, 447, 450
CD2AP gene, in Alzheimer’s disease, 190, 191
CDC (Centers for Disease Control and Prevention), 41, 110, 208, 395
CELF1 gene, in Alzheimer’s disease, 190, 191
Celiac disease, 209–210
Center for Epidemiological Studies Depression Scale (CES-D), 6, 100,
243, 250, 251, 260, 263
Center for Substance Abuse Treatment, 462
Centers for Disease Control and Prevention (CDC), 41, 110, 208, 395
Centers for Medicare and Medicaid Services (CMS), 679, 691, 720,
721, 722, 723
National Partnership to Improve Dementia Care, 724–725
Nursing Home Quality Initiative, 722, 723
Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy, 199
Cerebrospinal fluid (CSF)
analysis of
in Alzheimer’s disease, 112–113, 128
in Creutzfeldt-Jakob disease, 113, 209, 209
in delirium, 163
in dementia, 186, 188
in frontotemporal lobar degeneration, 113
in mild cognitive impairment, 184
in primary central nervous system vasculitis, 209
in syphilis, 110
in normal-pressure hydrocephalus, 206
Cerebrovascular disease, 45, 54. See also Stroke
alcohol use and, 470, 634
dementia due to, 184, 190, 199–200 (See also Vascular
neurocognitive disorder)
neuropsychological assessment in, 136, 139–140
prevalence of, 12, 46
 infarcts, 99, 117, 118, 178–179, 189, 200, 620
sleep disturbances and, 43
CES-D (Center for Epidemiological Studies Depression Scale), 6, 100,
243, 250, 251, 260, 263
Chemistry tests, 108–109, 109
Chlamydia, 395
Chloral hydrate, 268–269, 448
Chlorpromazine, 317, 318, 551
CHMP2B gene, in frontotemporal lobar degeneration, 73
Cholinesterase Inhibitor and Atypical Neuroleptic in the Management
of Agitation in Alzheimer’s Disease (CALM-AD) study, 517
Cholinesterase inhibitors, 216–220, 218, 558–559, 559
adverse effects of, 211, 218, 441, 558, 559
in Alzheimer’s disease, 47, 193, 216–217, 218, 233, 558
for agitation, 517
for apathy, 229
apolipoprotein E and response to, 72, 193
combined with memantine, 47, 193, 218, 218, 219, 220, 559,
560
duration of treatment with, 219
for neuropsychiatric symptoms, 227–228
comparative efficacy of, 217
in delirium, 163
discontinuing before electroconvulsive therapy, 267
dosing of, 218, 219, 559
drug interactions with, 558, 559
effect on electroencephalogram, 120
efficacy of, 219
in frontotemporal lobar degeneration, 220, 558
in generalized anxiety disorder, 346
genotype and response to, 72
indications for, 558
in Lewy body neurocognitive disorder, 220, 558
mechanism of action of, 216–217
in mild cognitive impairment, 211, 558
in Parkinson’s disease dementia, 204, 220, 558
preparations of, 217, 218
 switching between, 219–220
use in nursing homes, 710, 712, 716–717
in vascular dementia, 220
Chromium intake, 633
Chronic disease, 45, 54. See also Medical conditions
Chronic obstructive pulmonary disease (COPD), 398, 509, 557
electroconvulsive therapy in, 598
sleep disturbances in, 442–443
use of benzodiazepines in, 443, 557
CIDI (Composite International Diagnostic Interview), 6, 9, 102
Cimetidine, 297
CIND. See Cognitive impairment not dementia
Ciprofloxacin, 549
Circadian rhythm disturbances, 435–436
Citalopram, 528
adverse effects of
cardiovascular effects, 114–115, 227, 516, 529, 532
cognitive effects, 532
for anxiety disorders, 361, 528
cytochrome P450 enzyme inhibition and drug interactions with,
535
for depression, 264, 265, 530, 532
dosing of, 114, 227, 265, 266, 529, 532, 533
for neuropsychiatric symptoms in dementia, 227, 529
agitation, 516, 518, 519
pharmacokinetics of, 533
use in nursing homes, 706
Citalopram for Agitation in Alzheimer Disease study, 227
CJD. See Creutzfeldt-Jakob disease
Clearance of drugs, 44, 53
Clinical Antipsychotic Trial of International Effectiveness (CATIE),
318
Alzheimer’s Disease study, 226, 321
Clinical Dementia Rating, 135
Clock Drawing test, 99, 136, 185
Clomipramine, 543
Clonazepam, 439, 442, 557
Clonidine, 399
Clozapine, 551
adverse effects of, 319, 398, 547, 551
dosing of, 551
for psychosis in Lewy body neurocognitive disorder, 322
for psychosis in Parkinson’s disease, 551
receptor blockade of, 550
for schizophrenia, 318, 319, 551
electroconvulsive therapy and, 591
CLU gene, in Alzheimer’s disease, 71, 190, 191
CMS. See Centers for Medicare and Medicaid Services
Cobalamin. See Vitamin B12
Cocaine, 112, 468, 478, 480
COGNISION trial, 120
Cognitive assessment, 52, 97–98
for delirium, 160
for dementia, 185–186
neuropsychological testing, 97, 99, 127–145
Cognitive-behavioral social skills training, in schizophrenia, 320
Cognitive-behavioral therapy (CBT), 650
for anxiety disorders, 333, 359–360, 363, 653–655
for depression, 263–264, 440, 650–651
for insomnia, 440, 442, 446–447
in nursing homes, 697
for persistent complex bereavement disorder, 425–426, 428
for personality disorders, 500, 656–657
for persons with cognitive impairment, 658–659
in schizophrenia, 316
for somatic symptom and related disorders, 382, 383
for substance-related disorders, 476, 655–656
Cognitive-behavioral therapy for insomnia (CBT-I), 440, 442, 447, 450
Cognitive distortions in depression, 254–255
cognitive restructuring of, 263–264
Cognitive effects
of drugs, 527
alcohol, 470
benzodiazepines, 360, 448, 450, 470
 chloral hydrate, 448
clozapine, 551
diphenhydramine, 470
lithium, 295, 553
memantine, 218
mirtazapine, 472
nonbenzodiazepine hypnotics, 448
olanzapine, 549
risperidone, 547
selective serotonin reuptake inhibitors, 532
topiramate, 556
tricyclic antidepressants, 228, 544
valproate, 554
of electroconvulsive therapy, 268, 269, 594, 596, 598
maintenance treatment, 607
Cognitive enhancers, 216–220, 218, 558–560, 559, 561. See also
Cholinesterase inhibitors; Memantine
use in nursing homes, 710, 712, 716–717
Cognitive functioning
age-related changes in, 46, 132–133
in normal aging, 132–133, 135, 144
processes of, 179
Cognitive impairment, 46–47. See also Memory impairment;
Neurocognitive disorder(s); specific syndromes
Alzheimer’s disease and, 134, 135, 139, 139, 189–199
in anxiety disorders, 357–359
bipolar disorder and, 291
delirium, 155–171
dementia, 177–233
depression and, 7, 138, 142–144, 246
diabetes mellitus and, 619
folate deficiency and, 111
four A’s of, 180
frontotemporal lobar degeneration and, 136, 140–141, 204–206
Huntington’s disease and, 137
hyperhomocysteinemia and, 111
hyponatremia and, 109
 hypothyroidism and, 111
impact on diet and physical fitness, 626–627
Lewy body neurocognitive disorder and, 136, 141–142, 200–202
mild, 182–184
normal-pressure hydrocephalus and, 137, 206–207
among nursing home residents, 691–693
Parkinson’s disease dementia and, 136, 141–142, 202–204
prevalence of, 8, 9–11, 10, 12
prion diseases and, 138, 208
progressive supranuclear palsy and, 137
psychotherapy for patients with, 650, 657–659, 660
schizophrenia and, 310
screening for, 6, 11
vascular neurocognitive disorder and, 136, 139–140, 199–200
vitamin B12 deficiency and, 111
Cognitive impairment not dementia (CIND), 182, 233
definition of, 178, 179
diagnosis of, 186, 187
prevalence of, 10, 11
risk factors for conversion to all-cause dementia, 182
Cognitive stimulation therapy (CST), 210, 659, 695
Cognitive therapy. See also Cognitive-behavioral therapy
for insomnia, 446
in nursing homes, 697
Cognitive training programs, computerized, 210
Cognitive triad, in depression, 264
Collaborative Psychiatric Epidemiology Surveys (CPES), 9, 24, 25
“Collective efficacy theory,” 23
Color Trail Making Test, 130
Color vision, 35
Communication
initial sessions with patient and family, 674–675
in management of neuropsychiatric symptoms of dementia, 225
with older adults, 90–91, 102–103, 104
strategies to reduce agitation, 512
Community housing with services, 3–4
Complete blood count (CBC), 108
Complicated grief therapy, 425
Composite International Diagnostic Interview (CIDI), 6, 9, 102
Compulsions, 340, 349, 350
Computed tomography (CT), 116
for agitation, 508
compared with magnetic resonance imaging, 117
in delirium, 163, 164
in dementia, 187
before electroconvulsive therapy, 267
radiation exposure from, 116
Concentration tests, 130
Confidentiality of genetic testing, 122
Confusion
drug-induced
memantine, 218
tricyclic antidepressants, 228
electroconvulsive therapy–induced, 268
hyponatremia and, 109
Confusion Assessment Method (CAM), 98–99, 156, 159, 171
Conscientiousness, 495, 498
Consortium for Research in ECT (CORE), 592
Consortium to Establish a Registry for Alzheimer’s Disease, 129, 139
Word List Memory Test, 130
Constipation
agitation and, 508, 509, 510, 514
delirium and, 162
depression and, 693
drug-induced, 45, 527
calcium supplements, 636
clozapine, 552
memantine, 218
olanzapine, 549
serotonin-norepinephrine reuptake inhibitors, 537
tricyclic antidepressants, 544
vortioxetine, 543
electroconvulsive therapy and, 598
neuropsychiatric symptoms of dementia and, 221, 222
 nutritional deficiencies and, 630
overflow incontinence and, 50
Construction praxis tests, 131, 135, 136, 138
Continuous positive airway pressure (CPAP), 229, 438
Conversion disorder (functional neurological symptom disorder), 373,
375, 377–379, 383
in DSM-5, 379
imaging studies in, 380
vs. neurological disease, 378, 382
prevalence of, 378
prognosis for, 378–379
psychodynamic theory of, 380
risk factors for, 378
symptoms of, 377
COPD. See Chronic obstructive pulmonary disease
COPE (Consortium for Research in ECT), 592
Coping strategies
bereavement and, 418–419, 421, 422, 423, 427, 428
depression and, 248, 264
education for enhancement of
individual problem-solving therapy, 651
in schizophrenia, 321
in substance-related disorders, 476
emotion-focused vs. problem-focused, 497
of family caregivers, 671, 672, 674, 681
assessment of, 678
for dementia patients, 193, 659, 675
sexual dysfunction and, 395, 400, 401
somatoform disorders and, 381
during subacute care in nursing homes, 727
support groups and, 679
Copy-number variations (CNVs), 64–65
Coronary artery disease, 42, 398. See also Myocardial infarction
electroconvulsive therapy and, 596–597
Corticobasal syndrome, 73, 188, 205, 206, 207
Corticosteroids, 110, 168, 339, 399
Alzheimer’s disease and, 213
Corticotropin, 38, 39
Corticotropin-releasing factor (CRF), 252, 625
Cortisol, 38, 51
in delirium, 162, 163, 164, 164
in depression, 252, 253
in generalized anxiety disorder, 357–358
in posttraumatic stress disorder, 358
CPAP (continuous positive airway pressure), 229, 438
CPES (Collaborative Psychiatric Epidemiology Surveys), 9, 24, 25
CR1 gene, in Alzheimer’s disease, 71, 190, 191
Creatinine, 108
Creatinine clearance, 43
Creutzfeldt-Jakob disease (CJD), 138, 186, 188, 207–210, 233
cerebrospinal fluid analysis in, 113, 209, 209
clinical presentation of, 208
criteria for, 209
diagnosis of, 208–209
electroencephalogram in, 113, 120, 186
imaging studies in, 113, 208, 209, 209
incidence of, 207
pathophysiology of, 207–208
CRF (corticotropin-releasing factor), 252, 625
CSF. See Cerebrospinal fluid
CST (cognitive stimulation therapy), 210, 659, 695
Cultural issues
beliefs about causes of mental illness, 34, 90
family care and, 676, 678
grief responses and, 420, 421, 424, 428, 439
personality disorders and, 492, 656
in psychotherapy, 650
stigma of mental illness, 673
CVLT-II (California Verbal Learning Test, 2nd Edition), 130, 135–138
Cyclothymic disorder, 283, 284
Cyproheptadine, 400
Cytochrome P450 enzyme system, 44, 529
AmpliChipR CYP450 Test of CYP2D6, 121
antidepressants and, 533–534
 benzodiazepines and, 557
carbamazepine and, 297, 555
cholinesterase inhibitors and, 559
olanzapine and, 549
valproate and, 554
Cytokines, 41, 43, 51, 164, 164, 627

DAPA-PC (Drug and Alcohol Problem Assessment for Primary Care),

475
DART-AD (Dementia Antipsychotic Withdrawal Trial in Alzheimer’s
Disease), 518
DBT (dialectical behavior therapy), for personality disorders, 500–
501, 650, 657
Deep transcranial magnetic stimulation (dTMS), 607, 608
Defenses, 496
hierarchy of adaptiveness of, 495, 496
interpretation of, 426
maturation across lifespan, 496, 500
Dehydration, 51, 635
agitation and, 508, 514
delirium and, 162, 619
dementia and, 221, 508
electroconvulsive therapy for patient with, 593, 600
endocrine changes and, 38, 39
laboratory testing in, 108, 112
lithium toxicity and, 553
Dehydroepiandrosterone (DHEA), 38, 51
Dehydroepiandrosterone sulfate (DHEA-S), 38, 252
Delayed ejaculation, 397
Delirium, 45, 155–171
with agitation, 160, 169, 170, 171, 507, 508
treatment of, 513–514
during alcohol or benzodiazepine withdrawal, 478, 513–514
assessment and diagnosis of, 156–163
assessment instruments, 98–99, 156–158, 159, 171
clinical presentations, 160–161
cognitive evaluation, 160
diagnostic criteria, 156, 158, 159
electroencephalography, 119, 161–162, 162
imaging studies, 161, 162, 163, 164–165
laboratory tests, 161, 162, 163
recommended workup, 161, 162
definition of, 155
differential diagnosis of, 161
vs. dementia, 46, 160, 161
due to medical conditions, 112, 161, 165, 167
economic costs of, 155
electroconvulsive therapy–induced, 596, 602–603
epidemiology of, 155–156, 157
hepatic encephalopathy, 514
in hospitalized patients, 155–156, 157, 168, 170
key points related to, 170–171
manic, 244, 258
medications associated with, 161, 165–166, 168, 171, 212, 527
anticholinergic agents, 45, 161, 163, 165–166, 168, 170, 212
management of, 170
polypharmacy, 165–166
mortality related to, 156
among nursing home residents, 156, 157, 691–692
outcomes of, 157, 170
pathophysiology of, 163–165, 164
postoperative, 156, 157, 165, 167, 168, 170, 514, 547, 548
prevention and management of, 155, 168–169, 170, 171
 nonpharmacological, 168–169
pharmacotherapy, 168, 513–514, 547, 548
risk factors for, 165, 166, 167
vitamin B12 deficiency and, 111
Delirium Observation Screening Scale, 156
Delirium Rating Scale, 156
Delusional depression, 96, 259. See also Psychotic depression
Delusional disorder, 15, 309, 313–315, 323
clinical features of, 313–314
epidemiology of, 314
imaging studies in, 315
pharmacotherapy for, 320
risk factors for, 314, 315
Delusions, 91, 309
agitation and, 508
Alzheimer’s disease and, 315–316, 316, 324
assessment of, 96
delirium and, 159, 160, 258
delusional disorder, 313–315
dementia and, 181, 669
depression and, 96, 259
generalized anxiety disorder and, 347
hoarding disorder and, 351
illness anxiety disorder and, 378
Lewy body neurocognitive disorder and, 201, 202, 317, 322, 517
mild cognitive impairment and, 182
among nursing home residents, 692, 716
obsessive-compulsive disorder and, 350
Parkinson’s disease and, 204, 317
antipsychotics for, 227
personality disorders and, 495, 502
pharmacotherapy for
citalopram, 529
rivastigmine, 517
prevalence of, 13, 309
schizophrenia and, 312, 313, 316
antipsychotics for, 317
Dementia, 177–233. See also Neurocognitive disorder(s); specific
types of dementia
with agitation, 359, 377, 441, 507–508, 514–515
nonpharmacological management of, 509–513
sexual aggression and, 405, 407
atypical antipsychotic–associated stroke and mortality risk in
elderly patients with, 225–226, 299, 317, 319, 322, 324, 514,
515–516, 545, 703, 716
clinical presentation of dementia syndrome, 179–182, 181
functional impairments, 180
neurological impairments, 182
neuropsychiatric symptoms, 180–182, 181, 193–195 (See
also Neuropsychiatric symptoms in dementia)
clinical presentation of milder cognitive syndromes, 182–184,
183
comorbidity with
alcohol use, 189, 471, 480
anxiety disorders, 358–359
bipolar disorder, 286, 287–288
depression, 181, 269–270
hoarding disorder, 349
conversion of mild cognitive impairment to, 182–184
definitions for, 46, 178–179, 179, 233
of depression, 143, 188–189
diagnosis and evaluation of, 46, 184–188, 187, 233
American Academy of Neurology guidelines for, 109–110
cognitive assessment, 185–186
electroencephalography, 119–120
history taking, 184–185
imaging studies, 118, 187–188
laboratory testing, 46, 186–188
cerebrospinal fluid analysis and plasma assays, 112–
113, 186, 188
neuropsychological assessment, 97, 99, 127–145, 135–138
differential diagnosis of, 186, 187, 233
vs. delirium, 46, 160, 161, 180
vs. mental retardation, 180
 in DSM-5, 180, 181, 182, 183
due to Alzheimer’s disease, 180.189–199, 190, 191, 197, 198
due to frontotemporal lobar degeneration, 204–206
due to hypothyroidism, 188
due to normal-pressure hydrocephalus, 188, 206–207
due to prion diseases and other rapidly progressive dementias,
207–210, 209
due to vitamin B12 deficiency, 111, 188
duration of, 177
economic costs of, 177
as geriatric syndrome, 45, 46–47
impact on diet and physical fitness, 626–627
institutionalization of persons with, 180, 182
key points related to, 233
Lewy body disorders, 200–204
Lewy body neurocognitive disorder, 201–202
Parkinson’s disease dementia, 202–204, 203
mortality and, 177, 182
among nursing home residents, 691–693
pain in, 377
personality changes in, 491, 492
prevalence of, 4, 11, 12, 26, 46, 177, 178
role of diet in etiology of, 189, 619–621
semantic, 73, 141, 204, 205
severity of, 186
sexual dysfunctions and, 181, 405–407
specific causes of, 188–189, 190
temporal onset of, 185
“treatable” and “untreatable” types of, 188, 233
vascular neurocognitive disorder, 199–200
Dementia Antipsychotic Withdrawal Trial in Alzheimer’s Disease
(DART-AD), 518
Dementia praecox, 311
Dementia treatment, 46–47, 210–233
adult day care, 231, 681
for cognitive symptoms, 47, 216–220, 218, 558–560, 559
disease-modifying therapies, 211, 213–216, 233
 for Alzheimer’s disease, 213–215
for normal-pressure hydrocephalus, 215–216
for other diseases, 215–216
for rapidly progressive dementias, 216
family care, 670–684 (See also Family)
four pillars of care, 211–212, 233
key points related to, 233
for milder cognitive syndromes, 210–211
multidisciplinary team for, 212
for neuropsychiatric symptoms, 221–230, 233
electroconvulsive therapy for depression, 269–270
in nursing homes, 697, 703–717, 704–715
principles of medication use, 212
psychotherapy, 650, 657–659, 660
supportive care, 211–212, 230–233, 232
Dementia with Lewy bodies (DLB). See Lewy body neurocognitive
disorder
Dementia With Lewy Bodies Consortium, 201
Demographic factors, 3–5
Dentition
changes with aging, 37
electroconvulsive therapy effects on, 598
Deoxyribonucleic acid (DNA), 62, 63, 123
copy-number variations in, 64–65
in frontotemporal lobar degeneration, 74
genome-wide association studies of, 65
noncoding, 62, 64, 65
single-nucleotide polymorphisms in, 62–64, 65
Department of Veterans Affairs (VA) facilities
alcohol use disorders in, 467
dementia and behavioral problems in, 692, 696
geriatric assessment in, 52
mortality risk of atypical antipsychotics in, 515
for bipolar disorder, 299
posttraumatic stress disorder in, 351
VA Community Living Centers, 696
Dependent personality disorder, 492, 494, 498, 657
Depression, 243–272
affect and mood in, 95
age at onset of, 254, 258, 260
bereavement and, 255, 256, 416, 419, 421, 422, 426
biological origins of, 251–254, 252, 271
endocrine changes, 252–253
genetics, 75, 79, 251–252
environmental factors and, 22, 79
medical and psychiatric comorbidity, 253–254
neurotransmitter dysfunction, 252
vascular depression, 252, 253
bipolar, 285, 298, 299, 554, 555
among caregivers of dementia patients, 256
clinical course and prognosis for, 245–251
coping behavior and, 248–249
mortality rates, 249–251
personality and, 249
social support and, 248
comorbidity with, 253–254
alcohol abuse, 254, 470, 480
Alzheimer’s disease, 47, 193, 228–229, 246
anxiety disorders, 7, 245, 254, 346, 348, 349, 355–357
cognitive impairment, 7, 138, 142–144, 246
dementia, 181, 269–270
dysthymia, 246, 260
medical conditions, 51–52, 111, 143, 245, 246–247, 248,
253–254, 260–262, 625
mild cognitive impairment, 182
pain, 377
Parkinson’s disease, 204
personality disorders, 254, 493, 657
schizophrenia, 310
sexual dysfunction, 397
sleep disturbances, 262, 440
substance misuse, 459
conceptualization of, 243–244
delusional, 96, 259
dementia of, 143, 188–189
diagnosis of, 244, 244, 258–262
adjustment disorder with depressed mood, 244, 261–262
depressive episode due to another medical condition, 244,
260–261
depressive episode with insufficient symptoms, 244, 260
major depressive disorder, 244, 258–259
with psychotic features, 259
persistent depressive disorder, 244, 259–260
diagnostic workup of, 262, 263, 272
dietary factors and, 262, 618, 621–624, 623, 639
“double,” 260
DSM-5 disorders relevant to, 243, 244, 244
epidemiology of, 244–245
etiology of, 251–258, 271
functional impairment in, 23, 143, 144, 243–244, 246, 247, 250,
253, 263, 421, 694
vs. grief, 418
hypothalamic-pituitary-adrenal axis in, 357
imaging studies in, 358
impact on diet and physical fitness, 625–626
key points related to, 271–272
with melancholia, 6, 100, 259, 265, 267, 590
neuropsychological assessment in neurocognitive disorder
associated with, 138, 142–145
among nursing home residents, 245, 692, 693–695, 729
prevalence of, 6, 11, 14–15, 16–17, 18, 143, 245
by race/ethnicity and immigration status, 9
in treatment settings, 18, 19, 245
psychological origins of, 252, 254–255
psychotic, 96, 244, 259, 367, 601, 684
rating scales for, 6, 52, 99–100, 243
screening for, 6, 52, 99–100, 245, 262
social origins of, 23, 243–244, 255–258, 271
substance/medication-induced, 244, 244
subtypes in later life, 244, 244, 245
suicide risk and, 262
 symptoms of, 4, 244, 244
in cyclothymic disorder, 284
prevalence of, 11
twin studies of, 22, 251
vascular, 252, 253, 262, 263
Depression treatment, 263–271
antidepressants, 264–266, 266, 272, 528–544 (See also specific
drugs and classes)
after course of electroconvulsive therapy, 592
STAR*D study of, 540, 541–542
use in dementia, 228–229
use in nursing homes, 705, 706, 708, 710, 717, 725
for bipolar depression, 298, 299, 554, 555
deep brain stimulation, 607, 609–610
duration of, 248
efficacy of, 247–248
electroconvulsive therapy, 247–248, 259, 266–270, 272, 590–591,
600
compared with repetitive transcranial magnetic stimulation,
608
maintenance treatment with, 592, 606–607
pharmacological maintenance to prevent relapse after, 592,
606
for psychotic depression, 367, 591
exercise, 628
family therapy, 270–271
to improve functioning, 7
key points related to, 272
mental health service use for, 24, 25, 26
in nursing homes, 705, 706, 708, 710, 717, 718, 725, 729
psychotherapy, 247, 263–264, 272, 650–653, 660
repetitive transcranial magnetic stimulation, 270, 608
St. John’s wort, 628
for treatment-resistant disease, 247–248
undertreatment, 25, 26
vagus nerve stimulation, 609
Desipramine, 543
 for depression, 265
dosing of, 265, 266, 544
therapeutic plasma level of, 265, 544
Desvenlafaxine, 536
cytochrome P450 enzyme inhibition and drug interactions with,
535
for depression, 536–537, 538
dosing of, 533, 538
pharmacokinetics of, 533
DETERMINE Checklist, 630
Detoxification, 478
Detrusor overactivity, 48
Dexmedetomidine, for electroconvulsive therapy, 603
DHEA (dehydroepiandrosterone), 38, 51
DHEA-S (dehydroepiandrosterone sulfate), 38, 252
Diabetes mellitus, 41, 45, 54
alcohol use and, 469, 470
Alzheimer’s disease and, 189, 213
atypical antipsychotic–induced, 109, 109, 299, 317, 319, 545
clozapine, 549
olanzapine, 549
quetiapine, 551
risperidone, 547
bipolar disorder and, 287, 288
cognitive impairment in, 619
depression and, 247, 253, 622, 694
psychotherapy for, 263
diet and exercise interventions for, 618, 619, 623, 635, 636
electroconvulsive therapy in, 597
laboratory testing for, 108, 112
medication use and, 527
neuropathy of
duloxetine for, 536
pregabalin for, 556
periodic limb movement disorder, restless legs syndrome and, 439
sexual dysfunction and, 396, 398
urinary incontinence and, 48
 vascular dementia and, 199
Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5),
333
anxiety disorders in, 334, 335
agoraphobia, 344
panic disorder, 345
recommendations of Anxiety Disorders Advisory Committee
to the Lifespan Disorders Work Group, 334, 336–337, 355
social anxiety disorder, 343
specific phobia, 342
bereavement in, 420–421
persistent complex bereavement disorder, 424
bipolar and related disorders in, 283–284
delirium in, 156, 158
delusional disorder in, 314
depressive disorders in, 243, 244, 244
diagnostic categories in, 14
case identification based on, 5–6
use for elderly persons, 15
hoarding disorder in, 351
major neurocognitive disorder in, 180, 181
mild neurocognitive disorder in, 11, 182, 183
obsessive-compulsive and related disorders in, 335
obsessive-compulsive disorder in, 350
personality disorders in, 492, 495, 498
sexual dysfunctions in, 395, 397
sleep disorders in, 435
somatic symptom and related disorders in, 373, 374, 375
conversion disorder, 378, 379
illness anxiety disorder, 377, 378
somatic symptom disorder, 375, 376
substance use disorder in, 464–465, 466
trauma- and stressor-related disorders in, 335
Diagnostic Interview Schedule (DIS), 6, 8
Diagnostic Interview Schedule for DSM-IV (DIS-IV), 102
Diagnostic reliability and validity, 7–8
Dialectical behavior therapy (DBT), for personality disorders, 500–
501, 650, 657
Diarrhea, 630
drug-induced
cholinesterase inhibitors, 218, 558, 559
selective serotonin reuptake inhibitors, 541
serotonin-norepinephrine reuptake inhibitors, 537
vilazodone, 543
Diazepam, 45, 448, 554, 557, 705
Diet and nutrition, 617–636, 638–639. See also specific nutrients
Alzheimer’s disease and, 189
effect on mental health and cognitive well-being, 618–619, 619
627
gastrointestinal changes with aging and, 37–38
impact of mental health status on, 625–627
alcoholism, 627
mood disorders, 625–626
stroke, dementia, and other brain diseases, 626–627
indirect effects on mental health, 624–625
interaction of treatments with, 627–629
diet and physical activity as psychiatric treatment, 628–629
drug-nutrient interactions, 628
monoamine oxidase inhibitors, 544, 628
drug side effects, 628
key points related to, 639
late-life depression and, 621–624, 623
Mediterranean diet, 620, 621, 622, 623, 634, 639
nutritional assessment, 629–630, 631
nutritional deficiency and schizophrenia risk, 22
nutritional issues and wellness barriers for older adults, 629
recommendations for, 632–, 636
dietary reference intakes, 632, 633
energy-yielding nutrients and alcohol, 632–635
nutritional supplements, 628–629, 635–636
water and fiber, 635
role in etiology of dementia, 189, 619–621
alcohol intake, 620
 fat intake, 620
fish intake, 620–621
vitamins, 621
Dietary reference intakes (DRIs), 632, 633
Dietary supplements, 628–629, 635–636
Diffusion-weighted imaging (DWI), 117, 117–118
in Creutzfeldt-Jakob disease, 209, 209
DiGeorge syndrome, 77
Digitalis, 597
Digoxin, 45, 399, 470
Diltiazem, 45, 557
Diphenhydramine, 448, 470
DIS (Diagnostic Interview Schedule), 6, 8
DIS-IV (Diagnostic Interview Schedule for DSM-IV), 102
Disability. See Functional status/impairment
DISC1 gene, in schizophrenia, 77
Disinhibition, 194, 501
agitation and, 513, 514
benzodiazepine-induced, 513
in dementia, 181
in frontotemporal lobar degeneration, 136, 140, 144, 204, 206
as personality factor, 498
in poststroke nursing home residents, 727
selective serotonin reuptake inhibitors for, 228, 529
sexual, 405, 406
Disopyramide, 399
Dissociation
conversion disorder and, 378
posttraumatic stress disorder and, 353, 354
Dissociative amnesia, 379, 380
Distribution of psychiatric disorders, 4, 8–18, 10, 12, 13, 16–17, 26.
See also Epidemiology of psychiatric disorders in elderly persons
in treatment settings, 15, 18, 19
Disulfiram, for alcohol dependence, 477
Diuretics
before electroconvulsive therapy, 595
incontinence due to, 48
 interaction with lithium, 295, 553
nocturia and, 444
sexual dysfunction and, 397, 398
Divalproex. See Valproate
Divorce, 22, 256, 396, 415, 424, 469
Dizziness
drug-induced buspirone, 557
carbamazepine, 555
memantine, 218
phosphodiesterase 5 inhibitors, 404
pregabalin, 556
quetiapine, 551
ramelteon, 448
rivastigmine, 218, 559
hyponatremia and, 109
DJ1/PARK7 gene, in Parkinson’s disease, 74, 75
DLB. See Lewy body neurocognitive disorder
DNA. See Deoxyribonucleic acid
Donepezil
adverse effects of, 218, 348, 558–559, 559
in Alzheimer’s disease, 47, 216–217, 218, 220, 558–559
for agitation, 517
combined with memantine, 559–560
dosing of, 218, 559
drug interactions with, 559
in mild cognitive impairment, 211
preparations of, 218
use in nursing homes, 710, 712, 716, 717
Dopamine
in Alzheimer’s disease, 196
in delirium, 164
in depression, 252
medication actions on
antipsychotics, 550, 551
bupropion, 228, 541
selective serotonin reuptake inhibitors, 545
in Parkinson’s disease, 203–204
 in schizophrenia, 78
Dopamine agonists
for Parkinson’s disease dementia, 215
for restless legs syndrome and periodic limb movement disorder,
439
sleep disturbances induced by, 442
Douglas Institute Centre for Studies on Prevention of AD (Montreal),
214
Down syndrome, 69
Doxepin, 543
for depression, 265, 266
compared with selective serotonin reuptake inhibitors, 530
dosing of, 266, 449
for insomnia, 448, 449–450
in Parkinson’s disease, 442
DRD2 gene, in schizophrenia, 78
DRIs (dietary reference intakes), 632, 633
Driving, 52, 180, 234
alcohol use and, 464, 470
assessing capacity for, 91, 128, 681, 682
medications affecting
benzodiazepines, 470
mirtazapine, 542
placing limitations on, 223, 682–683
signs of decline in skills for, 682
Drug absorption, 44
Drug and Alcohol Problem Assessment for Primary Care (DAPA-PC),
475
Drug clearance rate, 44, 53
Drug elimination half-life, 44–45, 53
antidepressants, 533–534
benzodiazepines, 448, 449, 556, 557
cholinesterase inhibitors, 559
lithium, 295
sleep medications, 448, 449, 450, 557
valproate, 554
Drug interactions, 212
 with alcohol, 462, 470
with benzodiazepines, 557
with bupropion, 535, 541
with carbamazepine, 296, 297, 516, 554, 555
with cholinesterase inhibitors, 558
with lamotrigine, 554, 555
with lithium, 295, 553
with mirtazapine, 542–543
with nonsteroidal anti-inflammatory drugs, 295, 532, 553
with olanzapine, 320
polypharmacy and, 50
with selective serotonin reuptake inhibitors, 93, 531, 532, 535
with serotonin-norepinephrine reuptake inhibitors, 535, 537
with trazodone, 535, 543
with valproate, 93, 296, 554
with vilazodone, 535
with vortioxetine, 535
with warfarin, 93, 296, 470, 532, 545
Drug metabolism, hepatic, 44
Drug protein binding, 44
Drug volume of distribution, 44
Dry mouth, drug-induced, 628
mirtazapine, 448
quetiapine, 550
serotonin-norepinephrine reuptake inhibitors, 537
trazodone, 542
tricyclic antidepressants, 544
DSM-5. See Diagnostic and Statistical Manual of Mental Disorders 5
Duloxetine, 536
for anxiety disorders, 361
cytochrome P450 enzyme inhibition and drug interactions with,
535, 537
for depression, 265, 266, 536–537, 538
in dementia, 228
dosing of, 266, 533, 538
hepatotoxicity of, 109
indications for, 536
 pharmacokinetics of, 533
DWI (diffusion-weighted imaging), 117, 117–118
in Creutzfeldt-Jakob disease, 209, 209
Dyslipidemia, atypical antipsychotic–induced, 109, 299, 317, 319,
547, 549, 551
Dyspareunia. See Genito-pelvic pain/penetration disorder
Dysthymia. See Persistent depressive disorder (dysthymia)

ECA (Epidemiologic Catchment Area) study, 6, 8, 15, 17, 18, 23, 24,
102, 245, 250, 285, 288, 338, 349, 467, 480
ECG. See Electrocardiography
Economic costs
of aging population, 4
of delirium, 155
of dementia, 177
ECT. See Electroconvulsive therapy
ED. See Erectile disorder
Educational strategies with families, 223, 225, 509–510, 680
EEG. See Electroencephalography
EIF4G1 gene, in Parkinson’s disease, 74
Ejaculation
delayed, 397
premature (early), 397, 404–405
Elder mistreatment, 670
Electrocardiography (ECG), 113–115. See also QTc interval
before/during drug treatment
carbamazepine, 297
tricyclic antidepressants, 265
drug effects on
antipsychotics, 114, 114, 514, 552
β-blockers, 114
citalopram, 114–115, 227, 516, 529, 532
lithium, 114, 114
mirtazapine, 540, 542
serotonin-norepinephrine reuptake inhibitors, 537
trazodone, 542
tricyclic antidepressants, 113–114, 114, 265
 before electroconvulsive therapy, 267
for suspected drug overdose, 113, 115
Electroconvulsive therapy (ECT), 589–607
for bipolar disorder, 249, 299, 591, 593, 606
for catatonia, 591
continuation or maintenance treatment with, 269, 592–593, 606–
607
for depression, 247–248, 259, 266–270, 590–591, 600
compared with antidepressants, 590
compared with repetitive transcranial magnetic stimulation,
608
in dementia, 269–270
effectiveness of, 266, 268–269
evaluation before initiation of, 266, 599–601
components of, 599
deciding whether to recommend ECT, 593, 599–600
informed consent, 600–601
medication management, 266, 267–268, 601
future of, 610
history of, 589–590
indications for, 590–591
key points related to, 610
for Parkinson’s disease, 591
patient/family education about, 266
response of older adults to, 591–592
risks and adverse effects of, 268, 593–599
cardiovascular disorders, 596–597
central nervous system disorders, 595–596
cognitive effects, 268, 269, 594, 596, 598, 607
endocrine disorders, 597
gastrointestinal disorders, 598
genitourinary disorders, 598
hematological disorders, 597–598
metabolic disorders, 597
mortality, 593–594
musculoskeletal disorders, 598
in older adults, 598–599
 pulmonary disorders, 598
for schizoaffective disorder, 591
for schizophrenia, 589, 590, 591
technique for, 268, 602–606
anesthesia, 602–603
anticholinergic medications, 268, 596, 597, 602
determining seizure adequacy, 268, 605
inpatient vs. outpatient settings, 602
number and frequency of treatments, 268, 605–606
physiological monitoring, 603
stimulus dosing, 604–605
stimulus electrode placement, 268, 603–604
trends in utilization of, 590
use in older adults, 269, 590
use in patients with medical illness, 270, 594–598
Electroencephalography (EEG), 119–120
in Creutzfeldt-Jakob disease, 113, 120, 186, 209
in delirium, 119, 161–162, 162, 187
in dementia, 119–120, 186–187
drug-induced abnormalities on
olanzapine, 549
risperidone, 547
for electroconvulsive therapy, 268, 599, 603
in frontotemporal lobar degeneration, 186
indications for, 119, 162
Electrolyte disorders, 43. See also specific electrolytes
agitation and, 509
delirium and, 46, 162, 163, 164, 169
laboratory testing for, 108–109, 163
before carbamazepine use, 296
lithium-induced, 553
sexual dysfunction and, 399
Elimination half-life of drugs, 44–45, 53
antidepressants, 533–534
benzodiazepines, 448, 449, 556, 557
cholinesterase inhibitors, 559
lithium, 295
 sleep medications, 448, 449, 450, 557
valproate, 554
Employment
of family caregivers, 670
of older persons, 4
retirement from, 33, 251, 261, 381, 395, 446, 464, 468, 494, 497
work rehabilitation programs for patients with psychosis, 321
Encephalopathy
cancer-associated, 207
due to alcohol intoxication, 207
Hashimoto’s, 207, 209
hepatic, 514, 591
limbic, 209
spongiform, 207, 208
subcortical arteriosclerotic, 267
Wernicke’s, 117, 117
Endocrine system
changes with aging, 38–41
adrenal androgens, 38
adrenal medulla and sympathetic nervous system, 39
antidiuretic hormone, 38
corticotropin and cortisol, 38
estrogen, 40–41
growth hormone, 39
insulin, 41
musculoskeletal effects of, 51
parathyroid hormone, vitamin D, and calcium regulation, 39
prolactin, 38
renin, angiotensin and aldosterone, 39
testosterone, 40
thyroid, 41
depression and, 252–253, 260
electroconvulsive therapy in disorders of, 597
Energy requirements with aging, 632
Environmental factors, 22, 26
assessment of, 93
falls due to, 47, 48
 interaction with genetic factors, 21–22, 66, 80
in depression, 22, 79
in management of neuropsychiatric symptoms of dementia, 225
nutritional status and, 629
EPESE. See Established Populations for Epidemiologic Studies of the
Elderly
EPHA1 gene, in Alzheimer’s disease, 190, 191
Epidemiologic Catchment Area (ECA) study, 6, 8, 15, 17, 18, 23, 24,
102, 245, 250, 285, 288, 338, 349, 467, 480
Epidemiology of psychiatric disorders in elderly persons, 3–26
anxiety disorders, 334–335, 338
bipolar and related disorders, 284–286
case identification, 4, 5–8
definition of, 3
delirium, 155–156, 157
delusional disorder, 314
demographic factors, 3–5
depression, 244–245
descriptive epidemiology, 5
distribution of disorders, 4, 8–18, 10, 12, 13, 16–17, 26
in treatment settings, 15, 18, 19
etiological studies, 5, 21–23
health service utilization, 5, 21–23
historical studies, 5, 18–20, 21
key points related to, 26
longitudinal studies, 8, 18, 23
Alzheimer’s disease and folate intake, 111
anxiety disorders, 333, 357
bereavement, 416, 418, 422, 423
bipolar disorder, 291
depression, 249, 253, 254, 255, 256
maturation of defenses, 496
nutrition and dementia, 620, 621, 622
personality disorders, 495, 496, 498, 503
schizophrenia, 310
substance-related disorders, 468, 480
 substance-related disorders, 8–9, 18, 459–460, 460, 461, 465–
468, 482
uses of epidemiological studies, 4–5
Epigenomics, 123, 123
Epilepsy. See also Seizures
electroconvulsive therapy in, 589, 601
electroencephalography in, 119
psychogenic nonepileptic seizures and, 378
schizophrenia and, 589
Epinephrine, 39, 164
Epworth Sleepiness Scale, 229
Erectile disorder (ED), 396, 397, 403–404, 408
Alzheimer’s disease and, 405
etiology of, 403
laboratory testing for, 399
testosterone deficiency and, 40
treatment of, 389, 400, 403–404
Erikson’s stage-theory of late-life development, 496, 500
Erythromycin, 297, 554, 557
Escitalopram, 528
adverse effects of
cardiovascular effects, 115, 227
cognitive effects, 532
for anxiety disorders, 361, 528
cytochrome P450 enzyme inhibition and drug interactions with,
535
for depression, 264, 528, 530, 532
with insomnia, 440
vs. serotonin-norepinephrine reuptake inhibitors, 536–537,
540
dosing of, 266, 533
indications for, 528
for neuropsychiatric symptoms in dementia, 227, 529
pharmacokinetics of, 533
Esophageal function, 37
Established Populations for Epidemiologic Studies of the Elderly
(EPESE), 34
 East Boston, 11, 12
Hispanic, 13, 22
Iowa, 13
North Carolina, 250
Estazolam, 448
Estrogen(s)
Alzheimer’s disease and, 189, 213
bone mass and, 42, 51
postmenopausal decline in production of, 40, 393, 394, 403
nocturia and, 443
symptoms related to, 444
to reduce aggression in dementia, 407, 518
replacement therapy with, 41
for psychosis, 312
thyroid effects of, 110
Eszopiclone, for insomnia, 448, 448, 449, 556, 557
in depression, 440
dosing of, 449
with hot flashes, 444
in Parkinson’s disease, 442
Ethical issues
Alzheimer’s prevention studies, 215
genetic testing, 120, 121–122, 123
genomic medicine, 80
sexuality and dementia, 405
Etiological studies of psychiatric disorders in elderly persons, 5, 21–
23, 26
Etomidate, for electroconvulsive therapy, 602
Euphoria
delirium and, 159
mania and, 244, 283, 284
orgasm and, 393
Evidence-Based Caregiver Intervention Resource Center, 673
Executive function, 46, 180
in Alzheimer’s disease, 134, 315
in bipolar disorder, 291
in cerebrovascular disease, 140
 in dementia, 181
discussing deficits with family, 674
effect of exercise programs on, 210
in frontotemporal lobar degeneration, 136, 140, 204
in generalized anxiety disorder, 357, 654
in hoarding disorder, 357
in Lewy body neurocognitive disorder, 201
in major neurocognitive disorder, 181
in mild neurocognitive disorder, 183
normal age-related declines in, 144
in normal-pressure hydrocephalus, 206
in Parkinson’s disease, 137, 202
effect of cholinesterase inhibitors on, 220
in personality disorders, 499
psychotherapy and, 654, 657–658
tests of, 99, 129, 130, 144, 185
in vascular dementia, 184
Exercise. See Physical activity
Exposure therapy
for anxiety disorders, 359–360, 653
for complicated grief, 425
Extrapyramidal symptoms
in Alzheimer’s disease, 201, 315
in corticobasal syndrome, 205
in Creutzfeldt-Jakob disease, 138, 208, 209, 209
drug-induced
antipsychotics, 322, 514, 515, 545
atypical antipsychotics, 321, 322, 515, 545, 547, 549,
551, 707–709, 711, 714
rivastigmine, 218
selective serotonin reuptake inhibitors, 536
in frontotemporal lobar degeneration, 205
in Lewy body neurocognitive disorder, 142
antipsychotic sensitivity and, 226–227, 322
in paraneoplastic syndromes, 209
in Parkinson’s disease, 137, 142
in progressive supranuclear palsy, 137
Extraversion, 193, 495, 498

Factitious disorder, 373

Falls, 34, 45, 47–48
causes of, 47
evaluation of, 47–48
family tolerance of, 95
fear of, 335, 336, 341, 352, 361, 658
insomnia and, 450
medication-related, 47, 212, 450, 527
antidepressants, 227, 228, 536, 718
benzodiazepines, 360, 450, 470, 557
morbidity and mortality from, 47
in nursing homes, 47, 718
prevalence of, 47
reducing risk of, 48
nonpharmacological strategies, 224
physical activity, 618
vitamin D and calcium, 618, 636
Family
assessment of, 93–95, 676–678
care coordination by, 670
care for dementia patient by, 230, 669–684
for agitation, 507–508
nonpharmacological strategies, 509–513
burden on, 180, 182, 206, 669–670
burnout of, 231
effect on rate of decline, 193
quality of life of, 669
respite for, 94, 232, 233, 672, 675, 676
safety issues for, 670, 672
working with, 669–684
diagnostic office visits with, 674
goals in, 672
key points related to, 684
over course of progressive impairment, 680–681
reminders for clinicians about, 671–672
 commitment to values of, 670, 671
contingency care plans for, 672
counseling of, 672, 673, 676, 678
denial of, 671
educational strategies for, 223, 225, 509–510, 680, 681
about electroconvulsive therapy, 266
elder mistreatment by, 670
expectations of psychiatrists, 675–676
flexibility of, 671
grief intervention for, 426
guilt feelings of, 675
helping to assess capacity of older adult, 681–684
capacity to live alone, 683
driving limitations, 682, 682–683
related to institutionalization, 683–684
inclusion in neuropsychological assessment, 129
as information seeker, 673–674
initial communication with patient and, 674–675
interdisciplinary partnerships with, 672–673, 684
key messages for, 681
of lesbian, gay, bisexual, or transgender persons, 677
monitoring quality of care provided by, 672
mood, anxiety, or substance-related disorders among, 256, 671,
672, 677
preventive self-care suggestions for, 676
selecting interventions for, 678–679
services for older adults provided by, 94
social isolation of, 675, 679, 680–681
support groups for, 673, 675, 678, 679
supportive care for, 230–233, 232
tolerance of behavioral problems by, 95, 670, 678
Family Caregiver Alliance’s LGBT Caring Community Online
Support Group, 677
Family Confusion Assessment Method, 158
Family consultant, 673
Family history, 92
Family studies, 61, 66
 of depression, 251
Family therapy, for depression, 270–271
FAST (Functional Adaptation Skills Training), 320
Fat intake, 620, 626, 633, 634
Fatal familial insomnia, 216
Fatigue
of family caregivers, 675
grief and, 416
hyponatremia and, 109
hypothyroidism and, 111
memantine-induced, 218
FDG (18fluorodeoxyglucose) PET imaging, 118
Fear. See also Anxiety; Worry
agitation and, 510, 511
in Cluster C personality disorders, 492, 494
cognitive-behavioral therapy for, 653
in delirium, 159
about electroconvulsive therapy, 590
of falling, 335, 336, 341, 352, 361, 658
of family caregivers, 674
in generalized anxiety disorder, 346
health-related, 374
in illness anxiety disorder, 378
of imminent neurocognitive disorder, 128
sexual dysfunction and, 396, 397
situational, 339, 340, 362
Fear disorders, 339, 341–346. See also Anxiety disorders
panic disorder, 341, 342–346, 345
phobias, 341–342
agoraphobia, 335, 336, 344
social anxiety disorder, 343
specific phobia, 336, 342
Felodipine, 45
Female orgasmic disorder, 396, 397, 404
Female sexual interest/arousal disorder, 397, 403, 404, 408
FERMT2 gene, in Alzheimer’s disease, 190, 191
Fever, 51, 162, 163, 680
 lamotrigine and, 555
mirtazapine and, 108
FGF20 gene, in Parkinson’s disease, 75
Fiber intake, 633, 635
Fibromyalgia, 442, 536, 556
Finasteride, 49
Finger Oscillation test, 131
Fish intake, 620–621, 623, 636
Fish oil supplements, 623, 636
Five-factor model of personality, 495, 498
Florbetaben, 118
Florbetapir, 118, 188, 196
Florida Brief Intervention and Treatment for Elders (BRITE) project,
655–656
Fluency tests, 130, 133
Flumazenil, 601
Flumetamol, 118
Flunitrazepam, 443
Fluorescent treponemal antibody test, 110
18Fluorodeoxyglucose (FDG) PET imaging, 118

Fluoxetine, 528
combined with olanzapine, for bipolar disorder, 298
for depression, 264, 265, 266, 530, 532
with insomnia, 440
dosing of, 265, 266, 533
drug interactions with
bupropion, 541
cytochrome P450 enzyme inhibition and, 535, 541
valproate, 554
warfarin, 93
indications for, 528
pharmacokinetics of, 533
switching to monoamine oxidase inhibitor from, 266
for vasomotor menopausal symptoms, 444
Flurazepam, 448, 449, 557
Fluvoxamine, 528
 cytochrome P450 enzyme inhibition and drug interactions with,
535
olanzapine, 549
for depression, 530, 532
dosing of, 532, 533
indications for, 528
pharmacokinetics of, 533
Folate
deficiency of, 111, 621
alcoholism and, 627
laboratory testing for, 111, 262
dementia and, 189, 621
depression and, 262, 622
L-methylfolate treatment, 628
selective serotonin reuptake inhibitor response and, 628
dietary intake of, 633
mild cognitive impairment and, 210
supplementation of, 635–636
Follicle-stimulating hormone, 40
Four pillars of dementia care, 211–212, 233
Fractures
electroconvulsive therapy–related, 268, 598
hip
alcohol consumption and, 470
delirium and, 169
depression and, 247, 253
due to falls, 47
medication–related, 536, 557
subacute nursing home care for, 727
imaging of, 115, 116, 267
incontinence and, 50
medication-related, 527
antidepressants, 227, 536, 540
atypical antipsychotics, 545
benzodiazepines, 470, 557
bisphosphonates, 42
minimizing risk during exercise, 638
 nutritional deficiencies and, 625
benefits of vitamin D and calcium supplementation, 636
osteoporotic, 36, 268, 638
estrogen replacement therapy and, 41
skull, 116
vertebral, 36, 268
Frailty, 45, 50–51, 52, 54
agitation and, 513
physical restraint for, 718
definition of, 51
delirium and, 155, 513
dementia and, 215, 228, 513
depression and, 246–247, 694
inadequate energy intake and, 632
of nursing home residents, 690, 694, 717, 718, 732
nutritional, 625, 632
pharmacotherapy and
antidepressants, 228
mirtazapine, 542
selective serotonin reuptake inhibitors, 532, 717
venlafaxine, 717
benzodiazepines, 470, 557
effect on drug protein binding, 44
lithium, 295
for nursing home residents, 717, 732
Frontal Assessment Battery, 131, 136, 185
Frontotemporal lobar degeneration (FTLD; frontotemporal dementia),
190, 204–206
behavioral variant, 73, 141, 204
clinical presentations of, 73, 141, 204
corticobasal syndrome and, 205
diagnosis of, 206
genetic testing, 73–74, 81
plasma assays, 113
TDP-43, 73, 113, 141, 190, 206
differentiation from Alzheimer’s disease, 118, 206
genetics of, 73–74, 113, 206
 with motor neuron disease, 73, 141, 205
neuropathology of, 73, 74, 140, 141, 190, 192, 196, 198–199,
205–206
neuropsychological assessment in, 136, 140–141, 144
personality changes in, 73, 136, 140, 190, 204, 499
pharmacotherapy for, 233
antidepressants, 228
cholinesterase inhibitors, 220
prevalence of, 140, 204
primary progressive aphasia, 73, 140–141, 204–205
progressive supranuclear palsy and, 205
with psychosis, 317
semantic dementia, 73, 141, 204, 205
Functional Adaptation Skills Training (FAST), 320
Functional magnetic resonance imaging, 116
in dementia, 188
in generalized anxiety disorder, 358
in somatic symptom and related disorders, 380
Functional neurological symptom disorder. See Conversion disorder
Functional status/impairment, 46. See also Activities of daily living
performance; Instrumental activities of daily living performance
agoraphobia and, 336
Alzheimer’s disease and, 190, 192–193, 194, 195
pharmacotherapy effects on, 213, 217, 219
with psychosis, 316
assessment of, 51, 52, 91, 101, 104
functional analysis, 222–223
instrument for, 101
neuropsychological evaluation, 128, 129, 132
by occupational therapist, 186, 231
bipolar disorder and, 288, 289, 291
capacity to live alone and, 683
case identification based on, 6–7
conversion disorder and, 378
delirium and, 155, 157, 165, 167, 170
dementia and, 180, 185, 186, 187, 659
 depression and, 23, 143, 144, 243–244, 246, 247, 250, 253, 263,
421, 694
exercise and, 637, 638
falls and, 352, 618
frailty and, 51
frontotemporal lobar degeneration and, 144
generalized anxiety disorder and, 347
Lewy body neurocognitive disorder and, 141, 142
mild cognitive impairment and, 135, 184
of nursing home residents, 692, 693, 694, 720, 728, 731
in special care units, 726, 727
nutritional status and, 630, 634
pain and, 377
Parkinson’s disease and, 141
personality disorders and, 491, 492
schizophrenia and, 310–311
somatoform disorders and, 374, 376, 381
substance-related disorders and, 459, 469
vascular dementia and, 200
working with families of patients with, 94, 669, 674
Funeral observances, 420
FUS gene, in frontotemporal lobar degeneration, 73, 141

Gabapentin
for bipolar disorder, 556
dosing of, 556
for neuropathic pain, 556
for restless legs syndrome and periodic limb movement disorder,
439
for vasomotor menopausal symptoms, 444
GAD. See Generalized anxiety disorder
GAF (Global Assessment of Functioning) Scale, 289
Gait disturbances. See also Ataxia
dementia and, 182
drug-induced
antipsychotics, 515, 549, 709
bupropion, 541
 falls and, 48
hyponatremia and, 109
Lewy body neurocognitive disorder and, 201
normal-pressure hydrocephalus and, 137, 206, 215–216
Parkinson’s disease and, 137, 202
prion diseases and, 120, 208, 209
vascular neurocognitive disorder and, 200
Galantamine
adverse effects of, 211, 218, 559
for Alzheimer’s disease, 47, 216–217, 218, 220, 558
dosing of, 218, 559
drug interactions with, 559
in mild cognitive impairment, 211
preparations of, 218
Gallbladder function, 38
Gastrointestinal system
changes with aging, 37–38, 529
drug effects on, 45, 527
calcium supplements, 636
chloral hydrate, 448
cholinesterase inhibitors, 218, 558, 559
clozapine, 552
memantine, 218
olanzapine, 549
phosphodiesterase 5 inhibitors, 404
selective serotonin reuptake inhibitors, 227, 264–265, 532,
541
serotonin-norepinephrine reuptake inhibitors, 537
tricyclic antidepressants, 544
vilazodone, 543
vortioxetine, 543
electroconvulsive therapy effects on, 598
GDS (Geriatric Depression Scale), 6, 18, 52, 100, 131, 243, 262, 263,
706, 729
Gender factors, 4
anxiety disorders and, 339
bereavement and, 415–416, 421–422
 bipolar disorder and, 286
dietary reference intakes and, 633
late-onset schizophrenia and, 311–312
prolactin levels and, 38
restless legs syndrome and, 439
sexual behavior and, 390
sexual response cycle and, 393–395, 394
sexually transmitted diseases and, 395
substance-related disorders and, 465, 468
prescription drugs, 469
treatment response and, 479
suicide and, 20
Generalized anxiety disorder (GAD), 346–349
age at onset of, 337
case example of, 346
chronicity of, 348
clinical features of, 339, 340, 346, 348
cognitive deficits in, 357
comorbidity with
dementia, 358
depression, 7, 346, 348, 349, 355
diagnosis in older adults, 336
in DSM-5, 347
hypothalamic-pituitary-adrenal axis in, 357–358
iatrogenic outcomes of lack of detection of, 346, 348
imaging studies in, 358
poststroke, 339
prevalence of, 15, 16–17, 18, 334, 338, 339, 347–348
treatment of
pharmacotherapy, 361, 528
psychotherapy, 359, 360, 653–654, 659
Genetic Information Nondiscrimination Act, 67, 122
Genetic risk factors for psychiatric disorders, 21–22, 26
interaction with environmental factors, 21–22, 66, 79, 80
Genetic testing, 66–67, 80, 81, 107, 120–122, 123
for Alzheimer’s disease, 70–72, 188
apolipoprotein E ε4 allele, 71–72, 120
 early-onset, 70
late-onset, 71–72
confidentiality of, 122
ethical and psychological concerns in, 121–122
for frontotemporal lobar degeneration-associated genes, 73–74
HLA-B*1502 allele test, 121, 297
for Parkinson’s disease, 75
pharmacogenomics, 121
Genetics, 65–66, 68–81
of Alzheimer’s disease, 22, 61, 64, 66, 68–72, 189–192, 191, 620
of bipolar disorder, 75, 251
definitions related to, 63–64
of depression, 22, 75, 79, 251–252
vascular depression, 252
family assessment of, 92
of frontotemporal lobar degeneration, 73–74, 113, 206
key points related to, 80–81
modes of inheritance, 66
of obsessive-compulsive disorder, 349
of Parkinson’s disease, 64, 74–75
of schizophrenia, 75–79
Genito-pelvic pain/penetration disorder, 41, 396, 397
Genome-wide association studies (GWASs), 64, 65, 67, 77–78, 79
in Alzheimer’s disease, 66, 71, 72, 190–192
in schizophrenia, 78
Genomics in geriatric psychiatry, 61–67, 123
copy-number variations, 64–65
de novo mutations, 65
genomic medicine, 66, 80
Human Genome Project, 61, 62, 122
practical framework for clinician, 65–66
single-nucleotide polymorphisms, 62–64
Genotype, 63
Geriatric assessment, 51–53, 54
components of, 52
definition of, 52
effectiveness of, 52–53
 in-home, 52
neuropsychological, 97, 99, 127–145, 180, 185–186
to prevent delirium, 169
psychiatric interview, 89–104
Geriatric Depression Scale (GDS), 6, 18, 52, 100, 131, 243, 262, 263,
706, 729
Geriatric Mental State Schedule, 100–101
Geriatric syndromes, 45–51
falls, 47–48
frailty, 50–51
key points related to, 54
memory loss and dementia, 46–47
polypharmacy, 50
urinary incontinence, 48–50
Geriatrician, 53, 54
Gerstmann-Sträussler-Scheinker syndrome, 208
“Get up and go” test, 52
Gingko biloba, 210, 213
Global Assessment of Functioning (GAF) Scale, 289
Glomerular filtration rate, 44, 527, 529
Glucose dysregulation, 41, 108, 619. See also Diabetes mellitus;
Hyperglycemia; Hypoglycemia
atypical antipsychotic–induced, 109, 109, 299, 317, 319, 545,
547, 549, 551
delirium and, 164, 167
medroxyprogesterone-induced, 407
Glutamate
in Alzheimer’s disease, 199
in bipolar disorder, 291
in delirium, 164
medication actions on
acamprosate, 478
memantine, 217, 559
in schizophrenia, 78
Glycopyrrolate, for electroconvulsive therapy, 602
Go4Life program, 636
Gonadotropin-releasing hormone, 40
Gonorrhea, 395
GPNMB gene, in Parkinson’s disease, 75
GRIA1 gene, in schizophrenia, 78
Grief reaction, 14, 415. See also Bereavement
as adjustment to permanent loss, 416–418
anticipatory, 415, 419
assessment measure for, 423
chronic, 418–419
course of, 418–420
culture and, 420, 421, 424, 428, 439
vs. depression, 418
duration of, 417
interventions for, 424–427
losses associated with, 415
normal vs. abnormal, 419–420, 428
resolution of, 417, 418
risk factors for intensification of, 421–424
stages of, 416–417
traumatic, 419
GRIN2A gene, in schizophrenia, 78
GRM3 gene, in schizophrenia, 78
GRN gene, in frontotemporal lobar degeneration, 73
Grooved Pegboard test, 131
Group psychotherapy
for depression, 651, 652
in nursing homes, 697, 698–702, 729
for patients with cognitive impairment, 658, 729
Growth hormone, 39, 51
Growth hormone–releasing hormone, 39
Guilt feelings of family caregivers, 675
GWASs. See Genome-wide association studies

Hachinski scale for vascular neurocognitive disorder, 99

Halazepam, 557
Hallucinations, 91
agitation and, 508
effect of carbamazepine on, 516, 716
 during alcohol withdrawal, 478
Alzheimer’s disease and, 142, 315, 316, 316, 324
assessment of, 96
definition of, 96
delirium and, 159, 160, 161
depression and, 96, 259
Lewy body neurocognitive disorder and, 136, 142, 190, 201, 202,
317
cholinesterase inhibitors for, 220, 322, 517
nonpharmacological management of, 224
among nursing home residents, 692
Parkinson’s disease and, 202, 204, 317
antipsychotics for, 227
drug-induced, 204
personality disorders and, 502
pharmacotherapy for
antipsychotics, 227, 317
cholinesterase inhibitors, 220, 322, 517
citalopram, 529
prevalence of, 309
schizophrenia and, 312, 314, 316
vascular neurocognitive disorder and, 182, 317
Haloperidol
adverse effects of, 322, 514
mortality risk, 516
QTc interval prolongation, 114, 514
sexual dysfunction, 398
for agitation in dementia, 515, 517, 519
for delirium, 168, 170, 514
electroconvulsive therapy–induced, 602–603
before electroconvulsive therapy, 269
for psychosis in Alzheimer’s disease, 322
for schizophrenia, 318
for sleep disorders in dementia, 229
use in nursing homes, 707
Haplotype, 63
Hashimoto’s encephalopathy, 207, 209
Headache, 376, 674
celiac disease and, 210
deep brain stimulation–associated, 610
drug-induced
buspirone, 557
memantine, 218
phosphodiesterase 5 inhibitors, 404
quetiapine, 550
rivastigmine, 218
selective serotonin reuptake inhibitors, 264
serotonin-norepinephrine reuptake inhibitors, 537
vilazodone, 543
electroconvulsive therapy–induced, 268
in menopausal women, 393
primary central nervous system vasculitis and, 209
prion diseases and, 208
substance-related disorders and, 472
transcranial magnetic stimulation–associated, 608
Health Care Financing Administration, 720, 722
Health insurance. See also Medicaid; Medicare
Genetic Information Nondiscrimination Act, 67, 122
Health promotion, 617–618
Hearing impairment/loss, 35, 45, 53
agitation and, 508
delusional disorder and, 314
psychosis and, 313
sleep disturbance and, 444–445
testing for, 52
Heart changes with aging, 35–36
HELP (Hospital Elder Life Program), 168–169
Helping Older People Experience Success (HOPES), 321–322
Helplessness, 91, 221, 264, 494
learned, 194, 732
Hematological system
changes with aging, 42–43
drug effects on
carbamazepine, 297, 516, 555
 clozapine, 108, 319
lithium, 108
mirtazapine, 108, 542
selective serotonin reuptake inhibitors, 532
serotonin-norepinephrine reuptake inhibitors, 537
testosterone, 403
valproate, 296, 554
electroconvulsive therapy effects on, 597–598
tests of, 108
Hepatic drug metabolism, 44
Hepatic effects of drugs
alcohol, 470
carbamazepine, 555
duloxetine, 109
medroxyprogesterone, 407
nefazodone, 543
tacrine, 217, 558
testosterone, 403
valproate, 109, 296, 554
venlafaxine, 109
Hepatic encephalopathy, 514, 591
Herbal supplements, 628–629
for Alzheimer’s disease, 217
delirium and, 162, 166
in mild cognitive impairment, 210
Heroin, 468
Herpes, genital, 395
Hip fracture
alcohol consumption and, 470
delirium and, 169
depression and, 247, 253
due to falls, 47
medication–related, 536, 557
subacute nursing home care for, 727
Hippocampus
atrophy of
Alzheimer’s disease and, 118, 196
 depression and, 253, 358
on magnetic resonance imaging, 117, 118, 187–188
in bipolar disorder, 292
frontal theta activity and volume of, 120
in posttraumatic stress disorder, 358
sclerosis of, 179
in frontotemporal lobar degeneration, 206
Histamine type 2 (H2) blockers, 165, 168, 399
before electroconvulsive therapy, 598
Historical studies of psychiatric disorders in elderly persons, 5, 18–20,
21
History taking, 51, 52, 89–93
context, 92–93
for delirium, 161, 162
for dementia, 184–185
family history, 92
medical history, 91, 93
medication history, 50, 93, 104
for nutritional assessment, 630
past history, 91–92
for personality disorders, 498
present illness, 89–91
sexual history, 398
for substance use, 472–473
Histrionic personality disorder, 92, 492, 494, 498, 499
HLA-B*1502 allele test, 121, 297
HLA-DRB5/HLA-DRB1 gene, in Alzheimer’s disease, 190
Hoarding disorder, 349
clinical features of, 339, 340
cognitive deficits in, 357
diagnosis in older adults, 337
in DSM-5, 334, 335, 351
among nursing home residents, 349
Homeostasis, 34, 51, 53
Homocysteine, 111–112, 189, 554, 620, 622, 635
Homosexuality, 391
Hopelessness, 91, 252, 254, 261, 264, 696, 700
HOPES (Helping Older People Experience Success), 321–322
Hopkins Verbal Learning Test—Revised, 130, 135
Hormone replacement therapy for menopausal women, 41
sexuality and, 390, 393, 401, 403
Hospital Elder Life Program (HELP), 168–169
Hot flashes, 41, 393, 444
HPA axis. See Hypothalamic-pituitary-adrenal axis
5-HT. See Serotonin
Human Genome Project, 61, 62, 122
Human immunodeficiency virus (HIV) infection, 109, 395, 422
laboratory testing for, 110, 186
neurocognitive disorder due to, 181, 183, 188
Humor, 496, 512, 671, 676
Humor therapy, 696
Huntington’s disease, 97, 137, 181, 183, 188
Huperzine, for Alzheimer’s disease, 217
9-Hydroxyrisperidone. See Paliperidone
Hyperactivity, 95
agitation and, 507, 508, 514, 693
delirium with, 158, 159, 160, 507, 508
depression with, 693
of nursing home residents, 693
sexual, 406
Hypercholesterolemia, 45, 54
Hyperglycemia, 41, 108, 619
atypical antipsychotic–induced, 545
delirium and, 164
Hyperhomocysteinemia, 111–112, 189
valproate-induced, 554
Hyperkalemia, 39, 597
Hyperparathyroidism, 39, 42, 591
Hyperprolactinemia, 117, 117
antipsychotic-induced, 117, 317, 398, 400, 547, 548, 551
Hypersomnia, 205, 258, 439, 443
Hypersomnolence disorder, 435
Hypertension, 45, 54, 99
Alzheimer’s disease and, 189, 192
 bipolar disorder and, 287, 293
drug-induced
psychostimulants, 545
serotonin-norepinephrine reuptake inhibitors, 537
electroconvulsive therapy and, 268, 596, 597, 602
stress incontinence and, 49
vascular dementia and, 199
vascular depression and, 253
Hypertensive crisis
during electroconvulsive therapy, 597
monoamine oxidase inhibitor-induced, 544, 628
Hyperthyroidism, 111, 111, 294
anxiety disorders and, 345, 347, 354, 356
electroconvulsive therapy in, 597
Hypoactive delirium, 158, 159, 160
Hypochondriasis, 7, 19, 373, 377, 380, 382. See also Illness anxiety
disorder
Hypocretin/orexin receptor antagonist, for insomnia, 448, 449
Hypoglycemia, 108, 164, 619
Hypogonadism, 40, 45, 394, 403
Hypokalemia, 597
Hypomania, 283, 284, 288
Hyponatremia, 38
dilutional, 635
drug-induced, 527
carbamazepine, 555
mirtazapine, 542
selective serotonin reuptake inhibitors, 108–109, 227, 532
serotonin-norepinephrine reuptake inhibitors, 537
trazodone, 542
electroconvulsive therapy and, 596
signs and symptoms of, 108–109
Hypopnea, 437
Hypotension
drug-induced, 212, 527
antipsychotics, 317, 318, 547, 551
phosphodiesterase 5 inhibitors, 404
 serotonin-norepinephrine reuptake inhibitors, 537
trazodone, 265, 448, 542
tricyclic antidepressants, 114, 228, 543
falls due to, 136, 228
Hypothalamic-pituitary-adrenal (HPA) axis, 38. See also Cortisol
in delirium, 164
in depression, 357
in generalized anxiety disorder, 357–358
Hypothyroidism, 46, 48, 111, 111, 188
lithium-induced, 111, 295
Hypoxemia, 161, 437, 442, 443
Hysteria, 380

IADLs. See Instrumental activities of daily living performance

ICD. See International Statistical Classification of Diseases and
Related Health Problems, 10th Revision criteria
ICU (intensive care unit) patients, delirium in, 155, 156, 157, 165, 168
Identity reconstruction, 417
IGF-1 (insulin-like growth factor), 39, 41
Illness anxiety disorder, 90, 373, 375, 377, 383
in DSM-5, 378
Iloperidone, 550, 552
Imaging studies, 107, 115–119, 123. See also specific imaging
modalities
for agitation, 508
in Alzheimer’s disease, 118, 119, 128, 195–196
in bipolar disorder, 292–294
computed tomography, 116
in Creutzfeldt-Jakob disease, 113, 209, 209
in delirium, 161, 162, 163, 164–165
in delusional disorder, 315
in dementia, 118, 187–188
in depression, 358
before electroconvulsive therapy, 267
in frontotemporal lobar degeneration, 206
in generalized anxiety disorder, 358
indications for, 117
 in late-onset schizophrenia, 312
in Lewy body neurocognitive disorder, 201
magnetic resonance imaging, 116–118
functional, 116
in mild cognitive impairment, 184
in normal-pressure hydrocephalus, 206
in Parkinson’s disease dementia, 204
plain film radiography, 115
positron emission tomography, 116, 118–119
amyloid PET imaging, 99, 116, 118–119, 188, 196
FDG-PET imaging, 118, 196
tau PET imaging, 119
in prion diseases, 119, 208, 209, 216
single-photon emission computed tomography, 116
in somatic symptom and related disorders, 380
in vascular dementia, 200
in vascular depression, 262, 263
Imipramine, 543
efficacy compared with other antidepressants, 530–531, 539
for urge incontinence, 49
Immune system changes with aging, 34, 42–43, 51, 53
Incoherence, 97, 159, 160
Incontinence
agitation and, 508
caregiver education about management of, 221
dementia and, 182
depression and, 253
family tolerance of, 95, 678
fear of, 344
among nursing home residents, 690, 727
sexual dysfunction and, 396
substance-related disorders and, 472
urinary, 48–50 (See also Urinary incontinence)
vascular dementia and, 200
Infection(s), 51
HIV, 109, 395, 422
laboratory testing for, 110, 186
 neurocognitive disorder due to, 181, 183, 188
immune response to, 34, 43, 53
sexually transmitted, 395
urinary tract, 48, 51, 112, 221, 509, 515, 711
Informed consent
for antipsychotic use, 518
for electroconvulsive therapy, 600–601
for genetic testing, 67
for imaging studies, 116
Inheritance modes, 66. See also Genetics
Injuries. See Falls; Fractures; Traumatic brain injury
INPP5D gene, in Alzheimer’s disease, 190, 191
Insomnia, 5, 435, 451. See also Sleep disorders
alcohol use and, 481
Alzheimer’s disease and, 441
assessment of, 445
bereavement and, 427, 440
causes of, 446
cerebrovascular disease and, 443
delirium and, 159
depression and, 255, 258, 437.440
drug-induced (See Sleep effects of drugs)
fatal familial, 216
generalized anxiety disorder and, 437
menopause-related, 444
pain and, 378, 437, 442
Parkinson’s disease and, 442
periodic limb movement disorder and, 438
prion disease and, 208
rebound, 440
sleep apnea and, 438
suicide and, 440
treatment of, 446–450, 451
cognitive-behavioral therapy, 446–447
pharmacotherapy, 447–450, 448
in nursing homes, 704, 705
Institute of Medicine, 25
 Committee on Nursing Home Regulation, 719
Dietary Reference Intakes, 632, 633
Institutionalization of older adults. See also Nursing homes
bipolar disorder and, 285
delirium and, 155, 157
dementia and, 180, 182
Alzheimer’s disease, 194, 195, 324, 406
for nocturnal sleep disruption, 441
for sexually inappropriate behavior, 406
depression and, 248
falls and, 352
family history of, 92
in nursing homes, 689–733
nutrition and, 629, 634
vitamin D supplementation, 48
schizophrenia and, 15, 310, 313
Instrumental activities of daily living (IADLs) performance
assessment of, 52
dementia and, 180, 181, 183, 186
supportive care for, 231, 232
falls and, 47
Insulin, 41
dose adjustment for electroconvulsive therapy, 597
intranasal, for Alzheimer’s disease, 47, 215
Insulin-like growth factor (IGF-1), 39, 41
Insulin resistance, 41, 51
Intellectual functioning
age-related decline in, 46
assessment of, 97, 98
in dementia, 46
tests of, 130
Intensive care unit (ICU) patients, delirium in, 155, 156, 157, 165, 168
Interdisciplinary partnerships with family, 572–673, 684
International Genomics of Alzheimer’s Project, 190
International HapMap Project, 65
International Society to Advance Alzheimer’s Research,
Neuropsychiatric Syndromes of AD Professional Interest Area, 194
International Statistical Classification of Diseases and Related Health
Problems, 10th Revision (ICD-10) criteria
for anxiety disorders, 334
for delirium, 156, 159
Interpersonal psychotherapy (IPT)
for depression, 247, 652
for persistent complex bereavement disorder, 425
for personality disorders, 500
for persons with cognitive impairment, 658
Intracranial hemorrhage, electroconvulsive therapy and, 595
IPT. See Interpersonal psychotherapy
Iron intake, 633
Irritability, 674
chronic grief and, 419
deep brain stimulation–related, 610
delirium and, 159
dementia and, 181
effects on family, 674, 677
generalized anxiety disorder and, 346, 347, 348
hypomania and, 284
mania and, 258, 283
mild cognitive impairment and, 182
among nursing home residents, 692, 704, 706, 727
personality disorders and, 501
posttraumatic stress disorder and, 351, 352, 354
Irritable bowel syndrome, 263, 375
Isosorbide, interaction with phosphodiesterase 5 inhibitors, 404
ITIH3 gene, 78
Itraconazole, interaction with buspirone, 557
Judgment of Line Orientation Test, 131, 137, 138

Kava kava, 166

Ketamine, for electroconvulsive therapy, 602
Ketoconazole, 399
Kidney changes with aging, 39, 43–44, 527, 529
drug prescribing and, 44, 53–54
Kidney function tests, 108

Labetalol, 602
Laboratory testing, 107–123
for agitation, 508
for alcohol and drug use, 112, 475
in bipolar disorder, 294
for carbamazepine use, 296–297
in delirium, 161, 162, 163
in dementia, 46, 186–188
 cerebrospinal fluid analysis and plasma assays, 112–113
in depression, 262, 263
for diabetes mellitus, 108, 112
electrocardiography, 113–115, 114
before electroconvulsive therapy, 267, 599
electroencephalography, 119–120
genetic testing, 66–67, 80, 81, 107, 120–122
imaging studies, 115–119, 117
key points related to, 123
for mental status changes, 108, 112, 115, 119, 162, 508
to monitor for metabolic effects of atypical antipsychotics, 109,
319
for nutritional assessment, 630
omics technologies, 122–123, 123
serologic tests, 107–108
chemistry tests, 108–109, 109
hematologic tests, 108
for HIV infection, 110
for syphilis, 109–110
testosterone level, 40
thyroid function tests, 110–111, 111
vitamin B12, folate, and homocysteine levels, 111–112
for sexual dysfunction, 399
for sleep disorders, 445
toxicology tests, 112, 475
urinalysis, 112
Lacunar infarcts, 117, 117, 179, 200
Lamotrigine, 554–555
adverse effects of, 297–298, 555
for bipolar disorder, 295, 297–298, 554–555
drug interactions with, 554, 555
interaction with valproate, 296
pharmacokinetics in elderly persons, 297
Language
age-related changes in, 46
assessment of, 99, 129
tests of, 130, 133
Language deficits
Alzheimer’s disease and, 134
delirium and, 158, 160
dementia and, 179, 180, 181, 183, 184
frontotemporal lobar degeneration and, 73, 140, 190, 204–205,
206
Lewy body neurocognitive disorder and, 142
prion diseases and, 208
vascular neurocognitive disorder and, 136
LASA (Longitudinal Aging Study Amsterdam), 13, 23, 255, 334, 338
LBD. See Lewy body neurocognitive disorder
Learning, 46, 53
Leiden 85+ Study, 13, 23
Leipzig Longitudinal Study of the Aged, 12
Lennon, John, 33, 34
Lesbian, gay, bisexual, or transgender (LGBT) persons, 109, 391, 677
Leukocytosis, 51
lithium-induced, 108
Leukoencephalopathy, 199
Leukopenia, drug-induced
carbamazepine, 297
clozapine, 319
Leuprolide, 399
Levomilnacipran, 536
cytochrome P450 enzyme inhibition and drug interactions with,
535
for depression, 537, 538
dosing of, 266, 533, 538
pharmacokinetics of, 533
Lewy bodies, 178, 200, 203
Alzheimer’s disease with, 179
in cognitively normal persons, 178, 179
Lewy body disorders, 190, 200–204
clinical presentations of, 201
neuropathology of, 142, 178–179, 200, 202
neuropsychological assessment in, 136, 137, 141–142, 144
pharmacotherapy for psychosis in, 322, 547
 α-synuclein in, 74, 141, 190, 200, 203, 203, 441
Lewy body neurocognitive disorder (Lewy body neurocognitive
disorder (DLB)), 190, 200–202
clinical presentation of, 142, 201
cognitive enhancers for, 220
course and prognosis of, 202
diagnosis of, 201
differential diagnosis of, 202
imaging studies in, 201
neuropsychological assessment in, 136, 141–142, 144
prevalence of, 12, 46, 201
with psychosis, 317, 322, 517
treatment of, 233
antidepressants for depression, 228
neuroleptic sensitivity and, 136, 190, 201, 226–227, 322,
517
for psychosis, 322, 517, 547
rivastigmine for neuropsychiatric symptoms, 517
Lexical fluency tests, 130
LGBT (lesbian, gay, bisexual, or transgender) persons, 109, 391, 677
Life events
bereavement, 415–428
financial problems, 256
as focus of cognitive-behavioral therapy, 651
health problems (See Medical conditions)
legal problems, 256
marital problems/divorce, 22, 255, 256, 261, 396, 415, 424, 469
personality disorders and, 497
retirement, 33, 251, 261, 381, 395, 446, 464, 468, 494, 497
as risk factors for psychiatric disorders, 22–23
adjustment disorder with depressed mood, 261–262
anxiety associated with medical illness, 356
depression, 79, 245, 247, 248, 252, 254, 255
hoarding disorder, 337, 349
mania, 249
personality disorders, 497
substance-related disorders, 468
Life expectancy, 4, 33–34, 53
Life review therapy, 652, 653
Ligament changes with aging, 42
Limbic encephalopathy, 209
Lithium, 553–554
adverse effects of, 295, 553
cognitive effects, 553
delirium, 553
hypothyroidism, 111, 295
renal effects, 108, 553
sexual dysfunction, 399
for bipolar disorder, 295, 553
dosing of, 249, 295, 300, 553
drug interactions with, 295, 553
effect on suicidality, 554
electrocardiogram effects of, 114, 114
electroconvulsive therapy and, 267, 595, 601
laboratory monitoring for use of, 112
neuroprotective effects of, 554
pharmacokinetics of, 295, 553
prophylactic, after course of electroconvulsive therapy, 592
therapeutic plasma level of, 112, 295
toxicity of, 295, 553
for treatment-resistant depression, 553
Liver
changes with aging, 38, 527, 529
drug metabolism by, 44
Liver function tests, 109, 163, 186
Living arrangements of older adults, 3–4
assisted living facilities, 212, 629, 676, 679, 684, 690, 691, 696
living alone, 232, 625, 670
assessing capacity for, 681, 684
documenting problems with, 244
nursing homes, 689–733
Long-term care. See also Nursing homes
behavioral problems of residents in, 693
agitation, 515
 dementia among residents in, 11, 231, 670
depression among residents in, 18, 245, 693
selective serotonin reuptake inhibitors for, 528, 530–531
elders living in facilities for, 3–4
genetic discrimination and, 67
nutritional assessment of residents in, 629
pain among residents in, 376
prevalence of psychiatric disorders among residents in, 9, 11, 18
quality of facilities for, 679
sexuality in settings for, 389, 391–392, 406, 407
somatic preoccupation among residents in, 381
Long-Term Care Minimum Data Set, 630
Longitudinal Aging Study Amsterdam (LASA), 13, 23, 255, 334, 338
Lorazepam, 448, 556, 557, 710
Loxapine, use in nursing homes, 704, 705
LRRK2 gene, in Parkinson’s disease, 74, 75
Lumbar puncture, 162, 163, 206, 215
Lung changes with aging, 36–37
Lurasidone, 552
for bipolar depression, 298
receptor blockade of, 550
Luteinizing hormone, 40

Macular degeneration, age-related, 35, 45

Magnesium
dietary intake of, 629, 633
plasma level of, 109
delirium and, 164
as indication for electrocardiogram, 115
Magnetic resonance imaging (MRI), 116–118
for agitation, 508
in bipolar disorder, 292–294
compared with computed tomography, 117
compared with positron emission tomography, 118
in Creutzfeldt-Jakob disease, 113, 209, 209
in delirium, 163, 164
in delusional disorder, 315
 in dementia, 118, 187–188
diffusion-weighted imaging, 117, 117–118, 209, 209
before electroconvulsive therapy, 267
in frontotemporal lobar degeneration, 190
functional, 116
in dementia, 188
in generalized anxiety disorder, 358
in somatic symptom and related disorders, 380
indications for, 117, 117, 118
in prion diseases, 208, 209
in vascular dementia, 200
in vascular depression, 253, 262, 263
Major depressive disorder, 244, 244, 258–259. See also Depression
Male hypoactive sexual desire disorder, 397
Mania, 283–284. See also Bipolar and related disorders
age at onset of, 249, 289–290
antidepressant-precipitated, 298
clinical course of, 249, 285, 288–289
clinical presentation of, 244, 258
dementia and, 288
diagnosis of, 258
differential diagnosis of, 161, 258, 294
electroconvulsive therapy for, 299, 591, 593
maintenance treatment, 606
imaging studies of, 293, 294
poststroke, 292
medical conditions and, 287
mortality and, 288
pharmacotherapy for, 553
antidepressants, 298
antipsychotics, 298–299, 547, 550, 551
carbamazepine, 296–297, 555
lamotrigine, 297, 555
lithium, 295, 553–554
valproate, 296, 554
prevalence of, 245, 285
sexually inappropriate behavior and, 406, 407
Manic delirium, 244, 258
Mannitol, for lithium toxicity, 553
MAOIs. See Monoamine oxidase inhibitors
MAPT gene, in frontotemporal lobar degeneration, 73
Marijuana, 112, 462, 480
Marital problems/divorce, 22, 255, 256, 261, 396, 415, 424, 469
Masturbation, 390, 404, 406
Mattis Dementia Rating Scale, 129
Maximizing Independence (MIND) at Home study, 212, 230
Maximum oxygen consumption, 36, 37
Mayo Clinic Study of Aging, 182
McCartney, Paul, 33, 34
MCI. See Mild neurocognitive disorder
MDS (Minimum Data Set), 18, 156, 630, 691
Medic Alert + Alzheimer’s Association Safe Return program, 675
Medicaid, 33
nursing homes certified by, 720, 729
Medical conditions, 4
agitation due to, 508, 509
alcohol use and, 469–470
anxiety disorder due to, 355, 356
anxiety disorders comorbid with, 354–355, 356
bipolar and related disorder due to, 283, 284
bipolar disorder comorbid with, 287
chronic, 45
delirium due to, 112, 161, 165, 167
depression comorbid with, 51–52, 111, 143, 245, 246–247, 248,
253–254
depression due to, 244, 244, 260–262
diet and exercise to delay onset of, 618
falls due to, 48
frailty and, 51
mental status changes due to, 51
nutritional status and, 629
pain due to, 376
personality change due to, 492
psychiatric illness exacerbated by, 51–52
 sexual dysfunction and, 396, 398, 400
sleep disorders and, 436–437, 442–445
somatic symptom and related disorders and, 374, 382, 383
use of electroconvulsive therapy in, 270, 594–598
Medical Expenditures Panel Survey (MEPS), 690, 692
Medical history, 91, 93
Medicare, 33, 93
Prospective Payment System, 727
reimbursement by
for amyloid PET imaging, 119
for FDG-PET imaging, 118
for functional brain imaging, 188
for nursing home care, 690, 724, 727
mental health services, 728, 729
Medication history, 50, 93, 104
Mediterranean diet, 620, 621, 622, 623, 634, 639
Medroxyprogesterone, for sexual aggression, 407
MEF2C gene, in Alzheimer’s disease, 190, 191
Melancholia, 6, 100, 102, 259, 265, 267, 590
Melatonin, 195
in Alzheimer’s disease, 195
in delirium, 164
in dementia, 230, 441
Melatonin receptor agonist. See Ramelteon
Memantine, 559–560
adverse effects of, 218
in Alzheimer’s disease, 193, 216, 217–219, 218, 558, 559–560
for agitation, 517
for apathy, 229
combined with cholinesterase inhibitors, 47, 218, 219, 220,
559, 560
for neuropsychiatric symptoms, 227–228
dosing of, 218, 560
in Lewy body neurocognitive disorder, 220, 560
mechanism of action of, 217
for neuropsychiatric symptoms, 227–228, 229, 517
in Parkinson’s disease dementia, 560
 preparations of, 217, 218
use in nursing homes, 717
Memorial Delirium Assessment Scale, 157
Memory impairment, 46–47, 53
Alzheimer’s disease and, 46, 134, 135, 139, 139, 193
bipolar disorder and, 291
delirium and, 160
electroconvulsive therapy–induced, 268, 269, 594, 596
maintenance treatment, 607
frontotemporal lobar degeneration and, 136
generalized anxiety disorder and, 357
Huntington’s disease and, 137
hydrocephalus and, 137
Lewy body neurocognitive disorder and, 136
mild cognitive impairment and, 135, 139, 139
neurocognitive disorder associated with depression and, 138, 143
normal age-related, 128, 132, 135
Parkinson’s disease dementia and, 137, 202, 204
posttraumatic stress disorder and, 357
progressive supranuclear palsy and, 137
vascular neurocognitive disorder and, 136, 139–140
Memory tests, 97–98, 130, 135
Memory training, 210
Mendel, Gregor, 61
Mendelian disease, 63, 66, 67, 76
familial early-onset Alzheimer’s disease, 68
Parkinson’s disease, 74
Menopause-related symptoms
estrogen loss and, 40–41
hormone replacement therapy for, 390, 393
sexuality and, 393, 394
sleep disturbance and, 444
Mental Alternation Test, 185
Mental health service use, 5, 8, 23–25, 26, 649
for bipolar disorder, 288, 289
for depression, 24, 25, 26
family history of, 92
 in-home, 650
in nursing homes, 689, 718, 728, 729, 730–733
psychotherapy, 696–697, 698–702
pharmacotherapy, 24–25
racial differences in, 24, 25
for schizophrenia, 15
Mental retardation, 180
Mental status changes, 51, 674
agitation and, 508
asking patient about, 674
delirium and, 158–160, 162
drug-induced, 47, 51
laboratory workup for, 108, 112, 115, 508
electroencephalogram, 119, 162
nutritional status and, 619
Mental status examination, 89, 90, 95–98
abstract thinking, 98
affect and mood, 95
appearance, 95
calculation, 98
in dementia, 46, 186
disturbances in thought content, 96
disturbances of thought progression, 96–97
memory and cognitive status, 97–98
orientation, 98
perception, 96
psychomotor activity, 95–96
suicidal thoughts, 97
MEPS (Medical Expenditures Panel Survey), 690, 692
Metabolic disorders. See also Diabetes mellitus; Dyslipidemia; Weight
gain
atypical antipsychotic–induced, 109, 299, 317, 319, 545, 547,
549, 551
electroconvulsive therapy in, 597
Metabolomics, 123
Methohexital, for electroconvulsive therapy, 602
L-Methylfolate, for depression, 628
Methylphenidate, 544–545
adverse effects of, 545
for antidepressant-induced sexual dysfunction, 400
for apathy
in dementia, 229
in depression, 266, 544
in depression, 544–545
Metoclopramide, before electroconvulsive therapy, 598
Microhemagglutination assay for Treponema pallidum, 110
Midazolam, 557, 602
Mild neurocognitive disorder (mild cognitive impairment (MCI)),
182–184
conversion to dementia, 182–184
definition of, 178, 179
in DSM-5, 11, 182, 183
due to Alzheimer’s disease, 134
imaging studies in, 118
neuropathology of, 184, 214
neuropsychological testing in, 139
NIA-AA proposed criteria for, 183, 184
nonpharmacological interventions for, 210
Parkinson’s disease dementia and, 202
pharmacotherapy for, 210–211
prevalence of, 10, 11, 182
Milnacipran
cytochrome P450 enzyme inhibition and drug interactions with,
535
for depression, 537, 538
dosing of, 533
for fibromyalgia, 536
pharmacokinetics of, 533
MIND (Maximizing Independence) at Home study, 212, 230
Mineral supplements, 635
Mini-Cog, 160
Mini-Mental State Examination (MMSE), 6, 52, 97, 99, 130, 185, 246,
263, 287–288, 624, 658
Mini Nutritional Assessment (MNA), 630, 631
Mini-Nutritional Assessment Short-Form (MNA-SF), 630
Minimum Data Set (MDS), 18, 156, 630, 691
Minnesota Multiphasic Personality Inventory—2, 131
Mirtazapine, 540, 541–542
adverse effects of, 108, 397, 448, 542
cardiovascular effects, 540, 542
sexual dysfunction, 397, 400
for antidepressant-induced sexual dysfunction, 400, 541
in dementia
for depression, 228
for sleep disorders, 230
for depression, 265, 539, 540, 541–542
combined with selective serotonin reuptake inhibitors, 541
combined with venlafaxine, 540, 541–542
compared with paroxetine, 530
in dementia, 228, 529
dosing of, 230, 265, 266, 534, 539
drug interactions with, 542–543
for insomnia, 230, 448, 450
mechanism of action of, 541
overdose of, 542
pharmacokinetics of, 534
for posttraumatic stress disorder, 361
Mitochondrial encephalopathy with lactic acidosis and strokelike
episodes, 199
MMSE. See Mini-Mental State Examination
MNA (Mini Nutritional Assessment), 630, 631
MNA-SF (Mini-Nutritional Assessment Short-Form), 630
Mobility
agitation and, 508
Alzheimer’s disease and, 193, 202
assessment of, 52
cognitive status and, 624
delirium and, 169, 170
dependent personality disorder and, 494
depression and, 247, 254
fear of falling and, 352
 of nursing home residents, 697, 721, 736
nutrition and, 626
psychotherapy techniques and, 660, 697
sleep disturbances and, 444–445
MoCA (Montreal Cognitive Assessment), 99, 130, 160, 185
Modified Mini-Mental State (3MS), 185
Monoamine oxidase inhibitors (MAOIs), 543, 544. See also specific
drugs
adverse effects of
hypertensive crisis, 544, 628
sexual dysfunction, 399
for depression, 265–266, 266, 540, 544
discontinuing before electroconvulsive therapy, 266, 267
dosing of, 266, 544
drug and dietary interactions with, 544, 628
switching from selective serotonin reuptake inhibitors to, 266
for symptoms of personality disorders, 502
Monongahela Valley Independent Elders Survey, 10
Montgomery-Åsberg Rating Scale for Depression, 100
Montreal Cognitive Assessment (MoCA), 99, 130, 160, 185
Mood
assessment of, 95
definition of, 95
depressed, 20, 91, 95, 251, 255, 258
adjustment disorder with, 244, 244, 260, 261–262
bereavement and, 418, 421
omega-3 fatty acid intake and, 623
pharmacotherapy for nursing home residents with, 705, 706
physical activity and, 624
tests of, 131
Mood Disorder Questionnaire, 285
Mood disorders
bipolar and related disorders, 244, 283–300
depressive disorders, 243–272
impact on diet and physical fitness, 625–626
Mood stabilizers, 552–556, 560, 561. See also specific drugs
for agitation in dementia, 516, 519
 for bipolar disorder, 249, 295–298
carbamazepine, 555
gabapentin, 556
lamotrigine, 554–555
lithium, 553–554
oxcarbazepine, 555
pregabalin, 556
sexual dysfunction and, 399
for somatic symptom and related disorders, 382
for symptoms of personality disorders, 502
topiramate, 556
use in nursing homes, 707, 709–711, 715, 716
valproate, 554
Morphine, 45, 518
Mortality
of bereaved spouse, 421
bereavement and, 415–418
bipolar disorder and, 288, 299
death of spouse, 251, 256, 381, 415–416, 417, 419, 422, 423,
427–428
delirium and, 156
dementia and, 182
Alzheimer’s disease, 177, 192
depression and, 249–251
electroconvulsive therapy-associated, 593–594
falls and, 47
frailty and, 51
medication-related risk of
atypical antipsychotics, 225–226, 229, 317, 319, 322, 324,
514, 515–516, 545, 546, 703, 716
benzodiazepines and benzodiazepine receptor agonists, 557
mirtazapine, 542
trazodone, 543
schizophrenia and, 309–310
from suicide, 5, 20, 21 (See also Suicidal ideation or behavior)
Motor neuron disease, frontotemporal lobar degeneration with, 73,
141, 205
Mourning, 416, 420, 421. See also Bereavement; Grief reaction
Mouth guard, for electroconvulsive therapy, 598
MS4A6A gene, in Alzheimer’s disease, 190, 191
Multidomain Alzheimer Preventive Trial, 215
Multilingual Naming Test, 40
Multiple Sleep Latency Test, 445
Multisensory stimulation methods, 222, 695–696
Muscle relaxants, for electroconvulsive therapy, 602
Muscle-strengthening activities, 637, 638
Musculoskeletal system
benefits of physical activity for, 618
changes with aging, 41–42, 45, 51, 529
electroconvulsive therapy effects on, 598
minimizing risk during exercise, 638
Music therapy, 222, 696
Myocardial infarction, 51
agoraphobia and, 336
Alzheimer’s disease and, 192
calcium supplementation and, 636
delirium and, 161
depression and, 247, 253, 261, 625
electroconvulsive therapy risks and, 596
sexual dysfunction and, 396, 398
testosterone replacement therapy and, 40

Naltrexone, for alcohol dependence, 477

Namaste Care, 695–696
Naproxen, for Alzheimer’s disease prevention, 215
Narcissistic personality disorder, 492, 494, 497, 499
Narcolepsy, 435
Narcotics Anonymous, 476
National Comorbidity Survey Replication (NCS-R), 6, 9, 14, 15, 16,
24, 285, 334, 338
National Consumer Voice for Quality Long-Term Care, 679
National Council on Aging, 390
National Epidemiologic Survey on Alcohol and Related Conditions
(NESARC), 8, 14, 15, 16–17, 18, 480
National Health and Nutrition Examination Survey (NHANES), 24–
25, 630, 632
National Institute for Health and Care Excellence, 186, 220
National Institute of Mental Health (NIMH), 298
Clinical Antipsychotic Trials of Intervention Effectiveness, 318
Collaborative Psychiatric Epidemiology Surveys, 9
Epidemiologic Catchment Area study, 8
Research Domain Criteria, 333, 341
study of valproate and lithium in late-life mania, 295, 296
National Institute on Aging (NIA), 678
Alzheimer’s Disease Education and Referral Center, 678
Go4Life campaign, 636
guidelines for diagnosis of Alzheimer’s disease, 46, 113
proposed criteria for mild cognitive impairment, 183, 184
National Institute on Alcohol Abuse and Alcoholism, 8, 462, 627
National Jewish Health, 400
National Nursing Home Survey (NNHS), 689, 691, 716, 718, 724,
725, 726, 729, 733
National Partnership to Improve Dementia Care, 724–725
National Resource Center on LGBT Aging, 677
National Survey on Drug Use and Health, 13, 460, 461, 465, 468
Natriuretic hormone, 38, 39
Nausea/vomiting, 630
during alcohol withdrawal, 478
drug-induced carbamazepine, 555
cholinesterase inhibitors, 218, 558, 559
selective serotonin reuptake inhibitors, 532, 628
bupropion for, 541
mirtazapine for, 541
serotonin-norepinephrine reuptake inhibitors, 537
valproate, 296, 554
vilazodone, 543
vortioxetine, 543
hyponatremia and, 108, 109
panic disorder and, 345
NCS-R (National Comorbidity Survey Replication), 6, 9, 14, 15, 16,
24, 285, 334, 338
NEECHAM Confusion Scale, 156
Nefazodone, 397, 400, 535, 540, 543
NEO Personality Inventory—Revised (NEO PI-R), 498
NESARC (National Epidemiologic Survey on Alcohol and Related
Conditions), 8, 14, 15, 16–17, 18, 480
Neuritic plaques
in Alzheimer’s disease, 118–119, 179, 179, 190, 196, 198, 198,
203
therapies targeting, 213–214
in cognitively normal persons, 198
in Lewy body neurocognitive disorder, 200
Neurocognitive disorder(s), 177–233. See also Dementia
differentiating common forms of, 133–142, 135–138
in DSM-5, 180
major neurocognitive disorder, 180, 181
mild neurocognitive disorder, 11, 182, 183
due to Alzheimer’s disease, 180.189–199, 190, 191, 197, 198
due to frontotemporal lobar degeneration, 204–206
due to normal-pressure hydrocephalus, 206–207
due to prion diseases and other rapidly progressive dementias,
207–210, 209
key points related to, 233
Lewy body disorders, 200–204
Lewy body neurocognitive disorder, 201–202
Parkinson’s disease dementia, 202–204, 203
neuropsychological assessment of, 97, 99, 127–145, 135–138
psychomotor activity in, 95–96
screening for, 98–99
traumatic brain injury and, 22, 181, 183, 185, 189
treatment of, 46–47, 210–233
vascular neurocognitive disorder, 184, 199–200
Neurofibrillary tangles, 119, 178, 179, 179, 190, 195, 196, 198, 200,
203
Neuroimaging. See Imaging studies
Neuroleptic malignant syndrome, 226, 318
Neurological disorders
bipolar disorder and, 287, 288, 290, 299
 central sleep apnea due to, 438
dementia and, 186
depression and, 145
cognitive-behavioral therapy for, 658
electroconvulsive therapy in, 598
vs. frontotemporal lobar degeneration, 141
vs. prion disease, 113
somatic symptom and related disorders and, 378, 380, 382
somatization and, 380
Neurological examination, 52
in bipolar disorder, 294
in delirium, 162
in dementia, 186
in depression, 262
after a fall, 47, 48
in personality disorders, 499
Neuropathology, 178
of Alzheimer’s disease, 70, 134, 178–179, 189, 196–199, 197,
198
in asymptomatic persons, 178–179, 215
cholinesterase inhibitors and, 558
Down syndrome and, 69
effect on pain perception, 377
Lewy body neurocognitive disorder and, 202
Parkinson’s disease and, 200, 203, 203
with psychosis, 316
vascular dementia and, 199, 200, 215
of bipolar disorder, 293
of Creutzfeldt-Jakob disease, 207
of frontotemporal lobar degeneration, 73, 74, 140, 141, 190, 192,
196, 198–199, 205–206
of Lewy body disorders, 142, 178–179, 200, 202
of mild cognitive impairment, 184, 214
of Parkinson’s disease, 74, 201, 203, 204
Neuropsychiatric Inventory, 193, 195, 717
Neuropsychiatric Inventory—Clinician rating scale (NPI-C), 186
Neuropsychiatric symptoms (NPSs) in dementia, 180–182, 181
 agitation, 507–519
Alzheimer’s disease, 193–195
assessment of, 185–186
contributing causes of, 221, 222
impact on outcomes, 221
management of, 221–230, 233
caregiver and staff education for, 223, 225
DICE mnemonic for, 221
electroconvulsive therapy for depression, 269–270
nonpharmacological, 222–223, 224–225
in nursing homes, 223, 695–696
pharmacological, 223–230
antidepressants for comorbid depression, 228–229
antipsychotics, 226–227, 546, 548
for apathy, 229
cholinesterase inhibitors and memantine, 227–228
guidelines for, 226
selective serotonin reuptake inhibitors, 227, 529, 532
for sleep disturbances, 229–230
psychotherapy, 223
mild cognitive impairment, 182, 183
among nursing home residents, 692–693, 695–696
Parkinson’s disease, 204
prevalence of, 221
prion diseases, 208
Neuropsychiatric Syndromes of AD Professional Interest Area (NPS-
PIA), 194
Neuropsychological assessment, 97, 99, 127–145, 180, 185–186
in Alzheimer’s disease, 128, 129, 132, 134, 135, 139, 144
with psychosis, 315–316
in Creutzfeldt-Jakob disease, 138
in frontotemporal lobar degeneration, 136, 140–141, 144
in geriatric settings, 128–132
in Huntington’s disease, 137
in hydrocephalus, 137
inclusion of family in, 129
interpretation of, 132
 key points related to, 144–145
in late-onset schizophrenia, 312
in Lewy body neurocognitive disorder, 136, 141–142, 144
in mild cognitive impairment, 135
in neurocognitive disorder associated with depression, 138, 142–
145
of normal aging, 132–133, 135, 144
in Parkinson’s disease neurocognitive disorder, 137, 141–142,
144, 203
process of, 128–129
in progressive supranuclear palsy, 137
purposes of, 128
tests for, 129, 130–131
in vascular neurocognitive disorder, 136, 139–140
Neuropsychological Assessment Battery, 129
NeuroQuant software, 118
Neuroticism, 495, 498
anxiety and, 339
depression and, 252, 254–255
somatic symptom and related disorders and, 379, 380
Neurotransmitters. See also specific neurotransmitters
in Alzheimer’s disease, 196
in delirium, 164
in depression, 79, 251, 252, 252
in Parkinson’s disease dementia, 203–204
Neutropenia, drug-induced
carbamazepine, 555
mirtazapine, 542
NHANES (National Health and Nutrition Examination Survey), 24–
25, 630, 632
NIA. See National Institute on Aging
Nicotine patch, in mild cognitive impairment, 210
Nifedipine, 45
Nightmare disorder, 435
Nightmares
delirium and, 159
drug-induced
 cholinesterase inhibitors, 558
dopamine agonists, 442
Parkinson’s disease and, 204
posttraumatic stress disorder and, 351
NIMH. See National Institute of Mental Health
Nitrates
for electroconvulsive therapy, 596
interaction with phosphodiesterase 5
inhibitors, 404
Nitrazepam, 557
Nitroglycerin, interaction with phosphodiesterase 5 inhibitors, 404
NME8 gene, in Alzheimer’s disease, 190, 191
NNHS (National Nursing Home Survey), 689, 691, 716, 718, 724,
725, 726, 729, 733
Nocturia, 45, 48, 49, 443–444, 635
Nocturnal penile tumescence, 399
Nonarteritic anterior ischemic optic
neuropathy, phosphodiesterase 5
inhibitor–induced, 404
Nonbenzodiazepine hypnotics, 168, 441, 443, 448, 448–449, 450,
556–557. See also specific drugs
Non–rapid eye movement sleep arousal disorders, 435
Nonsteroidal anti-inflammatory drugs (NSAIDs), 44
in Alzheimer’s disease, 189, 213
drug interactions with
lithium, 295, 553
selective serotonin reuptake inhibitors, 532
in mild cognitive impairment, 210
Norepinephrine
age-related changes in, 36, 39
in delirium, 164
in depression, 252
mirtazapine actions on, 541
in Parkinson’s disease, 203
in psychosis, 316
Norepinephrine transporter, 251
Normal-pressure hydrocephalus (NPH), 118, 134, 137, 188, 206–207,
595
shunt placement for, 215–216
Nortriptyline, 543
adverse effects of, 544
during bereavement, 425
for depression, 247, 265, 266
compared with other antidepressants, 530, 531, 538
after course of electroconvulsive therapy, 592
in nursing home residents, 694, 706, 717
dosing of, 265, 266, 544
therapeutic plasma level of, 265, 544
use in nursing homes, 717
NPH. See Normal-pressure hydrocephalus
NPI-C (Neuropsychiatric Inventory—Clinician rating scale), 186
NPS-PIA (Neuropsychiatric Syndromes of AD Professional Interest
Area), 194
NPSs. See Neuropsychiatric symptoms in dementia
NRXN1 gene, in schizophrenia, 77
NSAIDs. See Nonsteroidal anti-inflammatory drugs
Nun Study, 200
Nurse practitioners, 730, 732
Nurses, 25, 93, 212, 221, 320, 672–673, 684
in nursing homes, 695, 723, 731, 732
Nursing Delirium Screening Checklist, 156
Nursing Home Compare Web site, 722, 725
Nursing Home Quality Initiative, 722
Nursing Home Reform Act, 720, 722
Nursing homes, 689–733. See also Long-term care
adequacy of mental health care in, 728–730
changing patterns of psychiatric care in, 722–728
antidepressant drug use, 725
antipsychotic drug use, 723–725
physical restraint use, 725–726
special care units, 726–727
subacute care, 727–728
falls in, 47, 718
family stress related to placement of older adults in, 683–684
federal regulations and psychiatric care in, 719–722, 733
frailty of residents in, 690, 694, 717, 718, 732
functional impairment of residents in, 692, 693, 694, 720, 726,
727, 728, 731
history of deficient mental health care as impetus for reform in,
718–719
inadequate treatment of depression, 719
misuse of psychotropic drugs, 718–719
physical restraints, 718
key points related to, 733
Medicare reimbursement for care in, 690, 724, 727
mental health services, 728, 729
model for mental health service delivery in, 730–733
intrinsic system, 731–732
professional system, 732–733
National Nursing Home Survey, 689, 691, 716, 718, 724, 725,
726, 729, 733
populations of, 689–690
progress in treatment of psychiatric disorders in, 695–717
nonpharmacological management of behavioral
disturbances, 695–696
pharmacotherapy, 697, 703–717, 704–715, 733
antidepressants, 705, 706, 708, 710, 717, 718, 725, 729,
733
antipsychotics, 697, 703, 704–714, 716, 721, 723–725,
733
cognitive enhancers, 710, 712, 716–717
mood stabilizers, 707, 709–711, 716
psychotherapy, 696–697, 698–702, 733
psychiatric disorders of residents in, 690–695
alcohol-related disorders, 465–467
bipolar disorder, 245, 285
cognitive disorders and behavioral disturbances, 691–693
delirium, 156, 157, 691–692
depression, 245, 692, 693–695
hoarding disorder, 349
 personality disorders, 502
prevalence of, 18, 19, 690–695, 733
quality measures in, 722, 723
regular reassessments of residents in, 720–721
rights of residents of, 721
sexuality of residents in, 391–392
urinary incontinence among residents in, 48
use of physical restraints in, 695, 701, 718, 719–720, 733
adverse effects of, 718
chemical restraints and, 718–719
decline in, 725–726
regulations for, 721, 722, 723
in special care units, 726, 727
Nutrition. See Diet and nutrition
Nutritional assessment, 629–630, 631
Nutritional supplements, 628–629, 635–636

OARS (Older Americans Resources and Services) Multidimensional

Functional Assessment Questionnaire, 101, 244
Obesity, 45, 54, 618, 619. See also Weight gain
Alzheimer’s disease and, 189, 213
atypical antipsychotic–induced, 299, 317, 319
depression and, 622, 626
diet, physical activity and, 618, 619
OBRA-87 (Omnibus Budget Reconciliation Act of 1987), 720, 726,
731
Obsessions, 340, 349, 350
Obsessive-compulsive and related disorders, 333, 335
Obsessive-compulsive disorder (OCD), 349
clinical features of, 339, 340
diagnosis in older adults, 337
in DSM-5, 334, 350
genetics of, 349
prevalence of, 16, 334, 338
Obsessive-compulsive personality disorder, 260, 380, 492, 494, 656,
657
OCD. See Obsessive-compulsive disorder
Olanzapine, 548–549
adverse effects of, 318, 319, 549
cognitive effects, 549
metabolic effects, 547, 549
mortality risk in elderly dementia patients, 516
sexual dysfunction, 398
for delirium, 168, 514, 548–549
for delusional disorder, 320
dosing of, 320, 549
drug interactions with, 320
for mania, 298, 549
for neuropsychiatric symptoms in dementia, 226, 548
agitation, 515, 519
for psychosis
in Alzheimer’s disease, 316, 321
in Lewy body disorders, 322, 549
schizophrenia, 318, 319, 548
very-late-onset schizophrenia-like psychosis, 320
for psychotic depression, 549
receptor blockade of, 550
for tardive dyskinesia, 318
use in nursing homes, 697, 709–711
Olanzapine-fluoxetine combination, for bipolar depression, 298
Older Americans Resources and Services (OARS) Multidimensional
Functional Assessment Questionnaire, 101, 244
Omega-3 fatty acids, 620–621, 634
in bipolar disorder, 628
in depression, 622–623
in schizophrenia, 628
Omega-6 fatty acids, 620, 634
Omics technologies, 122–123, 123
Omnibus Budget Reconciliation Act of 1987 (OBRA-87), 720, 726,
731
Openness, 495, 498
Opioids
delirium induced by, 165, 166
overdose of, 20
 urine toxicology testing for, 112
withdrawal from, 478
Oral glucose tolerance test, 108
Orientation, assessment, 98, 130
Orthostatic hypotension
drug-induced, 212, 527
antipsychotics, 317, 318, 547, 551
serotonin-norepinephrine reuptake inhibitors, 537
trazodone, 265, 448, 542
tricyclic antidepressants, 114, 228, 543
falls due to, 136, 228
use of phosphodiesterase 5 inhibitors in men with, 404
Osteoarthritis, 45, 54, 442
Osteopenia, 45, 117
Osteoporosis, 36, 45, 618
bisphosphonates for, 42
depression and, 247, 268
electroconvulsive therapy in patients with, 598, 603
estrogen loss and, 40
exercise for, 618, 636, 638
fractures due to, 36, 268, 638
prolactin elevation and, 551
testosterone deficiency and, 42
Over-the-counter drug misuse/abuse, 459, 461, 464, 482
correlates and risk factors for, 468–469
epidemiology of, 467
screening and diagnosis of, 473, 475
Overdose of drug
assessing risk for, 683
electrocardiogram for, 113, 115
mirtazapine, 542
opioids, 20
selective serotonin reuptake inhibitors, 264
serotonin-norepinephrine reuptake inhibitors, 537
toxicology testing for, 112
tricyclic antidepressants, 113
Overflow incontinence, 49–50
Oxazepam, 557, 704
Oxcarbazepine
for bipolar disorder, 295, 555
use in nursing homes, 715, 716
Oxidative stress, 36, 291, 618
Oxybutynin, 49
Oxygen consumption, 36, 37

Pacing, 96, 693

Pain, 376–377
assessment of, 377
conditions associated with, 376–377, 442
genito-pelvic pain/penetration disorder, 41, 396, 397
management in nursing home residents with dementia, 518
neuropathic
duloxetine for, 536
gabapentin for, 556
pregabalin for, 518, 556
use of bupropion in, 541
prevalence of, 376
sleep disturbance and, 377, 442
somatization and, 377
Pain disorder, 373
Paliperidone, 547–548
adverse effects of, 548
long-acting injectable, 548
receptor blockade of, 550
for schizoaffective disorder, 547
for schizophrenia, 319, 548
Pancreatic β cell dysfunction, 38
Pancreatic function, 38
Pancreatitis, drug-induced
alcohol, 465, 470
atypical antipsychotics, 109, 545
valproate, 109, 296, 554
Panic attacks, 336, 340, 341, 342–343, 344, 345, 346, 356, 362
Panic disorder, 342–346
 case example of, 342
clinical features of, 339, 340, 342–343
diagnosis in older adults, 336
in DSM-5, 345
prevalence of, 15, 16–17, 18, 334, 338, 342–343
sexual dysfunction and, 397
Paranoia, 96, 97, 109
agitation and, 508
in Alzheimer’s disease, 315, 316, 324
prevalence of, 13, 309
Paranoid delusions, 313
in Alzheimer’s disease, 315, 324
in delirium, 160
Paranoid personality disorder, 314, 379, 492, 494, 498, 499, 656, 657
Paranoid schizophrenia, 312
Parathyroid hormone (PTH), 39, 44
PARK2 gene, in Parkinson’s disease, 74, 75
PARK16 gene, in Parkinson’s disease, 75
Parkinsonism
Alzheimer’s disease and, 200
antipsychotic-induced, 226–227, 318
Lewy body disorders and, 74, 142, 201, 202, 226–227
use of haloperidol in patients with, 514
vascular neurocognitive disorder and, 200
Parkinson’s disease (PD), 200
deep brain stimulation for, 609–610
depression and, 260
electroconvulsive therapy for, 591
genetic testing for, 75
genetics of, 64, 74–75
motor symptoms of, 74
neuropathology of, 74, 201, 203
Alzheimer’s disease and, 203, 203
among nursing home residents, 691
with psychosis, 317
antipsychotics for, 322, 547
psychotherapy in, 658
 sleep disorders in, 202, 204, 441–442
Parkinson’s disease dementia (PDD), 190, 200, 202–204
Alzheimer’s disease pathology and, 200
clinical presentation of, 142, 201
imaging studies in, 204
neuropsychological assessment in, 137, 141–142, 144, 203
neurotransmitters involved in, 203–204
among nursing home residents, 691
pharmacotherapy for, 215, 220, 227, 233, 547
prevalence of, 74, 141, 202
risk factors for, 202
Paroxetine, 528
for depression, 264, 265, 528, 530, 532
bereavement-related, 425
among nursing home residents, 710, 717
dosing of, 265, 266, 533
drug interactions with
bupropion, 541
cytochrome P450 enzyme inhibition and, 535, 541
indications for, 528
for panic disorder, 360
pharmacokinetics of, 533
use in nursing homes, 710
for vasomotor menopausal symptoms, 444
Past history, 89–91
Patient Health Questionnaire, 6
Patient Health Questionnaire (PHQ-9), 729
PD. See Parkinson’s disease
PDD. See Parkinson’s disease dementia
PDE5 (phosphodiesterase 5) inhibitors, 404, 405
PEDAL (Programa de Entrenamiento para el Desarrollo de Aptitudes
para Latinos), in schizophrenia, 320
Penile duplex ultrasonography, 399
Penile intercavernosal injections, 404
Penile prosthesis, 403
Perceptual disturbances. See also Delusions; Hallucinations
assessment of, 7, 96
 delirium and, 159, 160, 161
delusional disorder and, 315
dementia and, 181, 183
Pergolide, 545
Periodic limb movement disorder (PLMD), 230, 435, 438–439, 445
Peroneal nerve palsy, 262
Perphenazine, 227, 318
Persistent complex bereavement disorder, 244, 244, 258, 423, 424
treatment of, 424–426
Persistent depressive disorder (dysthymia), 244, 244, 255, 259–260,
355
antidepressants for, 530, 537
clinical course of, 246, 248
depression comorbid with, 246, 260
diagnosis of, 102, 248, 259–260
prevalence of, 16, 17, 245
testosterone levels in men with, 252–253
Personality, 492
depression and, 249, 254–255
five-factor model of, 495, 498
Personality changes, 495, 499, 674
alcohol use and, 471
Creutzfeldt-Jakob disease and, 209
dementia and, 491, 492
due to another medical condition, 492
frontotemporal lobar degeneration and, 73, 136, 140, 190, 204,
499
normal-pressure hydrocephalus and, 206
Personality disorders, 491–503
adult development and, 496–497, 503
classification of, 492–493, 494
Cluster A, 492, 494, 656
Cluster B, 492, 493, 494, 496
Cluster C, 492, 494, 656–657
comorbidity with
bipolar disorder, 287
delusional disorder, 314
 depression, 254, 493, 503, 657
dysthymia, 260
somatic symptom disorders, 379–380
definitions related to, 492
in DSM-5, 492, 495, 498
evaluation of, 497–500
key points related to, 503
among nursing home residents, 502
other or unspecified, 493
prevalence, criteria, and controversies about, 491, 493–496, 503
dimensional approach, 495
validity of diagnostic criteria across lifespan, 495
treatment of, 491–492, 500–502, 503
caregiver education, 501–502
pharmacotherapy, 501, 502
psychotherapy, 500–501, 650, 656–657, 660
Personality Inventory for DSM-5 (PID-5), 498–499
Personality tests, 131
Pessimism, 271
PET. See Positron emission tomography
Peyronie’s disease, 403
PGRN gene, in frontotemporal lobar degeneration, 73, 74, 113
Pharmacodynamics in elderly persons, 44, 45, 527
Pharmacogenomics, 121
Pharmacokinetics in elderly persons, 44–45, 53–54, 212, 527, 529
absorption, 44
adverse drug effects and, 527
antidepressants, 533–534
buspirone, 557
carbamazepine, 297, 555
clearance rate, 44
elimination half-life, 44–45
lamotrigine, 297
lithium, 295, 553
valproate, 296, 554
volume of distribution, 44
Phenelzine, 266, 544
Phenobarbital, 554, 555
Phenotype, 64
Phentolamine, 399
Phenytoin, 110, 112, 296, 554, 555
Pheochromocytoma, 597
Phobic disorders, 341–342
agoraphobia, 336, 341–342, 344
clinical features of, 339, 340
diagnosis of, 341
prevalence of, 334, 338
sexual, 397
social anxiety disorder, 336, 341, 343
specific phobia, 336, 341, 342
Phosphodiesterase type 5 (PDE5) inhibitors, 404, 405
PHQ-9 (Patient Health Questionnaire), 729
Physical activity, 617–619
for Alzheimer’s disease prevention, 215
benefits of, 636
bone density and, 42
for depression, 628
as determinant of cognitive status and mood, 624
effect on mental health and cognitive well-being, 618–619, 619
effect on muscle mass, 42
heart function during, 36
impact of mental health status on physical fitness, 625–627
alcoholism, 627
mood disorders, 625–626
stroke, dementia, and other brain diseases, 626–627
to improve respiratory function, 37
indirect effects on mental health, 624–625
initiating a fitness program, 636
interaction of treatments with, 627–629
key points related to, 639
in mild cognitive impairment, 210
minimizing risk during, 638
to prevent falls, 48
recommendations for older adults, 636–637
 special caveats for older adults, 638
Physical Activity Guidelines for Americans, 636
Physical examination, 52
in delirium, 158, 161, 162
in depression, 262, 263
before electroconvulsive therapy, 267
after a fall, 47–48
for nutritional deficiencies, 630
in personality disorders, 499
for sexual dysfunction, 398–399
for sleep disturbances, 445
for thyroid disease, 111
in vascular dementia, 200
Physical restraints
delirium and, 165, 167, 169, 170
reducing use of, 48, 223
use in nursing homes, 695, 701, 718, 719–720, 733
adverse effects of, 718
chemical restraints and, 718–719
decline in, 725–726
regulations for, 721, 722, 723
in special care units, 726, 727
Physical therapy program
for generalized anxiety disorder, 346
in-home, 94
for neuropsychiatric symptoms, 222, 224
to prevent falls, 48
for sexual dysfunction, 400
for stress incontinence, 49
Physicians’ Health Study II, 635
Physiological changes of aging, 34, 35–44
cardiovascular system, 35–36, 53
effects on drug prescribing, 44, 53–54
endocrine system, 38–41
gastrointestinal system, 37–38
hematological and immune systems, 42–43, 53
key points related to, 53–54
 musculoskeletal system, 41–42, 45, 51
renal system, 43–44
respiratory system, 36–37
sexual response cycle, 393–395, 394
vision and hearing, 35, 45, 52, 53
PiB (Pittsburgh compound B), 188
PICALM gene, in Alzheimer’s disease, 191, 191
Pick bodies, 141, 206
Pick’s disease, 190, 204. See also Frontotemporal lobar degeneration
PID-5 (Personality Inventory for DSM-5), 498–499
PINK1 gene, in Parkinson’s disease, 74, 75
Piribedil, 210, 545
Pittsburgh compound B (PiB), 188
Plain film radiography, 115
PLMD (periodic limb movement disorder), 230, 435, 438–439, 445
PLST (progressively lowered stress threshold) theory of dementia, 659
Pneumonia, 34, 51, 161
Polymorphisms, genetic, 64
single-nucleotide, 62–64, 64, 65
Alzheimer’s disease and, 72
depression and, 79
genome-wide association studies of, 65
schizophrenia and, 78–79
Polymyalgia rheumatica, 45
Polypharmacy, 45, 50, 52, 54, 527
delirium and, 165–166
drug-drug interactions and, 212
nutritional status and, 628
substance-related disorders and, 467
Polysomnography, 262, 263, 438–439, 442, 445
Poor metabolizers, 121
Population aging, 3–4, 25, 26, 33, 53, 177
Positron emission tomography (PET), 116, 118–119
amyloid PET imaging, 99, 116, 118–119, 188, 196
in delirium, 163
in dementia, 188
in fatal familial insomnia, 216
 FDG-PET imaging, 118
in Alzheimer’s disease, 118, 196
in Lewy body neurocognitive disorder, 201
in mild cognitive impairment, 184
in Parkinson’s disease dementia, 204
tau PET imaging, 119
Posttraumatic stress disorder (PTSD), 351–352
case example of, 351
clinical features of, 340, 351–352
cognitive deficits in, 357
comorbidity with
bipolar disorder, 286
depression, 355
diagnosis in older adults, 337
in DSM-5, 334, 335, 353–354
prevalence of, 16–17, 334, 338, 352
as risk factor for dementia, 359
treatment of
exposure therapy, 359
pharmacotherapy, 361
Potassium
dietary intake of, 629
plasma level of aldosterone and, 39
delirium and, 167
electroconvulsive therapy and, 597
as indication for electrocardiogram, 115
laboratory testing for, 109
PPA (primary progressive aphasia), 73, 140–141, 188, 190, 204–205
Pramipexole, 439, 545
Prazosin
for agitation in dementia, 517, 518, 519
in posttraumatic stress disorder, 361
sexual dysfunction induced by, 399
Predictors Study, 195
Prednisone, in Alzheimer’s disease, 213
Pregabalin, 556
adverse effects of, 556
 dosing of, 556
for generalized anxiety disorder, 361, 556
for neuropathic pain, 518, 556
Premature (early) ejaculation, 397, 404–405
Prescribing practices
for atypical antipsychotics, 545–546
Beers Criteria for Potentially Inappropriate Medication Use in
Older Adults, 50, 165, 168
pharmacodynamics and, 45, 527
pharmacokinetics and, 44–45, 53–54, 212
polypharmacy and, 50
Prescription drug misuse/abuse, 459, 461, 464, 482
of benzodiazepines, 465
Brief Intervention and Treatment for Elders approach for, 655–
656
correlates and risk factors for, 468–469
epidemiology of, 467
psychiatric comorbidity with, 469
screening and diagnosis of, 93, 471, 472, 475
withdrawal from, 478
Presenilin 1 (PSEN1) mutations
Alzheimer’s disease and, 68–70, 189, 191, 198
testing for, 70
Presenilin 2 (PSEN2) mutations
Alzheimer’s disease and, 68–70, 189, 191
testing for, 70
Present illness, 89–91
Present State Exam, 100
Prevalence of psychiatric disorders, 4, 8–18, 10, 12, 13, 16–17, 26. See
also Epidemiology of psychiatric disorders in elderly persons; specific
disorders
in treatment settings, 15, 18, 19
Prevention
of Alzheimer’s disease, 214–215
of delirium, 168–169, 170, 171
of falls, 48, 224, 618, 636
Priapism, trazodone-induced, 265, 448, 542
Primary progressive aphasia (PPA), 73, 140–141, 188, 190, 204–205
Primidone, 554
Prion diseases, 207–210
amyloid PET imaging in, 119
diagnosis of, 208–209, 216
differential diagnosis of, 209–210
electroencephalogram in, 120
imaging studies in, 119, 208, 209, 216
neurocognitive disorder due to, 181, 183, 188, 207–210
rapidly progressive dementia in, 185
treatment of, 216
Prion protein, 207, 208
PRNP gene, 208
Problem Related to Living Alone, 244
Problem-solving therapy (PST), for depression, 651–652
Procainamide, 114
Programa de Entrenamiento para el Desarrollo de Aptitudes para
Latinos (PEDAL), in schizophrenia, 320
Progressive supranuclear palsy, 73, 137, 205, 206, 207
Progressively lowered stress threshold (PLST) theory of dementia, 659
Prolactin level, 399
changes with aging, 38
elevation of, 117, 117
antipsychotic-induced, 117, 317, 398, 400, 547, 548, 551
Promazine, 546, 548
Propanolamine, 49
Propranolol
for agitation in dementia, 517, 518, 519
depression induced by, 93
Prospective Payment System, 727
Prostate cancer, 49, 403
Prostate-specific antigen, 399
Protein, dietary, 633, 634
Protein binding of drugs, 44
Proteomics, 123, 123
Proverb interpretation, 98
PSEN1. See Presenilin 1 mutations
PSEN2. See Presenilin 2 mutations
Pseudodementia, 143, 189, 594, 596
Pseudoseizures, 377, 378, 382
PST (problem-solving therapy), for depression, 651–652
Psychiatric disorders in older adults, 65–66, 68–81
case identification for, 4, 5–8
diagnostic instruments for, 6
distribution of, 4, 8–18, 10, 12, 13, 16–17
in treatment settings, 15, 18, 19
epidemiological studies of, 4–26
etiological studies of, 5, 21–23
health service utilization for, 5, 23–25
historical trends of, 5, 18–20, 21
impact on quality of life, 4
latent subtypes of, 7
medical comorbidity with, 4
medical illness and, 51–52
screening for, 6
symptoms of, 89–90
communicating with patients about, 90–91
history taking for, 89–91
prevalence of, 3, 5, 7, 9, 11, 13, 14, 15, 18, 19
in treatment settings, 15, 18, 19
Psychiatric Genomics Consortium, 78
Psychiatric interview, 89–104
for case identification, 5–8
communication with older adults, 90–91, 102–103, 104
elements of, 90
family assessment, 93–95
history, 89–93
context, 92–93
family history, 92
medical history, 91, 93
medication history, 50, 93, 104
past history, 91–92
present illness, 89–91
key points related to, 103–104
mental status examination, 95–98
for personality disorders, 498
rating scales, 98–101
for depression, 99–100
 general assessment scales, 100–101
for neurocognitive disorders, 98–99
structured diagnostic interviews, 101–102, 104
transference during, 103
Psychiatric Status Schedule, 100
Psychiatric syndromes, 7, 26
Psychodynamic theory
of conversion disorder, 378
of somatization, 380
Psychodynamic therapy
for depressoin, 660
for persistent complicated bereavement disorder, 426
in sex therapy, 401
for somatic symptom and related disorders, 380, 382
Psychological factors affecting other medical conditions, 373
Psychomotor activity
age-related changes in, 46
agitated, 95–96, 507–519 See also (Agitation)
assessment of, 95–96
in delirium, 158, 160
in depression, 95, 258, 259, 262
vs. bereavement, 421
in neurocognitive disorders, 95–96
retarded, 95, 96, 143
Psychopharmacology, 527–560
antidepressants, 528–544
bupropion, 534, 535, 539, 540–541
cytochrome P450 enzyme inhibition and drug interactions
with, 535
for depression, 530–531, 538–539
mirtazapine, 534, 539, 541–542
monoamine oxidase inhibitors, 543, 544
nefazodone, 535, 543
pharmacokinetics of, 533–534
selective serotonin reuptake inhibitors, 528–536, 530–531,
533, 535
 serotonin-norepinephrine reuptake inhibitors, 533, 535, 536–
540, 538
trazodone, 534, 542–543
tricyclic antidepressants, 543–544
vilazodone, 534, 535, 539, 543
voritoxetine, 534, 535, 539, 543
anxiolytics and sedative-hypnotics, 556–558
benzodiazepines and benzodiazepine receptor agonists, 556–
557
buspirone, 557–558
atypical antipsychotics, 545–552
aripiprazole, 551–552
asenapine, 552
clozapine, 551
iloperidone, 552
lurasidone, 552
olanzapine, 548–549
paliperidone, 547–548
quetiapine, 549–551
receptor blockade of, 550
risperidone, 546–547
ziprasidone, 552
cognitive enhancers, 558–560
cholinesterase inhibitors, 558–559, 559
memantine, 559–560
key points related to, 560–561
mood stabilizers, 552–556
carbamazepine, 555
gabapentin, 556
lamotrigine, 554–555
lithium, 553–554
oxcarbazepine, 555
pregabalin, 556
topiramate, 556
valproate, 554
pharmacodynamics in elderly persons, 45, 527
pharmacogenomics, 121
 pharmacokinetics in elderly persons, 44–45, 53–54, 212, 527, 529
polypharmacy, 45, 50, 52, 54, 527, 628
delirium and, 165–166
drug-drug interactions and, 212
substance-related disorders and, 467
psychostimulants, 544–545
Psychopharmacotherapy. See also specific drugs and classes
adherence to, 527
adverse effects of, 527–528
for aggression, 321
sexual, 407
for agitation, 47, 226, 321, 515–519, 519
for alcohol dependence, 477–478
for Alzheimer’s disease, psychosis, 321–322
Beers Criteria for Potentially
Inappropriate Medication Use in Older Adults, 50, 165, 168
for bereavement
complicated, 425
normal grief, 427
for bipolar disorder, 295–299, 552–556
for delirium, 168, 170, 171
postsurgical prevention and management, 168, 514, 547, 548
for delusional disorder, 320
for dementia
Alzheimer’s disease, 46–47, 213–214
cognitive symptoms, 216–220, 218, 558–560
mild cognitive impairment, 210–211
neuropsychiatric symptoms, 223–230, 226
Parkinson’s disease dementia, 215, 220, 227
rapidly progressive dementias, 216
for depression, 264–266, 266, 272, 528–544
family history of response to, 92
for generalized anxiety disorder, 360–361
for inappropriate sexual behaviors, 407
management for electroconvulsive therapy, 266, 267–268, 601
in nursing homes, 697, 703–717, 704–715, 732
antidepressants, 705, 706, 708, 710, 717, 718, 725, 729, 733
 antipsychotics, 697, 703, 704–714, 716, 721, 723–725, 733
history of misuse of, 718–719
regulations for use of, 721
for persistent depressive disorder (dysthymia), 530, 537
for personality disorders, 501, 502
for posttraumatic stress disorder, 361
for psychosis, 545–552
in Lewy body disorders, 322
for schizophrenia, 317–320, 324
for sleep disorders, 447–450, 448
in dementia, 229–230
for somatic symptom and related disorders, 382–383
utilization by older adults, 24–25, 26
for very-late-onset schizophrenia-like psychosis, 320
Psychosis/psychotic symptoms, 309–324, 313
Alzheimer’s disease and, 72, 193, 195, 315–316, 316, 321–322,
324, 517
assessment of, 101
atypical antipsychotics for, 545–546
in Alzheimer’s disease, 321
in nursing homes, 697
in schizophrenia, 319–320
bipolar disorder and, 291
delirium and, 170
delusional disorder, 313–315
dementia and, 181, 693
with agitation, 514
escitalopram for, 529
depression and, 244, 259, 601, 684
electroconvulsive therapy for, 259, 267
due to electrolyte abnormalities, 109
folate deficiency and, 111
frontotemporal lobar degeneration and, 205, 317
hyperthyroidism and, 111
key points related to, 323–324
Lewy body neurocognitive disorder and, 201, 317
management during electroconvulsive therapy, 268
 medication-related
bupropion, 541
methylphenidate, 545
among nursing home residents, 692, 693, 697, 716
Parkinson’s disease and, 202, 204, 317
personality disorders and, 501
prevalence of, 11, 13, 309
schizophrenia, 309–313, 314
sensory deficits and, 312–313
sexual dysfunction and, 397–398
treatment of, 317–323
key points related to, 324
pharmacotherapy, 317–320
for psychosis of Alzheimer’s disease and other
neurocognitive disorders, 321–323
psychosocial interventions, 316, 317, 320–321, 323, 324
very-late-onset schizophrenia-like psychosis, 313, 314
vitamin B12 deficiency and, 111
Psychosocial interventions
for dementia, 659, 696
in nursing homes, 696, 697, 701, 723, 724, 731, 732
for psychotic disorders, 316, 317, 320–321, 323, 324
for substance-related disorders, 476
Psychostimulants, 544–545
anxiety induced by, 339
for apathy in dementia, 229
interaction with warfarin, 545
Psychotherapy, 649–660. See also specific therapies
in anxiety disorders, 359–360, 363, 653–655, 660
individual cognitive-behavioral therapy, 653–655
relaxation training, 655
attitudes of older adults about, 649–650
in depressive disorders, 247, 263–264, 272, 650–653, 660
group-based cognitive-behavioral therapy, 651
group-based problem-solving therapy, 652
individual cognitive-behavioral therapy, 650–651
individual problem-solving therapy, 651–652
 interpersonal psychotherapy, 652
other techniques, 653
future research on, 660
key points related to, 660
modifications for older adults, 650
in nursing homes, 696–697, 698–702, 732
options for delivery of, 650
in Parkinson’s disease, 658
in persistent complex bereavement disorder, 425–426, 428
in personality disorders, 500–501, 656–657, 660
cognitive-behavioral therapy, 656–657
dialectical behavior therapy, 500–501, 650, 657
in persons with cognitive impairment, 223, 650, 657–659
in psychosis of Alzheimer’s disease, 316
in schizophrenia, 316
in somatic symptom and related disorders, 382
in substance-related disorders, 655–656
brief interventions, 475–476
cognitive-behavioral therapy, 655–656
screening, brief intervention, and referral to treatment, 656
utilization by older adults, 649
Psychotic depression, 96, 244, 259, 601, 684
electroconvulsive therapy for, 367, 591
PTH (parathyroid hormone), 39, 44
PTK2B gene, in Alzheimer’s disease, 190, 191
PTSD. See Posttraumatic stress disorder
Pulmonary changes with aging, 36–37
Pyridoxine. See Vitamin B6

QIOs (Quality Improvement Organizations), 724–725

QTc interval
calculation of, 115
drug-induced prolongation of, 527
antipsychotics, 114, 114, 514
ziprasidone, 114, 552
citalopram, 114–115, 227, 516, 529, 532
mirtazapine, 540, 542
 trazodone, 542
tricyclic antidepressants, 114, 265
Quality Improvement Organizations (QIOs), 724–725
Quality Indicator Survey for nursing homes, 722
Quality of life
agitation and, 507, 519
effect of cholinesterase inhibitors on, 517
anxiety disorders and, 359
cognitive-behavioral therapy effects on, 359, 653
generalized anxiety disorder, 346
bipolar disorder and, 289, 291
cognitive disorders and, 127, 145, 188
neuropsychiatric symptoms, 194, 221
Parkinson’s disease dementia, 202
prion diseases, 216
treatment effects on, 211, 212, 226, 229, 231, 659
depression and, 194
diet, physical activity and, 617–619, 619, 624, 625, 637, 639
effect of in-home geriatric assessment on, 52
of families/caregivers, 231, 669, 675, 676
of nursing home residents, 697, 701, 723
posttraumatic stress disorder and, 351
schizophrenia and, 311
risperidone effects on, 546
sexual activity and, 390
sleep disorders and, 194, 435, 439, 446
substance-related disorders and, 461, 464
urinary incontinence and, 48
Quazepam, 448, 557
Quetiapine, 549–551
adverse effects of, 319, 547, 550–551
mortality risk in elderly dementia patients, 299, 516
sexual dysfunction, 398
for bipolar disorder, 298, 550
for delirium, 514, 550
for delusional disorder, 320
for depression, 550
 dosing of, 320
for generalized anxiety disorder, 361
in hyperprolactinemia, 117
for neuropsychiatric symptoms in dementia, 549–550
agitation, 515, 519
for psychosis, 318, 550
in Alzheimer’s disease, 321
very-late-onset schizophrenia-like psychosis, 320
receptor blockade of, 550
for sleep disorders
in dementia, 230
in Parkinson’s disease, 442
use in Lewy body disorders, 322, 550
use in nursing homes, 697, 713, 716–717
Quinidine, 114, 544

Race/ethnicity, 4
antidepressant use and, 25
apolipoprotein E ε4 allele, Alzheimer’s disease risk and, 70–71
cultural norms and bereavement responses, 420
depression and, 9
mental health service use and, 24
pharmacogenomic testing and, 121
HLA-B*1502 allele test, 121, 297
suicide mortality and, 20, 26
vascular depression and, 253
Radiography, plain film, 115
Ramelteon, 443, 448, 448, 449
Rapid eye movement (REM) sleep behavior disorder, 435
Lewy body neurocognitive disorder and, 201
Parkinson’s disease and, 202, 204, 441
quetiapine for, 230
Rapid plasma reagin test, 110
Rapidly progressive dementias (RPDs), 207–210
differential diagnosis of, 209–210
nonprion causes of, 207
prion diseases, 207–209, 207–210
 treatment of, 216
Rash, drug-induced
carbamazepine, 297, 555
lamotrigine, 297, 555
Rating scales, 98–101. See also Assessment instruments
Receptors
acetylcholine
muscarinic, 547, 549, 550, 551, 552
nicotinic, 217
α-adrenergic, 39, 542, 550, 551
β-adrenergic, 39
age-related changes in, 527
angiotensin II, 252
atypical antipsychotic blockade of, 550, 551, 552
dopamine D2, 550, 551
glucocorticoid, 164
histamine H1, 551
insulin, 41
serotonin
5-HT1A, 541, 543
5-HT2A, 252, 542, 550
Relaxation techniques
for anxiety disorders, 359, 360, 654, 655, 660
for delirium, 170
for insomnia, 446
for nursing home residents, 697, 702
for sexual dysfunctions, 403, 404
Reliability of diagnosis, 7–8
Religious Order Study, 200
Religious participation
bereavement and, 419, 420, 421
effect on recovery from depression, 248, 264
of family, 681
psychotherapy and, 650
REM sleep behavior disorder. See Rapid eye movement sleep behavior
disorder
Remifentanil, 602
Reminiscence therapy, 210, 653
in nursing homes, 697, 698–702
Renal effects of drugs
angiotensin-converting enzyme inhibitors, 44
gabapentin, 556
lithium, 108, 553
nonsteroidal anti-inflammatory drugs, 44
Renal system changes with aging, 39, 43–44, 527, 529
drug prescribing and, 44, 53–54
Renin, 39, 44
Repetitive transcranial magnetic stimulation (rTMS), for depression,
270, 608
Research Domain Criteria, 333, 341
Reserpine, 267, 399
Resident Assessment Instrument, 720
Respiratory system changes with aging, 36–37
Respite care, 94, 232, 233, 672, 675, 676, 720
Restless legs syndrome (RLS), 229, 230, 435, 439, 451
Restlessness
during alcohol withdrawal, 478
Alzheimer’s disease and, 193, 195
generalized anxiety disorder and, 346, 347
sexually inappropriate behavior and, 406
Retirement, 33, 251, 261, 381, 395, 446, 464, 468, 494, 497
Rey Auditory Verbal Learning Test, 130, 135
Rey-Osterrieth figure, 136
Ribonucleic acid (RNA), 62, 63, 123
messenger, 62, 63
noncoding, 62, 63, 64, 77, 78
schizophrenia and, 78
Rigidity
in corticobasal syndrome, 205
in Lewy body neurocognitive disorder, 201
in Parkinson’s disease, 74, 142
in progressive supranuclear palsy, 137, 205
pupillary, 35
Risk factors for psychiatric disorders in elderly persons, 21–23
environmental factors, 22
genetic factors, 21–22
social factors, 22–23
Risperidone, 546–547
adverse effects of, 319, 546, 547
hyperprolactinemia, 117, 547
metabolic effects, 547
mortality and stroke risk in elderly dementia patients, 299,
516, 546
sexual dysfunction, 398
for agitation, 515
in Alzheimer’s disease, 47, 518, 546
in bipolar disorder, 547
for delirium, 514, 547
for delusional disorder, 320
dosing of, 320, 547
for generalized anxiety disorder, 361
long-acting injectable, 546–547
for mania, 298
for neuropsychiatric symptoms in dementia, 226, 546
agitation, 47, 518, 546
for psychosis
in Alzheimer’s disease, 316, 321
schizophrenia, 318, 319, 546–547
very-late-onset schizophrenia-like psychosis, 320
receptor blockade of, 550
for tardive dyskinesia, 318
use in Lewy body disorders, 547
use in nursing homes, 697, 703, 707, 708, 711, 712
Rivastigmine, 216–217, 558
adverse effects of, 218, 559
in Alzheimer’s disease, 47, 217, 218, 220
for agitation, 517
delirium and, 168
dosing of, 218, 559, 559
in Parkinson’s disease dementia, 204, 220
 preparations of, 218, 220
patch, 217, 220, 559
for psychosis in Lewy body neurocognitive disorder, 322, 517
use in nursing homes, 716
RLS (restless legs syndrome), 229, 230, 435, 439, 451
RNA. See Ribonucleic acid
Rofecoxib, in mild cognitive impairment, 210
Ropinirole, 439, 545
Rosalynn Carter Institute for Caregiving, 673
RPDs. See Rapidly progressive dementias
rTMS (repetitive transcranial magnetic stimulation), for depression,
270, 608

Safe Return program, 675

Safe-sex measures, 395
Salicylates, 112
Saliva production, 37
Sarcopenia, 41–42, 45
SBIRT (screening, brief intervention, and referral to treatment), for
substance-related disorders, 656
Schedule for Affective Disorders and Schizophrenia, 261
Schedule of Recent Events, 22
Schizoaffective disorder, 15, 320
electroconvulsive therapy for, 591
paliperidone for, 547
Schizoid personality disorder, 314, 492, 494, 656
Schizophrenia, 309–313, 314
early-onset, in older adults, 309–311, 323
cognition in, 310
depression in, 310
functional capacity and, 310–311
longitudinal studies of, 310
quality of life and, 311
genetics of, 61, 75–79
common variants, 78
noncoding RNA, 78
overlap with other psychiatric disorders, 75–76, 78–79
 rare mutations, 76
structural variants, 76–77
key points related to, 323–324
late-onset, 311–313, 323
clinical presentation of, 312
gender and, 311–312
imaging studies of, 312
risk factors for, 311
sensory deficits and, 312–313
medical comorbidity with, 52
negative symptoms of, 310, 311, 312, 313, 314, 397, 545, 591
positive symptoms of, 310, 311, 312, 313, 317, 323, 397–398
prevalence of, 15, 310
vs. psychosis of Alzheimer’s disease, 315, 316
sexual dysfunction and, 397–398
treatment of, 316, 317–323
electroconvulsive therapy, 589, 590, 591
omega-3 fatty acids, 628
pharmacotherapy, 317–320 (See also Antipsychotics)
psychosocial interventions, 320–321
vs. very-late-onset schizophrenia-like psychosis, 313, 324
Schizophreniform disorder, 95, 102
Schizotypal personality disorder, 492, 494
SCID (Structured Clinical Interview for DSM-IV), 101–102
SCID-II (Structured Clinical Interview for DSM-IV Personality
Disorders), 498
Screening
for cognitive impairment, 6, 11
for depression, 6, 52, 99–100, 245, 262
instruments for, 6, 98–101 (See also Assessment instruments)
for neurocognitive disorders, 98–99
nutritional, 629–630, 631
for substance-related disorders, 471–475, 474, 482
Screening, brief intervention, and referral to treatment (SBIRT), for
substance-related disorders, 656
SCUs (special care units) in nursing homes, 726–727
β-Secretase inhibitors, for Alzheimer’s disease, 213
γ-Secretase inhibitors, for Alzheimer’s disease, 47
Sedation, drug-induced, 527
antipsychotics, 318
carbamazepine, 297, 555
gabapentin, 556
olanzapine, 549
trazodone, 265
valproate, 554
Sedative-hypnotics
benzodiazepine receptor agonists, 168, 441, 443, 448, 448–449,
450, 556–557
benzodiazepines, 556–557, 560, 561
in bereavement, 427, 439
delirium induced by, 165, 166, 168
electroconvulsive therapy and, 267–268
for sleep disorders, 447–450, 448
in nursing homes, 704, 705
rebound insomnia after discontinuation of, 440
utilization by older adults, 25
Seizures. See also Epilepsy
celiac disease and, 210
deep brain stimulation–induced, 610
dementia and, 182
drug-induced
bupropion, 541
clozapine, 551
electroconvulsive therapy–induced, 267–268, 589–590, 595–598,
602–605
on electroencephalogram, 119, 162, 162
limbic encephalopathy and, 209
nocturnal, 445
NRXN1 mutations and, 77
vs. pseudoseizures in conversion disorder, 377, 378, 382
psychogenic nonepileptic, 378
repetitive transcranial magnetic stimulation–induced, 270, 608
somatic symptom disorders and, 382
substance-related disorders and, 472
 alcohol withdrawal, 478
Selective serotonin reuptake inhibitors (SSRIs), 528–536, 560. See
also specific drugs
adverse effects of, 264–265, 532, 536
apathy, 227, 545
bleeding, 532
cognitive effects, 532
falls, 718
gastrointestinal effects, 532
hyponatremia, 108–109, 227, 532
sexual dysfunction, 397, 399, 407
antidotes for, 400
for anxiety disorders, 333, 360, 361, 363, 528–529
for bereavement
complicated, 425
normal grief, 427
in dementia
for depression, 228
for neuropsychiatric symptoms, 227, 529, 532
for depression, 264–265, 266, 528
antidepressant augmentation of, 540, 541
clinical trials in geriatric patients, 528, 530–531
comparative efficacy and tolerability of, 532
compared with serotonin-norepinephrine reuptake inhibitors,
530–531, 536, 540
in dementia, 228
efficacy compared with electroconvulsive therapy, 590
methylphenidate and, 545
dosing of, 265, 266, 531–532, 532, 533
drug interactions with, 532
bupropion, 541
cytochrome P450 enzyme inhibition and, 535
warfarin, 93, 532
indications for, 528
overdose of, 264
for personality disorders, 501, 502
pharmacokinetics of, 533
 safety of, 264
for somatic symptom disorders, 382
suicide risk and, 536
switching to monoamine oxidase inhibitors from, 266
use in bipolar disorder, 298
use in nursing homes, 705, 706, 708, 710, 717
for vasomotor menopausal symptoms, 444
Selegiline transdermal patch, 544
Selenium, 633, 635
Self-efficacy
of caregivers, 672, 678
depression and, 255
schizophrenia and, 321
Self-esteem
bereavement and, 428
depression and, 271
mania and, 258
personality disorders and, 494, 497
psychotherapy in nursing homes for enhancement of, 696, 697,
700, 701
reminiscence therapy for improvement of, 653
substance use and, 469, 479
Self-help groups. See also Support groups
for bereaved persons, 426
for substance-related disorders, 476–477
Semagacestat, for Alzheimer’s disease, 47
Semantic dementia, 73, 141, 204, 205
Semantic fluency
in Alzheimer’s disease, 134, 135
tests of, 130
Sensate focus exercises, 402, 404
Sensorimotor tests, 131
Sensory deficits, 35, 45, 52, 53
agitation and, 508
delusional disorder and, 314, 315
psychosis and, 312–313
sleep disturbance and, 444–445
Sequenced Treatment Alternatives to Relieve Depression (STAR*D)
study, 540, 541–542
Serologic tests, 107–108
chemistry tests, 108–109, 109
for frontotemporal lobar degeneration, 113
hematologic tests, 108
for HIV infection, 110
for nutritional assessment, 630
for syphilis, 109–110
testosterone level, 40
thyroid function tests, 110–111, 111
toxicology, 112
vitamin B12, folate, and homocysteine levels, 111–112
Serotonin
in Alzheimer’s disease, 196
in delirium, 164
in depression, 79, 251, 252, 252
essential nutrients for production of, 622
in Parkinson’s disease, 203
receptors for
5-HT1A, 541, 543
5-HT2A, 252, 542, 550
Serotonin-norepinephrine reuptake inhibitors (SNRIs), 536–540, 560.
See also specific drugs
adverse effects of, 537, 540
cardiovascular effects, 537, 540
for anxiety disorders, 361
cytochrome P450 enzyme inhibition and drug interactions with,
535, 537
for depression, 265, 266, 536–537, 538
clinical trials in geriatric patients, 536
compared with selective serotonin reuptake inhibitors, 530–
531, 536, 540
in dementia, 228
dosing of, 266, 533, 538
indications for, 536
overdose of, 537
 pharmacokinetics of, 533
Serotonin syndrome, 266, 537, 541, 542, 550, 558
Serotonin transporter, in depression, 79, 247, 251, 252
Sertraline, 528
for anxiety disorders, 360, 361
cytochrome P450 enzyme inhibition and drug interactions with,
535
for depression, 92, 264, 265, 531, 532
bereavement-related, 425
in dementia, 227, 228, 516, 529
among nursing home residents, 708, 717
vs. tricyclic antidepressants, 544
vs. venlafaxine, 540, 717
dosing of, 265, 266, 531, 533
indications for, 528
for neuropsychiatric symptoms in dementia, 227
pharmacokinetics of, 533
use in nursing homes, 708, 717
Services and Advocacy for Gay, Lesbian, Bisexual and Transgender
Elders, 677
Sex hormone–binding globulin, 40
Sex therapy, 401–402, 404, 408
Sexual aversion, 397
Sexual dysfunctions, 389, 396–408
assessment of, 398–399
in dementia, 181, 405–407
drug-induced, 396–398, 399, 400–401, 537
drug holidays for, 400
in DSM-5, 396, 397
hyperprolactinemia and, 117
key points related to, 408
medical conditions and, 396, 398, 400
prevalence of, 396
psychiatric comorbidity with, 397–398
psychogenic, 396
treatment of, 399–402, 408
erectile disorder, 400, 403–404
 female orgasmic disorder, 404
female sexual interest/arousal disorder, 403
for medication effects, 400–401
patient education about ways to enhance sexual function,
399–400, 401
for persons with a disability, 400
premature (early) ejaculation, 404–405
sex therapy, 401–402
Sexual history, 398
Sexual phobias, 397
Sexuality, 389–395
aging gay and lesbian persons, 391
dementia and, 405–407
key points related to, 408
in long-term care settings, 391–392, 406
staff education about, 407
safe-sex measures, 395
sexual behaviors in late life, 389–391
sexual response cycle and aging, 392–395, 394
Sexually transmitted diseases (STDs), 395
SGA (Subjective Global Assessment), 630
Short Category Test, 130, 136
Short Portable Mental Status Questionnaire, 160
SIADH. See Syndrome of inappropriate antidiuretic hormone secretion
Sick role, 374, 381
Sildenafil
for erectile disorder, 400, 404
for female orgasmic disorder, 404
Single-nucleotide polymorphisms (SNPs), 62–64, 64, 65
Alzheimer’s disease and, 72
depression and, 79
genome-wide association studies of, 65
schizophrenia and, 78–79
Single-photon emission computed tomography (SPECT), 116
in delirium, 163
in dementia, 188, 196
in Lewy body neurocognitive disorder, 201
SLC2A9 gene, in Alzheimer’s disease, 72
SLC6A4 gene, in depression, 79
SLC24A4/RIN3 gene, in Alzheimer’s disease, 190, 191
Sleep apnea, 435, 437–438, 442, 443, 451, 557
alcohol use and, 480
central, 437, 438
evaluation of, 445
nocturia and, 443
obstructive, 229, 437–438
Sleep disorders, 7, 11, 14, 435–451. See also Insomnia
in DSM-5, 435
evaluation of, 445
polysomnography, 262, 263, 438–439, 442, 445
family tolerance of, 95
influence of aging on sleep and circadian functions, 436, 437
key points related to, 451
medical conditions and, 436–437, 442–445
alcohol use/withdrawal, 478, 480–481
cerebrovascular disease, 443
chronic obstructive pulmonary disease, 442–443
loss of hearing, vision, and mobility, 444–445
menopause-related symptoms, 444
nocturia, 443–444
pain, 376, 442
prevalence of, 435
primary, 437–439
breathing-related sleep disorders, 437–438
periodic limb movement disorder and restless legs
syndrome, 438–439
psychiatric disorders and, 436–437
Alzheimer’s disease, 193, 194–195, 440–441
bereavement, 416, 439–440
delirium, 160, 170
dementia, 181, 224
depression, 262, 263, 440
frontotemporal lobar degeneration, 205
Parkinson’s disease, 204, 441–442
 prion diseases, 208
treatment of
in dementia, 229–230
for insomnia, 446–450
Sleep effects of drugs
cholinesterase inhibitors, 218
donepezil, 218
dopamine agonists, 442
galantamine, 559
selective serotonin reuptake inhibitors, 264
theophylline, 443
Sleep hygiene
in anxiety disorders, 360
in dementia, 221, 224, 229, 231, 441
Sleep log, 445, 447
Sleep restriction therapy, 447
Smoking, 189, 210, 215, 261
SNCA gene, in Parkinson’s disease, 74, 75
Snellen eye chart, 52
Snoezelen rooms, 222, 696
SNPs. See Single-nucleotide polymorphisms
SNRIs. See Serotonin-norepinephrine reuptake inhibitors
Social anxiety disorder (social phobia), 341
clinical features of, 339
diagnosis in older adults, 336
in DSM-5, 343
prevalence of, 16, 17, 18, 341
Social isolation, 25, 53, 91, 98
bereavement and, 425
depression and, 244, 247, 251
family support programs to reduce risks of, 675, 679, 680–681
nutritional effects of, 625
personality disorders and, 494
posttraumatic stress disorder and, 337
progressive impairment and, 680
somatoform disorders and, 376, 381
substance-related disorders and, 472
Social risk factors for psychiatric disorders, 22–23, 26
depression, 23, 243–244, 255–257
effect on recovery, 248
with psychosis, 259
subsyndromal, 260
schizophrenia, 311
Social Security, 33
Social skills training, in schizophrenia, 316, 320
Social support, 256–257
assessment of, 52
bereavement and, 421, 423, 424, 428
depression and, 246, 247, 248, 250, 255, 256–257
effect on recovery from psychiatric disorders, 23
for families, 679
psychotherapy for enhancement of, 649, 672
Social workers, 25, 94, 212, 221, 672–673, 684
Socioeconomic status, 8
delusional disorder and, 315
depression and, 252, 255, 256, 260
HIV infection and, 109
somatic symptom disorders and, 377, 380, 383
substance-related disorders among women and, 469
Socioemotional selectivity theory, 257, 497
Sodium plasma level, 108–109, 164. See also Hyponatremia
Solanezumab, for Alzheimer’s disease, 47, 213, 214
Solifenacin, 49
Somatic symptom and related disorders, 373–383
alexithymia and, 379, 380–381
clinical features of, 374–375
conversion disorder (functional neurological symptom disorder),
377–379, 379
in DSM-5, 373, 374, 375
etiology of, 379–381, 380
illness anxiety disorder, 377, 378
key points related to, 383
medical conditions and, 374, 382, 383
prevalence of, 373–374, 380
 psychiatric comorbidity with, 374, 379–380
psychodynamic theory of, 380
somatic symptom disorder, 375–377, 376
treatment of, 381–383
Somatic symptom disorder, 373, 374, 375–377, 382, 383
clinical course of, 375–376
in DSM-5, 375, 376
epidemiology of, 375
imaging studies in, 380
vs. medical illness, 376, 383
pain and, 376–377
prevalence of, 376
Somatization disorder, 102, 373, 375–376, 382
Somatoform disorders, 373
Somatostatin, 39
Somnolence, drug-induced
atypical antipsychotics, 515, 550, 551, 707, 708, 709, 711, 712,
714
L-dopa, 215
lamotrigine, 555
pregabalin, 556
valproate, 296, 710, 716
SORL1 gene, in Alzheimer’s disease, 189–190, 191
Special care units (SCUs) in nursing homes, 726–727
Specific phobia, 341
clinical features of, 339
diagnosis in older adults, 336
in DSM-5, 342
prevalence of, 14, 15, 16–17, 18
SPECT. See Single-photon emission computed tomography
Spongiform encephalopathies, 207–208. See also Prion diseases
SRR gene, in schizophrenia, 78
SSRIs. See Selective serotonin reuptake inhibitors
St. John’s wort, 166, 628
STAR*D (Sequenced Treatment Alternatives to Relieve Depression)
study, 540, 541–542
Status epilepticus, 162, 268, 595
STBD1 gene, in Parkinson’s disease, 75
STDs (sexually transmitted diseases), 395
STEP-BD (Systematic Treatment Enhancement Program for Bipolar
Disorder), 289, 298
Stevens-Johnson syndrome
carbamazepine and, 121
lamotrigine and, 297, 555
Stigmatization
of 12-step program attendance, 477
bereavement after stigmatized death, 422, 428
genetic testing and, 122
of mental illness, 673
of sexuality in long-term care settings, 391
of treatment seeking, 649
Stimulants. See Psychostimulants
Stimulus control therapy, 446, 447
Strengthening exercises, 637, 638
Stress. See also Life events
acute stress disorder, 339, 352
anxiety and, 339
delirium and, 163–164, 164
depression and, 255–256
personality disorders and, 497
posttraumatic stress disorder (PTSD), 351–352
progressively lowered stress threshold theory of dementia, 659
as risk factor for psychiatric disorders, 22–23
sexual dysfunction and, 396
somatic symptom disorders and, 379
Stress incontinence, 48–49
Stroke. See also Cerebrovascular disease
agitation and, 509
agoraphobia and, 336, 341
alcohol use and, 470, 634
apathy and, 194
atypical antipsychotic–related risk in elderly dementia patients,
317, 319, 322, 324, 545, 546, 703
bupropion contraindicated for patients with, 541
 delirium and, 156, 157, 162, 165, 167
depression and, 143, 253, 260
antidepressants for, 530, 537
vascular, 253, 622
diet, physical activity and, 618, 624, 626, 627, 636
effect on testing for cerebrospinal fluid 14-3-3 protein, 113
electroconvulsive therapy and, 595
estrogen replacement therapy and, 41, 393
generalized anxiety disorder and, 339
genetic factors and, 79
hyperhomocysteinemia and, 111
insomnia and, 443
mania and, 249
neuroimaging in, 292
mirtazapine-associated risk for, 542
prion disease and, 208
schizophrenia and, 312, 314
selective serotonin reuptake inhibitors and, 227, 264
sexual dysfunction and, 396, 398, 406
subacute nursing home care after, 727
testosterone replacement therapy and, 40
urinary incontinence and, 48
vascular dementia and, 99, 139, 199, 200, 215
venlafaxine-associated risk for, 540
Stroop Color and Word Test, 130, 136
Structured Clinical Interview for DSM-IV (SCID), 101–102
Structured Clinical Interview for DSM-IV Personality Disorders
(SCID-II), 498
Structured diagnostic interviews, 101–102, 104
Stupor, 96, 159, 160
STX1B gene, in Parkinson’s disease, 75
Subacute care in nursing homes, 727–728
Subjective Global Assessment (SGA), 630
Sublimation, 496
Substance/medication-induced bipolar and related disorders, 283, 284
Substance/medication-induced depressive disorder, 244, 244
Substance/medication-induced major neurocognitive disorder, 181
Substance/medication-induced mild neurocognitive disorder, 183
Substance/medication-induced sexual dysfunction, 397
Substance/medication-induced sleep disorder, 435
Substance-related and addictive disorders, 459–482. See also Alcohol-
related disorders; Alcohol use
comorbidity with, 479–481, 482
Alzheimer’s disease, 189, 471, 480
bipolar disorder, 286–287
depression, 254, 470, 480
pain, 377
sleep disorders, 480–481
consequences of, 469–471
correlates and risk factors for, 468–469
epidemiology of, 8–9, 18, 459–460, 465–468, 482, 655
alcohol, 459–460, 460, 465–467
illicit drugs, 459–460, 461, 467–468
prescription and over-the-counter drugs, 467
future directions related to, 481
guidelines and classification of, 461–465
spectrum of substance use, 462–464
substance use disorder, 464–465, 466
key points related to, 482
screening and diagnosis of, 471–475, 482
assessing frequency and quantity of use, 472–473
timeline followback method, 472
biological markers/laboratory testing, 112, 475
potential barriers to, 471–472
prescription drug misuse, 93, 471, 472, 475
standardized instruments for, 471, 473–475, 474
treatment of, 460–461, 475–479, 482
brief interventions and therapies, 475–476
for detoxification and withdrawal, 478
factors affecting response and adherence to, 479
pharmacotherapy, 477–478
psychosocial treatments, 476
twelve-step programs, 476–477
Substance use disorders, 464
 in DSM-5, 464–465, 466
Succinylcholine, for electroconvulsive therapy, 602
Suicidal ideation or behavior, 7
assessing risk for, 97, 262
bipolar disorder and, 289
depression and, 262
effect of lithium on, 554
historical studies of mortality from, 5, 20, 21, 26
psychosis of Alzheimer’s disease and, 316
race/ethnicity and, 20, 26
schizophrenia and, 310, 316
selective serotonin reuptake inhibitors and, 536
Sundowning, 193, 195, 441, 510, 514
Support groups
for bereaved persons, 426
for dementia patients, 511
for families, 673, 675, 678, 679
for lesbian, gay, bisexual, and transgender persons, 677
for schizophrenia patients, 320
twelve-step programs for substance-related disorders, 476–477
Suppression, 496
Surgery
for deep brain stimulation, 609, 610
delirium after, 156, 157, 165, 167, 170
pharmacological prevention and management of, 168, 514,
547, 548
for erectile dysfunction, 403
for obstructive sleep apnea, 438
selective serotonin reuptake inhibitor–associated bleeding after,
532
somatization disorder and, 375
for urinary incontinence, 49, 50
for vagus nerve stimulation, 609
Suspiciousness, 7, 494, 498, 508, 509, 674
Suvorexant, for insomnia, 448, 449
Sydney Memory and Aging Study, 10
Symbol Digit Modalities Test, 130
Sympathetic nervous system, 36, 39, 51
Symptoms of psychiatric disorders, 89–90. See also Aggression;
Agitation; Behavioral disturbances; Paranoia; Psychosis/psychotic
symptoms
agitation, 7, 91, 95–96, 507–519
communicating with older adults about, 90–91
history taking for, 89–91
neuropsychiatric symptoms in dementia, 180–182, 181
prevalence of, 3, 5, 7, 9, 11, 13, 14, 15, 18, 19
in treatment settings, 15, 18, 19
Syncope, 115
drug-induced
cholinesterase inhibitors, 558
serotonin-norepinephrine reuptake inhibitors, 537
trazodone, 542
Lewy body neurocognitive disorder and, 201
Syndrome of inappropriate antidiuretic hormone secretion (SIADH),
drug-induced
carbamazepine, 297
quetiapine, 550–551
selective serotonin reuptake inhibitors, 532
serotonin-norepinephrine reuptake inhibitors, 537
α-Synuclein, 74, 141, 190, 200, 203, 203, 441
Syphilis, 46, 186, 395
serologic tests for, 109–110
Systematic Treatment Enhancement Program for Bipolar Disorder
(STEP-BD), 289, 298

T lymphocytes, 43
T3 (triiodothyronine), 41, 110–111, 111, 262, 263
T4 (thyroxine), 41, 110–111, 111, 262, 263, 630
Tachycardia, electroconvulsive therapy–induced, 602
Tacrine, 216, 217, 558
Tadalafil, for erectile disorder, 400, 404
T’ai chi, 638
Tardive dyskinesia, 101, 313, 314, 317, 318, 321, 323, 324, 550, 703
Task structuring, 225
Tau proteins, 188
in Alzheimer’s disease, 71, 112, 119, 122, 128, 196, 197, 198,
203, 316
therapies targeting, 213
in corticobasal degeneration, 73
in frontotemporal lobar degeneration, 73, 113, 141, 190, 205–206
in Parkinson-plus syndromes, 113
positron emission tomography imaging of, 118, 119
in progressive supranuclear palsy, 73
TBI. See Traumatic brain injury
TCAs. See Antidepressants, tricyclic
tDCS (transcranial direct current stimulation), 607, 608–609
TDEEs (total daily energy expenditures), 632
TDP-43 (transactive response DNA-binding protein 43), 73, 113, 141,
190, 206
Temazepam, 448, 449, 557
Temperament, 284, 492
Temporal arteritis, 45
Tendon changes with aging, 42
Terfenadine, 297
Testosterone
age-related decline in, 40, 252, 394
bone mass and, 51
replacement therapy with, 40
adverse effects of, 403
in depression, 253
for erectile disorder, 403
for female orgasmic disorder, 404
for female sexual interest/arousal disorder, 403
testing for deficiency of, 40
Texas Revised Inventory of Grief—Present (TRIG-Present), 423
Theophylline, 45, 443
electroconvulsive therapy and, 595, 598
interaction with lithium, 295
Therapeutic plasma level
of carbamazepine, 516
of lithium, 112, 295
 of tricyclic antidepressants, 112, 265, 544
of valproate, 296
Thiamine intake, 633
Thioridazine
delirium and, 168
QTc interval prolongation induced by, 114, 552
use in nursing homes, 704, 705
Thiothixene
before electroconvulsive therapy, 269
use in nursing homes, 706
Thirst response, 635
Thought disturbances
assessment of, 96–97
in delirium, 160
3MS (Modified Mini-Mental State), 185
Thrombocytopenia, drug-induced, 108
valproate, 296, 554
Thrombophlebitis, prevention during electroconvulsive therapy, 597–
598
Thyroid changes with aging, 41
Thyroid disorders. See Hyperthyroidism; Hypothyroidism
Thyroid function tests, 110–111, 111, 262, 263, 294
Thyroid-stimulating hormone (TSH), 110–111, 111
Thyroxine (T4), 41, 110–111, 111, 262, 263, 630
Thyroxine-binding globulin, 41, 110
Timeline followback (TLFB) method, to assess substance use, 472
TMS. See Transcranial magnetic stimulation
Tolterodine, 49
Topiramate, 554, 556
Torsades de pointes, drug-induced
antipsychotics, 114, 114
citalopram, 114–115, 227, 532
mirtazapine, 540, 542
Total daily energy expenditures (TDEEs), 632
Toxicology tests, 112, 475
Trail Making Test, 130, 133, 135–137
Training of mental health workers, 25
 in nursing homes, 695, 696, 724, 725, 730, 731
to prevent delirium, 169
Transactive response DNA-binding protein 43 (TDP-43), 73, 113, 141,
190, 206
Transcranial direct current stimulation (tDCS), 607, 608–609
Transcranial magnetic stimulation (TMS), 607, 607–608
deep TMS, 608
repetitive TMS for depression, 270, 608
safety of, 607, 608
technique for, 607–608
Transcriptomics, 123, 123
Transference, 103
Transurethral resection of prostate, 50
Tranylcypromine, 266, 540, 542, 544
Trauma- and stressor-related disorders, 333
acute stress disorder, 339, 352
in DSM-5, 335
posttraumatic stress disorder, 351–352, 353–354
Traumatic brain injury (TBI), 22
agitation and, 509
conversion disorder and, 378
due to falls, 47
electroencephalography for, 119
imaging studies for, 162, 163
inappropriate sexual behavior and, 406
mania and, 249, 294
neurocognitive disorders due to, 22, 181, 183, 185
Alzheimer’s disease, 189
personality disorders and, 499, 502
Trazodone, 542–543
adverse effects of, 265, 448, 542–543
for antidepressant-induced sexual dysfunction, 400
cytochrome P450 enzyme inhibition and drug interactions with,
535, 543
for depression, 265, 542–543
compared with other antidepressants, 538
dosing of, 265, 266, 534, 542
 mechanism of action of, 542
for neuropsychiatric symptoms of dementia, 227, 230, 441, 517,
542
pharmacokinetics of, 534
for sleep disorders, 230, 441, 448, 450, 542
Treatments for psychiatric disorders
brain stimulation therapies, 589–611, 607
deep brain stimulation, 607, 609–610
electroconvulsive therapy, 266–270, 589–607
transcranial direct current stimulation, 607, 608–609
transcranial magnetic stimulation, 270, 607, 607–608
vagus nerve stimulation, 607, 609
nutrition and physical activity, 617–639
pharmacotherapy, 527–560
psychotherapy, 649–660
working with families, 669–684
TREM gene, in Alzheimer’s disease, 71
Tremor
alcohol-related, 475, 478
conversion disorder and, 377
corticobasal syndrome and, 205
drug-induced
galantamine, 559
lithium, 295, 553
selective serotonin reuptake inhibitors, 264, 541
valproate, 554
Lewy body neurocognitive disorder and, 201
clozapine for, 322
Parkinson’s disease and, 74
progressive supranuclear palsy and, 137
Triazolam, 448, 557
for insomnia, 444, 449
in chronic obstructive pulmonary disease, 443
in dementia, 229
Tricyclic antidepressants (TCAs). See Antidepressants, tricyclic
Triflusal, in mild cognitive impairment, 210
TRIG-Present (Texas Revised Inventory of Grief—Present), 423
Triiodothyronine (T3), 41, 110–111, 111, 262, 263
TSH (thyroid-stimulating hormone), 110–111, 111
Twelve-step programs, 476–477
Twin studies, 61
of Alzheimer’s disease, 189
of depression, 22, 251
of personality change, 495

Ubiquitin-positive inclusions, in frontotemporal lobar degeneration,

73, 113, 141, 206
Ultrarapid metabolizers, 121
United Ostomy Associations of America, 400
Urethritis, nongonococcal, 395
Urge incontinence, 48, 49
Urinalysis, 112
Urinary incontinence, 45, 46, 48–50, 54
caregiver education about management of, 221
depression and, 253
family tolerance of, 95, 678
Lewy body neurocognitive disorder and, 202
medical consequences of, 50
medications and
atypical antipsychotics, 515
serotonin-norepinephrine reuptake inhibitors, 537
normal-pressure hydrocephalus and, 137, 206
among nursing home residents, 690
overflow, 49–50
polypharmacy and, 50
prevalence of, 48
stress, 48–49
transient, 48
treatment of, 49–50
urge, 48, 49
Urinary retention, 162
depression and, 693
drug-induced, 45, 527
serotonin-norepinephrine reuptake inhibitors, 537
 electroconvulsive therapy and, 598
Urinary tract infection (UTI), 48, 51, 112, 221, 509, 515, 711
Urine drug screening, 112, 475
UTI (urinary tract infection), 48, 51, 112, 221, 509, 515, 711

VA facilities. See Department of Veterans Affairs facilities

Vagus nerve stimulation (VNS), 607, 609
Validity of diagnosis, 7–8
Valproate (divalproex), 554
adverse effects of, 296, 554
hepatotoxicity, 109
mortality risk in dementia patients, 515–516
pancreatitis, 109
sexual dysfunction, 399
for bipolar disorder, 249, 295, 296, 554
dosing of, 296
drug interactions with, 93, 296, 554
pharmacokinetics of, 296, 554
preparations of, 296
therapeutic plasma level of, 296
use in dementia, 516, 554
use in nursing homes, 709–711, 716
Vancomycin, 45
Vardenafil, for erectile disorder, 400, 404
Vascular changes with aging, 35–36
Vascular depression, 252, 253, 262
Vascular neurocognitive disorder (vascular dementia), 184, 190, 199–
200
alcohol intake and, 620
Alzheimer’s disease and, 199, 200, 215
clinical presentation of, 199–200
diagnosis of, 200
genetic forms of, 199
managing risk factors for, 215
neuropsychological assessment in, 136, 139–140
among nursing home residents, 691
prevalence of, 12, 46
 progression of, 200
spectrum of, 199
VCP gene, in frontotemporal lobar degeneration, 73
Velocardiofacial syndrome, 77
Venereal Disease Research Laboratory test, 110
Venlafaxine, 536–540
adverse effects of, 540
hepatotoxicity, 109
sexual dysfunction, 397, 399
for anxiety disorders, 361
cytochrome P450 enzyme inhibition and drug interactions with,
535, 537
for depression, 265, 536, 538
combined with aripiprazole, 552
combined with bupropion, 541
combined with mirtazapine, 540, 541–542
compared with selective serotonin reuptake inhibitors, 530–
531, 536
in dementia, 228
dosing of, 228, 265, 266, 533, 538
indications for, 536
pharmacokinetics of, 533
use in frail nursing home patients, 540, 717
use in nursing homes, 717
for vasomotor menopausal symptoms, 444
Venous thromboembolism, atypical antipsychotic–induced, 545
Verapamil, 557
Verbal fluency tests, 130, 133, 135, 137, 138
Vertebral fractures, 36
electroconvulsive therapy–related, 268
Very-late-onset schizophrenia-like psychosis (VLOSLP), 313, 314,
320, 324
Veterans Affairs (VA) facilities. See Department of Veterans Affairs
facilities
Vilazodone, 543
adverse effects of, 543
 cytochrome P450 enzyme inhibition and drug interactions with,
535
for depression, 265, 539, 540, 543
dosing of, 266, 534
mechanism of action of, 543
pharmacokinetics of, 534
Violence, 677. See also Aggression
bereavement after death due to, 422, 428
dementia and, 181
posttraumatic stress disorder after exposure to, 351, 353
VIPR2 gene, in schizophrenia, 77
Vision impairment/loss, 35, 45, 53
agitation and, 508
phosphodiesterase 5 inhibitor–induced, 404
in prion diseases, 208
psychosis and, 313
psychotherapy for patients with, 650
sleep disturbance and, 444–445
testing for, 52
Visuoperception tests, 131
Visuospatial deficits
Alzheimer’s disease and, 134, 135
Creutzfeldt-Jakob disease and, 138
delirium and, 158, 160
dementia and, 46
depression and, 143
Lewy body neurocognitive disorder and, 136, 142, 143, 144, 200,
201
normal aging and, 132, 135
Parkinson’s disease and, 202
testing for, 99, 130, 132, 135, 136
vitamin B12 and folate deficiencies and, 111
Vitamin A, 633, 635
Vitamin B6
Alzheimer’s disease and, 111
depression and, 622
dietary intake of, 633
 mild cognitive impairment and, 210
supplementation of, 635
Vitamin B12
deficiency of, 621
laboratory testing for, 46, 111, 162, 186, 262
neuropsychiatric effects of, 111
prevalence of, 111
delirium and, 162, 163
dementia and, 46, 111, 186, 188, 189, 621
depression and, 262, 622
dietary intake of, 189, 633
folate and, 111, 189
supplementation of, 635
in mild cognitive impairment, 210
Vitamin C
Alzheimer’s disease and, 189
dietary intake of, 633
supplementation of, 635
Vitamin D, 39
Alzheimer’s disease and, 189
cognitive function and, 621
dietary intake of, 629, 633
hydroxylation of, 44
supplementation of, 48, 636
Vitamin E
dietary intake of, 629, 633
in mild cognitive impairment, 210
supplementation of, 635
Vitamin intake and dementia, 621
Vitamin K intake, 633
Vitamin supplements, 635
in mild cognitive impairment, 210
VLOSP (very-late-onset schizophrenia-like psychosis), 313, 314, 320,
324
VNS (vagus nerve stimulation), 607, 609
Volume of distribution of drugs, 44
Vortioxetine, 543
 adverse effects of, 543
cytochrome P450 enzyme inhibition and drug interactions with,
535
for depression, 265, 539, 540, 543
dosing of, 266, 534, 543
mechanism of action of, 543
pharmacokinetics of, 534
VPS35 gene, in Parkinson’s disease, 74
VSNL1 gene, in Alzheimer’s disease, 72

WAIS-IV. See Wechsler Adult Intelligence Scale, 4th Edition

Wandering, 181, 195, 212, 230, 441, 514
assessing risk for, 683
family tolerance of, 95
nonpharmacological management of, 223, 224, 232
caregiver help for, 675, 680
by nursing home residents, 692, 693
Safe Return program for, 675
Warfarin, 44
drug interactions with
alcohol, 470
psychostimulants, 545
selective serotonin reuptake inhibitors, 93, 532
valproate, 296
to prevent thrombophlebitis during electroconvulsive therapy, 598
Water exercises, 638
Water intake, 635. See also Dehydration
Wechsler Adult Intelligence Scale, 4th Edition (WAIS-IV), 130, 133,
135–138
Digit Span Backward subtest, 135–137
Digit Span subtest, 135
Wechsler Memory Scale, 4th Edition (WMS-IV), 130, 135
Weight gain
atypical depression and, 626
drug-induced
atypical antipsychotics, 109, 299, 319, 547, 549
lithium, 295
 medroxyprogesterone, 407
mirtazapine, 448, 542
testosterone, 403
valproate, 296, 554
Weight loss, 45, 51, 630
dementia and, 626–627
depression and, 246, 262
drug-induced
cholinesterase inhibitors, 218, 558
selective serotonin reuptake inhibitors, 265, 628
topiramate, 556
low-carbohydrate diets for, 634
nutritional assessment for, 630
tube feedings for, 627
Wernicke-Korsakoff syndrome, 480, 627
Wernicke’s encephalopathy, 117, 117
WHO. See World Health Organization
Widowhood/widowerhood, 22, 415, 417, 419, 424–425, 428. See also
Bereavement
duration of, 415
mortality and, 421
prevalence of, 415
substance use and, 464, 468, 469
Wisconsin Card Sorting Test, 130, 136, 137
Wisdom and aging, 257–258, 272
Withdrawal from drugs, 478
alcohol, 112, 478
benzodiazepines for, 513–514
benzodiazepines, 478
WMH (World Mental Health surveys, 9
WMS (Wechsler Memory Scale, 4th Edition), 130, 135
Women’s Health Initiative, 41
“Word salad,” 160
Work rehabilitation programs for patients with psychosis, 321
World Health Organization (WHO), 9
Composite International Diagnostic Interview, 6, 9, 102
guidelines for management of bereavement, 427
World Health Organization Disability Assessment Schedule 2.0
(WHODAS 2.0), 100
World Mental Health (WMH) Survey Version of the Composite
International Diagnostic Interview, 6, 102
Worry, 339, 340, 357, 498. See also Anxiety; Fear
cognitive function and, 357
depression and, 348
generalized anxiety disorder and, 336, 339, 346–348, 347
imaging studies of, 358
treatment of, 360, 654, 659
insomnia and, 446
panic disorder and, 345
Worthlessness, feelings of, 258.259, 264, 421

Yohimbine, 400

Zaleplon, for insomnia, 448, 449, 556, 557

ZCWPW1 gene, in Alzheimer’s disease, 190, 191
Zeitgebers, 436
Zinc intake, 633
Ziprasidone, 552
adverse effects of, 398, 552
QTc interval prolongation, 114, 552
for delirium, 514
for mania, 298–299
receptor blockade of, 550
for schizophrenia, 318
Zolpidem, for insomnia, 448, 448, 449, 557
in chronic obstructive pulmonary disease, 443
in depression, 440
with hot flashes, 444
in Parkinson’s disease, 442
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