Antidepressant augmentation with metyrapone for treatment-resistant depression (the ADD study): a double-blind, randomised, placebo-controlled trial
Antidepressant augmentation with metyrapone for treatment-resistant depression (the ADD study): a double-blind, randomised, placebo-controlled trial
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DOI：
10.1016/s2215-0366(15)00436-8
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发表时间：
2016-02-01
影响因子：
64.3
通讯作者：
Watson, Stuart
中科院分区：
文献类型：
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作者：
McAllister-Williams, R. Hamish;Anderson, Ian M.;Watson, Stuart
背景许多重性抑郁症患者患有难治性抑郁症，定义为对连续两个疗程的抗抑郁药没有足够的反应。一些证据表明，抗糖皮质激素增强抗抑郁药可能是有效的抑郁症患者。我们的目的是测试的概念证明的甲吡酮的增强在临床相关人群的难治性depression.Methods的患者中的α-肾上腺素能抗抑郁药的双盲，随机，安慰剂对照试验招募患者从七个英国国家卫生服务（NHS）的心理健康信托从三个地区（英格兰东北部，英格兰西北部，和利兹和布拉德福德地区）。符合条件的患者年龄为18-65岁，患有难治性抑郁症（汉密尔顿抑郁评定量表17项评分>= 18，马萨诸塞州综合医院难治性抑郁分期评分为2-10），并接受单药或联合抗抑郁治疗（包括多巴胺能药物）。患者通过一个集中的网络系统随机分配（1：1）到甲吡酮（500毫克，每日两次）或安慰剂，除了他们现有的抗抑郁药方案，为期21天。采用2或4个区组大小进行排列区组随机化，按中心和初级或二级护理环境分层。主要结局是随机化后5周蒙哥马利-艾斯伯格抑郁量表（MADRS）评分的改善，在第5周完成MADRS评估的所有随机分配患者的改良意向治疗人群中进行分析。该研究具有国际标准随机对照试验编号（ISRCTN 45338259）并在欧盟临床试验登记处注册，编号2009-015165- 31。结果2011年2月8日至2012年12月10日期间，招募并随机分配了165名患者（甲吡酮组83例，安慰剂组82例），其中143例（87%）完成了主要结局评估（甲吡酮组69例[83%]，安慰剂组74例[90%]）。在5周时，MADRS评分在两组之间没有显著差异（21。甲吡酮组7分[95%CI 19.2-24.4] vs安慰剂组22.6分[20.1-24.8];校正的平均差异为-0.51分[95%CI-3.48至2.46]; p=0.74）。甲吡酮组83名患者中有4名（5%）和安慰剂组82名患者中有6名（7%）报告了12起严重不良事件，其中没有一起与研究治疗有关。甲吡酮组58例（70%）患者发生134起不良事件，而安慰剂组45例（55%）患者发生95起事件，其中甲吡酮组有11例（8%）事件，在安慰剂组中，由主要研究者在发生时判断可能与研究药物有关。抗抑郁药在NHS内具有广泛代表性的难治性抑郁症患者人群中无效，因此目前在常规临床实践中不是难治性抑郁症患者的选择。需要进一步的研究来澄清这种增强是否可能有益于可证实的下丘脑-垂体-肾上腺轴异常的亚群。
Background Many patients with major depressive disorder have treatment-resistant depression, defined as no adequate response to two consecutive courses of antidepressants. Some evidence suggests that antiglucocorticoid augmentation of antidepressants might be efficacious in patients with major depressive disorder. We aimed to test the proof of concept of metyrapone for the augmentation of serotonergic antidepressants in the clinically relevant population of patients with treatment-resistant depression.Methods This double-blind, randomised, placebo-controlled trial recruited patients from seven UK National Health Service (NHS) Mental Health Trusts from three areas (northeast England, northwest England, and the Leeds and Bradford area). Eligible patients were aged 18-65 years with treatment-resistant depression (Hamilton Depression Rating Scale 17-item score of >= 18 and a Massachusetts General Hospital Treatment-Resistant Depression staging score of 2-10) and taking a single-agent or combination antidepressant treatment that included a serotonergic drug. Patients were randomly assigned (1: 1) through a centralised web-based system to metyrapone (500 mg twice daily) or placebo, in addition to their existing antidepressant regimen, for 21 days. Permuted block randomisation was done with a block size of two or four, stratified by centre and primary or secondary care setting. The primary outcome was improvement in Montgomery-Asberg Depression Rating Scale (MADRS) score 5 weeks after randomisation, analysed in the modified intention-to-treat population of all randomly assigned patients that completed the MADRS assessment at week 5. The study has an International Standard Randomised Controlled Trial Number (ISRCTN45338259) and is registered with the EU Clinical Trial register, number 2009-015165-31.Findings Between Feb 8, 2011, and Dec 10, 2012, 165 patients were recruited and randomly assigned (83 to metyrapone and 82 to placebo), with 143 (87%) completing the primary outcome assessment (69 [83%] in the metyrapone and 74 [90%] in the placebo group). At 5 weeks, MADRS score did not significantly differ between groups (21 . 7 points [95% CI 19.2-24.4] in the metyrapone group vs 22.6 points [20.1-24.8] in the placebo group; adjusted mean difference of -0.51 points [95% CI -3.48 to 2.46]; p=0.74). 12 serious adverse events were reported in four (5%) of 83 patients in the metyrapone group and six (7%) of 82 patients in the placebo group, none of which were related to study treatment. 134 adverse events occurred in 58 (70%) patients in the metyrapone group compared with 95 events in 45 (55%) patients in the placebo group, of which 11 (8%) events in the metyrapone group and four (4%) in the placebo group were judged by principle investigators at the time of occurrence to be probably related to the study drug.Interpretation Metyrapone augmentation of antidepressants is not efficacious in a broadly representative population of patients with treatment-resistant depression within the NHS and therefore is not an option for patients with treatment-resistant depression in routine clinical practice at this time. Further research is needed to clarify if such augmentation might benefit subpopulations with demonstrable hypothalamic-pituitary-adrenal axis abnormalities.