Muscarinic drug shows efficacy in schizophrenia but much is left to be discovered

Affecting 1% of the global population and among the top-20 causes of disability worldwide, schizophrenia consists of positive (hallucinations and delusions), negative (blunted affect and social withdrawal), and cognitive (memory and learning problems) symptoms. 1 Jauhar S Johnstone M McKenna PJ Schizophrenia. Lancet. 2022; 399: 473-486 Summary Full Text Full Text PDF PubMed Scopus (245) Google Scholar Despite advances in understanding the neurobiology of schizophrenia, all current antipsychotics act as antagonists or partial agonists to the dopamine D2 receptors. However, these drugs have far from optimal efficacy (about one in three patients are resistant to treatment), have limited effects on negative and cognitive symptoms, and are associated with disabling side-effects, such as sedation, extrapyramidal and metabolic symptoms, and sexual and endocrinological problems. 1 Jauhar S Johnstone M McKenna PJ Schizophrenia. Lancet. 2022; 399: 473-486 Summary Full Text Full Text PDF PubMed Scopus (245) Google Scholar Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trialIn the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D2 dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia. Full-Text PDF