Prenatal atypical antipsychotic exposure

产前非典型抗精神病药物暴露

• 批准号: 9069456
• 负责人: MICHAEL JOSEPH OWENS
• 金额: $ 32.03万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/9069456
• 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; 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; Population; Pregnancy; Process; Psychotic Disorders; Psychotic Mood Disorders; Public Health; Publications; Publishing; RNA Splicing; Rattus; 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; male; methylation pattern; monoamine; novel; offspring; olanzapine; pediatrician; postnatal; pre-clinical; pregnant; prenatal; prenatal exposure; programs; prospective; quetiapine; receptor; relapse risk; relating to nervous system; reproductive; risk minimization; skills; transcriptome; transcriptome sequencing; treatment choice; valproate; whole genome

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(申请人提供)：未经治疗的双相情感障碍对母亲有严重的后果，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的使用越来越多，胎儿接触这些药物的相关增加。由于许多药物在人类和啮齿动物之间的药代动力学有很大的差异，我们已经证明了许多精神药物在实验室动物中的“行为活性”剂量不能反映/模拟人类的实际临床暴露，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必要性。使用大鼠模型，这项研究提供了临床相关的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，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将在整个妊娠期间为动物提供临床相关和经验证的药物暴露，用于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：奎硫平/去甲奎硫平、奥氮平和利培酮/帕利培酮。特定目标2将提供对断奶前和青少年(出生后23-35天)发育(运动和认知)的行为评估，假设与车辆对照组相比，产前接触非典型抗精神病药物会改变正常发育。特殊目标3将利用我们在两个大脑区域(额叶皮质和海马体)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 具体目标2。我们还将分析从这些后代中收集的白细胞，这些白细胞可能会提供生物标志物，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，这些信息可以根据特定基因的已知功能(S)转化为临床评估领域，可能是跟踪这些儿童的儿科医生最密切关注的领域。这些研究的重点是临床疗效大致相似的单一类药物，可能会直接指导医生和患者确定哪种药物可能提供的风险最小。