CLINICAL SYNTHESIS
Late Life Depression: The Essentials and the Essential
Distinctions
Sehba Husain-Krautter, M.D., Ph.D., and James M. Ellison, M.D., M.P.H.
Late life depression (LLD), a familiar syndrome, is not differ-
entiated in the DSM-5. LLD can resemble depressive syn-
dromes in younger adults but it differs in demographic
characteristics, phenomenology, prognosis, treatment, sui-
cide risk, relationship to other disorders, and etiology. Older
depressed adults often present with fewer major depressive
symptoms, less emphasis on mood disturbance, greater
preoccupation with somatic or psychotic symptoms, and
misleading cognitive deficits. LLD’s relationships with med-
ical and neurocognitive symptoms and with inflammatory
and immune factors are complex. Formal screening tools
In the extended family of DSM-5 diagnoses, late life depression
(LLD) is the unacknowledged relative who awaits a formal invi-
tation to the party. The DSM-5 states that “there are no clear
effects of current age on the course or treatment response of
major depressive disorder” (1); however, evidence suggests
that there are multiple differentiated presentations of depression
more characteristic of its appearance in later years. LLD shares
features with depressive syndromes found among younger
adults, but it also differs in many ways, not only in demographic
characteristics but also in etiology, phenomenology, prognosis,
acute treatment, maintenance treatment, suicide risk, and rela-
tionship to other medical and psychiatric disorders. Because of
its differences from depression among younger adults, LLD risks
going undetected or being mismanaged. In this overview, we
highlight the essential characteristics of LLD and emphasize
the most important differences between late life and earlier
depression with the objectives of improving recognition and
treatment of this common and debilitating disorder.
DEMOGRAPHIC CHARACTERISTICS
Depression is one of the more common psychiatric syndromes
among older adults, and it presents in many guises. No official
set of diagnostic criteria defines the diagnosis of LLD. By con-
vention, this term typically denotes the presence of a depres-
sive syndrome consistent with DSM criteria in an adult age 65
or older. The prevalence of major depressive disorder among
community-dwelling older adults is estimated at 1%–4%
282 focus.psychiatryonline.org
and biopsychosocial assessment informs diagnosis and
treatment. Evidence supports the effectiveness of lifestyle
interventions, several psychotherapies, and a variety of
somatic treatment approaches. Comorbid medical disor-
ders must be taken into account when planning treatment.
In this article, the authors describe the characteristics of
LLD, present an approach to assessment and management,
and recommend that future DSM editions include a new
specifier to differentiate LLD from other depressive syndromes.
Focus 2021; 19:282–293; doi: 10.1176/appi.focus.20210006
(2). Taking various settings into consideration, another 10%–
50% of older adults manifest clinically significant depressive
symptoms below the threshold of major depressive disorder
(3, 4). In primary care settings, higher rates of major depres-
sive disorder are seen, an estimated 6%–9% (5). The highest
rates of late life major depressive disorder are seen in long-
term care facilities, where up to 25% of residents warrant
that diagnosis; moreover, another estimated 30%–50% of res-
idents manifest clinically significant depressive symptoms (6).
Notably, LLD is an important antecedent to suicide in later
life, which occurs at a higher rate than among the young.
Depression is known to be the strongest risk factor for suicide
among older adults (7). In 2000, the World Health Organiza-
tion estimated suicide rates of men and women, age 75 and
older, to be 50 and 16 per 100,000, respectively (8).
Although the prevalence of major depressive disorder is
lower among older adults than among younger adults, milder
depressive symptoms are more highly prevalent among older
adults (2, 9). These clinically significant depressive symptoms,
sometimes referred to as “minor depression,” can be a debil-
itating contributor to the psychiatric morbidity of the aging
population (10).
SYMPTOMS AND SYNDROMES OF LLD
The DSM-5 diagnosis of major depressive disorder provides a
useful basic framework for detection of depression through
the life cycle; however, the sensitivity and specificity of
Focus Vol. 19, No. 3, Summer 2021

DSM-5 mood states and neurovegetative features differ
between younger and older adults. Although the presentation
of depressive episodes is heterogeneous at all ages, the
“background noise” of symptoms reflecting age-associated med-
ical burden and the frequent focus of older adults on somatic
symptoms or psychotic concerns rather than depressed mood
require clinicians to think beyond DSM-5 vegetative symptoms
in diagnosing LLD. Disturbed sleep, energy, concentration,
appetite, or activity among older adults can reflect various phys-
iologic changes or medical disorders common to later life. As a
result, the use of these symptoms in diagnosing LLD may lead to
an overly inclusive approach that results in too many false pos-
itive diagnoses. However, when people with LLD fail to report
mood changes characteristic of depression, which can occur
for a variety of reasons, the diagnosis of LLD may be prema-
turely dismissed and a potential treatment opportunity lost.
An additional diagnostic consideration with LLD concerns
the broad range of ages that make up “late life.” Older adults
range from ages 65 to 100. Although the effects of age are indi-
vidualized, increasing age amplifies the diversity of the older
population and the symptoms, medical conditions, and func-
tional status of individuals. The “young-old” group contains
many individuals who perform at a high level in social and
occupational domains, whereas the “old-old” group contains
a much higher proportion of individuals who are retired,
socially isolated, or compromised by impaired health and
diminished function. Given the interactions between these
variables and the phenomenology of mood disorders, LLD is
not surprisingly a heterogeneous disorder with various pre-
sentations and disparate treatment needs.
Notably, these presentations include at least the following
entities: recurrence of earlier onset major depressive disorder
(9); the syndrome of subsyndromal depression, with symp-
toms too few for major depression; depression lacking a
prominent low mood (i.e., depression without sadness) (11);
depression with emphasis on somatization, including concern
about pain, bodily dysfunction, or cognition; depression with
psychotic features; depressive symptoms secondary to general
medical conditions; depressive symptoms secondary to sub-
stance or medication use; and depressive symptoms associ-
ated with neurocognitive disorders. Episodes of depression
that represent a late life recurrence of a longstanding mood
disorder are grouped with other LLD depressive syndromes;
however, these episodes may represent a significantly differ-
ent condition because most LLD episodes are not preceded
by earlier episodes (12). One study reported that as many as
71% of the older adults with depression enrolled in a home
health care program were experiencing their first episode of
depression (13). LLD in the context of bipolar disorder, which
is less frequent than unipolar LLD, is beyond the scope of this
article and has been recently reviewed elsewhere (14).
ETIOLOGIC THEORIES
Multiple factors can contribute to LLD. In any affected indi-
vidual, one or more of these might be the most critical to
Focus Vol. 19, No. 3, Summer 2021
HUSAIN-KRAUTTER AND ELLISON
FIGURE 1. Factors that contribute to late life depression
Immune and Cardiovascular and other
inflammatory non-neurodegenerative
mechanisms medical illnesses
Other factors Neurodegenerative
Late life diseases
depression
Epigenetic and
Psychosocial factors genetic factors
Dysfunctional reward Depression-Executive
processing Dysfunction Syndrome
recognize or address. The most prominent of the proposed
contributors to LLD are illustrated in Figure 1 and discussed
in the subsequent text.
Immune and Inflammatory Mechanisms
Dysregulation of the immune system, as a consequence of age
or disease, appears to be an important factor in LLD (15). The
multiple mechanisms by which aging alters immune function
are referred to collectively as “immunosenescence” (16).
Increased levels of proinflammatory mediators with aging
have been demonstrated in several cross-sectional studies
(17). Evidence also suggests that a muted or inhibited immune
response contributes to the maladies associated with an aging
immune system. Proinflammatory changes in particular can
alter communication between the peripheral and central ner-
vous system immune systems (18), dampened the normal anti-
inflammatory response, and facilitate a chronic proinflamma-
tory state in the brain which leads to production of proinflam-
matory cytokines and harmful reactive oxygen and nitrogen
species (18).
Immunosenescence can be further exacerbated by adverse
psychosocial factors. In particular, evidence is increasing that
psychosocial stressors can stimulate proinflammatory mole-
cules such as elevated interleukin-6 (IL-6), tumor necrosis
factor-alpha (TNF-a), and interferon-gamma (IFN-g) (19). A
proinflammatory milieu is also promoted by adverse lifestyle
factors such as a diet high in sugar or saturated fat content,
smoking, or increased body mass index. The proinflammatory
cytokine, IL-6, has been consistently found to be increased in
depressive disorders, and treatment with antidepressants sig-
nificantly decreases peripheral levels of IL-6 (20). Elevated
IL-6 levels in the cerebrospinal fluid have been correlated
with increased suicide risk and with attempt severity (21).
Meta-analysis has shown that peripheral levels of other
inflammatory molecules such as TNF-a, IL-13, IL-18, IL-12,
soluble IL-2 receptor, IL-1 receptor antagonist, and soluble
TNF receptor 2 were elevated in individuals with major
depression compared with control groups.
Besides looking at peripheral markers, a cross-sectional
positron emission tomography study used F-FEPPA ligand
to measure the association of translocator protein total distri-
bution volume (TSPO VT), a marker of microglial activation,
with the duration of untreated major depressive disorder. A
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positive association between the duration of illness and TSPO
VT was found (22). Alternatively, studies of healthy partici-
pants demonstrate that classic depressive symptoms can be
induced by infusing endotoxin, which triggers cytokine
release (23). Although the exact role of each of these inflam-
matory molecules and processes is still not fully understood,
clear evidence exists to show that these immune mediators
are dysregulated and sometimes correlated to disease severity
in depressive disorders.
Cardiovascular Mechanisms
Aging is associated with increased vascular dysfunction
(24). As people age, two major changes affect the arteries:
large artery stiffening and endothelial dysfunction. Stiffen-
ing of the large arteries diminishes elasticity and compli-
ance (25). Endothelial dysfunction is associated with a
significant increase in the production of a wide range of
cytokines, exacerbating the heightened inflammatory state
of the aging vasculature (26). The vascular hypothesis of
depression proposes “cerebrovascular disease may predis-
pose, precipitate, or perpetuate some geriatric depressive
syndromes” (27). Vascular depression, named for this
hypothesis, is characterized by executive dysfunction, psy-
chomotor retardation, disability disproportional to the
severity of depression, and greater relapse risk (28). Pres-
ence of moderate to severe white matter hyperintensities
on neuroimaging studies, interpreted as corresponding to
cerebral small vessel disease, is a typical feature of vascular
depression (29). These white matter changes are also asso-
ciated with a slower response to citalopram treatment (30),
a finding suggestive of slower antidepressant responsive-
ness in general.
Cerebrovascular Disease
In individuals with disrupted cerebrovascular function as a
result of cerebrovascular accident (CVA or stroke), depres-
sion is common and described as “poststroke depression”
(PSD). Every year, more than 795,000 CVAs occur in the
United States (31), and about one-third of affected individu-
als develop PSD (32). In contrast to vascular depression, PSD
is a disorder of larger blood vessels. It develops in the weeks
and months following a CVA and can continue for many
years (33). The correlation of PSD with CVA lesion location
is controversial, but left hemispheric location or proximity to
the frontal pole have been proposed as probable PSD risk
factors (34). Bilateral basal ganglia damage appears to be
associated with apathetic depression (32). Current research
approaches are moving beyond a focus on lesion location
to consider the effect of CVA on larger brain networks using
techniques such as diffusion tensor imaging. Along these
lines, one study has linked poststroke apathy to damage to
the genu and splenium of the corpus callosum, left anterior
corona radiata, and white matter of the frontal gyrus, thereby
interconnecting brain regions involved in tasks such as deci-
sion making, emotional regulation, and reward-processing
(35).
284 focus.psychiatryonline.org
Non-Neurodegenerative Medical Illnesses
The bidirectional relationship between LLD and medical ill-
ness is an especially important consideration because of the
high medical burden among older adults and the frequent
ambiguity of symptom etiology. Research has shown that
many medical diseases induce or mimic depressive symptoms.
Conversely, depression can manifest itself in somatic symp-
toms or exacerbation of medical illness. Among the medical
conditions associated with depressive symptoms, the most
frequent are cardiopulmonary disorders, cerebrovascular
disease, endocrine conditions, autoimmune disorders, neo-
plasms, and neurological conditions.
Some 80% of older individuals live with at least one
chronic health condition, and 50% have two or more. There-
fore, the co-occurrence of depressive and medical symptoms
is not unexpected. The frequency of co-occurrence, however,
suggests more than coincidence. The prevalence of major
depressive disorder among patients with coronary heart dis-
ease is estimated to be between 15% and 23% (36). Among
people with diabetes mellitus, the prevalence of major depres-
sive disorder is estimated to be 12%; moreover, subsyndromal
depressive symptoms are reported to be present in 15%–35%
(37). One meta-analysis found the mean prevalence of mean-
ingful depressive symptoms to be 8%–24% in patients with
cancer and the prevalence of major depressive disorder to
be 13% (38). Among patients with multiple sclerosis, the esti-
mated prevalence of major depression is reported to be
between 19% and 54% (39). Although major depressive disor-
der is common in individuals with medical illness, the preva-
lence of subsyndromal symptoms is even higher. Milder
depressive symptoms contribute to a self-perception of poorer
health and can affect self-care and the course of a patient’s
medical illness.
The evaluation of depression in an individual with comor-
bid medical illness requires considerable clinical judgment
when deciding which symptoms might best be attributed to
one or the other etiology. Excess disability related to depres-
sion or depressive disturbances of mood, energy, appetite,
sleep, and interest can be falsely attributed to a medical disor-
der, obscuring the presence of a potentially treatable mood
disorder contribution.
Neurodegenerative Disorders
The neurocognitive disorders deserve special attention in a
discussion of medical disorders associated with depressive
symptoms. Here, again, the relationship is bidirectional and
can be ambiguous. Some evidence supports the idea that
depression is a risk factor for the development of dementia,
or major neurocognitive disorder as it is now termed. Depres-
sion can also be a consequence of cognitive decline, both as a
psychological reaction to self-observed diminished function
and also as a physiological consequence of neurodegenerative
changes. In some cases, the onset of depressive symptoms
reflects a prodromal phase of dementia (40). Cognitive symp-
toms attributed to a primary mood disorder have been labeled
“pseudodementia,” a term that is appropriately giving way to
Focus Vol. 19, No. 3, Summer 2021

a more accurate designation, the “dementia syndrome of
depression.” This newer term validates cognitive symptoms
in depression as genuine dysfunction rather than purely psy-
chodynamic or factitious. Controversy exists as to whether
depression-related cognitive symptoms represent unmasking
of a latent cognitive decline, because some longitudinal stud-
ies have reported a high rate of subsequent dementia among
patients whose depressive episodes included acutely revers-
ible cognitive symptoms (41).
In contrast to the treatment of depressive symptoms asso-
ciated with the dementia syndrome of depression, the treat-
ment outcome for depressive symptoms accompanying a
primary dementia is often disappointing. Despite some posi-
tive studies, the preponderance of evidence, including a large
recent study, suggests that antidepressants have limited value
in this endeavor (14, 42). For clinicians, a general consider-
ation is to evaluate the response to treatment and avoid pro-
longing an ineffective antidepressant trial when the target of
treatment, depressive symptoms in a person with dementia,
is failing to respond despite a reasonable trial.
Epigenetic and Genetic Factors
The contribution of epigenetic and genetic factors to the risk
for LLD is an area of current growing interest. A sizable
French investigation (the European/Australasian Stroke Pre-
vention in Reversible Ischaemia Trial [ESPRIT]) of neuropsy-
chiatric disorders in 302 participants age 65 and older
suggested that a decrease in methylation of a specific seroto-
nin transporter gene (SLC6A4) might increase the risk for
LLD (43). Another meta-analysis has linked two additional
genes that affect hippocampal plasticity and stress reactivity,
apolipoprotein E (APOE) and brain-derived neurotrophic fac-
tor (BDNF), with LLD (44). Although the number of genetic
studies is limited at present, current evidence suggests that
the genetic associations of LLD may differ from those in youn-
ger adults (45).
Depression-Executive Dysfunction Syndrome
The depression-executive dysfunction syndrome (DEDS)
attributes a characteristic depressive syndrome (with specific
cognitive and mood manifestations and a poorer response to
antidepressant treatment) to the disruption of frontostriatal-
limbic pathways among older adults (15, 46, 47). The etiology
of this condition can be vascular but can also include other
causes. The clinical profile of DEDS is characterized by apa-
thy; anhedonia; trouble with planning, initiating, and complet-
ing goal-directed activities; lack of insight; suspiciousness; and
pronounced disability (15). Apathy, in this syndrome, has been
associated with damage to cortical-subcortical networks asso-
ciated with emotion regulation, reward, and goal-directed
behavior (48).
A meta-analysis concluded that among the domains of
executive functions, planning and organization were the
ones significantly associated with poor response to antide-
pressant treatment (46). In addition to executive dysfunction
predicting poorer response to antidepressants, a marker of
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HUSAIN-KRAUTTER AND ELLISON
executive dysfunction (decreased brain activation measured
by functional magnetic resonance imaging during the Wiscon-
sin Card Sorting Task) predicted poor outcome to a psycho-
therapeutic intervention (cognitive-behavioral psychotherapy)
among individuals with LLD (49).
Dysfunctional Reward Processing
Abnormalities in the reward processing system characterized
by a reduction in reward responsiveness have also been sug-
gested as a contributing factor (50); this finding is further dis-
cussed in the Psychotherapy section in relationship to the role
of Engage therapy.
Psychosocial Factors
Adverse life events, lack of social support, loneliness, and
lower income are among the psychosocial risk factors associ-
ated with LLD (51). Loneliness, even in prepandemic times,
has been identified as an important stressor in later life. In a
large longitudinal cohort study of older adults, 43% reported
feeling lonely (52). In another study, the long-term trajectory
of depression was affected by loneliness in a cohort of elderly
Finnish adults (53). The mechanisms underlying the associa-
tion between loneliness and LLD are not entirely clear, but
various theories have been proposed. Perceived isolation or
loneliness results in increased sympathetic tone, increased
systemic inflammation, and decreased sleep (54), which, in
turn, exacerbate depressive symptoms. During the later years
of life, when social interactions may be restricted, disruption
of the dyadic relationship takes on a particular importance
in exacerbating depression; this relationship must also be
taken into account when implementing treatment interven-
tions. Complex persistent bereavement disorder overlaps
symptomatically with LLD, or can co-occur, and both disor-
ders have been associated with increased morbidity and mor-
tality. Following the loss of a spouse, the period of greatest
relative mortality risk occurs between 7 and 12 months after
the event (55).
Bereavement is one of the psychosocial stressors that
increases suicide risk. Assessment of suicide risk, which is
an essential component in the evaluation on an individual
with LLD, is therefore very important when bereavement
has occurred. Suicide risk can be reduced by recognizing
reduced social support, by screening for suicidal ideation or
behavior, and by enrolling high-risk individuals in appropriate
follow-up (such as that described in the innovative Prevention
of Suicide in Primary Care Elderly: Collaborative Trial [PROS-
PECT], which evaluated suicide risk in a primary care setting
to prevent adverse outcomes) (7).
Other Factors
Prescribed medications, sometimes helpful for a medical
condition or believed to reduce symptoms such as insomnia,
may inadvertently contribute to the symptoms of LLD.
Angiotensin-converting enzyme (ACE) inhibitors, beta block-
ers, corticosteroids, and other medications used by many
older adults have been linked with initiation or exacerbation
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TABLE 1. Instruments used to screen for late life depressiona (CBC), comprehensive meta-
Time required for bolic panel, and thyroid-stimu-
Who No. of administration In public lating hormone (TSH). When
Instrument administers? items (minutes) domain? clinically indicated, additional
SELFCARE (D) Self 12 5–7 Yes tests such as estradiol and testos-
Center for Epidemiological Self 20 20 Yes terone levels as well as vitamin D
Studies Depression Scale
(64), vitamin B12 (65, 66), or
Center for Epidemiological Self 10 10 Yes
Studies Depression Scale-10 folate (67, 68) levels are also
Geriatric Depression Scale-Long Self 30 5–7 Yes checked. C-reactive protein lev-
Form els can assess the presence of
Geriatric Depression Scale-Short Self 15 5–7 Yes an ongoing inflammatory pro-
Form
cess. On the basis of the history
Patient Health Questionnaire-2 Self 2 5 Yes
Patient Health Questionnaire-9 Self 9 5 Yes and physical examination, one
Cornell Scale for Depression in Provider 19 1 19 20 Yes may also consider neuroimaging
Dementia and sleep assessment for
Beck Depression Inventory Self 21 10 No selected patients.
Hamilton Depression Rating Provider 21 20 Yes
Objective assessment of
Scale
Montgomery-Åsberg Provider 10 20–30 Yes depressive symptoms using an
Depression Rating Scale appropriate rating scale can
a
More information and links to instruments are available at https://www.apa.org/depression-guideline/assessment.
help to guide and monitor effec-
tive treatment. Table 1 provides a
list of instruments that can be
of depressive symptoms (56). The effect of aging on the hor- used to screen and track treatment outcomes among older
monal internal milieu is also significant. Postmenopausal individuals. Providers are encouraged to use the tools that
loss of normal estradiol cycling has been proposed to increase are best suited to their patients and practice settings. Each
depressive symptoms in LLD via effects on neurotransmitter instrument has a relatively high and comparable degree of
and mood regulatory systems. Specific estrogen receptor poly- sensitivity and specificity, but these measures vary depending
morphisms have been associated with heightened depression on the studied populations; a detailed summary of these var-
risk among older women, and maintenance of normal estro- iations is beyond the scope of this article. In addition, a cogni-
gen levels is important for several brain regions vulnerable tive screening test such as the Saint Louis University Mental
to age-related changes (e.g., the prefrontal cortex and hippo- Status Examination (69) or the Montreal Cognitive Assess-
campus) (57). ment (70) should be part of the routine assessment of LLD
One review has called attention to the possibility that this because of the frequent co-occurence of cognitive symptoms
hormonal change is growing in importance as increased life among people with LLD. The presence of these symptoms
expectancy prolongs the duration of postmenopausal life may indicate the prodrome of a neurocognitive disorder
(58). Testosterone, too, may play a role in mood regulation, (71). Regardless of whether these symptoms are prodromal
and testosterone levels appear to be of significance in both to neurocognitive decline, their presence may be clinically sig-
men and women. Augmentation with low-dose testosterone, nificant, and their response to treatment may be important to
in one trial, improved depressive symptoms among women measure.
(59), although the association between depression and low
testosterone in other studies has been inconsistent (60, 61).
TREATMENT APPROACH
Among hypogonadal men with depression, exogenous supple-
mentation of testosterone has been reported to be beneficial Psychosocial and somatic treatment interventions have each
(62, 63). been shown to be effective in treating LLD. Nonpharmacolog-
ical strategies, alone or with somatic therapies, should be
strongly considered and discussed when planning initial treat-
ASSESSMENT
ment because they can be highly effective and are preferred by
Comprehensive biopsychosocial assessment is warranted many patients.
when an older adult presents with depressive symptoms.
Evaluation begins with a careful history of prior episodes Physical Activity
and risk factors, delineation of symptoms, exclusion of Encouraging appropriate physical activity is both preventive
symptom-inducing or treatment-complicating medical dis- and therapeutic with respect to LLD. Physical inactivity
eases or toxins (including medications and recreational sub- among older adults is associated with depression and cogni-
stances), and identification of acute suicide risk. Laboratory tive deficits, whereas greater midlife physical activity is linked
evaluation, to rule out treatable medical disorders that mimic with lower depressive symptomatology in later life. A study of
depression, routinely includes the complete blood count 140 patients showed that engagement in physical activity was

286 focus.psychiatryonline.org Focus Vol. 19, No. 3, Summer 2021


associated with lower levels of depression and anxiety (72).
Exercise has been shown to reduce inflammation and oxida-
tive stress (73). Evidence indicates that physical exercise can
be comparable with antidepressant medication in achieving
therapeutic response rates (74, 75); moreover, the addition
of exercise to pharmacological treatment is linked to higher
and faster remission rates in LLD (76). Although aerobic activ-
ity has been consistently shown to be effective in LLD (77),
the dose-response relationship has yet to be fully established
(78).
Restful Sleep
Reduced ability to initiate and maintain sleep, especially after
age 50, is part of the normal aging process (79). Disturbed
sleep, however, is also a characteristic feature of depression
that may even anticipate mood symptoms during a depressive
episode. When both sleep disturbance and mood symptoms
are present, the trajectory of depression is likely to include
longer and more severe episodes as well as higher relapse
rates (80). In addition, incomplete resolution of insomnia por-
tends relapse of other depressive symptoms (81). Conse-
quently, addressing insomnia, discussing sleep hygiene, and
incorporating sleep measures into follow-up care are crucial
ingredients of LLD care. In pilot studies, newer nonpharma-
cologic modalities such as brief behavioral treatment for
insomnia show promise in effectively treating insomnia
among older adults (82).
Appropriate Nutrition and Microbiome Health
A growing body of research supports and characterizes the
clinical significance of a gut-brain axis and elucidates a
possible contribution of gut microbiome dysfunction to
depressive symptoms. This relationship may reflect the asso-
ciation between inflammatory states and gut barrier health
(83). Additional evidence suggests that alterations in the gut
microbiome affect serotonin levels in the central and periph-
eral nervous system. Probiotics have been shown to improve
depressive symptoms, decrease levels of inflammatory
markers, and increase serotonin availability (84). These com-
pelling data suggest the value of additional research among
patient populations.
Additional Lifestyle Factors
Smoking is associated with higher rates of depression among
older adults compared with those who have never smoked
(85). For this and other health reasons, smoking cessation
should be encouraged and assisted. At-risk and problem
drinking of alcohol also elevate the potential for depressive
symptoms. The co-occurrence of alcohol use disorders and
depression increases the potential for poor mental and general
health outcomes among older adults. Alcohol dependence is
both a risk factor for LLD and an obstacle to effective treat-
ment (70). Addressing alcohol misuse in late life is important.
Targeted screening that takes into account alcohol consump-
tion and life context can help to identify older adults at higher
risk for excessive or problematic drinking (86), which is a
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HUSAIN-KRAUTTER AND ELLISON
problem in its own right that also undermines treatment
of LLD.
PSYCHOTHERAPY AND SOMATIC TREATMENT
INTERVENTIONS
Psychotherapy
Evidence-based psychotherapies, alone or with pharmaco-
therapy, are recommended for older individuals with mild
to moderate depression (70); they are also recommended for
individuals with inadequate or adverse response to therapeu-
tic doses of antidepressants or who are at risk for drug inter-
actions secondary to polypharmacy, which is a particularly
important concern among older adults. However, cognitive
and sensory impairments as well as access issues such as ther-
apist unavailability, impaired patient mobility, and limited
transportation options can interfere with this form of treat-
ment. Randomized controlled trials have provided support
for the efficacy of several psychotherapeutic approaches,
which can be chosen and customized on the basis of individ-
ual needs and resources. Cognitive-behavioral therapy (CBT),
problem-solving therapy (PST), interpersonal therapy (IPT),
and Engage therapy (87) have been shown effective in treating
LLD (88). Each of these approaches is amenable to delivery
within a time frame that is customized for the individual, in
briefer sessions if necessary and in a problem-focused manner.
CBT, which is based on the premise that inaccurate beliefs
lead to maladaptive thoughts and behaviors, is an established
and effective approach to treating LLD. In CBT, the therapist
is an interactive coach and teacher, helping a patient to iden-
tify and alter dysfunctional cognitions while also encouraging
behavioral activation and the scheduling of pleasant events. A
recent multicenter study showed CBT, with modifications, to
be effective in treating LLD (89). These modifications concern
both the delivery of treatment and the content of sessions
(90). Older adults sometimes find it easier to participate in
shorter but more numerous sessions. Engagement with the
issues can be enhanced through use of summarization and
symptom assessment. Behavioral interventions should target
the concerns most relevant to older adults, such as counteract-
ing loneliness through an increase in social engagement.
PST conceptualizes depression as a consequence of a skill
deficit. Acting as a sort of project manager and coach, the PST
therapist helps a patient with depression to learn and apply
new skills or to utilize abilities that were not learned or
have fallen into disuse (91). The PST therapist teaches effec-
tive problem-solving techniques by providing a structured
approach for defining a goal, planning a strategic solution,
and monitoring progress toward success, which can be used
in diverse populations (92). In one studied cohort, PST was
significantly more efficacious than supportive therapy in
reducing suicidality among older adults with major depressive
disorder and significant executive dysfunction (93). This and
other evidence suggest that PST may even have a role in treat-
ing older adults with depression and mild degrees of cognitive
impairment (94).
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TABLE 2. Antidepressants and augmenters commonly used in the to life changes as treatable life disruptions rather than
pharmacotherapy of late life depressiona moral failures. Redefining problems in this way reduces
Antidepressant class and medication Typical dose (mg/day) self-blame and clarifies the relationship between depres-
SSRI sive symptoms and life events. Identifying and processing
Citalopram 10–20 the precipitating circumstances with IPT can counteract
Escitalopram 5–20 depressive symptoms.
Fluoxetine 10–40 Engage therapy claims to differ from other psychothera-
Sertraline 50–200
pies as a result of its grounding in the principles of the
Vortioxetine 10–20
Vilazodone 10–40 Research Domain Criteria (RDoC) initiative, an effort to inte-
Paroxetine 10–30 grate multiple levels of evidence (genetics, molecules, cells,
SNRI circuitry, behavior, physiology, and self-report) to explore
Venlafaxine 75–225 basic elements of functioning to better understand and treat
Desvenlafaxine 25–50
mental illness. Engage therapy postulates that depression
Duloxetine 30–120
Levomilnacipran 20–120 reflects dysfunction of the positive valence (reward) system,
TCA and it uses reward exposure as its principal intervention to
Nortriptyline 20–150 depressive symptoms (96). In RDoC terms, the commonly
Desipramine 50–200 encountered barriers to treatment response are negativity
MAOI
bias (negative valence system dysfunction), apathy (arousal
Tranylcypromine 30–60
Phenelzine 60–90 system), or emotional dysregulation (cognitive control dys-
Selegiline (Emsam)b 3–6c function). Strategies targeting these dysfunctions are added
Miscellaneous antidepressants when needed. For example, methods for addressing negativity
Bupropion 100–300 bias can include discussing or writing alternative positive
Mirtazapine 15–45
explanations to negative thoughts. Strategies for addressing
Esketamine 84d
Agomelatinee (104) 25–50 apathy can consist of prompts to initiate action plans or
Antipsychotic-antidepressant even reminders from others. Emotional dysregulation can be
Quetiapine 100–600 countered by mindfulness activities such as meditation or
Antidepressant combinations deep breathing (96).
SRI1mirtazapinef
An additional promising related nonpharmacologic
SRI1bupropionf
Bupropion1mirtazapinef approach, computerized cognitive remediation, uses com-
Augmenters puter software designed to provide training in cognitive con-
Lithium carbonate (105)g trol and to enhance responsiveness of the reward system (97).
Triidothyronine (106) 25–50h This type of approach is personalized and continuously adapts
Methylphenidate (107) 2.5–5i
its level of difficulty on the basis of the individual’s aptitude,
Aripiprazole (108) 10–15
Brexpiprazole (109) 1–3 both at baseline and through the course of treatment; this
Testosteroneb (110) 100–200j approach also provides consistent supportive feedback to
a
SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine
avoid frustration or discouragement (15).
reuptake inhibitor; TCA, tricyclic antidepressant; MAOI, monoamine oxidase
inhibitor; SRI, serotonin reuptake inhibitor. Pharmacotherapy
b
Available for transdermal administration.
c
Per 24 hours.
Despite research demonstrating the importance of psychoso-
d
Twice per week. cial factors, the treatment of LLD in specialty settings or pri-
e
Not available in the United States. mary care very often relies upon the use of pharmacotherapy.
f
In combination, doses up to individual agent maximum levels can be used
with caution and appropriate monitoring.
Studies have shown that among older individuals with moder-
g
Dosed to target $0.5 mmol/L. ate to severe depression, antidepressants are more efficacious
h
Dosed in micrograms. when compared with placebo (81). Any of the FDA-indicated
i
Twice per day.
j
Intramuscular/weekly.
antidepressants may be used, with a reported response rate of
50%–65% in randomized controlled trials with intention to
treat compared with a 25%–30% response to placebo treat-
IPT was designed to address depression arising from ment. The intention to treat remission rate with treatment is
alterations in one’s interpersonal environment. It focuses lower: 30%–40% versus 15% for placebo (98). Individual risks
on one or two of four areas frequently encountered in and benefits are likely to vary as a result of pharmacokinetic
LLD: role transitions (significant life change), role disputes and pharmacodynamic differences that affect the interaction
(conflict with a partner or another person), death of a loved between patient and medication. In cases of treatment resis-
one (complicated grief ), and interpersonal deficits (isola- tance, augmentation strategies and coprescribing have suc-
tion and loneliness or lack of a purpose) (95). Individuals cessfully been used. Table 2 lists some of the commonly
with LLD often blame themselves inaccurately, and an used antidepressants and augmenters in LLD with typical
IPT therapist can help the individual reframe the reactions dosing ranges (99–106).

288 focus.psychiatryonline.org Focus Vol. 19, No. 3, Summer 2021


It is not our goal here to offer TABLE 3. Pharmacologic basis of adverse medication effects in the pharmacotherapy of late life
a
specific guidance regarding choice depression
of antidepressant, an exhaustive Medication property
list of antidepressants, or the pro- NE reuptake blockade
cedure for dosing and monitoring
treatment, all of which have been Serotonin reuptake blockade
reviewed extensively elsewhere
Dopamine reuptake blockade
(107). General pharmacotherapy
Histamine H1 receptor antagonism
principles in LLD include choos-
ing a medication with an eye to Muscarinic receptor antagonism
potential adverse effects, starting
at a low dose, increasing gradually NE a 1 receptor antagonism
to optimal benefit, and discontinu-
a
ing after nonresponse or appropri- NE, norepinephrine; GI, gastrointestinal; EPS, extrapyramidal symptoms; CNS, central nervous system.
ate response and maintenance.
Treatment-resistant depression often requires the use of an
augmenter or combination intervention, whereas depression
with psychotic features usually requires the combination of
an antidepressant with an antipsychotic medication. After
remission is achieved, relapse and recurrence rates are dimin-
ished by maintenance pharmacotherapy. The focus in success-
ful treatment of LLD must reach beyond treatment of the
individual episode and take into account the long-term view,
which includes maintenance therapy for prevention of future
episodes. In the context of recurrent LLD episodes, extended
maintenance pharmacotherapy has been suggested, and lim-
ited evidence is available to help the clinician assess the opti-
mal time for antidepressant discontinuation (108).
As in the adult population, careful management of adverse
effects is an essential element of successful pharmacotherapy.
Selective serotonin reuptake inhibitors are commonly associ-
ated with gastrointestinal side effects, changes in weight,
hyponatremia, sexual dysfunction, and bruising; they are
much less frequently associated with some more serious
adverse effects, including gastrointestinal bleeding and car-
diac arrhythmias. Tricyclic antidepressant (TCA) use has
been associated with sedation, postural hypotension, and anti-
cholinergic side effects such as blurred vision, constipation,
urinary retention, and confusion. Less frequent but more
severe events include delirium and cardiac conduction distur-
bances, including ventricular arrhythmias that account for the
lethality of TCA overdose.
Broadly, antidepressant side effects can be anticipated on
the basis of the medications’ pharmacokinetic characteristics
and the pharmacodynamic properties of the medications
listed in Table 3; practitioners can anticipate and monitor
parameters accordingly. In general, our recommendation is
that for older individuals with LL D whose symptoms are
managed with antidepressants, providers should consider
obtaining a baseline electrocardiogram, CBC, and basic meta-
bolic panel before initiating medications. These parameters
can be reviewed after dose titration or as clinically indicated.
Neuromodulation
Electroconvulsive therapy (ECT) remains an effective but
underused treatment option for LLD (109, 110). ECT is
Focus Vol. 19, No. 3, Summer 2021
HUSAIN-KRAUTTER AND ELLISON
Possible clinical consequences
Tremors, tachycardia, erectile and ejaculatory dysfunction,
elevated blood pressure
GI symptoms, sexual dysfunction, EPS, bruising and
bleeding, bone mass density loss
Activation, aggravation of psychosis
CNS depressant potentiation, sedation, weight gain,
hypotension
Blurred vision, dry mouth, constipation, urinary retention,
cognitive dysfunction
Some antihypertensive potentiation, postural hypotension,
dizziness, reflex tachycardia
especially useful among individuals with antidepressant intol-
erance or nonresponse; it is also beneficial when treating LLD
associated with delusions, catatonia, and mania (87). The
acute antidepressant efficacy of ECT has repeatedly been
shown superior to other antidepressant treatment modalities,
including pharmacotherapy and psychotherapy. Because of its
rapid effect, ECT is the treatment of choice for patients who
are urgently ill, including those with psychosis and strong sui-
cidal ideation from depression. ECT treatment of LLD can be
associated with transient memory disturbance and significant
posttreatment relapse rates; however, the procedure is consid-
ered relatively safe for older adults and has been demon-
strated to be one of the most effective treatment options for
LLD (111). No definitive guideline has identified the optimal
number of ECT treatments for patients with LLD. One influ-
ential suggestion, from the 2009 Prolonging Remission In
Depressed Elderly (PRIDE) study, is to provide at least four
additional maintenance ECT treatments following a success-
ful course of ECT, with further treatments as clinically indi-
cated (112).
Repetitive transcranial magnetic stimulation (rTMS) is an
additional neuromodulatory approach that has consistently
been reported as safe and well tolerated with minimal cogni-
tive adverse effects and a low dropout rate. Evidence of
efficacy of rTMS in treating patients with LLD who have
failed antidepressant treatments, including patients with
treatment-resistant vascular depression (113), has generated
interest in its use as a first line treatment. Many clinicians
and patients see it as an alternative to medications suitable
for individuals hesitant to undergo or unable to tolerate
ECT. Older individuals require some modifications of rTMS
administration, such as adjustment of the treatment schedule
and the use individualized treatment protocols. Identification
of factors predictive of rTMS response will further improve
its therapeutic potential (114). Deep rTMS is a technical
refinement that compensates for age-associated brain atrophy,
which increases the distance of the brain from the applied
magnetic field. A recent study showed that delivery of
deep rTMS using an H1 coil over the dorsolateral and
ventrolateral prefrontal cortex achieved a higher remission
rate than sham rTMS (40.0% vs. 14.8%) and may be especially
focus.psychiatryonline.org 289
LATE LIFE DEPRESSION
suitable for use among patients with treatment-resistant
LLD (115).
Collaborative Care
Given the shortage of geriatric psychiatrists and the preva-
lence of LLD, researchers have explored methods for improv-
ing the recognition and management of LLD in primary care
settings. The IMPACT study, which is one of the larger treat-
ment trials for LLD, showed that a collaborative care model
can increase the effectiveness of treating LLD in primary
care settings. Older adults are more likely to seek depression
treatment from a primary care provider than from a mental
health specialist; however, treatment as usual in primary
care may is less efficacious than collaborative treatment in
the primary setting that incorporates guidance from a depres-
sion care specialist.
Results from the IMPACT study showed that at 12 months,
about half of the primary care patients receiving collaborative
care for depression reported at least a 50% reduction in
depressive symptoms compared with only 19% of those in
usual care. Surveys conducted 1 year after the study showed
that the benefits of the IMPACT intervention persisted at
follow-up assessment (116). Other collaborative care models,
some of which engage community health workers, have also
been successful. These models present an effective and afford-
able approach that can improve engagement of different
racial-ethnic minority groups within the LLD population (117).
CONCLUDING COMMENTS
Depression is not a normative aspect of the aging process, but
it is an often overlooked or undertreated psychiatric disorder
among older adults. The consequences of failing to recognize
and adequately treat LLD include impaired functional capac-
ity and diminished quality of life. In later life, the most fre-
quent psychiatric antecedent of suicide is depression. People
with LLD are most often identified and treated in primary
care settings. Whether in primary care or specialized settings,
attentive and comprehensive assessment is required to avoid a
missed diagnosis or ineffective treatment plan. Early detection
and management are both desirable and challenging.
Older adults are especially vulnerable to suboptimal out-
come because of age-associated variant presentations, medical
comorbid conditions, cognitive impairment, and social deter-
minants that interfere with treatment. LLD is amenable to
lifestyle interventions, psychotherapy, or somatic approaches,
including antidepressant therapy and neurotherapeutic
approaches. Appropriate management is associated with rea-
sonably high rates of response and remission, although maxi-
mal improvement may be more limited or require a longer
duration of treatment. Individuals with vascular depression
or the depression-executive dysfunction syndrome, for exam-
ple, have been shown to respond less fully and more slowly to
conventional antidepressant pharmacotherapy (15, 30).
Given the common presentation of treatment resistance
among patients with LLD, further research is needed to guide
290 focus.psychiatryonline.org
clinicians who treat older adults with depression who fail to
respond well to typical initial approaches. Psychotherapy plays
a valuable role and can be modified to target the special needs
of older adults. Antidepressants have been shown effective, but
side effects require attentive management. Augmentation and
coprescribing strategies effective in younger adults are used in
treating people with resistant LLD, but further evaluation
among older adults is needed to propose evidence-based path-
ways for management. Additional areas for investigation
include the potential preventive value of lifestyle interventions
such as physical and mental activity, nutrition, social engage-
ment, and management of sleep disturbances.
As primary care practitioners increase their competence in
treating LLD, the psychiatrist’s role is often consultative. Psy-
chiatrists are in a unique position to assist and educate pri-
mary care colleagues in recognizing and treating LLD in its
various manifestations. A psychiatric perspective can be valu-
able in identifying important medical and psychosocial deter-
minants that are less amenable to pharmacotherapy but must
be addressed to achieve an optimal outcome.
Because LLD can vary from the depressive syndromes seen
among younger adults with respect to detection and manage-
ment, it may be valuable to call attention to its distinct char-
acteristics in the classification of mood disorders. Currently,
several variants of major depressive disorder with differential
presentations or treatment requirements are highlighted
through the use of specifiers such as “with anxious distress,”
“with mixed features,” “with melancholic features,” “with
atypical features,” “with mood-congruent psychotic features,”
“with mood-incongruent psychotic features,” or “with
peripartum onset.” Inclusion of a specifier for “with late
life onset” in future DSM editions would emphasize the
uniqueness of LLD and remind clinicians that this particular
mood disorder syndrome may be associated with different
approaches to prognosis, risk assessment, evaluation, acute
treatment, and follow-up care.
AUTHOR AND ARTICLE INFORMATION
Zucker Hillside Hospital, North Shore, Long Island Jewish Health System,
Glen Oaks, New York (Husain-Krautter); Litwin-Zucker Research Center
for the Study of Alzheimer’s Disease, Feinstein Institute for Medical
Research, Manhasset, New York (Husain-Krautter); Swank Center for
Memory Care and Geriatric Consultation, ChristianaCare, Wilmington,
Delaware (Ellison); Sidney Kimmel College of Medicine, Thomas Jeffer-
son University, Philadelphia (Ellison). Send correspondence to Dr. Ellison
(james.m.ellison@christianacare.org).
The authors report no financial relationships with commercial interests.
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