SAN FRANCISCO — Treatment with lumateperone was associated with a 63% lower risk for relapse compared with placebo in patients with schizophrenia, new trial data showed.
Findings from the phase 3, double-blind, randomized trial revealed that 84% of lumateperone patients were relapse-free at 6 months, with no clinically meaningful changes in prolactin, cardiometabolic parameters, or weight.
Relapse prevention is not only important for providing stability to patients with schizophrenia but also for their overall life expectancy, principal investigator Christoph Correll, MD, highlighted. Patients with schizophrenia have a life expectancy that is 15 years shorter than the general population and research shows each relapse increases mortality risk.
Based on results from the trial, lumateperone received FDA approval in April for schizophrenia relapse prevention.
“Having a medication that can navigate that, where patients stay in treatment, where they have a relapse reduction by 63% already at 6 months and pay little of a price in terms of side effects is a very strong suit,” Correll, professor of psychiatry at the Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, told Medscape Medical News.
Findings from the trial were presented on May 19 at the American Psychiatric Association (APA) 2026 Annual Meeting.
Antipsychotic Adherence Challenges
An estimated 3 million people in the US have schizophrenia. Antipsychotics are the gold-standard treatment, although side effects and metabolic issues can make adherence difficult for some patients.
Lumateperone, a second-generation antipsychotic, was previously shown to reduce symptoms of schizophrenia with a favorable safety profile in short-term clinical trials. While the mechanism of lumateperone is unknown, current evidence suggests its effects are mediated through serotonergic and dopaminergic activity.
To measure the drug’s efficacy and safety, researchers analyzed data from 592 patients aged 18-60 years in an open label run-in period of 6 weeks. All patients had a confirmed diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score of 70-120 at screening and baseline.
Of these, 327 progressed to a 12-week open-label stabilization period, with stabilization defined as a PANSS score ≤ 60 points, a 20% or greater reduction in PANSS total score from baseline, a Clinical Global Impressions – Severity (CGI-S) score ≤ 4, and no issues with tolerability or suicidal ideation.
For the double-blind portion of the trial, 224 patients were randomly assigned in a 1:1 ratio to receive either 42 mg of lumateperone (mean age, 45 years; 73% men; 77% White individuals) or placebo (mean age, 45 years; 70% men; 84% White individuals) for 26 weeks.
The primary endpoint was relapse, defined as one or more of the following: psychiatric hospitalization or increased psychiatric care, increase on PANSS total score, aggressive behavior, an increase of 2 points or more on the CGI-S score, and suicidal or homicidal ideation.
Lower Relapse Risk
Patients who received lumateperone reported a 63% reduction in relapse risk (hazard ratio [HR], 0.37; P = .0002) and a 51% reduction in the risk for all-cause discontinuation compared with placebo (HR, 0.49; P = .0007).
At 6 months, 84% of lumateperone patients were relapse-free. Fewer relapses occurred with lumateperone compared with placebo (16.4% vs 38.6%), corresponding to a number needed to treat of 5, which is considered clinically relevant.
In total, 69% of patients who received lumateperone completed the 6-month study compared with 47% of those who received placebo. The most common reason for discontinuation was withdrawal of consent.
Treatment-emergent adverse events were mild or moderately severe and the most common among lumateperone patients was headache.
Dopamine modulators can cause motor side effects such as involuntary movements but because lumateperone has a lower postsynaptic blockade than other antipsychotics, the risk for these side effects is lower, Correll highlighted. The rates of extrapyramidal side effects were low and similar to placebo.
In addition, there were no clinically meaningful changes in prolactin or cardiometabolic parameters and weight changes were similar among both groups.
A Vehicle to Stability
Patients who have schizophrenia may have “less access to things that we take for granted in terms of having relationships, a job, and having stability is I think something that’s very important to improve outcomes,” Correll said. “Relapse prevention is one of our main vehicles to get there. There are no skills in pills but we can use this stability to then rehabilitate patients and help them fulfill their goals.”
Commenting on the findings for Medscape Medical News, Sofia Matta, MD, said the reduction in relapse risk and proportion of patients who remained relapse-free over 6 months is promising.
“At the same time, I would be cautious about viewing time to relapse as the sole or ultimate measure of success in schizophrenia treatment,” said Matta, an instructor of psychiatry at Harvard Medical School in Boston who was not part of the study.
“Relapse prevention is critically important, but it does not fully capture cognition, quality of life, interpersonal functioning, recovery, or overall well-being,” she added.
Matta also noted the encouraging safety profile as tolerability improves treatment adherence.
Correll and Matta both agree that additional research is needed. One possibility, Correll said, would be a study that pairs lumateperone with a psychosocial intervention to evaluate effects for patient functionality and quality of life. Matta said she would like to see comparative studies and longer-term real-world data, which would help clinicians assess where lumateperone fits within the treatment landscape relative to other antipsychotics.
The study was funded by Intra-Cellular Therapies, Inc., which is now part of Johnson & Johnson. Correll disclosed serving as a consultant/advisor to pharmaceutical companies. Matta had no relevant disclosures.
