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

Q2 Pharmacology, Toxicology and Pharmaceutics F1000Research Pub Date : 2025-01-02 eCollection Date: 2024-01-01 DOI:10.12688/f1000research.155356.2

Spyridon Siafis, Nobuyuki Nomura, Johannes Schneider-Thoma, Irene Bighelli, Alexandra Bannach-Brown, Fiona J Ramage, Francesca Tinsdeall, Ioannis Mantas, Sameer Jauhar, Sridhar Natesan, Anthony C Vernon, Andrea de Bartolomeis, Sabine M Hölter, Natascha I Drude, Ulf Tölch, Wulf-Peter Hansen, Virginia Chiocchia, Oliver D Howes, Josef Priller, Malcolm R Macleod, Georgia Salanti, Stefan Leucht

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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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精神病动物模型中的毒蕈碱受体激动剂和阳性变构调节剂：系统回顾和荟萃分析的方案。

背景：毒蕈碱受体激动和阳性变构调节是一种治疗精神病的有希望的作用机制，在大多数d2r阻断抗精神病药物中不存在。Xanomeline是一种M1/ m4偏好激动剂，在后期临床试验中显示出疗效，更多的化合物正在研究中。因此，我们旨在综合有关毒蕈碱受体激动剂和阳性变构调节剂在精神病动物模型中的临床前疗效的证据，为指导药物开发提供独特的见解和循证信息。方法：我们计划对体内动物研究进行系统回顾和荟萃分析，比较毒蕈碱受体激动剂或阳性变构调节剂与对照条件和现有d2r阻断抗精神病药物在任何方法下诱导与精神病相关的行为改变的动物中的作用。我们将通过搜索多个电子数据库来确定符合条件的研究。至少两名独立审稿人将使用预先指定的表格进行研究选择和数据提取，并使用sycle的工具评估偏倚风险。我们的主要结果包括运动活动和脉冲前抑制的标准化平均差异测量。我们将检查与精神病相关的其他行为读数作为次要结果，如社会互动和认知功能。考虑到数据的非独立性，我们将使用具有预定义随机效应结构的多级元分析来综合数据。在元回归中，我们将从预定义的动物种群、模型和干预的特征列表中探索潜在的异质性来源。我们将考虑一个自行开发的工具来评估证据的可信度，该工具考虑了证据的内部和外部有效性。协议注册：PROSPERO-ID: CRD42024520914。

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来源期刊

F1000Research Pharmacology, Toxicology and Pharmaceutics-Pharmacology, Toxicology and Pharmaceutics (all)

CiteScore

5.00

自引率

0.00%

发文量

1646

审稿时长

1 weeks

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