Treatment-emergent adverse events were reported in 46.5% of placebo group and 58.1% of the lumateperone group.
Lumateperone as adjunctive therapy led to greater symptom improvement for those with major depressive disorder and a history of inadequate therapeutic response to prior medication compared with placebo, data show.
“Despite available treatments, many patients continue to experience persistent symptoms, underscoring an unmet need for additional treatment options,” Suresh Durgam, MD, chief medical officer at Intra-Cellular Therapies, an affiliate of Johnson & Johnson, told Healio about the research published in the Journal of Clinical Psychiatry.
“Caplyta offers a potentially new treatment option for these patients, without the need for titration and similar-to-placebo effects on weight gain and other metabolic side effects,” he continued.
Prior research has established that approximately 50% of individuals with MDD fail to achieve an adequate antidepressant therapy (ADT) response, defined as at least a 50% improvement in symptom severity at 6 to 8 weeks of treatment.
Durgam and colleagues conducted a global, randomized, double-blind, placebo-controlled, phase 3 clinical trial investigating safety and efficacy of lumateperone (Caplyta, Johnson & Johnson) as adjunctive therapy in adults with MDD who had a documented history of inadequate ADT response.
In July, Johnson & Johnson submitted a supplemental new drug application to the FDA for lumateperone in treating adults with schizophrenia.
The study included 485 individuals aged 18 to 65 years who previously were prescribed one or two ADTs during a current depressive episode with no resolution, as well as Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 24 or higher, Clinical Global Impression Scale-Severity (CGI-S) score of 4 or higher and Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score of 14 or more.
“The mechanism of action of Caplyta is unknown. However, it is thought to result from its modulation of multiple neurotransmitter systems in key brain regions involved in mood regulation,” Durgam said. “Serotonin, dopamine and glutamate pathways are implicated in depression in the cortical and subcortical circuits, including prefrontal cortex and limbic system.”
Following a 2-week screening period, all participants were randomly assigned on a 1:1 basis for 6 weeks to receive either 42 mg oral lumateperone (n = 242; mean age, 45 years; 65.6% women) or matching placebo (n = 243; mean age, 45 years; 65.8% women), followed by a 1-week safety follow-up interval.
Both the primary and secondary endpoints for the study were the change from baseline to day 43 in MADRS Total and CGI-S scores, with standard safety metrics also assessed.
Safety and efficacy checks occurred roughly on a weekly basis, beginning around day 1, then on or about days 8, 15, 22, 29, 36 and 43. Safety follow-up was conducted around day 50.
The final safety population comprised 484 individuals, and the modified intent-to-treat population included 481 enrollees.
The researchers found that treatment with lumateperone plus ADT led to greater mean improvement in total scores by day 43 compared with placebo in all three metrics.
In MADRS, the change was a reduction of 10 points in the placebo group and 14 for those given lumateperone; for CGI-S, the differences were a 1 point reduction for placebo and 1.5 for lumateperone; and for QIDS-SR-16, the change was a 5-point reduction for placebo and 8 points for lumateperone.
Durgam and colleagues additionally reported that lumateperone plus ADT was generally well-tolerated, with treatment-emergent adverse events occurring in 46.5% of the placebo plus ADT group and in 58.1% of the lumateperone plus ADT group.
The most common treatment-emergent adverse events were dry mouth (10.8%), fatigue (9.5%) and tremor (5%). The researchers also found little emergence of suicidal ideation for both groups, with a lesser number in the drug treatment cohort.
“This improvement demonstrates that patients experienced tangible reductions in depressive symptoms,” Durgam said. “If approved, these attributes suggest Caplyta may offer another treatment option for MDD patients.”
Supplemental new drug application submitted to U.S. FDA for CAPLYTA (lumateperone) with data demonstrating significant schizophrenia relapse prevention compared to placebo. https://www.jnj.com/media-center/press-releases/supplemental-new-drug-application-submitted-to-u-s-fda-for-caplyta-lumateperone-with-data-demonstrating-significant-schizophrenia-relapse-prevention-compared-to-placebo. Published July 8, 2025. Accessed Aug. 27, 2025.
