Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia

N Engl J Med. 2021 Feb 25;384(8):717-726. doi: 10.1056/NEJMoa2017015.


Background: 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.

Methods: In this double-blind, phase 2 trial, we 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 Positive and Negative Syndrome Scale (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.

Results: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups.

Conclusions: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; number, NCT03697252.).

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / therapeutic use*
  • Benzilates / adverse effects
  • Benzilates / therapeutic use*
  • Cholinergic Antagonists / adverse effects
  • Cholinergic Antagonists / therapeutic use*
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Humans
  • Least-Squares Analysis
  • Male
  • Middle Aged
  • Muscarinic Agonists / adverse effects
  • Muscarinic Agonists / therapeutic use*
  • Nortropanes / adverse effects
  • Nortropanes / therapeutic use*
  • Pyridines / adverse effects
  • Pyridines / therapeutic use*
  • Schizophrenia / drug therapy*
  • Thiadiazoles / adverse effects
  • Thiadiazoles / therapeutic use*


  • Antipsychotic Agents
  • Benzilates
  • Cholinergic Antagonists
  • Drug Combinations
  • Muscarinic Agonists
  • Nortropanes
  • Pyridines
  • Thiadiazoles
  • trospium chloride
  • xanomeline

Associated data