N e u ro l o g i c C h a n g e s an d

D e p re s s i o n
a,b, a,b,c,d
Ryan D. Greene, Psy D *, Sophia Wang, MD

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 chal-
lenging 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.

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

Disclosure Statement: S. Wang receives grant support from NIA (#2P30AG010133). R. Greene
has nothing to disclose.
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 Implemen-
tation 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.
E-mail address: [email protected]

Psychiatr Clin N Am - (2017) -–-

https://doi.org/10.1016/j.psc.2017.10.009 psych.theclinics.com
0193-953X/17/Published by Elsevier Inc.
2 Greene & Wang

terminology used in earlier literature and within the International Classification of Dis-
eases, 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 va-
riety 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 po-
tential reversible causes of cognitive impairment in mind (eg, substance use, meta-
bolic 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 disor-
der. 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 def-
icits 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, wors-
ening 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 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, anti-
cholinergics, opiates, non-narcotic pain medications (ie, tramadol), hypnotics, and an-
tipsychotics 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 in-
fectious contributions to cognitive and/or affective symptoms.
 Neurologic Changes and Depression 3

Risk Factors
The interactions between medical illnesses, depression, and cognitive impairments
are typically multidirectional, making it difficult to distinguish causes of current symp-
tom 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 fail-
ure11,12 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 in-
crease 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 associ-
ated 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 vocab-
ulary knowledge remain stable.21 Generally, good management of multiple health fac-
tors, 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.
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 impair-
ments on cognitive testing have shown conflicting findings, ranging from a positive
correlation23–25 to no association.26 However, in longitudinal studies, subjective cogni-
tive impairments have been associated with higher rates of incident cognitive impair-
ment 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 (Ab) 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.
4 Greene & Wang

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 depres-
sion 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 struc-
tural 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], Ab, 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 longitudi-
nal study showed that APOE ε4 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 Ab 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 depres-
sion 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
 Neurologic Changes and Depression 5

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 def-
icits. Although chronic distress has been associated with disruption in the HPA axis,
research on this relationship with comorbid cognitive impairments has been vari-
able.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 asso-
ciated with a higher severity of emotional distress in nondemented individuals.59 For
individuals with MCI, depression was associated with reduced thickness of the ento-
rhinal 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 net-
works) 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 asso-
ciated with the clinical features in late-life depression (eg, apathy and executive
dysfunction). In one study, the cognitive control network 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 im-
aging pattern suggestive of AD,64 whereas another did not replicate this relationship.65
Research with an amyloid and neurofibrillary tangle binding agent (FDDNP) for individ-
uals 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
Ab 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.
6 Greene & Wang

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 us-
ing 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 in-
dividuals 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 pat-
terns of thought and behavior contribute to the development of emotional distress,
such as depression. CBT focuses on breaking the links between dysfunctional cogni-
tions, 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.

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 effec-
tively treats late-life depression. Furthermore, these findings are supported by another
meta-analysis indicating PST was more effective than several other psychother-
apies.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
 Neurologic Changes and Depression 7

primary care–based PST, problem adaptation therapy, and home-bound PST for indi-
vidual 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 re-
view 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 psychopha-
rmacologic 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, ex-
ercise has the potential to improve cognitive functioning in older adults as well. Partic-
ularly, executive functions, for example, planning, working memory, problem-solving,
and so forth, seem to have robust benefits from aerobic exercise.89
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 tradi-
tional treatments of mental health issues. Internet-based psychotherapies92 and exer-
gaming93 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.
8 Greene & Wang

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 symp-
toms, physical functioning, and cognitive functioning as well as reductions in inflam-
matory 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 symp-
toms 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 anes-
thetic, has been shown to have rapid antidepressant efficacy in individuals with refrac-
tory major depressive disorder (MDD).103 Moreover, initial studies have not shown
there to be lasting neurocognitive deficits secondary to ketamine treatment 1 week af-
ter 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 se-
rotonin 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 Alter-
natively, there seems to be more compelling evidence of cognitive benefits from
SNRIs.107,108 Alternatively, antidepressants with anticholinergic effects (ie, many tricy-
clic 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, 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
 Neurologic Changes and Depression 9

and include disorientation after each ECT session and both anterograde and retro-
grade 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 de-
creases 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 per-
formances.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 suc-
cessful 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, nu-
cleus 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 depres-
sion 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 treat-
ments, 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.

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