Muscarinic Treatment for Schizophrenia: A Presynaptic Answer to a Presynaptic Problem

CONFERENCE REPORTER

For more than 7 decades, antipsychotic treatment has relied on one mechanism: nonselective blockade of postsynaptic dopamine receptors. A new class of medications now targets the presynaptic dopamine excess thought to drive psychosis. Christoph U. Correll, MD, shared his insights on this new class of medications at the 2026 Jersey City Psychiatry Conference.

Correll described the first treatment in this class. The US Food and Drug Administration (FDA) approved xanomeline-trospium (Cobenfy) for adults with schizophrenia in September 2024. It was the first antipsychotic approved in decades that does not act directly on dopamine receptors.¹ Xanomeline is a muscarinic M1/M4 receptor agonist. It is paired with trospium, a peripherally restricted muscarinic antagonist that limits side effects outside the brain.

Rethinking the Cholinergic System

Correll said the field has long assumed psychosis is a dopamine problem alone and has given "short shrift" to the cholinergic system. He described that system as an orchestrator that balances the brain's brake, GABA, and its gas pedal, glutamate, both of which feed into dopamine.

Because the new approach does not act on postsynaptic dopamine receptors at all, Correll noted that patients avoid the adverse effects associated with dopamine blockade.

Regional Selectivity

Correll explained that muscarinic stimulation works differently in different brain regions. In the frontal lobe, it increases glutamate and dopamine activity. Further downstream, in the associative striatum where psychosis is thought to originate, it lowers dopamine at the presynaptic level.

"Basically, we now have for a presynaptic problem, a presynaptic answer, and for a regionally selective problem, we have a regionally selective answer," said Correll.

In the phase 3 EMERGENT-2 trial, xanomeline-trospium significantly reduced Positive and Negative Syndrome Scale (PANSS) total scores compared with placebo at week 5. The most common adverse effects were cholinergic, including nausea, dyspepsia, constipation, and vomiting.²

Dr Correll is professor at the Institute of Behavioral Science, Feinstein Institutes for Medical Research; medical director of the Recognition and Prevention Program in the Department of Psychiatry at Zucker Hillside Hospital; and professor of Psychiatry and Molecular Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.

References

1. FDA approves drug with new mechanism of action for treatment of schizophrenia. News release. September 26, 2024. Accessed October 7, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia

2. Kaul I, Sawchak S, Correll CU, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024;403(10422):160-170.