Efficacy and Safety of Lumateperone and Other Atypical Antipsychotics Approved as Adjunctive Treatment for Major Depressive Disorder in the United States: A Network Meta-Analysis.

INTRODUCTION

Atypical antipsychotics are common adjunctive therapies for major depressive disorder (MDD) with inadequate antidepressant (ADT) response. In 2025, lumateperone was approved in the US as adjunctive treatment for adults with MDD, and comparative evidence is lacking. This network meta-analysis compared the efficacy and safety of lumateperone with those of other approved atypical antipsychotics for MDD.

METHODS

Registrational randomized clinical trials as documented in US product labeling (RCTs; N = 10; aripiprazole, brexpiprazole, cariprazine, lumateperone, and quetiapine XR) were used to build a star-shaped, 11-treatment-dose node network anchored on placebo + ADT. Outcomes available for ≥ 9 RCTs were considered. Efficacy outcomes comprised change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS), MADRS response and remission, and change from baseline in Clinical Global Impression-Severity (CGI-S) scale. Safety outcomes included weight change from baseline, akathisia, and somnolence. A fixed-effect Bayesian approach was applied. Pairwise treatment effects were compared; a probability of superiority > 85% (< 15%) indicated favored (unfavored) treatment. Network-wide treatment ranking was estimated using Surface Under the Cumulative Ranking (SUCRA) curves.

RESULTS

Based on MADRS change from baseline, all atypical antipsychotics were favored versus placebo + ADT, with mean difference from placebo highest for lumateperone 42 mg/day (- 4.70). Other efficacy endpoints showed a consistent pattern, with active treatments favored over placebo + ADT across most nodes for response (10/11), remission (6/11), and CGI-S change (10/11). SUCRA ranking placed lumateperone as the treatment with the highest likelihood of being most efficacious across endpoints. Treatments differed in their safety profiles. Lumateperone was the only node with no weight gain relative to placebo and ranked first for weight-related safety outcomes. Lumateperone also ranked better than average for akathisia risk but below average for somnolence risk.

CONCLUSION

Lumateperone represents an effective adjunctive therapy for adult MDD, with no weight change.