Efficacy and safety of adjunctive therapy with lumateperone in major depressive disorder: a randomized-, double-blind, placebo-controlled clinical trial

This study aimed to investigate the effects of lumateperone as a combination therapy with sertraline in major depressive disorder (MDD). The 8-week, double-blind, placebo-controlled trial was registered with the Iranian Registry of Clinical Trials (registration date: 2022-03-01, registration number: IRCT20090117001556N141). Patients with MDD were randomized to receive either sertraline (100 mg/day) combined with lumateperone (42 mg/day) or sertraline (100 mg/day) with placebo. The Hamilton Depression Rating Scale (HDRS) was used to assess treatment efficacy. Fifty-eight patients with MDD were analyzed (age: 36.91 ± 9.81 and male: 69.0%). The two groups were comparable across baseline sociodemographic and clinical characteristics except for marital status. There was a significant time × treatment interaction on HDRS ( P = 0.027), suggesting greater improvement in depressive symptoms following the lumateperone adjuvant therapy. Compared with the placebo group, a significantly larger proportion of individuals receiving lumateperone experienced an HDRS reduction rate greater than or equal to 50% at weeks 4 (90.0 vs. 60.7%, P = 0.014) and 8 (100 vs. 82.1, P = 0.021). However, the remission rate was not different. No serious adverse events were reported. This study suggests that lumateperone can be considered an effective and safe adjuvant treatment for MDD. Future larger clinical trials with extended follow-up periods are needed to confirm its efficacy for clinical use.