Optimizing Pharmacotherapy for Depression during Pregnancy (OPTI-MOM)

 描述(申请人提供)：重度抑郁障碍是最常见的妊娠并发症之一，7.5%的妇女在怀孕9个月期间发生事件，6.5%的妇女在产后头3个月发生事件。OPRC提交的这份意见书的首要目标是制定指南，以优化SSRI抗抑郁药在孕妇中的安全性和有效性。这一应用响应了OPRC RFA的几个优先事项，包括建立跨学科方法来了解药物的药代动力学和/或药效学。PI团队包括医学硕士凯瑟琳·L·威斯纳(精神病学)、凯瑟琳·斯蒂卡医学博士(产科)和阿尔弗雷德·乔治医学博士(药物基因组学)。行政核心将为与OPRC网络以及在下面确定的具有很强互补性的3个主要OPTI-MOM项目内进行合作提供基础设施：1.临床研究项目。-评估孕期和产后期药物的安全性和毒性。妊娠期间和出生后血浆SSRI和代谢物浓度的进行性变化将在观察性研究中确定。将对抑郁和焦虑症状和副作用进行一系列评估，以评估它们与怀孕期间每月一次和出生后两次的血浆浓度之间的关系。为了评估受试者的代谢表型，将给出一种探针药物鸡尾酒，以评估妊娠晚期(活动变化最大的时候)与出生后未怀孕状态相比的CYP2D6、2C19、2C9和3A4的活性。2.基础/转译研究项目--进行临床研究，以了解与怀孕有关的药物反应和处置变化的机制，并确定安全有效地治疗与怀孕有关的疾病的生物标记物。在这项研究中，我们将研究基因组变异对个体间的影响 在妊娠期间SSRI剂量、血浆浓度和药效学的差异，重点是参与SSRI代谢的基因，负责SSRI进入中枢神经系统的药物转运体，以及编码SSRI靶标的基因，涉及治疗效果。3.试点项目--评估药物在孕期、产后和出生后发育阶段的安全性和毒性。该项目将确定与新生儿SSRI禁欲综合征相关的母婴血浆浓度和药物遗传学特征。将评估孕妇和胎儿的CYP和P-糖蛋白基因型与SSRI药物浓度和新生儿禁欲综合征的关系。

 DESCRIPTION (provided by applicant): Major Depressive Disorder is one of the most common complications of pregnancy, with 7.5% of women having an incident episode during the 9 months of pregnancy and 6.5% with an episode in the first 3 months postpartum. The overarching goal in this OPRC submission is to develop guidelines to optimize the safety and effectiveness of SSRI antidepressant treatment in pregnant women. This application responds to several priorities from the OPRC RFA, including establishing interdisciplinary approaches to understand the pharmacokinetics and/or pharmacodynamics of medications. The PI team includes Katherine L. Wisner, MD MS (psychiatry); Catherine Stika, MD (obstetrics), and Alfred George, MD (pharmacogenomics). The Administrative Core will provide the infrastructure for collaboration with the OPRC network and within the 3 main OPTI-MOM projects identified below, which have strong complementarity: 1. The Clinical Research Project. -Assess the safety and toxicity of drugs during pregnancy and the postpartum periods. The progressive changes in plasma SSRI and metabolite concentrations across pregnancy and after birth will be determined in an observational study. Serial evaluations of depressive and anxiety symptoms and side effects will be obtained to evaluate their association with plasma concentrations at monthly intervals during pregnancy and twice post-birth. To assess the subjects' metabolic phenotypes, a probe drug cocktail will be given to evaluate the activities of CYP2D6, 2C19, 2C9 and 3A4 during the third trimester (when activity change is maximal) compared to the non-pregnant state after birth. 2. The Basic/Translational Research Project -Perform clinical research to understand mechanisms of pregnancy related changes in drug response and disposition and --Identify biomarkers for safe and effective treatment of pregnancy-related conditions. In this study we will investigate the impact of genomic variability on inter-individual differences in SSRI dosing, plasma concentrations and pharmacodynamics during pregnancy, with a focus on genes involved in the metabolism of SSRIs, drug transporters responsible for SSRI access to the central nervous system, and genes encoding SSRI targets involved in therapeutic efficacy. 3. The Pilot Project -Assess the safety and toxicity of the drugs during pregnancy, postpartum, and in postnatal periods of development. This project will determine the maternal-fetal plasma concentrations and pharmacogenetic characteristics associated with neonatal SSRI abstinence syndrome. Maternal and fetal CYP and P-glycoprotein genotypes will be assessed for their relationship to SSRI drug concentrations and neonatal abstinence syndrome.