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

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. 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. 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. Lumateperone represents an effective adjunctive therapy for adult MDD, with no weight change. Major depressive disorder is relatively common, and many adult patients do not experience sufficient improvement with antidepressant therapy alone. When this occurs, clinicians may prescribe an atypical antipsychotic to be taken with antidepressants. In 2025, lumateperone was approved in the US as an add-on treatment for adults with major depressive disorder. This network meta-analysis compared the efficacy and safety of lumateperone with those of other atypical antipsychotics approved for add-on treatment of major depressive disorder across clinical trials done by each company to obtain approval by the United States Food and Drug Administration. Ten trials compared placebo with different dosages of aripiprazole, brexpiprazole, cariprazine, lumateperone, and quetiapine extended release (for a total of 12 options evaluated) when used together with antidepressant medication. The analysis focused on consistently used measures of depression severity and improvement, including changes in depression rating scale scores, rates of clinical response, and remission of symptoms. Safety outcomes such as weight change, akathisia (inner restlessness), and somnolence were also assessed. Across all measures of symptom improvement, most atypical antipsychotics were more efficacious than placebo. Lumateperone showed the highest likelihood of being the most effective treatment for all efficacy outcomes. Safety differed across treatments, with lumateperone uniquely showing no weight gain versus placebo and ranking better than average for akathisia (inner restlessness) and below average for somnolence. Overall, these results suggest that lumateperone represents an effective treatment used alongside antidepressants for adults with major depressive disorder, with no weight change.