Toward a Muscarinic Agent Solution for the Presynaptic Dopamine Problem in Schizophrenia

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CONFERENCE REPORTER

“It's new medicine, brand new mechanism, which is very distinct from what we have for the past 70 years,” Jonathan Meyer, MD said of new xanomeline-trospium (Cobenfy) treatment for schizophrenia during his talk at the Southern California Psychiatry Conference. Moving away from traditional dopamine blocking mechanisms, new treatments for schizophrenia pivot to target cholinergic pathways with muscarinic agents. Muscarinic agents may be a solution to the issue of excess dopamine in the presynapse, with xanomeline-trospium showing improvement of positive schizophrenia symptoms and no side effects of tardive dyskinesia like traditional prescriptions.

Gus Alva, MD, Jonathan Meyer, MD, and Chelsie Monroe, APN, presented these latest findings in schizophrenia medication in their session “Visualizing the Role of Novel Muscarinic Agents in the Management of Schizophrenia” at the 2025 Southern California Psychiatry Conference.¹

The long-held belief that positive symptoms of schizophrenia result from excess dopamine in the mesolimbic pathway has recently been questioned, with human models suggesting the issue may actually lie in presynaptic dopamine release specifically in the striatum. Clinicians have managed positive symptoms by using D2 antagonists for decades, but with new drug developments that can adjust presynaptic activity—rather than react to change postsynaptic activity—positive symptoms can be better managed.²

In this session, presenters detailed a promising alternative to D2 antagonists: targeting the muscarinic acetylcholine receptors (focused on M1 and M4) as a way to regulate dopamine release presynaptically without blocking dopamine receptors directly. This new investigational therapy combines xanomeline, a selective M1 and M4 agonist, with trospium, a peripheral anticholinergic that avoids unwanted side effects by limiting activity outside the central nervous system.

The unique action of xanomeline-trospium modulates neurotransmitter pathways upstream of dopamine, thereby avoiding the motor and endocrine side effects commonly seen with D2 antagonists. M1 receptor activation reduces dopamine indirectly through GABA and glutamate signaling, while M4 agonism acts from the lower level, modulating acetylcholine production in the ventral tegmental area. This mechanism allows for much stronger safety profiles because there is not a potential for major motor issues like tardive dyskinesia many patients can suffer from with traditional D2 antagonists.

Data showed significant reductions in Positive and Negative Syndrome Scale (PANSS) scores, with patients seeing average declines of 33.6 points by week 52. Most notably, there were no cases of tardive dyskinesia, and the most common side effects were brief and manageable cholinergic issues. Alva noted that xanomeline-trospium may be particularly beneficial for chronic schizophrenia patients who have not responded well to traditional treatments. While currently approved by the FDA as a monotherapy, discussions and research are ongoing about xanomeline-trospium’s potential use alongside other antipsychotics.

However, this new medication comes with important practical considerations for prescribers. Xanomeline-trospium must be taken 1 hour before or 2 hours after a meal, as taking it with food reduces trospium absorption by up to 90%. If a patient has issues with nausea due to being unable to take xanomeline-trospium with food, extra trospium can be added to their regimen to reduce these side effects. Starting xanomeline-trospium also involves titration to mitigate cholinergic side effects like urinary or bowel issues caused by trospium. Patients who are already on other antipsychotic medications also may need a closely watched cross titration process, as many traditional medications have anticholinergic properties that can interfere with xanomeline-trospium.

With this new muscarinic focused approach, there is less focus on reacting to downstream, postsynaptic effects of excess dopamine, and instead xanomeline-trospium alters presynaptic dopamine. The FDA approval of xanomeline-trospium introduces a new chapter in schizophrenia treatment, offering long awaited relief from motor symptoms of traditional antipsychotics and lessening positive psychotic symptoms.

References

1. Alva G, Meyer J, Monroe C. Visualizing the Role of Novel Muscarinic Agents in the Management of Schizophrenia. Conference Proceedings of the Southern California Psychiatry Conference. July 2025;11-12. Huntington Beach, CA.

2. Kaul I, Sawchak S, Claxton A. et al. Efficacy of xanomeline and trospium chloride in schizophrenia: pooled results from three 5-week, randomized, double-blind, placebo-controlled, EMERGENT trials. Schizophr. 2024;10:102.