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Schizophrenia Care Is Evolving: An Expert-Led FAQ About Muscarinic Therapy

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Released: August 18, 2026

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The landscape of schizophrenia care is changing. Antipsychotic use carries with it the risk of adverse effects, including the development of drug-induced movement disorders as a result of the dopamine blockade they create. This expert-led FAQ highlights developments in muscarinic agonist pathways that circumvent this dopamine blockade and offer a promising safety profile. Learners will gain clarity on safety and efficacy, patient selection, FDA-supported recommendations on usage, and insights into supporting clinical trials. This activity empowers healthcare professionals with the knowledge needed to expand their current practice with improving patient outcomes at the forefront.

Leslie Citrome
Leslie Citrome, MD, MPH
Schizophrenia Care FAQ

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Key Takeaways
  • Xanomeline/trospium has a favorable adverse effect profile not associated with weight gain, drug-induced movement disorders, or prolongation of the ECG QT interval but can have potential gastrointestinal effects. Therefore, proper patient counseling on the dosing instructions is recommended to mitigate these effects.
  • Xanomeline/trospium is not approved as an adjunctive therapy, but patients switching from a different antipsychotic maintained symptom control and report no new safety signals, making it a promising option for patients who may need to switch medications to mitigate adverse events.
  • Clozapine remains the mainstay of therapy for treatment-resistant schizophrenia and is the only approved agent for this indication and for suicidality associated with schizophrenia and schizoaffective disorder.

Which patients do you think would benefit most from xanomeline/trospium monotherapy?
Xanomeline/trospium combination is not associated with weight gain/metabolic adverse effects, drug-induced movement disorders, hyperprolactinemia, or prolongation of the ECG QT interval. Patients who cannot tolerate antipsychotics because of these issues may benefit from monotherapy with xanomeline/trospium combination. Perhaps the population most likely to benefit would be first-episode or antipsychotic-naive patients, provided access to this agent is possible, as the risk for tardive dyskinesia can be avoided. However, patients will have to be able to adhere to xanomeline/trospium’s dosing instructions (twice daily without food) otherwise, trospium is not adequately absorbed and potential gastrointestinal adverse effects worsen.

Should xanomeline/trospium be initiated as monotherapy or added to an existing antipsychotic?
Xanomeline/trospium is approved as a monotherapy for the treatment of schizophrenia and not as an adjunctive therapy. The phase III ARISE trial (NCT05145413) examined if 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 (TRS) 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.

How would you decide between escalation to clozapine vs xanomeline/trospium for TRS?
Clozapine is the only FDA-approved agent for TRS as well as suicidality associated with schizophrenia or schizoaffective disorder. Clozapine also has robust antihostility and antiaggressive effects as established in double-blind randomized clinical trials, including in one trial where patients were selected on the basis of physical aggression. Clozapine’s mechanism of action is multifold, including likely muscarinic agonism, as well as glycine transport inhibition at the NMDA receptor, with limited activity at postsynaptic dopamine receptors.

Xanomeline/trospium combination has not been assessed in TRS, and functionally, the main effect of muscarinic agonism at M1 and M4 receptors is decreasing dopamine neurotransmission selectively in the part of the striatum that is thought to be responsible for the production of positive symptoms. This is similar to the end result of postsynaptic dopamine receptor blockade observed with first-generation and second-generation antipsychotics but without off-target blockade of dopamine receptors in the motor striatum. This is a large advantage but does not necessarily address TRS. At this time, clozapine is the evidence-based choice for TRS.

How should healthcare professionals switch or cross-taper a patient from an existing antipsychotic, such as olanzapine or high-dose quetiapine, to xanomeline/trospium?
Antipsychotics with significant anticholinergic activity, such as olanzapine and clozapine, can add to the effects of trospium contained in xanomeline/trospium. The prescribing information indicates that concomitant use of xanomeline/trospium with other antimuscarinic drugs that produce anticholinergic adverse reactions (eg, dry mouth, constipation) may increase the frequency and/or severity of such effects. Patients need to be monitored for increased anticholinergic adverse reactions when xanomeline/trospium is used concomitantly with other antimuscarinic drugs.

That said, an open-label phase IV clinical trial (NCT06924255) demonstrated that switching adult outpatients with schizophrenia from standard oral atypical antipsychotics to xanomeline/trospium resulted in maintained symptom stability with no new safety signals. Both faster (2-week) and slower (4-week) cross-titration strategies showed high treatment completion rates and no discontinuations because of a lack of efficacy. Participants were required to have been treated with an atypical oral antipsychotic at the same dosing regimen that was within the prescribing information specified dose range for schizophrenia for ≥6 weeks (medications included risperidone, paliperidone, aripiprazole, ziprasidone, quetiapine, lurasidone, lumateperone, brexpiprazole, olanzapine). Participants receiving first-generation (typical) antipsychotics or those being treated with clozapine were excluded from the study.

What are the most effective strategies for preventing and managing nausea and vomiting associated with xanomeline/trospium?
Ondansetron was the most commonly used antiemetic in the acute 5-week clinical trials, with approximately 4% of patients who were prescribed it as needed. Anecdotally, some patients may benefit from additional generic trospium given alongside xanomeline/trospium capsules. Others have found that skipping the middle dose (100 mg/20 mg) and going directly from 50 mg/20 mg to 125 mg/30 mg leads to better gastrointestinal tolerability. Adding trospium or skipping the middle dose has not been assessed in randomized clinical trials.

How does xanomeline/trospium compare with second-generation antipsychotics?
In indirect comparisons based on published data from trials of available antipsychotics approved for schizophrenia, xanomeline/trospium exhibited comparable or more robust number needed to treat estimates vs placebo and was the least likely agent to be associated with weight gain or somnolence/sedation.

Can xanomeline/trospium be used in schizoaffective disorder or other psychotic disorders, even though it is currently approved only for schizophrenia?
Given xanomeline’s mechanism of action of M1 and M4 muscarinic agonism leading to decreased dopaminergic activity in the part of the human striatum responsible for the production of psychotic symptoms (associative striatum), it would be expected that xanomeline would reduce psychotic symptoms in other disorders where there is excess dopaminergic activity in the associative striatum. Thus, one can anticipate xanomeline to work transdiagnostically for psychotic symptoms.

What is known about the safety and potential role of xanomeline/trospium in older adults, particularly those with dementia or Parkinson disease psychosis?
Controlled clinical studies of xanomeline/trospium did not include patients older than 65 years of age to determine whether they respond differently from younger adult patients. Prescribing information recommends that for older adults (aged 65 years or older), the maximum dose is 100 mg/20 mg twice daily because of heightened risks of urinary retention. Because of the absence of motor adverse effects, xanomeline/trospium may be particularly helpful in Parkinson disease psychosis, but this remains to be proven in randomized controlled trials. To date, no trials of xanomeline/trospium for behavioral and psychological symptoms of dementia have been completed, but multiple trials are underway to investigate this medication for psychosis and agitation in Alzheimer’s disease.

Your Thoughts
Have you used xanomeline/trospium in your practice? If so, what has been your strategy to mitigate any adverse effects? If not, what population of your patients do you believe could benefit from the inclusion of xanomeline/trospium in their treatment plan? Are there any unanswered questions you still have about xanomeline/trospium that you would like included in our next FAQ?

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What is the greatest barrier to using xanomeline/trospium in your practice?

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