Using allopregnanolone to probe behavioral and neurobiological mechanisms that underlie depression in women across perimenopausal stage

使用四氢孕酮探讨围绝经期女性抑郁症的行为和神经生物学机制

• 批准号: 10557128
• 负责人: Katherine Elizabeth Burdick
• 金额: $ 92.57万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557128
• 关键词: Acute; Affect; Aftercare; Age; Allopregnanolone; Animal Model; Anti-Anxiety Agents; Anti-Inflammatory Agents; Antidepressive Agents; Arousal and Regulatory Systems; Behavior; Behavioral; Behavioral Mechanisms; Biological; Biology; Brain; Brain-Derived Neurotrophic Factor; Clinical; Clinical Data; Cognitive; Data; Depressed mood; Depressive disorder; Double-Blind Method; Electroencephalography; Endocrine; Estradiol; FDA approved; Female; Future; Hormonal; Hour; Inflammation; Inflammatory; Infusion procedures; Intervention; Investigational Therapies; Link; Magnetic Resonance Spectroscopy; Measures; Medial; Mediating; Mediator; Menopausal Status; Menopause; Mental Depression; Modification; Molecular; Molecular Probes; Mood Disorders; N-acetylaspartate; Negative Valence; Neurobiology; Outcome; Ovulation; Pathway interactions; Perimenopause; Peripheral; Physiological; Physiological Processes; Placebo Control; Placebos; Population; Postpartum Depression; Postpartum Period; Prefrontal Cortex; Premenopause; Process; Progesterone; Randomized; Research Domain Criteria; Rest; Risk; Risk Factors; Role; Serum; Severities; Sleep; Steroids; Stimulus; System; Testing; Therapeutic; Therapeutic Effect; Translating; Wakefulness; Woman; associated symptom; attentional bias; behavioral construct; cohort; depressive symptoms; effective intervention; effective therapy; human model; improved; indexing; innovation; insight; men; neural; neural circuit; neurobiological mechanism; neurophysiology; neuroprotection; neurosteroids; new therapeutic target; novel; placebo controlled trial; pre-clinical; premenstrual dysphoric disorder; receptor; reproductive; rumination; sleep onset; sleep physiology; steroid hormone; targeted treatment

PROJECT SUMMARY Women are twice as likely as men to develop depression, and among some women, reproductive transitions trigger unique hormonal risks for reproductive-endocrine mood disorders. Changing reproductive steroid dynamics contribute female-specific endocrine risk factors in postpartum depression (PPD), premenstrual dysphoric disorder (PMDD), and perimenopausal depression (PeriDep). However, PeriDep lags far behind PPD and PMDD, each of which has FDA-approved therapies that leverage the reproductive endocrine changes underlying hormonally-linked depression. For example, the neurosteroid allopregnanolone (ALLO) in its proprietary form brexanolone has proven antidepressant efficacy for PPD. Endogenous ALLO levels decline after delivery, as women traverse menopause, and are lower in women with than without depression. Despite parallels to PPD, and despite the large population potentially affected by PeriDep—approximately 5.4 million women are perimenopausal annually—the contributions of ALLO to PeriDep have not been investigated. Key pilot data show a protective benefit of the ALLO precursor progesterone (P4) in PeriDep and that P4 correlates with advantageous neuroprotective, inflammatory, and neurophysiologic sleep profiles, all known ALLO targets. Thus, this project will use a mechanistic placebo-controlled trial to uncover the behavioral and neurobiological mechanisms through which ALLO exerts its therapeutic effects in women with PeriDep. Specifically, the project will examine key mechanistic targets underlying depression to include behavioral (Aim 1a: rumination, negative attentional bias), circuit-based (Aim 1b: functional connectivity within default mode network and between default mode and salience networks), molecular (Aim 2a: circulating and magnetic resonance spectroscopy neurotrophic and pro-inflammatory molecules), and physiological (Aim 2b: sleep EEG wake after sleep onset) outcomes. Eighty women with mild to severe PeriDep will be randomized to double-blinded placebo or ALLO administered as a 60-hour brexanolone infusion, stratified by early vs. late perimenopausal status. Analyses will test the acute (immediately post-treatment) and durable (30-days post-treatment) effects of ALLO on each of the selected mechanistic outcomes, mirroring the efficacy and biological data in human and animal models of PPD. Results will be integrated (Aim 3) to determine how each mechanistic outcome mediates ALLO’s effect on global measures of depression severity and to examine modification by depression illness course and early vs. late perimenopausal status. This innovative project pairing a mechanistic intervention with robust behavioral and neurobiological outcomes will exploit mechanistic pathways underlying the role of ALLO in PeriDep and translate findings to identify novel therapeutic targets that are specific for PeriDep.

项目概要 女性患抑郁症的可能性是男性的两倍，并且在某些女性中，生殖转变 改变生殖类固醇会引发生殖内分泌情绪障碍的独特荷尔蒙风险。 动力学有助于女性特有的内分泌危险因素，如产后抑郁症（PPD）、经前期 然而，PeriDep 远远落后于 PPD。 和经前抑郁症 (PMDD)，每种疾病都有 FDA 批准的利用生殖内分泌变化的疗法 潜在的与激素相关的抑郁症，例如，其神经类固醇四氢孕酮（ALLO）。 专有形式 brexanolone 已被证明对 PPD 具有抗抑郁功效。 分娩后，随着女性进入更年期，患有抑郁症的女性的抑郁症比没有抑郁症的女性要低。 与 PPD 类似，尽管有大量人口可能受到 PeriDep 的影响——大约 540 万 女性每年都会进入更年期——ALLO 对 PeriDep 的贡献尚未得到调查。 试点数据显示 ALLO 前体孕酮 (P4) 在 PeriDep 中的保护作用，并且 P4 相关 具有有利的神经保护、炎症和神经生理睡眠特征，所有已知的 ALLO 目标。 因此，该项目将使用机械安慰剂对照试验来揭示行为和神经生物学 ALLO 对患有 PeriDep 的女性发挥治疗作用的机制具体来说，是该项目。 将检查抑郁症背后的关键机制目标，包括行为（目标 1a：沉思、消极 注意偏差），基于电路（目标 1b：默认模式网络内以及默认网络之间的功能连接 模式和显着网络），分子（目标 2a：循环和磁共振波谱神经营养 和促炎分子）和生理（目标 2b：入睡后睡眠脑电图唤醒）结果。 80 名患有轻度至重度 PeriDep 的女性将被随机分配接受双盲安慰剂或 ALLO 治疗 作为 60 小时 brexanolone 输注，按早期与晚期围绝经期状态分层，分析将测试急性。 ALLO 对每个选定对象的（治疗后立即）和持久（治疗后 30 天）效果 机制结果，反映了 PPD 结果的人类和动物模型中的功效和生物学数据。 将被整合（目标 3）以确定每个机制结果如何调节 ALLO 对全球的影响 测量抑郁症的严重程度并检查抑郁症病程以及早期与晚期的改变 这个创新项目结合了行为和围绝经期的机械干预。 神经生物学结果将利用 ALLO 在 PeriDep 中作用的机制途径并转化 研究结果确定了针对 PeriDep 的新治疗靶点。