Mechanism of Action of Xanomeline and Trospium Chloride Capsules in Schizophrenia

In this segment of our HCPLive Special Report on the recent approval of xanomeline and tropism chloride capsules (Cobenfy) for schizophrenia, panelists discussed the drug’s unique mechanism, marking a significant departure from traditional antipsychotic treatments that focus on dopamine antagonism.

Formerly referred to as KarXT, xanomeline and tropism chloride capsules were approved by the US Food and Drug Administration (FDA) to treat schizophrenia on September 26, 2024. This medication offers a novel way to manage schizophrenia by modulating acetylcholine pathways, which indirectly affect dopamine release. Xanomeline, a muscarinic receptor agonist, specifically targets the M1 and M4 receptors in the brain, whereas trospium remains in the periphery to mitigate adverse events. Experts highlighted the importance of this alternative pathway in reducing common adverse events associated with dopamine receptor blockers, including weight gain, metabolic disturbances, and drug-induced movement disorders.

“I don't think we have to totally give up dopamine here. We're not asking clinicians to give up dopamine,” said Andrew J. Cutler, MD, who has researched dopamine theory of schizophrenia. “Acetylcholine, I like to say, dances with dopamine. So, if you lower acetylcholine, you're going to lower dopamine, and one way to do that is through these acetylcholine receptors the audience may know we have muscarinic and nicotinic, and these muscarinic receptors end up toning down the dopamine release. It’s very exciting because we maybe can get away from some of the collateral damage of… blocking these postsynaptic d2, receptors.”

Series Segments:

• Introductions
• Mechanism of Action of Xanomeline and Trospium Chloride Capsules
• Applying EMERGENT Trial Results to Real-World Clinical Practice for Schizophrenia
• Balancing the Benefits and Risks of Xanomeline and Trospium Chloride Capsules
• Unmet Needs, Future Research in Schizophrenia and Muscarinic Agonists

Subject Matter Experts

• Sam Clark, MD, PhD, (Moderator) is a former practicing psychiatrist and is the founder and chief executive officer of Terran Biosciences.
• Andrew Cutler, MD, is a clinical associate professor in the Department of Psychiatry and Behavioral Sciences at SUNY Upstate Medical University and the chief medical officer of the Neuroscience Education Institute.
• Rishi Kakar, MD, is a psychiatrist based out of southern Florida as well as the medical director and chief scientific officer of Segal Trials. Kakar served as the principal investigator on the pivotal EMERGENT trials.

Relevant disclosures for Cutler include Karuna, Bristol Myers Squibb, and others. Relevant disclosures for Kakar include Karuna, Bristol Myers Squibb, and others. Relevant disclosures for Clark include Terran Biosciences.