Reference: Lancet 2015 Dec 12;386(10011):2404 (level 1 [mid-level] evidence)
Major depression is a common and often undertreated illness in the elderly, associated with disability and mortality. Elderly patients with major depressive disorder are reported to have a high rate of resistance to treatment with first-line agents, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Aripiprazole, an atypical antipsychotic, has demonstrated benefit in adult patients with refractory depression when added to first-line agents. Little is known about the safety and efficacy of aripiprazole when used in elderly patients with depression. The 2015 Beers Criteria recommend avoiding the antipsychotic class for dementia and behavioral disturbances in the elderly due to risk of harms, but make exceptions for antipsychotic use in schizophrenia and bipolar disorder (American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015 Nov;63(11):2227). The Beers Criteria contain no recommendation regarding the use of antipsychotics for refractory major depression. The question remains: should we use adjunctive aripiprazole to treat elderly patients with treatment-resistant depression?
A recent randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of adding aripiprazole to the SNRI venlafaxine extended-release in 181 adults aged > 60 years (mean age 66 years, 57% female) with major depression resistant to venlafaxine alone. Treatment resistance was defined as a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 15 despite ≥ 12 weeks of treatment with venlafaxine extended release 150 – 300 mg/day with ≥ 4 weeks at highest tolerated dose. Patients were excluded if they had dementia, bipolar disorder, schizophrenia, psychosis, or substance misuse or dependence in the previous 6 months. Following the 12-week run-in period, participants underwent a 12-week treatment phase which included follow-up visits every 1-4 weeks. At these visits, aripiprazole dosages were increased from 2 mg daily to a target of 10 mg daily, with a maximum 15 mg daily as needed (median dose 7 mg). Patients who remitted during the first 12-week phase underwent an additional 12-week continuation phase.
Remission (defined as MADRS score of ≤ 10 at the final two follow-up visits) was achieved in 44% of patients in the aripiprazole group versus 29% in the placebo group (odds ratio [OR] 2, CI 1.1-3.7, NNT 7). For patients with remission in the first 12 weeks who were followed for an additional 12 weeks, relapse rates were similar at 13% and 8% (no p value reported). Secondary outcomes favoring aripiprazole included resolution of suicidal ideation (in 73% vs. 44% of patients, p=0.02, NNT=4) and reduced time to remission (p= 0.001). Patients in the aripiprazole group had increased rates of akathisia (26% vs. 12%, no p value reported) and parkinsonism (17% vs. 2%, no p value reported), but symptoms were usually mild. Dropout rates due to adverse events were low in each group (2% vs. 2%). There was no increased risk of tardive dyskinesia over 24 weeks in either group (0% vs 2%, no p value reported).
As an atypical antipsychotic, aripiprazole carries a black box warning for increased risk of death in the elderly (especially those with dementia-related psychosis). The cause of death is thought to be related to cardiovascular complications and infections. In this study, aripiprazole was not associated with increased cardiometabolic risk as measured by whole-body adiposity, lipids, or glucose, and rates of QTc prolongation were low (1% vs. 0%, no p value reported).
This study provides reliable evidence that the addition of aripiprazole to venlafaxine is effective for the treatment of refractory depression in elderly adults without other significant psychiatric comorbidities, and does not appear to increase the risk of serious adverse events. Clinicians may therefore feel more comfortable prescribing adjunctive aripiprazole to elderly patients with treatment-resistant depression, particularly those with persistent suicidal ideation. Patients should be counseled on the possible side effects of akathisia and parkinsonism. Overall, this study provides high level evidence regarding the benefits of adding aripiprazole at doses of 2-15 mg/day which may outweigh the risks for elderly adults struggling with treatment-resistant depression.
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