Phase 3 Data Bolster FDA Approval of Lumateperone as Adjunctive MDD Therapy, With Suresh Durgam, MD

New phase 3 data strengthen the clinical rationale behind the recent US Food & Drug Administration (FDA) approval of lumateperone (CAPLYTA) as an adjunctive treatment for major depressive disorder (MDD), according to study investigator Suresh Durgam, MD, chief medical officer of Intra-Cellular Therapies, a Johnson & Johnson company.

In an interview with HCPLive, Durgam said the newly published Study 502 was designed to replicate and extend earlier findings by specifically evaluating lumateperone added to ongoing antidepressant therapy in patients with an inadequate response.

“In this particular study, both the primary endpoint and secondary endpoints were statistically significant and robust, which showed that the patients who had inadequate response were beneficial on adding lumateperone on top of antidepressants,” Durgam said.

The FDA approved lumateperone in November 2025 as an adjunctive therapy for adults with MDD, a population in which nearly two-thirds of patients fail to respond adequately to standard oral antidepressants. Study 502 provides confirmatory phase 3 evidence aimed at helping clinicians better understand where lumateperone fits within an increasingly crowded adjunctive treatment landscape.

The randomized, double-blind, placebo-controlled trial enrolled 480 adults with DSM-5–defined MDD who had achieved < 50% response to 1 or 2 antidepressants during their current depressive episode. Patients received lumateperone 42 mg (n = 242) or placebo (n = 238) once daily in the evening, added to their existing antidepressant, for 6 weeks.

Lumateperone met its primary endpoint, significantly improving Montgomery-Åsberg Depression Rating Scale (MADRS) total scores compared with placebo (least squares mean difference [LSMD], −4.5) by day 43. The trial also met its key secondary endpoint of Clinical Global Impressions–Severity (CGI-S; LSMD, −0.5).

Separation from placebo emerged as early as 2 weeks, setting this antidepressant apart from others. Often, antidepressants take 4 – 8 weeks to go into effect. With lumateperone, patients do not have to wait a long period to see if the medication works for them.

Safety findings were consistent with lumateperone’s established profile. Although treatment discontinuation due to adverse events was greater with lumateperone than placebo, Durgam stressed that more than 89% of patients completed the study and that most adverse events were mild or moderate and resolved within 2 to 3 weeks. Notably, cardiometabolic parameters, weight gain, extrapyramidal symptoms, and prolactin levels were comparable to placebo.

Durgam said that the data reinforce lumateperone’s potential role for patients with partial or inadequate antidepressant response, particularly for those concerned about weight gain or metabolic burden, while providing clinicians with clearer guidance on efficacy, tolerability, and expectations early in treatment. The approval of lumateperone addresses the unmet need in patients with inadequate antidepressant response as only a few treatments are available.

“Adding this to that armamentarium for the prescriber’s toolbox will help as another option because of the robust efficacy and also the [low] side effect burden,” Durgam said.

References

1. Durgam S, Earley WR, Kozauer SG, et al. Adjunctive Lumateperone in Patients With Major Depressive Disorder: Results From a Randomized, Double-Blind, Phase 3 Trial. Am J Psychiatry. 2025;182(12):1072-1082. doi:10.1176/appi.ajp.20250292

2. FDA approval of CAPLYTA® (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder. JNJ.com. Published November 6, 2025. https://www.jnj.com/media-center/press-releases/fda-approval-of-caplyta-lumateperone-has-the-potential-to-reset-treatment-expectations-offering-hope-for-remission-in-adults-with-major-depressive-disorder

3. Derman C. Adjunctive Lumateperone Significantly Improves MDD Symptoms by Day 43. HCPLive. Published December 8, 2025. Accessed December 16, 2025. https://www.hcplive.com/view/adjunctive-lumateperone-significantly-improves-mdd-symptoms-day-43