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      Muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis: protocol for a systematic review and meta-analysis

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          Abstract

          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

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          Most cited references81

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          The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

          The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.
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            Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement

            Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Funding AcquisitionRole: MethodologyRole: Project AdministrationRole: SupervisionRole: Writing – Original Draft Preparation
                Role: Writing – Review & Editing
                Role: Methodology
                Role: Methodology
                Role: MethodologyRole: Writing – Review & Editing
                Role: MethodologyRole: Writing – Review & Editing
                Role: MethodologyRole: Writing – Review & Editing
                Role: MethodologyRole: Writing – Review & Editing
                Role: MethodologyRole: Writing – Review & Editing
                Role: MethodologyRole: Writing – Review & Editing
                Role: MethodologyRole: Writing – Review & Editing
                Role: MethodologyRole: Writing – Review & Editing
                Role: MethodologyRole: Writing – Review & Editing
                Role: MethodologyRole: Writing – Review & Editing
                Role: Methodology
                Role: MethodologyRole: Writing – Review & Editing
                Role: MethodologyRole: Writing – Review & Editing
                Role: Methodology
                Role: Methodology
                Role: MethodologyRole: Writing – Review & Editing
                Role: MethodologyRole: Writing – Review & Editing
                Role: ConceptualizationRole: Funding AcquisitionRole: MethodologyRole: Project AdministrationRole: SupervisionRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Journal
                F1000Res
                F1000Res
                F1000Research
                F1000 Research Limited (London, UK )
                2046-1402
                2 January 2025
                2024
                : 13
                : 1017
                Affiliations
                [1 ]German Center for Mental Health (DZPG), partner site München/Augsburg, Munich, Germany
                [2 ]Technical University of Munich, School of Medicine and Health, Department of Psychiatry and Psychotherapy, Munich, Germany
                [3 ]Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
                [4 ]QUEST Center for Responsible Research, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
                [5 ]Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK
                [6 ]Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
                [7 ]Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, UK
                [8 ]Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK
                [9 ]Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, UK
                [10 ]MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK
                [11 ]Department of Basic and Clinical Neuroscience, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, UK
                [12 ]Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences and Dentistry, University Medical School of Naples "Federico II", Naples, Italy
                [13 ]Institute of Developmental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
                [14 ]BASTA-Bündnis für psychisch erkrankte Menschen, Munich, Germany
                [15 ]Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
                [16 ]University of Edinburgh and UK DRI, Edinburgh, UK
                [17 ]Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité - Universitätsmedizin Berlin and DZNE, Berlin, Germany
                [1 ]Zhejiang University, Hangzhou, Zhejiang, China
                [1 ]Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology and Experimental Therapeutics,, University of Toledo, Toledo, OH, USA
                Psychiatry and Psychotherapy, Technische Universitat Munchen, Munich, Bavaria, Germany
                [1 ]Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, USA
                Psychiatry and Psychotherapy, Technische Universitat Munchen, Munich, Bavaria, Germany
                Author notes

                Competing interests: Spyridon Siafis: None. Nobuyuki Nomura: N.N. has received manuscript fees from Sumitomo Pharma. Johannes Schneider-Thoma: None. Irene Bighelli: None. Alexandra Bannach-Brown: None. Fiona J. Ramage: None. Francesca Tinsdeall: None. Ioannis Mantas: None. Sameer Jauhar: SJ has received honoraria for educational talks given for Boehringer Ingelheim, Lundbeck, Janssen, and Sunovion, and has advised on antipsychotics to LB Pharmaceuticals. Sridhar Natesan: None. Anthony Vernon: ACV has received research support from UCB S.A and Bit.Bio (https://www.bit.bio/) and has received honoraria for seminars at GlaxoSmithKline. Andrea de Bartolomeis: AdB has received research support from Janssen, Lundbeck, and Otsuka and lecture fees for educational meeting from Chiesi, Lundbeck, Roche, Sunovion, Vitria, Recordati, Angelini and Takeda; he has served on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and Takeda, Chiesi, Recordati, Angelini, Vitria. Sabine M. Hölter: None. Natascha I. Drude: None. Ulf Tölch: None. Wulf-Peter Hansen: None. Virginia Chiocchia: None. Oliver Howes: ODH has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neurocrine, Ontrack/ Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi and Viatris/ Mylan. He was previously a part-time employee of Lundbeck A/v. Dr Howes has a patent for the use of dopaminergic imaging. Josef Priller: None. Georgia Salanti: None. Malcolm R. Macleod: None. Stefan Leucht: SL has received received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Boehringer Ingelheim, Eisai, Ekademia, GedeonRichter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Otsuka, NovoNordisk, Recordati, Rovi, Teva.

                Competing interests: No competing interests were disclosed.

                Competing interests: I am an inventor on patents related to the use of muscarinic agonists and allosteric modulators for the treatment of neuropsychiatric disorders. I am also the founder and owner of Psyneurgy Pharmaceuticals LLC, a company focused on the development of treatments for neuropsychiatric disorders.

                Competing interests: Spyridon Siafis: None. Nobuyuki Nomura: N.N. has received manuscript fees from Sumitomo Pharma. Johannes Schneider-Thoma: None. Irene Bighelli: None. Alexandra Bannach-Brown: None. Fiona J. Ramage: None. Francesca Tinsdeall: None. Ioannis Mantas: None. Sameer Jauhar: SJ has received honoraria for educational talks given for Boehringer Ingelheim, Lundbeck, Janssen, and Sunovion, and has advised on antipsychotics to LB Pharmaceuticals. Sridhar Natesan: None. Anthony Vernon: ACV has received research support from UCB S.A and Bit.Bio (https://www.bit.bio/) and has received honoraria for seminars at GlaxoSmithKline. Andrea de Bartolomeis: AdB has received research support from Janssen, Lundbeck, and Otsuka and lecture fees for educational meeting from Chiesi, Lundbeck, Roche, Sunovion, Vitria, Recordati, Angelini and Takeda; he has served on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and Takeda, Chiesi, Recordati, Angelini, Vitria. Sabine M. Hölter: None. Natascha I. Drude: None. Ulf Tölch: None. Wulf-Peter Hansen: None. Virginia Chiocchia: None. Oliver Howes: ODH has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neurocrine, Ontrack/ Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi and Viatris/ Mylan. He was previously a part-time employee of Lundbeck A/v. Dr Howes has a patent for the use of dopaminergic imaging. Josef Priller: None. Georgia Salanti: None. Malcolm R. Macleod: None. Stefan Leucht: SL has received received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Boehringer Ingelheim, Eisai, Ekademia, GedeonRichter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Otsuka, NovoNordisk, Recordati, Rovi, Teva.

                Competing interests: No competing interests were disclosed.

                Competing interests: Spyridon Siafis: None. Nobuyuki Nomura: N.N. has received manuscript fees from Sumitomo Pharma. Johannes Schneider-Thoma: None. Irene Bighelli: None. Alexandra Bannach-Brown: None. Fiona J. Ramage: None. Francesca Tinsdeall: None. Ioannis Mantas: None. Sameer Jauhar: SJ has received honoraria for educational talks given for Boehringer Ingelheim, Lundbeck, Janssen, and Sunovion, and has advised on antipsychotics to LB Pharmaceuticals. Sridhar Natesan: None. Anthony Vernon: ACV has received research support from UCB S.A and Bit.Bio (https://www.bit.bio/) and has received honoraria for seminars at GlaxoSmithKline. Andrea de Bartolomeis: AdB has received research support from Janssen, Lundbeck, and Otsuka and lecture fees for educational meeting from Chiesi, Lundbeck, Roche, Sunovion, Vitria, Recordati, Angelini and Takeda; he has served on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and Takeda, Chiesi, Recordati, Angelini, Vitria. Sabine M. Hölter: None. Natascha I. Drude: None. Ulf Tölch: None. Wulf-Peter Hansen: None. Virginia Chiocchia: None. Oliver Howes: ODH has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neurocrine, Ontrack/ Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi and Viatris/ Mylan. He was previously a part-time employee of Lundbeck A/v. Dr Howes has a patent for the use of dopaminergic imaging. Josef Priller: None. Georgia Salanti: None. Malcolm R. Macleod: None. Stefan Leucht: SL has received received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Boehringer Ingelheim, Eisai, Ekademia, GedeonRichter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Otsuka, NovoNordisk, Recordati, Rovi, Teva.

                Author information
                https://orcid.org/0000-0001-8264-2039
                https://orcid.org/0000-0002-3448-9532
                https://orcid.org/0000-0002-3161-1395
                https://orcid.org/0000-0003-4878-5241
                https://orcid.org/0000-0001-9187-9839
                https://orcid.org/0000-0002-3830-8508
                https://orcid.org/0000-0002-4934-4352
                Article
                10.12688/f1000research.155356.2
                11751611
                39844929
                52895253-b7d6-4386-b069-b9009d8c4bfd
                Copyright: © 2025 Siafis S et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 December 2024
                Funding
                Funded by: Wellcome Trust
                Award ID: no.094849/Z/10/Z
                Funded by: Bundesministerium für Bildung und Forschung
                Award ID: 01EE2303B
                Award ID: 01KC2312
                Funded by: Medical Research Council-UK
                Award ID: MC_U120097115
                Federal Ministry of Education and Research 01KC2312
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Study Protocol
                Articles

                antipsychotic; schizophrenia; psychosis; muscarinic receptor; acetylcholine; meta-analysis

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