Metabolic Effects of Antipsychotics in Children

描述(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(T2 DM)在儿童中的患病率正在上升，据报道，美国儿童中的流行率。肥胖增加和胰岛素敏感性降低是发生血脂异常、代谢综合征、2型糖尿病、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人的影响最为明显，例如，一名20岁的非洲裔美国男性严重肥胖，预计将失去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，从而导致短期和长期的代谢风险。抗精神病药物在儿童中广泛使用，某些药物导致的体重和肥胖增加比这个年龄段的任何其他常用药物都要大。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，而不是肥胖，这表明了代谢风险的潜在额外机制。非典型抗精神病药物在儿童中的使用正在增加，并已被报道在各种精神疾病中对攻击性和易怒的疗效刺激。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影响，尽管有报道称体重增加的水平令人震惊。建议数 随机临床试验旨在评估在奥氮平(Zyprexa)、利培酮(Risperidone)或阿立哌唑(Abilify)前瞻性随机治疗12周期间，在各种儿童精神障碍的背景下，7-18岁有攻击性的抗精神病儿童使用非典型抗精神病药物的代谢安全性。主要目的是通过稳定同位素示踪法测量全身葡萄糖和脂肪动力学，评估抗精神病药物对1)骨骼肌(葡萄糖处置)、肝脏(葡萄糖产生)和脂肪组织(脂肪分解)的胰岛素作用，以及2)使用全身双能X射线吸收法(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。这项研究的次要目标包括评估治疗攻击性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靶点，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.