Xanomeline-trospium (CobenfyTM) for Schizophrenia: A Review of the Literature
Colin M. Smith1, Morgan Santalucia Augustine2, Jessica Dorrough3, Steven T. Szabo4, Särä Shadaram1, Elizabeth O.G. Hoffman5, Andrew Muzyk6
1Department of Behavioral Health, Phoenix Indian Medical Center, Indian Health Service, Phoenix, AZ, USA
2Department of Pharmacy, Duke University Hospital, Durham, NC, USA
3Department of Pharmacy, UNC Health Rex Hospital, Raleigh, NC, USA
4PsychFarm, Durham, NC, USA
5Department of Psychiatry and Division of Hospital Medicine, University of Michigan, Ann Arbor, MI, USA
6Department of Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC, USA
Correspondence to: Andrew Muzyk
Department of Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences, Room 237, JP Riddle Pharmacy Center, Buies Creek, NC 27506, USA
E-mail: Andrew.Muzyk@duke.edu
ORCID: https://orcid.org/0000-0002-6904-2466
Received: October 15, 2024; Accepted: October 21, 2024; Published online: November 13, 2024.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Schizophrenia is a chronic and severe mental illness associated with substantial morbidity and mortality. Antipsychotics primarily rely on direct dopamine blockade, leading to potential life-interfering adverse events. The purpose of this review is to describe the safety and efficacy of xanomeline-trospium (CobenfyTM), a Food and Drug Administration approved treatment for schizophrenia in adults. Xanomeline has a novel mechanism of action for the treatment of schizophrenia acting as a dual muscarinic-1 and muscarinic-4 preferring receptor agonist. Two phase 3 trials with a xanomeline- trospium up to 125 mg/30 mg 2 times daily for patients with schizophrenia saw significant reductions in PANSS positive and negative subscales, PANSS Marder negative factors, and CGI-S scale scores compared to placebo. The Cohen’s d effect for the primary endpoint was around 0.60 in both trials. The medication was well-tolerated in all clinical trials with the most common adverse events being rated as mild-to-moderate. Two long-term, open-label studies with xanomeline-trospium showed that after 52 weeks of treatment more than 75% of participants achieved a > 30% improvement on PANSS total score with a mean decrease in score by 33.3 points. Other improvements were reductions in PANSS positive and negative subscales, PANSS Marder negative factor score, and CGI-S score. In both long-term studies, patients previously in the placebo groups during either phase 2 or phase 3 trials achieved a statistically significant improvement on all efficacy measures starting at week 2. These data suggest that xanomeline-trospium is an effective and well tolerated treatment for schizophrenia with a novel mechanism of action.
Keywords: Schizophrenia; Cholinergic antagonists; Acetylcholine; Antipsychotic agents; Psychotic disorders

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