TY - JOUR
T1 - Muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis
T2 - protocol for a systematic review and meta-analysis
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
N1 - Copyright: © 2025 Siafis S et al.
PY - 2024/1/15
Y1 - 2024/1/15
N2 - BACKGROUND: 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.METHODS: 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.
PROTOCOL REGISTRATION: PROSPERO-ID: CRD42024520914.
AB - BACKGROUND: 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.METHODS: 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.
PROTOCOL REGISTRATION: PROSPERO-ID: CRD42024520914.
KW - Psychotic Disorders/drug therapy
KW - Animals
KW - Disease Models, Animal
KW - Systematic Reviews as Topic
KW - Allosteric Regulation/drug effects
KW - Muscarinic Agonists/pharmacology
KW - Meta-Analysis as Topic
KW - Receptors, Muscarinic
KW - Humans
KW - Antipsychotic Agents/therapeutic use
U2 - 10.12688/f1000research.155356.2
DO - 10.12688/f1000research.155356.2
M3 - Article
C2 - 39844929
SN - 2046-1402
VL - 13
SP - 1017
JO - F1000Research
JF - F1000Research
ER -