Cholinergic Agonist and Peripheral Antagonist for Schizophrenia

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Posted by Carla Rothaus

Was the combination oral agent xanomeline–trospium effective in reducing the degree of psychosis in the trial by Brannan et al.? 

Brannan et al. conducted a phase 2 trial that assessed the efficacy and safety of the combination oral agent xanomeline–trospium in patients with acute exacerbations of schizophrenia. Read the NEJM Original Article here.

Clinical Pearls

Q: What is the rationale for using xanomeline to treat schizophrenia?

A: Although antipsychotics that are approved for schizophrenia work primarily by antagonizing D2 dopamine receptors, evidence suggests that the muscarinic cholinergic system is also involved in the pathophysiology of schizophrenia. Xanomeline is an oral muscarinic cholinergic receptor agonist that is devoid of direct effects on dopamine receptors and that preferentially stimulates M1 and M4 muscarinic cholinergic receptors, which have been implicated in the pathophysiology of schizophrenia.

Q: Why was trospium added to xanomeline in the trial by Brannan et al.?

A: Antipsychotic drugs are associated with adverse events such as extrapyramidal symptoms, sedation, weight gain, metabolic disturbances, and hyperprolactinemia that contribute to poor medication adherence and relapses of psychosis. Trospium chloride is an oral pan-muscarinic receptor antagonist that is approved for the treatment of overactive bladder in the United States and the European Union. In a phase 1 trial involving healthy volunteers, the incidence of cholinergic adverse events was approximately 50% lower when trospium was added to xanomeline than when xanomeline alone was used; these findings suggest a potential way to stimulate brain muscarinic receptors with therapeutic antipsychotic doses of xanomeline while limiting these adverse events.


Morning Report Questions

Q: Was the combination oral agent xanomeline–trospium effective in reducing the degree of psychosis in the trial by Brannan et al.?

A: A combination of the muscarinic receptor agonist xanomeline and the anticholinergic agent trospium resulted in greater reductions than placebo in the degree of psychosis according to the scores on several scales. The change in the Positive and Negative Syndrome Scale total score from baseline to week 5 (the primary end point) was –17.4 points in the xanomeline–trospium group and –5.9 points in the placebo group (least-squares mean difference, –11.6 points; 95% confidence interval, –16.1 to –7.1; P<0.001). Because the trial was conducted over a period of only 5 weeks, longer and larger trials are required to establish the efficacy and safety of xanomeline–trospium in the treatment of psychosis. 

Q: Describe some of the adverse events associated with xanomeline–trospium in the trial by Brannan et al.

A: Cholinergic or anticholinergic adverse events were more frequent in the xanomeline–trospium group than in the placebo group; in the xanomeline–trospium group, these adverse events began soon after the initiation of treatment. 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. The most common adverse events in the xanomeline–trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The resting heart rate increased more in the xanomeline–trospium group than in the placebo group. There were no syncopal events, and the incidences of weight gain, somnolence, restlessness, and extrapyramidal symptoms were similar in the two groups. Scores on the scales that measure extrapyramidal features were similar in the two groups.

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