Antipsychotic efficacy of muscarinic receptor agonists and positive allosteric modulators

Examination of preclinical antipsychotic efficacy of muscarinic receptor agonists and positive allosteric modulators: A systematic review and meta-analysis of animal models of psychosis

Antipsychotics targeting the dopamine 2 receptor have been the foundation of schizophrenia treatment for over 70 years. However, these drugs are often characterized by limited efficacy and significant side effects. The search for alternative mechanisms of action is therefore crucial. In this context, the recent approval of xanomeline-trospium, a muscarinic M1/M4-preferring agonist, in the United States in September 2024 has sparked renewed interest. This drug is the first antipsychotic that does not target dopamine receptors and has demonstrated efficacy in clinical trials.

Several other compounds targeting muscarinic receptors are currently under development. These substances employ various approaches to selectively modulate specific muscarinic receptor subtypes (e.g., selective M4 orthosteric agonists or positive allosteric modulators). While preclinical studies have shown promising results, the clinical efficacy of these drugs has not been consistently confirmed.

Preclinical animal studies remain central to drug development. In animal models of psychosis, laboratory methods such as the administration of stimulants are often used to induce psychosis-like behaviors. Substances that effectively alleviate these behaviors are considered potential antipsychotic candidates. These studies are essential for understanding underlying mechanisms and identifying specific muscarinic receptor subtypes that contribute to antipsychotic efficacy. However, systematic approaches to evaluate the translatability of these preclinical findings to clinical studies are still lacking.

This project aims to conduct a systematic review and meta-analysis to evaluate the efficacy of muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis. Advanced data synthesis methods and rigorous assessments of bias will be employed to identify promising compounds and mechanisms. The findings aim to support the development of new therapies, improve the design of preclinical studies, and expand treatment options for schizophrenia.

The project is funded by the Federal Ministry of Education and Research (BMBF) (FKZ 01KC2312).

The protocol of the project was published in F1000 and registererd with PROSPERO (ID: CRD42024520914).

Contact: Spyridon Siafis, MD