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）是全球残疾的主要原因，在 女人就像男人一样。妇女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早期。更年期重大抑郁症（MMDD）是 通常伴随着干扰功能和福祉的合并症条件，包括热 闪烁，认知投诉，焦虑，疲劳和睡眠失调。尽管抑郁症的风险升高 在这个人群中，很少有安慰剂对照试验可以治疗MMDD。许多女人喜欢 抗抑郁药或雌激素替代疗法MMDD的典型治疗选择的替代方案。 重要的是，尽管有一个 到目前为止，数据的匮乏以支持此类化合物的功效或安全性。 妊娠烯醇酮是一种内源性神经类固醇，由大脑中的胆固醇和肾上腺制成 在美国作为非处方补品出售。临床前文学表明 妊娠类似物在抑郁症动物模型中有效。低脑脊液水平 据报道，抑郁症，焦虑症中血清低和顶叶低的血清水平较低的人有妊娠 自杀的人的水平。我们进行了两项安慰剂对照的外源性研究 抑郁症患者的怀孕烯醇酮。第一项研究表明抑郁症的减少较大 双极抑郁症和MDD患者混合样本中怀孕的症状。第二项研究 专注于躁郁症抑郁症，再次发现抑郁症状有了更大的改善 怀孕烯醇比安慰剂。两项研究中都耐受了孕烯酮的耐受性。女人表现出更强大的 在试点研究和40岁以上的女性中，反应比男性的反应比 年轻妇女。此外，观察到认知的改善（例如记忆）在孕妇中观察到 妇女和抑郁症状的减轻与血液妊娠水平的增加密切相关。 鉴于妊娠烯酮的广泛可用性以及有希望的临床前和临床数据，特别是 妇女，我们提出了与MDD（MMDD）更年期过渡中妇女中这种补充剂的试验。 一个两场（达拉斯和波士顿），随机，双盲，安慰剂对照试验的16周 使用创新的顺序平行的MMDD，提议在40岁以上的144名女性中提议怀孕烯醇酮 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 认知将被评估。血清神经类固醇水平将在基线和退出时获得。经验丰富的 研究团队将进行临床试验。主要调查人员各自拥有18年以上的经验 对情绪障碍患者进行临床试验。共同研究人员还具有广泛的临床和 神经类固醇，统计和情绪障碍治疗的研究经验。