Aripiprazole Augmentation Improves Response in Tx-Resistant Depression

Different pills that are different colors
Different pills that are different colors
Augmenting antidepressant treatment with aripiprazole led to a greater response than switching to or augmenting with bupropion.

In the VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) randomized clinical trial, augmenting antidepressant treatment with aripiprazole led to a greater response than switching to or augmenting with bupropion in patients with treatment-resistant major depressive disorder.1

An estimated 16.1 million adults in the United States suffer from major depressive disorder, and less than one-third of patients adequately respond to their first course of antidepressant medication.2,3 Common alternate strategies for these patients include switching to the antidepressant bupropion and adjunctive use of either bupropion or the antipsychotic aripiprazole.4

Although preliminary findings support the effectiveness of switching to or augmenting with bupropion or aripiprazole, these and other agents have not been compared in adequately powered clinical trials.5,6 In the current study, researchers examined the effectiveness of and adverse effects associated with 3 strategies commonly used with patients who do not respond to an initial round of treatment: switching to bupropion sustained release, augmenting treatment with bupropion sustained release, or augmenting treatment with aripiprazole.

The sample included 1522 patients at 35 US Veterans Health Administration medical centers with a diagnosis of major depressive disorder and a suboptimal response to previous antidepressant treatment. Response was considered suboptimal if scores on the 16-Item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) questionnaire indicated severe depression after 6 weeks of treatment, or moderately severe depression after 8 weeks of treatment.

Patients were randomly assigned to 1 of 3 conditions: switching to bupropion (n = 511), bupropion augmentation (n = 506), or aripiprazole augmentation (n = 505). Remission during the 12-week acute treatment phase served as the primary outcome, as indicated by QIDS-C16 scores ≤5 at 2 consecutive visits. Response, relapse, and adverse effects were examined as secondary outcomes.

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Among the 74.7% of patients who completed the acute treatment phase, the following results were observed:

  • Remission rates were 22.3% in the switch group vs 26.9% in the bupropion augmentation group and 28.9% in the aripiprazole augmentation group.
  • Remission was higher in the aripiprazole group compared with the switch group (relative risk, 1.30; 95% CI, 1.05-1.60; P =.02).
  • The aripiprazole group demonstrated a greater response (74.3%) than the switch group (62.4%; relative risk, 1.19; 95% CI, 1.09-1.29; P <.001) or the bupropion augmentation group (65.6%; relative risk, 1.13; 95% CI, 1.04-1.23; P =.003).
  • There were no significant differences between treatments, in terms of relapse outcomes
  • The bupropion switch (24.3%) and augmentation (22.5%) groups experienced more frequent anxiety than the aripiprazole group (16.6%).
  • The aripiprazole group experienced more frequent adverse effects such as fatigue, weight gain, somnolence, and akathisia compared with the other groups.

Future research should analyze the benefits and risks of augmenting with aripiprazole, considering the modest reduction in depression observed in the current study together with the risk for adverse effects. “Although use of the augment-aripiprazole strategy as an alternative treatment may offer an increased likelihood of remission, patients should be alerted to the risk of weight gain in a process of shared decision making,” and metabolic values should be regularly monitored, the authors wrote.


  1. Mohamed S, Johnson GR, Chen P, et al. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial. JAMA. 2017;318(2):132-145.
  2. Center for Behavioral Health Statistics and Quality. Key substance use and mental health indicators in the United States: results from the 2015 National Survey on Drug Use and Health. Accessed August 24, 2017.
  3. Kolovos S, van Tulder MW, Cuijpers P, et al. The effect of treatment as usual on major depressive disorder: a meta-analysis. J Affect Disord. 2017;210:72-81.
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  5. Rush AJ, Trivedi MH, Wisniewski SR, et al. . N Engl J Med. 2006;354:1231-1242.
  6. Arbaizar B, Dierssen-Sotos T, Gómez-Acebo I, Llorca J. Aripiprazole in major depression and mania: meta-analyses of randomized placebo-controlled trials. Gen Hosp Psychiatry. 2009;31(5):478-483.