For decades, dopamine antagonists have been the primary treatment for psychotic disorders like schizophrenia. While effective, these drugs can have significant side effects. First-generation drugs like haloperidol can cause extrapyramidal symptoms (EPS), while second-generation agents like risperidone are known to induce weight gain and hyperprolactinemia. These adverse effects often limit patient compliance, underscoring the need for alternative therapies. Cobenfy, a combination of xanomeline and trospium chloride, is the first non-dopamine antagonist antipsychotic approved to treat schizophrenia. Xanomeline is a muscarinic cholinergic receptor agonist that preferentially stimulates cerebral M1 and M4 receptors, which are involved in schizophrenia pathophysiology. Trospium is a peripheral-acting antimuscarinic agent included to mitigate xanomeline's cholinergic effects. Cobenfy's side effects are primarily gastrointestinal and include nausea (19%), dyspepsia (18%), constipation (17%), and vomiting (15%). It is contraindicated in patients with liver disease and conditions that may be exacerbated by trospium's anticholinergic effects (e.g., urinary retention, reduced GI motility). It comes in a capsule taken twice daily, at least one hour before or two hours after a meal, as food reduces its absorption by 90%.

Providers treating schizophrenia now have an alternative to dopamine antagonists, which have been the only option since the approval of chlorpromazine in 1954. In two studies (see links below), Cobenfy reduced the score on the Positive and Negative Syndrome Scale (range 30 - 210, with higher scores indicating worse symptoms) by 11 points more than placebo. Head-to-head studies with dopamine antagonists are needed to truly define Cobenfy's therapeutic value.

• Xanomeline-Trospium vs Placebo for Schizophrenia in Adults, Lancet (2024) [Pubmed abstract]
• Xanomeline-Trospium vs Placebo for Schizophrenia in Adults, NEJM (2021) [Pubmed abstract]
• Cobenfy review