PREPRINT v2 — not peer-reviewed. Updated 2026-04-24. Background and Hypothesis: Xanomeline-trospium (Cobenfy), the first non-dopaminergic antipsychotic approved in over 30 years, received FDA approval for schizophrenia in September 2024. We hypothesized that its muscarinic M1/M4 agonist mechanism produces a safety profile characterized by gastrointestinal and cholinergic adverse events, with reduced metabolic and extrapyramidal burden compared with D2 antagonists. Study Design: We conducted a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) from Q4 2024 to Q4 2025. Signals were identified using a four-method battery (ROR, PRR, IC, EBGM), with consensus defined as positivity on three or more methods. Active-comparator analyses compared xanomeline-trospium against six D2 antagonists using Bonferroni-corrected ROR. Pre-registered on OSF (doi:10.17605/OSF.IO/2PWUD). Reported per READUS-PV. Study Results: Among 1,808,859 deduplicated cases, 1,423 listed xanomeline-trospium as suspect. We identified 56 consensus signals (37 pharmacological, 19 disease manifestations). Dominant signals were gastrointestinal (nausea ROR 7.5, vomiting 8.4, constipation 6.5) and muscarinic/anticholinergic (urinary retention 44.0, drooling 61.0). Weight gain (ROR vs olanzapine: 0.11) and extrapyramidal symptoms were significantly lower versus all comparators. All events were early-onset (median 0-3 days). E-values indicated 46 of 56 signals were robust to unmeasured confounding. Conclusions: The post-marketing safety profile confirms a predominantly gastrointestinal and cholinergic adverse event burden with substantially lower metabolic and extrapyramidal reporting than D2 antagonists. Drooling and urinary retention warrant targeted monitoring during treatment initiation.
Hayden Farquhar (Fri,) studied this question.