One-third of schizophrenia patients show a lack of response to conventional antipsychotic drugs because of adverse effects and limited efficacy. Emerging treatments target muscarinic and nicotinic receptors, leveraging cholinergic dysfunction implicated in the pathophysiology of schizophrenia.

To evaluate the efficacy and safety of cholinergic modulators in schizophrenia.

Reviewers extracted data from clinical trials sourced via MEDLINE/PubMed, Embase, Scopus, Cochrane databases and registries. Quality was assessed with a risk-of-bias tool and a random-effects model estimated effect size. Subgroup analysis, meta-regression and sensitivity analysis were performed as needed, adhering to PRISMA guidelines.

A total of 30 randomised controlled trials (3128 participants) tested cholinergic modulators as monotherapy or adjunct therapy. They did not significantly improve Positive and Negative Syndrome Scale (PANSS) total scores (standardised mean difference (SMD): −0.38; 95% CI: −0.93, 0.18; moderate certainty evidence) but did improve negative symptom scores (SMD: −0.42; 95% CI: −0.59, −0.25; moderate certainty evidence). Muscarinic agonists improved total (SMD: −0.57; 95% CI: −0.72, −0.42), positive (SMD: −0.58; 95% CI: −0.73, −0.43) and negative symptoms of PANSS (SMD: −0.40; 95% CI: −0.59, −0.21), as well as Clinical Global Impression-severity (CGI-S) (SMD: −0.48; 95% CI: −0.65, −0.31). Nicotinic agonists aided negative symptoms (SMD: −0.28; 95% CI: −0.47, −0.09) and CGI-S (SMD: −1.31; 95% CI: −2.38, −0.24). Adverse events were higher (odds ratio: 1.21; 95% CI: 0.94, 1.56) in the experimental group.

Cholinergic modulators significantly improve negative symptoms, with muscarinic agonists showing improvement across symptom domains and severity, without notable differences in adverse effects from placebo. Most studies were at low bias risk; evidence quality ranged from very low to moderate.