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REVIEW article

Front. Psychiatry
Sec. Psychopharmacology
Volume 15 - 2024 | doi: 10.3389/fpsyt.2024.1421554

The potential of muscarinic M1 and M4 receptor activators for the treatment of cognitive impairment associated with schizophrenia

Provisionally accepted
Samantha E. Yohn Samantha E. Yohn 1*Philip D. Harvey Philip D. Harvey 2Stephen K. Brannan Stephen K. Brannan 1William P. Horan William P. Horan 1
  • 1 A Bristol Myers Squibb Company, Karuna Therapeutics, Inc., Boston, United States
  • 2 University of Miami, Coral Gables, Florida, United States

The final, formatted version of the article will be published soon.

    Cognitive impairment is a core symptom of schizophrenia and a major determinant of poor longterm functional outcomes. Despite considerable efforts, we do not yet have any approved pharmacological treatments for cognitive impairment associated with schizophrenia (CIAS). A combination of advances in pre-clinical research and recent clinical trial findings have led to a resurgence of interest in the cognition-enhancing potential of novel muscarinic acetylcholine receptor (mAChR) agonists in schizophrenia. This article provides an overview of the scientific rationale for targeting M1 and M4 mAChRs. We describe the evolution of neuroscience research on these receptors since early drug discovery efforts focused on the mAChR agonist xanomeline. This work has revealed that M1 and M4 mAChRs are highly expressed in brain regions that are implicated in cognition. The functional significance of M1 and M4 mAChRs has been extensively characterized in animal models via use of selective receptor subtype compounds through neuronal and non-neuronal mechanisms. Recent clinical trials of a dual M1/M4 mAChR agonist show promising, replicable evidence of potential pro-cognitive effects in schizophrenia, with several other mAChR agonists in clinical development.

    Keywords: muscarinic, Cognition, Acetylcholine, cognitive impairment associated with schizophrenia, Schizophrenia

    Received: 23 Apr 2024; Accepted: 03 Sep 2024.

    Copyright: © 2024 Yohn, Harvey, Brannan and Horan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Samantha E. Yohn, A Bristol Myers Squibb Company, Karuna Therapeutics, Inc., Boston, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.