Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment

Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's 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. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia.Graphical AbstractKarXT, a promising medication for schizophrenia, combines xanomeline, an agonist for muscarinic receptors M1 and M4, with trospium, an antimuscarinic agent. Xanomeline can effectively penetrate the blood-brain barrier (BBB), allowing it to target and stimulate muscarinic receptors in the brain, leading to decline or eliminate of positive and negative symptoms as well as cognitive improvement. On the other hand, trospium lacks the ability to cross the BBB and primarily acts as an antimuscarinic agent in peripheral organs, reducing the potential side effects associated with xanomeline. These findings underscore the potential of KarXT as a viable treatment option for schizophrenia, offering symptom relief while minimizing the adverse effects typically associated with xanomeline as a monotherapy.