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毒蕈碱型胆碱能受体激动剂和外周拮抗剂治疗精神分裂症
Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia


Stephen K. Brannan ... 其他 • 2021.02.25
相关阅读
• 精神分裂症 • 一种治疗精神分裂症的非D2受体结合药物

摘要


背景

毒蕈碱受体激动剂占诺美林(xanomeline)具有抗精神病特性,并且不具有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效应。占诺美林联合曲司氯铵治疗精神分裂症患者的疗效和安全性尚不明确。

 

方法

在这项双盲、2期试验中,我们以1∶1的比例将精神分裂症患者随机分组,两组分别接受为期5周的每日2次占诺美林-曲司氯铵(剂量逐渐增加,最大剂量为每次125 mg占诺美林和30 mg曲司氯铵)或安慰剂治疗。主要终点是阳性和阴性症状量表(Positive and Negative Syndrome Scale,PANSS;评分范围为30~210分,评分较高表示精神分裂症症状较严重)总分从基线至第5周的变化。次要终点包括PANSS阳性症状子评分的变化、临床总体印象-严重程度(Clinical Global Impression-Severity,CGI-S)量表评分(评分范围为1~7分,评分较高表示疾病较严重)、PANSS阴性症状子评分的变化、PANSS Marder阴性症状子评分的变化以及根据CGI-S为1分或2分判定的有应答患者百分比。

 

结果

共计182例患者被纳入研究,90例被分配接受占诺美林-曲司氯铵治疗,92例被分配接受安慰剂治疗。在占诺美林-曲司氯铵组和安慰剂组中,基线时的PANSS总分分别为97.7分和96.6分。在占诺美林-曲司氯铵组和安慰剂组中,从基线至第5周的变化分别为-17.4分和-5.9分(最小二乘均值差异,-11.6分;95%置信区间[CI],-16.1~-7.1;P<0.001)。除了有CGI-S应答的患者百分比之外,占诺美林-曲司氯铵组的其他次要终点结果均显著优于安慰剂组。占诺美林-曲司氯铵组最常见的不良事件包括便秘、恶心、口干、消化不良和呕吐。两组中嗜睡、体重增加、不安和锥体外系症状的发生率相似。

 

结论

在此项为期5周的试验中,占诺美林-曲司氯铵组的PANSS总分降幅超过安慰剂组,但伴发了胆碱能和抗胆碱能不良事件。我们需要开展规模更大、持续时间更长的试验,从而确定占诺美林-曲司氯铵对精神分裂症患者的疗效和安全性(由Karuna Therapeutics和维康基金会[Wellcome Trust]资助,在ClinicalTrials.gov注册号为NCT03697252)。





作者信息

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.
From Karuna Therapeutics, Boston (S.K.B., S.S., A.C.M., S.M.P.); Columbia University Vagelos College of Physicians and Surgeons, New York (J.A.L.); and Indiana University School of Medicine, Indianapolis (A.B.). Address reprint requests to Dr. Paul at Karuna Therapeutics, 33 Arch St., Suite 3110, Boston, MA 02110, or at steve@karunatx.com.

 

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