BACKGROUND An oral compound, SEP-363856, that does not act on dopamine D2 receptors but has agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) receptors, may represent a new class of psychotropic agent for the treatment of psychosis in schizophrenia. METHODS We performed a randomized, controlled trial to evaluate the efficacy and safety of SEP-363856 in adults with an acute exacerbation of schizophrenia. The patients were randomly assigned in a 1:1 ratio to receive once-daily treatment with SEP-363856 (50 mg or 75 mg) or placebo for 4 weeks. The primary end point was the change from baseline in the total score on the Positive and Negative Symptom Scale (PANSS; range, 30 to 210; higher scores indicate more severe psychotic symptoms) at week 4. There were eight secondary end points, including the changes from baseline in the scores on the Clinical Global Impressions Severity (CGI-S) scale and the Brief Negative Symptom Scale (BNSS). RESULTS A total of 120 patients were assigned to the SEP-363856 group and 125 to the placebo group. The mean total score on the PANSS at baseline was 101.4 in the SEP-363856 group and 99.7 in the placebo group, and the mean change at week 4 was -17.2 points and -9.7 points, respectively (least-squares mean difference, -7.5 points; 95% confidence interval, -11.9 to -3.0; P = 0.001). The reductions in the CGI-S and BNSS scores at week 4 were generally in the same direction as those for the primary outcome, but the results were not adjusted for multiple comparisons. Adverse events with SEP-363856 included somnolence and gastrointestinal symptoms; one sudden cardiac death occurred in the SEP-363856 group. The incidence of extrapyramidal symptoms and changes in the levels of lipids, glycated hemoglobin, and prolactin were similar in the trial groups. CONCLUSIONS In this 4-week trial involving patients with an acute exacerbation of schizophrenia, SEP-363856, a non-D2-receptor-binding antipsychotic drug, resulted in a greater reduction from baseline in the PANSS total score than placebo. Longer and larger trials are necessary to confirm the effects and side effects of SEP-363856, as well as its efficacy relative to existing drug treatments for patients with schizophrenia. (Funded by Sunovion Pharmaceuticals; ClinicalTrials.gov number, NCT02969382.).

中文翻译：

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一种非D2-受体结合药物，用于治疗精神分裂症。

背景口服化合物SEP-363856不作用于多巴胺D2受体，但对痕量胺相关受体1（TAAR1）和5-羟基色胺1A（5-HT1A）受体具有激动剂活性，可能代表一类新的精神药物，用于治疗精神分裂症的精神病。方法我们进行了一项随机对照试验，以评估SEP-363856在成人精神分裂症急性加重期的疗效和安全性。患者以1：1的比例随机分配，每天接受一次SEP-363856（50 mg或75 mg）或安慰剂治疗4周。主要终点是第4周的阳性和阴性症状量表（PANSS；范围从30到210；较高的分数表示更严重的精神病症状）的总得分与基线相比的变化。有8个次要终点，包括临床总体印象严重程度（CGI-S）量表和简短阴性症状量表（BNSS）的得分相对于基线的变化。结果SEP-363856组共120例患者，安慰剂组125例。SEP-363856组的PANSS基线平均总得分为101.4，安慰剂组为99.7，第4周的平均变化分别为-17.2分和-9.7分（最小二乘均差-7.5）点； 95％置信区间，-11.9至-3.0； P = 0.001）。第4周时CGI-S和BNSS分数的下降通常与主要结果的下降方向相同，但并未对结果进行多次比较调整。SEP-363856的不良事件包括嗜睡和胃肠道症状；SEP-363856组发生了1例心脏猝死。在试验组中锥体外系症状的发生率和脂质，糖化血红蛋白和催乳激素水平的变化相似。结论在这项为期4周的涉及精神分裂症急性加重的患者的试验中，SEP-363856（一种非D2受体结合型抗精神病药）与安慰剂相比，其PANSS总评分较基线水平下降幅度更大。为了确认SEP-363856的作用和副作用，以及相对于现有的精神分裂症患者药物治疗的疗效，需要更长的和更大的试验。（由Sunovion Pharmaceuticals资助； ClinicalTrials.gov编号，NCT02969382。）。与催乳素在试验组中相似。结论在这项为期4周的涉及精神分裂症急性加重的患者的试验中，SEP-363856（一种非D2受体结合型抗精神病药）与安慰剂相比，其PANSS总评分较基线水平下降幅度更大。为了确认SEP-363856的作用和副作用，以及相对于现有的精神分裂症患者药物治疗的疗效，需要更长的和更大的试验。（由Sunovion Pharmaceuticals资助； ClinicalTrials.gov编号，NCT02969382。）。与催乳素在试验组中相似。结论在这项为期4周的涉及精神分裂症急性加重的患者的试验中，SEP-363856（一种非D2受体结合型抗精神病药）与安慰剂相比，其PANSS总评分较基线水平下降幅度更大。为了确认SEP-363856的作用和副作用，以及相对于现有的精神分裂症患者药物治疗的疗效，需要更长的和更大的试验。（由Sunovion Pharmaceuticals资助； ClinicalTrials.gov编号，NCT02969382。）。为了确认SEP-363856的作用和副作用，以及相对于现有的精神分裂症患者药物治疗的疗效，需要更长的和更大的试验。（由Sunovion Pharmaceuticals资助； ClinicalTrials.gov编号，NCT02969382。）。为了确认SEP-363856的作用和副作用，以及相对于现有的精神分裂症患者药物治疗的疗效，需要更长的和更大的试验。（由Sunovion Pharmaceuticals资助； ClinicalTrials.gov编号，NCT02969382。）。