Metabolic Effects of Antipsychotics in Children

描述（由申请人提供）：超重和肥胖、胰岛素抵抗、高血糖、血脂异常和2型糖尿病（T2DM）在儿童中的患病率正在增加，据报道在美国儿童中流行。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、2型糖尿病、心血管疾病（如心肌梗死和中风的风险）、其他不良健康结果和社会心理功能下降的主要危险因素。肥胖导致的寿命缩短对年轻人的影响最为显著，例如，一名严重肥胖的20岁非裔美国男性预计将减少20年的寿命。某些药物会增加局部脂肪组织质量和胰岛素抵抗，增加短期和长期的代谢风险。抗精神病药物在儿童中广泛使用，在这个年龄组中，某些药物比其他常用药物更容易增加体重和肥胖。最近的研究还表明，一些抗精神病药物可能独立于肥胖影响胰岛素敏感性，提示代谢风险的潜在附加机制。非典型抗精神病药物在儿童中的使用正在增加，并受到各种精神疾病中攻击和易怒的报道效果的刺激。然而，尽管有报道称体重增加达到了惊人的水平，但还没有针对儿童的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影响。提出的

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.