CNSPulse
T36

LUMATEPERONE VERSUS OTHER ADJUNCTIVE ATYPICAL ANTIPSYCHOTICS FOR MAJOR DEPRESSIVE DISORDER: A NETWORK META-ANALYSIS OF COMPARATIVE EFFICACY AND SAFETY

Andrew Cutler — Anaïs Lemye2, Qiaoyi Zhang3, Carol Mao3, Todor I Totev4, Marjolaine Gauthier-Loiselle2, Yujie Wu4, Jingyi Liu2, Mahmoud Hashim5, Madhav Namjoshi3, John J Sheehan3, Dominic Pilon2, Patrick Lefebvre2, Antoine El Khoury3, Leslie Citrome6, Andrew J. Cutler, MD7 1SUNY Upstate Medical University, 2Analysis Group ULC, Montreal, 3Johnson and Johnson, Raritan, 4Analysis Group, Inc., Boston, 5Johnson and Johnson, Leiden, South Holland, 6New York Medical College, 7SUNY Upstate Medical University; Neuroscience Education Institute

2026 ASCP Annual Meeting

Objectives

In 2025, the US FDA approved lumateperone, an atypical antipsychotic, as adjunctive treatment for major depressive disorder (MDD). This network meta-analysis (NMA) compared efficacy and safety of lumateperone with other approved atypical antipsychotics: aripiprazole, brexpiprazole, cariprazine, and quetiapine XR in patients with MDD and inadequate response to antidepressants (ADT).

Methods

Ten short-term, randomized, double-blind, placebo-controlled registration trials formed a star-shaped network of 11 treatment-and dose-specific nodes anchored on placebo+ADT. Trial design, eligibility criteria, and baseline characteristics were similar across trials, yielding broadly comparable populations of adults with MDD and inadequate response to an ADT. Most trials were Phase 3 with a 6-week double-blind period; one trial was Phase 2 with an 8-week double-blind period. Outcomes consistently reported and available for ≥9/10 trials were included. Efficacy outcomes were Montgomery–Åsberg Depression Rating Scale (MADRS) change from baseline, MADRS-based response and remission, and Clinical Global Impression–Severity (CGI-S) change from baseline. Safety outcomes included proportion of patients with ≥7% weight increase from baseline, akathisia, and somnolence. Fixed-effect Bayesian NMAs were conducted. Analyses used 3 Markov Chain Monte Carlo simulations with 30,000 iterations each, including 20,000 burn-in iterations. Normal likelihoods were used for continuous outcomes and binomial likelihoods for binary outcomes with non-informative priors. Treatment effects versus placebo+ADT were estimated; a probability of superiority > 85% ( < 15%) indicated that the treatment was favored (unfavored) over placebo+ADT. Network-wide treatment rankings were summarized using surface under the cumulative ranking curve (SUCRA).

Results

All treatment-dose nodes were favored versus placebo+ADT for MADRS change from baseline at Week 6, with similar patterns observed for other efficacy outcomes (response: 10/11, remission: 6/11, CGI-S change: 10/11). SUCRA ranking consistently placed lumateperone first across all efficacy outcomes. Safety profiles varied across treatments. Risk of ≥7% weight increase was unfavorable versus placebo+ADT for 6/11 treatment-dose nodes. Lumateperone was the only treatment-dose favored versus placebo+ADT and ranked first for the lowest risk of ≥7% weight increase. Risk of akathisia was unfavorable versus placebo+ADT for 9/11 treatment-dose nodes, with lumateperone ranking third best after placebo+ADT. Risk of somnolence was unfavorable versus placebo+ADT for 10/11 treatment-dose nodes, with lumateperone ranking sixth best after placebo+ADT.

Conclusion

Guidelines recommend treatment modification until patients with MDD reach remission, and during their treatment journey patients frequently need to change therapies due to inadequate symptom relief and adverse events. In this NMA, adjunctive lumateperone demonstrated a favorable efficacy profile relative to other approved adjunctive antipsychotics. While safety profiles varied across atypical antipsychotics, lumateperone showed a favorable profile for the weight-related and akathisia endpoints, and less favorable for somnolence risk. Physicians should carefully balance efficacy and safety risks with individual patients when selecting adjunctive atypical antipsychotics for MDD to optimize patient care.