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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：
8843911
负责人：
MICHAEL JOSEPH OWENS
金额：
$ 31.8万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8843911
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 Health Heavy Metals Hippocampus (Brain)Human Individual Investigation Joints Laboratory Animals Length Leukocytes Major Depressive Disorder Measures Mental Health Mental disorders Methods Modeling Molecular Target Monitor Mood stabilizers Mothers Motor Neurobiology Nicotine Outcome Parents Patients 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 behavioral study clinical decision-making clinical efficacy clinical risk clinically relevant design epigenome epigenomics evidence based guidelines exposed human population frontal lobe in utero male methylation pattern monoamine novel offspring olanzapine pediatrician postnatal pre-clinical pregnant prenatal prenatal exposure programs prospective 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对母亲有严重后果，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替代品，胎儿暴露于这些药物的相关增加。由于人类和啮齿类动物之间许多药物的药代动力学存在很大差异，我们已经证明，许多精神病药物在实验室动物中的“行为活性”剂量不能反映/模拟实际的人类临床暴露，我们已经发表了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。使用大鼠模型，该研究提供了对临床相关胎儿暴露的严格控制，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Emory University Women's Mental Health Program中最常用的非典型抗精神病药物（奎替鲁/诺奎替鲁、奥氮平和利培酮/帕潘立酮）在整个妊娠期的临床相关和经验证的药物暴露。具体目标2将提供断奶前和幼龄（出生后23-35天）发育（运动和认知）的行为评估，假设产前暴露于非典型抗精神病药物与溶剂对照相比改变了正常发育。具体目标3将利用我们在两个大脑区域（额叶皮层和海马）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靶点，并与以下行为研究相关：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影响的重要基础科学信息，这些信息可以根据特定基因的已知功能转化为临床评估领域，这些领域可能是儿科医生最密切关注的。这些研究的重点是单一类别的药物，通常具有相似的临床疗效，可以直接指导医生和患者确定哪种药物可能提供最小的风险。