Review of Next-Generation Non-Dopaminergic Antipsychotic Agents Targeting Central Muscarinic Receptors

Review Article

Abstract

Schizophrenia treatment is mainly hindered by exclusive therapeutic dependence on postsynaptic dopamine receptor blockade. While first- and second-generation antipsychotics show measurable efficacy against acute positive symptoms, their therapeutic impact on negative symptoms and cognitive deficits remains profoundly limited. Their adverse effects include metabolic syndromes, extrapyramidal motor dysfunction, hyperprolactinemia, and tardive dyskinesia. The clinical approval of xanomeline-trospium indicates the first novel pharmacological mechanism for schizophrenia in over seven decades. Central muscarinic acetylcholine receptor subtypes, predominantly  and , modulate frontostriatal and mesolimbic circuitry without direct antagonism of postsynaptic dopamine  receptors. Agonism of striatal  receptors mobilize postsynaptic 2-arachidonoylglycerol synthesis, which acts via retrograde presynaptic cannabinoid  receptor signaling to attenuate hyperactive mesolimbic dopamine release. Cortical and hippocampal  receptor activation potentiates N-methyl-D-aspartate receptor conductance, ameliorating prefrontal microcircuit hypofunction and supporting cognitive processing. Co-formulation of the centrally active, non-selective  preferring agonist xanomeline with trospium chloride, a quaternary ammonium peripheral anticholinergic that does not cross the blood-brain barrier, mitigates dose-limiting peripheral cholinergic adverse effects. Pivotal Phase 2 and Phase 3 trials have confirmed significant reductions in positive and negative symptoms alongside favorable metabolic, motor, and prolactin profiles. Translation into real-world clinical practice necessitates close attention to transient autonomic alterations, dosing schedules, somatic comorbidities, and global access paradigms. Muscarinic receptor therapeutics introduce a vital non-dopaminergic paradigm shift, repositioning neurochemical balancing across cortico-striato-thalamic circuits