Download the full version of the ebook at ebookfinal.

com

Bipolar Disorders Basic Mechanisms and Therapeutic

Implications 2nd edition Medical Psychiatry Jair
C. Soares

https://ebookfinal.com/download/bipolar-disorders-basic-
mechanisms-and-therapeutic-implications-2nd-edition-medical-
psychiatry-jair-c-soares/

OR CLICK BUTTON

DOWNLOAD EBOOK

Download more ebook instantly today at https://ebookfinal.com

Instant digital products (PDF, ePub, MOBI) available
Download now and explore formats that suit you...

Research Advances in Genetics and Genomics Implications

for Psychiatry 1st Edition Nancy C. Andreasen

https://ebookfinal.com/download/research-advances-in-genetics-and-
genomics-implications-for-psychiatry-1st-edition-nancy-c-andreasen/

ebookfinal.com

Synthetic Nucleic Acids as Inhibitors of Gene Expression

Mechanisms Applications and Therapeutic Implications 1st
Edition Levon Michael Khachigian (Editor)
https://ebookfinal.com/download/synthetic-nucleic-acids-as-inhibitors-
of-gene-expression-mechanisms-applications-and-therapeutic-
implications-1st-edition-levon-michael-khachigian-editor/
ebookfinal.com

Metal Based Neurodegeneration From Molecular Mechanisms to

Therapeutic Strategies 2nd Edition Robert Crichton

https://ebookfinal.com/download/metal-based-neurodegeneration-from-
molecular-mechanisms-to-therapeutic-strategies-2nd-edition-robert-
crichton/
ebookfinal.com

Itch Basic Mechanisms and Therapy Basic and Clinical

Dermatology 1st Edition Gil Yosipovitch

https://ebookfinal.com/download/itch-basic-mechanisms-and-therapy-
basic-and-clinical-dermatology-1st-edition-gil-yosipovitch/

ebookfinal.com
Deadly Karate Blows The Medical Implications Adams

https://ebookfinal.com/download/deadly-karate-blows-the-medical-
implications-adams/

ebookfinal.com

Handbook of Diagnosis and Treatment of Bipolar Disorders

1st Edition Terence A. Ketter

https://ebookfinal.com/download/handbook-of-diagnosis-and-treatment-
of-bipolar-disorders-1st-edition-terence-a-ketter/

ebookfinal.com

Chromosomal Instability and Aging Basic Science and

Clinical Implications 1st Edition Fuki Hisama

https://ebookfinal.com/download/chromosomal-instability-and-aging-
basic-science-and-clinical-implications-1st-edition-fuki-hisama/

ebookfinal.com

Gene and Cell Therapy Therapeutic Mechanisms and

Strategies 4th Revised edition Edition Nancy Smyth
Templeton
https://ebookfinal.com/download/gene-and-cell-therapy-therapeutic-
mechanisms-and-strategies-4th-revised-edition-edition-nancy-smyth-
templeton/
ebookfinal.com

Developing Cognitive Control Processes Mechanisms

Implications and Interventions Volume 37 1st Edition
Philip David Zelazo
https://ebookfinal.com/download/developing-cognitive-control-
processes-mechanisms-implications-and-interventions-volume-37-1st-
edition-philip-david-zelazo/
ebookfinal.com
 BIPOLAR
DISORDERS
 BIPOLAR
DISORDERS
Basic Mechanisms
and Therapeutic Implications
Second Edition

Edited by
Jair C. Soares
University of North Carolina School of Medicine
Chapel Hill, North Carolina, USA
Allan H. Young
University of British Columbia
Vancouver, British Columbia, Canada
Informa Healthcare USA, Inc.
52 Vanderbilt Avenue
New York, NY 10017

# 2007 by Informa Healthcare USA, Inc.

Informa Healthcare is an Informa business

No claim to original U.S. Government works

Printed in the United States of America on acid-free paper
10 9 8 7 6 5 4 3 2 1

International Standard Book Number-10: 0-8493-9897-5 (Hardcover)

International Standard Book Number-13: 978-0-8493-9897-1 (Hardcover)

This book contains information obtained from authentic and highly regarded sources. Reprinted
material is quoted with permission, and sources are indicated. A wide variety of references
are listed. Reasonable efforts have been made to publish reliable data and information, but the
author and the publisher cannot assume responsibility for the validity of all materials or for the
consequence of their use.

No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any elec-
tronic, mechanical, or other means, now known or hereafter invented, including photocopying,
microfilming, and recording, or in any information storage or retrieval system, without written
permission from the publishers.

For permission to photocopy or use material electronically from this work, please access www.
copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc.
(CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization
that provides licenses and registration for a variety of users. For organizations that have been
granted a photocopy license by the CCC, a separate system of payment has been arranged.

Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and
are used only for identification and explanation without intent to infringe.

Library of Congress Cataloging-in-Publication Data

Bipolar disorders : basic mechanisms and therapeutic implications—2nd ed./edited
by Jair C. Soares, Allan H. Young.
p. ; cm. -- (Medical psychiatry ; 35)
Includes bibliographical references and index.
ISBN-13: 978-0-8493-9897-1 (hardcover : alk. paper)
ISBN-10: 0-8493-9897-5 (hardcover : alk. paper)
1. Manic-depressive illness. I. Soares, Jair C. II. Young, A. H. (Allan H.) III. Series.
[DNLM: 1. Bipolar Disorder--diagnosis. 2. Bipolar Disorder--therapy. W1
ME421SM v.35 2007/ WM 207 B61649 2007]
RC516.B5275 2007
616.890 5- -dc22 2006103138

Visit the Informa Web site at

www.informa.com

and the Informa Healthcare Web site at

www.informahealthcare.com
B Preface

Since the first edition of our book was published, increasing progress has been
seen in the understanding of the basic mechanisms involved in the pathophysiol-
ogy of bipolar mood disorders. When our first edition was prepared, there was
comparatively little research being conducted on the mechanisms involved in
this disorder. Recent years have seen an increasing interest in this field and an
increasing amount of activity. Important research initiatives have begun to eluci-
date the pathophysiology of this disorder. These research initiatives are beginning
to lead to breakthroughs in the understanding of the causation of bipolar mood dis-
orders and the development of novel treatments. Some of these new advances have
recently translated into newer treatments available for these disorders.
Of particular importance is the development of newer tools from neuro-
psychopharmacology, which have provided new ways to study various brain
systems, including post-receptor and transcriptional mechanisms. Developments
in neuroimaging have made possible the in vivo study of brain anatomy, neuro-
transmission, and metabolic processes. Important tools from genetics are becoming
available and are being applied to further the understanding of mechanisms
involved in bipolar disorders. Cognitive neuropsychology has also provided
improved tools for the more refined study of brain functions in these disorders.
These novel research avenues have provided new dimensions in exploring the bio-
logical mechanisms involved. New therapeutic developments have already become
available in the past few years. These advances are expected to gradually continue
to translate into new approaches for the treatment of bipolar disorder over the next
few to several years.
The updated findings from this research have not been comprehensively sum-
marized in a book focused specifically on the biological underpinnings of bipolar
mood disorders. There are some excellent books available on the subject of
bipolar disorders, but their focus is primarily on diagnostic issues, course of
illness, and treatment. To fill this gap, we are proud to present the second edition
of our book, Bipolar Disorders: Basic Mechanisms and Therapeutic Implications. This
volume presents outstanding manuscripts by the leaders in the particular areas
of biological research pertinent to bipolar disorders. Among other very important
topics, we have included chapters on genetics, neuroimaging, neuropsychology,
investigations of post-receptor and transcriptional abnormalities, potential inter-
actions between biology and psychosocial factors, childhood onset and late-life
bipolar disorder, and several other important topics. A chapter on the implications
of these research areas for ongoing therapeutic developments in this field is also
included. The potential therapeutic implications of new research, as in the first
edition, are emphasized throughout the book.
We are very happy to have had the collaboration of some of the leading scien-
tists in their respective fields of research, and believe this volume will be a valuable
resource for researchers in this field and in related areas. It is presented as a
iii
iv Preface

complete and accessible reference to the most updated information on the biologi-
cal basis and therapeutics of bipolar mood disorders. It should be useful as sup-
plemental reading for graduate and postgraduate courses on the neurobiology of
mental illness. Mental health practitioners will find it extremely useful as an
updated source with the most recent research progress in this field. We hope you
will share our excitement with these new developments.

Jair C. Soares
Allan H. Young
B Contents

Preface . . . . iii
Contributors . . . . vii

1. Classification of Bipolar Disorders—Implications for Clinical Research 1

Ralph W. Kupka and Willem A. Nolen

2. Prospects for the Development of Animal Models for the Study

of Bipolar Disorder 19
Haim Einat, Alona Shaldubina, Yuly Bersudsky, and R. H. Belmaker

3. Abnormalities in Catecholamines and the Pathophysiology

of Bipolar Disorder 33
Amir Garakani, Dennis S. Charney, and Amit Anand

4. Cholinergic-Muscarinic Dysfunction in Mood Disorders 67

David S. Janowsky and David H. Overstreet

5. Serotonergic Dysfunction in Mood Disorders 89

J. John Mann and Dianne Currier

6. Cell Membrane and Signal Transduction Pathways—Implications for the

Pathophysiology of Bipolar Disorders 109
Guang Chen and Husseini K. Manji

7. Searching for a Cellular Endophenotype for Bipolar Disorder 131

Francine M. Benes

8. The Hypothalamic–Pituitary –Adrenal Axis in Bipolar Disorder 145

David J. Bond and Allan H. Young

9. Brain Imaging Studies in Bipolar Disorder 161

E. Serap Monkul, Paolo Brambilla, Fabiano G. Nery,
John P. Hatch, and Jair C. Soares

10. Sleep and Biological Rhythms Abnormalities in the

Pathophysiology of Bipolar Disorders 189
Stephany Jones and Ruth M. Benca

11. Hypothesis of an Infectious Etiology in Bipolar Disorder 209

Robert H. Yolken and E. Fuller Torrey
v
vi Contents

12. EEGs and ERPs in Bipolar Disorders 221

R. Hamish McAllister-Williams

13. Genetics of Bipolar Disorder 233

Nick Craddock

14. Neurocognitive Findings in Bipolar Disorder 251

David C. Glahn and Carrie E. Bearden

15. Biology vs. Environment: Stressors in the Pathophysiology

of Bipolar Disorder 275
Morgen A. R. Kelly, Stefanie A. Hlastala, and Ellen Frank

16. The Kindling/Sensitization Model: Implications for the Pathophysiology of

Bipolar Disorder 297
Robert M. Post

17. Biologic Factors in Different Bipolar Disorder Subtypes 325

Michael A. Cerullo and Stephen M. Strakowski

18. Biological Factors in Bipolar Disorder in Childhood and Adolescence 343

Melissa A. Brotman, Daniel P. Dickstein,
Brendan A. Rich, and Ellen Leibenluft

19. Biological Factors in Bipolar Disorders in Late Life 361

R. C. Young, J. M. deAsis, and G. S. Alexopoulos

20. Perspectives for New Pharmacological Interventions 377

Charles L. Bowden

21. Physical Comorbidity in Bipolar Disorder 387

Paul Mackin and Sylvia Ruttledge

22. Toward a Pathophysiology of Bipolar Disorders 401

John F. Neumaier and David L. Dunner

Index . . . . 409
B Contributors

G. S. Alexopoulos Institute for Geriatric Psychiatry, Weill Medical College

of Cornell University, and New York Presbyterian Hospital, White Plains,
New York, U.S.A.

Amit Anand Department of Psychiatry, Indiana University School of Medicine,

Indianapolis, Indiana, U.S.A.

Carrie E. Bearden Semel Institute for Neuroscience and Human Behavior,

University of California, Los Angeles, California, U.S.A.

R. H. Belmaker Division of Psychiatry, Faculty of Health Sciences, Ben-Gurion

University of the Negev, Beer Sheba, Israel

Ruth M. Benca Department of Psychiatry, University of Wisconsin –Madison,

Madison, Wisconsin, U.S.A.

Francine M. Benes Department of Psychiatry, Harvard Medical School, Boston,

Massachusetts, U.S.A.

Yuly Bersudsky Division of Psychiatry, Faculty of Health Sciences, Ben-Gurion

University of the Negev, Beer Sheba, Israel

David J. Bond Mood Disorders Centre of Excellence, University of British

Columbia, Vancouver, British Columbia, Canada

Charles L. Bowden University of Texas Health Science Center at San Antonio,

San Antonio, Texas, U.S.A.

Paolo Brambilla Department of Pathology and Experimental and Clinical

Medicine, Section of Psychiatry, University of Udine, Udine, and Scientific
Institute IRCCS E. Medea, Bosisio Parini, Italy

Melissa A. Brotman Mood and Anxiety Disorders Program, National Institute

of Mental Health, Department of Health and Human Services, National Institutes
of Health, Bethesda, Maryland, U.S.A.

Michael A. Cerullo Division of Bipolar Disorders Research, Department

of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio,
U.S.A.

Dennis S. Charney Department of Psychiatry, Mount Sinai School of Medicine,

New York, New York, U.S.A.
vii
viii Contributors

Guang Chen Laboratory of Molecular Pathophysiology, Mood and Anxiety

Disorders Research Program, National Institute of Mental Health, Bethesda,
Maryland, U.S.A.
Nick Craddock Department of Psychological Medicine, Wales School of
Medicine, Cardiff University, Cardiff, U.K.
Dianne Currier Department of Psychiatry, Columbia University, New York,
New York, U.S.A.
J. M. deAsis Institute for Geriatric Psychiatry, Weill Medical College of Cornell
University, and New York Presbyterian Hospital, White Plains, New York, U.S.A.
Daniel P. Dickstein Mood and Anxiety Disorders Program, National Institute of
Mental Health, Department of Health and Human Services, National Institutes of
Health, Bethesda, Maryland, U.S.A.
David L. Dunner Department of Psychiatry and Behavioral Sciences, University
of Washington, Seattle, Washington, U.S.A.
Haim Einat College of Pharmacy, University of Minnesota, Duluth,
Minnesota, U.S.A.
Ellen Frank Western Psychiatric Institute and Clinic, University of Pittsburgh
School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
Amir Garakani Department of Psychiatry, Mount Sinai School of Medicine,
New York, New York, U.S.A.
David C. Glahn Department of Psychiatry and Research Imaging Center,
University of Texas Health Science Center at San Antonio, San Antonio,
Texas, U.S.A.
John P. Hatch Mood Disorders Clinical Neurosciences Program, Department of
Psychiatry, and Department of Orthodontics, University of Texas Health Science
Center at San Antonio, San Antonio, Texas, U.S.A.
Stefanie A. Hlastala Children’s Hospital and Regional Medical Center, Seattle,
Washington, U.S.A.
David S. Janowsky Department of Psychiatry, University of North Carolina,
Chapel Hill, North Carolina, U.S.A.
Stephany Jones Department of Psychiatry, University of Wisconsin– Madison,
Madison, Wisconsin, U.S.A.
Morgen A. R. Kelly Western Psychiatric Institute and Clinic, University
of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
Ralph W. Kupka Bipolar Disorders Program, Altrecht Institute for Mental Health
Care, Utrecht, The Netherlands
Ellen Leibenluft Mood and Anxiety Disorders Program, National Institute of
Mental Health, Department of Health and Human Services, National Institutes of
Health, Bethesda, Maryland, U.S.A.
Contributors ix

Paul Mackin School of Neurology, Neurobiology, and Psychiatry, University of

Newcastle upon Tyne, Newcastle upon Tyne, U.K.
Husseini K. Manji Laboratory of Molecular Pathophysiology, Mood and Anxiety
Disorders Research Program, National Institute of Mental Health, Bethesda,
Maryland, U.S.A.
J. John Mann Department of Psychiatry, Columbia University, New York, New
York, U.S.A.
R. Hamish McAllister-Williams School of Neurology, Neurobiology, and
Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne, U.K.
E. Serap Monkul Mood Disorders Clinical Neurosciences Program, Department
of Psychiatry, University of Texas Health Science Center at San Antonio, San
Antonio, Texas, U.S.A., and Department of Psychiatry, Dokuz Eylül University
School of Medicine, Izmir, Turkey
Fabiano G. Nery Mood Disorders Clinical Neurosciences Program, Department
of Psychiatry, University of Texas Health Science Center at San Antonio,
and Audie L. Murphy Division, South Texas Veterans Health Care System,
San Antonio, Texas, U.S.A., and Institute of Psychiatry, University of São Paulo
School of Medicine, São Paulo, Brazil
John F. Neumaier Department of Psychiatry and Behavioral Sciences, University
of Washington, Seattle, Washington, U.S.A.
Willem A. Nolen Department of Psychiatry, University Medical Center
Groningen, Groningen, The Netherlands
David H. Overstreet Center for Alcohol Studies, Department of Psychiatry,
University of North Carolina, Chapel Hill, North Carolina, U.S.A.
Robert M. Post Mood and Anxiety Disorders Program, National Institute of
Mental Health, Department of Health and Human Services, National Institutes
of Health, Bethesda, Maryland, U.S.A.
Brendan A. Rich Mood and Anxiety Disorders Program, National Institute of
Mental Health, Department of Health and Human Services, National Institutes
of Health, Bethesda, Maryland, U.S.A.
Sylvia Ruttledge School of Neurology, Neurobiology, and Psychiatry, University
of Newcastle upon Tyne, Newcastle upon Tyne, U.K.
Alona Shaldubina Division of Psychiatry, Faculty of Health Sciences, Ben-Gurion
University of the Negev, Beer Sheba, Israel
Jair C. Soares Center of Excellence for Research and Treatment of Bipolar
Disorders, Department of Psychiatry, University of North Carolina School of
Medicine, Chapel Hill, North Carolina, U.S.A.
Stephen M. Strakowski Division of Bipolar Disorders Research, Department of
Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.
x Contributors

E. Fuller Torrey Stanley Medical Research Institute, Chevy Chase, Maryland,

U.S.A.
Robert H. Yolken Stanley Division of Developmental Neurovirology, Johns
Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.
Allan H. Young Mood Disorders Centre of Excellence, University of British
Columbia, Vancouver, British Columbia, Canada
R. C. Young Institute for Geriatric Psychiatry, Weill Medical College of Cornell
University, and New York Presbyterian Hospital, White Plains, New York, U.S.A.
B 1 Classification of Bipolar Disorders—
Implications for Clinical Research
Ralph W. Kupka
Bipolar Disorders Program, Altrecht Institute for Mental Health Care,
Utrecht, The Netherlands

Willem A. Nolen
Department of Psychiatry, University Medical Center Groningen,
Groningen, The Netherlands

INTRODUCTION
The classification of mood disorders has been a subject of scientific debate for more
than 2500 years (1,2), and a precise delineation of these illnesses and its various
clinical manifestations has yet to emerge. Many aspects of this discussion have
recently been reviewed by Akiskal (2) and supplemented by commentaries from
authoritative researchers. In this chapter we will give an overview of the current
classification, the boundaries of bipolar disorder with other major psychiatric
illnesses, the validity and reliability of diagnosis, and the implications for neurop-
sychiatric research. As all classifications that are based on clinical description rather
than on etiology and pathophysiology are deemed to be temporary, we will begin
with a brief historical overview and end with some areas that need further
clarification.

A BRIEF HISTORY OF MOOD DISORDER

Mania and melancholia, already described by Hippocrates (460 –377 BC ), were
linked as manifestations of one illness by Aretaeus of Cappadocia (c. 150 AD ). His
conception of mania being a consequence of melancholia was adopted throughout
the Middle Ages and Renaissance by writers such as Vesalius, Burton, Willis, and
Boerhaave (1). It was not until the 19th century that longitudinal clinical course
was taken into account in the description of psychopathology. In 1854, Falret and
Baillarger simultaneously but independently described a pattern of illness in
which mania, depression, and a symptom-free interval appeared in more or less
regular cycles over time (1). In addition to these severe forms of circular and peri-
odic insanity, in 1882, Kahlbaum described cyclothymia and dysthymia with milder
degrees of excitement and depression (1). It was Kraepelin who in 1899 brought all
affective syndromes together under the name of manic-depressive insanity: circular
and periodic forms, unipolar mania, recurrent depression, milder manifestations,
and even subclinical forms that were considered part of personal predisposition
or temperament (3). From his longitudinal descriptions of many cases he could
not delineate clear boundaries between these clinical pictures and hypothesized
that they were all manifestations of the same disease process. These observations
from the pre-pharmacological era are of great importance for the understanding
1
2 Kupka and Nolen

of the natural course of bipolar disorder, since most patients in later longitudinal
studies have received both acute and prophylactic treatment, which may have
modified the course of illness for the better or the worse (4).
In 1957, Leonhard (5) proposed the distinction between unipolar depression
and bipolar illness, which was supported by Angst (6) and by Perris in 1966 (7),
and by Winokur, Clayton, and Reich in 1969 (8). Subsequently, the unipolar –
bipolar distinction was adopted by the American classification diagnostic and
statistical manual of mental disorders-III (DSM-III) in 1980 (9), and the revised
edition (DSM-III-R) in 1987 (10). At the same time the WHO classification Inter-
national Classification of Diseases-9 (ICD) (1978) (11) still described all types of
depressive and other forms of affective disorders under the category of manic-
depressive psychosis. However, in the current ICD-10 (1992) (12), bipolar affective
disorder is classified next to recurrent depressive disorder.

CURRENT CLASSIFICATION: DSM-IV AND ICD-10

DSM-IV (13) describes mood disorders in three parts: mood episodes, mood
disorders, and specifiers, that is, characteristics of the most recent episode or the
longitudinal course of recurrent illness. Mood episodes (manic, hypomanic,
depressive, or mixed) are building blocks of mood disorders, and cannot be diag-
nosed as separate illnesses. Mood disorders are subdivided in depressive disorders
and bipolar disorders, and two disorders based on etiology: somatic illness and
substance abuse (Table 1). Specifiers describing the most recent episode refer to
severity, whether or not it is in remission, and the presence of psychotic features
or other clinical characteristics (Table 2). Longitudinal course specifiers refer to
the degree of interepisodic recovery, seasonal pattern, and rapid cycling. These
elements of classification aim at identifying relatively homogeneous subgroups,
and are further enhanced by providing more or less detailed diagnostic criteria
for every category described (see next section).
Compared to the DSM-IV, the text revision published in 2000 (DSM-IV-TR)
(14) did not change the mood disorders section, nor the section on schizoaffective
disorders. Therefore, we further refer to DSM-IV.
Unlike previous editions of DSM and ICD, DSM-IV and ICD-10 agree
on major aspects of the classification of mood disorders, although there are
several differences, as outlined in Table 1. One major difference is that ICD-10
allows for classifying a single manic/hypomanic or a single depressive episode
next to bipolar affective disorder and recurrent depressive disorder, whereas
in DSM-IV a single manic episode is always considered as being part of bipolar
disorder, and likewise a single depressive episode is classified as major depressive
disorder. Both classification systems agree that the relatively rare condition
of repeated mania without a history of depressive episodes should be classified
as bipolar disorder. A recent study from the Zurich group suggested that
patients with a history of only mania(s) (M), or of mania(s) with only mild
depression(s) (Md), have a lower morbidity risk in first degree relatives and a
better prognosis than bipolar I patients with both mania(s) and full depression(s)
(MD) (15).
DSM-IV gives a detailed definition of bipolar II disorder, characterized by one
or more major depressive episodes accompanied by at least one hypomanic episode
in the absence of a history of manic or mixed episodes (16,17). In contrast, in ICD-10,
bipolar I and II disorders are not classified separately, but the latter is included in
Classification of Bipolar Disorders 3

TABLE 1 DSM-IV Classification of Mood Disorders with Corresponding ICD-10 Classification

DSM-IV/DSM-IV-TRa Codeb ICD-10c Code
Depressive disorders
Major depressive disorder
Single episode 296.2x Depressive episode F32.0–9
Recurrent 296.3x Recurrent depressive disorder F33.0–9
Dysthymic disorder 300.4 Dysthymia F34.1
Depressive disorder NOS 311 Other depressive episode F32.9
Other recurrent depressive F33.9
disorder
Bipolar disorders
Bipolar I disorder
Single manic episode 296.0x Manic (including hypomanic) F30.x
episode
d
Hypomanic 296.40 Bipolar disorder, hypomanice F31.0
Manicd 296.4x Bipolar disorder, manice F31.1–2
Mixedd 296.6x Bipolar disorder, mixede F31.6
Depressedd 296.5x Bipolar disorder, depressede F31.3–5
Unspecifiedd 296.7 Bipolar disorder, unspecifiede F31.9
Bipolar II disorder 286.89 Other bipolar affective disorder F31.8
Hypomanicd
Depressedd
Cyclothymic disorder 303.13 Cyclothymia F34.0
Bipolar disorder NOS 296.80 Other bipolar affective disorder F31.8
Mood disorder due to
General medical condition 293.83 Organic mood disorders (manic/ F06.30–33
(depressive/manic/ bipolar/depressive/mixed)
mixed)
Substance induced mood 292.84 Psychotic disorder due to F1x.54
disorder (depressive/ Psychoactive F1x.55
manic/mixed) Substance abuse F1x.56
(depressive/manic/mixed)
Mood disorder NOS 296.90 Other mood disorders F38
Unspecified mood disorders F39
Schizoaffective disorder f 295.70 Schizoaffective disordersf F25
Bipolar type Manic type F25.0
Depressive type Depressive type F25.1
Mixed type F25.2
a
DSM-IV-TR is unchanged from DSM-IV with regard to mood disorders.
b
For fifth digit see Table 2.
c
Not all ICD-10 subcategories are listed.
d
Most recent episode.
e
Current episode.
f
Included in the section: schizophrenia and other psychotic disorders.
Abbreviations: DSM, Diagnostic and Statistical Manual of Medical Disorders; ICD, International Classification of
Diseases; NOS, not otherwise specified.

the category of “other bipolar affective disorders,” without further description.

However, in ICD-10 “bipolar affective disorder, current episode hypomanic”
could also include those patients who have never experienced a full manic
episode, that is, those with bipolar II disorder.
The problem of distinguishing hypomania from normal mood swings on the
one hand and from mania on the other, which may occur in any classification, will
be discussed in the next section.
4 Kupka and Nolen

TABLE 2 Diagnostic and Statistical Manual of Mental Disorders-IV Specifiers for Mood Disorders
Specifiers for most recent episodea Code Longitudinal course specifiersa
Severity
Mild xxx.x1
Moderate xxx.x2
Severe xxx.x3
Severe with psychotic features xxx.x4
Mood-congruent psychotic features
Mood-incongruent psychotic features
Course
In partial remission xxx.x5 With/without interepisode
recovery
In full remission xxx.x6 Seasonal patternb
Chronicb Rapid cyclingc
Postpartum onset
Associated features
Catatonic features
Melancholic featuresb
Atypical featuresb
a
DSM-IV-TR is unchanged from DSM-IV with regard to mood disorders.
b
Specifier only for depressive episodes.
c
Specifier only for bipolar I and II disorders.

MANIA AND HYPOMANIA

At the core of the manic syndrome is a persistently elevated, expansive and/or irri-
table mood during at least seven days (or any duration when hospitalized),
accompanied by symptoms such as increased self-esteem, over-optimism or even
grandiosity, pressure of speech, racing thoughts, distractibility, increased energy,
increased sexual drive, overactivity or agitation, and loss of inhibitions leading to
reckless involvement in pleasurable, hazardous, or embarrassing activities that
may have serious marital, social, financial, or judicial consequences. Finally,
symptoms cause marked impairment in social or occupational functioning. Error
of judgment and lack of insight, which are often seen in manic patients, are
not specifically included in DSM-IV diagnostic criteria. Even patients who did
previously acknowledge having bipolar disorder may lose insight during a next
manic episode. Highly characteristic of the manic syndrome is a decreased
need for sleep combined with an increased feeling of energy, which is quite
distinct from insomnia in depression or other psychiatric disorders where the
diminished sleep coincides with feeling tired. In severe mania, psychotic symptoms
may occur, either mood-congruent such as delusions of grandiosity, or mood-
incongruent, such as persecutory delusions.
Diagnosing “classic” mania should not be too difficult a task for any clinician
with some experience. However, during an initial interview, an intelligent patient
may temporarily mislead the clinician by dissimulating the presence or the severity
of his symptoms and by finding apparently meaningful explanations for his
behaviors. In such cases, information from nurses and especially from close rela-
tives should confirm the diagnosis of mania. The latter may be even truer in case
of hypomania.
In DSM-IV, a hypomanic episode has essentially the same clinical features as a
manic episode, but lasts a shorter period. In hypomania, there is an unequivocal
Classification of Bipolar Disorders 5

change from normal functioning, which is observable by others, lasting at least four
days. This separates hypomania from normal elevations of mood or the very mild
mood elevations that occur in cyclothymic disorder. On the other hand, the
symptoms are not severe enough to cause “marked impairment in social or
occupational functioning” as in mania. In the ICD-10 clinical descriptions and diag-
nostic guidelines (12) hypomania does not lead to “severe or complete disruption of
work or result in social rejection,” although “considerable interference with work or
social activity is consistent with a diagnosis of hypomania.” Thus, ICD-10 hypoma-
nia includes conditions that would justify a diagnosis of (mild) mania according to
DSM-IV criteria. Interestingly, the ICD-10 diagnostic criteria for research (18) are
more in accordance with DSM-IV, stating that hypomania leads to “some inter-
ference with personal functioning in daily living.” The problems that arise when
defining the boundary between hypomania and (mild) mania are discussed by
Goodwin, who points out that this boundary depends entirely upon the meaning
of ill-defined qualifying words like “some,” “considerable,” “marked,” “severe,”
or “complete” functional impairment (19). He also notes a tendency to avoid the
somewhat pejorative diagnosis of “mania” in favor of “hypomania” in clinical
settings.
The validity of a minimum duration of four days for a hypomanic episode
has been tested by the Zurich group that found that patients with brief hypomania
of one to three days duration did not significantly differ from those whose
hypomanic episodes lasted at least four days (20).
In patients presenting with a current depressive episode, a history of prior
hypomanic episodes is easily missed, especially since depression is the prevailing
condition in bipolar II disorder (21). Thus, many of these patients will be misdiag-
nosed as suffering from (recurrent) unipolar depression. Revealing past hypomanic
episodes may benefit from systematic inquiry in all aspects of the syndrome,
especially the behavioral symptoms rather than elevation of mood. Patients and
relatives will remember the short nights and the energetic overactivity more
sharply than a period of cheerfulness or irritability.
In a recent survey among U.S. citizens using the Mood Disorders Question-
naire (22), which systematically checks (hypo)manic symptoms, 3.7% screened
positive for bipolar I or II disorder. Of these, only 19.8% had previously received
a diagnosis of bipolar disorder, 31.2% had received a diagnosis of unipolar
depression, and 49.0% had received neither of these diagnoses (23).
Hypomanic or manic episodes may appear relatively late in the course of
bipolar disorder, inevitably leading to an initial diagnosis of unipolar depression.
The rate of spontaneous conversion from unipolar to bipolar mood disorder has
been estimated at median 9.7%, with a reported maximum of up to 37.5% (24).
Over the course of 11 years, hypomanic or manic episodes occurred in 12.5% of
559 prospectively followed unipolar patients (25). This phenomenon may in
part explain the long delay between the occurrence of first mood symptoms and
the diagnosis of bipolar disorder, which was on average 10 years in a survey
among DMDA members (26) and also among clinical populations (27).

DEPRESSION
Depression is the main burden of bipolar illness. Longitudinal follow-up data from
the Collaborative Depression Study showed that patients with bipolar I disorder,
despite adequate treatment, on average reported depressive symptoms in 31.9%,
6 Kupka and Nolen

TABLE 3 Clues of Bipolarity in Patients with Major Depressive Episodes

Episode features Longitudinal illness history
Rapid onset and end of episode Family history of bipolar disorder
Brief episodes (,2 weeks) First episode at younger age (,25)
Psychotic features Frequent episodes
Atypical features History of brief major depressive episodes
Psychomotor retardation and anergia History of mania or hypomania
Hypersomnia History of antidepressant-induced hypomania
Mood lability History of postpartum depression
Nonresponse to antidepressants Cyclothymic or hyperthymic temperament
Response to lithium

manic/hypomanic symptoms in 8.9%, and cycling/mixed symptoms in 5.9% of

weeks (28). In bipolar II disorder these percentages were even 50.3%, 1.3%, and
2.3% of weeks, respectively (28). The Stanley Foundation Bipolar Network reported
similar outcomes in treated bipolar I patients using daily prospective life chart data:
on average they were depressed 35.6% of the time, manic/hypomanic 12.6%, and
ultradian cycling 3.3% (29). Another research group using prospective life chart
data also found a depression-to-mania rating of 5.9 in bipolar I and 13.7 in
bipolar II patients (30).
Although a depressive episode in the course of bipolar disorder in general
has the same clinical features as unipolar depression, and both conditions have
identical diagnostic criteria in DSM-IV and ICD-10, cross-sectional as well as longi-
tudinal studies have revealed some features that may distinguish bipolar from
unipolar depression (31 – 37). These features are summarized in Table 3.
In patients with depression, a family history of bipolar disorder may point
to a bipolar course. The occurrence of brief episodes is also associated with
bipolar depression. DSM-IV requires for a major depressive episode a minimum
duration of at least two weeks. This may be appropriate in most cases of unipolar
depression and many cases of bipolar disorder, but patients with bipolar disorder
often also have brief episodes with rapid onset and remission, which may have
the full range of severities (32). Prospective life chart data from the Stanley Foun-
dation Bipolar Network showed that even patients with a nonrapid cycling
course have on average twice as many brief depressive episodes, that is, of less
than two weeks duration, than full-duration episodes (29). This was similar with
regard to brief manic and hypomanic episodes.

MIXED STATES
In mixed states the complexity of bipolar disorder reaches its maximum. Pure
depression and pure mania are the prototypical endpoints on a continuum of beha-
vioral and emotional disturbances. Mixed states have originally been described by
Kraepelin and his contemporary Weygandt as various admixtures of three dimen-
sions: mood, thinking, and psychomotor activity (38). They distinguished six
subtypes: depression with flight of ideas, excited depression, depressive-anxious
mania, mania with thought poverty, inhibited mania, and manic stupor.
In DSM-IV, a patient with a mixed episode meets both criteria for a manic
episode and a major depressive episode during at least one week, and may experi-
ence rapidly alternating moods of sadness, irritability, and dysphoria. It is thus
Classification of Bipolar Disorders 7

essentially a type of manic episode that also contains full syndromal depression
(“mixed mania”), which may be uncommon in clinical settings (39). This narrow
definition excludes many patients with combinations of syndromal and subsyndro-
mal symptoms of either polarity, for example, those with isolated depressive symp-
toms during a manic episode (“mixed mania”) or with some manic symptoms
during a major depressive episode (“mixed depression”). The prevalence of such
more broadly defined mixed states in clinical practice is probably much higher
than DSM-IV mixed episodes. It is estimated that mixed states occur in about
30% to 40% of acutely manic patients (32,40). Dysphoric mania, defined as a full
manic syndrome with the simultaneous presence of some depressive symptoms,
was present in 37% of manic patients in a clinical setting (41). In a recent study
among 908 treated bipolar outpatients mixed hypomania, that is, the co-occurrence
of depressive symptoms in patients with a hypomanic episode, was found in 57%
of visits for hypomanic episodes (42). Mixed hypomania was equally prevalent in
patients with bipolar I and II disorder, but more prevalent in women.
The concept and the terminology of mixed states are prone to confusion.
ICD-10 takes a somewhat broader view than DSM-IV on mixed states, defined
as either a mixture or a rapid alternation (usually within a few hours) of manic,
hypomanic, and depressive symptoms; the minimum duration of mixed episodes
is two weeks. The term “dysphoric mania,” originally meant to indicate a mixed
state, may be wrongly used to indicate “classic” mania with predominantly irritable
rather than euphoric mood. Moreover, the distinction between these two conditions
may be difficult and it is unclear whether this is clinically relevant since the
evidence that mixed states should be regarded as separate clinical entities is
controversial (40).
It is of clinical importance that mixed mania is less responsive to treatment, in
particular with lithium, than “classic” euphoric mania (43).

ANTIDEPRESSANT-INDUCED MANIA AND HYPOMANIA

According to DSM-IV, patients with unipolar major depression who become hypo-
manic or manic when treated with antidepressants receive an additional diagnosis
of substance-induced mood disorder with manic features. In these cases, it is
assumed that the manic syndrome is a direct physiological effect of antidepressant
medication, and such an episode should not lead to a diagnosis of bipolar disorder.
This also applies for mood episodes induced by other medications, alcohol, or drugs
of abuse. The concept that antidepressant-induced (hypo)mania in (unipolar) major
depression is not indicative of bipolar disorder has been strongly debated, and
evidence for an opposite point of view was recently reviewed by Chun and
Dunner (24). They found that cases of treatment-induced hypomania in 121
studies of antidepressants in major depressive disorder patients were relatively
rare, and within the rate of spontaneous conversion from unipolar to bipolar
disorder. They conclude that these patients should be recognized as having
bipolar disorder, and propose a revision of this category in DSM-V. Another argu-
ment for this position is that according to most guidelines, patients with a bipolar
depression should not be treated with an antidepressant alone, but only in combi-
nation with antimanic agents, that is lithium, an anticonvulsant, or, according to
some guidelines, an atypical antipsychotic. It appears logical to apply the same
approach for depressed patients with a history of an antidepressant-induced
hypomanic or manic episode, since when treated with antidepressant monotherapy
8 Kupka and Nolen

there is a significant risk of another switch. Finally, it is also of interest that with-
drawal of antidepressants can induce mania (44). It is likely that for this condition
the same diagnostic considerations are relevant.

DIFFERENTIAL DIAGNOSIS: THE BOUNDARIES OF BIPOLAR DISORDER

External Boundaries
Cyclothymic disorder can be seen as the borderland between bipolar disorder
and normal mood fluctuations. Patients with cyclothymia exhibit mood instability,
that is (often numerous) periods with hypomanic symptoms that never meet cri-
teria for a manic episode and with depressive symptoms that never meet criteria
for major depressive episodes over the course of at least two years. A family
history of mood disorders is more common in cyclothymic patients in whom the
disorder proceeds to a full-blown bipolar disorder in the course of their life.
Borderline personality disorder is another disorder with affective instability.
Therefore, it may be difficult to distinguish borderline personality disorder from
cyclothymia and also from bipolar I or bipolar II disorder with rapid cycling
(i.e., at least four episodes per year) and especially ultrarapid cycling (i.e., mood
switches within a week of at least four episodes per month) or ultradian cycling
(i.e., mood switches within a single day) (45). Moreover, both conditions may
coexist. A controversial point of view is whether borderline personality disorder
in fact is part of the bipolar spectrum (2,46 – 48).
Schizoaffective disorder, bipolar type, fills the gap between mania with mood-
incongruent psychotic features and schizophrenia. A considerable number of
severely ill patients admitted to psychiatric hospitals have manic or depressive
episodes co-occurring with symptoms characteristic of schizophrenia, including
mood-incongruent delusions or hallucinations. In addition, patients have delusions
or hallucinations in the absence of prominent mood symptoms. The definition of
schizoaffective disorders has varied over the years among classification systems
and is still diffuse and uncertain (49). According to DSM-IV, such patients are classi-
fied as schizoaffective disorder when the co-occurrence of mood and psychotic
symptoms as described occurs during the same period of illness, which may last
for years. Nevertheless this definition is difficult to use in clinical practice, as
shown by the small interrater reliability when diagnosing patients with these
problems (50). It challenges the classic Kraepelinian dichotomy between manic-
depressive illness and schizophrenia, and may be an indication of a considerable
genetic overlap between these two groups of major psychiatric disorders (51).
Another diagnostic category that fits in the grey zone between bipolar
disorder and schizophrenia but has been omitted in DSM-IV and ICD-10 is
cycloid psychosis, as described by Leonhard (4). These conditions combine poly-
morphous psychotic symptoms with an episodic course and a generally favorable
prognosis (52).
The boundary between recurrent unipolar depression and bipolar disorder
has already been discussed, and will be further addressed in the section on the
bipolar spectrum. If one accepts the unipolar – bipolar dichotomy then the question
arises at which point these disorders split. This depends on the definition of
hypomania and its lower limit towards normality, being the mildest manifestation
of bipolarity. Current debate concentrates on the number of hypomanic symptoms
needed, and the minimum duration of a hypomanic episode. DSM-IV requires four
days, although at that time no data were present to determine whether three days
Classification of Bipolar Disorders 9

would have been better (53). Recent studies by Angst et al. in Zurich (20) showed
that hypomanic episodes of one to three days were of comparable clinical
significance. Including brief hypomanic episodes into the definition of bipolar II
disorder changes the rate of all major and minor forms of unipolar versus bipolar
disorder (see later) (20).
Another area of potential diagnostic confusion lies in the distinction between
agitated unipolar depression and bipolar mixed states, especially the “mixed
depression” described earlier. There is some research evidence that agitated
unipolar depression is part of the bipolar spectrum (54).

Internal Boundaries
Separating bipolar II from bipolar I disorder depends on the definition of hypomania
and its upper limits towards mania (see earlier). In the longitudinal Collaborative
Depression Study, patients with bipolar I disorder had more severe episodes
whereas those with bipolar II disorder had a substantially more chronic course
with significantly more major and minor depressive episodes and shorter inter-
episodic well intervals (55). The authors conclude that these differences justify
classification as two separate subtypes, although the overall clinical similarities of
these subtypes suggest that they exist in a disease spectrum (55).
Rapid cycling, defined as the occurrence of at least four distinct mood
episodes in one year, has been introduced as a course specifier of bipolar I and II
disorder in DSM-IV (53,56). Rapid cycling is not mentioned at all in ICD-10.
Taking a conventional categorical approach, a meta-analysis of 20 studies compar-
ing rapid cyclers and nonrapid cyclers revealed some significant differences apart
from episode frequency, in particular a slight overrepresentation of women and of
bipolar II subtype among rapid cyclers (57). Associated with rapid cycling there
was also a trend for depressive episode at onset of illness, a history of serious
suicide attempts, a family history of affective disorder, and nonresponse to
lithium prophylaxis. However, recent large studies (29,58,59) have shed doubt
over the higher prevalence of rapid cycling among bipolar II patients. Moreover,
if one takes a dimensional approach, differences occur gradually with increasing
episode frequency and never reveal a cut-off point at four episodes per year or at
any other episode frequency, suggesting that rapid cycling is not a distinct
subtype but merely an extreme on a continuum of cycle frequency (29).
Finally, the boundary between mania and depression is blurred in patients
with mixed states. There is also a potential overlap between mixed states with
rapid mood shifts on the one hand, and ultra-rapid or ultradian cycling (45,47)
on the other. The latter conditions are not defined in DSM-IV but can be classified
as mixed episodes or alternatively in the residual category Bipolar Disorder Not
Otherwise Specified. A summary of key criteria defining the major boundaries of
bipolar disorder is given in Table 4.

THE BIPOLAR SPECTRUM CONCEPT

A broad definition of manic-depressive illness was originally proposed by Kraepe-
lin (3), and reintroduced by Akiskal (2,60,61), Goodwin and Jamison (32), Cassano
(63), and Angst (64), amongst others. This so-called bipolar spectrum includes syn-
dromal and subsyndromal clinical conditions beyond the more narrowly defined
DSM-IV and ICD-10 classifications of bipolar disorder. In recent years, different
10 Kupka and Nolen

TABLE 4 Key Boundaries of Bipolar Disorders in DSM-IV

Boundary Criteria defining boundary
Normal mood fluctuations versus dys/ Occurrence and severity of depressive and
hyper/cyclothymic temperament hypomanic symptoms
versus mood disorder
Unipolar depression versus bipolar II Number and duration of hypomanic symptoms
disorder
Bipolar II versus bipolar I disorder Impairment and duration of manic symptoms
Bipolar I versus schizoaffective disorder Timing of psychotic symptoms
Schizoaffective disorder versus Balance of psychotic and affective symptoms
schizophrenia
Rapid cycling versus nonrapid cycling Occurrence of 4 distinct mood episodes/year
course
Source: From Ref. 73.

variants of a bipolar spectrum have been presented; an example as proposed by

Akiskal is given in Table 5.
The bipolar spectrum concept puts emphasis on validators other than polarity
(i.e., the occurrence of mania), such as a recurrent (“cycling”) course of illness, posi-
tive family history of mood disorder, and unfavorable outcome of antidepressant
treatment (62). In such a broad definition, recurrent brief depressions (“cycling
within the depressive pole”) that do not respond to or even get worse with
antidepressants may be part of the spectrum. Lifetime prevalence rates of bipolar
spectrum disorders range from 2.8% to 6.6% of the population (65).
One major rationale for a bipolar spectrum is that the application of narrow
diagnostic criteria may result in misdiagnosis of many cases that would benefit
from other treatments: mood stabilizing drugs rather than antidepressants.
A major objection towards the concept of a bipolar spectrum is that it shows
an expansive trend, incorporating subsyndromal conditions and conditions that
are only in part characterized by affective instability, such as borderline personality
disorder (66). This may weaken the core concept of bipolar disorder, which appears
to be a circumscript clinical entity suitable for genetic, biological, and treatment
studies (66). Reanalyzing the data of the epidemiologic catchment area (ECA)
study by taking into account all subsyndromal manic symptoms resulted in a
lifetime prevalence rate of 5.1% on top of the 0.8% for manic episodes (bipolar I)
and 0.5% for hypomanic episodes (bipolar II), yielding a total of 6.4% for bipolar
spectrum disorders (67). The prevalence of bipolar (and unipolar) mood disorders

TABLE 5 A Bipolar Spectrum as Proposed by Akiskal

Bipolar 12 Schizobipolar disorder
Bipolar I Manic-depressive illness
Bipolar I 12 Depression with protracted hypomania
Bipolar II Depression with spontaneous hypomanic episodes
Bipolar II 12 Depression superimposed on cyclothymic temperament
Bipolar III Recurrent depression with antidepressant-induced hypomania
Bipolar III 12 Recurrent depression with alcohol/substance-induced hypomania
Bipolar IV Depression superimposed on hyperthymic temperament
Bipolar V Recurrent depression (5 episodes)
Source: From Ref. 61.
Classification of Bipolar Disorders 11

is further exploded when thresholds are set even lower, such as in the Zurich
studies (20). Relaxing duration and severity criteria for hypomania resulted in an
almost equal lifetime prevalence of 24.6% for the depressive spectrum (including
major depression, dysthymia, minor depression, and brief recurrent depression)
and 23.7% for “soft” bipolar spectrum (including bipolar I and broadly defined
bipolar II, minor bipolar disorder, cyclothymia, and pure hypomania) (20). These
authors state that 11% constitutes the spectrum of bipolar disorders proper, and
another 13% “probably represent the softest expression of bipolarity intermediate
between bipolar disorder and normality.” If almost a quarter of the population is
included, it is questionable whether such broad definitions are still meaningful
indicators of psychopathology, given the lifetime prevalence of core bipolar I dis-
order of 0.5% in the same cohort, which is consistent with other epidemiological
studies (19).

ASSESSMENT OF BIPOLAR DISORDER

Diagnostic assessment of bipolar disorders has several aspects: a lifetime diagnosis
according to DSM-IV of ICD-10, a diagnosis of the current mood episode or a state
of interepisodic remission, rating the severity of the current mood disturbance, and
depicting the longitudinal course of the illness.
A diagnosis of bipolar disorder in clinical research settings is commonly
obtained by applying one of the semi-structured interviews for axis I diagnoses
by trained clinicians, such as the Structured Clinical Interview for DSM-IV axis I
disorders, Research Version, Patient Edition (SCID-I/P) (68), the related Mini
International Neuropsychiatric Interview (MINI) (69), or the Schedules for
Clinical Assessment in Neuropsychiatry (SCAN) (70). In epidemiological studies,
fully structured interviews are used, often by trained lay interviewers, such as
the Composite International Diagnostic Interview (CIDI) (71) (REF WHO). All
these instruments arrive at current or lifetime DSM-IV (SCID) or DSM-IV and
ICD-10 (SCAN, CIDI) diagnoses. Since each diagnostic criterion of each mood
episode as well as every psychotic symptom is rated separately, these instruments
are suitable for assessing symptom profiles beyond the diagnostic boundaries
described earlier. Semistructured interviews by trained clinicians may be somewhat
more specific in diagnosing bipolar disorder than structured interviews by lay
interviewers (72).
An self-rated instrument for screening for bipolar disorder is the Mood
Disorders Questionnaire (MDQ) (22), which has been applied in a large U.S.
population sample (23) and various European countries, and actually checks the
previous presence of manic symptoms according to DSM-IV criteria. If rated
positive it should be followed by a clinical interview.
A dimensional scale that was designed to serve as an adjunct to conventional
categorical diagnosis is the Bipolar Affective Disorder Dimension Scale (BADDS)
(73). It provides a description of some of the basic features of an individual’s
lifetime experience of psychopathology relevant to the bipolar spectrum. The
scale is mainly based on the ICD-10 criteria and has four dimensions: (i) mania:
the presence and severity of manic syndromes; (ii) depression: the presence and
severity of depressive syndromes; (iii) psychosis: the presence of psychotic symp-
toms and the balance of mood and psychotic symptomatology; and (iv) incon-
gruence: the mood congruence of psychotic symptoms and the temporal
relationships between affective and psychotic symptomatology. Using multiple
12 Kupka and Nolen

data sources, every subject is scored in the range 1–100 on each of the four
dimensions. The instrument was developed within the context of family studies,
and incorporates the boundaries between unipolar, bipolar, schizoaffective,
and schizophrenic disorders (Table 4). It retains a measure of severity and also
includes mild or subclinical cases, and avoids hierarchical loss of information
inherent to classification systems. BADDS appears to be especially suitable to
assess bipolar spectrum disorders next to or beyond the strict DSM-IV or ICD-10
categories.
There are various symptom rating scales for measurement of severity of
mania and depression, such as the Young Mania Rating Scale (YMRS) (74), the
Bech Rafaelsen Mania Scale (BR-MAS) (75), the Hamilton Rating Scale for
Depression (HAMD) (76), the Montgomery Åsberg Depression Rating Scale
(MADRS) (77), and the Inventory of Depressive Symptomatology (IDS) (78). The
latter includes many “atypical” symptoms, which frequently occur in bipolar
depression, and is thus particularly suitable for this condition.
A problem typical for the assessment of change in bipolar disorder is that
improvement of a depressive episode may go hand in hand with emerging
mania, and vice versa, and that rapid changes of polarity may add to the overall
illness burden beyond depressive and manic symptoms per se. To address this
problem, the Clinical Global Impressions scale, Bipolar Version (CGI-BP), was
designed (79). This is a modification of the original CGI scale, providing global
severity ratings of both depression and mania, as well as a global severity rating
of overall bipolar disorder. A similar set of CGI scales was designed for the assess-
ment of change in clinical trials (79).
These scales all make a cross-sectional assessment of the manic or depressive
episode with a time span ranging from two days to two weeks. Given the waxing
and waning course of bipolar disorder, repeated cross-sectional assessments will
not reveal the frequently occurring mood episodes in between. For continuous
longitudinal assessments, either retrospective or prospective, a graphic method
such as the NIMH-Life Chart Methodology (NIMH-LCM) is more suitable
(Fig. 1) (80,81). This instrument has been validated in recent years (82,83), and is
available in a clinician-rated and a self-rated version. A similar instrument
for longitudinal assessment is the prospectively self-rated computerized ChronoR-
ecord (84).

FIGURE 1 One-year prospective daily life chart showing prototypical bipolar I disorder with a
continuous “rapid cycling” course in a man aged 67 with an illness history of over 50 years. Mania
above and depression below baseline. Source: From Ref. 29.
Classification of Bipolar Disorders 13

DIAGNOSTIC VALIDITY AND IMPLICATIONS FOR

NEUROPSYCHIATRIC RESEARCH
Although our current diagnostic categories have limited validity and are provi-
sional until external validators are identified, the availability of clear diagnostic
categories with its criteria has nevertheless greatly improved the reliability of
diagnosis in clinical and research settings. In most neurobiological, genetic, and
treatment studies of bipolar disorder, subjects will have received a diagnosis of
(DSM-IV) bipolar disorder. Also, further distinctions are often made between
subjects with bipolar I or bipolar II disorder and subjects with a rapid cycling
course versus with slower cycle frequencies of less than four mood episodes per
year (often indicated as nonrapid cyclers). As discussed earlier, the boundaries
between these categories are arbitrary, and it is unlikely that these boundaries,
which are entirely based on clinical descriptive criteria, exactly point out the
potential boundaries between distinct disorders with a different etiologic or patho-
physiological background (73,85).
Dimensional diagnoses tend to be impractical and difficult to communicate
(85). However, the concurrent use of categorical and dimensional diagnostic
instruments as proposed by Craddock et al. (73) may be particularly appropriate
in bipolar spectrum disorders. The bipolar spectrum concept provides a compro-
mise, since its prototypical categories lie along a unipolar –bipolar continuum
and on continuums with other diagnoses such as psychotic disorders. It is also
useful for clinical practice, alerting clinicians to search for clues for bipolar disorder
in patients with mood disorders and treat them according to the best available evi-
dence. However, for neurobiological research, a broadly defined bipolar spectrum
as a whole may be over inclusive. Investigating relatively homogeneous subgroups
delineated by relatively narrow diagnostic categories that are now widely accepted
(major unipolar depression, bipolar I and bipolar II disorder) within the entire
bipolar spectrum could help to identify biological markers and the genetics for
core syndromes. Comparing shared and unshared neurobiological and genetic
features may eventually lead to subgroups that are more firmly based on etiology
and pathophysiology. This may also shed light on the true nature of overlapping
areas between prototypical phenotypes, such as “pseudo-unipolar” and schizoaf-
fective disorders.
The longitudinal evolution of bipolar disorder makes every diagnostic
assessment in a given individual temporary, since apparent unipolar depression
can turn out to be bipolar disorder, bipolar II disorder can progress to bipolar
I disorder, and bipolar disorder can deteriorate to schizoaffective disorder.
This may be particularly problematic in studies of unipolar depression. Patients
who have only had depressive episodes at the time of their participation in
such a study, but at a later point show features of bipolar disorder, may
compromise the identification of potential differences between unipolar and
bipolar disorder.

TOWARDS DSM-V
Despite the limitations and pitfalls of categorical diagnostic classifications (85),
DSM-IV and ICD-10 have greatly improved the reliability of the different mood
disorder diagnoses. For the sake of continuity in epidemiologic, neurobiologic,
and genetic research, we should be reluctant to change diagnostic criteria for
14 Kupka and Nolen

mood episodes and mood disorders as long as there is no compelling evidence to do

so. Still, there are certain areas that are open for change.
First, the very restrictive definition of mixed episodes, in particular the
requirement of full syndromal criteria for mania and depression, could be
relaxed, as outlined earlier. Given all the possible variants of mixed states, it is
obvious that they can occur not only in bipolar I but also in bipolar II disorder.
Second, there is now enough evidence to include antidepressant-induced
(hypo)mania in the diagnostic category of bipolar disorder. Psychoactive substance-
or treatment-induced (hypo)mania could be a separate subcategory (bipolar III
disorder), or an episode specifier of bipolar I and II disorder.
Third, a better-operationalized and more consistent definition of the hypoma-
nia – mania boundary would improve the delineation of bipolar II versus bipolar I
disorder, even if it remains uncertain whether these subtypes are fundamentally
different.
Fourth, the concept of rapid cycling, which represents a dimension rather
than a subtype, could be defined along a continuum as proposed either by counting
episodes over a certain time period (e.g., a year) or at least by dividing it into
more subcategories (nonrapid, rapid, ultra-rapid, and ultradian cycling) as
suggested by Kramlinger and Post (45) which allows for the inclusion of briefer
but still significant episodes (29).
Finally, a specifier for depressive episodes indicating bipolarity in up till then
unipolar patients, including features as summarized in Table 3, could alert
clinicians and researchers for latent bipolar disorder, without prematurely crossing
the boundaries of the current diagnostic classifications.

CONCLUSION
Polarity and cyclicity have been described as core dimensions of manic-depressive
illness (Fig. 1) (32), which, despite its heterogeneity, can still be regarded as one of
the most consistently described disorders in psychiatry (2,12). From these dimen-
sions, a bipolar spectrum can be constructed, and within this bipolar spectrum,
various subtypes have been defined. In this chapter we have highlighted the
main areas of uncertainty and controversy about the internal and external bound-
aries of this spectrum, which rely exclusively on clinical description and still
lack external validators. It may well be that the most specific validators for
bipolar disorder will be revealed by studying patients with the core bipolar I syn-
drome (66). Eventually, neurobiological and genetic studies must not only provide
such validators for accurate and valid diagnoses, but above all direct towards a
more targeted treatment for the individual patient with a variant of bipolar
spectrum disorder.

REFERENCES
1. Jackson SW. Melancholia and Depression. From Hippocratic Times to Modern Times.
New Haven: Yale University Press, 1986.
2. Akiskal H. Classification, diagnosis, and boundaries of bipolar disorders: a review.
In: Maj M, Akiskal HS, Lopez-Ibor JJ, Sartorius N, eds. Bipolar Disorder. Evidence and
Experience in Psychiatry. Vol. 6. Chichester: Wiley, 2002.
3. Kraepelin E. Psychiatrie. Ein Lehrbuch für Studirende und Aerzte. II. Band. Sechste
Auflage. Leipzig: Verlag Barth, 1899.
Classification of Bipolar Disorders 15

4. Angst J, Sellaro R. Historical perspectives and natural history of bipolar disorder. Biol
Psychiatry 2000; 48:445–457.
5. Leonhard K. Aufteilung der endogenen Psychosen. Berlin: Academie Verlag, 1957.
6. Angst J. Zur Ätiologie und Nosologie endogener depressiver Psychosen. Berlin:
Springer Verlag, 1966.
7. Perris C. A study of bipolar (manic-depressive) and unipolar recurrent depressive
psychoses. Acta Psychiatr Scand 1966; 42(suppl 194):68– 82.
8. Winokur G, Clayton PJ, Reich T. Manic-Depressive Illness. St. Louis: Mosby, 1969.
9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 3rd ed. (DSM-III). Washington DC: American Psychiatric Press, 1980.
10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 3rd ed.—Revised (DSM-III-R). Washington DC: American Psychiatric Press,
1987.
11. World Health Organization. The ICD-9 Classification of Mental and Behavioural
Disorders. Clinical Descriptions and Diagnostic Guidelines. Geneva: WHO, 1978.
12. World Health Organization. The ICD-10 Classification of Mental and Behavioural
Disorders. Clinical Descriptions and Diagnostic Guidelines. Geneva: WHO, 1992.
13. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. (DSM-IV). Washington DC: American Psychiatric Press, 1994.
14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Dis-
orders. 4th ed.—Text Revision (DSM-IV-TR). Washington DC: American Psychiatric
Press, 2000.
15. Angst J, Gerber-Werder R, Zuberbuhler HU, Gamma A. Is bipolar I disorder hetero-
geneous? Eur Arch Psychiatry Clin Neurosci 2004; 254:82 –91.
16. Dunner DL, Tay LK. Diagnostic reliability of the history of hypomania in bipolar II
patients and patients with major depression. Compr Psychiatry 1993; 34:303– 307.
17. Berk M, Dodd S. Bipolar II disorder: a review. Bipolar Disord 2005; 7:11 – 21.
18. World Health Organization. The ICD-10 Classification of Mental and Behavioural
Disorders. Diagnostic Criteria for Research. Geneva: WHO, 1993.
19. Goodwin G. Hypomania: what’s in a name? Br J Psychiatry 2002; 181:94– 95.
20. Angst J, Gamma A, Benazzi F, Ajdacic V, Eich D, Rossler W. Toward a re-definition of
subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor
bipolar disorders and hypomania. J Affect Disord 2003; 73:133– 146.
21. Judd LJ, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history
of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry
2003; 60:261–269.
22. Hirschfeld RM, Williams JB, Spitzer RL, et al. Development and validation of a screening
instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J
Psychiatry 2000; 157:1873–1875.
23. Hirschfeld RM, Calabrese JR, Weissman MM, et al. Screening for bipolar disorder in the
community. J Clin Psychiatry 2003; 64: 53–59.
24. Chun BJ, Dunner DL. A review of antidepressant-induced hypomania in major
depression: suggestions for DSM-V. Bipolar Disord 2004; 6:32– 42.
25. Akiskal HS, Maser JD, Zeller PJ, et al. Switching from “unipolar” to bipolar II. An 11-year
prospective study of clinical and temperamental predictors in 559 patients. Arch Gen
Psychiatry 1995; 52:114–123.
26. Lish JD, Dime-Meenan S, Whybrow PC, Price RA, Hirschfeld RM. The National
Depressive and Manic-depressive Association (DMDA) survey of bipolar members.
J Affect Disord 1994; 31:281–294.
27. Suppes T, Leverich GS, Keck PE, et al. The Stanley Foundation Bipolar Treatment
Outcome Network. II. Demographics and illness characteristics of the first 261 patients.
J Affect Disord 2001; 67:45–59.
28. Judd LJ, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly
symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002; 59: 530 –537.
29. Kupka RW, Luckenbaugh DA, Post RM, et al. A comparative study of rapid and non-
rapid cycling bipolar disorder using daily prospective mood ratings in 539 out-patients.
Am J Psychiatry 2005; 162:1273–1280.
16 Kupka and Nolen

30. Joffe RT, MacQueen GM, Marriott M, Trevor Young L. A prospective, longitudinal study
of percentage of time spent ill in patients with bipolar I or bipolar II disorders. Bipolar
Disorders 2004; 6:62–66.
31. Beigel A, Murphy DL. Unipolar and bipolar affective illness. Differences in clinical
characteristics accompanying depression. Arch Gen Psychiatry 1971; 24:215– 220.
32. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York: Oxford University
Press, 1990.
33. Winokur G, Coryell W, Endicott J, Akiskal H. Further distinctions between manic-
depressive illness (bipolar disorder) and primary depressive disorder (unipolar
depression). Am J Psychiatry 1993; 150:1176 –1181.
34. Winokur G, Coryell W, Keller M, Endicott J, Akiskal H. A prospective follow-up of
patients with bipolar and primary unipolar affective disorder. Arch Gen Psychiatry
1993; 50:457–465.
35. Mitchell PB, Wilhelm K, Parker G, Austin MP, Rutgers P, Malhi GS. The clinical features
of bipolar depression: a comparison with matched major depressive disorder patients.
J Clin Psychiatry 2001; 62:212–216.
36. Ghaemi SN, Hsu DJ, Ko JY, Baldassano CF, Kontos NJ, Goodwin FK. Bipolar spectrum
disorder: a pilot study. Psychopathology 2004; 37:222– 226.
37. Bowden CL. A different depression: clinical distinctions between bipolar and unipolar
depression. J Affect Disord 2005; 84:117–125.
38. Marnereos A. Origin and development of concepts of bipolar mixed states. J Affect
Disord 2001; 67:229–240.
39. Swann AC. Depression, mania, and feeling bad: the role of dysphoria in mixed states.
Bipolar Disord 2000; 2:325–327.
40. McElroy SL, Keck PE Jr, Pope HG Jr, Hudson JI, Faedda GL, Swann AC. Clinical and
research implications of the diagnosis of dysphoric or mixed mania or hypomania.
Am J Psychiatry 1992; 149:1633–1644.
41. Akiskal HS, Hantouche EG, Bourgeois ML, et al. Gender, temperament, and the clinical
picture in dysphoric mixed mania: findings from a French national study (EPIMAN).
J Affect Disord 1998; 50:175–186.
42. Suppes T, Mintz J, McElroy SL, et al. Mixed hypomania in 908 patients with bipolar dis-
order evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a
sex-specific phenomenon. Arch Gen Psychiatry 2005; 62:1089– 1096.
43. Swann AC, Bowden CL, Morris D, et al. Depression during mania. Treatment response
to lithium or divalproex. Arch Gen Psychiatry 1997; 54:37– 42.
44. Andrade C. Antidepressant-withdrawal mania: a critical review and synthesis of the
literature. J Clin Psychiatry 2004; 65:987–993.
45. Kramlinger KG, Post RM. Ultra-rapid and ultradian cycling in bipolar affective illness.
Br J Psychiatry 1996; 168:314–323.
46. Paris J. Borderline or bipolar? Distinguishing borderline personality disorder from
bipolar spectrum disorders. Harv Rev Psychiatry 2004;12:140– 145.
47. Mackinnon DF, Pies R. Affective instability as rapid cycling: theoretical and clinical
implications for borderline personality and bipolar spectrum disorders. Bipolar
Disord 2006; 8:1–14.
48. Akiskal HS, Yerevanian BI, Davis GC, King D, Lemmi H. The nosologic status of borderline
personality: clinical and polysomnographic study. Am J Psychiatry 1985;142:192–198.
49. Marneros A, Rottig S, Wenzel A, Bloink R, Brieger O. Schizoaffective mixed states.
In: Marneros A, Goodwin F, eds. Bipolar Disorders. Mixed States, Rapid Cycling and
Atypical Forms. Cambridge: University Press, 2005:187– 206.
50. Maj M, Pirozzi R, Formicola AM, Bartoli L, Bucci P. Reliability and validity of the DSM-
IV diagnostic category of schizoaffective disorder: preliminary data. J Affect Disord
2000; 57:95–98.
51. Craddock N, Owen MJ. The beginning of the end for the Kraepelinian dichotomy. Br J
Psychiatry 2005; 186:364–366.
52. Beckmann H, Pfuhlmann B. Re-examining the bipolar-schizophrenia dichotomy. In:
Kasper S, Hirschfeld RMA, eds. Handbook of bipolar disorder. Diagnosis and
therapeutic approaches. New York: Taylor and Francis, 2005:37– 48.
Classification of Bipolar Disorders 17

53. Dunner DL. Bipolar Disorders in DSM-IV: Impact of rapid cycling as a course modifier.
Neuropsychopharmacology 1998; 19:189–193.
54. Benazzi F, Koukopoulos A, Akiskal HS. Toward a validation of a new definition of
agitated depression as a bipolar mixed state (mixed depression). Eur Psychiatry 2004;
19:85–90.
55. Judd LL, Akiskal HS, Schettler PJ, et al. The comparative clinical phenotype and long
term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct
disorders? J Affect Disord 2003; 73:19–32.
56. Bauer MS, Calabrese J, Dunner DL, et al. Multisite data reanalysis of the validity of rapid
cycling as a course modifier for bipolar disorder in DSM-IV. Am J Psychiatry 1994;
151:506–515.
57. Kupka RW, Luckenbaugh DA, Post RM, Leverich GS, Nolen WA. Rapid and non-rapid
cycling bipolar disorders: a meta-analysis of clinical studies. J Clin Psychiatry 2003;
64:1483–1494.
58. Coryell W, Solomon D, Turvey C, et al. The long-term course of rapid-cycling bipolar
disorder. Arch Gen Psychiatry 2003; 60:914 –920.
59. Schneck CD, Miklowitz DJ, Calabrese JR, et al. Phenomenology of rapid cycling bipolar
disorder: data from the first 500 participants in the Systematic Treatment Enhancement
Program. Am J Psychiatry 2004; 161:1902–1908.
60. Akiskal HS. The bipolar spectrum: new concepts in classification and diagnosis. In:
Grinspoon L, ed. Psychiatry Update 1983. Washington: American Psychiatric Press,
1983.
61. Akiskal HS. The bipolar spectrum: history, description, boundaries, and validity.
In: Kasper S, Hirschfeld RMA, eds. Handbook of Bipolar Disorder. Diagnosis and
Therapeutic Approaches. New York: Taylor and Francis, 2005:49– 68.
62. Katzow JJ, Hsu DJ, Nassir Ghaemi S. The bipolar spectrum: a clinical perspective.
Bipolar Disord 2003; 5:436–442.
63. Cassano GB, Rucci P, Frank E, et al. The mood spectrum in unipolar and bipolar
disorder: arguments for a unitary approach. Am J Psychiatry 2004; 161:1264– 1269.
64. Angst J, Cassano G. The mood spectrum: improving the diagnosis of bipolar disorder.
Bipolar Disord 2005; 7(suppl 4):4 –12.
65. Dunner DL. Clinical consequences of under-recognized bipolar spectrum disorder.
Bipolar Disorders 2003; 5:456–463.
66. Baldessarini RJ. A plea for the integrity of the bipolar disorder concept. Bipolar disorders
2000; 2:3 –7.
67. Judd LL, Akiskal HS. The prevalence and disability of bipolar spectrum disorders in the
US population: re-analysis of the ECA database taking into account subthreshold cases.
J Affect Disord 2003; 73:123–131.
68. First MB, Gibbon M, Spitzer RL, Williams JBW. Structured Clinical Interview for DSM-IV
Axis I Disorders: SCID-I/P (Version 2.0). New York: Biometrics Research Department,
1996.
69. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric
Interview (M.I.N.I.): the development and validation of a structured diagnostic psychia-
tric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59(suppl 20):22– 33.
70. Wing JK, Babor T, Brugha T, et al. SCAN. Schedules for Clinical Assessment in
Neuropsychiatry. Arch Gen Psychiatry 1990; 47:589– 593.
71. Robins LN, Wing J, Wittchen HU, et al. The Composite International Diagnostic
Interview. An epidemiologic Instrument suitable for use in conjunction with
different diagnostic systems and in different cultures. Arch Gen Psychiatry 1988; 45:
1069 –1077.
72. Regeer EJ, ten Have M, Rosso ML, Hakkaart-van Roijen L, Vollebergh W, Nolen WA.
Prevalence of bipolar disorder in the general population: a Reappraisal Study of the
Netherlands Mental Health Survey and Incidence Study. Acta Psychiatr Scand 2004;
110:374–382.
73. Craddock N, Jones I, Kirov G, Jones L. The Bipolar Affective Disorder Dimension Scale
(BADDS)—a dimensional scale for rating lifetime psychopathology in bipolar spectrum
disorders. BMC Psychiatry 2004; 4:19.
18 Kupka and Nolen

74. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity
and sensitivity. Br J Psychiatry 1978; 133:429–435.
75. Bech P, Rafaelsen OJ, Kramp P, Bolwig TG. The mania rating scale: scale construction
and inter-observer agreement. Neuropharmacology 1978; 17:430– 431.
76. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;
23:56–62.
77. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change.
Br J Psychiatry 1979; 134:382–389.
78. Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of Depressive
Symptomatology (IDS): psychometric properties. Psychol Med 1996; 26:477– 486.
79. Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the Clinical
Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry
Res 1997; 73:159–171.
80. Post RM, Roy-Byrne PP, Uhde TW. Graphic representation of the life course of illness in
patients with affective disorder. American Journal of Psychiatry 1988; 145:844– 848.
81. Leverich GS, Post RM. Life Charting of Affective Illness. CNS Spectrums 1998; 3:21– 37.
82. Denicoff KD, Leverich GS, Nolen WA, et al. Validation of the prospective NIMH-Life-
Chart Method (NIMH-LCM-p) for longitudinal assessment of bipolar illness. Psychol
Med 2000; 30:1391–1397.
83. Meaden PM, Daniels RE, Zajecka J. Construct validity of life chart functioning scales for
use in naturalistic studies of bipolar disorder. J Psychiatr Res 2000; 34:187– 192.
84. Bauer M, Grof P, Gyulai L, Rasgon N, Glenn T, Whybrow PC. Using technology to
improve longitudinal studies: self-reporting with ChronoRecord in bipolar disorder.
Bipolar Disord 2004; 6:67–74.
85. Kendell R. The choice of diagnostic criteria for biological research. Arch Gen Psychiatry
1982; 32:1334–1339.
B 2 Prospects for the Development of Animal
Models for the Study of Bipolar Disorder
Haim Einat
College of Pharmacy, University of Minnesota, Duluth, Minnesota, U.S.A.

Alona Shaldubina, Yuly Bersudsky, and R. H. Belmaker

Division of Psychiatry, Faculty of Health Sciences, Ben-Gurion University of the Negev,
Beer Sheba, Israel

INTRODUCTION
Attitudes towards the study of lithium on behavior in animals and humans have
often been influenced by preconceived notions of the nature of psychiatry and
psychopharmacologic treatment. Many psychiatrists would like to see psychophar-
macological agents as “magic bullets” in a sense similar to antibiotics. Antibiotics
are not expected to have effects on organisms that are not infected with bacteria;
effects that do occur are seen as side effects unrelated to the mode of action. Thus
neuroleptic dopamine-blocking drugs are believed by many psychiatrists to have
no effects on persons who are not psychotic; antidepressants are seen as distin-
guished from stimulants of abuse as not having mood-elevating effects in the
absence of depression. The study of lithium’s effects has often been carried out in
a similar tradition. Moreover, lithium is seen as a difficult drug to give to normal
volunteers for the period of three weeks or a month that would approximate the
amount of time necessary for significant effect on a manic episode.

PSYCHOSTIMULANT-INDUCED MODELS
Animal studies have been a mainstay of the study of lithium effects on behavior
other than clinical studies of psychophathology. These animal studies were
reviewed in 1991 (1) and again in 2003 (2). The overriding majority of studies in
this field has used the concept of pharmacologically induced mania and depression
and has attempted to show lithium prevention. The usual agent for pharmacologi-
cal induction of mania has been amphetamine, although more specific and direct
dopamine agonists such as quinpirole have also been used (3). Using reserpine
or tetrabenazine to induce depression has also been studied (4,5). A background
concept has been the fact that low dose amphetamine has effects primarily on
open field activity whereas higher dose amphetamine causes stereotypy (6,7).
Dopamine blockers are well known to block both the low dose hyperactivity and
the high dose stereotypy of amphetamine, and this nicely fits their usefulness in
both mania and schizophrenia (8). Further support for the amphetamine-induced
hyperactivity model comes from the association of psychostimulants with the
onset of mania in susceptible individuals (9,10) and from some clinical studies
that support an effect of lithium in preventing the behavioral effects of stimulants
in people (11,12). To delineate the differences between the dissimilar responses to

19
20 Einat et al.

doses of amphetamine, attempts have been made to differentially look at the

effect of lithium pretreatment on low dose amphetamine effects versus high dose
amphetamine effects, the hypothesis being that lithium as an antimanic agent
will prevent the effects of low-dose amphetamine but because it is devoid of true
antipsychotic properties it will not be able to affect amphetamine-induced stereo-
typy. Often an underlying biochemical hypothesis was that low-dose amphetamine
released mostly serotonin and noradrenaline whereas high dose amphetamine
released more dopamine. All of these assumptions, hypotheses, and preconcep-
tions are today viewed skeptically. They were heuristic as hypotheses that
generated much good research; however, the yield of robust replicable data has
been poor. Given the fact that modern studies of psychopharmacologic agents
often require hundreds of patients to show statistically significant effects, it may
not be surprising that animal studies with 10 to 15 rats in each group often come
up with conflicting results. The heterogeneity of the amphetamine response is
well known (13), and lithium response may also be heterogeneous in outbred rat
strains (14,15). We shall discuss later the possibility of using this heterogeneity in
responses to advance research.
The effect of lithium to block hyperactivity in rats has also been given new
impetus by a paper from Caron’s group (16). They injected dopamine transporter
knockout mice with lithium (50, 100, or 200 mg/kg) a half hour after they were
placed in an open field and found significant reduction in horizontal activity in
mice injected with 100 and 200 mg lithium. This paradigm had previously been
used by Nixon et al. (17) and positive results had also been found. However, in
humans even very high doses of lithium do not have immediate effects in mania
but clearly do have side effects such as nausea and muscle weakness. Therefore,
it is difficult to evaluate these acute effects reported by Caron’s group (16),
especially in the light of the long history of contradictory results in this field.
Several reports demonstrate inhibition of amphetamine-induced hyperactivity by
acute and chronic lithium pretreatment in rats and mice (7,15,18 – 23). However,
other publications show absence of lithium effect in this model (8,24 – 27).
New data coming from Manji’s laboratory (28) also indicate that lithium’s effects
on amphetamine hyperactivity may be related to genetic background. A compre-
hensive study of 12 strains of mice (three outbred and nine inbred strains) shows
that acute lithium injection at 100 mg/kg attenuated amphetamine-induced
hyperactivity in four strains, had no effect in four strains, and augmented the
effects of amphetamine in one strain (other strains did not respond to amphetamine
treatment at the dose used). Moreover, chronic oral lithium treatment at concen-
trations that had been previously demonstrated to result in therapeutic blood
levels (four weeks, 2.4 g/kg in food), resulted in similar effects with acute admin-
istration in some strains but not in all (28). All in all, these results suggest that
the effects of lithium on amphetamine hyperactivity may be strain (genetically)
dependent and that there may be different mechanisms that are involved in
the short term (acute) and long term (chronic) effects of lithium in this model.
An additional level of complexity in evaluation of lithium’s effects on the
response to amphetamine is added by the fact that behavioral responses to
psychostimulants are strongly affected by the testing environment and pro-
cedure. These variations are more prominent during chronic psychostimulant
treatment but are also apparent after acute administration (29). For example,
hyperactivity measures had been shown to increase more in large open field
arena compared to smaller activity monitors (30) and an environment that is
Prospects for the Development of Animal Models 21

similar to the home cage had been demonstrated to hinder the development of
ambulatory activity (31).
It is possible to give amphetamine or methylphenidate to humans on chronic
lithium and this was done in many studies (11,14,21,32,33). While some have
claimed marked effects of lithium to attenuate the amphetamine-induced response,
others have found no effect at all (32). The numbers on subjects in these studies
are smaller than the large numbers of patients required to show a lithium effect
in a clinical situation and human heterogeneity may be the answer to the con-
tradictory results. We await a clear paradigm that will give robust findings in the
amphetamine hyperactivity model of mania in humans as in rodents. Perhaps
the issue is blood lithium levels since these have varied greatly between studies
and usually levels of 0.7 mM have been considered sufficiently similar to human
treatment to be an acceptable model. It is unclear why behavioral effects are so
difficult to demonstrate, whereas biochemical effects of lithium in normal subjects
are marked and highly replicable (34).
Interestingly, the notion of endophenotypes that had recently been strongly
emphasized in the research of bipolar disorder had renewed the interest of
scientists in the strength of amphetamine-induced behaviors and underlying
brain changes as important modeling tools.
Endophenotypes are quantifiable components in the genes-to-behaviors
pathways, distinct from psychiatric symptoms that make genetic and biological
studies of etiologies for disease categories more manageable (35). In the context
of modeling, endophenotypes approach can be helpful as it reduces the complexity
of symptoms and multifaceted behaviors, resulting in units of analysis that are
simpler to model in animals (36).
One of the tentative endophenotypes that had been repeatedly suggested
for bipolar disorder is dysregulation of dopaminergic function and hypersensi-
tivity to psychostimulants. This possible endophenotype was suggested based on
significant data in both human and animal studies. Impaired brain reward path-
ways, enhanced rewarding effects of psychostimulants in patients with affective
illness, possible relationship between dopamine release in the ventral striatum,
euphoric responses, and some evidence for genetic variance that may explain the
individual differences in brain response to psychostimulants all suggest that beha-
vioral changes observed after exposure to amphetamine may be useful as marker
for bipolar disorder (37). However, this new line of study, exploring amphetamine
responses not as a model of mania but as a model of an endophenotype of
bipolar disorder, must include additional experimentation that will look beyond
hyperactivity into different facets of amphetamine-induced behavior, the possible
relationship between such behaviors, the effects of mood stabilizers, and the
genetic predisposition related to individual variability in responses to amphet-
amine as well as to lithium effects on amphetamine-induced behavior. Some
suggestions along these lines are detailed later in this chapter.

LITHIUM AS AN ANTIDEPRESSANT
Beyond the amphetamine-related models, a very exciting advance in this field has
occurred recently, in a paper by O’Brien et al. (38) who used a specific regimen of
lithium administration to mice: mice received 0.2% lithium chloride in food for a
period of five days followed by 0.4% for 10 additional days and reported robust
effects in the Porsolt forced swim test. Previous studies of lithium in Porsolt
22 Einat et al.

forced swim test were equivocal, although Bourin’s group (39,40) showed that
lithium could reliably potentiate the effects of other antidepressants. The study of
Bourin et al. (39,40) used an acute lithium dose but it fit the preconceived notion
that in the clinic lithium is an augmenter of antidepressant response and not a
powerful antidepressant itself. However, the paradigm of O’Brien et al. (38)
suggests a powerful effect of lithium in the Porsolt forced swim test. This is unlikely
to be an artifact, since activity in the Porsolt forced swim test requires an increase in
struggling behavior. Previous concerns about lithium artifacts have usually pointed
out that lithium patients experience some sense of malaise and muscle weakness
and nausea. These would be unlikely to cause the reported effects in the Porsolt
forced swim test.
We (41) have been able to replicate the O’Brien et al. (38) finding and have
shown that it is dependent on blood levels. Blood levels greater than 1 mM are
necessary for the robust effect that O’Brien et al. (38) finds, whereas blood levels
of 0.7 mM show no effect in the Porsolt forced swim test at all. Many studies of
chronic lithium in the past were quite satisfied with levels of 0.7 mM on the
average and even studies with higher blood levels had a significant portion of
the animals with blood levels below 0.7 mM. This robust effect of lithium on the
Porsolt forced swim test provides an opening for behavioral pharmacological
analysis in the future. For instance, questions can be asked such as whether pre-
treatment with PCPA, a serotonin synthesis inhibitor, will prevent the effect of
lithium in the Porsolt forced swim test or whether presynaptic 5HT1a/1b or postsyn-
aptic 5HT2 or b-adrenergic receptors agonists/antagonists will modulate this effect.
˙
A recent hypothesis of antidepressant action is induction of neurogenesis in the
hippocampus. It could be an interesting question, whether TrkB (BDNF) receptor
agonists/antagonists will affect the lithium’s antidepressant effect in the Porsolt
forced swim test. Interestingly, inhibition of the Erk-MAP kinase pathway was
demonstrated to decrease immobility time in the forced swim test (42). However,
the same treatment also increased activity in an open field and this effect was
ameliorated by chronic lithium treatment. Hence, suggesting that the effects of
Erk inhibition is less likely to be antidepressant-like and more likely to be pro-
manic (42), a notion that is further supported by other studies on the behavioral
effects of manipulating the Erk pathway (43,44). A key question would be
whether other mood stabilizers such as valproate have a similar effect in the
Porsolt swim test. Another key question will be whether the weight loss due to
reduced appetite in chronically lithium-treated rats might cause increased activity
in the Porsolt swim test. This needs to be done by “yoking” mice to others who are
eating lithium and let them eat only the exact same amount a day as the lithium-
treated animals eat. It is also possible to add a nontoxic bitter taste to the control
food to reduce the food intake and to see if this affects Porsolt results. Our
finding that lithium effects in the Porsolt swim test require a blood level greater
than 1 mM is actually congruent with clinical reports that the antidepressant
effects of lithium require higher blood levels than the prophylactic effect.

CURRENT PROBLEMS AND POSSIBLE SOLUTIONS

Although there were some advances in modeling bipolar disorders, it appears that
the field had been quite limited for many years compared with model development
for other psychiatric disorders. It is possible that, at least in part, the nature of the
disease that includes oscillating between depression and mania episodes hindered
Prospects for the Development of Animal Models 23

scientists from making serious attempts to model it. Just a few attempts were done
over the years to model the entire scope of bipolar disorder with manipulations
such as sleep deprivation (45) or intermittent cocaine administration (46), but for
a variety of reasons, these tentative models did not become a central tool to
explore the biology of bipolar disorder or to screen new drugs for it (2,47).

Bioassays
Attempts had also been made over the years to develop models that are more
a bioassay than a comprehensive behavioral model. An example of such incomplete
model is the study of Bersudsky et al. (48) showing lithium inhibition of
forskolin-induced hypoactivity. This study is based on the fact that lithium bio-
chemically inhibits forskolin induced rises in cyclic AMP. The behavioral finding
is therefore a bioassay of the chemical finding. However, to become a model it
would need to be corroborated by a finding that forskolin induces hypoactivity
or a depressive-like syndrome in humans. Another example is lithium augmenta-
tion of pilocarpine-induced seizures. This phenomenon had been repeatedly
demonstrated and can be used to explore lithium-mimetic drugs. Furthermore,
the increase in seizure susceptibility after lithium treatment was demonstrated to
be dependant on inositol depletion as it is blocked by inositol administration (49)
and augmented by inositol reuptake inhibition (50). Since the inositol depletion
theory (51) is one of the leading hypotheses regarding the therapeutic effects of
lithium, the use of pilocarpine-induced seizures as a rudimentary screening
model can be justified. However, the behavioral phenomenon is unrelated to the
features of the disease and therefore the utility of this paradigm as a real model
is questionable.
Whereas the models mentioned above did contribute to the research efforts on
bipolar disorder and its treatment, there is clearly a lack of better and more appro-
priate animal models for the disease. This deficiency is repeatedly emphasized as
one of the major problems hindering bipolar disorder research (52). Some new
approaches recently suggested in the literature are summarized below.

Modeling Facets of the Disease

One relatively simple approach stays within the realm of modeling based on face
validity, that is, the similarity in behavior observed in the disease and in the
model (53), and looking at components of the behavior rather than the entire
disease (54). However, in contrast to present work that is based mainly on very
few behavioral components of bipolar disorder (e.g., hyperactivity as a model
for manic behavior), this approach suggests a more comprehensive battery of
tests and models that will explore a broader range of the behavioral facets of the
disease. Accordingly, it may be possible to develop separate models for facets of
mania such as activity or restlessness; extreme irritability; reduced sleep; provoca-
tive, intrusive, or aggressive behavior; increased sexual drive; abuse of drugs; dis-
tractibility or reduced ability to concentrate; and poor judgment. Furthermore,
many such models were already developed in the context of research of other
disorders but they must be validated for bipolar disorder (54). If some of these
models can be validated, it may be possible to develop a battery of models that
will be appropriate for the screening of possible new mood stabilizers or to test
new hypotheses regarding the underlying biology of the disorder. One example
of such an initial validation attempt was recently demonstrated with a model for
24 Einat et al.

aggression (55). Since intrusive and aggressive behaviors are one of the facets of
mania, this study tested the validity of a commonly used test for aggression, the
resident intruder paradigm in mice, as a tentative model for this facet of mania.
The results of the study demonstrate that chronic administration of lithium or
valproate, at therapeutically relevant doses, ameliorates the aggressive behavior
in the resident intruder paradigm without affecting other aspects of social behavior.
Accordingly, this study suggests that the paradigm has predictive validity and can
be used as part of a battery of models for the study of new mood stabilizers (54).
Additional new models emphasized aggression in a competition for food task
(56) and irritability measured as resistance to capture (57,58).
Interestingly, even within this relatively simple approach, a number of candi-
date manipulations were identified that had been previously demonstrated
to result in a number of behavioral changes that are similar to facets of mania.
Therefore, if all these specific models will be validated, the resulting battery will
represent a group of bipolar-like behaviors (54). For example, psychostimulant
administration does not result only in hyperactivity (as discussed above) but was
also reported to induce reduced sleep, distractibility, risk taking behavior, and
increased responses to reward—all facets of mania (54).

From Molecules to Behavior

Although the approach described above may be conducive to further research,
modeling methods that concentrate on face validity of one component of the
disorder have been repeatedly criticized (59). Recent developments in basic
studies of the etiology of bipolar disorder coming from research using modern
techniques of brain imaging and novel methods of molecular biology may now
assist in the search for more comprehensive models that can be based more on
construct validity than on face validity, that is, models that will be developed
based on a possible mechanism rather than on behavioral similarities. One possible
strategy that can be employed was recently alluded to in a paper from the Soares
group (59). These authors suggest that genetic models can now be developed
for the disease and show that appropriate and relevant genes can be identified
by comparing genetic changes in available animal models to changes in patients.
For example, Machado-Vieira et al. (59) summarize findings regarding the genes
encoding GRK proteins and show they are related to defects in dopamine trans-
mission, to behavioral sensitization to psychostimulants in animals, and to a
more severe form of bipolar disorder in patients. Furthermore, postmortem
studies have shown changes in GRK genes in the prefrontal cortex of patients
who suffered from severe mood disorders (59). Altogether, the authors suggest
that modifications of the GRK genes (using transgenic techniques in mice for
example) may result in a better model for the disease that will be hypothesis-driven.
Other genes and intracellular pathways had been implicated during the last
decade in bipolar disorder and indeed some of these ideas can be used to create
hypothesis-driven models with strong construct validity.
Manipulations of many of these tentative genes proteins and intracellular
pathways in animals do indeed result in behaviors that resemble bipolar disorder
and were recently summarized in a review paper (44). Data regarding a variety of
manipulations, pharmacological and genetic, were summarized, and the conclusion
of the authors was that there is strong evidence for the involvement of PKC, GSK3,
and the Erk-pathway in bipolar-like changes with some evidence supporting
Prospects for the Development of Animal Models 25

additional mechanisms including AMPA receptors, inositol, glucocorticoid recep-

tors, and Bcl-2 (44). Much of the behavioral information presented in that review
was collected while studying other disorders or the functions of normal brain beha-
vior and studies in the context of bipolar disorder are now needed to further explore
the role of these molecules and pathways in bipolar-like behavior in animals. Yet,
the data support the notion that bipolar-like behavioral changes correspond with
manipulations of bipolar-related molecules and this now may be a reasonable
approach to develop more specific, hypothesis-driven models for the disease.

Individual Variability
Further exploration of the relationship between specific genes, molecules, path-
ways, and behavioral models, may be enhanced by looking at individual variability
of responses. The issue of individual differences in behavioral modeling has been
grossly neglected for many practical reasons, but this neglect may represent one
of our major failures. It is apparent that the etiology of bipolar disorder (as
of other psychiatric and nonpsychiatric diseases) is based on an interaction
between the underlying genetics and the environmental effects on the biology
where susceptible individuals that are exposed to environmental precipitating
factors will express the disease phenotype (60 –62). However, in most of our
attempts to model bipolar disorder we expose a group of “normal” animals to a
specific manipulation (whether it is a lesion, a drug, or an environmental stimulus),
and we expect them to become “sick” and allow us to explore possible new thera-
pies or the underlying biology of the “sickness.” Alternatively, with the develop-
ments in transgenic technology, we manipulate a mouse gene that is implicated
in bipolar disorder or its treatment and expect the entire population of mutant
mice to behave differently than the wild type controls. These approaches to
modeling can be helpful when there is an expectancy that a single gene mutation
may be responsible for a major part of a disease or its treatment, but this is probably
not the case for bipolar disorder, and accordingly, this approach may be limited to
demonstrating involvement of specific genes in the disease.
Any scientist who has been studying behavior knows the wide range of indi-
vidual variability within groups. Usually we try to overcome this variability by
increasing group size, but further attention to individual responses may in fact
be conducive to our research. If indeed subgroups of animals within a group
exposed to a specific manipulation can be identified as responders versus non-
responders (higher vs. lower behavioral change), it will enable us to (i ) use the
responders as a better model for the disease and (ii) explore the biological differ-
ences between the subgroups. Some work using such methods has been done in
the context of other psychiatric disorders with interesting results demonstrating a
relationship between the extent of a behavioral response and biological changes
(63– 66). For example, Cohen and her colleagues (67 –69) exposed outbred rats to
a traumatic experience (inescapable cat odor) and tested them for anxiety-like
measures immediately and 10 days after the exposure. Whereas all rats showed
anxiety-like responses immediately after exposure, only about 30% of animals
remained anxious at the later testing. Interestingly, the animals that had a long-
term effect on behavior also had long lasting changes in physiological measures
(heart rate variability) and biochemical measures (higher plasma corticosterone
and ACTH levels, increased sympathetic activity, diminished vagal tone, and
increased sympathovagal balance) suggesting that these animals may be an
26 Einat et al.

excellent model for post-traumatic stress disorder (66). It may now be interesting to
explore the underlying genetic differences that may account for the differential
responding in these subgroups of outbred rats. A number of attempts to look at
individual variability have also been done in the context of depression and
bipolar disorder (65,70,71), but for most of it, scientists who identified differential
responses tried to amplify them by breeding the different subgroups to create
different lines of responders versus nonresponders (72,73). This approach may
clarify some of the genetics by making an extreme “caricature” of the initial
strain. However, the process of inbreeding may also mask the variability of the
normal population since other biological changes that evolve during inbreeding
may overshadow the specific differences that were responsible for the initial differ-
ential responses.
Research that emphasizes diversity in responding presents two main pro-
blems. First, a technical issue: if we want to identify subgroups in a general popu-
lation, we must start with a much larger number of animals. In light of constraints
such as money, space, and constant ethical concerns about animal research, this
may not always be easy. The second problem is more conceptual. Looking at
individual variability demands that we first identify subgroups within a population
and then test them in the context of our study. For example, if one hypothesizes
that animals that show a higher response to psychostimulants may model the
susceptibility of manic patients to these drugs and wants to test the effects of a
new mood stabilizer in this model, the first stage would be to treat a large group
of animals with a psychostimulant, identify the high- versus low-responding
subgroups, then treat with the new mood stabilizer, and see if indeed it has an
effect in the susceptible group but not in the resilient animals (as we may expect
from a good mood stabilizer). However, in testing for the effects of the new drug,
the behavior is not only influenced by the new treatment or the initial differences
between the subgroups, but also by the experience the animals had during the
screening procedure. Yet, if we can identify screening procedures that are mini-
mally intrusive or invasive, further attention to individual variability may open
many new avenues for our research and may result in significantly better models.

Modeling Endophenotypes
An additional approach that in a way combines many of the tentative methods
described above is modeling endophenotypes of disease. As mentioned earlier,
endophenotypes are quantifiable components in the genes-to-behaviors pathways,
distinct from psychiatric symptoms. Endophenotypes are heritable; they are
associated with illness in the population; they are state-independent (manifest in
an individual whether or not illness is active) and may need to be elicited by a
challenge (36). In the context of animal models, it is important to emphasize that
endophenotypes are not synonymous with symptoms. As such, an animal model
of an endophenotype of bipolar disorder may not have face validity for any facet
of the disease but will have strong construct validity for the endophenotype [for
in-depth discussion of the validity of models in psychiatry see (2,47,74)]. Animal
models based on the endophenotypes approach may not be ideal for drug screening
purposes but may have great importance in the attempts to explore genes and
validate neurobiological mechanisms in model organisms (36).
Current theories regarding tentative endophenotypes for bipolar disorder
based on genetic and biological studies of patients and families include attention
Prospects for the Development of Animal Models 27

deficits, circadian rhythm instability, irregularities in motivation and reward, brain

structural changes, increased sensitivity to stress and psychostimulants, and
limbic-hypothalamo-pituitary-adrenocortical (LHPA) axis malfunction (36,37).
Animal models that will represent any of these tentative endophenotypes will be
helpful to decipher the biological basis of these specific endophenotypes and the
relationship between a specific endophenotype and susceptibility to the disease.
Models for endophenotypes can be developed genetically, by modulation of
specific genes that are implicated in the endophenotype, but can also be developed
based on individual variability within groups of “normal” animals as described
above. For example, it was recently demonstrated that the aggression displayed
in the resident-intruder test is ameliorated by chronic mood stabilizers treatment
(55). This behavior had been previously shown to be LHPA-axis dependent
(56,75) and it would be interesting to see now if variability in this behavior may
be related to other behavioral measures related to the LHPA axis and to any specific
genetic features (55).

CONCLUSIONS
There are several directions in which this field can go heuristically:
1. Development of an entirely novel model. For instance, dogs are more difficult to
study than rats, involving more expense and greater ethical concerns. However,
male dogs exposed to the scent of vaginal secretions of a female dog in heat
become hyperactive, aggressive, hypersexual, and will not sleep or eat for
days while under the influence of this scent. Since hypersexuality and hyper-
activity are clearly parts of mania and since a new love affair is a frequent
stimulus for the onset of a manic episode, this model could have face validity.
The effects of lithium and other mood stabilizers on this model could be an
important direction. The biochemical effects of the pheromones of female
canines in heat on the brain of the male dog might also elicit important
information.
Recent papers (16,38) suggest that the classic field of study of lithium effects on
amphetamine hyperactivity or on the forced swim test might actually have been
a correct direction and that the contradictory results might have been due to
inadequate lithium dosing. A major effort is now underway to resolve
whether this is the case. If so, studies of other mood stabilizers and the bio-
chemical effects of higher dose lithium in these models could lead to rapid
new information.
2. Validation of additional facets of the disease may provide researchers with a
larger and broader arsenal of tools to explore the different components of
mania and depressive behavior, especially in the context of drug and mutant
animals screening (54).
3. Further attention to individual variability in behavioral response may be critical
for the development of more clinically relevant models and can forward the
understanding of genetic differences that may account for behavioral diversity.
Individual variability can also be of great importance in the exploration of
models for the endophenotypes of disease.
4. The notion of endophenotypes in bipolar disorder, suggesting an intermediate
level of exploration between symptoms and disease that may be genetically and
biologically relevant, poses a set of new challenges in modeling (36). Each of the
28 Einat et al.

tentative endophenotypes of bipolar disorder includes a set of biological and

behavioral components that may be possible to model using either genetic tech-
niques or other manipulations. Appropriate models for endophenotypes will
have a major impact on further research into this rejuvenated hypothesis.
Animal models for bipolar disorder have been used for many decades with
significant success in studies related to both the development of new drugs and
the exploration of the biological basis of the disorder. Yet, it is now clear that
with the recent major developments in molecular and genetic methodologies and
brain imaging techniques, the available models cannot adequately respond to the
new challenges (52,76). It is now the time for behavioral scientists to make a
major effort, possibly combining all the approaches discussed above, to detect,
create, and validate new models that may provide better and more adequate
tools to further the research of bipolar disorder.

REFERENCES
1. Kofman O, Belmaker RH. Animal models of mania and bipolar affective disorders,
In: Soubrie P, ed. Anxiety, Depression and Mania. New York: Karger, 1991:103– 121.
2. Einat H, Manji HK, Belmaker RH. New approaches to modeling bipolar disorder.
Psychopharmacol Bull 2003; 37(1):47–63.
3. Shaldubina A, Einat H, Szechtman H, et al. Preliminary evaluation of oral anticonvul-
sant treatment in the quinpirole model of bipolar disorder. J Neural Transm 2002;
109(3):433–440.
4. Lerer B, Ebstein RP, Felix A, et al. Lithium amelioration of reserpine-induced hypoactiv-
ity in rats. Int Pharmacopsychiatry 1980; 15(6):338– 343.
5. Einat H, Karbovski H, Korik J, et al. Inositol reduces depressive-like behaviors in
two different animal models of depression. Psychopharmacology (Berl) 1999; 144(2):
158 –162.
6. Belmaker RH, Lerer B, Klein E, et al. The use of behavioral methods in the search for
compounds with lithium-like activity. In: Levy A, Spiegelstein MY, eds. Behavioral
Models and the Analysis of Drug Action. Amsterdam: Elsevier, 1982:343– 356.
7. Borison RL, Sabelli HC, Maple PJ, et al. Lithium prevention of amphetamine-induced
“manic” excitement and of reserpine-induced “depression” in mice: possible role of
2-phenylethylamine. Psychopharmacology (Berl) 1978; 59(3):259– 262.
8. Ebstein RP, Eliashar S, Belmaker RH, et al. Chronic lithium treatment and dopamine-
mediated behavior. Biol Psychiatry 1980; 15(3):459– 467.
9. Anand A, Verhoeff P, Seneca N, et al. Brain SPECT imaging of amphetamine-induced
dopamine release in euthymic bipolar disorder patients. Am J Psychiatry 2000;
157(7):1108 –1114.
10. Murphy DL, Brodie HK, Goodwin FK, et al. Regular induction of hypomania by L-dopa
in “bipolar” manic-depressive patients. Nature 1971; 229(5280):135 – 136.
11. Huey LY, Janowsky DS, Judd LL, et al. Effects of lithium carbonate on methylphenidate-
induced mood, behavior, and cognitive processes. Psychopharmacology (Berl) 1981;
73(2):161–164.
12. Van Kammen DP, Murphy DL. Attenuation of the euphoriant and activating effects of d-
and l-amphetamine by lithium carbonate treatment. Psychopharmacologia 1975;
44(3):215–224.
13. Tecce JJ, Cole JO. Amphetamine effects in man: paradoxical drowsiness and lowered
electrical brain activity (CNV). Science 1974; 185(149):451 –453.
14. Angrist B, Gershon S. Variable attenuation of amphetamine effects by lithium. Am J
Psychiatry 1979; 136(6):806–810.
15. Gould TJ, Keith RA, Bhat RV. Differential sensitivity to lithium’s reversal of amphet-
amine-induced open-field activity in two inbred strains of mice. Behav Brain Res
2001; 118(1):95–105.
Prospects for the Development of Animal Models 29

16. Beaulieu JM, Sotnikova TD, Yao WD, et al. Lithium antagonizes dopamine-dependent
behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc
Natl Acad Sci USA 2004; 101(14):5099–5104. Epub 2004 Mar 24.
17. Nixon MK, Hascoet M, Bourin M, et al. Additive effects of lithium and antidepressants
in the forced swimming test: further evidence for involvement of the serotoninergic
system. Psychopharmacology (Berl) 1994; 115(1 –2):59– 64.
18. Berggren U. Effects of chronic lithium treatment on brain monoamine metabolism and
amphetamine-induced locomotor stimulation in rats. J Neural Transm 1985; 64(3– 4):
239 –250.
19. Berggren U, Tallstedt L, Ahlenius S, et al. The effect of lithium on amphetamine-induced
locomotor stimulation. Psychopharmacology (Berl) 1978; 59(1):41– 45.
20. Berggren U, Engel J, Liljequist S. The effect of lithium on the locomotor stimulation
induced by dependence-producing drugs. J Neural Transm 1981; 50(2 – 4):157– 164.
21. Flemenbaum A. Does lithium block the effects of amphetamine? A report of three cases.
Am J Psychiatry 1974; 131(7):820–821.
22. Hamburger-Bar R, Robert M, Newman M, et al. Interstrain correlation between beha-
vioural effects of lithium and effects on cortical cyclic AMP. Pharmacol Biochem
Behav 1986; 24(1):9–13.
23. Lerer B, Globus M, Brik E, et al. Effect of treatment and withdrawal from chronic lithium
in rats on stimulant-induced responses. Neuropsychobiology 1984; 11(1):28– 32.
24. Arriaga F, Dugovic C, Wauquier A. Effects of lithium on dopamine behavioural super-
sensitivity induced by rapid eye movement sleep deprivation. Neuropsychobiology
1988; 20(1):23–27.
25. Cappeliez P, Moore E. Effects of lithium on an amphetamine animal model of bipolar
disorder. Prog Neuropsychopharmacol Biol Psychiatry 1990; 14(3):347– 358.
26. Fessler RG, Sturgeon RD, London SF, et al. Effects of lithium on behaviour induced
by phencyclidine and amphetamine in rats. Psychopharmacology (Berl) 1982; 78(4):
373 –376.
27. Pittman KJ, Jakubovic A, Fibiger HC. The effects of chronic lithium on behavioral and
biochemical indices of dopamine receptor supersensitivity in the rat. Psychopharma-
cology (Berl) 1984; 82(4):371–377.
28. Gould TD, O’Donnell KC, Picchini AM, Manji HK. Strain differences in lithium attenu-
ation of D-amphetamine-induced hyperlocomotion: a mouse model for the genetics of
clinical response to lithium. Neuropschopharmacology 2006.
29. Einat H, Einat D, Allan M, et al. Associational and nonassociational mechanisms in
locomotor sensitization to the dopamine agonist quinpirole. Psychopharmacology
(Berl) 1996; 127(2):95–101.
30. Decker S, Grider G, Cobb M, et al. Open field is more sensitive than automated activity
monitor in documenting ouabain-induced hyperlocomotion in the development of an
animal model for bipolar illness. Prog Neuropsychopharmacol Biol Psychiatry 2000;
24(3):455–462.
31. Einat H, Szechtman H. Environmental modulation of both locomotor response and
locomotor sensitization to the dopamine agonist quinpirole. Behav Pharmacol 1993;
4(4):399–403.
32. Silverstone PH, Pukhovsky A, Rotzinger S. Lithium does not attenuate the effects of
D-amphetamine in healthy volunteers. Psychiatry Res 1998; 79(3):219–226.
33. Wald D, Ebstein RP, Belmaker RH. Haloperidol and lithium blocking of the
mood response to intravenous methylphenidate. Psychopharmacology (Berl) 1978;
57(1):83–87.
34. Ebstein R, Belmaker R, Grunhaus L, et al. Lithium inhibition of adrenaline-stimulated
adenylate cyclase in humans. Nature 1976; 259(5542):411 – 413.
35. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and
strategic intentions. Am J Psychiatry 2003; 160(4):636– 645.
36. Gould TD, Gottesman II. Psychiatric endophenotypes and the development of valid
animal models. Genes Brain and Behavior 2006; 5(2):113 – 119.
37. Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK. Toward constructing an
endophenotype strategy for bipolar disorder. Biological Psychiatry 2006; 60(2):93– 105.
30 Einat et al.

38. O’Brien WT, Harper AD, Jove F, et al. Glycogen synthase kinase-3beta haploinsufficiency
mimics the behavioral and molecular effects of lithium. J Neurosci 2004; 24(30):
6791 –6798.
39. Bourin M, Hascoet M, Colombel MC, et al. Differential effects of clonidine, lithium
and quinine in the forced swimming test in mice for antidepressants: possible roles of
serotoninergic systems. Eur Neuropsychopharmacol 1996; 6(3):231– 236.
40. Redrobe JP, Bourin M. Evidence of the activity of lithium on 5-HT1B receptors in the
mouse forced swimming test: comparison with carbamazepine and sodium valproate.
Psychopharmacology (Berl) 1999; 141(4):370–377.
41. Bersudsky Y, Shaldubina A, Belmaker RH. Lithium’s effect in forced-swim test is blood
level dependent but not dependent on weight loss. Behav pharmacol 2007; 18(1):77– 80.
42. Einat H, Yuan P, Gould TD, et al. The role of the extracellular signal-regulated kinase
signaling pathway in mood modulation. J Neurosci 2003; 23(19):7311 – 7316.
43. Einat H, Manji HK, Gould TD, et al. Possible involvement of the ERK signaling cascade
in bipolar disorder: behavioral leads from the study of mutant mice. Drug News
Perspect 2003; 16(7):453–463.
44. Einat H, Manji HK. Cellular plasticity cascades: gene to behavior pathways in animal
models of bipolar disorder. Biological Psychiatry 2006; 59(12):1160 – 1171.
45. Gessa GL, Pani L, Fadda P, et al. Sleep deprivation in the rat: an animal model of mania.
Eur Neuropsychopharmacol 1995; 5(suppl):89 –93.
46. Antelman SM, Caggiula AR, Kucinski BJ, et al. The effects of lithium on a potential
cycling model of bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 1998;
22(3):495–510.
47. Einat H, Kofman O, Belmaker RH. Animal models of bipolar disorder: from a single
episode to progressive cycling models. In: Myslobodsky M, Weiner I, eds. Contemporary
Issues in Modeling Psychopharmacology. Boston: Kluwer Academic Publishers,
2000:165–180.
48. Bersudsky Y, Patishi Y, Bitsch Jensen J, et al. The effect of acute and chronic lithium on
forskolin-induced reduction of rat activity. J Neural Transm 1997; 104(8– 9):943– 952.
49. Kofman O, Sherman WR, Katz V, et al. Restoration of brain myo-inositol levels in rats
increases latency to lithium-pilocarpine seizures. Psychopharmacology (Berl) 1993;
110(1 –2):229–234.
50. Einat H, Kofman O, Itkin O, et al. Augmentation of lithium’s behavioral effect by inositol
uptake inhibitors. J Neural Transm 1998; 105(1):31– 38.
51. Berridge MJ, Irvine RF. Inositol phosphates and cell signalling. Nature 1989; 341(6239):
197 –205.
52. Nestler EJ, Gould E, Manji H, et al. Preclinical models: status of basic research in
depression. Biol Psychiatry 2002; 52(6):503–528.
53. Willner P. The validity of animal models of depression. Psychopharmacology (Berl) 1984;
83(1):1–16.
54. Einat H. Modelling facets of mania — new directions related to the notion of
endophenotypes. J Psychopharmacol 2006; 9:9.
55. Einat. Establishment of a battery of simple models for facets of bipolar disorder: a
practical approach to achieve increased validity, better screening and possible insights
into endophenotypes of disease. Behavior Genetics 2007; 37(1):244–255.
56. Malatynska E and Knapp RJ. Dominant-submissive behavior as models of mania and
depression. Neurosci Biobehav Rev 2005; 29(4 –5):715– 737.
57. Kalynchuk LE, Pinel JP, Treit D, et al. Changes in emotional behavior produced by
long-term amygdala kindling in rats. Biol Psychiatry 1997; 41(4):438– 451.
58. Kalynchuk LE, Pinel JP, Treit D, et al. Persistence of the interictal emotionality produced
by long-term amygdala kindling in rats. Neuroscience 1998; 85(4): 1311 – 1319.
59. Machado-Vieira R, Kapczinski F, Soares JC. Perspectives for the development of animal
models of bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2004;
28(2):209–224.
60. Shih RA, Belmonte PL, Zandi PP. A review of the evidence from family, twin and
adoption studies for a genetic contribution to adult psychiatric disorders. Int Rev
Psychiatry 2004; 16(4):260–283.
Prospects for the Development of Animal Models 31

61. Kieseppa T, Partonen T, Haukka J, et al. High concordance of bipolar I disorder in a

nationwide sample of twins. Am J Psychiatry 2004; 161(10):1814 – 1821.
62. Craddock N, Jones I. Molecular genetics of bipolar disorder. Br J Psychiatry 2001;
178(suppl 41):S128–S133.
63. Isgor C, Slomianka L, Watson SJ. Hippocampal mossy fibre terminal field size is
differentially affected in a rat model of risk-taking behaviour. Behav Brain Res 2004;
153(1):7–14.
64. Kabbaj M, Devine DP, Savage VR, et al. Neurobiological correlates of individual differ-
ences in novelty-seeking behavior in the rat: differential expression of stress-related
molecules. J Neurosci 2000; 20(18):6983–6988.
65. Taghzouti K, Lamarque S, Kharouby M, et al. Interindividual differences in active and
passive behaviors in the forced-swimming test: implications for animal models of
psychopathology. Biol Psychiatry 1999; 45(6):750– 758.
66. Cohen H, Zohar J. An animal model of posttraumatic stress disorder: the use of cut-off
behavioral criteria. Ann NY Acad Sci 2004; 1032:167– 178.
67. Cohen H, Zohar J, Matar M. The relevance of differential response to trauma in an
animal model of posttraumatic stress disorder. Biol Psychiatry 2003; 53(6):463– 473.
68. Cohen H, Zohar J, Matar MA, et al. Setting apart the affected: the use of behavioral
criteria in animal models of post traumatic stress disorder. Neuropsychopharmacology
2004; 29(11):1962–1970.
69. Cohen H, Zohar J, Matar MA, et al. Unsupervised fuzzy clustering analysis supports
behavioral cutoff criteria in an animal model of posttraumatic stress disorder. Biol
Psychiatry 2005; 58(8):640–650. Epub 2005 Jun 22.
70. Nielsen CK, Arnt J, Sanchez C. Intracranial self-stimulation and sucrose intake differ as
hedonic measures following chronic mild stress: interstrain and interindividual
differences. Behav Brain Res 2000; 107(1–2):21–33.
71. Dietz DM, Tapocik J, Gaval-Cruz M, et al. Dopamine transporter, but not tyrosine
hydroxylase, may be implicated in determining individual differences in behavioral
sensitization to amphetamine. Physiol Behav 2005; 86(3):347–355. Epub 2005 Aug 29.
72. Overstreet DH, Rezvani AH, Janowsky DS. Genetic animal models of depression and
ethanol preference provide support for cholinergic and serotonergic involvement in
depression and alcoholism. Biol Psychiatry 1992; 31(9):919– 936.
73. Kamens HM, Burkhart-Kasch S, McKinnon CS, et al. Sensitivity to psychostimulants in
mice bred for high and low stimulation to methamphetamine. Genes Brain Behav 2005;
4(2):110–125.
74. Willner P, ed. Behavioral models in psychopharmacology: theoretical, industrial and
clinical perspectives. In: Behavioral Models in Psychopharmacology. Cambridge:
Cambridge University Press, 1991:3 –19.
75. Ebner K, Wotjak CT, Landgraf R, et al. Neuroendocrine and behavioral response to social
confrontation: residents versus intruders, active versus passive coping styles. Horm
Behav 2005; 47(1):14–21.
76. Tecott LH, Nestler EJ. Neurobehavioral assessment in the information age. Nat Neurosci
2004; 7(5):462–466.
B 3 Abnormalities in Catecholamines and the
Pathophysiology of Bipolar Disorder
Amir Garakani and Dennis S. Charney
Department of Psychiatry, Mount Sinai School of Medicine, New York,
New York, U.S.A.

Amit Anand
Department of Psychiatry, Indiana University School of Medicine, Indianapolis,
Indiana, U.S.A.

INTRODUCTION
The catecholamine (CA) hypothesis of bipolar disorder (BD)—a deficiency of CA in
depression and excess in mania—was proposed nearly three decades ago. CA
abnormalities remain the most replicated finding in the pathophysiology of BD.
However, the role of CA abnormalities in the pathophysiology of BD still
remains unclear. For example, it is unclear whether changes in CAs seen in
manic and depressed states are secondary to the mood state or primary, and it
remains to be clarified whether abnormalities in the CA system are presynaptic
or postsynaptic. Rapid advances in the field of neuroscience in the last three
decades have increased our knowledge of the role of CAs in the working of the
nervous system and provided new tools to explore CA abnormalities. Clinical
research in CA abnormalities in BD has evolved from measurement of changes in
CAs in bodily fluids and peripheral tissue to neuroendocrine challenge studies to
molecular analysis of postmortem tissue and direct visualization of CA system
with brain imaging methods such as single photon emission computed tomography
(SPECT) and positron emission tomography (PET).
Preclinical and clinical literature on the role of CAs in depression and
psychiatric illnesses and mode of action of psychotropic drugs is fairly extensive.
In this review, the main focus is on studies that have specifically investigated the
role of CAs in BD. There are only a few preclinical studies regarding pathophysiol-
ogy of BD because of a lack of suitable animal models for bipolar illness. However,
there is an extensive preclinical literature regarding pathophysiology of depression
using animal models of depression. In this review, findings from depression
research are reviewed where they are relevant to understanding of pathophysiol-
ogy of BD.
This chapter first reviews the role of CAs in physiology of mood and mood
regulation. Next, studies that have investigated CA abnormalities in BD, using
different methodological paradigms, are reviewed. The interaction of CAs with
other neuromodulators is discussed, and a model for the role of CAs in mood
regulation is presented. Finally, methodological difficulties in conducting research
in the pathophysiology of BD and future directions of research in this area are
discussed.

33
34 Garakani et al.

NEUROCHEMISTRY AND NEUROPHYSIOLOGY OF

CATECHOLAMINE
Neurochemistry and Neurophysiology of the Dopaminergic System
Dopaminergic cell bodies located in the ventral mesencephalon form most dopamine
(DA) cell bodies and project widely throughout the central nervous system (CNS).
These cell bodies give rise to the nigrostriatal, mesocortical, and mesolimbic DA pro-
jections. A separate set of dopaminergic cell bodies projecting to the hypothalamus
and pituitary arise from a different brain region—the arcuate nucleus—and are
referred to as the tuberoinfundibular (TIDA) and tuberohypophysial neurons (2).
The arcuate nucleus receives input from cortical regions and is involved in
production of hormones such as growth hormone (GH) and prolactin in response to
different mood states.
Dopamine receptors have traditionally been divided into D1 and D2 types
based on the presence and absence of a positive coupling between receptors and
adenylate cyclase activity. D1 receptors mediate the dopamine-stimulated increase
in adenylate cyclase activity. D2 receptors are thought to mediate effects that are
independent of D1-mediated effects and also to exert an opposing influence on
adenylate cyclase activity (3). Recently, a number of subtypes of these receptors
have been discovered that are of particular importance to the study of psychiatric
disorders. D3 receptors, a subtype of D2 receptors, and D5 receptors, a subtype
of D1 receptors, are present in high levels in the limbic brain structures. The D4
receptor, a subtype of D2 receptor that has high levels in the frontal cortex,
midbrain, amygdala, medulla, and lower levels in the basal ganglia, has been
implicated in the action of clozapine, which reverses both the negative and positive
symptoms of schizophrenia (4). Self et al. (5) have described opposite modulation of
reward behavior by D1 and D2 receptors agonists. D1 receptor agonists decrease
the reinforcement of reward-seeking behavior, whereas D2 receptor agonists
increase reinforcement of reward-seeking behavior (5). It can be postulated that
the state of anhedonia seen in depression could be a manifestation of either increase
in activity of the D1 receptors and/or a decrease in activity at the D2 receptor site
and opposite changes could lead to mania.

Role of Dopamine in Reward Mechanisms

Dopamine has been implicated in the neurochemical mechanisms involved in
reward behavior. Schultz (6) has reported that DA neurons in the ventral tegmen-
tal area (VTA) and substantia nigra are preferentially activated in response to a
novel rewarding stimulus and encode for reward predictability. Wainer (7), in a
series of studies, reported that anhedonia seen in an animal model of depression
is related to dopamine receptor subsensitivity that is reversed by a variety of
antidepressant drugs. Furthermore, the reward potential of a number of addict-
ing drugs such as cocaine and opiates seem to be mediated via the mesolimbic
dopamine pathways involving the nucleus accumbens (3). Alteration in
reward-related behavior has been thought to be central to the pathophysiology
of BD (8,9). Mesocortical and mesolimbic dopaminergic pathways have been
shown to be involved in reward-related behavior. Manic behavior is frequently
associated with reward-seeking behavior and depression with withdrawal and
inability to derive pleasure from a rewarding stimulus (anhedonia). Therefore,
it is likely that abnormalities of mesocorticolimbic dopamine system may be
present in BD.
Abnormalities in Catecholamines 35

NEUROCHEMISTRY OF THE NORADRENERGIC SYSTEM

The major noradrenergic (NA) nucleus in the brain is the locus coeruleus (LC),
which is located on the floor of the fourth ventricle in the rostra/pons (10). NA
neurons give rise to diffuse axonal projections and innervate virtually all areas of
the brain and spinal cord. The mammalian brain also contains smaller collections
of additional NA neurons and adrenergic neurons that are located in discrete
regions of the pons and medulla. These neurons show more restricted patterns of
axonal projections. The NA cell bodies exert influence on the brain and the body.
Therefore, they are involved in both modulating brain function and producing
the body’s response to emotions.
The NA cell bodies projecting to other brain regions seem to exert a modula-
tory effect on the target site. Not all NA-containing nerve terminals in the cortex
make synaptic contact with the local cortical neurons; rather, some of these
neurons release NA in a manner similar to that through which hormones are
secreted and thus have generalized effects on the CNS regions (11). The LC is
also very sensitive to both external environmental stimuli and also changes in the
body’s internal homeostasis. The LC output is involved in flight-and-fight
responses and regulates level of arousal, the responses of the sympathetic
nervous system including pulse rate and blood pressure, and the signaling of the
danger signal of the organism.
LC neurons receive a number of inputs that provide information about
the state of the body’s external and internal environment. These inputs include
other neurotransmitter systems, for example, the serotonin [5-hydroxytryptamine
(5-HT)], opioid, gamma aminobutyric acid (GABA), acetylcholine (ACh),
dopamine, and glutamate systems. A number of peptides influence the firing
rate of the LC neurons, most notable being the corticotropin-releasing hormone
(CRH). Finally, the NA system itself provides negative feedback to the LC
neurons (10,12). The synthetic pathway for CA involves a series of enzymatic
reactions. Tyrosine hydroxylase is the rate-limiting enzyme for the synthesis of
both norepinephrine (NE) and DA. Dopamine 3-hydroxylase, which converts
DA to NE, is present only in NA neurons. In adrenergic neurons, the enzyme
phenylethanolamine-N methyl transferase converts NE to epinephrine.
Adrenergic receptors have been classified as being either a- or b-adrenergic
subtype. Each of these subtypes has two secondary subtypes, (a l and a2; b1 and
b2). Each of these receptors has been cloned (4). Variant forms of these receptors
may exist with different regional distributions and functional properties.
Activation of the b-adrenergic receptors leads to physiological responses by stimu-
lating adenylate cyclase via coupling with Gs protein (13). Activation of the
al-adrenergic receptors leads to physiological responses through activation of Gx
proteins (13). Activation of a2-adrenergic receptors leads to physiological responses
via coupling with Gi and or Go proteins, which leads to activation of specific Kþ
channel and/or inhibition of adenylate cyclase (13). There are also a2-adrenorecep-
tors present on 5HT neuron terminals in the hippocampus, and electrophysiological
studies suggest that they exert a tonic inhibitory influence on the firing of 5HT
neurons (14).

Role of Norepinephrine in Reward Mechanisms

As noted earlier, abnormalities in reward mechanisms are likely to be present in BD.
DA function has been implicated in maintenance of reinforcing properties of a
Exploring the Variety of Random
Documents with Different Content
 CHAPTER XIX
KIT TAKES HIS CUE
Wheeler put down the Montreal newspaper and knitted his brows.
Snow beat the office windows and the lamp burned unsteadily. A
savage wind screamed in the trees and the river brawled. Winter
ought to have begun, and Wheeler had expected keen frost to follow
the snow, but all the snow that fell melted, and when it went cold
rain swelled the pools along the muddy track.
Had the frost arrived, Wheeler would have sent off most of the
men and cut expenses by keeping only the limited number he could
usefully employ. Now, however, he must carry on as long and fast as
possible. The drawback was, he might not finish all he began, and
when the spring floods hurled the ice floes against the piers, girders
and columns must be firmly stayed. A Canadian river’s breaking is an
impressive spectacle.
In the meantime, frost and thaw and rain embarrassed the gangs.
The boys did not earn their pay, and at the head office construction
costs were keenly scrutinized. Then, as soon as the real frost did
begin, the company would call Wheeler East and he must fix on the
proper man to superintend the cutdown gang. Austin was a good
engineer, but sometimes he got sick, and he could not handle the
boys like young Carson. Austin’s soberness was not altogether an
advantage; when the gang was tired and sullen, Carson’s humorous
banter went farther than a command.... Wheeler turned his head,
for the door rattled and Kit came in.
Kit’s long boots were muddy and wet snow stuck to his slickers.
He shook the melting slush from his hat, and when he faced
Wheeler his look was grim. Wheeler thought the boy was riled.
“Hello!” he said. “Is somebody making trouble?”
 “The boys are not,” said Kit. “Have you decided who’s to stay at
the bridge?”
“You’re pretty frank,” Wheeler remarked. “If you like, you can
have the job.”
“Then, I suppose you’re sending Austin to the workshops?”
“Where the company sends Austin has nothing to do with you.”
“You stated something like that before. Well, all I’m entitled to say
is, if Austin goes, I won’t stay.”
Wheeler smiled, a rather grim smile. He began to see a light, and
he admitted the boy had grit.
“You reckon, unless you see us out, we can’t put the bridge
across?”
“I’m not a fool,” said Kit. “Engineers are pretty numerous. All the
same, there’s something you ought to weigh: for a time the job
would bother a fresh man.”
“It’s possible,” Wheeler agreed. “I begin to get your argument,
but go ahead——”
Kit’s eyes twinkled. In a way, his talking to Wheeler was
humorous. The fellow was his commanding officer and his rule was
firm. Kit had thought to annoy him, but so far as he could see,
Wheeler was not annoyed. Well, if he wanted to argue, Kit was
willing.
“Austin knows his job, and I am, so to speak, his understudy.
Then it’s important that the boys know us. I expect you have got a
pick on Austin and thought you’d ship him off and give me his part.
The plan won’t work.”
“Now I get you; but you can’t bluff a big Canadian company. You
claim, unless we hold on to Austin, you will let us down? We’ll risk it.
When do you pull out?”
Kit had thought to conquer; but perhaps in a sense, he had
conquered, since Wheeler could not use him.
“I imagine I’m engaged for a month——”
Wheeler laughed and indicated a chair. “If you’re resolved, we
won’t hold you longer than you want; but suppose you let me talk?
To begin with, I have not a pick on Austin. Bob’s a useful man, but I
don’t know if he’s the proper man to stay at the bridge. If you quit,
you’ll get your pay up to date, but you want to consider. In winter,
Canada’s a pretty hard country. You’d find the labor agents have no
use for a tenderfoot, and the cheap boarding-houses are crowded by
broken roustabouts, waiting for the spring. Since the war I reckon
the dollar hotels have shut down. However, if your wad is big——”
“My wad is not big. For all that, I’m not going to take Austin’s
post.”
“Very well! You claimed you were not a fool. Suppose I send you
East? If the company tried you out at the office, would it meet the
bill?”
“I’d be glad to go,” said Kit. “Since I meant to bluff you, you’re
generous.”
“Then, it’s fixed, but until the frost stops us, we want you at the
bridge. I guess that’s all, and you won’t talk to Austin about it.”
Kit went off. He had not helped Austin, but he had done all he
promised to do, and to know he would pay for his meddling was
some relief. Since he could not bluff Wheeler, there was no use in
hurting himself.
For a week, rain and snow embarrassed the workmen. Sometimes
in the morning the mud about the camp was frozen and hoar frost
sparkled on the trees, but in a few hours the rain began. The
swollen river undermined the bank, and the material stacked along
the track sank in the mire. To handle the wet and greasy steel was
awkward, but arctic winter would soon arrive, and the work was
stubbornly pushed on.
Then a telegram called Wheeler to the company’s office and the
strain got worse, for the gangs did not stop at night, and somebody
besides the foremen must be about. Kit thought the extra effort
bothered Austin, and when he returned one stormy evening to the
shack he found Bob by the stove. His face was pinched and he was
wrapped in a blanket.
“I was forced to stop, but I’m getting warm,” he said in an
apologetic voice. “If you think all’s pretty straight, I’ll go to bed after
supper. A good sleep will fix me up.”
Kit said he did not expect trouble, and for an hour or two he
meant to loaf. To pull off his muddy boots and wet slickers was some
relief, and after supper he carried his chair to the stove and lighted
his pipe. Austin, sitting opposite rested his feet on a box. His pose
was slack, and sometimes he shivered.
“After all, I don’t think you ought to complain about the
company’s sending you off,” Kit remarked.
“I don’t know that I do complain,” Austin rejoined. “If I was often
bothered like this, I’d be resigned to quit, but I’m persuaded the
trouble’s going. One can stand for keen frost—to wear wet clothes,
to jump up as soon as you get to sleep and tumble about in the rain
and dark is another proposition. To-night my back hurts and I’m dull
and cold, but I expect to be all right in the morning.”
Kit doubted, but he said: “Mrs. Austin would sooner you were at
the drawing office.”
“Carrie’s glad,” Austin agreed. “Still at Toronto she was rather
important, and she ought to have cultivated friends. She likes music
and pictures and so forth, but so long as my pay is small she must
go without. I had hoped to get ahead and give her a better time. To
be beaten by a weak body is riling.”
“Philosophy’s the proper plan; but perhaps you ought to go to
bed.”
“I’ll go soon. Now I’ve got myself fixed right and my back is
easier, I don’t want to move.”
Kit said nothing. Snow beat the windows and the iron roof rattled;
he was tired and frankly did not want to face the storm. The stove-
front got red and the heat was soothing. For an hour he resolved to
let himself go slack.
By and by a foreman pushed back the door. He breathed fast, and
his look was grim.
“We have got the brace across at the end pier, but the ends won’t
meet the bolt holes in the lugs.”
Austin threw off the blanket and jumped up.
“Are the ends much short?”
 “Maybe an inch, but we can’t spring the frames. I’ve sent for jacks
and the chain tackle. Looks as if the outside lug wasn’t plumb in line
——”
“Get to it,” said Austin. “I’ll be along in a few minutes.”
The other went off, and Kit was sorry Wheeler was not about. He
thought a screw pile carrying a column had sunk. The brace the men
tried to fix would support the column, but the bolts must reach the
holes. A bridge is not geometrically accurate and one must
sometimes spring a member to its place. In a snowstorm, however,
to force the stiff frames to meet would be hard.
“Stop by the stove,” he said. “As soon as I think we win out, I’ll
send you word.”
“I’m going,” Austin rejoined. “When Wheeler’s not around I’m in
control. Besides, if I go sick when I’m wanted, the company would
be entitled to keep me at the office. I can’t risk it.”
They disputed, but Austin was firm and Kit helped him pull on his
thick clothes. When he picked up Austin’s slicker he saw the back
was torn.
“A bolt end,” said Austin. “I helped the boys throw some heavy
stuff from a trolley.”
“Take my coat,” said Kit, and when he put on Austin’s he turned
his head and smiled.
In a way, Bob’s obstinacy was justified, for the man who makes
good is the man who is where he is wanted; but Kit began to see a
plan. He had stated that he was Austin’s understudy, and the torn
slicker was his cue. The tear was conspicuous and was made when
the men were about. Now, however, Kit had got the coat, the night
was dark, and the snow was thick. If Austin were knocked out, Kit
thought he could play his part.
“You’re stubborn, Bob, but let’s get off,” he said.
 CHAPTER XX
Austin’s understudy
Snow blew about the bridge and the savage wind screamed in the
lattice. The planks laid across the ties were slippery; the flames from
the throbbing blast-lamps slanted, and sometimes all was dark. Then
the white fires leaped up and a dazzling illumination touched the
netted steel. At awkward spots Kit seized Austin’s arm. Bob was not
steady, the planks were narrow, and if one went across the edge one
would plunge to the river.
For a few moments the wind dropped, and the reflections
flickered across the shore end of the bridge. The steep bank was
faced by stone, and broken rock was stacked along the line. To
grade the approach to the bridge was the railroad company’s
business, but Kit supposed he could use their material.
“I think we’ll dump some rock about the shaky pile,” he said.
Austin’s brain was dull and to keep his feet was hard, but he
nodded.
“Very well. Send a gang along.”
“You are chief. The order ought to come from you,” Kit remarked.
A few minutes afterwards they met the foreman.
“We’re surely up against it,” said the man. “The outside column’s
sagging. If we could bolt up the truss, we might hold her, but the
straps won’t come across.”
“Turn out a fresh gang,” Austin ordered. “Load up rock and run
the trolleys across the bridge. Then rig a derrick and dump the
stuff.”
“A great notion!” said the foreman. “I’ll get busy.”
He vanished in the snow, and Austin leaned against the lattice.
 “I’m rattled, Kit, but I think you’ve got it. If the pile sinks, the lot
will go.... But what about dumping some bags of cement?”
“Wheeler’s construction boss, and we don’t know what he’d do,”
Kit replied. “To move the cement might bother him, but, if he
wanted, he could dredge up the broken rock. You, however, ought to
be in bed.”
“If I’d gone to bed, I’d acknowledge I ought not to hold my post.
I’ve got to stay with it.”
“Oh, well, your cap will blow off,” said Kit, and pulling down the
oilskin cap, he firmly tied the strings.
At the end of the bridge they stopped. The beam from the lamps
did not travel far, and in front was a dark gap. Twenty feet below,
the river brawled among the piers and its turmoil faintly pierced the
scream of the gale. A ladder went down into the tossing snow, and
one heard chains rattle and hoarse shouts. Then a slanted flame
leaped upright, and platforms and workmen’s figures got distinct. Kit
thought Austin ought not to go down, but Bob was obstinate and he
could not force him back.
He went in front, and where it was possible, steadied the other.
By and by he pulled Austin on to a platform, and bracing himself
against the gale, he looked about. The snow blew obliquely across
the bridge and the light was puzzling. Sometimes shining columns
and skeleton trusses cut the hazy background; sometimes the
flames sank and the netted steel melted in the gloom.
Men, balanced awkwardly on narrow bars, steadied a big steel
frame suspended by wire tackles. Another group hauled on a chain
and when they reached for a fresh hold the platform rocked. Two or
three more, on the beams overhead, turned a screw. The suspended
frame did not altogether span the gap and reach the fastenings on
the pillar. To pull the mass into line looked impossible, but one must
try, and the screws and multiplying tackle were powerful. Kit
touched Austin.
“I think she’ll come across, and if we can get the bolts through
the bottom lugs, we ought to fix the top. Anyhow, I’ll go up. Keep
the boys to it.”
 He had got Austin’s coat and, in the snow and turmoil, he thought
the men would not know him from Bob; they were much the same
height and build. Jumping for a tie-rod, he went up into the snow,
and when a beam from a lamp searched the spot he reached, the
torn slicker was conspicuous. Underneath were two small platforms
and the angry flood. His hands were numb and his skin smarted, but
after all the snow was wet. Flesh and blood could not labor in the
frost that dries the snow to dust.
He shouted. A straining wire rope groaned and the bottom of the
truss jarred the column. Kit took a bolt from a workman and went
down an inclined rod. A man on the opposite column waved his
arms, as if to indicate that the end was fast, and Kit guided the
bored steel strap to the proper spot. The end moved very slowly, but
it did move; the holes were almost opposite, and although the heavy
frame oscillated in the wind, he thought in a few moments he would
push in the bolt. Then a noise disturbed him and he saw Austin was
coming up.
Kit frowned. Bob ought not to risk the climb; but he must
concentrate on guiding the strap to the socket and he could hardly
use his stiff hands. He pushed the bolt through the holes and
straightened his back. The job was not finished, but the worst strain
was over. They had put the truss where it ought to go and the bolts
would hold until all was fast.
Then Kit remembered Austin. Bob had stopped, as if he saw he
was not needed. He turned and pushed his hand along a bar, and Kit
thought he meant to go down. A foreman shouted, and the wire
tackles running from the girder overhead went slack. A big iron
pulley dropped a foot or two and the hook it carried disengaged. Kit
doubted if the hook struck Austin, but it looked as if he heard the
noise and tried to avoid the shock. His boots rattled on the iron and
his shoulders went back. Kit saw he was letting go, and he swung
himself down to a fresh support and put his arm round the other.
“Stick tight!” he said. “I’ll help you to the ladder.”
They reached the ladder, but the effort cost Kit much, and when
he saw Austin take hold he stopped to get his breath.
 “If you can reach the platform, we’ll send you up in the skip,” he
gasped.
“I think I can make it,” said Austin, and they went down.
At the platform Kit pushed Austin to a tool-box. Snow blew about,
the lamp’s flame tossed and all was indistinct. The current broke
noisily against the piers and the wind screamed in the bridge. When
a foreman advanced Kit bent his head.
“The boys have rigged the derrick. Shall we start in to dump the
rock?”
Kit nodded, and when the man vanished, touched Austin.
“Don’t talk, Bob. Let me handle things. We’ll soon have all fixed.”
“I don’t want to talk,” said Austin. “I want to lie down.”
Kit waited with some anxiety. Bob was obviously ill, but the men
must not know, and Kit hoped the skip would soon arrive. By and by
a big steel bucket swung across the platform and a load of broken
rock splashed in the river. Austin got into the skip awkwardly, for Kit
dared not help, but when he jumped on the edge and seized the
chain, he called the foreman.
“Keep going! I’ll be back as soon as possible.”
The bucket went up and stopped at the plankway along the
bridge. Kit saw the gang was occupied, and putting his arm round
Austin, steered him to an unloaded trolley. Austin leaned against him
and Kit imagined he did not know where they went. When they got
on board he shouted for two or three men.
“My office! Shove her along!”
The trolley rolled ahead and the tossing fires melted in the snow.
The trees along the track bent in the wind and the noise was like the
roar of the sea. One could not see four yards in front; but at length
a faint glimmer pierced the snow and the trolley stopped. Austin got
down, Kit signalled the others to go back, and when the trolley
vanished guided Austin to the door. When they got inside, Austin
dropped into a chair. His eyes were half shut, he shivered and his
face was gray.
“I expect the pulley hit me, although I didn’t feel the knock,” he
said. “However, I ought not to quit——”
 “Since all was straight before you went you needn’t bother,” Kit
replied in a cheerful voice. “But put your feet on the box, I’m going
to pull off your boots.”
Austin gave him a dull, puzzled look.
“You were on the tie-rod? I’ve a notion I came near to letting go;
but I don’t remember much——”
“Oh, well,” said Kit, “it doesn’t matter, and the boys want me. I’ll
help you to bed.”
He pulled off Austin’s clothes and put him in his bunk. Austin said
nothing and after a few minutes Kit thought him asleep. He dared
not stop, and throwing Austin’s torn slicker under some clothes, he
got his own coat and faced the gale.
Some time after daybreak he started for the office. He was
exhausted and the morning was very cold. The wind had dropped,
the sky was clear, and the snow on the planks was hard. Shining
icicles hung from the ironwork and Kit concluded winter had at
length arrived. At the bridge-head a man stopped him.
“Did the pulley hit you, Mr. Carson? I reckoned she was going to
knock you off the frame.”
“I got two or three knocks,” Kit replied with a laugh. “On the
whole, I imagine cooking’s a softer job than running a bridge gang.”
He stopped for a few minutes at the bunkhouse, and then went to
the office. Austin had got up and some color had come back to his
skin. Kit pulled off his long boots and lighted a cigarette. The stove
was red hot, and after the cold and strain he was willing to relax.
“How are you, Bob?” he asked.
Austin said he was shaky, but he expected soon to be better and
he must try to get about. Kit agreed. If it were but for an hour or
two, Bob ought to superintend.
“Jock will send us breakfast in a few minutes,” he said. “When you
have got some food you might take a walk along the girder. Put on
your big coat and skin-cap. The cold is fierce.”
“Your plan’s rather obvious, Kit. However, I expect I must play up;
people indulge you. I don’t know another man who could persuade a
camp cook to serve breakfast when it was not the proper time.”
 “Well, you see, I was Jock’s piper. Besides, you’re not forced to
advertise that you’re not very fit. When you were wanted, you were
on the spot.”
“I doubt if I helped much,” said Austin in a thoughtful voice.
“When the boys let go the tackle, you jumped across and helped me
down—did you not? Perhaps it’s strange, but I don’t remember all
we did.”
“It isn’t strange,” said Kit. “The wind was savage and the snow
was thick. We were highly strung and I suppose we worked
mechanically. All we knew was, we must get the truss across. Well,
before you went the truss was in place.”
“When did I go?”
“Now I’m beaten! When I stopped I felt as if I’d fought the gale
for a week. Anyhow, it was some time in the morning and the worst
strain was over. I expect you saw we didn’t need you and you went
slack.”
“You are a good pal,” Austin remarked in a meaning voice. “Well, I
wonder——”
Kit frowned. He thought he had cheated the workmen, but unless
he cheated Austin he had not gained much. Bob would not allow
himself to be rewarded for another’s efforts. Moreover, he was not a
fool and Kit was tired.
“Sometimes you’re horribly obstinate, but if you’re not satisfied,
you must talk to the boys. They saw you about and they’ll admit
they took your orders. If you study the job, I expect you’ll see the
orders were good.”
Austin’s look was thoughtful, but Kit imagined he was to some
extent convinced, and soon afterwards the cook carried in their
breakfast.
After a few days Wheeler arrived and approved all the others had
done. When he had examined their work he called Kit to his office.
“You’ll be glad to hear we have arranged for Austin to take
control?”
“I think you have got the proper man, but when we talked about
it you did not agree.”
 Wheeler shrugged. “My word goes, but I’m not head boss. At all
events, you didn’t put across your bluff and have got to quit! Now
the frost’s begun, we’ll break the gangs and you can pull out for the
workshops.”
“So long as you have given me another post I mustn’t grumble,”
Kit remarked with a smile. “In fact, on the whole, I think my luck is
pretty good. To bluff a big construction company is rash.”
Wheeler gave him a queer look. “Well, I don’t know if you’d
hesitate about bluffing a construction gang! All the same, if you stay
with it at the shops, I’ll send for you when we start up in spring.
Now you had better pack your trunk. A train goes down the line in
the afternoon.”
Kit packed his trunk, and at dusk a locomotive and a row of flat
cars rolled across the old wooden bridge. The cook and a foreman
put Kit’s trunk in the calaboose, and for a few minutes he talked to
Austin and looked about.
The snowy woods shone in the sunset and the broad white plain
melted in ethereal blue; by contrast, the open channel of the river
was black like ink. Two or three faint plumes of smoke went straight
up, and along the bridge a few hammers beat. That was all and Kit
felt the camp was strangely quiet. Winter had arrived. Then
somebody signalled and Austin gave Kit his hand.
“Good luck!” he said. “Stay with it, partner. I think Wheeler bets
on you; he’ll see you get your chance.”
Kit jumped for the step, the bell clanged, and the train steamed
away into the gloom. When a brakesman pulled the door across, Kit
sat down and lighted his pipe. Rob had kept his post and that was
something, but he had given up his and for four or five months his
work would be monotonous and unimportant. He had seen himself
triumphant at the bridge; to copy plans at the drawing office was
another thing. Although he felt he had taken the proper line, he
wondered whether Evelyn would approve. Mrs. Haigh certainly
would not.
 CHAPTER XXI
JASPER EXPERIMENTS
Dinner was over at Netherhall, and Mrs. Carson’s party had gone
to the drawing-room. Mrs. Carson was conservative and she refused
to banish the early-Victorian walnut furniture. She claimed Gibbons
carved the noble fireplace, but the plate glass carried across above
the big grate did not altogether stop the smoke. Tall brass pillars
supported oil lamps; the piano and card-table were lighted by
candles in old silver sticks.
Although the furniture was ugly, the spacious room had dignity
and Mrs. Carson harmonized. Her mouth was thin and her face was
pinched. Sometimes her look was mean, she was frankly
parsimonious, and her clothes were not good, but her stamp was
the stamp of the proud old school.
For Netherhall, the party was large. Jasper had arrived from
Liverpool; he had rooms at Sheffield and London, but his habit was
to stop for a day or two with his brother. Agatha had arrived from
the hospital, and Ledward from town. When he was bored he visited
at Netherhall. Ledward was Mrs. Carson’s favorite and he cleverly
cultivated her. Mrs. Carson knew her nephew, but she was flattered.
Mrs. Haigh and Evelyn were her friends, and as a rule they came
across when she had other guests.
“You were at Liverpool?” she said to Jasper.
“I was sending off a man to Montreal. I myself ought to have
gone, but when the St. Lawrence freezes one must go by Halifax or
New York, and now I get old I begin to hate the shaking cars.”
Smoke whirled about the glass shield, rain beat the windows, and
the trees by the river roared like the sea.
 “I should hate the steamer,” Mrs. Carson remarked. “So long as
another was willing to go for me, I would be content.”
“The trouble is, I’m forced to be content. Ambitious young men,
keen to undertake my job, are numerous, but I doubt their talent,
and since I have not an engineer relation I must hold out as long as
possible.”
“We thought Kit might have helped,” Alan Carson remarked.
“Kit had other plans,” said Jasper dryly and turned to Agatha.
“You are an independent lot. When I could have got you an easier
post you stuck to your hospital.”
“At the hospital I have some authority, and one likes to
command,” said Agatha, smiling. “Independence is attractive.”
“Sometimes it’s expensive. I suppose you get news from your
brother?”
“Kit has not written to me for some time. All I know is he was
engaged at a Manitoba bridge.”
“We got two letters,” said Mrs. Haigh. “The first was optimistic; Kit
was to stay at the bridge for the winter and superintend. The other
was rather apologetic. He had given up his post and was going to
the company’s workshops.”
“He stated he had resigned his post?”
“The engineer at the bridge wanted him to stay. Kit’s grounds for
refusing were not very clear and his note was short.”
“Kit’s habit is to resign his posts. To know he was not forced to do
so is some comfort,” Mrs. Carson remarked.
“He was certainly not forced,” said Evelyn, with an angry blush.
“We don’t know why he went, but his object was good.”
Jasper gave her a queer, fixed look and then studied Mrs. Haigh.
She obviously agreed with Evelyn, but he thought Kit’s not remaining
at the bridge had annoyed her. In fact, since he imagined she did
not like to own Kit had omitted to seize his opportunity, her
frankness was perhaps strange. Mrs. Haigh, however, knew where
frankness paid.
“Do you know who are his employers?” he inquired.
 Mrs. Haigh stated the company’s title, and Alan looked up with
surprise. Jasper smiled ironically.
“I was willing to go without my nephew’s help, but I didn’t reckon
on his joining my antagonists,” he said and turned to Mrs. Carson.
“The company is the competitor of a Canadian house in which I’m
interested. Just now, a railroad weighs its tenders for some
important contracts against ours.”
“You don’t imply that Kit knew?” Evelyn rejoined.
“It’s possible he did not. For all that, I imagine the bridge
company knew whom they employed. When one engages an
engineer one makes inquiries, and a number of people know I
support the opposition.”
“I don’t see the others’ object,” said Alan in a disturbed voice.
“It looks like a joke, but Canadian engineers are not remarkably
humorous. Then, although I expect they found out about Kit’s
leaving the shipyard, they risked engaging him.”
“Kit was not bound to enlighten the people,” Mrs. Haigh remarked.
“Something depends upon one’s point of view,” Jasper replied,
and turned to Agatha. “What do you think about it?”
“When Kit was engaged his employers knew all that weighed
against him.”
“If they found out he was your nephew, they perhaps hoped they
might use him,” said Mrs. Carson.
Agatha looked up, but she saw Evelyn’s eyes sparkle and she
waited.
“Then they were very foolish; Kit would not take a bribe to be
shabby,” Evelyn declared, and Jasper gave her an indulgent smile.
“On the whole, I agree. There’s another thing; Canadians are not
fools, and if they studied Kit for a very short time, they’d be satisfied
he had not much talent for intrigue. Well, I think we’ll let it go.”
Mrs. Carson beckoned her husband, and Mrs. Haigh and Jasper
went with them to the card-table, but Agatha stopped in the corner
by the fireplace. She had studied the others and now she pondered.
 Mrs. Carson was frankly spiteful; she, no doubt, felt Kit had
humiliated his relations and ought to be punished. Alan was Kit’s
friend, but he dared not oppose his wife, and Agatha thought
Jasper’s remark about the Carsons’ independence carried a sneer.
Since Evelyn was not plucky, her championing Kit was curious;
Agatha wondered whether she had reckoned on her mother’s
support. Yet, as a rule, Mrs. Haigh played up to Mrs. Carson.
Moreover, she was something of an adventuress and Kit was poor
and, so to speak, in disgrace. Agatha admitted she did not see much
light.
Ledward had said nothing, but the ground was awkward, and his
habit was to be tactful. Although Agatha thought Evelyn attracted
him, Ledward was not the man to marry a poor wife. Agatha did not
see him carried away by romantic passion. Harry was clever and had
made his mark at Oxford, but, although he was not rich, he was
apparently satisfied to do nothing. Now he talked to Evelyn and
Evelyn smiled.
Jasper excited Agatha’s curiosity. She imagined he had studied the
group with a sort of ironical humor, and when he talked about Kit
she got a hint of antagonism. She thought it strange, because the
old fellow was rather inscrutable; and if he were antagonistic, she
fancied he would not be willing for the others to know. Well, there
was not much use in speculating, and she joined Evelyn.
When Agatha sat down Ledward went off. For a young man he
was rather fat; but he was a handsome fellow and marked by a
cultivated urbanity. Agatha let him go and turned to Evelyn. “You’re
loyal,” she said. “I thought you plucky!”
“Kit’s my lover. I promised to marry him when he makes good.”
“Then the stipulation was not, if he made good?”
“Sometimes you’re like Jasper Carson; one doubts if you are kind.”
“I’m Kit’s sister; perhaps I’m shabbily jealous,” Agatha replied.
“Oh, well, I’m going to be frank. Mrs. Carson hates Kit and
mother’s afraid of her; she punishes people who do not agree. I
really think I was noble, because when we got Kit’s last letter I was
annoyed. I felt he had thrown away another chance.”
 Agatha’s look got sympathetic. “Since to go cost him something, I
expect he went because he was convinced he ought to go.”
“It’s possible,” Evelyn agreed in a moody voice. “Kit’s romantic
and sometimes I’d sooner he was selfish. We don’t yet altogether
know why he gave up his post at the shipyard; but, if he had
thought only for himself, he need not have done so. Now I wonder
whether he has not again allowed his rash generosity to carry him
away.”
Agatha had speculated about something like that. Evelyn knew
her lover, but it looked as if she did not approve. In the
circumstances, for her to do so would perhaps be hard.
“Sometimes I feel Kit does not think of me,” Evelyn resumed, and
although she blushed her look was calculating. “We are poor and I
hate poverty. The proper plan was to make a good marriage. Yet I
stuck to Kit. To talk about it jars, but I’m human and I’m bothered.
For one thing, mother indulged me although she knew I was foolish,
and I’d hate to feel Kit had disappointed her.”
“Kit does not disappoint his friends,” Agatha remarked in a quiet
voice.
“But he ought to be ambitious. One must not be generous where
another is forced to pay. Kit does not weigh things; I expect he’s
plunged into a fresh entanglement, but he ought not to be rash. You
see, I must stop at dreary Netherdale. Then people know Kit’s
poverty, and when they pretend to sympathize I feel they sneer. Mrs.
Carson’s remarks hurt worse because she was persuaded they were
justified. There’s the trouble—it looks as if the people who doubted
Kit were justified——”
Agatha was disturbed. Evelyn’s loyalty cost her something and
might yet cost her much. So far she had paid, but Agatha wondered
whether she could keep it up. Evelyn was selfish and rather shabbily
ambitious. All the same, one must acknowledge her part was hard.
“You must not exaggerate, my dear,” she said. “Kit has talent, and
he’ll soon make progress.” After a time the card party broke up. Alan
Carson and Ledward went to the billiard-room and Agatha went for a
book. When she came back she saw Jasper in the hall and she
stopped.
“It looked as if Miss Haigh gave you her confidence,” he said.
“Evelyn was angry. Aunt was not kind.”
“So far as she sees, my sister-in-law is sincere. Do you imply that
her unkindness was all that bothered Miss Haigh?”
“You implied that our talk was confidential,” Agatha rejoined. “In a
way, I’m sorry for Evelyn. You don’t like her?”
“You’re blade-straight and keen as steel,” said Jasper with a dry
smile. “Well, I own I don’t like Mrs. Haigh and one inherits much. I’d
sooner trust a fool than a calculating woman.”
“It doesn’t look as if Evelyn calculated. She means to stick to Kit.”
“I wonder whether you thought it remarkable,” Jasper observed.
Agatha said nothing and he resumed: “Had you chosen a wife for
your brother, would you have chosen Miss Haigh?”
“Perhaps I would not. Our business, however, is not to choose
Kit’s wife, and we ought not to meddle.”
“Then Miss Haigh has your support?”
“She has my sympathy,” Agatha replied, and Jasper gave her a
queer smile and went off.
For a few minutes Agatha stopped by the fire in the hall. On the
whole she liked Jasper Carson, but he puzzled, and sometimes
daunted her. Now she saw he had tried to find out if she believed
Evelyn really meant to stick to her lover, and she thought his interest
ominous. When she went back to the drawing-room, Jasper was not
about and Mrs. Carson said he and Ledward had gone to smoke.
In the smoking-room Jasper gave Ledward a cigar.
“You ought to have an occupation, Harry. Have you thought about
it?”
“I rather thought I might be a barrister, but I don’t know.... One
must keep twelve terms at an inn; something like three years before
one can start.”
Jasper nodded. “Then, unless you’re lucky and remarkably
talented, the reward’s not large. What about business?”
 “If I sold all I have got, the sum I could invest would not carry me
far, and since I’m not much attracted, I’d hesitate to face the risk.
Then, if I took a post, I imagine the pay would be small, and so long
as I’m not extravagant I can meet my bills.”
“You might resolve to marry. When one is married one’s bills go
up.”
“It’s possible,” Ledward agreed in a careless voice. “So far, I have
not thought much about marriage.”
“Suppose I offered you a good post?”
“That’s another thing. I’d weigh your offer.”
“Very well! I’m getting old and begin to feel I need help. Although
I can buy help, I want a man I know, whose interests would be
mine. At one time I thought I might use Kit, and by and by he might
carry on the forge, but I saw the plan would not work.”
Ledward thought his luck was good. Jasper was not looking for a
clerk; he implied he wanted a man who would take control when he
was forced to let things go. In fact, he really wanted something like
an heir. Kit was his relation, but he had not taken the proper line and
now Jasper hinted that he had done with him. All the same, one
must use some caution.
“The difficulty is, I am not an engineer.”
“At Oxford you were a mathematician, and I want help to handle
rather complicated finance. If you are willing, I’ll try you out.”
“I’m keen, sir,” Ledward replied.
“Then, I must arrange for you to meet me at my town office. If I
am satisfied, you will not grumble about the pay.”
“Thank you,” said Ledward. “In the meantime, would you sooner I
did not talk about it?”
“I think we will not yet announce our agreement,” Jasper replied.
“For one thing, I don’t know if you have the qualities I want; and
then you may not like your job.”
 CHAPTER XXII
MRS. HAIGH REVIEWS HER PLANS
Ledward went to the London office and for a time was at the
bookkeeper’s desk. At the beginning the bookkeeper, who did not
need much help, speculated about his employer’s object, but he
soon admitted that Ledward had qualities he had not thought to find
in a fashionable loafer. Jasper Carson, however, did not want a clerk.
All he really wanted only he himself knew. In the meantime, he
meant Harry to be useful.
Ledward was something of a Hedonist. He took the pleasures he
could get without much risk and effort, and when he did make an
effort he wanted a reward. He was not remarkably scrupulous, but
he observed conventional rules and went soberly because he knew
one must pay for indulgence.
For all that, he was interested and Jasper’s business transactions
fired his imagination. Ledward frankly acknowledged the old fellow’s
cleverness. Jasper was not as rich as his relations thought; for the
most part, he used others’ money and all he earned was re-invested
in fresh ventures. His finance, however, was sound and honest, and
his shares were worth a considerable sum.
Ledward began to think himself fortunate. Engineering was not
his line, but he had a talent for calculation. He knew his help was
worth something and Jasper had indicated that his reward might be
generous. He wanted money; for one thing he wanted to marry
Evelyn.
Ledward was not romantic, and he knew Evelyn. Then he knew
Mrs. Haigh, and Evelyn was her daughter. In a sense, she was not
fastidious, and he knew her shallow; shallow was perhaps the proper
word, because her cleverness, so to speak, was surface cleverness
and selfish. For all that, she attracted him and he was moved by her
beauty. When he could support a wife he meant to marry Evelyn,
and her having engaged to marry Kit was not an obstacle. After a
time, Jasper one morning came to the office.
“My relations have not heard you have joined me, and since you
are going to stay, perhaps they ought to know,” he said. “On
Wednesday my sister-in-law and her party will arrive. She and Alan
go to Hampshire, and Mrs. Haigh visits with some friends in Surrey.
They will be in town for a day or two and will dine with me on
Wednesday evening. I thought we might announce our agreement.
You perhaps are not engaged?”
Ledward said he had not an engagement, and his satisfaction was
keen, for he had not known if Jasper wanted him to stay. Sometimes
the old fellow indulged his freakish humor, and Ledward knew he
studied him. Although he had said nothing about Evelyn, Ledward
supposed she would arrive with Mrs. Haigh. Perhaps Jasper had
wanted to see if he would inquire.
“Then we’ll fix it,” said Jasper, and presently went off.
The dinner was at a famous hotel, and Ledward had thought to
get there early and meet Evelyn before his employer was about, but
he was occupied by some intricate accounts. Jasper had given him
the awkward job, which could not be left for the morning, and when
Ledward reached the hotel the party waited in the big glass-roofed
court.
Crossing the floor, he gave the others an interested glance. Mrs.
Carson’s smile was friendly and Mrs. Haigh’s polite. Ledward thought
she speculated about his being Jasper’s guest. Evelyn’s look was
puzzled, and he doubted if Jasper had told his guests for whom they
waited.
“I’m sorry, sir, but I felt I must finish the piece of work, and when
I got away the traffic stopped my cab.”
Jasper nodded, and Alan Carson laughed.
“For you to be strenuously occupied is something fresh!”
“Harry’s business was rather important and I’m accountable for
his being late. The work that delayed him was mine,” Jasper
remarked. “However, I expect our table’s ready. Shall we go in?”
 The head waiter led them across the polished floor, and when
they sat down Jasper engaged the others in careless talk. Ledward
said nothing; he felt when Jasper wanted him to speak he would get
his cue. The old fellow, so to speak, was a good stage manager. In
the meantime, Harry studied the group.
Jasper was urbanely inscrutable, but one got a sense of
command. Alan tried to control his curiosity. Mrs. Carson’s clothes
were out-of-date, but she and Jasper wore a stamp the others did
not. Yet Mrs. Haigh and Evelyn were fashionable and harmonized
with the expensively dressed crowd. By and by Mrs. Carson turned
to Ledward.
“You are quiet, Harry, and we have not heard from you since you
went back to town. Have you begun your studies for the Bar?”
“I have not,” said Ledward smiling, and noting Jasper’s glance,
resumed: “I rather think I have got a better job!”
“Harry tries to flatter me,” Jasper remarked. “Not long since I
admitted I got old, and now he has agreed to help. I’m glad to
acknowledge his help is worth something.”
“Then, he’s at your office?” said Alan with keen surprise.
“That is so,” Jasper agreed, and called a waiter. “By and by I
expect he will be my head man, and perhaps for you to wish the
combine good luck would not be theatrical.”
Ledward thought Jasper theatrical. At all events he had given the
announcement a dramatic touch, and Ledward saw he surveyed his
guests with dry amusement.
Mrs. Carson’s approval was obvious, but it looked as if Alan were
annoyed. Evelyn’s look got hard, and Mrs. Haigh’s face was slightly
red. She had got a nasty knock, but she lifted her glass.
“We knew your helper’s cleverness, but it seems he has abilities
we did not guess,” she said in a level voice. “I hope your experiment
will go as you expect!”
“Thank you,” said Jasper. “One likes one’s friends’ approval. So far
as the experiment has gone I have good grounds to be satisfied.”
“You have got the proper man,” said Mrs. Carson. “You would not
have been satisfied with Kit.”
 “It’s possible,” Jasper agreed, and Ledward fancied Mrs. Carson
had unconsciously given him his cue. “I had meant the post for Kit.
For one thing, he’s my relation and an engineer. I thought he might
by and by carry on the forge, but I acknowledge I’m sometimes
cheated.”
He began to talk about something else and Mrs. Haigh supported
him, but the effort cost her much, and when the others joined she
stopped and mused. The economy she was forced to practice jarred,
and Netherdale was a dreary spot; she liked to dine at expensive
hotels and mix with fashionable people. The music, the cultivated
voices, and the women’s jewels excited her, and she had thought,
for a day or two, to follow her bent and forget that she was poor.
Mrs. Haigh knew she had social talents, and had she the others’
chance, she could make her mark. Poverty was an awkward
obstacle, and in order to mend her broken fortunes she had planned
to use Evelyn’s beauty. Evelyn was young, and it looked as if she
were romantic, but Mrs. Haigh knew she had inherited much from
her. As a rule, she saw where her advantage was, and in puzzling
circumstances her judgment was unconsciously, and perhaps
instinctively, sound. For example, she had refused to let Kit go.
Now, however, Mrs. Haigh felt Kit had let her down. She doubted
if Jasper were often cheated, but he had cheated her and calm was
hard. All the same, Mrs. Haigh’s pluck was good, and she tried to be
philosophical. Since the plan from which she had hoped for much
would not work, she must make another. She was not yet beaten,
and she thought Jasper did not know his antagonist.
After dinner, Jasper and Alan went off for a smoke. When Alan
lighted a cigarette he frowned.
“You are a business man and perhaps I ought not to meddle; but
do you think you can trust Harry?”
“Ledward is your relation.”
“He’s my wife’s relation,” Alan rejoined. “I don’t imply that he’d
rob you; but, if he’s going to be useful, you must give him your
confidence....”
“To some extent, that is so. Well?”
 Alan hesitated. His habit was to hesitate and he said awkwardly:
“Where you have keen competitors, your servants must be stanch. If
I carried on a business like yours and engaged Harry, I’d use some
reserve.”
“Oh, well,” said Jasper, “I reckon I can trust the fellow as far as
I’m forced....” He stopped for a moment and lighted a cigarette, for
he wanted to strike a note he had struck before. Alan was dull and
would not think his doing so significant.
“Frankness is rather embarrassing,” he resumed. “You see. Kit is
my relation, but I don’t feel I could reckon on his trustworthiness.”
“Kit’s straight; we don’t know all,” said Alan stubbornly. “In fact,
I’m convinced he’s your proper helper and I thought you agreed.”
“You stated something like that before,” Jasper remarked, and
added with a smile: “Well, it looks as if you, and perhaps others, bet
on the wrong man.”
Alan frowned, and after a few minutes got up.
“My wife and Mrs. Haigh are going to the West End, and I believe
Evelyn means to look up a friend. Perhaps I’d better inquire when
they want to start.”
Soon after Jasper went to the smoking-room Ledward lighted a
cigarette in the court. A band played quiet music and people walked
about. Nobody came to Ledward’s corner and he was content to
muse. He saw Jasper had meant the others to know he, so to speak,
was the favorite, but the old fellow’s object was another thing.
Anyhow, Jasper had undertaken to push him ahead, and since his
word went, Ledward thought he was entitled to enjoy his
satisfaction.
By and by he saw Evelyn on the other side of the court. He
thought she looked for somebody, but he did not see the others and
he crossed the floor. Evelyn went to a bench under a palm and
Ledward sat down.
“I don’t think you congratulated me about my good luck,” he said.
Evelyn’s eyes sparkled. “For you to expect my congratulations was
rather remarkable! Although you were Kit’s friend, you took his
post.”
 “I sympathize with your annoyance, but you’re not just. You see, I
took nothing he wanted from Kit. All I got he, in a sense, had
already refused. Although he’s Jasper’s nephew, he made it plain
that he would sooner his uncle left him alone.”
“Perhaps that is so, Kit is independent,” Evelyn admitted.
“Very well! I’m not independent; for one thing I’m not rich and for
me to refuse a useful occupation and first-class pay was ridiculous.
Since Kit had gone off to Canada and joined his uncle’s competitors,
I seized the opportunity he rather scornfully neglected.”
Evelyn’s color got high and her look was hard, but it was not
because Ledward offended her. After all, Harry was logical, and Kit
was not. He was not rich and he ought to have cultivated his
relation, but he indulged his romantic pride. Then, when he began to
make progress, he again gave up his post. In fact, Kit did not think
for her. Ledward saw her pre-occupation and knew he had struck the
proper note.
“We mustn’t dispute about it and I like your championing Kit,” he
resumed.
“Ah,” said Evelyn moodily, “perhaps Kit needs a champion!”
Ledward let it go, and for a few minutes they talked about
something else. Then Mrs. Haigh and Mrs. Carson arrived.
“We must start, and I rather think you ought to go with us,” Mrs.
Haigh said to Evelyn.
“Clara expects me, and I can get a cab.”
Ledward thought Mrs. Haigh hesitated, and he saw his
opportunity.
“If you like and Evelyn agrees, I will take her to Miss Chisholm’s.”
Mrs. Haigh thanked him and soon afterwards the party went off.
Ledward imagined Evelyn had gone for her coat and he waited, but
when she rejoined him she wore her evening clothes.
“Mother is rather old-fashioned,” she remarked. “Since you offered
to see me out, I expect you have not an engagement?”
“I have not,” said Ledward. “When you are ready I’ll send for a
cab.”
 Evelyn smiled. “If you don’t mind, we might stay for a time. I like
the music and I like to see the people.”
“Then, we’ll stay as long as you like. But what about Miss
Chisholm? Will she not wait for you?”
“I’m not very keen about seeing Clara. All I wanted was not to be
forced to go with mother. Perhaps you know the Lomaxes?”
Ledward said he did not, and Evelyn resumed: “Oh well, they’re
sober, old-fashioned bores and I imagine Mrs. Carson will stay until
midnight and talk about people they knew when she was young.
Mother will play up; I rather think she’ll like it. But I’d soon be
horribly tired.”
“Then, let’s wait,” said Ledward. “The band is pretty good, and
you can study the fashions.”
Evelyn saw he wanted to wait, but she had reckoned on his
agreeing and her annoyance was gone. After all, his apology was
logical, and she was willing to use him.
“Perhaps I’m shabby, but I don’t mind very much,” she said.
“Since I’m in town only for a day or two, I want to use every minute.
I admit I like hotels and shops and fashionable crowds. All is
interesting, and after Netherdale, one needs some stimulation. Then,
you see, although Clara’s an art student, she’s not the modern sort.
She paints seriously, and I don’t know much about pictures. Now I
am in town I want to be excited and to feel I am alive.”
On the whole, Ledward thought she did not exaggerate. For a
young, ambitious girl Netherdale was dull, and he knew Mrs. Haigh’s
frugality. He sympathized with Evelyn and thought he could indulge
her.
“I’ve got something like an inspiration,” he remarked. “Suppose
you cut out your engagement with Miss Chisholm and we go to a
theatre? I know a good musical comedy and perhaps the house is
not full.”
“Oh,” said Evelyn, “it would be splendid! The drawback is, I’m
afraid mother would not be pleased.”
Ledward had remarked Mrs. Haigh’s willingness for him to convey
Evelyn to her friend’s studio. Moreover he thought a hint of intrigue
attracted the girl.
“We might look up Miss Chisholm for a few minutes and perhaps
take her with us,” he suggested carelessly. “Then, if our relations are
some time at the Lomaxes and we don’t stay for the last act——”
“I ought to refuse,” said Evelyn, and then gave Ledward a smile.
“Sometimes one does things one ought not. Let’s go!”
She went for her cloak. Ledward went to the telephone and
ordered a cab.
 CHAPTER XXIII
BLAKE’S CONFESSION
Evelyn went to the musical comedy and the excursion carried a
thrill. She was young, and to steal off with Ledward was something
of an adventure. Ledward knew Evelyn better than she imagined and
he humored her cleverly. Although he declared her going was
justified, he contrived to give the excursion a touch of intimate
secrecy. Evelyn had inherited some skill for intrigue, and she rather
liked to feel she and Harry were conspirators. In fact, she admitted
that for all to know she went with him would rob the evening of its
charm.
Three or four days afterwards Evelyn and a young relation started
for the post-office at a Surrey village. A long row of red-roofed
houses began by the railway and stopped at the wide heath; the
tarred road and high telegraph posts went on to London. Mrs. Haigh
had not gone back to town, and Evelyn began to feel that she was
bored. Her hosts were not fashionable, and the people she met did
not interest her. Then Hannah Grant was recently from school, and a
raw girl’s society had not much charm.
By and by a car crossed the heath and stopped by the post-office.
The driver called a telegraph boy and then went slowly up the street
as if he looked for a house. After a few moments Evelyn’s dulness
vanished; the man was Harry Ledward and she knew he looked for
Mrs. Grant’s. She waved and he stopped by the path.
“The weather’s good and when I got to the office Jasper stated I
might take a holiday,” he said. “I thought I’d look you up and risk
your being occupied. What does one do here on a fine afternoon?”
“We play golf,” Evelyn replied. “Sometimes we go for a walk.”
Ledward smiled and Hannah Grant gave him an approving look.
 “Sometimes one gets deadly bored,” she remarked. “Well, we can
give you tea and polite conversation, but perhaps you’d like a round
of golf? My handicap’s thirty and Evelyn foozles.”
“I’ve another plan,” said Ledward. “I wonder whether you and
Evelyn would like to run to town? But perhaps you go often and it
does not attract you much?”
“I go when return tickets are cheap,” Hannah replied. “If you want
to take Evelyn, you must take me. Mother and Mrs. Haigh are very
proper, but I don’t mind admitting I am not. Besides I’d love to go!”
“Then, jump up. Where’s your house?”
“At the end of the row; the pond is in front. Father declares it
gives the spot a rural touch and he likes the white ducks. The
drawback is the ducks are not its only occupants.... But get in,
Evelyn. Your part’s to persuade mother.”
“To begin with, we must persuade Evelyn,” said Ledward and
started the car.
Hannah smiled, but she said nothing, and when they stopped at a
new rough-cast house Ledward was not forced to use much
persuasion.
“I wonder whether you would like to see a play,” he said to Mrs.
Haigh. “There’s a rather good matinee, and I would drive you down
in the evening. The car carries four passengers.”
Mrs. Haigh and Mrs. Grant refused politely, but they agreed for
Evelyn and Hannah to go. The girls went off to get other clothes,
and Hannah stopped for a moment at Evelyn’s room.
“I like the lean, dark type, and Mr. Ledward’s rather fat; otherwise
I think him top-hole,” she said. “You feel he knows something; and
for the most part very young men are fools. Your mother’s a sport,
but since you have a lover in Canada, perhaps her letting you go
was strange.”
“Harry’s an old friend and almost like a relation,” Evelyn replied
and sent Hannah off, but when she shut the door she pondered.
Kit was in Canada. There was the trouble, because Evelyn felt he
need not have gone. She knew he had not cheated the shipyard
company. Kit did not cheat, but he was ridiculously proud and he
ought not to be generous where his generosity cost her much. Harry,
of course, was another sort, and Evelyn knew him selfish, but she
approved his cleverness, and to some extent he attracted her.
Anyhow, she liked excitement, and in a few days she would be back
at Netherdale. She got up and thoughtfully studied her clothes and
hats.
A week or two afterward, Jasper, going to a Cumberland
ironworks, stopped for the week-end at Netherhall. The evening he
arrived was cold and a savage wind beat the thick walls. After dinner
the party went to the drawing-room fire, and by and by a servant
carried in a card.
“The gentleman is in the hall.”
Alan Carson took the card and turned to Jasper. “Thomas Blake; a
Glasgow address! Looks like a business card. I don’t know the
fellow. Perhaps a shipbuilding customer has got on your track.”
“I’ll see what he wants,” said Jasper and went off with the
servant.
A fire burned in the big hall, but only one lamp was lighted and
the illumination did not carry far. A young man and woman waited
by the fireplace and got up when Jasper advanced. The girl’s look
was embarrassing and her face was pinched by cold. Her clothes
were ordinary outdoor clothes, and Jasper thought them cheap. The
young man’s look was resolute.
“Mr. Carson? Christopher Carson’s uncle?” he inquired.
Jasper was interested. He thought Blake wanted Alan, but he did
not yet know if the young fellow ought to see him.
“Christopher is my nephew. Perhaps you were his friend at the
shipyard?”
“He thought me his friend,” the other replied and indicated Mrs.
Blake. “I could not leave my wife in the car; when we were on the
moors the wind broke the hood. Besides, I rather wanted her
support.”
Jasper turned and pointed to a seat in the corner by the big grate.
“When the Hellan wind blows down the fells the cold is keen,” he
said, and rang for a servant. “Bring some wine and sandwiches, and