Considerations for Clinicians When Prescribing Muscarinic Modulators in Schizophrenia, with Chelsie Monroe

As Rishi Kakar, MD, lead investigator of the phase 3 EMERGENT trials, said during our latest Special Report, the US Food and Drug Administration (FDA) approval of xanomeline trospium chloride capsules (Cobenfy) is just the beginning of this “third wave” in this new paradigm of treating schizophrenia.

The FDA may have already approved xanomeline trospium chloride capsules but the research on muscarinic modulars for schizophrenia treatment is far from over.

Monroe presented on muscarinic modulators at the 2024 Southern California Psychiatry Conference on September 13, 2024, in Huntington Beach, California. In an interview with HCPLive following the meeting, Chelsie Monroe, a psychiatric nurse practitioner and founder of Balanced Mental Wellness, talked about the current modulators in development, including positive allosteric modulators and a M4 agonist.

Cobenfy is a combination of xanomeline (M1/M4 agonists) and trospium (peripheral antagonist). Although trospium counteracts the cholinergic adverse events, some patients may experience symptoms that fall into this category, such as nausea.

“There are some other agents being developed looking at m4 specifically,” Monroe told HCPLive. “Can we not necessarily target just m1 and just have m4 [targeted]? What would happen there? We're hoping to see some phase 3 trials results here soon to show us if that does make an effective difference.”

Monroe also talked about muscarinic modulators in terms of their advantage over traditional antipsychotics, how they address the unmet needs in schizophrenia management, and what clinicians should consider when incorporating muscarinic modulators into treatment plans.

Since Cobenfy contains an anticholinergic agent, Monroe said clinicians should be cautious when prescribing other anticholinergics on top of this medication. Many patients on schizophrenia are prescribed anticholinergic medication to prevent or manage other diseases. Patients should also take Cobenfy on an empty stomach due to the potential cholinergic adverse events.

“The metabolism of trospium actually drastically reduces if you add it with food,” Monroe said.

Monroe believes the arrival of muscarinic modulators represent a huge shift in the treatment landscape for schizophrenia since there has been no new classes of medications for this condition in 70 years.

For decades, psychiatrists have been prescribing antipsychotics that work off d2 receptors and are a solution for the post synaptic dopaminergic pathways. However, schizophrenia is a pre-synaptic dopamine issue.

“This is the first realm of agents that actually works on a different mechanism of action than typical d2 receptor blockade in all of our first- and second-generation antipsychotics, so it's really exciting,” Monroe said.

Monroe’s disclosures include Alkermes, Inc, Neurocrine Biosciences, Teva Pharmaceuticals, Asome Therapeutics, and ABBVIE Inc.

References

1. ^{Clark, S and Cutler, A. Unmet Needs, Future Research in Schizophrenia and Muscarinic Agonists. HCPLive. October 8, 2024. https://www.hcplive.com/view/unmet-needs-future-research-in-schizophrenia-and-muscarinic-agonists. Accessed October 9, 2024.}
2. ^{Derman, C. FDA Approves Xanomeline and Trospium Chloride (Cobenfy) for Schizophrenia. HCPLive. September 26, 2024. https://www.hcplive.com/view/fda-approves-xanomeline-and-trospium-chloride-cobenfy-for-schizophrenia. Accessed October 9, 2024.}
3. ^{Monroe, C. Emerging Muscarinic Therapies for Schizophrenia. Southern California Psychiatry Conference on September 13, 2024, in Huntington Beach, California.}