Acetylcholine and muscarinic receptor targeting in bipolar disorder: does xanomeline-trospium chloride and other investigational muscarinic agonists hold promise as mechanistically informed treatments for manic episodes, mixed features and cognitive deficits in bipolar disorder?

INTRODUCTION: Xanomeline-trospium chloride (Cobenfy, KarXT) received FDA approval on September 26, 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 also indicates that xanomeline-trospium chloride improves measures of cognition in Alzheimer's disease and schizophrenia. AREAS COVERED: Acetylcholine's physiology as well as evidence implicating disturbance in acetylcholine availability and/or its canonical receptors in mania and cognitive impairment in bipolar disorder is 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, mixed features 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, mixed features and/or cognitive impairment in bipolar disorder. Xanomeline-trospium chloride is safe and generally well tolerated and does not have depressogenic effects and/or increased suicidality in adults with schizophrenia. Whether other investigational muscarinic agonists (e.g. positive allosteric modulator [PAM] or orthosteric agonism of M4) are potentially efficacious in mania and/or cognitive impairment in bipolar disorder is a priority future research avenue.