BEYOND DOPAMINE BLOCKADE: MUSCARINIC RECEPTOR AGONISM AS A NOVEL THERAPEUTIC STRATEGY IN SCHIZOPHRENIA - A LITERATURE REVIEW OF XANOMELINE-TROSPIUM

Abstract

Background: Schizophrenia is a chronic mental illness affecting over 23 million people worldwide. Current pharmacotherapy, primarily based on dopamine D₂ receptor antagonism, is associated with significant adverse effects - including extrapyramidal symptoms, metabolic disturbances, and hyperprolactinemia - and up to 30% of patients show inadequate response. Aim: This review aims to present and synthesize the available evidence on xanomeline–trospium (Cobenfy®) - the first approved antipsychotic with a predominantly muscarinic mechanism of action - as a novel therapeutic option for schizophrenia. Methods: A narrative literature review was conducted in PubMed, Scopus, Web of Science, and Google Scholar databases up to June 2026, focusing on peer‑reviewed articles, clinical trials, and systematic reviews on xanomeline–trospium in schizophrenia. Results: Xanomeline–trospium demonstrated significant antipsychotic efficacy across the Phase 2 and Phase 3 EMERGENT trials, with moderate‑to‑large effect sizes (Cohen's d = 0.60). The safety profile is distinctly favorable: no extrapyramidal symptoms, weight gain, metabolic disturbances, or prolactin elevation were observed. Gastrointestinal adverse events (nausea, vomiting, constipation) were the most common but were generally mild, transient, and occurred early in treatment. Long‑term open‑label extension studies confirmed sustained efficacy and safety over 52 weeks, with ecological momentary assessment data indicating improvements in real‑world social functioning and positive affect. Conclusions: Xanomeline–trospium represents a promising alternative for schizophrenia treatment, particularly for patients intolerant to conventional antipsychotics or those with metabolic comorbidities. Its novel mechanism and favorable tolerability profile position it as a significant advancement in psychopharmacology. Further research is needed to clarify its role in treatment‑resistant schizophrenia and to confirm long‑term outcomes in diverse populations.