Xanomeline-Trospium: A Novel Therapeutic for the Treatment of Schizophrenia

This review describes a novel combination muscarinic agonist and antagonist, xanomeline-trospium, which was recently approved by the Food and Drug Administration (FDA) for schizophrenia. Efficacy and safety evidence from phase II and III clinical trials are reviewed. The MEDLINE and EMBASE databases were searched in 2024; terms included "xanomeline trospium" OR "xanomelinetrospium" OR "KarXT" OR "Cobenfy" AND "schizophrenia." The search was repeated in January 2025. gov was used to review ongoing or unpublished studies. Human subject studies of xanomeline-trospium were included. In phase III trials, xanomeline-trospium was superior to placebo for acute exacerbation of schizophrenia. EMERGENT-2 and EMERGENT-3 found patients improved by 9.6 and 8.4 points on the Positive and Negative Symptom Scale (PANSS), respectively, compared with placebo (95% confidence interval -13.9 to -5.2, P < 0.001 and -12.4 to -4.3, P < 0.001). Participants in EMERGENT-4, a long-term open-label extension study, who received the intervention in the randomized phases experienced a 9-point decrease in PANSS from the last result.Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:Xanomeline-trospium is a novel antipsychotic that is effective for treatment of schizophrenia and may have a favorable adverse effect profile in comparison with other antipsychotics due to its lack of dopamine receptor antagonism. Efficacy for improvement in negative symptoms and cognitive function in schizophrenia is promising. Xanomeline-trospium shows promising results for treatment of schizophrenia. Further studies with active comparators, larger sample sizes, and more patients with prominent negative symptoms are needed to corroborate efficacy and determine place in therapy.