Adjunctive Lumateperone Significantly Improves MDD Symptoms by Day 43

A recent phase 3 study showed that lumateperone 42 mg as an adjunctive to antidepressant therapy provided statistically significant improvement in depression symptoms and disease severity by day 43 among individuals with major depressive disorder (MDD).

This long-term pivotal data follows the US Food & Drug Administration (FDA) approval of lumateperone as an adjunctive therapy for MDD, announced by Johnson & Johnson on November 6, 2025. Lumateperone, an oral, once daily atypical antipsychotic, targets 3 neurotransmitters simultaneously: serotonin, dopamine, and glutamate. The drug acts as a 5-HT2A antagonist and modulates dopamine by partially agonizing presynaptic D2 receptors while blocking postsynaptic ones. It also influences D1 signaling, indirectly enhances AMPA and NMDA glutamatergic activity, and exhibits some CERT-inhibitory effects.”

“This complex mechanism, which includes all these 4 mechanisms, is the reason why we have seen a strong efficacy for this in this patient population,” said first author Suresh Durgam, MD, the chief medical officer and executive vice president at Intra-Cellular Therapies, in the American Journal of Psychiatry Podcast episode, December 2025: “December 2025: Adjunctive Lumateperone in Patients With Major Depressive Disorder: Results From a Randomized, Double-Blind, Phase 3 Trial.”

Durgam and colleagues conducted a phase 3, randomized, double-blind, placebo-controlled trial to assess lumateperone 42 mg as an adjunctive to antidepressant therapy in patients with MDD. Primary and secondary outcomes included change from baseline to day 43 in MADRS total score and Clinical Global Impressions Scale severity (CGI-S) score. Safety measures included adverse events, extrapyramidal symptoms, laboratory assessments, and suicidal ideation and behavior.

The sample included adults aged 18 – 65 years old who had DSM-5-defined MDD, an inadequate response to 1 or 2 antidepressant therapies in the current depressive episode, and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 24. Participants were randomized 1:1 to receive evening doses of lumateperone 42 mg plus their current antidepressant (n = 242) or placebo plus antidepressants (n = 238) for 6 weeks. The antidepressant used was the most recent medication to which the participant had shown an inadequate response (<50% improvement).

The trial met the primary and secondary endpoints, with lumateperone plus antidepressants significantly improving MADRS total score (least squares mean difference [LSMD] versus placebo, −4.5; effect size, −0.56) and CGI-S score (LSMD, −0.5; effect size, −0.51) versus placebo plus antidepressants at day 43. The lumateperone arm also had significantly improved patient-reported depression compared to the placebo arm at day 43 (16-item Quick Inventory of Depressive Symptomatology-Self-Report, total score, SMD, −2.2; effect size, −0.45)

The study also showed that lumateperone plus antidepressants was generally well tolerated, though more patients on lumateperone discontinued treatment due to treatment-emergent adverse events (12.4% vs 0.8%). Common adverse events included dizziness, somnolence, dry mouth, nausea, diarrhea, and fatigue. Lumateperone had a minimal risk of extrapyramidal symptoms and suicidal ideation; both arms had similar levels of cardiometabolic abnormalities and weight gain.

“This is not new from the standpoint of other atypical antipsychotics have been approved by the FDA for this purpose,” said Ned Kalin, editor-in-chief of the American Journal of Psychiatry and psychiatry department chair at the University of Wisconsin, in the podcast. He listed currently approved antipsychotics: neuropeprazole, brexpiprazole, preprazole, cryptozone, and the combination medication olanzapine/fluoxetine.

“So, we do have other agents in this class of drugs that are already shown and are approved by [the] FDA to help people with depression,” Kalin continued. “But this is another medicine, and it's really helpful for us because it's not identical to the other medications.”

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. December 2025: Adjunctive Lumateperone in Patients With Major Depressive Disorder: Results From a Randomized, Double-Blind, Phase 3 Trial. Apple Podcasts. Published December 2025. Accessed December 8, 2025. https://podcasts.apple.com/us/podcast/december-2025-adjunctive-lumateperone-in-patients-with/id253702215?i=1000739105366