Lumateperone as Adjunctive Therapy in Patients With Major Depressive Disorder: Results From a Randomized, Double-Blind, Phase 3 Trial
Introduction: Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and bipolar depression. This Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial (NCT04985942) investigated adjunctive lumateperone 42mg in patients with major depressive disorder (MDD) with inadequate response to antidepressant therapy (ADT).
Methods: Eligible adults met DSM-5 criteria for MDD with inadequate response to 1 to 2 courses of prior ADT and had Montgomery-Asberg 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. Patients were randomized to outpatient 6-week placebo or lumateperone 42mg adjunctive to ADT. Primary and key secondary efficacy endpoints were change from baseline to Day 43 in MADRS Total and CGI-S score, respectively. QIDS-SR-16 Total score and safety were evaluated.
Results: Of 484 patients treated (placebo, 243; lumateperone, 241), 93% completed treatment. Primary and key secondary endpoints were met for adjunctive lumateperone, with significantly greater improvement vs adjunctive placebo from baseline to Day 43 in MADRS Total score (least squares mean difference vs placebo [LSMD]=−4.9; effect size [ES]=−0.61; P < .0001) and CGI-S (LSMD=−0.7; ES=−0.67; P < .0001). Adjunctive lumateperone significantly improved QIDS-SR-16 Total score at Day 43 vs adjunctive placebo (LSMD=−2.4; ES=−0.47; P < .0001). Adjunctive lumateperone was generally safe and well-tolerated, consistent with prior studies. No serious adverse events occurred with lumateperone during treatment.
Conclusion: Lumateperone 42mg adjunctive to ADT demonstrated robust and clinically meaningful efficacy over adjunctive placebo to ADT and was generally safe and well-tolerated, indicating lumateperone as a promising adjunctive therapy to ADT for MDD in adults.
