A Neurosteroid Intervention for Menopausal and Perimenopausal Depression

摘要 严重抑郁障碍(MDD)是世界范围内导致残疾的主要原因，在 女人和男人一样。女性在更年期过渡期间患抑郁症的风险更高，这 包括围绝经期和绝经后早期。绝经期重度抑郁障碍(MMDD) 通常伴随着干扰功能和健康的共病情况，包括炎热 闪光、认知抱怨、焦虑、疲劳和睡眠失调。尽管患抑郁症的风险增加 在这一人群中，治疗mMDD的安慰剂对照试验很少。许多女性更喜欢 MMDD抗抑郁药或雌激素替代疗法的典型治疗选择的替代品。 重要的是，更年期妇女经常寻求综合治疗，如营养补充剂，尽管 到目前为止，支持这类化合物的有效性或安全性的数据很少。 孕烯醇酮是一种内源性神经类固醇，由大脑和肾上腺中的胆固醇组成。 在美国，这是一种非处方补充剂。临床前文献表明， 孕烯醇酮类似物在抑郁症动物模型中有效。低脑脊液水平 据报道，孕烯醇酮用于患有抑郁症、焦虑症患者的低血清水平和低顶叶皮质患者。 自杀者体内的水平。我们进行了两项安慰剂对照的先导性研究 孕烯醇酮在抑郁症患者中的应用。第一项研究表明抑郁症的减少幅度更大。 双相抑郁和MDD患者混合样本中孕烯醇酮的症状。第二项研究 关注双相抑郁，再次发现抑郁症状有更大的改善 孕烯醇酮而不是安慰剂。孕烯醇酮在两项研究中耐受性都很好。女性表现出更强健的 在先导研究中，男性的反应比男性强，40岁以上的女性的反应比男性强 年轻女性。此外，服用孕烯醇酮可改善患者的认知能力(如记忆力)。 女性和抑郁症状的减少与血液中孕烯醇酮水平的增加密切相关。 鉴于孕烯醇酮的广泛可获得性以及有前景的临床前和临床数据，特别是在 对于女性，我们建议在患有MDD(MMDD)的绝经过渡期妇女中试验这种补充剂。 一项为期16周的两点(达拉斯和波士顿)随机、双盲、安慰剂对照试验 孕烯醇酮建议用于144名40岁以上患有mMDD的女性，采用创新的序贯平行试验 比较临床试验设计。抑郁症状、焦虑症状、潮热、睡眠、生活质量和 将对认知能力进行评估。血清神经类固醇水平将在基线和退出时获得。一位经验丰富的人 研究团队将进行临床试验。首席调查员每人都有18年以上的经验。 对情绪障碍患者进行临床试验。联合调查人员还拥有广泛的临床和 神经类固醇的研究经验，统计学和情绪障碍的治疗。

Abstract Major depressive disorder (MDD) is a major cause of disability worldwide and is twice as common in women as in men. Women are at heightened risk for depression onset during the menopausal transition, which includes both perimenopause and early postmenopause. Menopausal Major Depressive Disorder (mMDD) is usually accompanied by comorbid conditions that interfere with functioning and wellbeing, including hot flashes, cognitive complaints, anxiety, fatigue and sleep dysregulation. Despite the elevated risk of depression in this population, there have been few placebo-controlled trials to treat mMDD. Many women prefer alternatives to the typical treatment options for mMDD of antidepressants or estrogen replacement therapy. Importantly, menopausal women often seek integrative treatments, such as nutritional supplements, despite a paucity of data thus far to support the efficacy or safety of such compounds. Pregnenolone is an endogenous neurosteroid that is made from cholesterol in the brain and adrenals that is sold as an over-the-counter supplement in the United States. Preclinical literature suggests that a pregnenolone analogue is effective in animal models of depression. Low cerebrospinal fluid levels of pregnenolone are reported in humans with depression, low serum levels in anxiety and low parietal cortex levels in people who commit suicide. We conducted two placebo-controlled pilot studies of exogenous pregnenolone administration in depressed patients. The first study showed a greater reduction in depressive symptoms with pregnenolone in a mixed sample of patients with bipolar depression and MDD. A second study focused on bipolar depression and again found a greater improvement in depressive symptoms with pregnenolone than placebo. Pregnenolone was well tolerated in both studies. Women showed a more robust response than men in both pilot studies and women over age 40 years showed a stronger response than did younger women. In addition, improvement in cognition (e.g. memory) was observed with pregnenolone in women and reduction in depressive symptoms strongly correlated with increases in blood pregnenolone levels. Given the wide availability of pregnenolone and the promising preclinical and clinical data, particularly in women, we propose a trial of this supplement in women in the menopausal transition with MDD (mMDD). A two-site (Dallas and Boston), randomized, double-blind, placebo-controlled trial of 16 weeks of pregnenolone is proposed in 144 women over age 40 with mMDD using an innovative sequential parallel comparison clinical trial design. Depressive symptoms, anxiety symptoms, hot flashes, sleep, quality of life and cognition will be assessed. Serum neurosteroid levels will be obtained at baseline and exit. An experienced research team will conduct the clinical trial. The principal investigators each have over 18 years of experience conducting clinical trials in patients with mood disorders. The co-investigators also have extensive clinical and research experience with neurosteroids, statistics and the treatment of mood disorders.