Muscarinic Therapies as a Catalyst for Change: Addressing Clinical Inertia in Schizophrenia Care

Why Muscarinic Modulation Now
Schizophrenia treatment continues to advance, with muscarinic pathway modulation providing a mechanically different option from traditional dopamine D2 receptor antagonists. In most patients who are not treatment-resistant, presynaptic dopamine overproduction in specific striatal circuits causes positive symptoms. Conventional antipsychotics mainly work by blocking postsynaptic D2 receptors, which can reduce psychosis but also disinhibit presynaptic dopamine release and affect multiple brain and peripheral pathways.¹ This non-specific approach leads to motor side effects via the nigrostriatal pathway, hormonal effects through the tuberoinfundibular pathway, and metabolic issues that impact adherence and long-term recovery. Muscarinic agonism offers a distinct strategy by targeting abnormal dopamine release upstream at its presynaptic source, with circuit selectivity that appears to spare motor and endocrine functions.²

Mechanism and Comparative Efficacy
Mechanism and comparative efficacy are central to the utility of xanomeline-trospium in a clinical setting. Effect sizes for muscarinic agonist-based treatment appear comparable to those observed with established second-generation agents, such as risperidone or olanzapine.³ The added benefit of xanomeline-trospium is not necessarily greater efficacy for positive symptoms alone, but the combination of efficacy in positive symptoms and, according to preliminary data, negative and cognitive symptoms, along with a long-term tolerability profile much more favorable than dopaminergic antipsychotics.⁴

Tolerability: What to Expect and How to Manage It
The usual side effects of dopaminergic drugs (sedation, weight gain, extrapyramidal symptoms, hyperprolactinemia) are no more likely with xanomeline-trospium than with placebo. Most of the side effects of xanomeline-trospium occur during titration and are self-limited. The most common are nausea, vomiting, constipation, or diarrhea, and can be explained easily through pro- and anticholinergic mechanisms.² To address these, it is important to educate patients on the need to take the medicine with an empty stomach to absorb trospium, and in the presence of nausea to use ondasetron during the titration phase. Most importantly, patients should be educated on the high likelihood of these adverse events so that they are anticipated, but also on their generally self-limited and benign nature. However, these should be monitored carefully in vulnerable populations, including older males prone to urinary retention or patients with GI issues that make them vulnerable to gastric hypomotility or complications of constipation. The drug should be avoided in individuals with moderate or severe liver or kidney impairment, or unmanaged narrow-angle glaucoma.

Dosing and Titration Strategy
FDA labeling recommends the titration that was used in the EMERGENT trials that led to the drug approval: 2 days of 50/20 mg, 100/20 mg days 3 to 7, and then increase to 125/30mg.⁵ Some data suggest that slower titration may prolong the duration of procholinergic side effects without decreasing its incidence, but in some cases clinicians opt for a slower titration strategy over 2 weeks, adding trospium 20mg daily if necessary to mitigate nausea. It is also important to consider the anticholinergic load that the patient is exposed to from drugs other than xanomeline-trospium, either when cross-titrated or used in augmentation. For example, individuals who are using xanomeline-trospium in combination with clozapine or olanzapine may want to be particularly attentive to anticholinergic side effects like constipation or urinary retention. The titration phase may ‘make or break’ the trial, and it is important that prescribers are very attentive to side effects, address them proactively, and assure patients that the most critical goal is to ‘get them over the hump’ in the initial few weeks. To this effect, making sure that xanomeline-trospium is taken on an empty stomach and proactive use of ondasetron is recommended. It is also important to emphasize that the available data favors the use of xanomeline-trospium in monotherapy rather than in combination, so cross-titration rather than polypharmacy is advised.

Patient Selection, Who Stands to Benefit Most
Good candidates for muscarinic therapy include individuals dissatisfied with current therapy due to adverse effects such as weight gain, metabolic disturbances, extrapyramidal symptoms, tardive dyskinesia, or hyperprolactinemia. Additionally, patients with predominantly negative symptoms and/or cognitive disfunction may see added benefits.^3,6 The data on these symptom domains is in monotherapy, and that is the way we would recommend this drug is used. Importantly preclinical data suggest that its combination with anticholinergic drugs that cross the blood–brain barrier may reduce efficacy.⁷ In real-world settings, polypharmacy is common, especially when olanzapine or clozapine serves as the backbone; however, controlled data are limited, and the anticholinergic load becomes a major concern.^8,9

Monitoring During Initiation and Early Maintenance
Set expectations about transient gastrointestinal side effects and ask patients to log symptoms for the first few weeks. Provide a simple action plan covering dose timing relative to meals, when to use a pre-dose antiemetic, when to add or reduce extra trospium, and when to contact the clinic for escalation. A short-term bowel regimen may be necessary for constipation; however, ongoing diarrhea or cramping should prompt reassessment of the timing and dose. Cardiovascular parameters require attention because muscarinic agonists can affect heart rate and blood pressure. Include office or home monitoring of vitals during the first month as part of standard education.¹⁰ Since adherence to an empty stomach regimen is critical, explore morning routines, work shifts, and bedtime habits to create a dosing plan that the patient can realistically follow.

Contraindications and Special Populations
Muscarinic therapy is unsuitable for individuals with urinary retention, significant hepatic or renal impairment, gastric retention, or untreated narrow-angle glaucoma. In older adults, use slower titration and a lower maximum dose, and monitor carefully for urinary retention.^11,12 Pregnancy and pediatric use are not established, so standard risk-benefit considerations apply, and alternative strategies are often preferred. Mild hepatic or renal impairment does not require a different starting dose, but closer monitoring for procholinergic and anticholinergic effects is recommended.^11-13

Practical Pearls for Everyday Clinics
Describe the mechanism in simple terms, highlighting that the medication works upstream of the dopaminergic system, rather than blocking postsynaptic dopamine receptors. Encourage patients to consider the trade-offs, such as the endocrine and metabolic risks of traditional D2 receptor antagonists in exchange for a brief period of nausea that the team will actively manage. If a patient is concerned about gastrointestinal effects, consider providing support upfront with ondansetron or temporary trospium supplementation, then reduce these aids after the initial adjustment. When switching medications, base the plan on the patient’s previous anticholinergic burden. If the regimen included benztropine or oxybutynin, plan and supervise an early taper during muscarinic titration. If the previous antipsychotic was strongly anticholinergic, avoid stacking central anticholinergic agents and only adjust the food timing rule when the clinical situation warrants, with clear instructions and early follow-up. Be flexible with the cross-titration pace; some patients reach their target within a week, while others may take three or four weeks to achieve it. The goal is not speed but stability and confidence.

Bottom Line for Current Practice
Currently, there is only one approved muscarinic option, with other agents still in development. However, achieving optimal outcomes depends on understanding the ideal implementation of this treatment. This involves selecting the right patient, setting realistic expectations, titrating carefully, managing early cholinergic side effects, and regularly reevaluating to ensure that the expected benefits are being achieved. For many patients, especially those early in their illness or suffering from metabolic or neurologic side effects of D2 blockade, muscarinic therapy can provide comparable control of positive symptoms while maintaining motor function and hormonal balance, and potentially aiding in control of negative and cognitive symptoms. Success relies less on new algorithms and more on consistently applying fundamental principles at the point of care.

References

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