Medication and psychotherapy treatments for posttraumatic stress disorder (PTSD) provide insufficient benefit for many patients. Substantial preclinical and clinical data indicate abnormalities in the hypothalamic-pituitary-adrenal axis, including signaling by corticotropin-releasing factor, in the pathophysiology of PTSD. We conducted a double-blind, placebo-controlled, randomized, fixed-dose clinical trial evaluating the efficacy of GSK561679, a corticotropin-releasing factor receptor 1 (CRF receptor) antagonist in adult women with PTSD. The trial randomized 128 participants, of whom 96 completed the 6-week treatment period. In both the intent-to-treat and completer samples, GSK561679 failed to show superiority over placebo on the primary outcome of change in Clinician-Administered PTSD Scale total score. Adverse event frequencies did not significantly differ between GSK561679- and placebo-treated subjects. Exploration of the CRF receptor single nucleotide polymorphism rs110402 found that response to GSK561679 and placebo did not significantly differ by genotype alone. However, subjects who had experienced a moderate or severe history of childhood abuse and who were also GG homozygotes for rs110402 showed significant improvement after treatment with GSK561679 ( = 6) but not with placebo ( = 7) on the PTSD Symptom Scale–Self-Report. The results of this trial, the first evaluating a CRF receptor antagonist for the treatment of PTSD, combined with other negative trials of CRF receptor antagonists for major depressive disorder, generalized anxiety disorder, and social anxiety disorder, suggest that CRF receptor antagonists lack efficacy as monotherapy agents for these conditions.

中文翻译：

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促肾上腺皮质激素释放因子受体 1 拮抗剂对患有创伤后应激障碍的女性无效


创伤后应激障碍（PTSD）的药物和心理治疗对许多患者来说并没有带来足够的益处。大量临床前和临床数据表明，在 PTSD 的病理生理学中，下丘脑-垂体-肾上腺轴存在异常，包括促肾上腺皮质激素释放因子的信号传导。我们进行了一项双盲、安慰剂对照、随机、固定剂量临床试验，评估 GSK561679（一种促肾上腺皮质激素释放因子受体 1（CRF 受体）拮抗剂）对患有 PTSD 的成年女性的疗效。该试验随机招募了 128 名参与者，其中 96 人完成了 6 周的治疗期。在意向治疗样本和完成样本中，GSK561679 在临床医生管理的 PTSD 量表总分变化的主要结果方面未能表现出优于安慰剂的优势。 GSK561679 和安慰剂治疗受试者之间的不良事件频率没有显着差异。对 CRF 受体单核苷酸多态性 rs110402 的探索发现，仅因基因型不同，对 GSK561679 和安慰剂的反应没有显着差异。然而，经历过中度或重度童年虐待史且同时也是 rs110402 GG 纯合子的受试者在接受 GSK561679 ( = 6) 治疗后，在 PTSD 症状量表 - 自我报告上表现出显着改善，但安慰剂 ( = 7) 没有显着改善。这项试验是首次评估 CRF 受体拮抗剂治疗 PTSD 的效果，结合 CRF 受体拮抗剂治疗重度抑郁症、广泛性焦虑症和社交焦虑症的其他阴性试验，结果表明 CRF 受体拮抗剂缺乏疗效，因为针对这些病症的单一疗法。