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Original Investigation
July 11, 2017

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial

Author Affiliations
  • 1Veterans Affairs (VA) New England Mental Illness Research, Education, and Clinical Center, VA Connecticut Healthcare System, West Haven
  • 2Yale University School of Medicine, West Haven, Connecticut
  • 3Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven
  • 4Louis Stokes VA Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio
  • 5Central Texas Veterans Healthcare System and Department of Psychiatry and Behavioral Science, Texas A&M Health Science Center College of Medicine, Temple
  • 6Central Texas Veterans Healthcare System, Temple
  • 7Tuscaloosa VA Medical Center, Tuscaloosa, Alabama
  • 8University of Alabama School of Medicine, Birmingham
  • 9Health Economics Resource Center, VA Palo Alto, Menlo Park, California
  • 10Department of Veterans Affairs, Office of Research and Development, Washington, DC
  • 11Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico
  • 12VA San Diego Healthcare System, San Diego, California
  • 13University of California, San Diego
  • 14Philadelphia VA Medical Center, Philadelphia, Pennsylvania
  • 15Cooperative Studies Program Central Office, Department of Veterans Affairs Office of Research and Development, Washington, DC
JAMA. 2017;318(2):132-145. doi:10.1001/jama.2017.8036
Key Points

Question  Is there a difference among pharmacotherapeutic approaches for treating patients with depression unresponsive to an antidepressant course?

Findings  In a 12-week follow-up of a randomized clinical trial of 1522 patients with major depressive disorder (85% men) unresponsive to previous antidepressant treatment, 29% achieved remission after augmenting their antidepressant with the antipsychotic aripiprazole vs 22% who switched to the antidepressant bupropion. Other remission comparisons were not significant.

Meaning  Augmentation with aripiprazole resulted in a statistically significant, but only modestly increased, likelihood of remission during 12 weeks of treatment compared with switching to bupropion alone.


Importance  Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant.

Objective  To determine the relative effectiveness and safety of 3 common alternate treatments for MDD.

Design, Setting, and Participants  From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks.

Interventions  Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase).

Main Outcomes and Measures  The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects.

Results  Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain.

Conclusions and Relevance  Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.

Trial Registration  clinicaltrials.gov Identifier: NCT01421342