Acetylcholine and muscarinic receptor targeting in bipolar disorder: does xanomeline-trospium chloride and other investigational muscarinic agonists hold promise as a mechanistically informed therapeutic treatment for mania, mixed features and cognitive deficits in bipolar disorder?
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Abstract
Introduction: Xanomeline-trospium chloride (Cobenfy, KarXT) received FDA approval on 26 September 2024, for the treatment of adults with schizophrenia. Xanomeline-trospium chloride is the first muscarinic M1, M4 acetylcholine receptor partial agonist approved to treat schizophrenia. Preliminary evidence indicates that xanomeline-trospium chloride improves measures of cognition in Alzheimer's disease and schizophrenia.
Areas covered: Acetylcholine's physiology and evidence implicating disturbance in acetylcholine and its canonical receptors in mania and cognitive impairment in bipolar disorder are synthesized. Extant efficacy, safety and tolerability data for xanomeline-trospium chloride in adults with schizophrenia are reviewed. Xanomeline-trospium chloride's clinical and pharmacological profile provides rationale for investigating its efficacy, safety and tolerability in the treatment of manic episodes and cognitive impairment associated with bipolar disorder.
Expert opinion: Xanomeline-trospium chloride is a mechanistically novel treatment for schizophrenia targeting cholinergic receptors as opposed to dopamine receptors and may have transdiagnostic efficacy in mania and/or cognitive impairment in bipolar disorder. Xanomeline-trospium chloride is safe and generally well tolerated and does not appear to have depressogenic effects and/or increased suicidality in adults with schizophrenia. Whether other investigational muscarinic agonists (e.g. positive allosteric modulator [PAM] of M4) are potentially efficacious in mania and cognitive impairment in bipolar disorder is a future research avenue.
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Expert Opinion on Investigational Drugs (ISSN 1354-3784 [print], 1744-7658 [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles and original papers on drugs in preclinical and early stage clinical development, providing expert opinion on the scope for future development.
The Editors welcome:
Reviews covering preclinical through to Phase II data on drugs or drug classes for specific indications, and their potential impact on future treatment strategies
Drug Evaluations reviewing the clinical and pharmacological data on a particular drug
Original Research papers reporting the results of clinical investigations on agents that are in Phase I and II clinical trials
The audience consists of scientists, managers and decision-makers in the pharmaceutical industry, and others closely involved in R&D.
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