METABOLIC EFFECTS OF ANTIPSYCHOTICS IN CHILDREN

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。超重和肥胖、胰岛素抵抗和2型糖尿病(T2 DM)在儿童中的患病率正在上升，这些疾病在美国儿童中的流行率也在上升。肥胖增加和相关的胰岛素敏感性降低，也称为胰岛素抵抗，是发展为T2 DM、心血管疾病(心血管疾病，如心肌梗塞和中风的风险)、其他不良健康后果和心理社会功能下降的主要危险因素。肥胖导致的寿命缩短对年轻、高危人群的影响最明显，严重肥胖的20岁非裔美国男性预计将失去20年的寿命。随着非典型抗精神病药物用于治疗行为障碍和其他攻击性行为障碍的使用增加，人们对抗精神病药物效应的担忧也增加了，包括体重增加、对血糖、血脂和肥胖的影响，重点是广泛使用的新药氯氮平和奥氮平。腹部肥胖症的增加会继而降低胰岛素敏感性，而抗精神病药物会增加肥胖症。然而，药物对血糖控制和胰岛素作用的影响也可能与肥胖程度的差异无关。本项目旨在a)评估部分抗精神病药物对骨骼肌(葡萄糖处理)、肝脏(葡萄糖产生)和脂肪组织(脂肪分解)胰岛素作用的影响，b)评估部分抗精神病药物对胰岛素分泌的影响，c)评估部分抗精神病药物对腹部脂肪质量、全身脂肪和总脱脂质量的影响，d)评估部分抗精神病药物对静息代谢率(碳水化合物和脂肪氧化)的影响，e)评估部分抗精神病药物对攻击症状疗效的影响。这些假设将包括：1)使用“金标准”稳定同位素示踪方法测量全身葡萄糖和脂肪动力学；2)使用双能X射线吸收法和磁共振成像测量身体成分；3)糖耐量和脂肪含量的纵向变化。这些目标将针对被诊断为品行障碍的非糖尿病儿童和青少年患者，他们从未接受过抗精神病药物治疗。迫切需要相关数据来瞄准基础研究，确定长期心血管后果，并计划治疗干预措施。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The prevalence of everweight and obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) are increasing in children, with epidemic rates of these conditions in children in the United States (US). Increased adiposity and related reductions in insulin sensitivity, also referred to as insulin resistance, are major risk factors for the development of T2DM, cardiovascular disease (CVD, e.g., risk of myocardial infarction and stroke), other adverse health outcomes, and reduced psychosocial function. Reduction in lifespan attributable to obesity impact younger, at-risk individuals most measurably, with severly obese 20 year-old African American males expected to lose 20 years of life. With the use of atypical antipsychotics for treatment of conduct disorder and other aggressive behavior disorders on the rise, concerns about antipsychotic effects, including weight gain, on glucose, lipids and adiposity have also increased, focusing on the widely-used newer medications, clozapine and olanzapine. Increased abdominal adiposity can secondarily decrease insulin sensitivity and antipsychotics can increase adiposity. However, medication effects on glucose control and insulin action may also occur independent of differences in adiposity. This project aims to a) evaluate effects of selected antipsychotic treatments on insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (lipolysis), b) evaluate effects of selected antipsychotic treatments on insulin secretion c) evaluate effects of selected antipsychotic treatments on abdominal fat mass, total body fat and total fat-free mass d) evaluate effects of selected antipsychotic treatment on resting metabolic rates (carbohydrate and fat oxidation) e) evaluate effects of selected antipsychotic treatments on efficacy for symptoms of aggression. These hypoetheses will be measuring 1) whole-body glucose and lipid kinetics with the use of "gold-standard" stable isotope tracer methodology, 2) body composition using dual energy x-ray absorptiometry and magnetic resonance imaging, and 3) longitudinal changes in glucose tolerance and lipid profiles. The aims will be addressed in non-diabetic child and adolescent patients diagnosed with conduct disorder who have never been treated with an antipsychotic medication. Relevant data is critically needed to target basic research, identify long-term cardiovascular consequences, and plan therapeutic interventions.