An RDoC Approach to Perinatal Affective Disorders: The Role of Neuroactive Steroids and Potential Threat

RDoC 治疗围产期情感障碍的方法：神经活性类固醇的作用和潜在威胁

• 批准号: 10464233
• 负责人: Elizabeth Wenzel
• 金额: $ 4.18万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464233
• 关键词: Acoustics; Acute; Address; Adverse effects; Affect; Allopregnanolone; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavioral; Biological; Biological Factors; Biological Markers; Complex; Data; Development; Diagnosis; Disease remission; Etiology; FDA approved; Female; First Pregnancy Trimester; Goals; Heterogeneity; Hormonal; Hormones; Individual; Infant Health; Investigation; Knowledge; Link; Longitudinal Studies; Low Birth Weight Infant; Low income; Maternal Health; Measures; Mediating; Mental Health; Metabolism; Modeling; Mood Disorders; Moods; Mothers; Pathogenesis; Patient Self-Report; Patients; Perinatal; Peripheral; Phenotype; Physiological; Populations at Risk; Postmenopause; Postpartum Period; Postpartum Women; Pregnancy; Pregnancy Trimesters; Pregnanolone; Pregnant Women; Premature Birth; Probability; Progesterone; Questionnaires; Recording of previous events; Reporting; Reproductive Endocrinology; Reproductive Physiology; Research; Research Domain Criteria; Research Personnel; Risk; Role; Second Pregnancy Trimester; Serum; Site; Startle Reaction; Structure of terminal stria nuclei of preoptic region; Symptoms; System; Third Pregnancy Trimester; Training; Variant; Woman; Work; anxiety symptoms; associated symptom; base; biological adaptation to stress; comorbidity; depressive symptoms; early pregnancy; experience; improved; indexing; intravenous injection; minority patient; mood symptom; negative mood; neural circuit; neurosteroids; patient population; perinatal mental health; perinatal women; peripartum depression; positive allosteric modulator; premenstrual dysphoric disorder; prevent; profiles in patients; receptor; receptor sensitivity; relating to nervous system; response; tool; transmission process; trauma exposure; women of color

PROJECT SUMMARY / ABSTRACT Perinatal depression (PND) affects 6.5%-12.9% of mothers, with comorbid perinatal anxiety (PNA) occurring in as many as 50% of cases. In low-income women of color, rates of these perinatal affective disorders (PNAD) are even higher. PNAD are associated with adverse effects on both maternal and infant health and can contribute to pre-term birth and low birth weight. It is important to further our understanding of PNAD to more efficaciously identify and treat women, especially in at-risk populations. We must also address the considerable heterogeneity of mental health symptoms and recognize the potential variations in pathogenesis and symptom profiles from patient to patient. To our knowledge, despite this heterogeneity, studies to date have investigated biomarkers of PNAD almost exclusively in relation to diagnoses rather than symptom phenotypes. The Research Domain Criteria (RDoC) framework is a tool for applying new, multi-level mechanistic investigational approaches to mental health, integrating self-report, behavioral, physiological and biological measures. RDoC tools have not yet been applied to identify transdiagnostic phenotypes of PNAD and their neural basis. Neuroactive steroid metabolites of progesterone fluctuate drastically during pregnancy and have been implicated in the pathogenesis of PNAD. These neuroactive steroids alter the neural circuitry (i.e., inhibitory GABAA receptor) modulating certain RDoC phenotypes, particularly potential threat, or responses to potentially aversive situations. Preliminary data show potential threat to be an RDoC phenotype common in PNAD, and neuroactive steroids to relate to PNAD. The next step is to link potential threat directly to neuroactive steroids, and to extend research to other metabolites of progesterone, particularly early in pregnancy when rates of PNAD are highest in women of color. The research goal of this proposal is to examine neuroactive steroid synthesis in relation to self-report and physiological measures of potential threat as well as PNAD symptoms in early pregnancy in low-income women of color. The specific aims are to (1) investigate acute increases in NAS synthesis as a mechanism of potential threat in early pregnancy; (2) investigate the association of NAS synthesis with depression and anxiety symptoms in early pregnancy, and whether potential threat mediates these associations; and (3) investigate the acoustic startle response as a physiological index of potential threat and GABAA receptor sensitivity to NAS during pregnancy. The training goals are to (1) develop a theoretical understanding of the RDoC framework and apply the framework to the study of perinatal mental health phenotypes; (2) acquire training in processing and analysis of neuroactive steroids, and gain knowledge of their association with PNAD; and (3) develop a detailed understanding of female reproductive physiology and endocrinology, and relate this to perinatal affective disorders. Ultimately, this training will allow the applicant to advance towards a goal of becoming an independent academic researcher studying the pathogenesis and heterogeneity of perinatal mental health in low income, minority patient populations.

项目概要/摘要 围产期抑郁症 (PND) 影响 6.5%-12.9% 的母亲，并存的围产期焦虑症 (PNA) 发生在 多达50%的病例。在低收入有色人种女性中，这些围产期情感障碍 (PNAD) 的发生率 甚至更高。 PNAD 对孕产妇和婴儿健康产生不利影响，并可能导致 导致早产和低出生体重。进一步加深我们对 PNAD 的理解以更有效地实现这一点非常重要 识别和治疗妇女，特别是高危人群中的妇女。我们还必须解决相当大的异质性 心理健康症状，并认识到发病机制和症状特征的潜在变化 病人对病人。据我们所知，尽管存在这种异质性，迄今为止的研究已经调查了 PNAD 几乎完全与诊断相关，而不是与症状表型相关。研究领域 Criteria (RDoC) 框架是一种应用新的、多层次机械研究方法来 心理健康，整合自我报告、行为、生理和生物测量。 RDoC 工具还没有 尚未应用于识别 PNAD 的跨诊断表型及其神经基础。神经活性类固醇 黄体酮的代谢物在怀孕期间剧烈波动，并且与发病机制有关 的PNAD。这些神经活性类固醇改变神经回路（即抑制性 GABAA 受体），调节某些 RDoC 表型，特别是潜在威胁或对潜在厌恶情况的反应。初步数据 显示出 PNAD 中常见的 RDoC 表型的潜在威胁，以及与 PNAD 相关的神经活性类固醇。 下一步是将潜在威胁直接与神经活性类固醇联系起来，并将研究扩展到其他领域 黄体酮代谢物，尤其是在怀孕早期，此时有色人种女性的 PNAD 发生率最高。 该提案的研究目标是检查神经活性类固醇合成与自我报告和 低收入妇女妊娠早期潜在威胁和 PNAD 症状的生理测量 的颜色。具体目标是 (1) 研究 NAS 合成的急剧增加作为潜在机制 怀孕早期的威胁； (2)探讨NAS合成与抑郁、焦虑的关联 怀孕早期的症状，以及潜在的威胁是否会介导这些关联； (3) 调查 声惊吓反应作为潜在威胁的生理指标和 GABAA 受体对 NAS 的敏感性 怀孕期间。培训目标是 (1) 形成对 RDoC 框架的理论理解 并将该框架应用于围产期心理健康表型的研究； (2) 接受加工培训 神经活性类固醇的分析，并了解它们与 PNAD 的关联； (3) 开发一个 详细了解女性生殖生理学和内分泌学，并将其与围产期情感联系起来 失调。最终，这种培训将使申请人能够朝着成为独立人士的目标迈进 研究低收入围产期心理健康发病机制和异质性的学术研究员， 少数患者群体。