Review of: Mohamed S et al, JAMA 2017;318(2):132–145

It seems like an endless debate: When a patient does not respond to the first trial of an antidepressant, what should we do? Switch to something else? Augment with another agent? If the latter, how often should that augmenting agent be an atypical antipsychotic? The VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) trial was conducted to answer some of these questions. Specifically, the study compared the effectiveness and adverse effects of switching to bupropion SR, augmenting with bupropion SR, or augmenting with aripiprazole.

In this randomized controlled trial, 1,522 patients with non-psychotic major depressive disorder (MDD) who had failed at least one adequate 6-week course of an SSRI, an SNRI, or mirtazapine were recruited from the Veterans’ Administration (VA). Most of the patients were male (85%) and white (69%), and had an average age of 54.4. Patients were randomly assigned to one of three groups: switching to bupropion (most common dose 200 mg twice daily, n = 511), augmenting with bupropion (most common dose also 200 mg twice daily, n = 506), or augmenting with aripiprazole (most common dose 10 mg daily, n = 505). After 12 weeks of treatment, remission and response rates were: switch-bupropion: remission 22%, response 62%; augment-bupropion: remission 27%, response 66%; augment-aripiprazole: remission 29%, response 74%. Augmenting with aripiprazole yielded statistically superior remission rates than switching to bupropion (P = .02) and superior response rates than either of the bupropion arms. Somnolence, akathisia, and weight gain occurred more frequently in the aripiprazole group. Most dramatically, in a subset of patients who continued the trial for 36 weeks, 25% of the aripiprazole group gained at least 7% of body weight as opposed to only 5% of both bupropion groups.

TCPR’s Take
Aripiprazole augmentation was the most effective strategy for patients who had not responded to a single antidepressant trial, beating both switching to and augmenting with bupropion. While aripiprazole’s superiority was not huge, it was clinically significant, with a number needed to treat (NNT) of around 10 when compared with switching to bupropion. But the price of this higher response rate is a cluster of side effects, including weight gain, akathisia, and somnolence. In addition, these results may not generalize to non-VA populations, such as women of any age and younger men. Nonetheless, this large and well-designed study should encourage us to consider aripiprazole augmentation as a solid second-step strategy in depression treatment.