Written By: Pharmacally Medical News Desk
The U.S. Food and Drug Administration (FDA) approved CAPLYTA® (lumateperone) on November 6, 2025, as an adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults. This approval represents CAPLYTA’s fourth indication, following its prior approvals for bipolar I and II depression and schizophrenia in adults. The marketing authorization holder (MAH) is Johnson & Johnson, following its acquisition of Intra-Cellular Therapies.
Approval was supported by positive results from two pivotal Phase 3, global, double-blind, placebo-controlled studies 501 (NCT04985942) and 502 (NCT05061706), which examined CAPLYTA as adjunctive therapy alongside standard oral antidepressants. Both trials met their primary endpoint statistically significant and clinically meaningful improvement in depressive symptoms at six weeks, measured by reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scores (-4.9 for Study 501, effect size 0.61; -4.5 for Study 502, effect size 0.56). Key secondary endpoints included changes in Clinical Global Impression Scale-Severity (CGI-S), which also showed marked improvements. Notably, separation from placebo occurred as early as one week in Study 501 and two weeks in Study 502. Open-label extension data indicated robust long-term benefits, with 80% of patients responding and 65% achieving remission (MADRS ≤ 10) by six months.
CAPLYTA’s safety profile in adjunctive MDD treatment is consistent with its earlier indications. In the pivotal trials and the 26-week open-label extension, the most common adverse events were somnolence, dizziness, dry mouth, nausea, fatigue and diarrhea. Extrapyramidal symptoms, weight gain and metabolic changes were uncommon. No cases of serious suicidal ideation or suicidal behavior were reported in the long-term study, but the FDA label includes a boxed warning for suicidal thoughts and behaviors in younger patients and the standard warning about increased mortality in elderly patients with dementia-related psychosis. Because cognitive and motor impairment can occur, and the drug may lower the seizure threshold, clinicians should monitor patients with relevant risk factors. Overall, the tolerability profile remained stable over short- and long-term treatment, with no new safety signals identified.
The precise mechanism for lumateperone’s antidepressant effects is not established; the FDA label notes it likely works via combined activity at central 5-HT2A receptors and dopamine D2 receptors and may modulate glutamatergic pathways and serotonin transport a multimodal profile that could underlie the observed clinical effects
CAPLYTA (lumateperone) 42 mg, now approved for adjunctive MDD therapy, expands its utility as a safe and effective option for adults suffering from persistent depressive symptoms. Major depressive disorder affects millions, with a sizable subset inadequately controlled on standard antidepressants alone making CAPLYTA’s adjunctive benefits especially impactful. This approval offers renewed hope for patients and clinicians seeking faster onset, high remission rates, and minimal safety concerns in MDD management.
Experts note the urgency of more effective adjunctive therapies for MDD given its heterogeneous nature and variable response to antidepressants. Roger S. McIntyre, M.D. (University of Toronto) emphasized CAPLYTA’s potential for early improvement and the promise of remission, aligning with patient goals for sustained wellness. Bill Martin, Ph.D. (J&J Global Neuroscience) highlighted the significance of CAPLYTA’s differentiated profile and favorable safety in resetting treatment expectations for patients and clinicians, projecting CAPLYTA as a candidate for a new therapeutic standard.
References
FDA approval of CAPLYTA® (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder, 06 November 2025, Johnson and Johnson, 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
Clinical Trial of Lumateperone as Adjunctive Therapy in the Treatment of Patients with Major Depressive Disorder, ClinicalTrials.gov ID NCT04985942, https://www.clinicaltrials.gov/study/NCT04985942
Multicenter Study of Lumateperone as Adjunctive Therapy in the Treatment of Patients With Major Depressive Disorder, ClinicalTrials.gov ID NCT05061706, https://www.clinicaltrials.gov/study/NCT05061706
Durgam S, Earley WR, Kozauer SG, Chen C, Lakkis H, McIntyre RS, Stahl S. Lumateperone as Adjunctive Therapy in Patients With Major Depressive Disorder: Results From a Randomized, Double-Blind, Phase 3 Trial. J Clin Psychiatry. 2025 Aug 25;86(4):25m15848. doi: 10.4088/JCP.25m15848. PMID: 40875502.
Durgam S, Earley W, Kozauer S, Chen C, Edwards J, Jain R. 612. Efficacy of lumateperone 42 mg in the treatment of major depressive disorder: a pooled analysis of phase 3 randomized controlled trials. Int J Neuropsychopharmacol. 2025 Aug 18; 28(Suppl 2):ii77–8. Doi: 10.1093/ijnp/pyaf052.153. PMCID: PMC12359771.