Adjunctive pimavanserin in schizophrenia: A systematic review and meta-analysis with a focus on negative-symptom...

Negative symptoms of schizophrenia are a major determinant of functional disability and remain a persistent unmet therapeutic need. Pimavanserin (NbN: serotonin 5-HT₂A receptor inverse agonist/antagonist) has been investigated as an adjunctive treatment for negative symptoms, but clinical evidence remains inconsistent. We conducted a systematic review and meta-analysis to evaluate the efficacy, safety, and tolerability of adjunctive pimavanserin in adults with schizophrenia. PubMed, Web of Science, Cochrane CENTRAL, Scopus, Ovid, Europe PMC, ClinicalTrials.gov, and the WHO ICTRP were searched from inception through August 2025. Randomized controlled trials comparing adjunctive pimavanserin with placebo were included. Random-effects meta-analyses were performed, and treatment effects were interpreted in relation to established minimal clinically important differences (MCIDs). Risk of bias was assessed using Cochrane RoB 2, and certainty of evidence was evaluated with GRADE. Four randomized controlled trials including 1676 randomized participants were identified, encompassing heterogeneous populations (acute exacerbation, inadequate response, and predominant negative symptoms). No clinically meaningful benefit was observed on the primary negative symptom endpoint used in predominant negative symptom studies (NSA-16). Small statistically significant reductions were observed for PANSS total and PANSS negative scores, but effect sizes remained well below MCID thresholds. No significant benefits were observed for other symptom domains or global outcomes. Pimavanserin was generally well tolerated, with no increased risk of serious adverse events or treatment discontinuation versus placebo. Overall, adjunctive pimavanserin demonstrates statistically detectable but clinically modest effects that do not support routine clinical use for negative symptoms of schizophrenia.