Efficacy and safety of the muscarinic receptor agonist KarXT (Xanomeline-Trospium) in schizophrenia: a systematic review, meta-analysis and Bayesian sensitivity analysis

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BACKGROUND: Schizophrenia significantly impacts global health, with existing treatments primarily focusing on positive symptoms and often causing considerable side effects. KarXT (Xanomeline-Trospium), a novel treatment combining xanomeline, a muscarinic M1/M4 receptor agonist, and trospium, targets a broader range of symptoms including negative and cognitive deficits, potentially with fewer side effects. This systematic review and meta-analysis evaluates the efficacy and safety of KarXT in treating schizophrenia, assessing symptom reduction and safety profiles compared to placebo. METHODS: We searched PubMed, Embase, and Web of Science up to November 10, 2024, for randomized controlled trials (RCTs) assessing the efficacy and safety of KarXT in schizophrenia. Data were pooled using a random-effects model, assessing outcomes like Positive and Negative Syndrome Scale (PANSS) scores and incidence of treatment-emergent adverse events (TEAEs). R software (Version 4.4.) was used for meta-analysis. RESULTS: Three RCTs involving 674 participants were included. KarXT significantly reduced total PANSS scores of mean difference (MD) -9.707 (95% CI: -12.329 to -7.085), with notable improvements in both negative (MD = -1.623; 95% CI: -2.461 to -0.785) and positive symptom subscales (MD = -3.213; 95% CI: -4.033 to -2.393). The treatment was associated with a higher incidence of TEAEs, predominantly constipation [risk ratio (RR): 2.77; 95% CI: 1.72-4.45] and nausea (RR: 4.87; 95% CI: 2.73-8.68) compared to placebo. Bayesian meta-analysis confirmed the results. CONCLUSION: KarXT offers significant improvements in both negative and positive symptoms of schizophrenia with a manageable safety profile. Its potential as a transformative treatment for schizophrenia highlights the need for further research to confirm these findings and to fully understand its long-term efficacy and safety.

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