Golier Julia A, Caramanica Kimberly, Michaelides Andreas C, Makotkine Iouri, Schmeidler James, Harvey Philip D, Yehuda Rachel
James J. Peters VA Medical Center, OOMH-526, 130 West Kingsbridge Road, Bronx, NY 10468, United States; Psychiatry Department, Icahn School of Medicine at Mount Sinai, 1428 Madison Ave, New York, NY 10029, United States.
James J. Peters VA Medical Center, OOMH-526, 130 West Kingsbridge Road, Bronx, NY 10468, United States.
Psychoneuroendocrinology. 2016 Feb;64:22-30. doi: 10.1016/j.psyneuen.2015.11.001. Epub 2015 Nov 10.
No pharmacological treatments have been demonstrated to effectively treat chronic multisymptom illness (CMI) in Gulf War veterans (GWV). This study assessed the effect of the glucocorticoid receptor antagonist mifepristone in GWV with CMI. A randomized, double-blind, cross-over trial of mifepristone, with two six-week treatment phases separated by a one-month washout period, was conducted at a Veterans Affairs (VA) hospital between 2008 and 2011. Participants were randomized to receive either 200mg of mifepristone per day or matched placebo first. The primary clinical outcome measure was change in self-reported physical health. Neurocognitive functioning and self-reported measures of depression, PTSD, and fatigue were secondary outcomes. Sixty-five participants enrolled, of whom 36 were randomized and 32 (mean age, 49.1 (7.2) years) completed the study. Physical and mental health status and neurocognitive functioning were poor at baseline. Mifepristone treatment was not associated with improvement in self-reported physical health (p=0.838) or in other self-reported measures of mental health. Mifepristone treatment was significantly associated with improvements in verbal learning (p=0.008, d=0.508), in the absence of improvement in other cognitive measures (working memory (p=0.914), visual learning (p=0.643) and a global composite measure (p=0.937). Baseline morning cortisol levels and lysozyme IC50-DEX, a measure of peripheral glucocorticoid sensitivity, displayed a significant relationship with endpoint verbal learning scores (p=0.012 and p=0.007, respectively). The magnitude of cortisol change during treatment mediated the improvement in verbal learning. This study was negative for the primary and secondary clinical outcomes. However, the data suggest a moderate dose of mifepristone may have circumscribed cognitive-enhancing effects in CMI. Further study is warranted to determine whether and through which mechanisms mifepristone treatment can yield clinically meaningful improvement in cognitive function in CMI or other neuropsychiatric conditions associated with HPA axis dysregulation.
尚无药理学治疗方法被证明能有效治疗海湾战争退伍军人（GWV）的慢性多症状疾病（CMI）。本研究评估了糖皮质激素受体拮抗剂米非司酮对患有CMI的GWV的疗效。2008年至2011年期间，在一家退伍军人事务（VA）医院进行了一项米非司酮的随机、双盲、交叉试验，有两个为期六周的治疗阶段，中间间隔一个月的洗脱期。参与者被随机分为先接受每天200毫克米非司酮或匹配的安慰剂。主要临床结局指标是自我报告的身体健康变化。神经认知功能以及自我报告的抑郁、创伤后应激障碍（PTSD）和疲劳指标为次要结局。65名参与者入组，其中36人被随机分组，32人（平均年龄49.1（7.2）岁）完成了研究。基线时身心健康状况和神经认知功能较差。米非司酮治疗与自我报告的身体健康改善（p = 0.838）或其他自我报告的心理健康指标改善无关。米非司酮治疗与言语学习改善显著相关（p = 0.008，d = 0.508），而其他认知指标（工作记忆（p = 0.914）、视觉学习（p = 0.643）和综合指标（p = 0.937））无改善。基线晨皮质醇水平和外周糖皮质激素敏感性指标溶菌酶IC50 - DEX与终点言语学习分数显示出显著关系（分别为p = 0.012和p = 0.007）。治疗期间皮质醇变化的幅度介导了言语学习的改善。本研究在主要和次要临床结局方面为阴性结果。然而，数据表明中等剂量的米非司酮可能对CMI有一定的认知增强作用。有必要进一步研究以确定米非司酮治疗是否以及通过何种机制能在CMI或其他与下丘脑 - 垂体 - 肾上腺（HPA）轴失调相关的神经精神疾病中产生具有临床意义的认知功能改善。
