Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia.
Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia.
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DOI：
10.1056/nejmoa2017015
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发表时间：
2021-02-25
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影响因子：
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通讯作者：
Breier A
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作者：
Brannan SK;Sawchak S;Miller AC;Lieberman JA;Paul SM;Breier A
毒蕈碱受体激动剂xanomeline具有抗精神病特性，并且缺乏多巴胺受体阻断活性，但会引起胆碱能不良事件。曲司铵是一种外周限制性毒蕈碱受体拮抗剂，可降低咕诺美林的外周胆碱能作用。合用克诺美林和曲司铵治疗精神分裂症患者的疗效和安全性尚不清楚。在这项双盲、2期试验中，我们将精神分裂症患者以1：1的比例随机分配接受每日两次的xanomeline-曲司铵（增加至每剂量最多125 mg xanomeline和30 mg曲司铵）或安慰剂，持续5周。主要终点是阳性和阴性综合征量表（PANSS;范围：30 - 210，评分越高表明精神分裂症症状越严重）总评分从基线到第5周的变化。次要终点为PANSS阳性症状分项评分的变化、临床疗效总评量表-严重程度（CGI-S）评分（范围1 - 7，评分越高表明疾病严重程度越高）、PANSS阴性症状分项评分的变化、PANSS Marder阴性症状分项评分的变化以及根据CGI-S评分为1或2的缓解患者百分比。共有182名患者入组，其中90名被分配接受克诺美林-曲司铵，92名接受安慰剂。在基线PANSS总评分为97.7，占诺梅林-曲司铵组和96.6，安慰剂组。从基线到第5周的变化，克诺美林-曲司铵组为-17.4分，安慰剂组为-5.9分（最小二乘均值差，-11.6分; 95%置信区间，-16.1至7.1; P<0.001）。除CGI-S应答患者百分比外，克诺美林-曲司铵组的次要终点结果明显优于安慰剂组。克诺美林-曲司铵组最常见的不良反应是便秘、恶心、口干、消化不良和呕吐。嗜睡、体重增加、坐立不安和锥体外系症状的发生率在两组中相似。在一项为期5周的试验中，与安慰剂相比，克诺美林-曲司铵导致PANSS总评分下降幅度更大，但与胆碱能和抗胆碱能不良事件相关。需要更大和更长的试验来确定克诺美林-曲司铵在精神分裂症患者中的疗效和安全性。（由Karuna Therapeutics和Wellcome Trust资助; ClinicalTrials.gov编号，NCT 03697252。
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. 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. 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. 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. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.)