Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and Schizoaffective disorder
Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and Schizoaffective disorder
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DOI：
10.1176/appi.ajp.161.6.975
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发表时间：
2004-06-01
影响因子：
17.7
通讯作者：
Rein, W
中科院分区：
文献类型：
--
作者：
Meltzer, HY;Arvanitis, L;Rein, W
目的：使用相同方案的四项研究评估了抗精神病药物的四种新型循证靶点的安全性和有效性：神经激肽 (NK3) 拮抗剂 (SR142801)、血清素 2A/2C (5-HT2A/2C) 拮抗剂 (SR46349B)、中枢大麻素 (CB1) 拮抗剂 (SR141716)、 方法：患有精神分裂症或分裂情感障碍的成人 (N=481) 以 3:11 的比例随机分配，接受固定剂量的研究药物、安慰剂或氟哌啶醇，为期 6 周。主要功效变量包括阳性和阴性症状量表总分相对于基线的变化、临床总体印象 (CGI) 的疾病严重程度评分、以及简明精神病评定量表 (BPRS) 的总分和精神病聚类评分。 结果：6 周时，氟哌啶醇治疗组的所有主要功效变量均比安慰剂组有显着改善（终点分析）， 表明研究的有效性。根据阳性和阴性症状量表总分、CGI 疾病严重程度评分和 BPRS 精神病聚类评分，接受 NK3 拮抗剂的组比接受安慰剂的组显示出显着更大的改善。接受5-HT2A/2C拮抗剂组的阳性和阴性症状量表总分和阴性分数的降低显着大于接受安慰剂的组。尽管对 NK3 拮抗剂的反应与血浆水平呈正相关，但 NK3 和 5-HT2A/2C 拮抗剂对精神病理学的改善小于氟哌啶醇。接受 CB1 和 NTS1 拮抗剂的组在任何结果指标上与接受安慰剂的组没有差异。所有研究药物均具有良好的耐受性。结论：本研究中使用的新颖设计允许使用较少数量的接受安慰剂的患者来测试四种新型化合物的功效。 NK3 和 5-HT2A/2C 拮抗剂显示出治疗精神分裂症和分裂情感障碍的功效。研究的局限性无法就 CB1 和 NTS1 拮抗剂治疗精神分裂症的疗效得出明确的结论。似乎有必要进一步研究这两种有前景的非多巴胺能机制来治疗精神分裂症和分裂情感障碍。
Objective: Four studies using identical protocols evaluated the safety and efficacy of four novel, evidence-based targets for antipsychotic agents: a neurokinin (NK3) antagonist (SR142801), a serotonin 2A/2C (5-HT2A/2C) antagonist (SR46349B), a central cannabinoid (CB1) antagonist (SR141716), and a neurotensin (NTS1) antagonist (SR48692).Method: Adults with schizophrenia or schizoaffective disorder (N=481) were randomly assigned in a 3:11 ratio to receive fixed doses of investigational drug, placebo, or haloperidol for 6 weeks. Primary efficacy variables included changes from baseline in total score on the Positive and Negative Syndrome Scale, severity of illness score on the Clinical Global Impression (CGI), and total score and psychosis cluster score on the Brief Psychiatric Rating Scale (BPRS).Results: Significantly greater improvement in all primary efficacy variables was seen in the group receiving haloperidol than in the group receiving placebo at 6 weeks (endpoint analyses), indicating the validity of the study. The group receiving the NK3 antagonist showed significantly greater improvement over baseline than the group receiving placebo as measured by Positive and Negative Syndrome Scale total score, CGI severity of illness score, and BPRS psychosis cluster score. Reductions in the Positive and Negative Syndrome Scale total and negative scores in the group receiving the 5-HT2A/2C antagonist were significantly larger than those in the group receiving placebo. The improvements in psychopathology produced by the NK3 and 5-HT2A/2C antagonists were smaller than those produced by haloperidol, although the response to the NK3 antagonist was positively correlated with plasma levels. The groups receiving the CB1 and NTS1 antagonists did not differ from the group receiving placebo on any outcome measure. All investigational drugs were well tolerated.Conclusions: The novel design used in this study permitted the use of a smaller number of patients receiving placebo to test the efficacy of the four novel compounds. The NK3 and 5-HT2A/2C antagonists showed evidence of efficacy in the treatment of schizophrenia and schizoaffective disorder. Study limitations preclude a definitive conclusion on the efficacy of CB1 and NTS1 antagonists in the treatment of schizophrenia. Further study of these two promising nondopaminergic mechanisms to treat schizophrenia and schizoaffective disorder appears indicated.