Roluperidone for Negative Symptoms of Schizophrenia: Insights from Development Experts

Roluperidone is currently in development for treatment of negative symptoms of schizophrenia, with a unique mechanism of action and symptom target area. After a previously declined new drug application (NDA) with the US Food and Drug Administration (FDA) in 2024, Minerva Neurosciences has returned with further data and plans for a phase 3 trial.¹ Roluperidone intends to treat specifically negative symptoms in schizophrenia with a lowered risk of adverse effects commonly seen in antipsychotics.²

Psychiatric Times: With its intended treatment of a particular symptom domain, how does roluperidone fulfill unmet needs in schizophrenia treatment?

Michael Davidson, MD; and Remy Luthringer, PhD: Negative symptoms of schizophrenia are a construct of several symptoms including avolition, asociality, anhedonia, alogia, and blunted affect (often called “The 5 As”).³ These are underdiagnosed and untreated. Negative symptoms are the main reasons for the poor social and vocational performance associated with schizophrenia; therefore, to improve the quality of life of individuals affected by schizophrenia it is essential to improve negative symptoms.

Current FDA-approved drugs for the treatment of schizophrenia ameliorate acute psychosis and reduce the risk of psychosis reemergence, but do not improve primary negative symptoms and occasionally produce secondary negative symptoms. Several hundreds of trials with multiple different drug classes attempting to show a therapeutic benefit on primary negative symptoms have failed; there are no FDA-approved drugs with an indication specific for the negative symptoms of schizophrenia.

Two randomized controlled trials conducted by Minerva have demonstrated that roluperidone showed improvement compared with placebo in improving negative symptoms and personal social performance and was very well tolerated. Furthermore, one of these trials in which cognitive performance was assessed, indicated that aspects of cognitive performance can also be improved by the drug. Roluperidone has been shown to improve negative symptoms, (and potentially cognitive performance) thereby significantly reducing the social and vocational impairment associated with schizophrenia. Minerva is about to start another confirmatory phase 3 trial to further evaluate these benefits. There are currently no drugs approved in the US for the treatment of negative symptoms in schizophrenia and, to the best of our knowledge, no experimental treatments in late-stage clinical trials for this indication and therefore we believe roluperidone, if approved, will fulfil a significant unmet need.

PT: What is unique about roluperidone’s mechanism of action?

Davidson and Luthringer: Most available antipsychotic drugs work via blockade of dopamine receptors but also block 5-HT2a receptors. Roluperidone is a sigma2, 5-HT2a, and Alpha1a receptor blocking drug with no direct effect on dopamine, histamine or other receptors. Furthermore, roluperidone increases the secretion of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor, which are proteins promoting neuronal growth, survival, and plasticity—we believe this may also contribute to the therapeutic effect of the drug. Since the pathophysiology of primary negative symptoms is still unknown, the precise interaction between roluperidone and negative symptoms is still being investigated. However, because roluperidone does not block dopamine receptors, it should not induce secondary negative symptoms, which are well known side effects related to many currently available antipsychotic treatments. In addition, based on Minerva’s previous monotherapy trials where patients are symptomatically stable on positive symptoms (psychosis, hallucinations, agitation) switching to roluperidone does not lead to reemergence of elevated positive symptoms. In addition, the level of relapses of psychosis over 1 year treatment duration remained low.

PT: Why is it important to evaluate negative schizophrenia symptoms in clinical trials with these patients who are relatively stable?

Davidson and Luthringer: The presence of negative symptoms are a major impediment to engaging in social and vocational activities and a contributor to poor quality of life. Without treatment, as patients age and schizophrenia symptoms worsen, they will suffer increasing levels of disability caused by negative symptoms and require more care. Conversely, positive symptoms often become apparent in patients as young adults (commonly in their 20s) which is typically the age when they are diagnosed with schizophrenia. At this stage of the disease, psychosis is usually intermittent and ameliorates over time, with or without use of antipsychotics. Even when positive symptoms have returned to normal levels, patients will still have underlying negative symptoms, and we believe that this is the optimal time to introduce roluperidone (ie, when the positive symptoms are not fluctuating erratically).

PT: Network analysis in a roluperidone trial revealed a potential connection between avolition and roluperidone’s effect; what does this mean for psychiatric treatments?

Davidson and Luthringer: Network analysis is a mathematical model in which the specific relationship between the scales’ individual component items is analyzed and given individual weight towards their contribution to the total score on the respective scale. In our case, the results indicate that among the items which make up the Positive and Negative Syndrome Scale (PANSS) negative symptoms subscale, avolition is the largest contributor to improvement in negative symptoms. It also appears that improvement in avolition is at the root of roluperidone-induced improvement in the total PANSS negative symptoms subscale score. Because avolition manifests across most of the psychiatric disorders listed in the Diagnostic and Statistical Manual, it is reasonable to hypothesize that roluperidone may benefit other mental disorders beyond negative symptoms in schizophrenia.

PT: What do the next steps look like for roluperidone’s development?

Davidson and Luthringer: Minerva will initiate a confirmatory phase 3 study in Q2 of 2026 which will evaluate treatment compared to placebo at 12 weeks as measured by Marder Negative Symptom Factor Score as the primary endpoint. The trial will also measure patient daily functioning as measured by the Personal and Social Performance Scale as a key secondary endpoint. We anticipate announcing top line results in H2 2027. As part of this trial, we will also evaluate positive symptom relapse rates in patients treated with roluperidone compared with patients treated with widely-prescribed antipsychotics as part of the longer-term safety analysis between weeks 12 and 52. If successful, this study will be part of the resubmission of an NDA to the FDA seeking approval for what would be the first FDA-approved therapy specifically indicated for the treatment of negative symptoms of schizophrenia.

Dr Davidson is chief medical officer at Minerva Neurosciences.

Dr Luthringer is chief executive officer at Minerva Neurosciences.

References

1. Rodriguez L. FDA verdict on roluperidone, the role of psychopharmacology in autism spectrum disorder, and management of behavioral emergencies. April 1, 2024. Accessed April 1, 2026. https://psychopharmacologyinstitute.com/publication/fda-verdict-on-roluperidone-the-role-of-psychopharmacology-in-autism-spectrum-disorder-and-management-of-behavioral-emergencies-2859/

2. Minerva Neurosciences announces first patient screened in global phase 3 confirmatory trial of roluperidone for the treatment of negative symptoms of schizophrenia. Press release. April 1, 2026. Accessed April 1, 2026. https://www.biospace.com/press-releases/minerva-neurosciences-announces-first-patient-screened-in-global-phase-3-confirmatory-trial-of-roluperidone-for-the-treatment-of-negative-symptoms-of-schizophrenia

3.Correll CU, Schooler NR. Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr Dis Treat. 2020;16:519-534.