Efficacy of xanomeline and xanomeline trospium in the treatment of cognitive impairment: A systematic review of preclinical and clinical trials.

The high prevalence, persistence and clinical burden of cognitive impairment on health outcomes in persons with schizophrenia and bipolar disorder invites the need for innovative, mechanistically informed pharmacotherapeutic interventions. Evidence implicates dysregulation of muscarinic signalling as a mediator of cognitive dysfunction, identifying it as a potential therapeutic target. In accordance with the PRISMA guidelines, a systematic search was performed using the following electronic databases: PubMed, Medline, Cochrane Library, PsycInfo, Embase, Scopus, and Web of Science. Databases were searched from inception to May 1, 2025. Study screening and selection was performed by three reviewers (K.V., B.S., and B.W.). Included studies reported on the effects of xanomeline and/or xanomeline trospium on cognitive function. A total of 24 studies were included in this review. Preclinical and clinical studies consistently demonstrate that xanomeline trospium is well tolerated in both short and long-term evaluations. Furthermore, xanomeline trospium has been associated with cognitive improvements in both animal models and clinical populations (e.g., Alzheimer's disease (AD), schizophrenia), including improvements in verbal learning, delayed memory, and reaction time. Xanomeline trospium, an FDA approved muscarinic M1/M4 partial agonist with demonstrated safety, tolerability, and efficacy, represents a novel pharmacological intervention for the treatment of schizophrenia. The convergence of preclinical and clinical findings supports the hypothesis that xanomeline trospium exerts direct pro cognitive effects in persons with schizophrenia, bipolar disorder, and potentially other neuropsychiatric conditions (e.g., AD). Limitations of the current study include limited indications investigated and the absence of a comprehensive analysis of xanomeline's overall neurobiologic effects.