Methodological Concerns in a Recently Published Systematic Review and Meta-Analysis of Xanomeline-Trospium in Schizophrenia : Re: Azargoonjahromi A, Nasiri H. Efficacy and Safety of KarXT (Xanomeline-Trospium; Cobenfy™) in Schizophrenia: A Systematic and Meta-Analysis Review of Randomized Controlled Trials. Psychiatric Quarterly. 2025. https://doi.org/10.1007/s11126-025-10226-7.

Abstract

This letter addresses significant methodological limitations in a recently published systematic review and meta-analysis evaluating the efficacy and safety of xanomeline-trospium (KarXT) in schizophrenia. A critical unit-of-analysis error is identified in the original review's Table 1, wherein multiple secondary and post hoc publications from a single randomized controlled trial (EMERGENT-1) were extracted and treated as completely independent studies. This unit-of-analysis error violates statistical independence assumptions and likely contributed to an implausible pooled effect size; however, additional discrepancies in data extraction or effect-size calculation may also have influenced the pooled estimate (d = 0.08) that sharply contradicts individual trial data. Additionally, the review lacks registered protocol details, structured risk-of-bias reporting, and safety outcome pooling. Readers and clinicians are cautioned against interpreting the pooled conclusions in isolation.