Disclosure Statement: S. Wang receives grant support from (#). R. Greene has nothing to disclose.

Neurologic Changes and Depression

Ryan D. Greene, Psy D a,b,*, Sophia Wang, MD a,b,c,d
a
Richard L. Roudebush VAMC, 1481 W. 10th Street, Indianapolis, IN 46202, USA
b
Department of Pyschiatry, Indiana University School of Medicine, Goodman Campbell Neuroscience
Center, 355 W. 16th Street, Indianapolis, IN 46202, USA
c
Center of Health Innovation and Implementation Science, Center for Translational Science and Innovation,
Indianapolis, IN, USA
d
Sandra Eskenazi Center for Brain Care Innovation, Eskenazi Hospital, Indianapolis, IN, USA
*
Corresponding author. [email protected]

This article covers current research on the relationship between depression and cognitive
impairment in older adults. First, it approaches the clinical assessment of late-life depression and
comorbid cognitive impairment. Cognitive risk factors for suicide are discussed. Research is then
provided on neuropsychological changes associated with depression, discussing subjective cognitive
impairment, mild cognitive impairment, and dementia profiles. Additionally, literature regarding
neuroimaging and biomarker findings in depressed older adults is presented. Finally, therapeutic
models for treatment of late-life depression are also discussed, including psychotherapy models,
holistic treatments, pharmacologic approaches, and brain-stimulation therapies.

Keywords: Major depressive disorder; Subjective cognitive impairment; Mild cognitive impairment;
Neurocognitive disorder; Neuropsychological testing; Neuroimaging; Psychotherapy; Antidepressants

KEY POINTS

• The assessment of late-life depression with comorbid cognitive impairment can be

challenging and requires a clear clinical history and a thorough medical and cognitive
assessment.
• There are several neuropsychological changes associated with late-life depression,
ranging from subjective cognitive complaints to mild cognitive impairment to dementia.
• Changes on neuroimaging and in several biomarkers (eg, apolipoprotein E e4 allele, beta-
amyloid, tau, neurotrophins, and so forth) have been associated with late-life depression.
• Multiple psychotherapeutic techniques have been found effective in the treatment of late-
life depression as well as holistic/nontraditional, pharmacologic, and brain-stimulation
approaches.

____________________________________________________

This is the author's manuscript of the article published in final edited form as:

Greene, R. D., & Wang, S. (2018). Neurologic Changes and Depression. The Psychiatric Clinics of North America, 41(1),
111–126. https://doi.org/10.1016/j.psc.2017.10.009
INTRODUCTION
Late-life depression affects 3.0% to 4.5% adults older than 65 years in the United States.1 For
many older adults with depression, affective symptoms are accompanied by cognitive difficulties,
which can range from subjective cognitive complaints to mild cognitive impairment (MCI) to
dementia. Epidemiologic findings suggest that late-life depression may be a risk factor for
dementia.2,3 Given the relatively high prevalence of depression in older adults and a growing
focus on modifiable risk factors for dementia, there is interest in better understanding the
complex relationship between depression and cognitive impairment. This review focuses on
individuals with unipolar depression without psychotic features with comorbid MCI or dementia.
To align with the terminology used in earlier literature and within the International Classification
of Diseases, Tenth Revision coding system, the authors use Diagnostic and Statistical Manual of
Mental Disorder (Fourth Edition, Text Revision) (DSM-IV TR) terminology (ie, MCI and
dementia) instead of the DSM-5 terminology for neurocognitive disorders.

Clinical Assessment of Late-Life Depression with Comorbid

Cognitive Impairment
Accurately diagnosing late-life depression can be challenging because of the wide variety of
symptom presentations.4 A few key points can guide the clinical evaluation of depression in older
adults with comorbid cognitive impairment. Specifically, these are (1) receiving a detailed history
from both the patients and their informants, (2) following patients longitudinally to monitor
symptom progression, and (3) interviewing with potential reversible causes of cognitive
impairment in mind (eg, substance use, metabolic problems, and so forth).
First, the most powerful diagnostic tool the clinician has is the clinical interview. Obtaining a
detailed history from both the patients and their informants will be a critical piece to determine
whether the patients have a primary mood and/or cognitive disorder. In certain cases, a detailed
neuropsychological evaluation may be necessary to delineate cognitive and mood symptoms.
Furthermore, neuropsychological testing is indicated when there are questions of multiple
comorbidities, questionable self- or informant-report, and to establish a baseline in mild dementia
and MCI cases. An accurate informant can be especially helpful, as many patients frequently
experience anosognosia (lack of awareness due to neurologic disease) about their cognitive
deficits or alexithymia (inability to describe one’s feelings). Patients may also experience
variations in their mood depending on the time of day (ie, diurnal variations); therefore, an
informant may be helpful in mapping the overall mood.
Second, clinicians can follow patients’ symptoms over time. This technique can be important
in the diagnosis of more complex cases when it is difficult to determine whether patients’ have
primary cognitive disorder, primary mood disorder, or both. Clinicians should determine whether
emotional and cognitive symptoms resolve, remain static, or progress over time. For example, if
the cognitive symptoms worsen despite stable or improved mood, this would suggest a primary
cognitive disorder. Alternatively, if the cognitive symptoms vary with emotional state, for
example, worsening with increased emotional distress, this would suggest a primary mood
disorder.
When patients present with both significant emotional and cognitive complaints,
clinicians should aggressively treat the depressive symptoms first and then reassess cognitive

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
symptoms after some resolution of the severe emotional distress. Literature has indicated that
mild to moderate depression is best treated with a combination of antidepressants and
psychotherapy.5 However, the patients’ cognitive capacity to engage in psychotherapy should
always be considered. Electroconvulsive therapy (ECT) and other brain-stimulation therapies are
generally reserved for severe or treatment-resistant cases.
Third, clinicians should always approach these complex cases considering potential reversible
causes of the patients’ mood and cognitive symptoms. One of the most overlooked, but easily
reversible, causes of cognitive impairment in older adults is medication side effects. Specifically,
research has shown that benzodiazepines, anticholinergics, opiates, non-narcotic pain medications
(ie, tramadol), hypnotics, and antipsychotics have been associated with cognitive symptoms.6
Substance use in older adults is frequently not explored thoroughly, particularly in regard to
alcohol and cannabis use.7 Finally, a thorough workup for late-life depression should also include
a comprehensive laboratory workup, assessing hematologic, metabolic, toxic, and infectious
contributions to cognitive and/or affective symptoms.

Risk Factors
The interactions between medical illnesses, depression, and cognitive impairments are
typically multidirectional, making it difficult to distinguish causes of current symptom
presentations. Men, Caucasians, and individuals with functional impairments were more likely to
present with affective symptoms of depression in MCI and early Alzheimer disease (AD).8
Cerebrovascular disease has been associated with both late-life depression and comorbid
executive dysfunction.9,10 Cognition and mood can also be impacted by other causes of organ
failure, including chronic renal failure11,12 and chronic obstructive pulmonary disease.13,14

SUICIDE AND COGNITION

The incidence of suicide among individuals aged 85 years and older in the United States is
17.8 deaths per 100,000 (compared with 15.0 deaths per 100,000 for those aged 65–84 years).15
Although aging alone may increase the suicide risk, further research is needed to clarify the
relationship between cognitive changes from aging and suicidality. The ventromedial prefrontal
cortices, which are important in reasoning and decision-making, may become impaired in later
adulthood16 and consequently increase the risk for suicidality. This impairment may be further
exacerbated by changes in social support, that is, depressed elders with suicide attempts tend to
have greater difficulties socially.17 Finally, many medical illnesses affecting older adults are often
accompanied by comorbid depression and cognitive impairments, likely predisposing the affected
older adult to suicidality.11,18,19

NEUROPSYCHOLOGICAL CHANGES IN DEPRESSION

Cognitive Aging
Cognitive aging is characterized by gradual changes in cognitive functioning associated with
normal aging.20 These changes can be variable between patients, are not secondary to a
neurodegenerative illness or typically accompanied by functional decline, and generally
accelerate in late life. Specific cognitive changes associated with aging include trouble with
memory recall and executive dysfunction and slowed processing speed. In contrast, visuospatial
skills, crystallized intelligence, and vocabulary knowledge remain stable.21 Generally, good
management of multiple health factors, including hypertension, diabetes, chronic obstructive
pulmonary disease, and so forth, and psychiatric disorders (including depression and anxiety) can
help mitigate some of the changes associated with normal aging.

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
Subjective Cognitive Impairment and Depression
Subjective cognitive impairment (SCI) refers to the perception of cognitive decline without
evidence of deficits on objective measures.22 Several cross-sectional studies on the relationship
between subjective cognitive complaints and objective impairments on cognitive testing have
shown conflicting findings, ranging from a positive correlation23–25 to no association.26 However,
in longitudinal studies, subjective cognitive impairments have been associated with higher rates
of incident cognitive impairment and dementia.22,27–29 Of note, multiple studies have shown that
subjective cognitive impairments are common in individuals with late-life depression, with ranges
falling from 50% to 70%.30,31 Interestingly, one prospective study showed that tau-mediated
degeneration, but not beta-amyloid (Aβ) deposition, was significantly higher in patients with MCI
compared with SCI.32 At this time, although there seems to be compelling evidence of a
relationship between SCI and depression, further research is needed to more fully understand the
causal relationship between the two.

Mild Cognitive Impairment and Depression

MCI is characterized by cognitive complaints (per the patients, informants, or observed by a
clinician), objective evidence of impairment, independence in functional abilities, and no
impairment in social or occupational functioning.33 The prevalence of depression in MCI varies
widely, with population-based estimates ranging from 3.0% to 83.0%, with a median prevalence
of 44.3%; alternatively, the prevalence of MCI in depression ranges from 30% to 50%.34–36 For
most individuals with late-life depression and comorbid cognitive impairment, the profile seems
to be a dys-executive pattern37 characterized by difficulties with working memory, set-shifting,
planning, and response inhibition. This syndrome suggests that cerebrovascular disease affects
white matter tracts in the fronto-striatal pathways, resulting in executive dysfunction and,
potentially, the affective symptoms of depression. Additionally, studies have found that late-life
depression is associated with a higher ischemic burden on structural MRI as well as impaired
executive and memory functions.38,39

Dementia and Depression

Longitudinal studies have provided information on the cognitive trajectories of those with
late-life depression. Potter and colleagues40 found that baseline impairments in encoding and
executive functioning in patients with depression seem to be risk factors for progression to
dementia. However, this progression seems to be highly variable. Steffens and colleagues41 found
that in a large group of nondemented depressed older adults, at the 2-year follow-up
approximately 25% had reverted back to normal cognitive functioning, 15% had progressed to
dementia, and the remainder continued to display cognitive impairments without functional
decline. Additional research has shown that although one would expect most individuals with
late-life depression and MCI to progress to a vascular dementia, these vascular risk factors may
simply serve to accelerate the AD process.34,42

BIOMARKERS
Apolipoprotein E, Beta-Amyloid, and Tau
Studies on various markers in neurodegenerative illnesses (ie, apolipoprotein E ε4 variant
[APOE ε4], Aβ, and tau) and late-life depression have been variable. Regarding APOE ε4, there
seems to be a significant relationship between depressive symptoms and APOE ε4 in regard to
progression from MCI to dementia. Specifically, a longitudinal study showed that APOE ε4

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
carriers with depression were 4.4 times more likely to progress to AD compared with non-APOE
ε4 carriers with depression.43 Meanwhile, a cross-sectional study found no relationship between
APOE ε4 status, depression, and cognition.44 Further research on the relation between Aβ and
APOE ε4 is mixed.45–48 Finally, although the relationship between tau protein and late-life
depression has not yet been clearly established, a longitudinal study indicated those with late-life
depression and elevated cerebrospinal fluid total tau levels progressed differently from MCI to
AD.49,50

Neurotrophins
Recent literature has indicated that individuals with late-life depression display a reduction of
neurotrophins, including nerve growth factor, glial-derived neurotrophic factor, and brain-derived
neurotrophic factor.51–53 However, Arnold and colleagues54 found that 2 neurotrophins
specifically associated with neurogenesis, long-term potentiation, and response to ischemic
injuries seemed to be increased in older adults with depressive symptoms: vascular endothelial
growth factor and hepatocyte growth factor (reflecting possible compensatory responses).

Hippocampal-Pituitary-Adrenal Axis, Insulin Pathway, and

Inflammation
There is limited evidence suggesting that the hippocampal-pituitary-adrenal (HPA) axis and
inflammation play a role in late-life depression with comorbid cognitive deficits. Although
chronic distress has been associated with disruption in the HPA axis, research on this relationship
with comorbid cognitive impairments has been variable.54,55 Interestingly, literature has provided
compelling evidence of hippocampal atrophy in individuals with severe depression and positive
inflammation biomarkers.56

NEUROIMAGING AND ELECTROPHYSIOLOGY

Structural MRI
With structural MRI, changes in both white and gray matter have been associated with late-life
depression and comorbid cognitive impairment compared with nondepressed older adults. In
support of the vascular hypothesis, suggesting that cerebrovascular disease is a major contributor
to late-life depression, longitudinal MRI studies have shown a correlation between the severity of
depression and white matter ischemic changes.57,58 Similarly, these white matter lesions,
especially when concentrated in anterior periventricular regions, have been associated with
comorbid executive dysfunction.
Gray matter changes seen in late-life depression may be part of the prodrome to AD.
Hippocampal atrophy, a well-known feature of AD, has also been shown to be associated with a
higher severity of emotional distress in nondemented individuals.59 For individuals with MCI,
depression was associated with reduced thickness of the entorhinal cortex, anterior cingulate
cortex, and bilateral dorsomedial and ventromedial prefrontal cortices.60–62

Functional MRI
The connectome (how the brain functions as a system of multiple connected networks) and
how pathophysiologic processes can disrupt the connectome are now major areas of research.
Recent functional MRI studies suggest that structural lesions associated with late-life depression
can also lead to the disruption of networks associated with the clinical features in late-life
depression (eg, apathy and executive dysfunction). In one study, the cognitive control network

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
and corticostriatal networks were shown to be linked to cognitive dysfunction (ie, executive
impairments) in late-life depression.63

PET Imaging and Florbetapir Imaging

PET imaging studies provide conflicting information. Specifically, one study found that some
patients with late-life depression and MCI showed a Pittsburgh compound B imaging pattern
suggestive of AD,64 whereas another did not replicate this relationship.65 Research with an
amyloid and neurofibrillary tangle binding agent (FDDNP) for individuals with MCI and
depression found variable temporal and parietal lobe binding.66,67 This finding was further
confirmed by research coming from the Alzheimer’s Disease Neuroimaging Initiative showing
that lifelong depressive symptoms reliably predicted Aβ accumulation in patients with MCI.68
These findings suggest that larger studies are needed to understand the complex PET imaging
relationship between depression and cognitive impairment.

Electrophysiology Markers
Using electroencephalogram (EEG) technology, individuals with late-life depression have
shown more slow-wave activity and prolonged P300a latencies, indicating decreased cerebral
arousal and information processing.69 Additional researching using a complex response inhibition
task showed decreased event potential localized to the anterior cingulate cortex in depressed older
adults.70 Although not diagnostic, these EEG findings may help shed light on the cognitive
deficits often reported by individuals with late-life depression.

PSYCHOTHERAPIES
Several evidence-based psychotherapies have been shown to be effective in the treatment of
late-life depression, even in those with associated cognitive impairments. Psychotherapy should
always be considered for individuals with MCI and early AD, especially, as older adults typically
only show an adequate response in approximately 30% after a trial of a first-line antidepressant.71

Cognitive Behavioral Therapy

Cognitive-behavioral therapy (CBT) has become one of the more common treatments for a
wide-range of disorders, including depression, posttraumatic stress disorder, anxiety, insomnia,
and so forth. It is based on the assumption that maladaptive patterns of thought and behavior
contribute to the development of emotional distress, such as depression. CBT focuses on breaking
the links between dysfunctional cognitions, emotions, and behaviors. One recent meta-analysis72
found that CBT and problem-solving therapy (PST) were more effective than other therapies in
treating late-life depression. Furthermore, research has shown CBT to be effective even when
applied to individuals with MCI.73

Interpersonal Therapy
Interpersonal therapy (IPT) concludes that the development of depressive symptoms is
influenced by the relationships between patients and their significant others. For treatment, it
combines techniques from supportive and psychodynamic therapies, focusing on interactions
between the therapists and the patients, with the goal of generalizing positive interactions toward
the patients’ significant others. IPT has been shown to be effective in the treatment of treatment-
resistant depression for younger to middle-aged adults,74 although there are fewer studies in older
adults. One study75 showed that IPT, when modified to include patients’ caregivers, was effective
in reducing depressive symptoms in cognitively impaired individuals.

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
Problem-Solving Therapy
PST focuses treatment on everyday problems, with the goal of improving coping skills to
prevent distress. The therapists work with the patients to identify problems, develop a set of
possible solutions, decide on one of these solutions, and then implement the solution (assessing
its success). Two meta-analyses76,77 have shown that PST effectively treats late-life depression.
Furthermore, these findings are supported by another meta-analysis indicating PST was more
effective than several other psychotherapies.72 In a multisite clinical trial of older adults with
depression and executive dysfunction, problem-solving was shown to be more effective than
supportive therapy in reducing depressive symptoms (persisting long after the 12 weeks of
treatment).78 Furthermore, late-life depression seems responsive to modified PSTs, including
primary care–based PST, problem adaptation therapy, and home-bound PST for individual with
cognitive impairments.79–81

Reminiscence and Life Review

Based on Erikson’s last stage of life span development focused on “meaning making,”
reminiscence and life review therapies were designed to treat psychological disorders in older
adults. The life review is a systematic process structured around life themes, such as one’s
childhood, parenthood, work productivity, and so forth. For treatment, the therapists work with
the patients to recall memories with the goal of focusing on positive life events and enhancing
well-being. The life review process then focuses on developing a narrative of the person’s life,
evaluating events and reframing and integrating them. There are 3 meta-analyses that have shown
reminiscence and life review therapies to be effective in treating late-life depression72,82,83;
however, these data were complicated by the variations in how these therapies are applied.

HOLISTIC AND OTHER NONTRADITIONAL

APPROACHES
Because of a variety of reasons, for many older adults, holistic and other nontraditional
approaches for treatment of depression may be more acceptable than psychopharmacologic and
psychotherapeutic approaches. First, as nontraditional treatments (eg, physical activity, art
therapy, meditation, and so forth) have been used by many for non–mental health reasons, older
adults may be more open to their use, especially if they have no history of psychiatric treatment.
Second, older adults may find it easier to speak with their physicians about their physical
symptoms than their emotional or cognitive complaints. Therefore, offering holistic and
nontraditional treatments, which may benefit both physical and mental health, may be more
acceptable. Third, as the mental health community has grown in the integration and study of
nontraditional treatments, the authors have found that, although not easy to study, these
approaches may offer unique benefits for the treatment of late-life depression.84

Physical Activity and Cognitive Training

Physical exercise has been shown to have a significant impact on both late-life depression and
cognition. A systematic review by Mura and Carta85 showed that most of the included studies
showed reductions in depressive symptoms (with no other interventions used). Multiple studies
have shown that exercise alone is equally effective, if not a powerful addition, to antidepressant
medications.86–88 Moreover, exercise has the potential to improve cognitive functioning in older
adults as well. Particularly, executive functions, for example, planning, working memory,
problem-solving, and so forth, seem to have robust benefits from aerobic exercise.89

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
 There also seems to be some evidence that cognitive training may have some cognitive
benefits in depressed older adults.90,91 However, further research needs to be done to examine
generalization from these effects to daily functioning.

Technological Interventions
Recent advances have allowed technological approaches to be combined with traditional
treatments of mental health issues. Internet-based psychotherapies92 and exergaming93 can
function independently or be further augmented with the use of mobile applications.94 However,
there is not yet compelling evidence for the effectiveness of these approaches with older adults.

Religion and Spirituality

With the increased importance of cultural competency in mental health research, the role of
religious and spirituality practices has gained recognition for the treatment of late-life depression.
For example, studies on the use of yoga and meditation have shown significant reductions in
depressive symptoms in older adults.95,96 However, the effects these practices have on cognition
are not yet well known. Finally, research on the use of tai chi with older adults suggests
improvements in depressive symptoms, physical functioning, and cognitive functioning as well as
reductions in inflammatory C-reactive protein.97,98

Music, Art, and Dance Therapy

Various art therapies have been shown to have positive effects on both mood and cognition.
Specifically, music therapy may improve depression and cognitive symptoms in older adults99,100
and dance therapy has shown a significant effect on mood.101,102

Ketamine
Recent literature has indicated that ketamine, typically used as an intravenous anesthetic, has
been shown to have rapid antidepressant efficacy in individuals with refractory major depressive
disorder (MDD).103 Moreover, initial studies have not shown there to be lasting neurocognitive
deficits secondary to ketamine treatment 1 week after administration, although there is an initial
slowing in processing speed.104

PHARMACOLOGIC APPROACHES
Antidepressants
Most of the recent literature on depression and cognition has focused on selective serotonin
reuptake inhibitors (SSRIs) and selective serotonin-norepinephrine reuptake inhibitors (SNRIs).
The results on SSRIs have been variable, depending largely on the medication being studied.
Specifically, sertraline was indicated to improve episodic memory and executive functions,9
whereas citalopram was shown to cause difficulties in response inhibition, verbal learning, and
processing speed.105,106 Alternatively, there seems to be more compelling evidence of cognitive
benefits from SNRIs.107,108 Alternatively, antidepressants with anticholinergic effects (ie, many
tricyclic antidepressants) likely have detrimental effects on cognition.109

Cholinesterase Inhibitors and N-Methyl-D-Aspartate Antagonists

Research on the use of cholinesterase inhibitors for late-life depression and comorbid MCI are
limited, with conflicting findings in terms of cognitive and mood outcomes. Interestingly,

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
research on donepezil has shown varying results, from positive effects on depression110,111 to no
positive effects.112 Memantine, an N-methyl-D-aspartate antagonist, has not been shown to have
any efficacy as a treatment of comorbid MDD.113–115

BRAIN STIMULATION THERAPIES

Electroconvulsive Therapy
Although initially developed for the treatment of psychotic symptoms, ECT has been shown to
be effective in the treatment of severe, treatment-resistant depression.116 Although not fully
understood, ECT is thought to release multiple neurotransmitters, including glutamate,
noradrenalin, dopamine, and serotonin.117,118 However, post-ECT cognitive adverse effects have
been found. These effects tend to be time limited and include disorientation after each ECT
session and both anterograde and retrograde amnesia, which can persist for 1 to 6 months after
the last session.117,119 More subtle cognitive deficits have also been shown to be time limited and
include decreases in processing speed, working memory, learning and memory, and executive
functions.120,121

Other Brain-Stimulation Therapies

Rather than using an electrical current, transcranial magnetic stimulation (TMS) uses an
electromagnet to stimulate brain regions. In one study, patients receiving repetitive TMS showed
improvement in depressive symptoms, functioning, and cognitive performances.122–124 Although
not yet used to study late-life depression with comorbid depression, this intervention seems to be
a promising area of future research.
Although deep brain stimulation (DBS) has been shown to be associated with successful
outcomes for treatment-resistant depression, responses differ among studies, with 6-month
success rates ranging from 41% to 66%.125–128 Several DBS targets have been studied, including
the subgenual cingulate region, subcallosal tracts, nucleus accumbens, ventral striatum, inferior
thalamic peduncle, and habenula. At this time, there is not compelling evidence for cognitive
benefits of DBS for patients with late-life depression and comorbid cognitive impairment.

SUMMARY
Although the understanding of the relationship between depression and cognition has grown
significantly over the past several years, researchers continue to uncover more details regarding
the complex interplay between these two factors. There have been several promising
developments recently, especially with advances in neuroimaging and biomarker research.
Additionally, although several therapeutic modalities have been researched for the treatment of
late-life depression, many of them have been limited by factors, including providers’ experience
and/or treatment availability. Given the current literature, optimal assessment and treatment of
older adults with depression should include multiple modalities, such as neuroimaging,
genotyping, and risk factor burden calculations, to better understand the patients’ prognosis and
potential treatment response. Future research should then focus on more individualized
treatments, pharmacologic and psychotherapeutic, for late-life depression in order to more
effectively treat both cognitive and affective symptoms.

ACKNOWLEDGMENTS
The authors thank Dr Fred Unverzagt for his irreplaceable expertise in this field and his
valuable contributions to this body of work.

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
REFERENCES
1. Eden J, LeM, Maslow K, et al, editors. The mental health and substance use workforce for
older adults: in whose hands? Washington, DC: Natl. Acad. Press; 2012.

2. Byers AL, Yaffe K. Depression and risk of developing dementia. Nat Rev Neurol 2011;7:323–
31.

3. Steenland K, Karnes C, Seals R, et al. Late-life depression as a risk factor for mild cognitive
impairment or Alzheimer’s disease in 30 US Alzheimer’s disease centers. J Alzheimers Dis
2012;31:265–75.

4. Blazer D. Depression in late life: review and commentary. J Gerontol A Biol Sci Med Sci
2003;58(3):249–65.

5. Karyotaki E, Smit Y, Holdt Henningsen K, et al. Combining pharmacotherapy and

psychotherapy or monotherapy for major depression? A meta-analysis on the long-term effects. J
Affect Disord 2016;194:144–52.

6. Islam MM, Iqbal U, Walther B, et al. Benzodiazepine use and rick of dementia in the elderly
population: a systematic review and meta-analysis. Neuroepidemiology 2016;47(3–4):181–91.

7. Blank K. Older adults & substance use: new data highlight concerns. SAMHSA News, Jan–
Feb. 2009. Available at: http://www.samhsa.gov/. Accessed June 12, 2017.

8. Apostolova LG, Di LJ, Duffy EL, et al. Risk factors for behavioral abnormalities in mild
cognitive impairment and mild Alzheimer’s disease. Dement Geriatr Cogn Disord 2014;37:315–
26.

9. Barch DM, D’Angelo G, Pieper C, et al. Cognitive improvement following treatment in late-
life depression: relationship to vascular risk and age of onset. Am J Geriatr Psychiatry
2012;20:682–90.

10. Sheline YI, Pieper CF, Wlesh-Bohmer K, et al. Support for the vascular depression
hypothesis in late-life depression: results of a 2-site, prospective, antidepressant treatment trial.
Arch Gen Psychiatry 2010;67(3):277–85.

11. Agganis BT, Weiner DE, Giang LM, et al. Depression and cognitive function in maintenance
hemodialysis patients. Am J Kidney Dis 2010;56:704–12.

12. Elias MF, Dore GA, Davey A. Kidney disease and cognitive function. Contrib Nephrol
2013;179:42–57.

13. Doyle T, Palmer S, Johnson J, et al. Association of anxiety and depression with pulmonary-
specific symptoms in chronic obstructive pulmonary disease. Int J Psychiatry Med 2013;45:189–
202.

14. Bratek A, Zawada K, Beil-Gawelczyk J, et al. Depressiveness, symptoms of anxiety and

cognitive dysfunctions in patients with asthma and chronic obstructive pulmonary disease

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
(COPD): possible associations with inflammation markers: a pilot study. J Neural Trans (Vienna)
2015;122:S83–91.

15. Am Found Suicide Prev. Facts and figures. New York: Am. Found. Suicide Prev; 2012.
Available at. https://www.afsp.org/understanding-suicide/facts-and-figures.

16. Conwell Y, Van Orden K, Caine ED. Suicide in older adults. Psychiatr Clin N Am
2011;34:451–68.

17. Szanto K, Dombrovski AY, Sahakian BJ, et al. Social emotion recognition, social
functioning, and attempted suicide in late-life depression. Am J Geriatr Psychiatry 2012;20:257–
65.

18. Chan SS, Lyness JM, Conwell Y. Do cerebrovascular risk factors confer risk for suicide in
later life? A case-control study. Am J Geriatr Psychiatry 2007;15: 541–4.

19. Kurella M, Kimmel PL, Young BS, et al. Suicide in the United States end-stage renal disease
program. J Am Soc Nephrol 2005;16:774–81.

20. Blazer DG, Wallace RB. Cognitive aging: what every geriatric psychiatrist should know. J
Geriatr Psychiatry 2016;24:776–81.

21. Harada CN, Natelson Love MC, Triebel KL. Normal cognitive aging. Clin Geriatr Med
2013;29(4):737–52.

22. Hill NL, Mogle J, Wion R, et al. Subjective cognitive impairment and affective symptoms: a
systematic review. J Gerontologist 2016;56(6):e109–27.

23. Amariglio RE, Townsend MK, Grodstein F, et al. Specific subjective memory complaints in
older persons may indicate poor cognitive function. J Am Geriatr Soc 2011;59(9):1612–7.

24. Jonker C, Launer LJ, Hooijer C, et al. Memory complaints and memory impairment in older
individuals. J Am Geriatr Soc 1996;44(1):44–9.

25. Montejo Carrasco P, Montenegro-Pena M, Lopez-Higes R, et al. Subjective memory

complaints in healthy older adults: fewer complaints associated with depression and perceived
health, more complaints also associated with lower memory performance. Arch Gerontol Geriatr
2017;70:28–37.

26. Minett TS, Da Silva RV, Ortiz KZ, et al. Subjective memory complaints in an elderly sample:
a cross sectional study. Int J Geriatr Psychiatry 2008;23(1): 49–54.

27. Dufouil C, Fuhrer R, Alperovitch A. Subjective cognitive complaints and cognitive decline:
consequence or predictor? The epidemiology of vascular aging study. J Am Geriatr Soc
2005;53(4):616–21.

28. Waldorff FB, Siersma V, Vogel A, et al. Subjective memory complaints in general practice
predicts future dementia: a 4-year follow-up study. Int J Geriatr Psychiatry 2012;27(11):1180–8.

29. Wang S, Blazer DG. Depression and cognition in the elderly. Annu Rev Clin Psychol
2015;11:331–60.

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
30. Bartley M, Bokde AL, Ewers M, et al. Subjective memory complaints in community dwelling
healthy older people: the influence of brain and psychopathology. Int. J Geriatr Psychiatry
2012;27(8):836–43.

31. Chu CS, Sun IW, Begum A, et al. The association between subjective memory complaint and
objective cognitive function in older people with previous major depression. PLoS One
2017;12(3):e0173027.

32. Wolfsgruber S, Polcher A, Koppara A, et al. Cerebrospinal fluid biomarkers and clinical
progression in patients with subjective cognitive decline and mild cognitive impairment. J
Alzheimers Dis 2017;58(3):939–50.

33. Langa KM, Levine DA. The diagnosis and management of mild cognitive impairment: a
clinical review. JAMA 2014;312(23):2551–61.

34. Bhalla RK, Butters MA, Becker JT, et al. Patterns of mild cognitive impairment after
treatment of depression in the elderly. Am J Geriatr Psychiatry 2009;17: 308–16.

35. Reinlieb M, Ercoli LM, Siddarth P, et al. The patterns of cognitive and functional impairment
in amnestic and non-amnestic mild cognitive impairment in geriatric depression. Am J Geriatr
Psychiatry 2014;22:1487–95.

36. Yeh YC, Tsang HY, Lin PY, et al. Subtypes of mild cognitive impairment among the elderly
with major depressive disorder in remission. Am J Geriatr Psychiatry 2011;19:923–31.

37. Morimoto SS, Alexopoulos GS. Cognitive deficits in geriatric depression: clinical correlates
and implications for current and future treatment. Psychiatr Clin N Am 2013;36:517–31.

38. Mackin RS, Nelson JC, Delucchi KL, et al. Association of age at depression onset with
cognitive functioning in individuals with late-life depression and executive dysfunction. Am J
Geriatr Psychiatry 2014;22:1633–41.

39. Salloway S, Malloy P, Kohn R, et al. MRI and neuropsychological differences in early- and
late-life-onset geriatric depression. Neurology 1996;46:1567–74.

40. Potter GG, Wagner HR, Burke JR, et al. Neuropsychological predictors of dementia in late-
life major depressive disorder. Am J Geriatr Psychiatry 2013;21: 297–306.

41. Steffens DC, McQuoid DR, Potter GG. Outcomes of older cognitively impaired individuals
with current and past depression in the NCODE study. J Geriatr Psychiatry Neurol 2009;22:52–
61.

42. Koenig AM, Bhalla RK, Meryl AB. Cognitive functioning and late-life depression. J Int
Neuropsychol Soc 2014;20:1–7.

43. Irie F, Masaki KH, Petrovitch H, et al. Apolipoprotein E epsilon4 allele genotype and the
effect of depressive symptoms on the risk of dementia in men: the Honolulu-Asia aging study.
Arch Gen Psychiatry 2008;65:906–12.

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
44. Bogner HR, Richie MB, de Vries HF, et al. Depression, cognition, and apolipoprotein E
genotype: latent class approach to identifying subtype. Am Geriatr Psychiatry 2009;17:344–52.

45. Blasko I, Kemmler G, Jungwirth S, et al. Plasma amyloid beta-42 independently predicts both
late-onset depression and Alzheimer disease. Am J Geriatr Psychiatry 2010;18:973–82.

46. Metti AL, Cauley JA, Newman AB, et al. Plasma beta amyloid level and depression in older
adults. J Gerontol A Biol Sci Med Sci 2013;68:74–9.

47. Sun X, Chiu CC, Liebson E, et al. Depression and plasma amyloid beta peptides in the elderly
with and without the apolipoprotein E4 allele. Alzheimer Dis Assoc Disord 2009;23:238–44.

48. Szanto K, Clark L, Hallquist M, et al. The cost of social punishment and highlethality suicide
attempts in the second half of life. Psychol Aging 2014;29: 84–94.

49. Schonknecht P, Pantel J, Kaiser E, et al. Increased tau protein differentiates mild cognitive
impairment from geriatric depression and predicts conversion to dementia. Neurosci Lett
2007;416:39–42.

50. Scogin F, Fairchild JK, Yon A, et al. Cognitive bibliotherapy and memory training for older
adults with depressive symptoms. Aging Ment Health 2014;18:554–60.

51. Diniz BS, Teixeira AL, Machado-Vieira R, et al. Reduced serum nerve growth factor in
patients with late-life depression. Am J Geriatr Psychiatry 2013;21: 493–6.

52. Diniz BS, Teixeira AL, Miranda AS, et al. Circulating glial-derived neurotrophic factor is
reduced in late-life depression. J Psychiatr Res 2012;46:135–9.

53. Erickson KI, Miller DL, Roecklein KA. The aging hippocampus: interactions between
exercise, depression, and BDNF. Neuroscientist 2012;18:82–97.

54. Arnold SE, Xie SX, Leung YY, et al. Plasma biomarkers of depressive symptoms in older
adults. Transl Psychiatry 2012;3(2):e65.

55. Kohler S, Thomas AJ, Lloyd A, et al. White matter hyperintensities, cortisol levels, brain
atrophy and continuing cognitive deficits in late-life depression. Br J Psychiatry 2010;196:143–9.

56. Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch
Gen Psychiatry 2000;57:925–35.

57. Krishnan KR, Taylor WD, McQuoid DR, et al. Clinical characteristics of magnetic resonance
imaging–defined subcortical ischemic depression. Biol Psychiatry 2004;55:390–7.

58. Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis:
mechanisms linking vascular disease with depression. Mol Psychiatry 2013;18: 963–74..

59. Taylor WD, McQuoid DR, Payne ME, et al. Hippocampus atrophy and the longitudinal
course of late-life depression. Am J Geriatr Psychiatry 2014;22:1504–12.

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
60. Lebedeva AK, Westman E, Borza T, et al. MRI-based classification models in prediction of
mild cognitive impairment and dementia in late-life depression. Front Aging Neurosci 2017;2:9–
13.

61. Xie C, Li W, Chen G, et al. The co-existence of geriatric depression and amnestic mild
cognitive impairment detrimentally affect gray matter volumes: voxelbased morphometry study.
Behav Brain Res 2012;235:244–50.

62. Zahodne LB, Gongvatana A, Cohen RA, et al. Are apathy and depression independently
associated with longitudinal trajectories of cortical atrophy in mild cognitive impairment? Am J
Geriatr Psychiatry 2013;21:1098–106.

63. Tadayonnejad R, Ajilore O. Brain network dysfunction in late-life depression: a literature

review. J Geriatr Psychiatry Neurol 2014;27:5–12.

64. Butters MA, Klunk WE, Mathis CA, et al. Imaging Alzheimer pathology in late-life
depression with PET and Pittsburgh compound-B. Alzheimer Dis Assoc Disord 2008;22:261–8.

65. Madsen K, Hasselbalch BJ, Frederiksen KS, et al. Lack of association between prior
depressive episodes and cerebral [11C]PiB binding. Neurobiol Aging 2012;33:2334–42.

66. Kumar A, Kepe V, Barrio JR, et al. Protein binding in patients with late-life depression. Arch
Gen Psychiatry 2011;68:1143–50.

67. Lavretsky H, Siddarth P, Kepe V, et al. Depression and anxiety symptoms are associated with
cerebral FDDNP-PET binding in middle-aged and older nondemented adults. Am J Geriatr
Psychiatry 2009;17:493–502.

68. Chung JK, Plitman E, Nakajima S, et al. Lifetime history of depression predicts increased
amyloid-B accumulation in patients with mild cognitive impairment. J Alzheimers Dis
2015;45(3):907–19.

69. Kohler S, Ashton CH, Marsh R, et al. Electrophysiological changes in late life depression and
their relation to structural brain changes. Int Psychogeriatr 2011;23:141–8.

70. Katza R, De Sanctisa P, Mahoneya JR, et al. Cognitive control in late-life depression:
response inhibition deficits and dysfunction of the anterior cingulate cortex. Am J Geriatr
Psychiatry 2010;18:1017–25.

71. Lenze EJ, Sheffrin M, Driscoll HC, et al. Incomplete response in late-life depression: getting
to remission. Dialogues Clin Neurosci 2008;10:419–30.

72. Cuijpers P, Karyotaki E, Pot AM, et al. Managing depression in older age: psychological
interventions. Maturitas 2014;79(2):160–9.

73. Joosten-Weyn Banningh LW, Kessels RP, Olde Rikkert MG, et al. A cognitive behavioural
group therapy for patients diagnosed with mild cognitive impairment and their significant others:
feasibility and preliminary results. Clin Rehabil 2008;22:731–40.

74. Hollon SD, Ponniah K. A review of empirically supported psychological therapies for mood
disorders in adults. Depress Anxiety 2010;27(10):891–932.

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
75. Miller MD, Reynolds CF 3rd. Expanding the usefulness of interpersonal psychotherapy (IPT)
for depressed elders with co-morbid cognitive impairment. Int J Geriatr Psychiatry 2007;22:101–
5.

76. Bell AC, D’Zurilla TJ. Problem-solving therapy for depression: a meta-analysis. Clin Psychol
Rev 2009;29(4):348–53.

77. Malouff JM, Thorsteinsson EB, Schutte NS. The efficacy of problem solving therapy in
reducing mental and physical health problems: a meta-analysis. Clin Psychol Rev 2007;27(1):46–
57.

78. Alexopoulos GS, Raue PJ, Kiosse sDN, et al. Problem-solving therapy and supportive therapy
in older adults with major depression and executive dysfunction: effect on disability. Arch Gen
Psychiatry 2011;68:33–41.

79. Arean P, Hegel M, Vannoy S, et al. Effectiveness of problem-solving therapy for older,
primary care patients with depression: results from the IMPACT project. Gerontologist
2008;48:311–23.

80. Arean PA, Raue P, Mackin RS, et al. Problem-solving therapy and supportive therapy in older
adults with major depression and executive dysfunction. Am J Psychiatry 2010;167:1391–8.

81. Kiosses DN, Arean PA, Teri L, et al. Home-delivered problem adaptation therapy (PATH) for
depressed, cognitively impaired, disabled elders: a preliminary study. Am J Geriatr Psychiatry
2010;18:988–98.

82. Bohlmeijer E, Smit F, Cuijpers P. Effects of reminiscence and life review on latelife
depression: a meta-analysis. Int J Geriatr Psychiatry 2003;18(12):1088–94.

83. Pinquart M, Forstmeijer S. Effects of reminiscence interventions on psychosocial outcomes: a

meta-analysis. Aging Ment Health 2012;16(5):541–58.

84. Ventegodt S, Merrick J. Meta-analysis of positive effects, side effects and adverse events of
holistic mind-body medicine (clinical holistic medicine): experience from Denmark, Sweden,
United Kingdom and Germany. Int J Adolesc Med Health 2009;21(4):441–56.

85. Mura G, Carta MG. Physical activity in depressed elderly: a systematic review. Clin Pract
Epidemiol Ment Health 2013;9:125–35.

86. Blumenthal JA, Babyak MA, Moore KA, et al. Effects of exercise training on older patients
with major depression. Arch Intern Med 1999;159(19):2349–56.

87. Bogner HR, Bruce ML, Reynolds CF 3rd, et al. The effects of memory, attention, and
executive dysfunction on outcomes of depression in a primary care intervention trial: the
PROSPECT study. Int J Geriatr Psychiatry 2007;22:922–9.

88. Mather AS, Rodriguez C, Guthrie MF, et al. Effects of exercise on depressive symptoms in
older adults with poorly responsive depressive disorder: randomised controlled trial. Br J
Psychiatry 2002;180:411–5.

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
89. Northey JM, Cherbuin N, Pumpa KL, et al. Exercise interventions for cognitive function in
adults older than 50: a systematic review with meta-analysis. Br J Sports Med 2017. [Epub ahead
of print].

90. Mowszowski L, Hermens DF, Diamond K, et al. Cognitive training enhances preattentive
neurophysiological responses in older adults “at risk” of dementia. J Alzheimers Dis
2014;41(4):1095–108.

91. Naismith SL, Diamond K, Carter PE, et al. Enhancing memory in late-life depression: the
effects of a combined psychoeducation and cognitive training program. Am J Geriatr Psychiatry
2011;19:240–8.

92. Donker T, Batterham PJ, Warmerdam L, et al. Predictors and moderators of response to
Internet-delivered interpersonal psychotherapy and cognitive behavior therapy for depression. J
Affect Disord 2013;151:343–51.

93. Rosenberg D, Depp CA, Vahia IV, et al. Exergames for subsyndromal depression in older
adults: a pilot study of a novel intervention. Am J Geriatr Psychiatry 2010;18:221–6.

94. Donker T, Petrie K, Proudfoot J, et al. Smartphones for smarter delivery of mental health
programs: a systematic review. J Med Internet Res 2013;15:e247.

95. Nash JD, Newberg A. Toward a unifying taxonomy and definition for meditation. Front
Psychol 2013;4:806.

96. Patel NK, Newstead AH, Ferrer RL. The effects of yoga on physical functioning and health
related quality of life in older adults: a systematic review and metaanalysis. J Altern Complement
Med 2012;18:902–17.

97. Lavretsky H, Alstein LL, Olmstead RE, et al. Complementary use of tai chi chih augments
escitalopram treatment of geriatric depression: a randomized controlled trial. Am J Geriatr
Psychiatry 2011;19:839–50.

98. Rogers CE, Larkey LK, Keller C. A review of clinical trials of tai chi and qigong in older
adults. West J Nurs Res 2009;31:245–79.

99. Cross K, Flores R, Butterfield J, et al. The effect of passive listening versus active observation
of music and dance performances on memory recognition and mild to moderate depression in
cognitively impaired older adults. Psychol Rep 2012;111:413–23.

100. Hars M, Herrmann FR, Gold G, et al. Effect of music-based multitask training on cognition
and mood in older adults. Age Ageing 2014;43:196–200.

101. McCaffrey R, Liehr P, Gregersen T, et al. Garden walking and art therapy for depression in
older adults: a pilot study. Res Gerontol Nurs 2011;4:237–42.

102. Murrock CJ, Graor CH. The effects of dance on depression, physical function, and disability
in underserved adults. J Aging Phys Act 2014;22(3):380–5.

103. Pehrson AL, Sanchez C. Serotonergic modulation of glutamate neurotransmission as a

strategy for treating depression and cognitive dysfunction. CNS Spectr 2014;19:121–33.

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
104. Murrough JW, Burdick KE, Levitch CF, et al. Neurocognitive effects of ketamine and
association with antidepressant response in individuals with treatmentresistant depression: a
randomized controlled trial. Neuropsychopharmacology 2015;40(5):1084–90.

105. Pimontel MA, Culang-Reinlieb ME, Morimoto SS, et al. Executive dysfunction and
treatment response in late-life depression. Int J Geriatr Psychiatry 2012; 27:893–9.

106. Sneed JR, Culang ME, Keilp JG, et al. Antidepressant medication and executive
dysfunction: a deleterious interaction in late-life depression. Am J Geriatr Psychiatry
2010;18:128–35.

107. Raskin J, Wiltse CG, Siegal A, et al. Efficacy of duloxetine on cognition, depression, and
pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-
controlled trial. Am J Psychiatry 2007;164:900–9.

108. Wesnes K, Bose A, Gommoll C, Chen C. Effects of levomilnacipran SR on measures of

attention in a phase 3 trial of major depressive disorder (MDD). Presented at NCDEU 53rdMeet.,
Am. Soc. Clin. Psychopharmacol., Hollywood, CA, May 28-31, 2013.

109. Khawam EA, Laurencic G, Malone DA. Side effects of antidepressants: an overview. Clevel
Clin J Med 2006;73:351–3, 356–61.

110. Pelton GH, Harper OL, Tabert MH, et al. Randomized double-blind placebocontrolled
donepezil augmentation in antidepressant-treated elderly patients with depression and cognitive
impairment: a pilot study. Int J Geriatr Psychiatry 2008;23:670–6.

111. Reynolds CF 3rd, Butters MA, Lopez O, et al. Maintenance treatment of depression in old
age: a randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of
donepezil combined with antidepressant pharmacotherapy. Arch Gen Psychiatry 2011;68:51–60.

112. Holtzheimer PE, Meeks TW, Kelley ME, et al. A double blind, placebo-controlled pilot
study of galantamine augmentation of antidepressant treatment in older adults with major
depression. Int J Geriatr Psychiatry 2008;23:625–31.

113. Lenze EJ, Skidmore ER, Begley AE, et al. Memantine for late-life depression and apathy
after a disabling medical event: a 12-week, double-blind placebocontrolled pilot study. Int J
Geriatr Psychiatry 2012;27:974–80.

114. Smith EG, Deligiannidis KM, Ulbricht CM, et al. Antidepressant augmentation using the N-
methyl-D-aspartate antagonist memantine: a randomized, doubleblind, placebo-controlled trial. J
Clin Psychiatry 2013;74:966–73.

115. Zarate CA Jr, Singh JB, Quiroz JA, et al. A double-blind, placebo-controlled study of
memantine in the treatment of major depression. Am J Psychiatry 2006;163:153–5.

116. Sackheim HA, Prudic J, Fuller R, et al. The cognitive effects of electroconvulsive therapy in
community settings. Neuropsychopharmacology 2007;32:244–54.

117. Lisanby SH. Electroconvulsive therapy for depression. New Engl J Med 2007; 357:1939–45.

Downloaded for Anonymous User (n/a) at Indiana University Ruth Lilly Medical Library from ClinicalKey.com by Elsevier on November 18, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
118. Wahlund B, van Rosen D. ECT of major depressed patients in relation to biological and
clinical variables: a brief overview. Neuropsychopharmacology 2003; 28(Suppl 1):S21–6.

119. McClintock SM, Choi J, Deng ZD, et al. Multifactorial determinants of the neurocognitive
effects of electroconvulsive therapy. J ECT 2014;30:165–76.

120. Semkovska M, McLoughlin DM. Objective cognitive performance associated with

electroconvulsive therapy for depression: a systematic review and metaanalysis. Biol Psychiatry
2010;68:568–77.

121. Sheline YI, Barch DM, Garcia K, et al. Cognitive function in late life depression:
relationships to depression severity, cerebrovascular risk factors and processing speed. Biol
Psychiatry 2006;60:58–65.

122. Ahmed MA, Darwish ES, Khedr EM, et al. Effects of low versus high frequencies of
repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in
Alzheimer’s dementia. J Neurol 2012;259:83–92.

123. Alexopoulos GS, Hoptman MJ, Kanellopoulos D, et al. Functional connectivity in the
cognitive control network and the default mode network in late-life depression. J Affect Disord
2012;139:56–65.

124. Alexopoulos GS, Murphy CF, Gunning-Dixon FM, et al. Microstructural white matter
abnormalities and remission of geriatric depression. Am J Psychiatry 2008;165:238–44.

125. Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood
disorders: implications for neurocircuitry models of depression. Brain Struct Funct 2008;213(1–
2):93–118.

126. Dubois B, Litvan I. The FAB: a frontal assessment battery at bedside. Neurology
2000;55:1621–6.

127. Greicius MD, Flores BH, Menon V, et al. Resting-state functional connectivity in major
depression: abnormally increased contributions from subgenual cingulate cortex and thalamus.
Biol Psychiatry 2007;62(5):429–37.

128. Kennedy SH, Giacobbe P, Rizvi SJ, et al. Deep brain stimulation for treatmentresistant
depression: follow-up after 3 to 6 years. Am J Psychiatry 2011;168(5): 502–10.