Results From 2 Randomized, Double-Blind, Placebo-Controlled Studies of the Novel NK1 Receptor Antagonist Casopitant in Patients With Major Depressive Disorder
Results From 2 Randomized, Double-Blind, Placebo-Controlled Studies of the Novel NK1 Receptor Antagonist Casopitant in Patients With Major Depressive Disorder
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DOI：
10.1097/jcp.0b013e31823608ca
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发表时间：
2011-12-01
影响因子：
2.9
通讯作者：
Fernandes, Sofia
中科院分区：
文献类型：
--
作者：
Ratti, Emiliangelo;Bellew, Kevin;Fernandes, Sofia
神经激肽（NK）受体拮抗剂治疗抑郁症的临床研究结果喜忧参半，III期研究未能实现II期研究中证明的早期承诺。在抑郁症门诊患者中进行的2项随机、安慰剂对照、双盲、II期试验中研究了Casopitant（一种可实现几乎完全受体结合的选择性NK 1拮抗剂），以检验实现抗抑郁疗效需要几乎完全NK 1受体结合的假设。研究092使用交互式语音应答系统招募基线汉密尔顿抑郁（17项，HAMD 17）总评分高于24分的抑郁患者，这些患者被随机分配至固定剂量的卡索匹坦30 mg/d、80 mg/d或安慰剂组，持续8周（n = 356）。研究096要求卡罗尔抑郁量表修订的自我评估评分高于24分，以随机分配至卡索匹坦120 mg/d、帕罗西汀30 mg/d（均通过强制滴定达到）或安慰剂组，持续8周（n = 362）。在研究092中，与安慰剂相比，卡索匹坦80 mg（而非30 mg）在主要结局指标方面实现了统计学显著性改善，第8周末次观察值较基线HAMD 17的结转变化（差异=-2. 7; 95%置信区间，-5. 1至-0. 4，P = 0. 023）。在研究096中，在HAMD 17终点时，卡索匹坦或帕罗西汀均未与安慰剂实现统计学分离（卡索匹坦差异= -1.7; 95% CI，-3.8至0.4，P = 0.282）。大多数患者对卡索匹坦和帕罗西汀的耐受性良好。这些研究表明，具有几乎完全受体占用的NK 1拮抗剂可能有效治疗抑郁症。
Clinical study results for neurokinin (NK) receptor antagonists in the treatment of depression have been mixed, with Phase III studies failing to fulfill the early promise demonstrated in Phase II studies. Casopitant, a selective NK1 antagonist that achieves nearly complete receptor occupancy was studied in 2 randomized, placebo-controlled, double-blind, Phase II trials in depressed outpatients to test the hypothesis that nearly complete NK1 receptor occupancy is required to achieve antidepressant efficacy. Study 092 used an interactive voice response system to recruit depressed patients with baseline Hamilton Depression (17-item, HAMD17) total scores higher than 24 who were randomized to fixed-dose casopitant 30 mg/d, 80 mg/d, or placebo for 8 weeks (n = 356). Study 096 required Carroll Depression Scale-Revised self-assessment scores of higher than 24 for randomization to casopitant 120 mg/d, paroxetine 30 mg/d (both reached via forced titration), or placebo for 8 weeks (n = 362). In study 092, casopitant 80 mg but not 30 mg achieved statistically significant improvement versus placebo on the primary outcome measure, week 8 last observation carried forward change from baseline HAMD17 (difference = -2.7; 95% confidence interval, -5.1 to -0.4, P = 0.023). In study 096, neither casopitant nor paroxetine achieved statistical separation from placebo at end point on HAMD17 (casopitant difference = -1.7; 95% CI, -3.8 to 0.4, P = 0.282). Casopitant and paroxetine were generally well tolerated in most patients. These studies suggest that NK1 antagonists that have nearly complete receptor occupancy may be effective in the treatment of depression.