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Central muscarinic cholinergic activation promising in schizophrenia

The New England Journal of Medicine
Reuters Health - 24/02/2021 - Combination therapy with xanomeline, a muscarinic-receptor agonist, and trospium, which limits xanomeline's cholinergic effects peripherally, appears to be effective against acute psychosis in people with schizophrenia, researchers have found.

On the 181-point Positive and Negative Symptom Scale, which measures the severity of schizophrenia symptoms, the combo from Karuna Therapeutics, known as KarXT, lowered the mean score of 90 volunteers in a phase-2 trial by 17.4 points.

The decline was 5.9 points among 92 placebo recipients (P<0.001), researchers report in the New England Journal of Medicine. Other scales showed a similar trend.

A statement from the company said that, "Historically, changes as small as five points have supported the approval of current antipsychotics."

The double-blind randomized trial lasted five weeks. Patients on active treatment received twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose).

There were no serious adverse events with the treatment, but dry mouth was nine times more common, constipation five times more common, nausea was four times more common, and dyspepsia and vomiting each seen twice as common in the drug group.

"However, the percentage of patients who discontinued either xanomeline-trospium or placebo was similar in the two groups, and the number of discontinuations due to adverse events that occurred during the treatment period was equal in the two groups," Dr. Stephen Brannan of Karuna Therapeutics, in Boston, and colleagues write.

"The incidences of nausea, vomiting, and dry mouth decreased over the course of the trial, but the incidence of constipation remained constant throughout the trial," they add.

Schizophrenia affects as much as 1% of the United States population and about a third of patients fail to respond to treatment.

"Longer and larger trials are required to establish the efficacy and safety of xanomeline-trospium in the treatment of schizophrenia," the researchers write.

SOURCE: https://bit.ly/37wEgW2 The New England Journal of Medicine, February 25, 2021.

By Reuters Staff

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