Adjunctive Lumateperone in Patients With Major Depressive Disorder: Results From an Additional Randomized, Double-Blind, Phase 3 Trial
Introduction: Lumateperone is an FDA-approved antipsychotic for schizophrenia and bipolar depression. This Phase 3, randomized, double-blind, placebo-controlled, multicenter trial (NCT05061706) investigated adjunctive lumateperone 42mg in patients with major depressive disorder (MDD) with inadequate antidepressant therapy (ADT) response.
Methods: Eligible adult outpatients met DSM-5 criteria for MDD with inadequate response to 1-2 prior ADT courses ( < 50% improvement on the Antidepressant Treatment Response Questionnaire) 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 6-week placebo or lumateperone 42mg adjunctive treatment to ADT. Primary and key secondary endpoints were change from baseline to Day 43 in MADRS Total score and CGI-S score. QIDS-SR-16 score and safety were also evaluated.
Results: Of 480 patients (placebo, 238; lumateperone, 242; mean age 46y, 70% women, 95% White), 89% completed treatment. Primary and key secondary endpoints were met with significant improvement for adjunctive lumateperone vs placebo from baseline to Day 43 in MADRS Total score (least squares mean difference vs placebo [LSMD]=−4.5; effect size [ES]=−0. 56; P < .0001) and CGI-S (LSMD=−0.5; ES=−0.51; P < .0001). Adjunctive lumateperone significantly improved QIDS-SR-16 Total score at Day 43 vs placebo (LSMD=−2.2; P < .0001). Adjunctive lumateperone was relatively well-tolerated, consistent with prior studies. Adverse events were mostly mild-to-moderate.
Conclusion: Lumateperone 42mg adjunctive to ADT demonstrated robust, clinically meaningful efficacy over adjunctive placebo to ADT and was generally safe and well-tolerated, indicating lumateperone is a promising treatment as adjunctive therapy to ADT for MDD in adults.
