Metabolic Effects of Antipsychotics in Children

抗精神病药物对儿童的代谢影响

• 批准号: 7096128
• 负责人: JOHN W. NEWCOMER
• 金额: $ 107.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-05 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096128
• 关键词: adipose tissue; adolescence (12-20); antipsychotic agents; bioenergetics; calorimetry; child behavior disorders; clinical research; clinical trial phase I; drug adverse effect; glucose metabolism; glucose tolerance test; glucose transport; human subject; human therapy evaluation; insulin sensitivity /resistance; lipid metabolism; magnetic resonance imaging; middle childhood (6-11); obesity; patient oriented research; pharmacokinetics; photon absorptiometry; risperidone; serotonin inhibitor

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.

描述（由申请人提供）：儿童中超重和肥胖、胰岛素抵抗、高血糖、血脂异常和 2 型糖尿病 (T2DM) 的患病率正在增加，据报告在美国儿童中流行。肥胖增加和相关的胰岛素敏感性降低是发生血脂异常、代谢综合征、T2DM、心血管疾病（例如心肌梗塞和中风的风险）、其他不良健康结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，一名严重肥胖的 20 岁非洲裔美国男性预计会损失 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代谢风险。抗精神病药物广泛用于儿童，某些药物比该年龄段的任何其他常用药物更能增加体重和肥胖。最近的研究还表明，一些抗精神病药物可能会影响胰岛素敏感性，而与肥胖无关，这表明代谢风险存在潜在的额外机制。非典型抗精神病药在儿童中的使用正在增加，并且由于报道的对各种精神疾病的攻击性和烦躁性的疗效而受到刺激。然而，尽管有报道体重增加达到惊人水平，但尚无针对儿童的研究敏感地量化广泛使用的非典型抗精神病药物的不良代谢影响。拟议的 随机临床试验旨在评估 7-18 岁未接受抗精神病药物治疗且患有各种儿童精神疾病且有攻击行为的儿童在接受奥氮平 (Zyprexa)、利培酮 (Risperdal) 或利培酮 (Risperdal) 前瞻性随机治疗 12 周期间，非典型抗精神病药物的代谢安全性阿立哌唑（Abilify）。主要目的是通过使用稳定同位素示踪方法测量全身葡萄糖和脂质动力学来评估抗精神病治疗对以下方面的影响：1) 骨骼肌（葡萄糖处理）、肝脏（葡萄糖产生）和脂肪组织（脂肪分解）中的胰岛素作用，以及 2 ）使用全身双能 X 射线吸收测定法 (DEXA) 和腹部磁共振成像 (MRI) 测量全身脂肪和腹部脂肪量。该研究的次要目的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，确定更多基础研究的目标，并指导临床决策。