Background <p>Treatment-resistant schizophrenia (TRS) is defined as nonresponse to at least two adequate antipsychotic trials at therapeutic doses for six or more weeks. Currently, clozapine is the only antipsychotic approved for TRS by the FDA and a plethora of evidence indicates that it is the most efficacious antipsychotic for treatment of chronic and refractory cases of schizophrenia. However, its utilization is often limited by metabolic, hematologic, and anticholinergic side effects. Notably, clozapine-induced obsessive-compulsive symptoms (OCS) or obsessive-compulsive disorder (OCD) have been increasingly recognized, attributed to its potent serotonergic antagonism. In 2024, the FDA approved xanomeline-trospium, a dual agent combining a central muscarinic M1/M4 agonist with a peripheral antimuscarinic, which offers a novel approach to treating psychosis. Early evidence suggests comparable efficacy to other antipsychotics, with fewer metabolic and extrapyramidal side effects. We present a case of a woman with longstanding schizophrenia and clozapine-induced OCD successfully transitioned to xanomeline-trospium, resulting in remission of both psychotic and obsessive-compulsive symptoms.</p> Case presentation <p>A 57-year-old woman with a chronic history of schizophrenia, requiring multiple hospitalizations and maintenance electroconvulsive therapy (ECT), stabilized on clozapine 300&#xa0;mg nightly after failing several antipsychotics. Despite adherence, she exhibited persistent hallucinations, negative symptoms, and later developed clozapine-induced OCD characterized by intrusive counting and numerical obsessions refractory to high-dose sertraline. Due to distressing OCD and passive suicidal ideation, she was admitted for a discontinuation of clozapine and initiation of xanomeline-trospium. Clozapine was tapered and discontinued before initiating xanomeline-trospium, titrated to 100&#xa0;mg/20&#xa0;mg twice daily. Within one week after starting xanomeline-trospium, her counting obsessions resolved, psychosis improved, and suicidality resolved. At discharge, three weeks post-admission, she remained stable on xanomeline-trospium, ziprasidone, and sertraline, with complete remission of hallucinations and obsessions.</p> Conclusion <p>This case highlights a successful switch from clozapine to xanomeline-trospium for management of chronic schizophrenia and clozapine induced OCD. The patient’s improvement raises important considerations regarding clozapine-induced OCD, cautious discontinuation, and the benefit of muscarinic receptor agonists. Xanomeline-trospium may represent a viable alternative for patients intolerant of clozapine.</p> Clinical trial number <p>Not applicable.</p>