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.

项目摘要 女性患抑郁症的可能性是男性的两倍，在某些女性中，生殖过渡的可能性是 触发独特的马雌性风险，以引发生殖 - 内分泌情绪障碍。改变生殖类固醇 动力学在产后抑郁症（PPD）中造成女性特异性内分泌危险因素 烦躁的疾病（PMDD）和绝经性抑郁症（Peridep）。但是，Peridep滞后于PPD 和PMDD，每种都有FDA批准的疗法，可利用复制性内分泌变化 基础荷尔蒙连接抑郁症。例如，神经类固醇（allo）在其中 Brexanolone的专有形式已证明PPD已证明抗抑郁药效率。内源性同素水平下降 分娩后，随着女性穿越绝经，在没有抑郁症的女性中，女性低。尽管 与PPD的相似之处，dospite可能受Peridep影响的大量人口 - 大约540万 妇女是围绝经期的年度 - 尚未调查Allo对Peridep的贡献。钥匙 试验数据显示，Peridep中Allo前体孕酮（P4）的受保护益处，P4相关 具有有利的神经保护性，炎症性和神经生理睡眠谱，所有已知的Allo靶标。 那就是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在Peridep女性中执行其治疗作用的机制。具体来说，该项目 将检查抑郁症基础的关键机械目标以包括行为（目标1a：反省，负面） 注意偏见），基于电路（AIM 1B：默认模式网络内的功能连接性以及默认之间的功能连接性 模式和显着网络），分子（目标2A：循环和磁共振光谱神经营养 和促炎分子）和生理学（AIM 2B：睡眠开始后的脑电图唤醒）。 八十名轻度至重度Peridep的妇女将随机分配给双盲安慰剂或给药 作为60小时的Brexanolone输注，由早期与晚期临时状态分层。分析将测试急性 （治疗后立即）和耐用（处理后30天）Allo对每个选定的影响 机械结果，反映了PPD人类和动物模型中的效率和生物数据。结果 将集成（目标3），以确定每个机械结果如何介导Allo对全球的影响 抑郁严重程度的措施和通过抑郁症疾病课程和早期与晚期进行检查 围绝经状态。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中作用的机械途径并翻译 确定针对Peridep的新型治疗靶标的发现。