Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial

Abstract

Background: Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo.

Methods: We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047.

Findings: From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables.

Interpretation: In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism.

Funding: National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

Conflict of interest statement

Declaration of Interests: Dr. Lenze has received research support from the National Institute of Mental Health (NIMH), National Institute on Aging (NIA), National Center for Complementary and Integrative Health (NCCIH), Roche, Lundbeck, the Sidney R. Baer Foundation, the Taylor Family Institute for Innovative Psychiatric Research, the Barnes-Jewish Foundation, and the McKnight Brain Research Foundation.

Dr. Mulsant currently receives research funding from Brain Canada, the CAMH Foundation, the Canadian Institutes of Health Research, and the US National Institute of Health (NIH). During the last five years, he also received research support from Bristol-Myers Squibb (medications for a NIH-funded clinical trial), Eli-Lilly (medications for a NIH-funded clinical trial), and Pfizer (medications for a NIH-funded clinical trial). He directly owns stocks of General Electric (less than $5,000).

Dr. Blumberger has received research support from the Canadian Institutes of Health Research (CIHR), Brain and Behavior Research Foundation (formerly NARSAD), National Institute of Health (NIH), Temerty Family through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Research Institute. He receives research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and he is the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He also receives in-kind equipment support from Magventure for an investigator-initiated study. None the above represent a conflict of interest with manuscript under consideration.

Dr. Karp has received medication supplies for investigator initiated trials from Pfizer and Reckitt Benckiser.

Dr. Newcomer reports Data Safety Monitoring Board for Bristol-Myers Squibb, Data Safety Monitoring Board for Merck, honoraria from VIVUS, Data Safety Monitoring Board from Amgen.

Dr. Anderson reports receiving grant support from the NIH grants P30 MH090333, R01 MH090250, R01 MH084921.

Dr. Dew receives grant support from the National Institutes of Health, and serves on the editorial boards of numerous clinical journals. None of these activities represent a conflict of interest with the manuscript under consideration.

Dr. Butters has received research support from the National Institutes of Health. She served as a consultant for Medtronic and Northstar Neuroscience from whom she received remuneration for neuropsychological evaluations performed within the context of clinical trials. She also served as a consultant for GlaxoSmithKline, from whom she received remuneration for participating in cognitive disorder diagnostic consensus conferences for research participants in a clinical trial. None of the above represents a conflict of interest with the manuscript under consideration.

Ms. Stack and Ms. Begley report no conflicts.

Dr. Reynolds reports receiving pharmaceutical support for NIH-sponsored research studies from Bristol-Myers Squibb, Forest, Pfizer, and Lilly; receiving grants from the National Institute of Mental Health, National Institute on Aging, National Center for Minority Health Disparities, National Heart Lung and Blood Institute, Center for Medicare and Medicaid Services (CMS), Patient Centered Outcomes Research Institute (PCORI), the Commonwealth of Pennsylvania, the John A Hartford Foundation, National Palliative Care Research Center (NPCRC), Clinical and Translational Science Institute (CTSI), and the American Foundation for Suicide Prevention; and serving on the American Association for Geriatric Psychiatry editorial review board. He has received an honorarium as a speaker from MedScape/WEB MD. He is the co-inventor (Licensed Intellectual Property) of Psychometric analysis of the Pittsburgh Sleep Quality Index (PSQI) PRO10050447 (PI: Buysse).

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Enrollment and Outcomes

Figure 2. Reduction in Depressive Symptoms during Augmentation with Aripiprazole or Placebo

Montgomery-Asberg Depression Rating Scale (MADRS) mean scores (± standard error bars) plotted at the protocol specified sampling times in the augmentation phase. Number of patients at each time is indicated at the bottom of the plot. Analyses used time as a continuous measure calculated using dates. Based on the BIC, a cubic model best fit the trajectory of MADRS scores over the span. The model indicates that both groups showed improvement over time but the aripiprazole group showed a significantly greater improvement. Based on the modeled data, the aripiprazole group decreases approximately 7.5 points over 12 weeks while the placebo group decreases approximately 5.0 points over the same time period.

Figure 3. Changes in Cardiometabolic Parameters during Augmentation with Aripiprazole or Placebo

mean (SD) total fat change was +0.54 kg (1.98) with aripiprazole (n=81) vs. −0.06 (2.08) with placebo (n=83), F (1,160)=3.49, p=0.064. Mean (SD) total weight change was +1.93 kg (3.00) with aripiprazole (n=84) vs. 0.01 (3.15) with placebo (n=85), F(1,165)=16.26, p