Metabolic Effects of Antipsychotics in Children

描述（由申请方提供）：超重和肥胖、胰岛素抵抗、高血糖、血脂异常和2型糖尿病（T2 DM）在儿童中的患病率正在增加，在美国报告了儿童中的流行率。肥胖增加和相关的胰岛素敏感性降低是血脂异常、代谢综合征、T2 DM、心血管疾病（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人的影响最大，例如，严重肥胖的20岁非洲裔美国男性预计将失去20年的寿命。某些药物可增加局部脂肪组织质量和胰岛素抵抗，导致短期和长期代谢风险。抗精神病药物广泛用于儿童，某些药物在此年龄组中比任何其他常用药物产生更大的体重和肥胖增加。最近的研究还表明，一些抗精神病药物可能会影响胰岛素敏感性独立于肥胖，这表明一个潜在的代谢风险的额外机制。非典型抗精神病药在儿童中的使用正在增加，并且已被各种精神疾病中的攻击性和易怒的疗效所刺激。然而，没有一项儿童研究敏感地量化了广泛使用的非典型抗精神病药物的不良代谢作用，尽管有报告称体重增加达到了惊人的水平。拟议 一项随机临床试验，旨在评估奥氮平（再普乐）、利培酮（利培酮）或阿立哌唑（阿立哌唑）12周前瞻性随机治疗期间，7-18岁未接受过抗精神病药物治疗的具有攻击性的儿童在各种儿童精神疾病背景下的非典型抗精神病药物代谢安全性。主要目的是评价抗精神病药物治疗对以下方面的影响：1）通过使用稳定同位素示踪剂方法测量全身葡萄糖和脂质动力学，在骨骼肌（葡萄糖处置）、肝脏（葡萄糖产生）和脂肪组织（脂解）中的胰岛素作用; 2）使用全身双能X线吸收测定法（DEXA）和腹部磁共振成像（MRI）对全身脂肪和腹部脂肪质量的影响。该研究的次要目的包括评估治疗攻击和易怒症状的有效性。迫切需要相关数据来评估儿童抗精神病药物治疗的风险，确定额外基础研究的目标，并指导临床决策。

DESCRIPTION (provided by applicant): The prevalence of overweight and obesity, insulin resistance, hyperglycemia, dyslipidemia and type 2 diabetes mellitus (T2DM) are increasing in children, with epidemic rates reported in children in the United States. Increased adiposity and related reductions in insulin sensitivity are major risk factors for the development of dyslipidemia, metabolic syndrome, T2DM, cardiovascular disease (e.g., risk of myocardial infarction and stroke), other adverse health outcomes, and reduced psychosocial function. Reductions in lifespan attributable to obesity impact younger individuals most measurably such that, for example, a severely obese 20 year-old African American male is expected to lose 20 years of life. Certain medications can increase regional adipose tissue mass and insulin resistance, contributing to short- and long-term metabolic risk. Antipsychotic medications are extensively used in children, with certain agents producing greater increases in weight and adiposity than any other commonly used drugs in this age group. Recent studies also indicate that some antipsychotics may affect insulin sensitivity independent of adiposity, suggesting a potential additional mechanism for metabolic risk. The use of atypical antipsychotics in children is increasing, and has been stimulated by reported efficacy for aggression and irritability in a variety of psychiatric conditions. However, no study in children has sensitively quantified the adverse metabolic effects of widely used atypical antipsychotics despite reports of alarming levels of weight gain. The proposed randomized clinical trial aims to assess the metabolic safety of atypical antipsychotics in antipsychotic-naive children aged 7-18 with aggression in the setting of various childhood psychiatric disorders during 12 weeks of prospective, randomized treatment with olanzapine (Zyprexa), risperidone (Risperdal) or aripiprazole (Abilify). The primary aims are to evaluate antipsychotic treatment effects on 1) insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (lipolysis) by measuring whole-body glucose and lipid kinetics with stable isotope tracer methodology, and 2) on total body fat and abdominal fat mass using whole body dual energy x-ray absorptiometry (DEXA) and abdominal magnetic resonance imaging (MRI). Secondary aims of the study include the assessment of the effectiveness for treatment of symptoms of aggression and irritability. Relevant data are critically needed to assess the risks of antipsychotic therapy in children, to identify targets for additional basic research, and to guide clinical decision-making.