Targeting muscarinic receptors in schizophrenia treatment: Novel antipsychotic xanomeline/trospium chloride

Abstract

This minireview explores the role of acetylcholine and muscarinic receptors in the pathophysiology of schizophrenia and summarizes the latest data on xanomeline/trospium chloride, a novel antipsychotic approved by the United States Food and Drug Administration in September 2024. Evidence suggests that cholinergic dysfunction, particularly an imbalance in the expression of the M1 and M4 muscarinic receptors, may contribute to the pathophysiology and symptoms of schizophrenia. Xanomeline/trospium chloride combines xanomeline, an M1 and M4 receptor agonist, with trospium chloride, a non-selective peripheral muscarinic receptor antagonist that reduces peripheral cholinergic side effects. Clinical trials have demonstrated significant reductions in the positive and negative symptoms of schizophrenia, with improvements in Positive and Negative Syndrome Scale scores observed as early as two weeks. A post-hoc analysis of one trial revealed cognitive improvements in patients with baseline cognitive impairment. This medication was generally well-tolerated, with mild-to-moderate gastrointestinal symptoms being the most common adverse events. While these results are promising, further research is needed to better understand its effectiveness and safety in real-world clinical practice, and to define its optimal role in managing this complex psychiatric disorder.

Keywords: Antipsychotic; Muscarinic receptors; Review; Schizophrenia; Trospium chloride; Xanomeline.