A new study showed significant efficacy of lumateperone 42 mg as maintenance treatment to prevent relapse in adults with schizophrenia.1 Data on this phase 3 study were presented at the 2025 European College of Neuropsychopharmacology Annual Congress in Amsterdam by Intra-Cellular Therapies.
Participants in this phase 3 double-blind, placebo-controlled, random withdrawal trial (NCT 04959032) were adults aged 18 to 60 years with a DSM-5 diagnosis of schizophrenia for over 1 year and a Positive and Negative Syndrome Scale (PANSS) score of 70 to 120. All patients first received lumateperone 42 mg for 18 weeks (6 weeks for run-in and 12 weeks for stabilization) and then stable patients were randomized to treatment or placebo. Randomization was 1:1 double-blind for lumateperone 42 mg of placebo for 26 weeks, or until relapse. 228 patients were stable after the introductory phase, with 114 receiving lumateperone and 114 receiving placebo. Notably, a greater proportion of white patients were stabilized and continued on to the double-blind phase. The primary endpoint studied was time to first symptom relapse during the blinded phase of treatment. The study also assessed general safety and time to all-cause medication discontinuation, including relapse, during the double-blind phase.
Stabilization after the introductory phase was defined by a PANSS score of 60 or lower, a 20% or greater reduction in PANSS total score from baseline, Clinical Global Impression Scale-Severity (CGI-S) score of 4 or less, no suicidal ideation, and no tolerability issues. Relapse was defined as 1 or more instance of psychiatric hospitalization or increased psychiatric care, aggressive/violent behavior or self-injury, or suicidal or homicidal ideation; a PANSS total score increase by 30% or greater; CGI-S score increase by 2 or more points; and a score above 4 on 1 or more of 7 specified PANSS items.
The trial met its primary endpoint, with lumateperone treatment significantly delaying time to relapse, compared with placebo (hazard ratio: 0.37; 95% CI: 0.22-0.65; P =.0002). Of the 228 patients in the double-blind phase, 130 (58%) completed treatment without relapse. Fewer relapses occurred in the lumateperone group vs placebo (n=18 treatment group vs n=44 placebo). Lumateperone was also found to delay time to all-cause discontinuation compared with placebo (P = 0.0007); rate of all-cause discontinuation was lower in the lumateperone treatment group than placebo (n=34 treatment and n=60 placebo). The most common treatment emergent adverse effects were headache during both the introductory and double-blind phase. Rates of extrapyramidal symptom related adverse events were low, and similar between treatment and placebo groups. There were no notable changes in prolactin or cardiometabolic parameters.
Lumateperone is a serotonin 5HT-2A receptor antagonist, a dopamine D2 receptor presynaptic partial agonist and postsynaptic antagonist, a D1 receptor-dependent indirect modulator of glumatergic AMPA and NMDA currents, and a serotonin reuptake inhibitor. Lumateperone is currently approved by the US Food and Drug Administration to treat schizophrenia, as monotherapy for depressive episodes associated with bipolar disorder, and as adjunctive therapy with lithium or valproate.2
These study findings are consistent with previous lumateperone trials demonstrating the drug as safe and well-tolerated, indicating benefits for long-term lumateperone treatment for adults with schizophrenia.3
References
1. Durgam S, Earley WR, Kozauer SG. Lumateperone for the prevention of relapse in patients with schizophrenia: results from a double-blind, placebo-controlled, randomized withdrawal, phase 3 trial. Poster presented at: 38th European College of Neuropsychopharmacology Annual Congress; October 11-14, 2025; Amsterdam, The Netherlands. Accessed October 13, 2025.
2. Caplyta (lumateperon) label. US Food and Drug Administration. Accessed October 13, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209500s000lbl.pdf
3. Tarzian M, Ndrio M, Chique B, et al. Illuminating hope for mental health: a drug review on lumateperone. Cureus. 2023;15(9):e46143.
