Xanomeline/trospium chloride (Cobenfy): A novel drug for schizophrenia

Abstract Schizophrenia is a disorder with disruptions in thought processes, emotional responsiveness, and perceptions. Thirty percent of schizophrenia patients are resistant to therapy. Many of the available drugs are not effective against negative symptoms and come with serious adverse reactions such as metabolic syndrome, extra pyramidal side effects, and proarrhythmogenic effects. Xanomeline is a dual M1/M4 muscarinic receptor agonist with no dopamine receptor blocking activity. Xanomeline combined with the peripheral muscarinic receptor antagonist trospium chloride minimizes peripheral muscarinic adverse effects. Studies related to xanomeline/trospium chloride were searched thoroughly in PubMed and Scopus site. This review summarizes the mechanism of action, preclinical and clinical findings, and reported adverse effects of Xanomeline–Trospium chloride in the treatment of schizophrenia. Phase 1 study supported the same by showing reduction of adverse events by 46% in the xanomeline/trospium group when compared to xanomeline alone. Phase 2 evaluation of xanomeline/trospium (50/20–125/30 mg BID) in schizophrenia showed good tolerability across all doses with minimal adverse effects. All the doses were tolerated with minimal side effects. Phase 3 trial met the primary and most of the secondary endpoints. The xanomeline/trospium combination was approved by the Food and Drug Administration in September 2024. Studies with larger sample size on long-term adverse effects of xanomeline and trospium are ongoing. This new approach toward schizophrenia could possibly pave the path to many other novel drugs in future.