METABOLIC EFFECTS OF ANTIPSYCHOTICS IN CHILDREN

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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增加，这些疾病在美国（US）儿童中的流行率也在增加。 肥胖增加和胰岛素敏感性的相关降低，也称为胰岛素抵抗，是T2 DM、心血管疾病（CVD，例如，心肌梗死和中风的风险）、其他不良健康后果和心理社会功能降低。 肥胖导致的寿命缩短对年轻的高危人群影响最大，20岁的非洲裔美国男性严重肥胖者预计会失去20年的寿命。 随着使用非典型抗精神病药物治疗品行障碍和其他攻击性行为障碍的增加，对抗精神病药物影响（包括体重增加）、血糖、血脂和肥胖的担忧也有所增加，重点关注广泛使用的新药氯氮平和奥氮平。 腹部肥胖增加可继发性降低胰岛素敏感性，抗精神病药物可增加肥胖。 然而，药物对血糖控制和胰岛素作用的影响也可能与肥胖的差异无关。 本项目的目的是a）评估选定的抗精神病药物治疗对骨骼肌胰岛素作用的影响（葡萄糖处置）、肝脏（葡萄糖生成）和脂肪组织（脂解），B）评价所选抗精神病药物治疗对胰岛素分泌的影响，c）评价所选抗精神病药物治疗对腹部脂肪量、总体脂和总去脂量的影响，d）评价所选抗精神病药物治疗对静息代谢率（碳水化合物和脂肪氧化）的影响。 这些假设将通过以下方式进行评估：1）使用“金标准”稳定同位素示踪剂法测定全身葡萄糖和脂质动力学，2）使用双能X射线吸收测定法和磁共振成像测定身体组成，以及3）葡萄糖耐量和脂质谱的纵向变化。 这些目标将在从未接受过抗精神病药物治疗的诊断为行为障碍的非糖尿病儿童和青少年患者中得到解决。 迫切需要相关数据来针对基础研究，确定长期心血管后果，并计划治疗干预。

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 overweight 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. Reductions in lifespan attributale to obesity impact younger, at-risk individuals most measurably, with severly obese20-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 projects aims to a) evaluate effects of selected antipsyochotic treatment 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 treatments on resting metabolic rates (carbohydrate and fat oxidation) e) evaluate effects of selected antipsychotic treatments on efficacy for symptoms of aggression. These hypotheses will be evaluated by measuring 1) whole-body glucose and lipid kinetics with the use of "gold standard" stable isotope tracer methodoloby, 2) body composition using dual energy x-ray absorptiometry and magnetic resonance imaging, adn 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.