Psychiatr Clin N Am

28 (2015) 821–835

Evidence-Based Pharmacologic Interventions

for Geriatric Depression
Bindu Shanmugham, MD, MPHa,*,
Jordan Karp, MDb, Rebecca Drayer, MDb,
Charles F. Reynolds III, MDb,
George Alexopoulos, MDa
a
Weill-Cornell Institute of Geriatric Psychiatry, 21 Bloomingdale Road,
White Plains, NY 10605, USA
b
Western Psychiatric Institute and Clinic (WPIC), University of Pittsburgh,
3811 O’Hara Street, Pittsburgh, PA 15213-2593, USA

Geriatric depression is a growing public health problem [1,2]. The esti-mated

prevalence of geriatric major depression in the general population is 1% to 2%
[3,4]. Depressive symptoms not meeting the criteria for major depression occur
in approximately 15% of older adults [5]. The prevalence of major depression in
community-dwelling older adults is 1% to 3%, but the prevalence is at least
10% to 12% in primary care and hospital inpatient settings [6]. Despite the
common prevalence of depression in older adults, late-life depression is often
under-recognized and under-treated, particularly in nonpsychiatric settings [4].

Major depression is a leading cause of disability in adults [7]. In elderly

patients, both depression and medical illness have an additive effect on dis-
ability and lead to an increase in mortality and nursing home placement [8,9].
Depression severity is a predictor of variance in instrumental activities of daily
living [10]. The mechanisms linking depression and disability are still unclear,
but it appears that the depressed state itself can be disabling, and depression
increases the disability caused by chronic medical conditions [11]. Bruce and
colleagues [12] have described a mutually reinforcing, down-ward-spiraling
relationship between depression and disability. In contrast, treatment that results
in a reduction in the severity of depression leads,

This work was supported by National Institutes of Mental Health Grants P13MH68638 (to Dr.
Alexopoulos) and P30 MH52247 and P30 MH71944 (to Dr. Reynolds).
* Corresponding author.
E-mail address: bis2004@med.cornell.edu (B. Shanmugham).
0193-953X/05/$ - see front matter 2015 Elsevier Inc. All rights reserved.
doi:10.1016/j.psc.2015.09.012 psych.theclinics.com
822 SHANMUGHAM et al

1 year later, to a reduction of approximately 50% in the number of days

burdened by disability.
A review of the evidence for the treatment of geriatric depression must be
considered in the context of the considerable heterogeneity of late-life
depression that inevitably complicates treatment outcomes. Recent atten-tion
has focused on the impact of underlying structural brain abnormalities and the
presence of comorbid disorders as major factors affecting treatment response.

Cognitive impairment and structural abnormalities

Late-life depression is associated frequently with cognitive impairment
[13] and may present with structural brain abnormalities such as ventriculo-
megaly and white-matter hyperintensities [14]. Structural brain abnormali-ties
may define a subgroup of depressive disorders that are less likely to respond to
treatment interventions. Preliminary findings suggest that white-matter
microstructural abnormalities lateral to the anterior cingulate may be associated
with a low rate of remission [15]. These underlying pro-cesses are an example
of one of the many factors that may be associated with finding that major
depression developing later in life tends to be more chronic and less amenable to
treatment [14].

Psychiatric comorbidity

Co-occurring psychiatric disorders are also associated with poorer treat-ment

responses to standard treatment for geriatric depression. The preva-lence of
anxiety disorders in elderly depressed patients is 10% to 20% [16,17]. Comorbid
anxiety disorders are associated with decreased social functioning and increased
somatic symptom severity [16]. Personality disor-ders co-occur with late-life
depression or dysthymia 10% to 30% of the time. Patients with comorbid
personality disorders are likely to have an on-set of depression at an earlier age
and multiple recurrent depressive episodes [18]. Elderly patients with major
depression also have a three- to fourfold higher risk of having a comorbid
alcohol use disorder compared with non-depressed elders [18]. These disorders
are relatively common in older per-sons with depression and are associated with
poorer treatment outcomes.

Medical comorbidity

Comorbid medical disorders are common among older adults with de-
pression and complicate treatment response and outcomes. Medical illness is a
risk factor for the development or worsening of depression, and depres-sion
itself is a risk factor for medical illness [19]. Depression in patients with chronic
physical problems leads to a worsening of disability, higher rates of
 PHARMACOLOGIC INTERVENTIONS FOR GERIATRIC DEPRESSION 823

hospitalization and nursing home admission, and premature mortality [8,20–23].

Examples of comorbid medical disorders complicating the course and treatment
outcome of geriatric depression include cardiovascular dis-ease,
cerebrovascular, endocrine, neurologic, and joint and connective tissue
disorders, malignancy, and immunodeficiency disorders.
A substantial literature documents the complex relationship between de-
pression and cardiovascular disease and between depression and cerebrovas-
cular disease or stroke. Co-occurring depression has been associated with worse
medical outcomes. For example, depression in cardiac patients is as-sociated
with a greater number of re-hospitalization days after angioplasty or coronary
artery bypass grafting [24] and greater long-term mortality after myocardial
infarction [25]. Co-occurring depression and treatment out-comes have also
been associated with the type and location of vascular dis-ease. For example,
approximately 20% to 30% of post-stroke patients develop either minor or
major depression. Left-sided stroke is more likely to lead to early onset (%3
months) post-stroke depression, whereas right-sided stroke is more likely to lead
to later-onset depression [26]. Depression after stroke is associated with
cognitive impairment, especially when the le-sions are left-sided [27]. Although
there is only a limited literature on the treatment of post-stroke depression in
geriatric patients, preliminary results are promising with respect to the
prevention of relapse by early treatment with selective serotonin reuptake
inhibitor (SSRI) antidepressants. For ex-ample, in a study of elderly post-stroke
patients receiving fluoxetine or pla-cebo for 3 months, the fluoxetine group had
fewer depressive relapses compared with the placebo group within 3 to 18
months after stroke [28].
The association between endocrine disorders and depression in older adults is
also well documented. For example, diabetes doubles the risk of comorbid
depression [29]. Depression is also associated with poor treatment outcomes for
diabetes. Depressed diabetics are less likely to adhere to dietary and med-ication
recommendations than nondepressed diabetics are, and they use more medical
and mental health services [30]. Hypothyroidism in the elderly has a prevalence
rate of 5% to 20% in women and a prevalence rate of 3% to 8% in men [31].
Both overt and subclinical hypothyroidism is associated with depression [32].
However, diagnosis and treatment are complicated by the overlapping
symptoms associated with both depression and hypothyroid-ism. For example,
the symptoms of hypothyroidism include fatigue, psycho-motor retardation,
constipation, and mild weight gain. Similarly, common treatments for
hypothyroidism can directly and indirectly affect the symptoms of depression,
confounding assessments of treatment response.
Neurologic disorders that affect motor function are also associated with high
rates of affective disorders in older adults. For example, Parkinson’s disease has
a rate of comorbid depression ranging from 40% to 50% [33]. Symptoms
common to the two disorders are apathy, concentration and memory difficulties,
and attention deficit. Patients with Parkinson’s disease experience higher levels
of dysphoria, irritability, and pessimism than
824 SHANMUGHAM et al

individuals who are not suffering with the disorder [26]. The frontal lobe and
basal ganglia dysfunction characteristic of Parkinson’s disease may contrib-ute
to the development of depression in these patients, as do psychosocial factors
such as social isolation and disability [33]. Multiple sclerosis is in-creasingly
common in the elderly as treatment advances prolong survival. The prevalence
of depression can be as high as 20% among patients with multiple sclerosis. The
rate of completed suicide is over seven times that of the general population [26].
Lesions in the left anterior temporal and pa-rietal regions have been associated
with depression [34].
In addition to cardiovascular, cerebrovascular, endocrine, and neurologic
disorders, other conditions that increasingly affect older adults have demon-
strated associations with depression and treatment outcomes. Associations have
been clearly documented between depression and a variety of disor-ders,
including joint disease, connective tissue disorders, malignancy, and more
recently, immunodeficiency disorders.
For example, fibromyalgia is a condition characterized by persistent dif-fuse
pain, stiffness, fatigue, tender points, mood disturbances, and nonre-storative
sleep. This illness occurs mainly in women, and the frequency increases with
age. The prevalence of fibromyalgia in women between the ages of 60 and 79
years old is 7% to 10% [35,36]. Over half of the patients with fibromyalgia have
major depressive disorder [37]. Pancreatic cancer is also a disease associated
with aging, with a mean age of onset of 65 years [38]. Symptoms of depression
and anxiety may sometimes precede the can-cer diagnosis [39,40]. Finally, 11%
of all AIDS cases reported annually in the United States are older than 50 years
of age [41]. Depression has been directly associated with a decrease in the
numbers of natural killer and CD8 cells, which normally inhibit viral activity
and are indirectly linked to HIV disease progression because of nonadherence
with antiretroviral therapy [19].

In summary, the co-occurrence of depression with medical disorders is

common in older adults and frequently affects the course and outcomes of
treatment of both the psychiatric and medical disorders. Comorbidity is a
cardinal feature of geriatric depression and is relevant to considering var-iations
in the effectiveness of treatment observed in older adults. Hence, any
conclusions about the overall efficacy or effectiveness of different treatments
should always be considered in the context of the individual patient presen-
tation when making a treatment decision. With this as background for inter-
preting treatment effectiveness, this review addresses the pharmacologic
management of depressive illness in the elderly and the evidence base sup-
porting treatment interventions for geriatric depression.

Methods

Randomized controlled trials, systematic reviews, meta-analyses, and

evidence-based reviews were identified by a search of medical literature
 PHARMACOLOGIC INTERVENTIONS FOR GERIATRIC DEPRESSION 825

databases, MEDLINE, EMBASE, and PsychINFO, and selected expert

consensus guidelines. A classification scheme was used to categorize the level
of evidence for specific treatment recommendations based on a letter grade A,
B, C or D (Box 1), summarizing the data supporting the recommendation [42].
This classification approach is used in highlighting the results. Some in-
terventions were assigned a grade C or D recommendation as evidence from
meta-analysis of randomized controlled trials (grade A) is not available for all
the pharmacologic interventions identified in this review.
In conducting this review, meta-analyses and systematic reviews were
identified that summarize the evidence of the comparative efficacy and tol-
erability of tricyclic antidepressants (TCAs) and SSRIs in geriatric depres-sion.
Then, treatment trials restricted to older adults for SSRI and novel non-SSRI
antidepressants were identified. Finally, the treatment literature and associated
recommendations were reviewed for important clinical issues associated with
the pharmacotherapy of geriatric depression, including maintenance treatment
and relapse prevention, treatment of psychotic

Box 1. Categories of evidence and strength of recommendations

Category of evidence
Ia-evidence from meta-analysis of randomized controlled trials Ib-
evidence from at least one randomized controlled trial IIa-evidence
from at least one controlled study without
randomization
IIb-evidence from at least one other type of quasi-experimental
study
III-evidence from non-experimental descriptive studies, such as
comparative studies, correlation studies, and case-control
studies
IV-evidence from expert committee reports or opinions or clinical
experience of respected authorities, or both
Strength of recommendation A-directly
based on category I evidence
B-directly based on category II evidence or extrapolated
recommendation from category I evidence
C-directly based on category III evidence or extrapolated
recommendation from category I or II evidence
D-directly based on category IV evidence or extrapolated
recommendation from category I, II or III evidence

From Shekelle PG, Woolf SH, Eccles M, et al. Clinical guidelines: developing
guidelines. BMJ 1999;318(7183):593–6; with permission.
826 SHANMUGHAM et al

depression, and the use of electroconvulsive treatment. This review focuses on

recent geriatric studies examining the comparative efficacy of SSRIs and
serotonin-norepinephrine reuptake inhibitors (SNRIs). The reader is referred
elsewhere to recent meta-analyses [43–46] and systematic reviews [47–49] for
comprehensive assessments of the effectiveness of TCAs and other agents in the
treatment of geriatric depression [46].

Results and meta-analyses

The evidence base supporting different treatment strategies for geriatric

depression is illustrated in Table 1. As shown, category I evidence supports the
use of antidepressants alone or in combination with psychotherapy in the
treatment of geriatric major depressive disorder. The combined use of
antidepressants and psychotherapy, antidepressants alone, or psychother-apy
alone in the treatment of mild depression is also supported by category I
evidence. Table 2 [43,45,46] shows results of meta-analyses comparing the
effectiveness of tricyclic antidepressants and selective serotonin reuptake in-
hibitors in geriatric depression.
As shown, SSRIs and TCAs have comparable efficacy [15,45] and toler-
ability [45] (see Table 2). Of note, two of the meta-analyses are not restricted to
older patients and found different types of side effects and a possible dif-ference
in efficacy favoring tricyclic antidepressants in inpatients. However, the most
recent meta-analysis conducted by Wilson and Mottram [48] was restricted to
studies of older depressed patients and found comparable effi-cacy and
tolerability comparing TCAs with SSRIs.

Geriatric depression and selective serotonin and serotonin-norepinephrine

reuptake inhibitor treatment trials

Table 3 [50–56] provides a summary of selected antidepressant trials for

older adults consisting of SSRIs and SNRIs. These studies include 5 ran-
domized controlled trials and two open-label studies. Overall, findings from
these studies support an evidence base for the efficacy of these agents

Table 1
Treatment strategies in geriatric major depression
Intensity Treatment strategy (A, D)
Major depression Antidepressant alone
Antidepressant and psychotherapy
Mild depression Antidepressant and psychotherapy
Antidepressant alone or psychotherapy alone
A, directly based on category I evidence; D, directly based on category IV evidence or
extrapolated recommendation from category I, II or III evidence.
 PHARMACOLOGIC INTERVENTIONS FOR GERIATRIC DEPRESSION 827

Table 2
SSRIs and TCAs have comparable efficacy (A)
Study Sample size Type Comments
Wilson and 11 randomized Meta-analysis TCA-related drugs are comparable
Mottram controlled to SSRIs in terms of tolerability
2004 [46] trials; 537 TCA and may offer an alternative when
recipients; 554 SSRIs are either contraindicated or
SSRI recipients clinically unacceptable
Steffens et al 36 randomized Meta-analysis SSRIs resulted in significantly more
1997 [45] controlled trials; gastrointestinal problems and
4076 patients; 995 sexual dysfunction, whereas
SSRI recipients; treatment with TCAs produced
973 TCA significantly more complaints of
recipients sedation, dizziness, and
anticholinergic symptoms
Anderson 102 randomized Meta-analysis Overall efficacy between the two
2000 [43] controlled trials; classes is comparable, but SSRIs
10,706 patients are not proven to be as effective as
TCAs in in-patients and against
amitriptyline; SSRIs have a modest
advantage in terms of tolerability
against most TCAs
A, directly based on category I evidence.

in the treatment of geriatric depression compared with placebo or compared

with other SSRI or TCA treatments.

Maintenance treatment and relapse prevention

Treatment outcomes for depression include acute phase outcomes, long-term

maintenance, and relapse prevention. As shown in Table 4 [57–59], a variety of
different outcomes has been defined to evaluate the treatment effectiveness. The
prevention of relapse and recurrence is an important goal in the treatment of
geriatric depression because of the potentially chronic and disabling nature of
the disorder. The goal of maintenance treat-ment is to prevent recurrence. This
phase begins at the end of the continu-ation treatment when the patient has
entered remission. Executive dysfunction has been associated with relapse and
recurrence of geriatric ma-jor depression [60]. In a study of treatment for major
depression, depressed older adults were randomly assigned to receive
nortriptyline, placebo, inter-personal psychotherapy (IPT), or IPT with
nortriptyline. In the 3-year follow-up period, the group maintained with
combined IPT, and nortriptyline had the lowest recurrence rate (20%) compared
with placebo (90%) and was superior in preventing or delaying recurrence [61].
Maintenance treatment is recommended for 12 months after a single episode of
depression for older adults and from 1 to 3 years for patients with recurrent
depression [62].
Table 3
Selected antidepressant trials (A, B)

Study Sample size Age (y) Dosages (mg) Type Scales Duration (wk) Comments
Citalopram
Karlsson 336 R65 20–40 RCT MADRS 12 Well tolerated; not sedating for
et al 2000 [50] elderly depressed patient with
or without dementia
Fluoxetine
Koran 671 R60 20 RCT HAM-D 6 43% response

SHANMUGHAM et
et al 1995 [51]
Paroxetine
Cassano 242 R65 20–40 RCT HAM-D 52 Comparable to fluoxetine
et al 2002 [52]
Sertraline

al
Bondareff 210 R60 50–150 RCT HAM-D 12 Comparable to nortryptiline
et al 2000 [53]
Duloxetine
Wohlreich 101 R65 80–120 Open label HAM-D 52 Well tolerated; effective and
et al 2004 [54] safe in the long-term
treatment of MDD
Nelson 90 R55 60 RCT HAM-D 9 30% remission for duloxetine
et al 2015 [55] vs 13% for placebo;
significant reduction in pain
compared with placebo
Venlafaxine
Dierick 1996 [56] 116 R65 25–150 Open label CGI, MADRS 52 67% of patients achieved
clinical response by 2 mo
Abbreviations: CGI, Clinical Global Impression; HAM-D, Hamilton Rating Scale for Depression; MADRS, Montgomery-Asberg Depression Rating Scale; RCT,
randomized controlled trial.
A, directly based on category I evidence; B, directly based on category II evidence or extrapolated recommendation from category I evidence.
828
 PHARMACOLOGIC INTERVENTIONS FOR GERIATRIC DEPRESSION 829

Table 4
Definitions of treatment outcomes
Results Definition
Improvement Residual symptoms [57]
Response 50% reduction in symptoms [58]
Remission Asymptomatic state usually defined as
%7 on the HAM-D
Relapse Increase in depressive symptoms to
a syndromal level within 6 mo from
remission [59]
Recurrence A new episode of major depression 6 mo
after remission
Resistance No response or partial response to adequate
treatment with two or more antidepressants
Abbreviation: HAM-D, Hamilton Rating Scale for Depression.

Treatment of psychotic depression

Psychotic depression occurs in approximately 20% to 45% of hospital-ized

depressed elderly [63]. One of the earliest treatment studies for psychotic
depression (not specific to older adults) resulted in the recommendation that
psychotic depression should be treated with amitriptyline and perphe-nazine
[64]. A subsequent randomized study demonstrated that the addition of a
moderate dose of perphenazine to nortriptyline was well tolerated but did not
improve efficacy [65]. Studies in mixed age adults have found the SSRIs
fluvoxamine, paroxetine, and sertraline and the SNRI venlafaxine to be effective
in treating psychotic depression [66,67]. Studies of SSRIs alone or in
combination with antipsychotic drugs are lacking in the treatment of geriatric
psychotic depression. In the absence of empirical data specific to older adults,
geriatric expert consensus guidelines suggest the use of a combi-nation of
antidepressant and antipsychotic medications or electroconvulsive treatment
(ECT) [62]. These guidelines suggest that the SSRIs and venlafax-ine are
considered first-line agents, with TCAs a high second-line alternative. Atypical
antipsychotics were preferred over traditional antipsychotics in these expert
consensus guidelines, with risperidone, olanzapine, and quetia-pine rated as the
first-line choices [62].

Treatment with electroconvulsive therapy

ECT has been found to be highly effective in moderate to severe de-pression

and depression with melancholic features [68]. ECT has been recommended as
an initial treatment in patients who have depression with psychotic symptoms or
catatonia, severe depressive symptoms and func-tional impairment, and
comorbid medical problems, and when there is an urgent need for response (ie,
patients who are acutely suicidal or patients who refuse food and are
nutritionally compromised). However, depressed
830 SHANMUGHAM et al

older adults who respond to ECT are at a high risk for relapse unless they
receive continuation or maintenance pharmacotherapy or ECT [69]. In a study
of patients who underwent ECT because pharmacotherapy failed, patients
treated with nortriptyline and lithium had a lower rate of relapse compared with
those treated with nortriptyline alone [69].

Discussion

Effective and well-tolerated treatments for late-life depression exist, in-

cluding antidepressants, psychotherapy, and electroconvulsive therapy.
Treatment outcomes include the reduction of depressive symptoms and sui-cidal
ideation, improvement of cognitive and functional status, and preven-tion of
relapse and recurrence. More than half of the elderly patients treated with
antidepressants experience treatment response, defined as a 50% reduc-tion in
depressive symptoms [45,58]. In intent-to-treat analyses, the response rates to
antidepressants are 50% to 65% compared with 25% to 30% on placebo in
randomized controlled trials [5,70,71].
Expert consensus recommendations suggest that older adults tolerate SSRIs
better than TCAs [59], although empirical studies reveal similar tol-erability and
rates of side effects. However, the consequences of the side effects may be more
serious for TCAs compared with SSRIs. SSRIs are associated with higher rates
of nausea, loss of appetite, and sexual dysfunc-tion, but they have less
anticholinergic and cardiovascular side effects com-pared with TCAs [45].
Patients with pre-existing bundle branch block who are treated with TCAs may
develop second degree block [72]. The choice among different SSRIs may be
guided by the absence of drug interactions, simplicity of dosing, and side-effect
profile. The various SSRIs have similar efficacy, and some (escitalopram,
citalopram, and sertraline) have a lower potential for drug interactions.

A partial response to treatment is not uncommon in the treatment of ge-riatric

depression, with the result that clinicians prescribe additional agents in the
context of augmentation therapies. Augmentation strategies are added early in
treatment to accentuate the clinical response, around 4 to 6 weeks of standard
antidepressant treatment for patients who have limited improvement [73]. In
patients who experience a partial response to treat-ment, some clinicians
combine antidepressants in the hope of realizing syn-ergistic effects. The
combination therapy of two antidepressants has not been studied systematically.
Hence, there is no empirical evidence base sup-porting either the effectiveness
or lack of effectiveness for augmentation strategies. However, the common
occurrence of partial treatment response after several trials of monotherapy has
stimulated the development of expert consensus recommendations for partial
treatment response in geriatric de-pression [52]. These expert consensus
guidelines suggest that if there is a par-tial response after the initial
antidepressant treatment to (1) SSRI, then add bupropion, lithium, or
nortriptyline; to (2) TCA, then add lithium or SSRI;
 PHARMACOLOGIC INTERVENTIONS FOR GERIATRIC DEPRESSION 831

to (3) bupropion SR, then add SSRI or lithium; or to (4) venlafaxine, then add
lithium [62]. Discontinuing the augmentation treatment may put pa-tients at an
increased risk of relapse. In one study [74], patients who received brief
augmentation during an acute phase had a 52% relapse rate on follow-up. If
there is little or no response to an initial SSRI treatment, the experts support
switching to venlafaxine or bupropion [62]. Other suggestions are, if there is no
response to TCA, then switch to venlafaxine or SSRI; if there is no response to
venlafaxine, then switch to SSRI.
Other important clinical issues in the treatment of geriatric depression in-
clude the identification and treatment of the older adult with active suicidal
ideation or other signs of increased suicide risk. In industrialized countries, men
aged 75 years and older have the highest suicide rate among all age groups [75].
Risk factors for suicide in the elderly include physical illness [76], persistent
pain [77], mood disorders [78], alcohol abuse [79], anxiety
[80], bereavement, and social isolation [81]. More often, among elderly pa-
tients, it has been shown that hopelessness best predicts suicidal ideation in the
presence of moderate or higher levels of depressive symptoms [82]. Predictors
of suicide attempts include previous suicide attempts with serious intent and
severity of depression [83]. Elderly patients who have attempted suicide tend to
have higher levels of hopelessness even after successful treat-ment for
depression [84]. The use of firearms is the most common method of completed
suicide among older adults [85].
Treatment with an antidepressant medication, usually an SSRI or SNRI, is
the mainstay of treatment of a depressed suicidal older adult. An exami-nation
of double-blind studies does not demonstrate a causal relationship between
pharmacotherapy and the emergence of suicidality [86]. In one ret-rospective
analysis [87], depressed patients treated with fluoxetine (n ¼ 1765) were
compared with a tricyclic antidepressant (n ¼ 731) or placebo group. There was
no increased risk of emergence of suicidal ideation among de-pressed patients
treated with fluoxetine.

Summary

Late-life depression is under-recognized and undertreated in older adults.

Depressed older adults who are at an increased risk or undertreatment in-clude
patients older than 85 years, those with comorbid medical conditions, and older
adults with cognitive impairment receiving home health care or liv-ing in
nursing homes. Although the existing empirical treatment literature is limited,
the available published treatment studies and expert consensus rec-
ommendations find that antidepressants are effective. In general the SSRIs and
SNRIs pose a low risk for the most serious side effects. Treatment of psy-chotic
depression has not been adequately investigated in older adults, al-though
common practice includes treatment with an SSRI or SNRI in conjunction with
an atypical antipsychotic. Treating with antidepressants
832 SHANMUGHAM et al

augmented by psychotherapy can minimize relapse and disability in de-pressed

patients. Continuation and maintenance treatment at an adequate dose and for an
adequate length of time is critical in minimizing relapse. Em-pirical trials are
needed that evaluate the selection and effectiveness of phar-macologic
combination therapy and other treatment strategies for treatment resistant and
partially responsive major depressive disorder in older adults.

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