Xanomeline/Trospium and suicide-related events in schizophrenia: an early pharmacovigilance analysis

Suicide remains a leading cause of mortality in schizophrenia, with clozapine being the only antipsychotic demonstrated to reduce suicide risk (1). Clozapine has a broad multi-receptor pharmacologic profile, including partial agonism at M1 and M4 muscarinic receptors; however, whether this mechanism contributes to its anti-suicidal effects remains unclear. Xanomeline/Trospium (X/T), a non-selective muscarinic receptor agonist with preferential M1/M4 activity, was approved by the FDA in September 2024 as the first antipsychotic with a novel mechanism of action in decades (2,3). Given this shared muscarinic activity, we conducted an early pharmacovigilance analysis examining suicide-related adverse event reports for X/T.

Suicide-related adverse event reports were identified using standardized MedDRA-coded terms for suicide attempts and completed suicides reported to the FDA Adverse Event Reporting System (FAERS) (4), during the first year following market introduction of X/T and comparator second-generation antipsychotics (SGAs). MedDRA terms indicative of depressive or affective disorders, such as mania, were excluded, as suicidality in such cases may reflect underlying psychiatric comorbidity rather than medication-related effects. The proportion of suicide-related adverse events relative to total adverse event reports was calculated for each medication during its first post-marketing year. Group differences were evaluated using chi-squared testing. Reporting odds ratios (RORs) were calculated to quantify disproportionality signals relative to all other drugs in FAERS, both during the first year after approval and cumulatively through January 2026. Consistent with standard pharmacovigilance methodology, a safety signal was defined as a lower bound of the 95% confidence interval exceeding 1.

Since marketing, 1,590 adverse event reports have been submitted for X/T, including 1,344 during the first post-marketing year. Within this period, suicide-related reports consisted of five completed suicides (0.4%) and one suicide attempt (0.06%). The X/T-treated population appeared younger than most comparator SGA cohorts, an important consideration given the elevated baseline suicide risk among younger individuals with schizophrenia. Despite this demographic profile, no disproportionality signal emerged for completed suicide relative to all other medications in FAERS (ROR 1.4, 95% CI 0.6-3.1; p=0.40). Among comparator SGAs, several agents demonstrated higher proportions of completed suicide reports and significant disproportionality signals. Olanzapine, Quetiapine, and Ziprasidone exhibited completed suicide proportions of 3.5%, 8.1%, and 5.5%, respectively, with elevated first-year RORs. In contrast, Aripiprazole showed no increased suicide reporting signal. For clozapine, 800 completed suicides (0.6%) and 627 suicide attempts (0.5%) were identified among 136,355 adverse event reports overall. Notably, no completed suicides were reported during clozapine’s first post-marketing year, although 11 suicide attempts (1.2%) were documented.

In this first real-world safety evaluation, X/T was not associated with a post-marketing signal for attempted or completed suicide within the first year and demonstrated relatively lower reporting rates of suicide events than SGAs. These findings reflect reporting patterns, not absolute risk; they are hypothesis-generating and warrant further investigation of potential muscarinic mechanisms, which may avoid neuroleptic dysphoria and akathisia, in relation to suicide risk (5).

References

1. Correll CU, Solmi F, Croatto G, Schneider LK, Rohani-Monfared M, Fairley L, Smith N, Bitter I, Gorwood P, Taipale H, Kirson NY, Gallego JA, De Hert M. Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors. World Psychiatry. 2022;21(2):248-271.
2. American Psychiatric Association. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. 3rd ed. Arlington, VA: American Psychiatric Publishing; 2020.
3. Meyer JM, et al. From theory to therapy: unlocking the potential of muscarinic receptor activation in schizophrenia with the dual M1/M4 muscarinic receptor agonist xanomeline and trospium chloride and insights from clinical trials. Int J Neuropsychopharmacol. 2025;28(4):pyaf015.
4. U.S. Food and Drug Administration. FDA adverse event reporting system (FAERS) public dashboard. Available from: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard.
5. Marder SR, Ostlund S. Dopamine-blocking antipsychotics: time for a new conversation with patients? JAMA Psychiatry. 2026;83(2):111-112.