COMPARATIVE EFFICACY AND SAFETY OF LUMATEPERONE AND OTHER ATYPICAL ANTIPSYCHOTICS APPROVED AS ADJUNCTIVE THERAPY FOR MAJOR DEPRESSIVE DISORDER: A NETWORK META-ANALYSIS
Author(s)
Andrew J. Cutler, MD1, Anaïs Lemyre, PhD2, Qiaoyi Zhang, MD, PhD3, Carol Mao, MS, MBA3, Todor I. Totev, MBA4, Marjolaine Gauthier-Loiselle, PhD2, Yujie Wu, PhD4, Jingyi Liu, MSc2, Mahmoud Hashim, PhD5, Madhav Namjoshi, PhD3, John J. Sheehan, PhD, RPh3, Dominic Pilon, MA2, Patrick Lefebvre, MA2, Antoine El Khoury, PhD, MS3, Leslie Citrome, MD, MPH6;
1SUNY Upstate Medical University, Syracuse, NY, USA, 2Analysis Group ULC, Montréal, QC, Canada, 3Johnson & Johnson, Raritan, NJ, USA, 4Analysis Group, Inc., Boston, MA, USA, 5Johnson & Johnson, Leiden, Netherlands, 6New York Medical College, Valhalla, NY, USA
1SUNY Upstate Medical University, Syracuse, NY, USA, 2Analysis Group ULC, Montréal, QC, Canada, 3Johnson & Johnson, Raritan, NJ, USA, 4Analysis Group, Inc., Boston, MA, USA, 5Johnson & Johnson, Leiden, Netherlands, 6New York Medical College, Valhalla, NY, USA
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 for MDD with 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. Eligibility and baseline characteristics were similar across trials. 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 ≥7% weight increase from baseline, akathisia, and somnolence. Fixed-effect Bayesian NMAs were conducted. 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. For ≥7% weight increase, 6/11 treatment-dose nodes were unfavorable versus placebo+ADT; only lumateperone was favored versus placebo+ADT and ranked first for the lowest risk. 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.
CONCLUSIONS: In this NMA, lumateperone demonstrated a favorable efficacy profile versus other approved adjunctive antipsychotics, with no increased risk of weight gain. Balancing efficacy and safety is crucial when selecting adjunctive antipsychotic treatment for MDD.
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. Eligibility and baseline characteristics were similar across trials. 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 ≥7% weight increase from baseline, akathisia, and somnolence. Fixed-effect Bayesian NMAs were conducted. 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. For ≥7% weight increase, 6/11 treatment-dose nodes were unfavorable versus placebo+ADT; only lumateperone was favored versus placebo+ADT and ranked first for the lowest risk. 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.
CONCLUSIONS: In this NMA, lumateperone demonstrated a favorable efficacy profile versus other approved adjunctive antipsychotics, with no increased risk of weight gain. Balancing efficacy and safety is crucial when selecting adjunctive antipsychotic treatment for MDD.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
CO60
Topic
Clinical Outcomes
Topic Subcategory
Clinical Outcomes Assessment, Comparative Effectiveness or Efficacy
Disease
SDC: Neurological Disorders