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Schizophrenia Treatment
A New Treatment Option for People With Schizophrenia

Released: March 27, 2025

Expiration: March 26, 2026

Leslie Citrome
Leslie Citrome, MD, MPH
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Key Takeaways
  • It is possible to treat schizophrenia with medications that do not block dopamine receptors.
  • Muscarinic agonism decreases dopamine release presynaptically, obviating the need for using dopamine receptor–blocking agents to treat schizophrenia.
  • A combination of xanomeline (a muscarinic agonist) and trospium (a peripherally acting muscarinic antagonist) is now available and is indicated for the treatment of schizophrenia.
  • Expect more muscarinic agonist medications for schizophrenia to be available in the future.

For about the past 70 years, the mainstay treatment of schizophrenia has been agents that block postsynaptic dopamine D2 receptors. Until now, the core feature of all available treatments for schizophrenia has been focused on postsynaptic activity, even though the pathophysiology appears to involve presynaptic dopaminergic dysfunction—specifically increased dopamine synthesis and release.

Muscarinic Mechanism of Action in Schizophrenia
A medication that uses a different approach than postsynaptic dopamine D2 receptor blockade is now available. Approved by the US FDA in 2024, this new agent is a combination of xanomeline, a muscarinic M1 and M4 receptor agonist, and trospium, an antimuscarinic agent that does not cross the blood–brain barrier. The mechanism of action for the treatment of schizophrenia is thought to be mediated by the central action of xanomeline by selectively decreasing the release of dopamine in the part of the human striatum thought to be responsible for the production of hallucinations and delusions. By avoiding dopamine D2 receptor blockade, the “collateral damage” of drug-induced movement disorders and prolactin elevation can be circumvented because the motor striatum and the tuberoinfundibular dopamine pathways are spared. Avoidance of blockade of other monoaminergic receptors can also reduce the risk of sedation, weight gain, and metabolic abnormalities that have been nettlesome with many of the traditional antipsychotics. Of note, the prescribing information for the xanomeline/trospium combination does not contain the word “antipsychotic” and is devoid of the class-level warnings and precautions, including the boxed bolded warning regarding mortality in elderly demented patients with psychosis, found across the board for the older agents.

Therapeutic Efficacy and Adverse Events of Muscarinic Targeting
The efficacy of the xanomeline/trospium combination is as good as, or better than, currently available first-line treatments for schizophrenia. However, xanomeline has peripheral promuscarinic activity, resulting in adverse gastrointestinal effects such as nausea and vomiting. This is mitigated in large part by the addition of trospium, an agent available on its own for the treatment of overactive bladder. Although the xanomeline/trospium combination was studied vs placebo using a mandatory titration schedule where the dose was increased over the course of a week, it could be that gastrointestinal tolerability would be better if the titration occurred at a slower rate. It is also possible that the available intermediate dose strength would be sufficiently efficacious in some patients. The potential benefit of adding the xanomeline/trospium combination to an established antipsychotic regimen is unknown. In the absence of additional studies that would answer these questions, practice-based evidence will help guide the healthcare professional.

Administration of Muscarinic Agents for Schizophrenia
Because trospium is not absorbed in the presence of food, xanomeline/trospium must be administered 1 hour before or 2 hours after a meal. Current recommendations are for twice daily dosing. Cholinergic side effects generally began within 2 weeks of starting the combination and were transient and mild or moderate in intensity. Having an antiemetic agent available may be helpful for patients who are vulnerable to developing nausea and/or vomiting. Combining xanomeline/trospium with other anticholinergic agents (including some antipsychotics such as olanzapine) may be problematic because of additive peripheral anticholinergic effects (for example, decreased gastrointestinal motility), as well as unpredictable central effects.

Future Directions in Muscarinic Targeting
The challenge now is for pharmaceutical companies to develop other muscarinic agonists for the treatment of schizophrenia, perhaps with a simpler dosing regimen without any gastrointestinal side effects, and without any monitoring requirements for heart rate and liver function. A long-acting injectable formulation would also be welcome. Thus far, NBI-1117568, a muscarinic M4 agonist, has shown promising results in early study, but emraclidine, a muscarinic M4-positive allosteric modulator has failed to consistently demonstrate efficacy. Other efforts are underway to develop other muscarinic M1 and/or M4 agonists/positive allosteric modulators. Who said innovation in this space is dead?

Your Thoughts
Are you interested in exploring how muscarinic-targeting medications like xanomeline/trospium might change your approach to treating patients with schizophrenia? Have you encountered any challenges with current antipsychotics that make you eager to try this new approach, or do you have questions about integrating it into your practice?

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How confident do you feel in explaining the differences between muscarinic receptor–based treatments and traditional dopamine-blocking antipsychotics?

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