A New Approach to Schizophrenia?

Combined treatment with xanomeline—an M1-/M4-selective muscarinic receptor agonist—and trospium—a peripherally restricted muscarinic receptor antagonist—brought about significant decreases in both positive and negative symptoms in acutely psychotic patients with schizophrenia, according to results from a study published in The New England Journal of Medicine.

“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,” explained lead author Stephen K. Brannan, MD, of Karuna Therapeutics, Boston, and fellow authors.

While xanomeline has no dopamine receptor-blocking activity, it has been shown to decrease psychotic symptoms. The dose-dependent cholinergic adverse events it can cause, however, are concerning. Trospium chloride is currently FDA approved for the treatment of overactive bladder, but a previous phase I study demonstrated that adding it to xanomeline may mitigate the incidence of cholinergic adverse events by as much as 50%.

For this randomized, double-blind, placebo-controlled phase II trial, Brannan and colleagues included 182 acutely psychotic inpatients with schizophrenia who were randomized to treatment with xanomeline-trospium (twice daily; increased to a maximum of 125 mg xanomeline/30 mg trospium per dose) or placebo for five weeks.

The primary outcome of the study was change from baseline in the total Positive and Negative Syndrome Scale (PANSS) score (range: 30-210, with higher scores indicating more severe schizophrenic symptoms). Secondary outcomes included changes in PANSS positive and negative symptom and PANSS Marder negative symptom subscores, Clinical Global Impression-Severity (CGI-S) scores (range: 1-7; higher scores indicate greater illness severity), and change in percentage of patients with a response as measured by CGI-S score of 1 or 2.

Significant changes from baseline PANSS total scores were seen in the group treated with xanomeline-trospium compared with placebo (−17.4 versus −5.9 points, respectively; least-squares mean difference: −11.6 points; 95% CI −16.1 to −7.1; P ˂ 0.001).

Change from baseline to week five of the study in PANSS positive symptoms score was greater in patients treated with xanomeline-trospium compared with placebo (−5.6 versus −2.4 points, respectively; least-squares mean difference; −3.2 points; 95% CI −4.8 to −17; P ˂ 0.001). Change from baseline in the PANSS negative symptom subscore was also greater in patients treated with xanomeline-trospium (−3.2 versus −0.9 points; least-squares mean difference: −2.3 points; 95% CI −3.5 to −1.1; P ˂ 0.001), as were Marder negative symptom subscores (−3.9 versus −1.3; least squares mean difference; −2.5 points; 95% CI −3.9 to −1.2; P ˂ 0.001).

Researchers found no significant differences, however, in the percentage of responses to treatment, as measured by CGI-S scores of 1 (normal) or 2 (borderline ill).

Twenty percent of patients in the xanomeline-trospium group discontinued treatment, compared with 21% in the placebo group, but adverse events were more common in those treated with the combination therapy (54% and 43%, respectively); the most common included constipation (17%), nausea (17%), dry mouth (9%), dyspepsia (9%), and vomiting (9%). None of these led to treatment discontinuation. The incidence of somnolence, weight gain, restlessness, and extrapyramidal symptoms was similar between groups.

The incidence of nausea, vomiting, and dry mouth in patients treated with xanomeline-trospium was highest at the beginning of the study and began soon after treatment initiation, but had decreased by the end of the study (nausea: 11% to 3%, respectively; vomiting: 6% to 1%; and dry mouth: 7% to 1%).

No patients had syncope, and changes in blood pressure and corrected QT intervals were similar between the groups, but resting heart rate increased more in those treated with xanomeline-trospium compared with placebo.

“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. 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 Brannan et al, calling for longer and larger clinical trials to assess the safety of this treatment.

Limitations of the study include its short duration, the use of inpatients, small placebo response, and the preponderance of Black patients (74% in treatment group, 76% in placebo).

1. In a five-week, phase II trial, acutely psychotic patients with schizophrenia who were treated with a combination of xanomeline and trospium saw greater decreases in the PANSS total score compared with placebo.

2. Cholinergic or anticholinergic adverse events were more frequent in the xanomeline–trospium group than in the placebo group.

Liz Meszaros, Contributing Writer, BreakingMED™

Cat ID: 146

Topic ID: 87,146,730,192,146,57,921,925