Gerald Maguire, MD: The Future of Acetylcholine and Muscarinic Receptors

Emerging therapies, such as xanomeline trospium chloride capsules (Cobenfy), offer a promising shift in schizophrenia treatment by improving positive, negative, and cognitive symptoms while minimizing adverse events.

At the Southern California Psychiatry Conference on September 13, 2024, Gerald A. Maguire, MD, director of residency training in Psychiatry at College Medical Center in Long Branch, California, and chief medical officer at AdhereTech, presented the session, “Rethinking Systems in Schizophrenia: Acetylcholine and Muscarinic Receptors.”

The presentation took place a couple of weeks before the US Food and Drug Administration (FDA) approved xanomeline trospium chloride capsules, formerly KarXT, for schizophrenia.

HCPLive spoke to Maguire about the role of acetylcholine and muscarinic receptors. Historically, schizophrenia medications targeted dopamine receptors, but lately, research has been showing the combination of xanomeline, an M1 and M4 agonist, and trospium, a peripheral antagonist improves symptoms of schizophrenia.

“We've had some inkling that dopamine and acetylcholine play a balance in schizophrenia,” Maguire said.

The interplay between dopamine and acetylcholine has been observed for years, back when investigators studied pathways leading to Parkinson’s. It also has been known for a while antipsychotic medications lead to too much dopamine blockage.

“There's also been this understanding that too much blockade of acetylcholine, too much of the muscarinic blockade, can lead to what looks like psychosis,” he said. “We've all remembered the concern about anticholinergic crisis, where one could be dry as a bone and hot as a hair and mad as a hatter, blind is a bat, et cetera. So that's been in our minds.”

It was later discovered xanomeline could improve symptoms of schizophrenia, but it led to many adverse events such as gastrointestinal issues

“So, the idea of adding a trospium, a peripheral anti-muscarinic compound, was a novel idea to add to the xanomeline such that you may be able to maintain that effect in the brain and develop more of a tolerable delivery throughout the body,” Maguire said.

The addition of trospium allows individuals to achieve the same benefit as a muscarinic agonism but without the peripheral anticholinergic or anti-muscarinic events.

“We may treat schizophrenia now not by just blocking dopamine two receptors, but in another way that actually addresses the real underlying pathophysiology, which is the presynaptic dopamine activity and decreasing that presynaptic dopamine activity as explained through agonism of the m1 and the m4 receptors,” he said.