JAMA Psychiatry
Adjunctive antipsychotics rank differently for efficacy and tolerability
Clinical Takeaway: FDA-approved atypical antipsychotics used adjunctively for major depressive disorder differ meaningfully in efficacy and acceptability. Lumateperone showed the greatest antidepressant efficacy, while aripiprazole ranked highest for overall acceptability, highlighting the importance of individualized treatment selection.
Many patients with major depressive disorder (MDD) fail to achieve remission with standard antidepressants alone, prompting use of adjunctive atypical antipsychotics. This systematic review and network meta-analysis compared currently FDA-approved agents to better clarify relative efficacy and tolerability.
The analysis included 22 short-term randomized studies involving more than 10,900 participants receiving adjunctive aripiprazole, brexpiprazole, cariprazine, lumateperone, quetiapine extended release (XR), or placebo. The primary outcomes were antidepressant response and treatment acceptability, measured by all-cause discontinuation.
Lumateperone showed the largest effect on antidepressant response, defined as at least 50% improvement in depressive symptoms, followed by aripiprazole and brexpiprazole. Aripiprazole demonstrated the highest overall acceptability, followed by cariprazine, while lumateperone ranked lowest for acceptability despite its efficacy advantage. Quetiapine XR showed comparatively lower efficacy and acceptability than several other agents.
Secondary outcomes evaluating symptomatic remission — indicating near resolution of depressive symptoms rather than partial improvement alone — generally mirrored the primary findings. Exploratory analyses also suggested differences in adverse effects across agents, including risk of clinically significant weight gain.
The authors noted that the analysis focused on short-term studies and highlighted a lack of adequately controlled long-term maintenance data for adjunctive atypical antipsychotics in MDD.
“FDA-approved atypical antipsychotic agents for MDD exhibit differential efficacy, acceptability, and tolerability relevant to treatment selection and sequencing,” concluded the study authors.
Source: McIntyre RS, et al. (2026, May 6). JAMA Psychiatry. Adjunctive Antipsychotics in Major Depressive Disorder: A Systematic Review and Network Meta-Analysis