Possible benefits beyond psychosis, and tips on managing side effects and reducing risks
STUDY: Rayfield A et al, Clin Psychopharmacol Neurosci 2026
STUDY TYPE: Review
FUNDING: Independent
Background
Xanomeline-trospium (Cobenfy) was approved in 2024 as the first schizophrenia drug that works without blocking dopamine. Xanomeline stimulates M1 and M4 muscarinic receptors in the brain, and trospium blocks muscarinic receptors in the body to limit side effects. This pharmacist-authored review summarizes the evidence published since approval.
The Study
- A narrative review of pooled and post hoc analyses of the three 5-week EMERGENT trials (640 patients).
- Also covers two 52-week open-label extensions, a dosing study, and indirect comparisons with other antipsychotics.
Results
In the pooled trials, the drug lowered the schizophrenia scale (PANSS) about 10 points more than placebo (Cohen’s d effect size moderate, 0.65), with separation by week 2. Number needed to treat was a respectable 5 for a 30% improvement, similar to other antipsychotics. Older patients benefited equally well.
It is not known to work in treatment resistance, and failed to augment other antipsychotics.
But does it bring benefits beyond psychotic symptoms? Maybe, this comes from analyses of subgroups, which is prone to errors and bias:
- Negative symptoms: a modest effect overall (effect size d of 0.42), but large in patients with prominent negative symptoms (d 1.18).
- Cognition: no overall effect, but improvement in the 45% who were cognitively impaired at baseline (d 0.54).
- Agitation: 46% responded versus 26% on placebo.
In the 52-week extensions, 69% of continuing patients improved by at least 30%.
Consider checking blood pressure and heart rate in the first two weeks, and screen for urinary retention, narrow-angle glaucoma, and liver disease before starting.
Side Effects
- Nausea (17% vs 3%), constipation (15% vs 5%), and vomiting (11% vs 1%), mostly fading within 2 weeks.
- Transient rises in heart rate and blood pressure in the first week.
- No weight gain, extrapyramidal symptoms, or prolactin rise. Patients lost about 2 kg over a year.
- A network meta-analysis found more all-cause discontinuation than with most antipsychotics.
Limitations
- Nearly all data are post hoc reanalyses of the same industry-funded 5-week trials.
- Long-term data are open-label with no comparison group.
- Lacking head-to-head trials with other antipsychotics and trials in first episode psychosis.
Practice Implications
- The strongest case for xanomeline-trospium is its side effect profile, particularly over the long term.
- Prepare for GI side effects. Paradoxically, they improve when taken on an empty stomach, at least 1 hour before or 2 hours after meals. After four months, they can probably take with food (according to a phase I study).
- Start 50/20 mg twice daily and titrate over the first week to 100/20 mg, then to 125/30 mg if needed. Learn more in the Carlat podcast.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
