Xanomeline-trospium in schizophrenia
- combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent.
- xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4) (1)
- was initially evaluated for the treatment of Alzheimer’s disease and schizophrenia
- however, drug development was stopped due to the severe cholinergic adverse effects
- in the CNS limbic and cortical regions have M1, M4, and dopaminergic receptors, which control cognition and affect (2)
- by targeting M1 and M4 receptors, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms in schizophrenia (1)
- trospium
- is not able to cross BBB, thereby not affecting M1 and M4 receptors
- acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs
Clinical trials investigating xanomeline-tropsium efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo (1).
The most common side effects of this combination include constipation, dry mouth, and nausea (2).
Reference:
- Azargoonjahromi A. Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment. Clin Drug Investig. 2024 Jul;44(7):471-493.
- Singh A. Xanomeline and Trospium: A Potential Fixed Drug Combination (FDC) for Schizophrenia-A Brief Review of Current Data. Innov Clin Neurosci. 2022 Oct-Dec;19(10-12):43-47.