Emerging non-D₂ receptor-based therapies for schizophrenia: a focus on muscarinic and glutamatergic pathways

Schizophrenia remains a highly disabling neuropsychiatric disorder, particularly due to the paucity of effective therapeutic interventions for negative symptoms and cognitive deficits. For more than seven decades, antipsychotic drug development has been overwhelmingly centered on dopamine D₂ receptor antagonism. A paradigm shift occurred in 2024 with the FDA approval of KarXT, a first-in-class muscarinic acetylcholine receptor agonist selectively targeting M₁ and M₄ subtypes, marking the first non-D₂ receptor-based antipsychotic approved in over 70 years. This review provides a systematic evaluation of emerging non-D₂ receptor-based therapeutic strategies for schizophrenia, with particular emphasis on the muscarinic cholinergic pathway (exemplified by KarXT) and the glutamatergic pathway (represented by GlyT1 inhibitors). Phase III clinical trial data demonstrate that KarXT significantly improves both positive and negative symptom domains, exhibits favorable metabolic safety relative to conventional antipsychotics, and shows no evidence of clinically meaningful weight gain or glucose dysregulation. Preliminary evidence from exploratory subgroup analyses suggests potential cognitive benefits in patients with baseline cognitive impairment, but these findings require prospective validation. Long-term safety data remain limited. In contrast, clinical trial outcomes for glutamatergic agents, including GlyT1 inhibitors, have been heterogeneous and inconsistent, leaving the therapeutic viability of this pathway uncertain. Collectively, muscarinic agonism constitutes the first clinically validated non-D₂ receptor-based mechanism in schizophrenia treatment. Advancing precision psychiatry will require rigorous head-to-head comparative trials and biomarker-informed patient stratification to extend therapeutic benefits beyond psychosis control to functional and cognitive recovery.