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Efficacy and safety of cholinergic modulators in patients with schizophrenia: meta-analysis of randomised controlled trials

Published online by Cambridge University Press:  02 May 2025

Amiya Shaju Open the ORCID record for Amiya Shaju [Opens in a new window] ,
Archana Mishra Open the ORCID record for Archana Mishra [Opens in a new window] ,
Debadatta Mohapatra Open the ORCID record for Debadatta Mohapatra [Opens in a new window] ,
Anand Srinivasan Open the ORCID record for Anand Srinivasan [Opens in a new window]  and
Rituparna Maiti Open the ORCID record for Rituparna Maiti [Opens in a new window]
Amiya Shaju
Affiliation:
Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, India
Archana Mishra
Affiliation:
Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, India
Debadatta Mohapatra
Affiliation:
Department of Psychiatry, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, India
Anand Srinivasan
Affiliation:
Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, India
Rituparna Maiti*
Affiliation:
Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, India
*
Correspondence: Rituparna Maiti. Email: [email protected]
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Abstract

Background

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.

Aims

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

Methods

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.

Results

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.

Conclusion

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.

Keywords

Acetylcholinesterase inhibitorscholinergic modulatorsmuscarinic agonistsnicotinic agonistsschizophrenia
Type
Review
Information
The British Journal of Psychiatry , First View , pp. 1 - 11
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Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of Royal College of Psychiatrists

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