Measurement of Cardiometabolic Risk in Antipsychotic-Treated Children

描述（由申请人提供）：此K23奖申请与最近的IOM研究优先列表中的多个主题领域以及最近的IOM报告简报和白宫“让我们行动”运动有关。该奖项将支持辅导，教学培训和额外的职业发展活动，为候选人提供特别适合在患有精神健康障碍的儿童的肥胖和代谢风险领域发展专业知识的机会。申请人的近期职业目标是进一步发展肥胖和心脏代谢风险的代谢机制测量方面的专业知识。申请人的长期职业目标是建立自己作为一个独立的调查研究儿童肥胖和心脏代谢风险的精神病人群。从计划的活动中产生的专业综合知识在儿童精神病学领域将是独一无二的，并将在未来几十年为这一高度优先、服务不足的主题领域提供所需的研究资源。近几十年来，美国儿童期肥胖和2型糖尿病的患病率（两者都是心血管风险的预测因子）已增加到流行病的比例。患有精神疾病的儿童，特别是那些接受抗精神病药物治疗的儿童，患肥胖症和相关风险状况的风险更高。尽管已知与儿童期发病与成人期发病肥胖相关的肥胖相关结局（包括过早死亡）增加，但对儿童中的这些风险仍然认识不足。各种评估心脏代谢风险的无创技术已开始应用于儿童，包括超声测量颈动脉内膜中层厚度（IMT），以及1H磁共振波谱（MRS）测量肝脏和心脏甘油三酯含量。这些措施允许早期，非侵入性的研究代谢风险。不幸的是，这些有希望的方法都没有应用于精神疾病儿童的高危人群，并且根本没有对儿童的心脏甘油三酯含量进行评估，这阻碍了风险的准确表征或干预措施的有效性，从而降低了这一脆弱人群的风险。本申请的研究部分侧重于使用敏感的疾病风险早期生物标志物，包括肝脏甘油三酯含量（HTGC）以及心脏甘油三酯含量（CTGC）和颈动脉IMT，分别与糖尿病和心血管疾病风险直接相关。这两项研究计划的总体目标是在接受治疗和未接受治疗的精神健康障碍儿童中使用这些敏感标志物表征可测量风险的水平，并评估在接受完善的行为减肥干预的儿童中使用这些生物标志物可以观察到的风险变化幅度。这将通过两项研究来完成：1）年龄、性别和体重指数（BMI）匹配的三组超重/肥胖儿童的CTGC、HTCG和IMT值的病例对照横断面比较：抗精神病药物治疗的精神病儿童;未接受抗精神病药物治疗的精神病儿童和未接受治疗但无精神病的儿童（也将包括一小部分瘦健康参与者的参考组）和2）12周行为减肥干预效果的随机对照试验（与饮食和运动教育相比），超重/肥胖抗精神病药物治疗儿童的HTGC和IMT（健康超重/肥胖儿童的小参考组将仅接受积极干预）。主要分析计划将分别使用ANOVA和ANCOVA来检验一组关于研究样本中心脏代谢风险水平的重点假设，以及已知减肥干预措施可以改变这些敏感风险生物标志物的程度。 ) 公共卫生相关性：近几十年来，儿童期肥胖和2型糖尿病这两种心脏代谢风险的预测因子已增加到流行病的比例，而接受抗精神病药物治疗的精神疾病儿童患肥胖、2型糖尿病和与心血管疾病相关的早期死亡率的风险更高。现有技术可用于代谢风险的早期非侵入性研究，例如肝脏和心脏脂质含量以及颈动脉壁斑块的成像，但尚未在精神病儿童的高危人群中进行研究。该K23奖将赞助一名候选人的职业发展，该候选人具有独特的资格，通过支持一项创新研究项目，进一步研究患有精神健康障碍的儿童的肥胖和代谢风险，该项目评估了这些敏感的早期生物标志物在患有精神健康障碍的儿童中的使用。

DESCRIPTION (provided by applicant): This K23 award application is relevant to multiple topic areas in the recent IOM research priority list, as well as the recent IOM report brief and White House "Let's Move" Campaign focused on childhood obesity. The award will support mentoring, didactic training and additional career development activities for a candidate uniquely suited to develop expertise in the area of obesity and metabolic risk in children with mental health disorders. The applicant's immediate career goals are to further develop expertise in the measurement of metabolic mechanisms underlying obesity and cardiometabolic risk. The applicant's long-term career goal is to establish herself as an independent investigator studying childhood obesity and cardiometabolic risk in psychiatric populations. The specialized combined expertise that will emerge from the planned activities will be unique in the field of child psychiatry and will provide a resource for needed research in this high-priority, underserved topic area for decades to come. The US prevalence of childhood-onset obesity and type 2 diabetes, both predictors of cardiovascular risk, have increased to epidemic proportions in recent decades. Children with mental illness, especially those treated with antipsychotic medications, are at additional risk for obesity and related risk conditions. Despite known increases in obesity-related outcomes, including premature mortality, associated with childhood-onset versus adult-onset obesity, there remains an under-appreciation of these risks in children. A variety of noninvasive techniques to assess cardiometabolic risk have begun to be applied in children, including carotid intima media thickness (IMT) measured by ultrasound, and hepatic and cardiac triglyceride content measured by 1H Magnetic Resonance Spectroscopy (MRS). These measures allow for the early, noninvasive study of metabolic risk. Unfortunately, none of these promising methods have been applied to the high-risk population of children with psychiatric disorders, and cardiac triglyceride content has not been evaluated in children at all, preventing accurate characterization of risk or the effectiveness of interventions the reduce risk in this vulnerable population. The research portion of this application focuses on the use of sensitive, early biomarkers of disease risk, including hepatic triglyceride content (HTGC), as well as cardiac triglyceride content (CTGC) and carotid IMT, directly relevant to diabetes and cardiovascular disease risk, respectively. The overall aim of this two-study research plan is to characterize the level of measurable risk using these sensitive markers in treated and untreated children with mental health disorders, and to evaluate the magnitude of change in risk that can be observed using these biomarkers in children receiving a well- established behavioral weight-loss intervention. This will be accomplished using two studies: 1) A case control cross sectional comparison of CTGC, HTCG and IMT values in three groups of overweight/obese children who are age-, gender- and body mass index (BMI) percentile-matched: antipsychotic treated mentally ill children; mentally ill children not treated with antipsychotics and untreated children with no mental illness (a small reference group of lean healthy participants will also be included) and 2) A randomized controlled test of the effects of a 12-week behavioral weight loss intervention (versus diet and exercise education) on CTGC, HTGC and IMT in overweight/obese antipsychotic-treated children (a small reference group of healthy overweight/obese children will receive the active intervention only). The primary analytic plan will utilize ANOVA and ANCOVA, respectively, to test a focused set of hypotheses concerning the level of cardiometabolic risk in the study samples and the extent to which known weight loss interventions can modify these sensitive risk biomarkers. ) PUBLIC HEALTH RELEVANCE: Childhood onset of obesity and type 2 diabetes, both predictors of cardiometabolic risk have increased to epidemic proportions in recent decades, and children with mental illness treated with antipsychotic medications are at additional risk for obesity, type 2 diabetes and early mortality related to cardiovascular disease. Techniques exist for the early, noninvasive study of metabolic risk, such as imaging of liver and heart lipid content, and carotid artery wall plaques, but have not been studied in the high-risk population of mentally ill children. This K23 award will sponsor the career development of a candidate uniquely qualified to further study obesity and metabolic risk in children with mental health disorders by supporting an innovative research project that evaluates the use of these sensitive, early biomarkers of carbiometabolic risk in children with mental health disorders.