The mechanism of action and clinical efficacy of xanomeline-trospium in schizophrenia: A comprehensive review

This narrative review summarizes the latest clinical evidence on xanomeline-trospium in schizophrenia, a first-in-class centrally acting dual-target muscarinic receptor modulator. Xanomeline-trospium combines the muscarinic receptor agonist xanomeline, with with functional preference for M1/M4 subtypes, and the peripherally acting muscarinic antagonist trospium chloride in a 4.2:1 ratio. Xanomeline mediates central therapeutic effects, whereas trospium mitigates xanomeline-induced peripheral adverse effects, including nausea, vomiting, and diarrhea. Five EMERGENT trials were reviewed, comprising three short-term efficacy studies and two long-term extension studies evaluating efficacy and safety. In five-week short-term trials, xanomeline-trospium significantly reduced total Positive and Negative Syndrome Scale (PANSS) total scores, with reductions in positive symptoms approximately 1.5-2 times greater and negative symptoms 1.5-3.5 times greater than those observed with placebo. In the EMERGENT-4 and EMERGENT-5 long-term extension trials, sustained therapeutic effects were observed along with potential improvements in quality of life in patients with mild-to-moderate schizophrenia over 52 weeks. Nevertheless, tolerability remains a major challenge, with high overall discontinuation rates (EMERGENT-4: 78.2% discontinuation; EMERGENT-5: 51% withdrawal). Notably, voluntary withdrawal accounted for a substantial proportion of discontinuations, exceeding adverse event-related withdrawals in certain subgroups. The most common adverse events included gastrointestinal symptoms (nausea, constipation, vomiting) and syncope. Compared with traditional dopamine D2 antagonists, xanomeline-trospium was associated with lower risks of weight gain, hyperprolactinemia, and extrapyramidal symptoms. Key limitations of this review include reliance on placebo-controlled trials without head-to-head comparisons, exclusion of treatment-resistant schizophrenia populations, and limited generalizability to outpatient settings due to the focus on acute inpatient cohorts. Future research should focus on identifying risk factors for early discontinuation and developing both pharmacological and non-pharmacological strategies to improve long-term adherence. Overall, as a novel non-dopaminergic antipsychotic strategy, xanomeline-trospium offers an important therapeutic option for patients who are intolerant to the metabolic or motor adverse effects of traditional antipsychotics, although challenges related to long-term adherence remain to be addressed.