REVIEW OF: Furukawa Y et al, Br J Psychiatry 2022;221(2):440–447

STUDY TYPE: Meta-analysis of randomized controlled trials

Aripiprazole is FDA approved for antidepressant augmentation, and although it is the best-studied atypical antipsychotic for this condition, practitioners have not yet nailed down what dose to prescribe. Guidelines recommend anywhere from 2 to 15 mg/day, but higher doses bring additional risks like akathisia, sedation, and metabolic problems. This meta-analysis aimed to find the optimal dose range.

The authors found 10 double-blind, placebo-controlled, randomized studies in which aripiprazole was added to an SSRI or SNRI antidepressant in patients with treatment-resistant depression. The definition of treatment resistance varied among the studies, which required an inadequate response to 1–3 antidepressant trials and lasting at least 6–12 weeks. Patients with other psychiatric and substance use disorders were excluded, as were any who had received electroconvulsive therapy in the last 10 years or had been on adjunctive antipsychotics in the three weeks before starting aripiprazole.

This yielded 2,625 patients, 55% female. Over half the studies took place in North America and about a third were conducted in Japan. Some studies compared augmentation with aripiprazole using a fixed-dose schedule and others allowed flexible dosing. Trials lasted six to eight weeks. Doses ranged from 2 to 20 mg/day. Reduction in the Montgomery-Åsberg Depression Rating Scale was the main outcome measure. Tolerability (dropouts due to adverse effects) and acceptability (dropouts for any reason) were also tracked.

The main finding was that efficacy was associated with doses between 2 and 5 mg, with no additional benefits at higher doses. Aripiprazole 4 mg resulted in a 36% improvement compared with 23% on placebo. The odds ratio of response gradually increased as the dose increased from 2 mg (1.46) to 4 mg (1.87), then leveled off at 5 mg (1.91). Doses beyond 5 mg were well tolerated but didn’t add clinical benefit.

One limitation is that the analysis involved multiple studies with varied doses that were not designed to test the hypothesis at hand. It is possible that some patients will do better at higher doses of adjunctive aripiprazole, but it is difficult to say who they are.

CARLAT TAKE

When using aripiprazole for antidepressant augmentation, 2–5 mg is the ideal range.