Targeting muscarinic receptors for treating schizophrenia

Schizophrenia is a chronic, disabling and potentially fatal psychiatric syndrome characterized by three primary symptom domains: positive, negative, and cognitive symptoms, for which current dopamine D₂ receptor antagonists provide only partial benefit and are limited by significant side effects. Muscarinic acetylcholine receptors (mAChRs), broadly expressed across cortical, striatal, and midbrain circuits, have emerged as promising targets for next-generation therapies. Among these, M₁ and M₄ receptor subtypes play key roles in regulating glutamatergic and dopaminergic transmission. Clinical studies with xanomeline, an orthosteric agonist with functional preference for M₁ and M₄ receptors, provided the first proof that mAChR agonists can reduce psychotic symptoms. Reformulation of xanomeline with trospium chloride, a peripherally-restricted mAChR antagonist, improved its tolerability and allowed confirmation of its efficacy in large Phase 2 and 3 trials. Current and future efforts are now focused on developing more selective orthosteric and allosteric mAChR agonists and more precisely characterizing their therapeutic activity (efficacy and safety) in clinical trials. These advances highlight mAChR pharmacology as a novel and clinically validated strategy that extends beyond dopamine D₂ receptor antagonism to potentially address the full spectrum of schizophrenia symptoms.