美国波士顿Karuna Therapeutics公司Steven M. Paul团队研究了毒蕈碱胆碱能受体激动剂和外周拮抗剂治疗精神分裂症的疗效。2021年2月25日，该研究发表在《新英格兰医学杂志》上。

毒蕈碱受体激动剂占诺美林具有抗精神病的特性，无多巴胺受体阻断活性，但会引起胆碱能不良事件。曲司氯铵是一种外周限制性毒蕈碱受体拮抗剂，可降低占诺美林的外周胆碱能作用。占诺美林和曲司氯铵联合治疗精神分裂症的疗效和安全性尚不清楚。

在这项双盲、临床2期试验中，研究组将精神分裂症患者按1：1随机分为两组，每天两次服用占诺美林-曲司氯铵或安慰剂，为期5周。主要终点为从基线检查到第5周阳性和阴性症状量表总分的变化（PANSS；范围：30到210，得分越高表明精神分裂症症状越严重）。次要终点为PANSS阳性症状分、临床总体印象-严重程度（CGI-S）量表得分（范围1-7，得分越高表示病情越严重）、PANSS阴性症状分、PANSS-Marder阴性症状分的变化，以及根据CGI-S评分为1或2的缓解患者所占百分比。

共有182名患者被纳入研究，其中90名患者接受占诺美林-曲司氯铵治疗，92名患者接受安慰剂治疗。占诺美林-曲司氯铵组基线时的PANSS总分为97.7分，安慰剂组为96.6分；从基线检查到第5周，占诺美林-曲司氯铵组的PANSS降低17.4分，安慰剂组则降低5.9分，差异显著。除CGI-S缓解的患者百分比外，占诺美林-曲司氯铵组的次要终点结局均明显优于安慰剂组。占诺美林-曲司氯铵组最常见的不良反应是便秘、恶心、口干、消化不良和呕吐。两组中嗜睡、体重增加、烦躁和锥体外系症状的发生率相似。

总之，在这项为期5周的试验中，占诺美林-曲司氯铵组的PANSS总分下降幅度大于安慰剂组，但与胆碱能和抗胆碱能不良事件有关。

附：英文原文

Title: Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia

Author: Stephen K. Brannan, M.D.,, Sharon Sawchak, R.N.,, Andrew C. Miller, Ph.D.,, Jeffrey A. Lieberman, M.D.,, Steven M. Paul, M.D.,, and Alan Breier, M.D.

Issue&Volume: 2021-02-24

Abstract:

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.

DOI: 10.1056/NEJMoa2017015

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2017015