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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-P (01))
Program Officer
Wagner, Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Newcomer, John W; Hennekens, Charles H (2007) Severe mental illness and risk of cardiovascular disease. JAMA 298:1794-6