TY  - JOUR
AU  - Siafis, Spyridon
AU  - Nomura, Nobuyuki
AU  - Schneider-Thoma, Johannes
AU  - Bighelli, Irene
AU  - Bannach-Brown, Alexandra
AU  - Ramage, Fiona J
AU  - Tinsdeall, Francesca
AU  - Mantas, Ioannis
AU  - Jauhar, Sameer
AU  - Natesan, Sridhar
AU  - Vernon, Anthony C
AU  - de Bartolomeis, Andrea
AU  - Hölter, Sabine M
AU  - Drude, Natascha I
AU  - Tölch, Ulf
AU  - Hansen, Wulf-Peter
AU  - Chiocchia, Virginia
AU  - Howes, Oliver D
AU  - Priller, Josef
AU  - Macleod, Malcolm R
AU  - Salanti, Georgia
AU  - Leucht, Stefan
TI  - 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]
JO  - F1000Research
VL  - 13
SN  - 2046-1402
CY  - London
PB  - F1000 Research Ltd
M1  - DZNE-2025-00693
SP  - 1017
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Systematic Reviews as Topic
KW  - Psychotic Disorders: drug therapy
KW  - Disease Models, Animal
KW  - Meta-Analysis as Topic
KW  - Allosteric Regulation: drug effects
KW  - Muscarinic Agonists: therapeutic use
KW  - Muscarinic Agonists: pharmacology
KW  - Antipsychotic Agents: therapeutic use
KW  - Antipsychotic Agents: pharmacology
KW  - antipsychotic; schizophrenia; psychosis; muscarinic receptor; acetylcholine; meta-analysis (Other)
KW  - Muscarinic Agonists (NLM Chemicals)
KW  - Antipsychotic Agents (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39844929
C2  - pmc:PMC11751611
DO  - DOI:10.12688/f1000research.155356.2
UR  - https://pub.dzne.de/record/279165
ER  -