A Neurosteroid Intervention for Menopausal and Perimenopausal Depression

神经类固醇干预治疗更年期和围绝经期抑郁症

• 批准号: 10359033
• 负责人: E SHERWOOD BROWN
• 金额: $ 69.62万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359033
• 关键词: Adrenal Glands; Affect; Age; Allopregnanolone; Alternative Therapies; Anhedonia; Animal Model; Antidepressive Agents; Anxiety; Biological Markers; Bipolar Depression; Bipolar Disorder; Blood; Boston; Brain; Cerebrospinal Fluid; Cholesterol; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Cognition; Cognitive; Complementary therapies; Conduct Clinical Trials; Data; Disease remission; Double-Blind Method; Estrogen Replacement Therapy; Estrogen Replacements; Estrogens; Fatigue; Funding; Hormonal; Hormones; Hot flushes; Human; Integrative Therapy; Intervention; Literature; Major Depressive Disorder; Mediating; Memory; Menopausal Symptom; Menopause; Mental Depression; Mental Health; Modeling; Mood Disorders; Moods; Neurobehavioral Manifestations; Norepinephrine; Outcome Measure; Parietal Lobe; Patients; Perimenopause; Personal Satisfaction; Persons; Pilot Projects; Placebo Control; Placebos; Population; Postmenopause; Pregnenolone; Prevalence; Principal Investigator; Progesterone; Quality of life; Randomized; Reporting; Research; Research Personnel; Risk; Safety; Sampling; Selective Serotonin Reuptake Inhibitor; Serotonin; Serum; Severities; Sex Differences; Short-Term Memory; Site; Sleep; Sleep disturbances; Symptoms; Time; Unipolar Depression; United States; United States National Institutes of Health; Woman; analog; antidepressant effect; anxiety symptoms; associated symptom; comorbidity; completed suicide; depressed patient; depression model; depressive symptoms; dietary supplements; disability; disorder control; double-blind placebo controlled trial; effective therapy; effectiveness trial; epidemiology study; experience; high risk; human model; improved; innovation; men; middle age; neuroprotection; neurosteroids; novel; older women; physical symptom; placebo controlled trial; pre-clinical; pre-clinical research; prospective; randomized placebo controlled trial; response; sex; statistics; symptomatic improvement; vasomotor symptoms; young woman

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.

抽象的 重度抑郁症 (MDD) 是全世界残疾的主要原因，其发病率是其他国家的两倍 女人就像男人一样。女性在更年期过渡期间患抑郁症的风险更高， 包括围绝经期和绝经后早期。更年期重度抑郁症 (mMDD) 是 通常伴有干扰功能和健康的共病，包括热 闪光、认知障碍、焦虑、疲劳和睡眠失调。尽管患抑郁症的风险较高 在这一人群中，几乎没有治疗 mMDD 的安慰剂对照试验。很多女性更喜欢 mMDD 的典型治疗方案包括抗抑郁药或雌激素替代疗法。 重要的是，更年期妇女经常寻求综合治疗，例如营养补充剂，尽管 迄今为止，缺乏数据支持此类化合物的功效或安全性。 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制成 在美国作为非处方补充剂出售。临床前文献表明 孕烯醇酮类似物对抑郁症动物模型有效。脑脊液水平低 据报道，患有抑郁症、焦虑症和低顶叶皮层的人血清中孕烯醇酮水平较低 自杀者的水平。我们进行了两项外源性安慰剂对照初步研究 抑郁症患者孕烯醇酮给药。第一项研究表明抑郁症有更大程度的减少 双相抑郁症和重度抑郁症患者混合样本中孕烯醇酮的症状。第二项研究 专注于双相抑郁症，并再次发现抑郁症状有更大的改善 孕烯醇酮优于安慰剂。孕烯醇酮在两项研究中均具有良好的耐受性。女性表现出更坚强的姿态 在两项试点研究中，女性的反应均高于男性，40 岁以上的女性则表现出比男性更强的反应 年轻女性。此外，还观察到孕烯醇酮可改善认知（例如记忆力）。 女性和抑郁症状的减少与血液孕烯醇酮水平的增加密切相关。 鉴于孕烯醇酮的广泛可用性以及有前景的临床前和临床数据，特别是在 对于女性，我们建议在患有抑郁症 (mMDD) 的绝经过渡期女性中试验这种补充剂。 一项为期 16 周的两中心（达拉斯和波士顿）随机、双盲、安慰剂对照试验 使用创新的顺序并行方法，建议对 144 名 40 岁以上患有 mMDD 的女性使用孕烯醇酮 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 将评估认知能力。将在基线和退出时获得血清神经类固醇水平。经验丰富的 研究小组将进行临床试验。主要研究者均拥有超过18年的经验 对情绪障碍患者进行临床试验。共同研究人员还拥有广泛的临床和 神经类固醇、统计学和情绪障碍治疗方面的研究经验。