Muscarinic agonists for schizophrenia: Bridging preclinical evidence and clinical enthusiasm

Antipsychotic drugs targeting dopamine receptors have been used to treat schizophrenia for decades, primarily alleviating positive symptoms such as hallucinations and delusions. However, they provide limited benefit for cognitive and negative symptoms-major contributors to poor outcomes-and are frequently associated with significant side effects. The recent approval of KarXT, the first muscarinic-targeting antipsychotic drug, marks a potentially important shift in therapeutic strategy. Here, we review the mechanism of action of xanomeline (the centrally active component of KarXT) and related compounds, using a RDoC-informed framework spanning receptor, cellular, systems, network and behavioural level. We interrogate the pharmacological profile of xanomeline at M₁-M₅ receptors, highlighting the role of receptor reserve in conferring partial agonist activity at M₁ and M₄ receptors in vivo. At a systems level, xanomeline is likely to act at M₁/M₄ receptors on glutamatergic afferents and cortical pyramidal neurons; M₂ receptors in the thalamic reticular nucleus; M₄ receptors in the striatum, on glutamatergic afferents and GABAergic direct pathway medium spiny neurons; and M₅ receptors on dopaminergic afferents in the striatum. We consider mechanistic overlap with clozapine, and the evidence that 5-HT_1A receptor partial agonist actions and 5-HT₇ receptor modulation may contribute to xanomeline's broader profile. We propose that combining muscarinic actions with activity at 5-HT receptors may enhance efficacy by restoring disrupted circuits and networks relevant to the full spectrum of symptoms, while reducing dopamine-mediated and metabolic side effects. In conclusion, muscarinic modulation is a promising direction not only for schizophrenia but potentially trans-diagnostically in psychiatry.