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Prenatal atypical antipsychotic exposure

产前非典型抗精神病药物暴露

基本信息

批准号：
8675273
负责人：
MICHAEL JOSEPH OWENS
金额：
$ 31.7万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675273
关键词：
Adolescent Advisory Committees Age Alcohols American College of Obstetricians and Gynecologists Animal Model Animals Antidepressive Agents Antipsychotic Agents Area Base Sequence Basic Science Behavior Behavior assessment Behavioral Binding Biological Assay Biological Markers Bipolar Disorder Birth Brain Brain region Caring Child Clinic Clinical Clinical assessments Cognitive Country Data Data Set Development Dose Drug Exposure Drug Kinetics Employee Strikes Epigenetic Process Escitalopram Exposure to Female Fostering Gene Expression Gene Expression Profile Generations Genes Genome Goals Guidelines Heavy Metals Hippocampus (Brain)Human Individual Investigation Joints Laboratory Animals Length Leukocytes Major Depressive Disorder Measures Mental Health Mental disorders Methods Methylation Modeling Molecular Target Monitor Mood stabilizers Mothers Motor Neurobiology Nicotine Outcome Parents Patients Pattern Perinatal Exposure Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Physicians Placenta Plastics Population Pregnancy Process Psychotic Disorders Psychotic Mood Disorders Public Health Publications Publishing RNA Splicing Rattus Relapse Relative (related person)Reporting Risk Risk-Benefit Assessment Risperidone Rodent Rodent Model Safety Serum Study models System Testing Time Translating Universities Variant Weaning Woman atypical antipsychotic base clinical decision-making clinical efficacy clinical risk clinically relevant design epigenome epigenomics evidence based guidelines exposed human population frontal lobe in utero male monoamine novel offspring olanzapine pediatrician postnatal pre-clinical pregnant prenatal prenatal exposure programs prospective public health relevance quetiapine receptor relating to nervous system reproductive risk minimization skills transcriptome sequencing valproate

项目摘要

DESCRIPTION (provided by applicant): Untreated bipolar disorder has severe consequences for the mother and there is increasing utilization of atypical antipsychotics as mood stabilizers and adjuncts to antidepressant therapy, with an associated increase in fetal exposure to these medications. Because of large differences in the pharmacokinetics of many drugs between humans and rodents, we have demonstrated that "behaviorally active" doses of many psychiatric drugs in laboratory animals do not reflect/model actual human clinical exposure and we have published on the need for clinically relevant and sustained drug administration in animal studies to mimic human exposures. Using a rat model, this study provides rigorous control of clinically relevant fetal exposure and will assess behavioral, gene expression and epigenomic changes in the offspring with an outcome that can inform clinical risks as well as identifying which medication may be the most appropriate clinical choice. Specific Aim 1 will provide animals with clinically relevant and verified drug exposure throughout gestation for the most commonly utilized atypical antipsychotics in the Emory University Women's Mental Health Program: quetiapine/norquetiapine, olanzapine, and risperidone/paliperidone. Specific Aim 2 will provide a behavioral assessment of development (motor and cognitive) prior to weaning and as juveniles (postnatal days 23-35) with the hypothesis that prenatal exposure to atypical antipsychotic drugs alters normal development compared to vehicle controls. Specific Aim 3 will utilize our skills in gene expression (transcriptome) and epigenetic analysis (whole genome methylation patterns) in two brain regions (frontal cortex and hippocampus) likely to be important targets for healthy neurobiological functioning and relevant to the behavioral studies in specific aim 2. We will also assay leukocytes collected from these offspring which might provide biomarkers as "windows" into the brain. These data will provide important basic science information regarding medication effects on the developing brain which can translate, based upon known function(s) of specific genes, into areas of clinical assessment that may be most closely watched by pediatricians following these children. The focus of these studies on a single class of medications, with generally similar clinical efficacy, may directly guide physicians and patients in determining which medication may provide the least risk.

描述（由申请人提供）：未经治疗的双相情感障碍会给母亲带来严重的后果，并且越来越多地使用非典型抗精神病药物作为情绪稳定剂和抗抑郁治疗的辅助药物，同时胎儿接触这些药物的机会也会增加。由于人类和啮齿动物之间许多药物的药代动力学存在巨大差异，我们已经证明，实验动物中许多精神药物的“行为活跃”剂量不能反映/模拟实际的人类临床暴露，并且我们已经发表了关于在动物研究中需要临床相关和持续的药物给药以模拟人类暴露的文章。这项研究使用大鼠模型，对临床相关的胎儿暴露进行严格控制，并将评估后代的行为、基因表达和表观基因组变化，其结果可以告知临床风险，并确定哪种药物可能是最合适的临床选择。具体目标 1 将为动物提供埃默里大学妇女心理健康计划中最常用的非典型抗精神病药物在整个妊娠期的临床相关且经过验证的药物暴露：喹硫平/去甲喹硫平、奥氮平和利培酮/帕利哌酮。具体目标 2 将提供断奶前和青少年（出生后 23-35 天）发育（运动和认知）的行为评估，假设与载体对照相比，产前接触非典型抗精神病药物会改变正常发育。具体目标 3 将利用我们在两个大脑区域（额叶皮层和海马体）的基因表达（转录组）和表观遗传分析（全基因组甲基化模式）方面的技能，这两个区域可能是健康神经生物学功能的重要目标，并与以下领域的行为研究相关：具体目标2。我们还将分析从这些后代中收集的白细胞，这些白细胞可能提供生物标志物作为进入大脑的“窗口”。这些数据将提供有关药物对发育中大脑的影响的重要基础科学信息，根据特定基因的已知功能，这些信息可以转化为跟踪这些儿童的儿科医生可能最密切关注的临床评估领域。这些研究的重点是单一类别的药物，具有大致相似的临床疗效，可以直接指导医生和患者确定哪种药物可以提供最小的风险。