Efficacy of Lumateperone 42 Mg in the Treatment of Major Depressive Disorder: A Pooled Analysis of Phase 3 Randomized Controlled Trials

Background Major depressive disorder (MDD) is a common and complex mental illness that is associated with multiple comorbidities, impaired functioning, and a heightened risk of suicide. Current treatments have limited response and remission rates and ≈50% of patients with MDD have inadequate antidepressant therapy (ADT) response. Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. The efficacy and safety of lumateperone adjunctive to ADT was evaluated in 2 Phase 3, randomized, double-blind, placebo-controlled studies (501, NCT04985942; 502, NCT05061706) in patients with MDD with inadequate ADT response. In both studies, lumateperone 42 mg + ADT met the primary endpoint, with significant improvement in depressive symptoms vs placebo + ADT, and was generally well tolerated. Aims & Objectives This pooled analysis of Study 501 and Study 502 assessed the efficacy of lumateperone 42 mg + ADT in patients with MDD with inadequate ADT response. Method Data were pooled from 2 studies that enrolled adults (18-65 years) who met DSM-5 criteria for MDD with inadequate response to 1-2 ADT in the current depressive episode, and had Montgomery-Åsberg Depression Rating Scale (MADRS) Total score ≥24, Clinical Global Impression Scale-Severity (CGI-S) score ≥4, and Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score ≥14. Primary and key secondary endpoints were the change from baseline to Day 43 in MADRS Total score and CGI-S score, respectively, analyzed using a mixed-effects model for repeated measures. Additional measures included response (≥50% MADRS Total score decrease) and remission (MADRS Total score ≤10), based on a logistic regression model. Change from baseline in QIDS-SR-16 Total score was evaluated using an analysis of covariance. Results The modified intent-to-treat population comprised 950 patients (lumateperone + ADT, n=471; placebo + ADT, n=479). Compared with placebo + ADT, lumateperone + ADT significantly improved MADRS Total score (least squares mean difference vs placebo [LSMD]=−4.7; effect size [ES]=−0.59; P<.0001) and CGI-S score (LSMD=−0.6; ES=−0.59; P<.0001) from baseline to Day 43. Rates of MADRS Total score response (lumateperone + ADT, 42.9%; placebo + ADT, 24.6%; P<.0001) and remission (lumateperone + ADT, 25.5%; placebo + ADT, 13.6%; P<.0001) were significantly greater with lumateperone + ADT vs placebo + ADT at Day 43. Self-reported depressive symptoms also significantly improved with lumateperone + ADT at end of treatment vs placebo + ADT (QIDS-SR-16 Total score, LSMD=−2.2; ES=−0.4; P<.0001). Discussion & Conclusions Lumateperone 42 mg + ADT demonstrated robust, clinically meaningful efficacy over placebo + ADT in this pooled analysis of 2 trials in patients with MDD with inadequate ADT response. These results indicate that lumateperone 42 mg is a promising treatment as adjunctive therapy to ADT to treat MDD in adults.