Brain exosome biomarker targets to optimize pharmacologic treatment of depression in pregnancy

脑外泌体生物标志物靶向优化妊娠期抑郁症的药物治疗

• 批准号: 10673014
• 负责人: Laura Goetzl
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673014
• 关键词: Affect; Antidepressive Agents; Binding Proteins; Biological Availability; Biological Markers; Blood; Brain; Central Nervous System; Clinical; Development; Dose; Evaluation; Fetus; Goals; Maternal Physiology; Mental Depression; Neonatal; Neonatal Abstinence Syndrome; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology Study; Pharmacotherapy; Pilot Projects; Pregnancy; Pregnant Women; Public Health; Risk; Sampling; Selective Serotonin Reuptake Inhibitor; Source; Testing; Third Pregnancy Trimester; Withdrawal Symptom; Woman; antepartum depression; drug metabolism; effective therapy; evidence base; exosome; fetal; fetus at risk; improved; response; safety assessment; targeted biomarker; temporal measurement

This proposal aims to determine whether biomarkers in central nervous system-derived exosomes are useful predictors of functional drug activity in the maternal and fetal brain in women treated for depression during pregnancy with selective-serotonin reuptake inhibitors (SSRIs). PAR-20-299 specifically requests translational projects that will enhance the usage of existing drugs for safer and more effective treatment. Barriers to pharmacologic studies to optimize drug treatment in pregnant women include changes in maternal physiology, circulating binding proteins, biologically available drug levels, and drug metabolism. Real-time measurements of fetal drug levels are not currently feasible. Purification of CNSEs from maternal blood allows non- invasive independent evaluation of both the maternal and fetal CNS SSRI targets without significant contamination from each other or non-CNS sources. The goal of this pilot project is to develop a new testing paradigm to rapidly identify women who are poor responders to SSRIs and to investigate the relationship between SSRI treatment, exosome marker levels, and maternal clinical response at a steady state for a given SSRI dose. We will use fetal CNSEs isolated from the same maternal samples to determine if fetuses at risk for neonatal withdrawal symptoms can be identified prior to delivery. This would allow for improved evidence-based management of maternal SSRI treatment in the third trimester based on individualized fetal/neonatal risk and ultimately has the potential to avoid unnecessary medication discontinuation. Completion of this project can change the paradigm for how we assess the safety and efficacy of psychoactive medications in pregnancy.

该提案旨在确定中枢神经系统中的生物标志物是否源自 外泌体是女性母体和胎儿大脑中功能性药物活性的有用预测因子 使用选择性血清素再摄取抑制剂（SSRI）治疗妊娠期间的抑郁症。 PAR-20-299 特别要求转化项目，以增强现有资源的使用 药物以实现更安全、更有效的治疗。优化药物的药理学研究的障碍 孕妇的治疗包括改变母体生理机能、循环结合 蛋白质、生物可利用药物水平和药物代谢。胎儿实时测量 药物水平目前不可行。从母血中纯化 CNSE 可以实现非 对母体和胎儿 CNS SSRI 目标进行侵入性独立评估，无需 彼此或非中枢神经系统来源的严重污染。该试点项目的目标是 开发一种新的测试范式，以快速识别对 SSRIs 反应不佳的女性， 调查 SSRI 治疗、外泌体标志物水平和母体之间的关系 给定 SSRI 剂量的稳态临床反应。我们将使用从 使用相同的母体样本来确定胎儿是否有新生儿戒断症状的风险 在交货前进行识别。这将有助于改进基于证据的管理 根据个体化胎儿/新生儿风险和妊娠晚期母亲 SSRI 治疗 最终有可能避免不必要的停药。完成此 该项目可以改变我们评估精神活性药物的安全性和有效性的范式 怀孕期间的药物。