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.

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.