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.

项目摘要 /摘要 围产期抑郁症（PND）影响6.5％-12.9％的母亲，合并症围产期焦虑（PNA）发生在 多达50％的病例。在有色人种的低收入妇女中，这些围产期情感障碍的发生率（PNAD） 更高。 PNAD与孕产妇和婴儿健康的不利影响有关，可以贡献 预期出生和低出生体重。重要的是要进一步了解PNAD，以便更有效 识别和治疗妇女，尤其是在高危人群中。我们还必须解决相当多的异质性 心理健康症状并认识到发病机理和症状概况的潜在变化 病人。据我们所知，尽管存在这种异质性，但迄今为止的研究已经调查了 PNAD几乎完全与诊断有关，而不是症状表型。研究领域 标准（RDOC）框架是应用新的多层次机械研究方法的工具 心理健康，整合自我报告，行为，生理和生物学措施。 RDOC工具没有 但是，被应用于识别PNAD的转诊表及其神经基础。神经活性类固醇 孕酮的代谢物在怀孕期间急剧波动，并与发病机理有关 Pnad。这些神经活性类固醇改变了神经回路（即抑制性GABAA受体）调节某些 RDOC表型，尤其是潜在的威胁或对潜在厌恶情况的反应。初步数据 显示出潜在的威胁是PNAD中常见的RDOC表型，而神经活性类固醇与PNAD相关。 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，特别是在妊娠早期PNAD率最高的有色女性。 该提案的研究目的是检查与自我报告有关的神经活性类固醇合成 低收入妇女怀孕早期怀孕的潜在威胁和PNAD症状的生理测量 颜色。具体目的是（1）研究NAS合成的急性增加作为潜在的机制 怀孕初期的威胁； （2）研究NAS合成与抑郁和焦虑的关联 怀孕早期的症状，以及潜在威胁是否介导这些关联； （3）调查 声学惊吓反应是潜在威胁和GABAA受体敏感性NAS的生理指数 怀孕期间。培训目标是（1）对RDOC框架建立理论理解 并将框架应用于围产期心理健康表型的研究； （2）接受处理培训 以及神经活性类固醇的分析，并了解其与PNAD的关联； （3）发展 对女性生殖生理学和内分泌学的详细了解，并将其与围产期情感联系起来 疾病。最终，这项培训将使申请人能够朝着成为独立的目标迈向 研究低收入围产期心理健康的发病机理和异质性的学术研究人员， 少数族裔患者人口。