Selective muscarinic receptor agonist shows promising results in schizophrenia

An American pilot study investigating the effects of xanomeline — a selective musarinic type 1 and type 4 (M1 and M4) receptor agonist — on schizophrenia has demonstrated positive therapeutic effects across multiple symptom domains. There is substantial room for improvement in the pharmacological management of schizophrenia across all three domains of symptoms: positive, negative and cognitive symptoms. Older antipsychotic agents are effective at improving positive symptoms, and atypical antipsychotic agents have shown modest efficacy in improving the negative symptoms of schizophrenia; however, the need exists for a therapeutic approach effective across multiple domains of schizophrenia. Recently, interest has centred on agents that exert antipsychotic effects using a mechanism other than dopamine receptor blockade. One such approach uses agonists with selective affinity for acetylcholine muscarinic receptors.  Shekhar et al. conducted a pilot study of xanomeline to assess its effects on schizophrenia. “The major functional roles of muscarinic receptor subtypes have been difficult to separate until recently due to a lack of selective pharmacological tools. However, the roles of muscarinic receptor subtypes and how they relate to potential treatment for schizophrenia are active areas of investigation,” the authors explained. They conducted a 4-week, double-blind, placebo-controlled trial involving 20 patients with schizophrenia. Following a one-week placebo run-in period, 10 subjects were randomly assigned to xanomeline (25 mg t.i.d) and the other 10 subjects were assigned to placebo treatment. The dose of xanomeline was titrated up to 225 mg/day over 6 days. The primary outcome measures were total symptom scores and improvement in scores on the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Results revealed statistically significant differences between xanomeline and placebo groups in PANSS total scores, as well as differences between groups in positive and negative symptom subscales and CGI scores. In the cognitive test battery, subjects in the xanomeline group showed the most prominent improvements in measures of verbal learning and short-term memory function. While no subjects discontinued the study due to adverse events, two subjects in the treatment group and three subjects in the placebo group discontinued due to lack of efficacy. The authors concluded that xanomeline has shown potential benefits across multiple symptom domains of schizophrenia.  “These data suggest that xanomeline may have a unique mode of antipsychotic action and may provide a novel approach to treating schizophrenia,” they surmised.   Reference Shekhar, A. Potter, W. et al. 2008, ‘Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia’ Am J Psychiatry; 165: 1033—1039....