Clinical Psychopharmacology and Neuroscience Papers in Press available online.

 
Xanomeline-trospium (Cobenfy): A novel treatment for schizophrenia
Andrew Muzyk 6,*, Colin M. Smith 1, Morgan S. Augustine 2, Jessica Dorrough 3, Steven T. SSzabo 4, Särä Shadaram1, Elizabeth O.G. Hoffman5
1Department of Behavioral Health, Phoenix Indian Medical Center, Indian Health Service, Phoenix, AZ, 2Department of Pharmacy, Duke University Hospital, Durham, NC, 3Department of Pharmacy, UNC Health Rex Hospital, Raleigh, NC, 4PsychFarm, Durham, NC, 5Department of Psychiatry and Division of Hospital Medicine, University of Michigan, Ann Arbor, MI, 6Department of Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC
Abstract
Schizophrenia is a chronic and severe mental illness associated with substantial morbidity and mortality. Although antipsychotics have been used for schizophrenia for nearly three quarters of a century, they 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 (Cobenfy), 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. Trospium antagonizes peripheral muscarinic receptors but does not cross the blood-brain barrier due to being a quaternary amine. Trospium was added to xanomeline to mitigate peripheral cholinergic adverse events. Two phase 3 trials with a xanomeline-trospium up to 125mg/30mg 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 that distinguishes it from other medications used for this indication.
Accepted Manuscript [Submitted on 2024-10-15, Accepted on 2024-10-21]