Reviewing Roluperidone as Treatment for Negative Symptoms in Schizophrenia

Minerva Neurosciences shared an updated review of roluperidone, an investigational therapy for negative symptoms of schizophrenia, which has been shown to improve primary negative symptoms in clinically stable patients who have a low relapse risk.¹ The presentation and discussion rested on clinical trial results, the phenotype of the target population, and relapse data for patients meeting the studies’ entry criteria, as presented by Remy Luthringer, PhD; Gregory Strauss, PhD; Brian Kirkpatrick, MD; and Christoph Correll, MD.

Looking at the molecule itself, roluperidone lacks direct dopamine blockade; its activity was attributed to 5-HT2A antagonism, sigma-2 receptor activity, and alpha-1 adrenergic activity, according to Luthringer. Completed studies tested 12 weeks of roluperidone monotherapy in stable patients. The 64 mg dose separated from placebo on the Marder negative symptom factor score (NSFS) in the phase 2b MIN-101C03 study.² Separation was less pronounced in the phase 3 MIN-101C07 study, which Correll characterized as near positive.³ Functioning, measured by the Personal and Social Performance (PSP) scale, improved versus placebo in both studies, according to Kirkpatrick.

With scoring, identical negative symptom scores can have different causes, according to Strauss. Primary negative symptoms were described as persistent and linked to disrupted corticostriatal circuitry, independent of depression, anxiety, positive symptoms, or antipsychotic effects. Secondary negative symptoms fluctuated with those factors. Treatments aimed at secondary sources often reduced negative symptoms in patients with secondary phenotypes but not primary ones. “If you have a patient who’s depressed, treat the depression. If their negative symptoms are driven by anxiety, give them an anxiolytic,” Strauss said.

Using an algorithm that weighted the likelihood that negative symptoms were primary by their persistence over time, the primary score was lower with roluperidone than with placebo (P = 0.03), while the secondary score did not differ (P = 0.61). Strauss argued that earlier trials reporting negative symptom benefit likely reflected improvement in secondary sources. Network analyses of MIN-101C03 showed that motivation improved first, followed by the other negative symptom domains. In MIN-101C07, treatment had a direct effect on the emotional withdrawal item, followed by improvement in the other domains. Role and social functioning improved in both studies.

Patients meeting the entry criteria—high negative and low positive symptoms—had a low relapse risk independent of treatment, according to Kirkpatrick. In the Clinical Antipsychotic Trials of Intervention Effectiveness study, which included almost 1500 patients from 47 US sites, about 68% to 69% of patients meeting the criteria remained relapse free vs 58% to 59% of those who did not, a significant difference. In a meta-analysis of about 9000 patients from drug discontinuation trials, relapse was lower in both roluperidone studies and in criteria-meeting patients receiving antipsychotics than in placebo-treated patients, although Kirkpatrick noted that not all P values were significant. Across 5 trials from 2 repositories, higher positive symptom scores increased relapse risk in a stepwise fashion, whereas higher negative symptom scores decreased it; an Italian cohort of 24 clinics showed the same pattern over 4 years. Kirkpatrick concluded that “there’s a consistently lower relapse risk in this population across decades, across national borders, across different studies, across various definitions of relapse, including hospitalization.” Antipsychotics did not often improve primary negative symptoms and could worsen secondary negative symptoms, he added.

Luthringer presented additional analyses of the 64 mg dose. In a responder analysis defined by at least 20% NSFS improvement, about 38% of patients receiving roluperidone responded vs about 22% receiving placebo. Responder analyses anchored to a 1-point improvement on the Clinical Global Impression–Severity scale and to a 10-point or greater improvement on PSP also favored roluperidone. Numbers needed to treat were 7, 8, and 9, which Luthringer said was in the range of antipsychotics and antidepressants. A global statistical test combining NSFS and PSP was highly significant in each study and when the studies were pooled.

In answering audience questions, Kirkpatrick and Correll anticipated that some patients could start roluperidone as monotherapy while others would continue antipsychotics, with possible slow tapering. Correll suggested that patients who are nonadherent, patients off antipsychotics with residual negative symptoms, and patients with a first episode could be early candidates. Clinicians routinely assessed positive and negative symptoms, but the finer points of negative symptom assessment were less well taught, Kirkpatrick highlighted.

References

1. Luthringer R, Strauss G, Kirkpatrick B, et al.Roluperidone for negative
symptoms of schizophrenia. Minerva Neurosciences. November 12, 2026.

2. Davidson M, Saoud J, Staner C, et al. Efficacy and safety of MIN-101: a 12-week randomized, double-blind, placebo-controlled trial of a new drug in development for the treatment of negative symptoms in schizophrenia. Am J Psychiatry. 2017;174(12):1195-1202.

3. Davidson M, Saoud J, Staner C, et al. Efficacy and safety of roluperidone for the treatment of negative symptoms of schizophrenia. Schizophr Bull. 2022;48(3):609-619.