Is muscarinic receptor agonist effective and tolerant for schizophrenia?

Several randomized clinical trials (RCTs) have recently examined the efficacy and tolerability of muscarinic receptor agonists in schizophrenia. However, whether therapeutics targeting muscarinic receptors improve symptom management and reduce side effects remains systemically unexplored.

Embase, PubMed, and Web of Science were searched from inception until Jan 9, 2025. Altogether, the efficacy and safety outcomes of four RCTs (397 individuals in the muscarinic receptor agonists group, and 374 in the placebo control group) were meta-analyzed. To compare scores of positive and negative syndrome scale (PANSS), response rate, discontinuation rate, and adverse events with muscarinic receptor agonists vs. placebo in patients with schizophrenia, scale changes were pooled as mean difference (MD) for continuous outcomes and risk ratio (RR) for categorical outcomes.

It revealed that muscarinic receptor agonists were superior to placebo in terms of decrease in the total PANSS score (MD, - 9.92; 95% CI, -12.46 to -7.37; I² = 0%), PANSS positive symptom subscore (MD, - 3.21; 95% CI, -4.02 to -2.40; I² = 0%), and PANSS negative symptom subscore (MD, -1.79; 95% CI, -2.47 to -1.11; I² = 48%). According to the study-defined response rate, the pooled muscarinic receptor agonists vs. placebo RR was 2.08 (95% CI, 1.59 to 2.72; I² = 0%). No significance was found in the discontinuation rate. Muscarinic receptor agonists were associated with a higher risk of nausea (RR = 4.61, 95% CI, 2.65 to 8.02; I² = 3%), and in particular, xanomeline-trospium was associated with risks of dyspepsia, vomiting, and constipation.

The findings highlighted an efficacy advantage with tolerated adverse event profiles for muscarinic receptor agonists in schizophrenia.