Journal Article

DZNE-2025-00693

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis: protocol for a systematic review and meta-analysis [version 2; peer review: 1 approved, 2 approved with reservations]

Siafis, S. ; Nomura, N. ; Schneider-Thoma, J. ; Bighelli, I. ; Bannach-Brown, A. ; Ramage, F. J. ; Tinsdeall, F. ; Mantas, I. ; Jauhar, S. ; Natesan, S. ; Vernon, A. C. ; de Bartolomeis, A. ; Hölter, S. M. ; Drude, N. I. ; Tölch, U. ; Hansen, W.-P. ; Chiocchia, V. ; Howes, O. D. ; Priller, J.DZNE* ; Macleod, M. R. ; Salanti, G. ; Leucht, S.

2025
F1000 Research Ltd London

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Please use a persistent id in citations: doi:10.12688/f1000research.155356.2

Abstract: Muscarinic receptor agonism and positive allosteric modulation is a promising mechanism of action for treating psychosis, not present in most D2R-blocking antipsychotics. Xanomeline, an M1/M4-preferring agonist, has shown efficacy in late-stage clinical trials, with more compounds being investigated. Therefore, we aim to synthesize evidence on the preclinical efficacy of muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis to provide unique insights and evidence-based information to guide drug development.We plan a systematic review and meta-analysis of in vivo animal studies comparing muscarinic receptor agonists or positive allosteric modulators with control conditions and existing D2R-blocking antipsychotics in animals subjected to any method that induces behavioural changes of relevance for psychosis. We will identify eligible studies by searching multiple electronic databases. At least two independent reviewers will conduct the study selection and data extraction using prespecified forms and assess the risk of bias with the SYRCLE's tool. Our primary outcomes include locomotor activity and prepulse inhibition measured with standardized mean differences. We will examine other behavioural readouts of relevance for psychosis as secondary outcomes, such as social interaction and cognitive function. We will synthesize the data using multi-level meta-analysis with a predefined random-effects structure, considering the non-independence of the data. In meta-regressions we will explore potential sources of heterogeneity from a predefined list of characteristics of the animal population, model, and intervention. We will assess the confidence in the evidence considering a self-developed instrument thatconsiders the internal and external validity of the evidence.PROSPERO-ID: CRD42024520914.

Keyword(s): Animals (MeSH) ; Systematic Reviews as Topic (MeSH) ; Psychotic Disorders: drug therapy (MeSH) ; Disease Models, Animal (MeSH) ; Meta-Analysis as Topic (MeSH) ; Allosteric Regulation: drug effects (MeSH) ; Muscarinic Agonists: therapeutic use (MeSH) ; Muscarinic Agonists: pharmacology (MeSH) ; Antipsychotic Agents: therapeutic use (MeSH) ; Antipsychotic Agents: pharmacology (MeSH) ; antipsychotic; schizophrenia; psychosis; muscarinic receptor; acetylcholine; meta-analysis ; Muscarinic Agonists ; Antipsychotic Agents

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Contributing Institute(s):

1. Translational Neuropsychiatry (AG Priller)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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Database coverage:
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