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

项目摘要 女性患抑郁症的可能性是男性的两倍，在一些女性中， 引发生殖内分泌情绪障碍的独特荷尔蒙风险。改变生殖类固醇 动力学有助于产后抑郁症（PPD），经前 焦虑障碍（PMDD）和围绝经期抑郁（PeriDep）。然而，PeriDep远远落后于PPD 和PMDD，每一种都有FDA批准的利用生殖内分泌变化的疗法， 潜在的精神抑郁症例如，神经类固醇别孕烯醇酮（ALLO）在其 专有形式Brexanolone已被证明对PPD具有抗抑郁功效。内源性ALLO水平下降 在分娩后，随着女性经历更年期，抑郁症女性的抑郁水平低于无抑郁症女性。尽管 与PPD相似，尽管可能受PeriDep-approximately 5.4 million影响的人群很大， 妇女每半年一次-ALLO对PeriDep的贡献尚未调查。关键 试验数据显示，在PeriDep中，ALLO前体孕酮（P4）具有保护作用，P4与 具有有利的神经保护、炎症和神经生理学睡眠特征，所有已知的ALLO靶点。 因此，该项目将使用一个机械安慰剂对照试验来揭示行为和神经生物学 ALLO在女性PeriDep患者中发挥治疗作用的机制。具体而言，该项目 我将研究抑郁症的关键机制目标，包括行为（目标1a：反刍，消极 注意力偏差），基于回路（目标1b：默认模式网络内和默认模式网络之间的功能连接 模式和显著性网络），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：睡眠发作后睡眠EEG唤醒）结果。 80名轻度至重度PeriDep女性将随机接受双盲安慰剂或ALLO给药 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 （治疗后立即）和持久（治疗后30天）ALLO对每种选定的 机制结果，反映了PPD的人类和动物模型中的疗效和生物学数据。结果 将被整合（目标3），以确定每个机制的结果如何介导ALLO对全球的影响 抑郁症严重程度的措施，并检查抑郁症病程和早期与晚期的修改 围绝经期状态。这个创新的项目将机械干预与强大的行为和 神经生物学结果将利用ALLO在PeriDep中作用的机制途径， 发现，以确定新的治疗目标，是特定的PeriDep。

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.