Lumateperone as an Adjunctive Therapy for MDD: In Conversation With the Primary Investigator

CLINICAL CONVERSATIONS

On November 6, 2025, the US Food and Drug Administration approved Johnson & Johnson’s lumateperone (Caplyta) as an adjunctive therapy for the treatment of adults with major depressive disorder (MDD).^1,2 There were 2 phase 3 double-blind, placebo-controlled clinical trials submitted to the FDA, Studies 501 and 502, that demonstrated Caplyta’s ability to improve depressive symptoms in patients with MDD. In the wake of this approval, Psychiatric Times sat down with Suresh Durgam, MD, the primary investigator on these trials, to discuss the data and what Caplyta can offer patients.

Psychiatric Times: As the primary investigator, what do you think is the most important finding(s) from Studies 501 and 502?

Suresh Durgam, MD: People living with MDD often spend years cycling through treatment options, searching for something that will provide adequate relief. For patients experiencing partial relief with their current treatment, adding Caplyta can offer hope that complete symptom relief is possible.

In the 2 pivotal trials, a large separation in total MADRS score was seen between Caplyta and placebo in Study 501 (-4.9 points, effect size 0.61) and Study 502 (-4.5 points, effect size 0.56) at 6 weeks. Importantly, early separation from placebo was seen as early as 1 week in Study 501 and 2 weeks in Study 502, which is particularly exciting, as other MDD treatments can take several weeks for patients to achieve a response.

PT: Can you speak to the efficacy and safety of Caplyta? How does its side effect profile differ from other atypical antipsychotics?

Durgam: It is well-known that troubling adverse effects like weight gain, increase in metabolic parameters (eg, cholesterol, triglycerides, glucose), extrapyramidal symptoms, prolactin increase, and sexual dysfunction are some of the common reasons that patients discontinue treatments for MDD, which is why it is so important to have new treatment options that are not only effective but also safe and well-tolerated.

Caplyta has the potential to address this significant unmet need, delivering robust efficacy as early as 1-to-2 weeks and with similar-to-placebo rates of weight gain, metabolic changes, prolactin, and reported sexual adverse effects.

Moreover, long-term data from the 6-month, open-label extension safety study (Study 503) showed Caplyta remained safe and well-tolerated over time—consistent with data from its established indications. This further reinforces the potential for Caplyta to become a new standard of care across multiple mental health disorders, including MDD.

PT: Long-term data from the 503 open-label extension safety study show that patients treated with Caplyta experienced low risk of weight gain, cardiometabolic effects, and extrapyramidal symptoms. Can you speak more on this? How could this help improve treatment adherence?

Durgam: Study 503 showed no new safety concerns and was consistent with the safety profiles observed in Studies 501 and 502. Over 26 weeks, patients continued to experience low risk of weight gain, cardiometabolic effects, and extrapyramidal symptoms, further reinforcing the strong safety and tolerability profile of Caplyta in this patient population.

PT: During the 26-week safety study, 65% of patients experienced remission—the ultimate goal of treatment. How could Caplyta, with results like these, change MDD treatment expectations?

Durgam: Remission is an important goal of MDD treatment, as patients who fail to achieve remission experience ongoing challenges in their daily lives. Despite treatment, 2 in 3 patients continue to experience lingering symptoms of depression, significantly impacting their quality of life. For patients who are experiencing partial relief from their oral antidepressants, adding Caplyta to their treatment plan can build on the benefit they are already receiving and offer hope that complete relief is possible.

In the long-term 26-week safety study (Study 503), 80% of MDD patients taking Caplyta responded to treatment and 65% of patients experienced remission (defined as MADRS total score ≤10). These results show that Caplyta provides patients with a safe, effective, and well-tolerated new treatment option that can enable a path to remission and reset expectations that lasting relief is possible.

PT: Is there anything else important you would like practicing clinicians to know?

Durgam: For any clinician and patient, the ultimate goal of MDD treatment is remission. With its robust efficacy and a favorable safety and tolerability profile, Caplyta offers clinicians a meaningful new option to help patients move beyond partial relief and toward lasting recovery.

PT: Thank you!

Dr Durgam is the executive vice president and the chief medical officer of Intra-Cellular Therapies Inc, a Johnson & Johnson company. He is also the Study 501 and Study 502 primary investigator.

References

1. Kuntz L. FDA approves Caplyta for adjunctive treatment of major depressive disorder. Psychiatric Times. November 6, 2025. https://www.psychiatrictimes.com/view/fda-approves-caplyta-for-adjunctive-treatment-of-major-depressive-disorder

2. FDA approval of CAPLYTA® (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder. News release. November 6, 2025. Accessed 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