Targeting muscarinic pathways in schizophrenia, is it the next "big thing" in psychiatry?
Figure: trial summary
Antipsychotic drugs are associated with adverse events such as extrapyramidal symptoms, sedation, weight gain, etc that contribute to poor medication adherence and relapses of psychosis. Moreover, 20 to 33% of patients do not have a response to conventional treatment. In the current issue of NEJM, Brannan et al have shown that a novel muscarinic agonist-antagonist combination xanomeline–trospium resulted in a greater decrease in the Positive and Negative Syndrome Scale (PANSS) total score than placebo in schizophrenic patients.
The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor–blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown.
In this double-blind, phase 2 trial, they randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline–trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the PANSS (range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression–Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2.
It was shown that:
- Treatment with xanomeline in combination with trospium was associated with greater decreases in positive and negative symptoms than was placebo over a period of 5 weeks.
- the combination was associated with significant benefits over placebo with respect to the PANSS positive and negative symptom subscores as well as categorical CGI-S scores and the PANSS Marder negative symptom subscore at week 5, but there was no significant between-group difference in the percentage of patients with global illness severity ratings of "normal" or "borderline ill" at week 5.
- Cholinergic or anticholinergic adverse events were more frequent in the xanomeline–trospium group than in the placebo group. However, the discontinuation rates were similar to placebo arm.
"Treatment with xanomeline–trospium resulted in cholinergic and anticholinergic adverse events but was not associated with a higher incidence of extrapyramidal symptoms or weight gain than placebo. Longer and larger trials are required to establish the efficacy and safety of xanomeline–trospium in the treatment of schizophrenia", concluded the authors.
Source: NEJM: N Engl J Med 2021; 384:717-726 DOI: 10.1056/NEJMoa2017015
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