LUMATEPERONE TREATMENT FOR MAJOR DEPRESSIVE EPISODES WITH MIXED FEATURES IN MAJOR DEPRESSIVE DISORDER AND BIPOLAR I OR BIPOLAR II DISORDER

Abstract Background The DSM-5 and DSM-5-TR define mixed features in major depressive disorder (MDD) or bipolar depression (BPD) as having subsyndromal manic or hypomanic symptoms nearly every day during the majority of days of a major depressive episode (MDE). Mixed features are common in MDD and BPD (25%-35%) and patients with mixed features have more severe symptoms, more comorbidities, increased suicide risk, and poorer treatment response than patients without mixed features. Aims & Objectives 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 an MDE in patients with MDD or BPD with mixed features. Method Eligible adults (18-75 years) had DSM-5 diagnosed MDD or bipolar I or II disorder with mixed features and were experiencing an MDE (Montgomery-Asberg Depression Rating Scale [MADRS] Total score>=24, Clinical Global Impression Scale-Severity [CGI-S] score>=4). Patients, stratified by MDD or BPD, were randomized 1:1 to 6-weeks treatment with lumateperone 42mg or placebo. The primary and key secondary efficacy endpoints were change from baseline to Day 43 in MADRS Total and CGI-S score, respectively, analyzed using a mixed- effects model for repeated measures. Three populations with mixed features were assessed: the overall combined MDD and BPD population, the individual MDD population, and the individual BPD population. Safety assessments included adverse events (AEs), laboratory parameters, vital signs, and extrapyramidal symptoms. Results In this study, 385 patients received treatment (placebo, n=193; lumateperone, n=192) and 344 (89.4%) completed the study. Patients with MDD or BPD and mixed features treated with lumateperone 42mg had significantly greater MADRS Total score improvement compared with placebo as indicated by mean change from baseline to Day 43 (placebo, n=191; lumateperone, n=192; least squares mean difference vs placebo [LSMD]=−5.7; 95% CI, −7.60, −3.84; effect size [ES]=−0.64; P<.0001). Improvements with lumateperone were also significant in individual patient populations with MDD with mixed features (placebo, n=92; lumateperone, n=92; LSMD=−5.9; 95%CI, −8.61, −3.29; ES=−0.67; P<.0001) or BPD with mixed features (placebo, n=99; lumateperone, n=100; LSMD=−5.7; 95%CI, −8.29, −3.05; ES=−0.64; P<.0001). Significant improvements compared with placebo were also observed for CGI-S, the key secondary endpoint, in the combined MDD and BPD population (LSMD=−0.6; 95%CI, −0.81, −0.39; ES=−0.59; P<.0001), individual MDD population (LSMD=− 0.6; 95%CI, −0.89, −0.27; ES=−0.57; P<.001), and individual BPD population (LSMD=−0.6; 95%CI, −0.91, −0.31; ES=−0.61; P<.0001). Lumateperone treatment was generally safe and well tolerated and consistent with prior studies. The most common treatment-emergent AEs with lumateperone (>=5% and twice placebo) were somnolence, dizziness, and nausea. No serious AEs were reported with lumateperone. Discussion & Conclusion Lumateperone 42mg demonstrated robust efficacy over placebo in patients with MDD or BPD with mixed features. Lumateperone was generally safe and well tolerated with no new safety concerns. These results suggest lumateperone 42mg is a promising new treatment for MDEs in MDD with mixed features or BPD with mixed features.