A new drug combination appears to significantly reduce symptoms of schizophrenia compared with placebo, according to the results of a phase 2 trial published this week in the New England Journal of Medicine.
The drugs are xanomeline, which has shown promise for Alzheimer’s disease, and trospium chloride, which is approved for overactive bladder and has been shown to reduce some of the gastrointestinal side effects of xanomeline.
Steven K. Brennan, M.D., chief medical officer of Karuna Pharmaceuticals, and colleagues randomly assigned 90 adults aged 18 to 60 with schizophrenia to receive twice-daily xanomeline-trospium and 92 patients to receive placebo for five weeks. For inclusion in the trial, patients were required to have a baseline Positive and Negative Syndrome Scale (PANSS) total score of 80 or more, with a score of at least 5 on one positive symptom item or at least 4 on two positive symptom items. (Positive symptoms refer to delusions, hallucinations, and other acute symptoms of psychosis; negative symptoms refer to symptoms such as social and emotional withdrawal.)
The study was funded and sponsored by Karuna Pharmaceuticals, which is investigating the drug combination.
The primary end point was the change from baseline to week 5 in the total score on the PANSS. Secondary endpoints included specific scores on the PANSS and scores on the Clinical Global Impression–Severity (CGI-S) scale.
The change in the PANSS total score from baseline to week 5 was significantly better in the xanomeline-trospium group: Scores dropped 17.4 points in the group receiving the drug combination versus 5.9 points in the placebo group. The results for the secondary end points, including PANSS positive and negative symptom subscores as well as CGI-S scores, were also significantly better in the xanomeline-trospium group than in the placebo group.
The most common adverse events associated with the drug combination were constipation, nausea, dry mouth, dyspepsia, and vomiting. None of these adverse events resulted in the participants’ discontinuation of xanomeline-trospium, and all of the adverse events were rated by site investigators as mild or moderate in severity.
William Carpenter, M.D., editor of Schizophrenia Bulletin and chair of the DSM-5 Task Force on Psychotic Disorders, told Psychiatric News that the results are potentially important because xanomeline-trospium targets different brain receptors than most other schizophrenia medications. Xanomeline acts on the cholinergic system, which regulates involuntary actions of the body such as muscle contraction and the dilation of blood vessels, but also influences memory and attention.
Carpenter said future research needs to determine whether more adverse events and more serious side effects are seen in larger samples over a longer period and whether the pattern of beneficial effects seen in the trial will also be seen when the drug combination is compared with other antipsychotics. Researchers also need to better pinpoint how xanomeline works in the brain to treat schizophrenia.
“What is exciting at this point is that it is not another ‘me-too’ drug,” Carpenter said.
(Image: iStock/Minerva Studio)
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