CATEGORY 1 CME
The goal of this activity is to review the available treatments for depression among older adults, including an evidence-based algorithm for the treatment of this condition.
At the end of this CE activity, participants should be able to:
1. Discuss the treatment options for depression among
2. Describe an evidence-based algorithm for the treatment of depression among older adults.
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(This is part 2 of a 2-part CME activity discussing depression in older adults.
Part 1 appeared in the March issue—Ed.)
Depression is not an uncommon condition among older adults, and it is often underdiagnosed in this population. Depression also results in greater rates of morbidity and mortality among older adults. The neurobiology of depression includes a complex interaction among various biological, psychological, and social factors. The identification of depression among older adults requires a thorough history, a focused physical examination, appropriate laboratory studies, and the use of neuropsychological testing when necessary.
Current available treatments for older adults with depression include psychotherapy, pharmacotherapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and collaborative care approaches.1-3 In addition, some evidence indicates that aerobic and supervised group exercise regimens may improve depressive symptoms among older adults.4 In this review, we assess the evidence for using psychotherapy, pharmacotherapy, ECT, TMS, and collaborative care approaches for the treatment of depression among older adults.
Several psychotherapeutic modalities can and should play a role in treating depression (Table 1). Cognitive behavioral therapy (CBT), reminiscence therapy (RT), brief dynamic therapy (BDT), problem-solving therapy (PST), and the combination of medication and interpersonal psychotherapy (IPT) have been shown to have moderate-to-large effect sizes when used for the treatment of depression in older adults.5-9 One meta-analysis found large effect sizes for CBT and RT and moderate effect sizes for psychodynamic therapy, psychoeducation, physical exercise, and supportive interventions.6 Another meta-analysis found that for the treatment of depression in older adults, CBT was more effective than wait-list controls and there were no significant treatment differences between CBT and psychodynamic therapy.7 A third meta-analysis found that the effect size indicating the difference between psychotherapy and control groups was 0.64 with a number needed to treat (NNT) of 3.8 These effects were maintained for at least 6 months with an effect size of 0.27. CBT (effect size, 0.45), life review therapy (effect size, 0.59), and PST (effect size, 0.46) were found to be effective for the treatment of depression among older adults. Evidence indicates that there is no significant difference when the therapy is delivered individually, in groups, or via a bibliotherapy format.6 Poorer response to psychotherapy among older adults with depression is noted among individuals who have greater baseline anxiety and stress levels, personality disorders, and reduced self-rated health scores.9
Available evidence indicates that, when used to treat depression in older adults, no significant differences are noted in efficacy among the various antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs), mirtazapine, bupropion, and tricyclic antidepressants (TCAs), with an NNT of 8 for all antidepressants combined.10 In their meta-analysis, Nelson et al found that bupropion, mirtazapine, serotonin norepinephrine reuptake inhibitors (SNRIs), and SSRIs were found to have greater, but still modest, efficacy in treating symptoms of depression among older adults when compared with placebo.11 A systematic review found that there is no significant difference in efficacy or adverse effect profile for dual-action antidepressants like SNRIs or TCAs when compared with single-action antidepressants like SSRIs in the treatment of depression in this patient population.12
SSRIs are considered first-line drugs for the treatment for depression in older adults, given their efficacy data and their relatively benign adverse-effect profile (Table 2).13 The most common adverse effects of SSRIs include nausea, diarrhea, anxiety, and sleep disturbance.14 The SNRIs venlafaxine and duloxetine have shown efficacy in the treatment of depression in older adults with relatively benign adverse-effect profiles.15,16 Mirtazapine has been found to have similar efficacy as paroxetine, but better tolerability profile when used to treat older adults with depression.17 Increased appetite and sedation have been the most common adverse effects noted when mirtazapine is used to treat older adults with depression.
TCAs are not considered first-line treatment for depression in older adults, despite good efficacy, because of their adverse-effect profile.18,19 When used to treat depression in this patient population, secondary amine TCAs, including nortriptyline and desipramine, are thought to be safer when compared with the tertiary amine TCAs like imipramine and amitriptyline.18,19 TCAs can be lethal in overdoses and hence should be used with caution among older adults with depression who have risk factors for suicide.19 The common adverse effects of TCAs include sedation, orthostatic hypotension, tachycardia, dry mouth, visual problems, dizziness, and weight gain.
A randomized controlled trial (RCT) found that older adults with depression who received vortioxetine had greater remission when compared with placebo.20 The drug was well tolerated, with nausea being the more common adverse effect in the drug group. On 2 cognitive tests, the participants who received vortioxetine did better than individuals who received placebo. Another RCT also indicated that quetiapine XR monotherapy was effective at improving depressive symptoms among older adults when compared with placebo, with improvement in symptoms noted as early as week 1.21 Common adverse events (noted in more than 10% of participants on quetiapine XR) were somnolence, headache, dry mouth, and dizziness.
According to another RCT, the addition of aripiprazole in treatment regimens for individuals 60 years or older who did not achieve remission of depression with venlafaxine resulted in a greater proportion of participants achieving and sustaining remission when compared with placebo.22 The odds ratio for remission with aripiprazole was 2.0 (P = .03) and the NNT was 6.6. Akathisia was the most common adverse effect of aripiprazole when compared with placebo (26% vs 12%), and Parkinsonism was more common in the aripiprazole group when compared with the placebo group (17% vs 2%).
In an RCT of 143 older adults with a diagnosis of MDD, Lavretsky et al compared treatment response for 3 treatment groups: (1) methylphenidate and placebo, (2) citalopram and placebo, (3) and citalopram and methylphenidate.23 The investigators found that significant improvements were noted for depression severity and cognitive performance in all 3 groups. But the improvement in depression severity and the global improvements were more significant in the citalopram and methylphenidate group when compared with the other groups. The rate of improvement was greater in the citalopram/methylphenidate group when compared with the citalopram/placebo group in the first 4 weeks of the trial. Among the 3 groups were no significant differences in cognitive improvement or the number of adverse effects.
Among older adults with depression, no published data support the use of vilazodone, levomilnacipran, ketamine, or brexpiprazole among these individuals.24
Among older adults with depression, available evidence indicates that the rates and speed of response are similar when either augmenting an antidepressant medication with lithium or another agent (a second antidepressant, buspirone, aripiprazole) or for switching from one antidepressant medication class to another class.25-31
To treat psychotic depression in older adults, available evidence from controlled studies indicates efficacy for nortriptyline, imipramine, mifepristone, a combination of fluoxetine and olanzapine, and ECT.32 It has been noted that the majority of individuals with psychotic depression do not require treatment with antipsychotic medications for more than 4 months.33
Evidence is emerging that ketamine and esketamine are beneficial in treating depression in older adults.34 Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist.35 Esketamine is an enantiomer of ketamine and is known to have higher affinity for NMDAR. Although ketamine’s mechanism of action as an antidepressant is not yet entirely known, both NMDAR inhibition–dependent and NMDAR inhibition–independent mechanisms have been proposed.
There are 2 controlled studies of ketamine for depression in older adults.36,37 The results of the first study showed a significant reduction in depressive symptoms with repeated subcutaneous ketamine administration among older adults with depression.36 However, in the second study, the primary outcome measure did not achieve significance in participants, but depression scores showed a decrease, with higher response and remission rates in the esketamine group when compared with the placebo group.37 The adverse effects from ketamine generally lasted only a few hours and resolved spontaneously. The common adverse effects seen among individuals receiving ketamine were perceptual disturbance, derealization, altered body perception, and altered time perception. The dissociative symptoms were dose related. Transient increase in systolic and diastolic blood pressures and heart rate were also noted, but they resolved spontaneously after a few hours. Palpitations, flushing, dizziness, paresthesia, fatigue, and sleepiness were also seen, as was poor concentration and feeling “spaced out,” but they resolved spontaneously as well. No cognitive adverse effects were noted in either trial from the use of ketamine.
Among older adults with depression, ECT has been found to be an effective treatment,38,39 especially in situations in which the individual has not responded to psychotherapy and/or pharmacotherapy.38 It also appears to produce a faster resolution of symptoms.40 Efficacy has been noted for both unilateral and bilateral ECT in the treatment of depression among older adults.38 However, unilateral ECT is preferred for short-term treatments (5 weeks or less) and bilateral ECT for longer-term treatments (at least 3 weeks).38
One systematic review found that the adverse effects of ECT in older adults with depression were often transient and limited.41 Better cognitive outcomes were also noted with unilateral when compared with bilateral ECT. Evidence also indicates that among older adults with depression, the placement of right unilateral and bitemporal leads, the use of brief pulse stimulus, and the use of dose titration of stimulus tends to reduce the cognitive adverse effects from the use of ECT.42 Hypertension and tachycardia may occur more frequently among older adults with the use of ECT, but they are often transient and mild.38
The US Food and Drug Administration (FDA) has approved repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression among adults who have failed 1 medication trial.43 When compared with ECT, rTMS does not require anesthesia, does not induce seizures, and does not cause any significant cognitive adverse effects.42 Discomfort caused by scalp or facial muscle twitching and headaches is the most common adverse effect, with seizures being a rare adverse effect of rTMS.43
Lisanby et al found that age (less than 55 vs at least 55 years) was not a predictor of response to rTMS when used among individuals with depression.44 Failure to respond to an adequate trial of an antidepressant medication in the current episode, the absence of a comorbid anxiety disorder, a higher baseline severity of depression, female gender, and a shorter duration of illness (less than 2 years) were the positive predictors of response to rTMS in this study.
In an RCT that evaluated the efficacy, tolerability, and cognitive effects of high-dose deep rTMS among individuals with LLD, the investigators found that remission rates were significantly higher with active rTMS when compared with sham rTMS (40.0% vs 14.8%, respectively) with an NNT of 4.45 The investigators did not find any changes on the measures of executive functioning or note any serious adverse effects. The adverse-effect profiles were similar between the 2 treatments except for pain, which was significantly more common in the active condition (16.0% vs 0%).
Vagal Nerve Stimulation
The FDA has approved vagal nerve stimulation (VNS) as an adjunctive and long-term treatment for recurrent or chronic major depressive episodes among adults aged at least 18 years who have had an insufficient response to at least 4 adequate antidepressant trials.42 In one study, the response rates for depression were 31% after 3 months, 44% after 1 year, and 42% after 2 years, with remission rates of 15% at 3 months, 27% at 1 year, and 22% at 2 years in individuals who received adjunctive VNS treatment.46 More than 80% of the individuals in this study were still receiving VNS at 2 years. We did not find any published controlled trials of VNS among older adults with depression in our review of the literature.
Expert Consensus Guideline
An expert consensus guideline indicates that, for minor depressive episodes among older adults, appropriate first-line treatments include an antidepressant alone, psychotherapy alone, or the combination of an antidepressant with psychotherapy.13 The combination of an antidepressant with psychotherapy is the most widely recommended first-line treatment for more severe depressive episodes. Treatment with an antidepressant alone is also considered a suitable alternative first-line treatment for these more severe episodes. First-line agents for the treatment of depression in older adults include SSRIs, especially citalopram, sertraline, and extended-release venlafaxine. Second-line agents include TCAs, bupropion, and mirtazapine. A 4- to 7-week trial on the maximally tolerated dose of an antidepressant is recommended prior to switching medications.
Among older adults, ECT is considered an appropriate alternate treatment for more severe depressive episodes, especially when the individual has failed adequate trials of at least 2 antidepressants, an acute suicide is risk is present, or when the use of antidepressants is unviable due to medical comorbidities.13
For the treatment of psychotic depression among older adults, the combination of an antidepressant and an antipsychotic medication is recommended as first-line treatment.13 An ECT trial is considered appropriate if there is inadequate response to pharmacotherapy or a need for faster resolution of symptoms. SSRIs and venlafaxine are considered first-line agents, with TCAs being considered alternative agents. Among older adults, atypical antipsychotics including risperidone, olanzapine, and quetiapine are first-line agents, with ziprasidone being a second-line agent.13
CBT, supportive psychotherapy, IPT, and PST are considered first-line psychotherapies among older adults with depression. For the treatment of a first major depressive episode, 1 year of treatment after the remission of symptoms is considered the appropriate duration of treatment. Among those individuals who have recurrent (at least 3) episodes of depression, longer-term treatment of at least 3 years is recommended.13 Table 2 describes a proposed algorithm for treatment of depression among older adults.13
Pharmacogenetics may provide valuable information on how medications should be prescribed to treat major psychiatric disorder among adults of all ages.47 However, available evidence from 2 randomized, prospective trials that tested the effects of pharmacogenetic screening on antidepressant treatment response among older adults did not provide support for the clinical use of pharmacogenetic testing methods that are currently available to guide the treatment with antidepressants among older adults.48,49 A recent systematic review concluded that pharmacogenetic testing should be considered for older adults with depression who have failed an antidepressant treatment trial or have experienced intolerable adverse effects.50 The authors indicated that carefully designed pharmacogenetic studies among older adults with depression should be conducted, taking into account clinical heterogeneity and genome-wide data.
Older adults with depression appear to be more likely to accept treatment when it is offered in the primary care setting.51 The success of treatment appears to improve with the involvement of a skilled and empathic care manager.52 Evidence is emerging that the symptoms of depression among older adults tend to improve with the use of collaborative care.53,54 Improvements in symptoms of depression, physical functioning, and quality of life were also noted with the use of collaborative care, which actively engaged older adults in the treatment of their depression in the Improving Mood – Promoting Access to Collaborative Treatment (IMPACT) program.54
The collaboration between trained psychiatric clinicians and primary care physicians who implemented a comprehensive depression management program improved outcomes among older adults with depression in the Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT).55 Greater and faster resolution of symptoms of depression, along with a faster rate of reduction in suicidal ideation, were noted in the intervention group when compared with individuals receiving usual care.56 Earlier and greater rates of remission of their depressive episodes were noted in individuals in the intervention group.57
Available data indicate efficacy for psychotherapy, pharmacotherapy, and ECT for the treatment of depression among older adults. There is also emerging evidence for the efficacy of ketamine, rTMS, and collaborative care approaches. The prompt identification of depression and the early initiation of treatment will help improve outcomes and thereby minimize suffering among this vulnerable population.
Dr Tampi is professor and chairman, Department of Psychiatry, Creighton University School of Medicine and Catholic Health Initiatives (CHI) Health Behavioral Health Services, Omaha, Nebraska. He is also an adjunct professor of psychiatry at Yale School of Medicine. Ms Tampi is cofounder and managing principal, Behavioral Health Advisory Group, Princeton, New Jersey.
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