Lumateperone Treatment for Major Depressive Episodes with Mixed Features in Major Depressive Disorder and Bipolar I or Bipolar II Disorder

This work was sponsored by Intra-Cellular Therapies, Inc. Background: Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. This randomized, double-blind, placebo-controlled, multicenter trial (NCT04285515) investigated the efficacy and safety of lumateperone 42mg for the treatment of a major depressive episode (MDE) in patients with major depressive disorder (MDD) or bipolar depression (BPD) with mixed features. Methods: Adults with DSM-5 diagnosed MDD or bipolar I or II disorder with mixed features experiencing an MDE (Montgomery-Asberg Depression Rating Scale [MADRS] Total score≥24, and a Clinical Global Impression Scale-Severity [CGI-S] score≥4) were randomized 1:1 to lumateperone 42mg or placebo. Primary and key secondary efficacy outcomes were change from baseline to Day 43 in MADRS Total score and CGI-S score, respectively. Safety was assessed. Results: Of 385 patients treated (placebo, n=193; lumateperone, n=192), 344 (89.4%) completed the study. MADRS Total score significantly improved with lumateperone 42mg compared with placebo in the combined MDD/BPD population (mean change from baseline to Day 43 least squares mean difference vs placebo (LSMD)=−5.7; 95% CI, −7.60, −3.84; effect size=−0.64; P.0001), with similar significant improvements (P.0001) in the individual MDD and BPD populations. Significant improvements were also observed for CGI-S in the combined MDD/BPD population (LSMD=−0.6; 95%CI, −0.81, −0.39; effect size=−0.59; P.0001) and individual MDD and BPD populations. Lumateperone treatment was generally safe and well tolerated and consistent with prior studies. Conclusions: Lumateperone 42mg demonstrated robust efficacy over placebo in patients with MDD or BPD with mixed features and was generally safe and well tolerated.