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Beyond Dopamine: Muscarinic Receptor Agonism as a New Mechanistic Frontier in Schizophrenia Care

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Released: October 21, 2026

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Muscarinic receptor agonism represents a novel approach to schizophrenia treatment that offers an alternative to traditional antipsychotic therapies. Learn more about the clinical implications of muscarinic receptor agonism, including its potential role in individualized treatment selection, emerging evidence regarding transitions from existing antipsychotics, and considerations for concomitant medication use. 

Rebecca DePalma
Rebecca DePalma, DMSc, PA-C
Muscarinic Receptor Agonism

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For decades, treatment options for schizophrenia have relied on dopamine D2 receptor blockade. Whether first- or second-generation antipsychotics, the central mechanism remained largely the same. However, in 2024, the FDA approved a new treatment option with a different mechanism of action, focused on muscarinic agonism. As more healthcare professionals integrate this new treatment approach into clinical practice, I want to address some of the most common questions in a way that's practical and grounded in what we actually know.

How does the muscarinic mechanism differ from what we've been doing?

Traditional antipsychotics work by blocking dopamine D2 receptors, particularly in the mesolimbic pathway. Muscarinic receptor agonism takes a different route entirely. In the approved treatment regimen, xanomeline/trospium, xanomeline is a dual M1/M4 muscarinic agonist, meaning it activates muscarinic receptors rather than blocking dopamine receptors directly. By doing so, it modulates cortical and striatal circuits in a way that indirectly influences dopamine pathways, without any direct D2 blockade.

M1 receptors are concentrated in the cortex and hippocampus and are associated with cognitive processes and cortical function. M1 agonism enhances cortical cholinergic signaling and is thought to improve cognition, with potential benefit for negative symptoms. M4 receptors regulate dopaminergic signaling in subcortical regions. Activating them indirectly decreases mesolimbic dopaminergic activity, which is thought to improve positive symptoms such as hallucinations and psychosis. So, in one mechanism, you have the potential to address symptom domains that have historically been difficult to treat together.

Muscarinic-based therapies may reduce the risk of dopamine-mediated adverse events (AEs) such as extrapyramidal symptoms and prolactin elevation, and may have a lower metabolic burden than many second-generation antipsychotics. However, they can introduce cholinergic side effects, particularly nausea, as well as anticholinergic AEs. Trospium, the second component of the new treatment regimen, is a peripherally acting muscarinic antagonist included specifically to reduce the peripheral cholinergic AEs that xanomeline would otherwise produce on its own.

Who are the right patients for this approach?

This is probably the question I hear most often. My thinking centers on a few distinct patient profiles:

  • Patients with inadequate response to dopamine antagonists—those who have tried multiple antipsychotics and continue to experience significant positive symptoms
  • Patients experiencing intolerable AEs with their current antipsychotic, particularly those struggling with EPS, prolactin elevation, or metabolic burden
  • Patients with prominent negative or cognitive symptoms, where dopaminergic agents have historically underperformed

Overall efficacy and tolerability profiles differ between agents and require individualized consideration. These treatment decisions are not one-size-fits-all, and the right choice depends on the specific patient in front of you.

How should we approach transitioning patients from direct dopamine antagonist to muscarinic receptor agonist?

Transitions should be gradual and individualized for each patient. The phase III, open-label EMERGENT-5 study evaluated patients with stable schizophrenia who discontinued their previous antipsychotic before initiating xanomeline/trospium without cross-titration and reported that psychiatric symptoms remained stable during the transition.

More recently, an 8-week, randomized, open-label switch study evaluated moving patients from a stable second-generation antipsychotic to xanomeline/trospium using either a 2-week or 4-week cross-titration schedule with a temporary overlap with the prior antipsychotic. Both schedules maintained clinical stability and were generally well tolerated, with no serious treatment-emergent AEs reported. Although these findings provide useful guidance, the studies did not directly compare switching with vs without cross-titration.

Close monitoring during the transition is essential. Relapse risk and patient-specific factors, including the reason for switching, should guide the pace and structure of the taper.

How should healthcare professionals counsel patients on treatment expectations to help improve adherence?

In a pooled safety analysis of the 5-week EMERGENT clinical trials, the most commonly reported AEs with xanomeline/trospium were nausea (18.5%), constipation (17.1%), dyspepsia (15.9%), and vomiting (13.5%). These AEs were generally mild to moderate in severity, and cholinergic AEs occurred most frequently during the first 2 weeks of treatment. Hypertension and tachycardia have also been reported, highlighting the importance of considering cardiovascular tolerability when selecting and monitoring treatment.

Before beginning treatment with xanomeline/trospium, it is important to discuss these AEs with patients. When discussing nausea, it is important to tell them that this is the most likely side effect they'll encounter, that it tends to be early and transient, and that there are concrete steps we can take to minimize it.

Xanomeline/trospium should be taken at least 1 hour before or 2 hours after a meal. Food substantially reduces trospium systemic exposure, which would undermine the very component designed to protect against peripheral cholinergic effects, including nausea.

Up-titration may also help. Increasing the dose from 100/20 mg to 125/30 mg increases the relative proportion of trospium to xanomeline, which may improve gastrointestinal tolerability. Dose adjustments should be individualized based on response and tolerability.

Prophylactic or symptomatic antiemetics may be considered in appropriate patients during initiation. There are no head-to-head studies comparing trospium with ondansetron for prevention of xanomeline-associated nausea, but they serve different purposes: trospium reduces peripheral muscarinic effects, whereas ondansetron is used to manage symptomatic nausea.

Can xanomeline/trospium be used concomitantly with other antipsychotics?

This is a frequent question I hear, and the answer requires some nuance. Xanomeline/trospium is FDA-approved for the treatment of schizophrenia in adults. The pivotal clinical trials evaluated xanomeline/trospium as monotherapy, and evidence regarding its long-term concomitant use with other antipsychotics remains limited. In the cross-titration study mentioned above, patients temporarily received both xanomeline/trospium and atypical antipsychotics during the taper period, but no new or unexpected safety signals were observed during the overlap period.

In addition, the phase III ARISE trial (NCT05145413) examined whether adding xanomeline/trospium to an antipsychotic (risperidone, paliperidone, aripiprazole, or their long-acting injectables; ziprasidone, lurasidone, or cariprazine) would lead to improved efficacy over the antipsychotic alone. They excluded patients receiving quetiapine, olanzapine, and clozapine because of concerns over additive anticholinergic effects. Patients with treatment-resistant schizophrenia were also excluded. The study did not meet its primary endpoint for statistical significance in reducing total Positive and Negative Syndrome Scale scores compared with the placebo group. However, the safety data remained consistent with previous standalone evaluations of xanomeline/trospium.

However, none of these findings should be extrapolated to long-term combination therapy, which requires further investigation.

Can xanomeline/trospium be used with concomitant GLP-1 receptor agonists?

There is no contraindication to concomitant use of xanomeline/trospium with GLP-1 receptor agonists. However, the prescribing information does include a warning about decreased gastrointestinal motility and the potential for GI adverse reactions. Since GLP-1 receptor agonists also slow gastric emptying and are associated with nausea, vomiting, and constipation, combining these agents may increase the risk or severity of GI effects. The decision to use these medications together should be individualized, with careful assessment of the risks and benefits and appropriate monitoring.

How do I introduce this medication to patients?

When discussing a new treatment option with patients, it is important to review efficacy and safety considerations in a clear way to meet the patient where they are in their care. I describe xanomeline/trospium as a new class of treatment that works differently from other antipsychotic therapy. You can explain that it does not block dopamine receptors but works through the brain's muscarinic system to modulate dopamine activity indirectly. Regardless, I try to frame this plainly: this is a fundamentally different approach, and that difference is the point.

It is also important to set realistic expectations upfront: symptom improvement may take time, treatment is likely long-term, and patients may experience early side effects (particularly nausea), but these are manageable and tend to improve over time. Engaging patients in understanding why this mechanism might work for them, and what to expect along the way, is one of the most important things we can do to support adherence and outcomes.

Your Thoughts

Muscarinic receptor agonism is a new therapeutic approach for patients with schizophrenia and provides a unique treatment pathway for our patients. Thoughtful patient selection, careful transition planning, and clear communication and patient education about what to expect are key to integrating this agent successfully into practice.

Have you begun incorporating xanomeline/trospium into your practice? What questions are your patients asking most, and how are you approaching the transition conversation? I'd welcome your perspective in the comments below.

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Which factor would most influence your decision to consider xanomeline/trospium for a patient with schizophrenia?

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