REVIEW OF: Terao I and Kodama W,  J Clin Psychopharmacol 2024; 44(4):413–417

STUDY TYPE: Systematic review and meta-analysis

Dopamine partial agonists are commonly used for treatment-resistant depression (TRD), but optimal doses are unclear. This study compared aripiprazole, brexpiprazole, and cariprazine as antidepressant augmentations for TRD.

Researchers analyzed data from 16 randomized, double-blind, placebo-controlled trials of 7,192 adults aged 18–65 who did not respond to at least 1 adequate antidepressant trial, evaluating augmentation with aripiprazole (up to 11.8 mg), brexpiprazole (up to 3 mg), or cariprazine (up to 3 mg). The primary outcome was the standardized mean difference (SMD) in the change in depressive symptoms, as measured by the Montgomery-Åsberg Depression Rating Scale, the Hamilton Rating Scale for Depression, and the Beck Depression Inventory. 

Augmentation with all the studied medications was more effective than placebo. Efficacy increased with increasing doses until plateauing at 5.5 mg of aripiprazole, 1.6 mg of brexpiprazole, and 1.5 mg of cariprazine. The SMDs at these doses were 0.38 (95% confidence interval [CI] [0.14, 0.62]), 0.31 (95% CI [0.13, 0.47]), and 0.13 (95% CI [0.016, 0.26]), respectively. For context, an SMD of 0.2 is considered a small effect, 0.5 a moderate effect, and 0.8 a large effect. Brexpiprazole was superior to cariprazine in several comparisons, but neither brexpiprazole nor cariprazine surpassed aripiprazole at any dose. These findings suggest a clear efficacy hierarchy: aripiprazole > brexpiprazole > ­cariprazine.

CARLAT TAKE
For antidepressant augmentation in TRD, think “ABC.” Aripiprazole may be the most effective dopamine partial agonist, followed by brexpiprazole. Both were associated with modest benefits, and both were superior to cariprazine. This study makes a case for keeping the doses relatively low: aripiprazole 5.5 mg, brexpiprazole 1.6 mg, and cariprazine 1.5 mg. However, there were several limitations to this study. The patient cohort did not include older adults, there was no comparison of side effect profiles, and the researchers did not control for specific antidepressants used.