Antipsychotics May Boost Outcomes in Refractory Depression

Deborah Brauser

July 19, 2017

Adding an antipsychotic to current treatment may improve outcomes in patients with refractory major depressive disorder (MDD), new research suggests.

A randomized study of more than 1500 adults with MDD showed that for those whose treatments were augmented with aripiprazole (Abilify, , Otsuka Pharmaceutical Co), remission rates at 12 weeks (the primary endpoint) were "modestly" yet significantly greater than remission rates for participants who were switched to the antidepressant bupropion (multiple brands), and response rates were significantly greater.

In addition, for participants who received adjunctive aripiprazole, reductions in depression symptom scores were greater than for participants in a third group for whom bupropion was added to their current antidepressant treatment.

Drowsiness, akathisia, and weight gain were the more commonly reported adverse events (AEs) for those receiving aripiprazole.

"We found that not all second-step treatments are created equal," lead author Somaia Mohamed, MD, PhD, Veteran Affairs (VA) New England Mental Illness Research, Education, and Clinic Center in West Haven, Connecticut, told Medscape Medical News.

Dr Somaia Mohamed

"I think the take-home message is to discuss with your patients what their options are, and to discuss the costs and benefits. For some patients, the pain and suffering of dealing with depression outweigh some of the side effects, such as weight gain," said Dr Mohamed, who is also in the Department of Psychiatry at Yale University.

The findings were published online July 11 in JAMA.

Reason for Optimism

"The primary objective of this randomized clinical trial was to compare the effectiveness and adverse effect profiles of 3 commonly used alternative MDD treatment strategies," write the investigators.

The Veterans Administration Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) trial was conducted between December 2012 and May 2015.

The researchers enrolled 1522 participants with MDD (85.25% men; mean age, 54.4 years) from 35 US VA health centers. All were randomly assigned to receive aripiprazole in addition to current treatment ("+aripiprazole," n = 505), bupropion in addition to current treatment ("+bupropion," n = 506), or bupropion by itself ("switchers," n = 511) for 12 weeks. Follow-up evaluations were conducted for up to 36 weeks.

The primary outcome was remission, defined as a score of 5 or less on the 16-item Quick Inventory of Depressive Symptomatology–Clinician Rated (QIDS-C) on two consecutive visits.

Secondary endpoints included response rates, defined as a 50% or greater reduction in QIDS-C score or a rating on the Clinical Global Impression (CGI) scale indicating the patient was much or very much improved; relapse rates during the follow-up phase; and any treatment-related adverse events.

The table below shows how the top outcomes differed between the groups.

Table. Outcomes at Week 12 for All 3 Treatment Groups

Endpoint +Aripiprazole (%) +Bupropion (%) Switchers (%)
Remission 28.9 26.9 22.3
>50% score reduction on QIDS-C 74.3 65.6 62.4
CGI Improvement 79.2 74.3 69.7


The +aripiprazole group demonstrated significantly greater improvement in comparison with the switcher group on the primary outcome (relative risk [RR], 1.30; P = .02) and on the two individual response outcomes (RR, 1.19 and 1.14, respectively; P < .001 for both comparisons).

This group also had a significantly greater reduction in QIDS-C score than the +bupropion group (RR, 1.13; P = .003).

There were no between-group differences in MDD relapse rates.

Of all participants, 10.8% experienced a total of 207 serious AEs, including eight deaths. However, the deaths were not judged to be related to treatment.

More of the switch group reported nonserious AEs (n = 1496) than did the +bupropion (n=1458) and +aripiprazole (n = 1405) groups.

Anxiety was significantly less frequent in the +aripiprazole group (16.6%) in comparison with the +bupropion and switcher groups (22.5% and 24.3%, respectively; P = .007), as were irritability, dry mouth, and decreased appetite.

Nonserious AEs that occurred in more members of the +ariprazole group than in the +bupropion and switcher groups included the following:

  • Fatigue (17.6% vs 13.0 and 13.5%, respectively),

  • Increased appetite (16.0% vs 8.7 and 7.4%),

  • Weight gain (5.7% vs 0.6 and 0.4%),

  • Akathisia, (14.9% vs 5.3 and 4.3%), and

  • Somnolence (14.5% vs 7.9 and 7.2%).

However, retention rates were greatest in the group that received aripiprazole (80.4% vs 74.7 and 69.1%, respectively); 75% of all participants completed the treatment phase.

"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," write the investigators.

However, Dr Mohamed said that she would not necessarily characterize the effect size as small but would instead say it was modest. "It wasn't huge," but even a modest improvement is reason to be optimistic, she said.

"Given the vast number of patients suffering from this disorder and the vast number who need second-step treatment because of their nonresponse to the first one, this could help many of them to decrease their suffering," she said.

"It's not a blockbuster effect, but it is one of the few studies that found differences between active treatments. This wasn't comparing to a sugar pill, and we found one treatment that worked better."

"Important Perspective"

Commenting on the findings, Maurizio Fava, MD, Division of Clinical Research, Massachusetts General Hospital, Boston, repeated to Medscape Medical News that the investigators' report of a modest yet significant advantage for the group that received the second-generation antipsychotic was especially important, given the fact that this patient population was "uniquely enriched with PTSD comorbidity."

Dr Fava, who was not involved with the research, writes in an accompanying editorial that the trial was conducted with "scientific rigor" and employed sophisticated methodology.

But he also notes that although the US Food and Drug Administration has approved three drugs, including aripiprazole, for treatment-resistant depression, a recent survey "indicated that atypical antipsychotic augmentation was only a fourth-line consideration, suggesting some reluctance to use this approach earlier in the algorithm."

The new study's results show that this strategy "should be considered earlier by clinicians," writes Dr Fava. He adds that the AE profile from the various treatments used should also help in deciding a patient's next-step treatment.

Overall, VAST-D "offers an important perspective on the role of treatment using this population commonly seen in VA clinics," Dr Fava concludes.

The study was funded by the VA Cooperative Studies Program. Dr Mohamed has reported no relevant financial relationships. Disclosures by the coauthors are included in the original article. Dr Fava has received research support, consulting fees, and speaker's honoraria from and holds patents and other equity in a variety of commercial interests. A full list of his disclosures is available online.

JAMA. Published online July 11, 2017. Abstract, Editorial

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