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Meta-Analysis
30 July 2026

Systematic review and network meta-analysis of the efficacy, safety and tolerability of xanomeline plus trospium chloride compared with eight oral antipsychotics for the acute treatment of schizophrenia

Authors: Conor Hickey https://orcid.org/0009-0002-2310-6265, Matthew F Sidovar, Andrea Garcia https://orcid.org/0000-0003-4388-2608, Ken Kramer https://orcid.org/0009-0008-5382-0287, Jen-Yu Amy Chang https://orcid.org/0000-0001-6660-5246, Katrin Kupas https://orcid.org/0009-0005-1082-7081, Vyshnavi Telukuntla, Jake Horgan, Haris Jameel https://orcid.org/0009-0006-0116-3110, Tracy Westley, Kristin K Gillard https://orcid.org/0000-0003-3342-2878 [email protected], and Andrew J CutlerAuthor Info & Affiliations
Volume 15, Number 8
https://doi.org/10.57264/cer-2026-0045
PDFFormats

Abstract

Aim: The recently approved first-in-class combination therapy xanomeline/trospium chloride (KarXT) demonstrated superiority over placebo in three randomized controlled trials (RCTs) of adults with schizophrenia. This analysis investigates its relative efficacy, safety and tolerability compared with eight second-generation antipsychotics for the acute treatment of schizophrenia via network meta-analyses (NMAs). Materials & methods: A 2019 systematic literature review was adapted and updated to identify RCTs of eight antipsychotics in adults with schizophrenia. NMAs were conducted to compare KarXT against these antipsychotics for 11 endpoints of interest, measured at 4–6 weeks, covering efficacy (Positive and Negative Syndrome Scale [PANSS]; Clinical Global Impressions – Severity [CGI-S]), safety (weight change, sedation and somnolence) and tolerability (discontinuation; all-cause and due to adverse events). Results: A network of 49 RCTs including 14,680 patients was formed. KarXT was associated with greater odds of clinical response (≥30% improvement in PANSS total score) than aripiprazole (odds ratio [OR]: 1.85; 95% credible interval [CrI]: 1.11, 3.11), brexpiprazole (OR: 2.23; 95% CrI: 1.34, 3.83) and cariprazine (OR: 2.05; 95% CrI: 1.19, 3.57); improved change from baseline (CFB) PANSS positive symptoms score versus brexpiprazole; improved CFB CGI-S score against aripiprazole, brexpiprazole, cariprazine and olanzapine; reduced odds of clinically significant (≥7%) weight gain over all comparators except clozapine (no data); improved CFB weight against brexpiprazole, clozapine, olanzapine, quetiapine and risperidone; and greater odds of all-cause discontinuation than aripiprazole, brexpiprazole, clozapine, lumateperone, olanzapine, quetiapine and risperidone. Conclusion: In this NMA, for patients receiving acute treatment for schizophrenia, KarXT compared favorably with second-generation antipsychotics on key efficacy endpoints and in terms of unwanted weight gain.

Plain language summary

What is this article about?

This study compared a newly approved medication, xanomeline/trospium chloride (KarXT), with eight oral antipsychotics commonly used in the US for the treatment of adults during acute episodes of schizophrenia. KarXT works differently than existing antipsychotics and has been shown in clinical trials to be effective versus placebo. In this study, an existing systematic literature review was adapted to find clinical trials of antipsychotics that were high-quality and had comparable study designs. An established statistical technique (network meta-analysis) was used to compare data from these trials with data from three KarXT trials, focusing on symptom improvement, adverse events and treatment tolerability after 4–6 weeks.

What were the results?

The analyses found that KarXT led to a higher chance of meaningful symptom improvement than aripiprazole, brexpiprazole and cariprazine. It also showed that KarXT led to larger improvements in some symptom severity scores compared with several other drugs. Importantly, it was less likely to cause significant weight gain than most comparators, a side effect that often reduces antipsychotic adherence. Safety and tolerability outcomes were generally comparable between the treatments, though findings suggested KarXT had a higher chance of all-cause discontinuation.

What do the results mean?

The results suggest KarXT could be a valuable option for patients and clinicians. Its use is associated with potential improvements in certain symptoms and a lower risk of problematic weight gain compared with other therapies, which may help support ongoing treatment and quality of life for adult patients.

Supplementary Material

File (supplementary materials.docx)

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