A Bayesian network meta-analysis of randomized controlled trials comparing the efficacy and safety of cholinergic modulators in schizophrenia

BACKGROUND: Emerging evidence suggests that the cholinergic system, through its modulation of dopamine via muscarinic and nicotinic receptors, holds therapeutic promise in schizophrenia. Xanomeline (M1/M4 muscarinic agonist) with trospium (muscarinic antagonist) was approved by the US-FDA, alongside emerging M4 and nicotinic modulators. To date, no network meta-analysis (NMA) has evaluated these agents for schizophrenia. Hence, the present NMA was conducted to evaluate and compare the efficacy and safety of cholinergic modulators in schizophrenia. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses - NMA guidelines, we conducted a Bayesian NMA of randomized controlled trials (RCTs) from MEDLINE/PubMed, Embase, Web of Science, Cochrane, and International Clinical Trials Registry Platform (ICTRP). Eligible RCTs assessed cholinergic modulators versus placebo in adults with schizophrenia. The primary outcome was a change in positive and negative syndrome scale (PANSS) total scores; secondary outcomes included PANSS subscales, scale for the assessment of negative symptoms, clinical global impression-severity (CGI-S), and adverse events. Data were extracted independently, and the risk of bias (ROB) was assessed using the Cochrane ROB 2 tool. A Bayesian NMA was conducted using the "gemtc" package in R, with Surface under the Cumulative Ranking (SUCRA) scores used to rank efficacy. RESULTS: The present NMA included 30 RCTs (3128 participants) assessing 14 interventions across 4 groups versus placebo. Muscarinic agonists (Standardized mean difference (SMD): -0.61; 95%credible interval (CrI): -0.97, -0.26) and nicotinic agonists (SMD: -0.26; 95%CrI: -0.51, -0.01) significantly reduced PANSS total scores, with muscarinic agonists ranking highest (SUCRA: 95.41%). Tropisetron 5 mg and xanomeline 125 mg showed significant efficacy. Muscarinic agonists improved PANSS positive, negative, and CGI-S scores. No significant difference in adverse events was observed. CONCLUSIONS: Tropisetron and xanomeline demonstrated better efficacy in reducing schizophrenia symptoms, offering a promising alternative to traditional antipsychotics with comparable safety. Further RCTs and NMAs are needed to confirm these findings and guide clinical practice.