Roluperidone
A medicine for negative symptoms, taken without an antipsychotic. The US regulator asked for another trial in 2024; it began in 2026, including in Bulgaria and Romania.
At a glance
- Type
- Medicine: serotonin 5-HT2A, sigma-2 and alpha-1A receptor blocker
- Used for
- Negative symptoms of schizophrenia, in people whose positive symptoms are stable
- Status
- In trials, in a phase 3 trial, including in Bulgaria and Romania
- Evidence
- EmergingHow evidence is rated
- Administration
- Tablets, once a day. In the trials, taken instead of an antipsychotic
- In Europe
- In a phase 3 trial in Bulgaria and Romania, as well as Serbia, Ukraine, Moldova and the United States
Clinical summaryFor health professionals
- Blocks 5-HT2A, sigma-2 and alpha-1A receptors; given as monotherapy after stopping antipsychotics (Davidson 2017).
- Phase 2b (Davidson 2017): 244 patients, 32 or 64 mg for 12 weeks; negative symptoms improved more than on placebo.
- Phase 3 (Davidson 2022): 513 patients, 12 weeks; at 64 mg the primary negative-symptom endpoint narrowly missed in the main analysis and was met in a modified one; functioning improved.
- FDA complete response letter, February 2024: asked for another positive trial, data with antipsychotics and longer exposure. Confirmatory phase 3 (C19): about 380 patients, 64 mg against placebo for 12 weeks; results expected in the second half of 2027.
What it is
Roluperidone is designed to treat negative symptoms, such as low motivation, withdrawal and blunted emotion. It blocks serotonin 5-HT2A, sigma-2 and alpha-1A receptors. In the trials, people stopped their antipsychotic and took roluperidone on its own.1
How well it works
In a phase 2b trial of 244 people over 12 weeks, negative symptoms improved more on roluperidone than on placebo.1 A phase 3 trial of 513 people narrowly missed its main goal at the higher dose, although it was met in a second analysis, and daily functioning improved.2
In February 2024, the US Food and Drug Administration declined to approve it and asked for another positive trial, data on its use with antipsychotics, and longer treatment at the higher dose.3 A confirmatory trial of about 380 people began in 2026, at about 40 sites in the United States and Europe, with results expected in the second half of 2027.4 In the European Union, it is authorised in Bulgaria and Romania.5
Side effects
In the trials, roluperidone was generally well tolerated.2
Alternatives
Pimavanserin (opens in a new tab), another 5-HT2A blocker, failed in a phase 3 trial for negative symptoms. Memantine (opens in a new tab) improved negative symptoms in small trials.
What we don’t know yet
- Whether the confirmatory trial shows a clear benefit.
- Whether it can be taken safely together with antipsychotics.
