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

项目总结 女性患抑郁症的可能性是男性的两倍，在一些女性中，生殖转换 引发生殖内分泌情绪紊乱的独特荷尔蒙风险。不断变化的生殖类固醇 动态因素在产后抑郁症(PPD)、经前女性特有的内分泌危险因素中的作用 烦躁不安(PMDD)和围绝经期抑郁症(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 潜在的荷尔蒙相关的抑郁症。例如，神经类固醇别孕酮(Allo)在其 专利形式的布沙诺龙已被证明对产后抑郁有效。内源性等位基因水平下降 产后，随着女性经历更年期，患有抑郁症的女性比没有抑郁症的女性更低。尽管 与PPD相似，尽管有大量人口可能受到PeriDep的影响-约540万 妇女每年都有围绝经期--Allo对围绝经期的贡献尚未得到调查。钥匙 试验数据显示，等位基因前体孕酮(P4)在PeriDep中具有保护作用，P4与 具有有利的神经保护、炎症和神经生理学睡眠特征，都是已知的Allo靶标。 因此，该项目将使用机械性的安慰剂对照试验来揭示行为和神经生物学 Allo在围产期妇女中发挥治疗作用的机制。具体地说，该项目 将检查抑郁症潜在的关键机制目标，以包括行为(目标1a：沉思，消极 注意偏差)，基于电路(目标1b：默认模式网络内和默认之间的功能连通性 模式和显著网络)、分子(目标2a：循环和磁共振波谱神经营养 和促炎分子)和生理结果(目标2b：睡眠脑电在睡眠开始后苏醒)。 80名患有轻度到重度围产期的妇女将随机接受双盲安慰剂或Allo治疗 作为60小时的布沙诺酮输注，根据围绝经期早期和晚期状况进行分层。分析将测试急性 (治疗后立即)和持久(治疗后30天)ALLO对选定的每个人的影响 机制结果，反映了PPD在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)以确定每个机械性结果如何调节ALLO对全球的影响 测量抑郁症的严重程度，并检查抑郁症病程和早期与晚期的改变 围绝经期状态。这一创新项目将机械干预与强大的行为和 神经生物学成果将利用等位基因在PeriDep和翻译中作用的机制途径 发现针对PeriDep的新的治疗靶点。

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.