Mifepristone Plasma Level and Glucocorticoid Receptor Antagonism Associated With Response in Patients With Psychotic Depression.
Mifepristone Plasma Level and Glucocorticoid Receptor Antagonism Associated With Response in Patients With Psychotic Depression.
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DOI：
10.1097/jcp.0000000000000744
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发表时间：
2017-10
影响因子：
2.9
通讯作者：
Schatzberg A
中科院分区：
文献类型：
--
作者：
Block T;Petrides G;Kushner H;Kalin N;Belanoff J;Schatzberg A
补充数字内容可在文本中找到。精神抑郁症没有食品和药物管理局批准的治疗方法。患者表现出下丘脑-垂体-肾上腺轴的显著失调，提供了生物靶向治疗的机会。本研究的目的是探讨米非司酮短期（7天）糖皮质激素受体拮抗剂治疗精神病性抑郁症的临床和生物学效应以及米非司酮血浆浓度的作用。这项双盲、随机研究在美国34个临床研究中心进行，纳入了诊断为精神疾病诊断和统计手册第四版、重度抑郁症、重度、具有精神病特征的患者。在为期56天的试验的第1天至第7天，患者接受每日、观察、门诊口服研究药物（米非司酮1200 mg或安慰剂），然后在第8天至第7天接受美国食品和药物管理局批准的单一抗抑郁药治疗。56。在第0、7、14、28、42和56天使用以下量表：简明精神病评定量表（BPRS）、BPRS阳性症状子量表、汉密尔顿抑郁评定量表和哥伦比亚自杀严重程度评定量表。主要终点是一项分类分析，评估第7天和第56天BPRS阳性症状子量表评分较基线降低50%或以上的患者比例，证明早期和持久的缓解。在第0、7、28和56天测量皮质醇和促肾上腺皮质激素。在第0天和第7天评估米非司酮血浆水平。一项中期分析表明，主要疗效终点不太可能达到，研究提前停止，计划招募的450名患者中有292名。虽然主要终点没有达到，但在预先设定的次要分析中，与从第28天开始接受安慰剂的患者相比，米非司酮血浆水平达到1637 ng/mL或更高（先验定义并称为高血浆水平; 66.7%的患者）的患者表现出精神病症状的统计学显著减少。该组在抑郁改善的汉密尔顿评定量表上也显示出非显著的数字优势。与安慰剂组相比，低剂量米非司酮组（<1637 ng/mL）没有观察到显著改善。两组之间的哥伦比亚自杀严重程度评定量表自杀倾向评分无显著差异。米非司酮1200 mg/d，连续7天是安全的，耐受性良好，使大多数治疗患者达到先验定义的治疗血浆水平1637 ng/mL，米非司酮水平与生物学效应和临床获益相关。
Supplemental digital content is available in the text. Psychotic depression has no Food and Drug Administration–approved treatment. Patients demonstrate significant dysregulation of the hypothalamic-pituitary-adrenal axis providing a biologically targeted treatment opportunity. The purpose of this study was to explore the clinical and biological effects of short-duration (7-day) glucocorticoid receptor antagonism with mifepristone and the role of mifepristone plasma levels in patients with psychotic depression. This double-blind, randomized study took place at 34 US clinical research centers and included patients with a diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive disorder, severe, with psychotic features. Patients underwent daily, observed, in-clinic administration of oral study drug (mifepristone 1200 mg or placebo) for days 1 to 7 of the 56-day trial, followed by treatment with a single Food and Drug Administration–approved antidepressant on days 8 to 56. The following scales were administered on days 0, 7, 14, 28, 42, and 56: Brief Psychiatric Rating Scale (BPRS), BPRS Positive Symptom Subscale, Hamilton Rating Scale for Depression, and Columbia-Suicide Severity Rating Scale. The primary end point was a categorical analysis evaluating the proportion of patients with 50% or greater reduction from baseline in BPRS Positive Symptom Subscale score on both days 7 and 56, demonstrating early and durable response. Cortisol and adrenocorticotropic hormone were measured on days 0, 7, 28, and 56. Mifepristone plasma levels were assessed on days 0 and 7. An interim analysis indicated that the primary efficacy end point was unlikely to be met, and the study was stopped early with 292 of the planned 450 patients enrolled. Although the primary end point was not met, in a secondary prespecified analysis, patients who attained a mifepristone plasma level of 1637 ng/mL or greater (defined a priori and termed the high plasma level; 66.7% of patients) demonstrated statistically significant reductions in psychotic symptoms compared with patients who received placebo starting on day 28. This group also showed nonsignificant, numeric superiority on Hamilton Rating Scale for Depression improvement. No significant improvements were observed in the low-mifepristone group (<1637 ng/mL) versus the placebo group. There were no significant differences in Columbia-Suicide Severity Rating Scale suicidality ratings between groups. Mifepristone 1200 mg daily for 7 days was safe and well tolerated, allowing most treated patients to achieve the a priori defined therapeutic plasma level of 1637 ng/mL, the mifepristone level associated with biological effect and clinical benefit.