How-To Guides

Xanomeline-trospium (XT) differs from standard antipsychotics because it acts through muscarinic M1 and M4 receptors rather than primarily blocking dopamine D2 receptors. In this report, the authors explain that M4 activation is thought to reduce presynaptic dopamine release and mainly address positive symptoms, while M1 activation may help with negative symptoms and potentially cognitive impairment through effects on frontal cortical circuits. XT is also described as the first FDA-approved treatment for schizophrenia that is not classified as an antipsychotic.

In pooled post-hoc analyses of the 5-week EMERGENT-1, EMERGENT-2, and EMERGENT-3 trials, XT separated from placebo on PANSS total and PANSS positive subscale scores at the first assessment, and the difference continued to widen through study end. Improvements in negative symptoms emerged more gradually, with early numerical differences that did not reach statistical significance until week 3. CGI-S scores showed statistically significant separation by week 2 and continued to improve through completion of the studies.

In the pooled 5-week EMERGENT 1-3 safety analysis, treatment-emergent adverse events were more common with XT than placebo (67.9% vs 51.3%), but discontinuation rates were similar (27.6% vs 22.7%). The report states that these adverse events were largely gastrointestinal and generally mild or moderate. Rates of extrapyramidal symptoms, somnolence, and weight gain remained low in both groups.

In the 52-week open-label EMERGENT-4 extension study, improvements in PANSS total score with XT were evident by week 2 and were sustained through week 52. By week 52, 68.6% of participants achieved at least 30% improvement in PANSS score, and 37.1% achieved at least 50% improvement. CGI-S improvement of at least 1 point was seen in 82.9% of the overall population, and 42.9% had CGI-S scores of 3 or less, indicating mild illness severity.

In EMERGENT-4, 53% of participants experienced at least 1 treatment-emergent adverse event, most of which were mild to moderate. The most frequent anticholinergic events were dry mouth (17.8%), constipation (9.9%), and dyspepsia (8.6%), while common procholinergic events were nausea (10.5%), vomiting (6.6%), and diarrhea (5.9%). The report states that these events typically occurred within the first 2 weeks, were self-limited, and rarely led to discontinuation.

The panel recommended starting outpatient XT at 50 mg/20 mg twice daily for 1 to 2 weeks, with efficacy and tolerability assessed at the first follow-up, ideally in person. If tolerated, the dose may be increased to 100 mg/20 mg, and then to 125 mg/30 mg with ongoing clinical monitoring based on the patient's care plan. The panel noted that most patients stabilize on 100 mg/20 mg to 125 mg/30 mg twice daily, although some patients, particularly younger patients or those earlier in illness, may do well on the starting dose.

XT should be taken without food because the report states that trospium chloride is not well absorbed when taken with food, which may weaken its peripheral anticholinergic effect. The authors note that nausea and vomiting can be problematic if XT is administered after a patient has eaten. For that reason, the panel emphasized counseling patients on fasted dosing when XT is started.

Yes. The panel recommended that all patients starting XT be co-prescribed a 14-day supply of ondansetron 4 mg at initiation, with instructions to re-dose after 30 minutes if symptoms persist. This recommendation was intended to reduce early nausea and vomiting, improve adherence, and lower the risk of early discontinuation.

Before starting XT, clinicians should perform careful medication reconciliation and reduce unnecessary anticholinergic burden whenever possible. The panel specifically highlighted diphenhydramine, medications for bladder control, COPD, Alzheimer disease, and Parkinson disease as important contributors to cholinergic or anticholinergic burden. The panel also emphasized monitoring for urinary retention, dry mouth, and constipation, and noted that XT may not be appropriate for men older than 50 years with a history of benign prostatic hyperplasia that may be associated with urinary retention.

The panel recommended a structured, clinician-guided cross-titration based on the pharmacologic class of the existing antipsychotic while starting XT at 50 mg/20 mg the same evening. In their guidance, risperidone- or paliperidone-type agents can often be tapered over several days, whereas quetiapine-, olanzapine-, or clozapine-type agents usually require a slower taper over 1 to 3 weeks to avoid rebound sedation or insomnia. Partial dopamine agonists such as aripiprazole, brexpiprazole, or cariprazine may generally be stopped more quickly because of their long half-lives.

Yes, but the panel recommended a tailored approach. In patients already maintained on a long-acting injectable (LAI), the report recommends initiating XT concomitantly with the LAI and then considering LAI dose reduction once the patient is stabilized on a maintenance dose of XT and symptoms improve. The panel framed this as a way to maintain or improve efficacy while reducing cumulative dopamine receptor burden.

The report states that its recommendations are based on early clinical experience and should be interpreted with caution. The authors specifically cite the absence of randomized head-to-head comparisons with standard antipsychotics, lack of long-term safety and functional outcome data, and the possibility that practice patterns may evolve as familiarity with XT increases. They also note that the panel's recommendations reflect experience treating approximately 200 patients with XT at the time of the meeting.