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

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.

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.

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.

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.