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: 10595551
• 负责人: Elizabeth Wenzel
• 金额: $ 4.27万
• 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/10595551
• 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; Diagnostic; Disease remission; Etiology; FDA approved; Female; First Pregnancy Trimester; Goals; Heterogeneity; Hormonal; Hormones; Individual; Infant; Infant Health; 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 Depression; 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; biological adaptation to stress; comorbidity; depressive symptoms; early pregnancy; experience; improved; indexing; intravenous injection; minority patient; mood symptom; negative mood; neural; 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; 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.

项目摘要/摘要 围产期抑郁(PND)影响6.5%-12.9%的母亲，并伴有围产期焦虑(PNA) 多达50%的案例。在低收入有色人种妇女中，这些围产期情感障碍的发生率(PNAD) 甚至更高。PNAD与对孕产妇和婴儿健康的不利影响有关，并可能有助于 早产和低出生体重。重要的是要加深我们对PNAD的理解，以便更有效地 识别和治疗妇女，特别是在高危人群中。我们还必须解决相当大的异质性 并认识到在发病机制和症状特征方面的潜在差异 病人对病人。据我们所知，尽管存在这种异质性，但到目前为止，研究已经调查了 PNAD几乎完全与诊断有关，而不是症状表型。研究领域 标准(RDoC)框架是一种工具，用于将新的、多层次的机械性调查方法应用于 心理健康，综合自我报告、行为、生理和生物措施。RDoC工具尚未 目前已被应用于PNAD的跨诊断表型及其神经基础的鉴定。神经活性类固醇 孕酮代谢产物在妊娠期间波动剧烈，并与其发病机制有关。 Pnad的。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 显示潜在的威胁是PNAD中常见的RDoC表型，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 孕酮的代谢物，特别是在怀孕早期，有色人种妇女的PNAD发生率最高。 这项建议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症状的生理指标 一种颜色。其具体目的是(1)研究NAS合成的急剧增加作为潜在的 妊娠早期的威胁；(2)NAS合成与抑郁和焦虑的关系 怀孕早期的症状，以及潜在的威胁是否中介了这些联系；以及(3)调查 声惊厥反应作为潜在威胁和GABA受体对NAS敏感性的生理指标 在怀孕期间。培训目标是(1)从理论上理解RDoC框架 并将该框架应用于围产期心理健康表型的研究；(2)获得加工训练 和分析神经活性类固醇，并了解它们与PNAD的关联；以及(3)开发一种 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 精神错乱。最终，这种培训将使申请者朝着成为独立人士的目标前进。 研究低收入人群围产期心理健康发病机制及异质性的学者， 少数族裔患者群体。