Dehydroepiandrosterone (DHEA) as augmentation of standard antidepressants in treatmentresistantdepression: a randomized controlled trial (DHEA-DE)

重度抑郁症（MDD）是世界范围内最紧迫的健康问题之一，多年来一直是所有医学疾病中残疾的五大主要原因之一。大约一半的抑郁症患者对最初的抗抑郁治疗没有反应，定义为“难治性抑郁症（TRD）的第1阶段”。一项系统性综述显示，与MDD相比，TRD与患者健康相关的生活质量较低和医疗费用较高有关。科克伦综述药物干预TRD的结论是，有一个迫切需要新的治疗方法，TRD是安全和有效的。在这方面，脱氢表雄酮（DHEA）是一个有前途的治疗选择。DHEA是一种内源性类固醇激素，主要从肾上腺释放，但它也在大脑内产生，并作为一种神经类固醇。荟萃分析显示，DHEA具有抗抑郁作用，在初步随机对照试验中对MDD和其他内科疾病患者的抑郁症状是安全的。此外，另一项荟萃分析和我们自己的数据表明，抑郁症患者的DHEA水平降低。然而，到目前为止，还没有关于DHEA治疗TRD的验证性试验，因此，本提案的主要目的是研究在标准抗抑郁药物的基础上添加DHEA是否比添加安慰剂在6周以上的TRD患者中更大程度地改善抑郁。在8个中心，我们将随机分配n = 320例患者（18 - 65岁），分别接受DHEA或安慰剂治疗，同时每位患者将继续使用标准抗抑郁药物。主要分析将通过重复测量的高斯线性模型（意向治疗样本）比较DHEA组和安慰剂组之间临床医生评定的蒙哥马利-艾斯伯格抑郁评定量表（MADRS）从基线至第6周的变化。关键次要终点包括反应（定义为MADRS评分较基线降低50%）、缓解（定义为MADRS评分< 10）和自报Beck抑郁量表评分从基线至第6周的变化。总之，我们建议以确证性方式检查口服DHEA作为TRD的安全且有希望的治疗选择。这种方法可以通过缓解抑郁症状来帮助个体患者，并可以减轻TRD作为公共卫生问题的负担。

Major Depressive Disorder (MDD) is one of the most pressing health problems worldwide and among the top five leading causes for years lived with disability among all medical diseases. About half of the depressed patients do not respond to initial antidepressant treatment defined as “stage 1 of treatment-resistant depression (TRD)”.A systematic review showed an association of TRD with lower patient health-related quality of life and higher medical costs compared to MDD. A Cochrane review of pharmacological interventions in TRD concluded that there is an urgent need for new treatment approaches in TRD that are safe and effective.In this respect, dehydroepiandrosterone (DHEA) is a promising treatment option.DHEA is an endogenous steroid hormone mostly released from the adrenal gland but it is also produced within the brain and acts as a neurosteroid. DHEA has been metaanalytically shown to elicit antidepressive effects and to be safe in MDD in pilot randomized controlled trials and for depressive symptoms in patients with other medical diseases. Furthermore, another meta-analysis and our own data have shown that DHEA levels are decreased in depressed patients. However, no confirmatory trial of add-on DHEA treatment in TRD has been conducted so far.Therefore, the primary aim of this proposal is to examine whether add-on DHEA tostandard antidepressant medication improves depression to a greater extent than addon placebo in patients with TRD over 6 weeks. In eight centers, we will randomize n = 320 patients (18 – 65 years) to either add-on DHEA or add-on placebo while every patient will continue standard antidepressant medication. The primary analysis will compare changes in the clinician-rated Montgomery-Asberg-Depression Rating Scale (MADRS) from baseline to week 6 between the DHEA and placebo group by means of a Gaussian linear model for repeated measures (intent-to-treat-sample). Key secondary endpoints include response (defined as 50% MADRS score reduction from baseline), remission (defined as MADRS score < 10), and change in self-report Beck Depression Inventory scores from baseline to week 6.In sum, we propose to examine oral DHEA as a safe and promising treatment option in TRD in a confirmatory manner. This approach could help the individual patient by relieving depressive symptoms and could reduce the burden of TRD as a public health issue.