Metabolic Effects of Antipsychotics in Children (MEAC)
The prevalence of overweight and obesity, insulin resistance, hyperglycemia, dyslipidemia and type 2 diabetes mellitus (T2DM) are increasing in children. Increased adiposity and related reductions in insulin sensitivity are major risk factors for the development of hyperglycemia, dyslipidemia, T2DM, and cardiovascular disease. Reductions in lifespan attributable to obesity impact younger individuals most measurably. Antipsychotic medications are extensively used in children, with certain agents producing greater increases in weight and adiposity than other commonly used drugs in this age group. Increased use of atypical antipsychotics in children has been stimulated by reported efficacy for behaviors such as aggression that can occur in a variety of disorders. However, no previous randomized clinical trial has sensitively quantified the metabolic effects of widely used atypical antipsychotics. This study would address clinically relevant questions concerning both the safety and efficacy of these agents in antipsychotic-naïve aggressive children with conduct disorder, with permitted co-morbidity for a variety of psychiatric conditions including attention deficit disorder, bipolar disorder, high functioning pervasive developmental disorder, autism and schizophrenia. The project aims to describe and compare the outcome of 12 weeks of prospective, randomized treatment with olanzapine, risperidone or aripiprazole on insulin action in skeletal muscle, liver and adipose tissue, insulin secretion, abdominal fat mass, total body and fat-free mass, resting metabolic rates, efficacy for symptoms of aggression and non-metabolic adverse events. Children aged 6-18 will be studied, exploring effects of stimulant therapy and age-related differences in vulnerability to treatment-induced adverse metabolic changes. Aims are addressed by measuring glucose and lipid kinetics with stable isotope tracers, area-under-the-curve for post-load insulin and c-peptide during frequently sampled oral glucose tolerance tests, body composition with dual energy x-ray absorptiometry and magnetic resonance imaging (MRI), indirect calorimetry and standardized assessments of efficacy and adverse events. Treatment effects will primarily be analyzed using repeated measures analysis of covariance (ANCOVA), controlling for baseline adiposity and other key risk variables. Relevant data are critically needed to target clinical therapy and basic research, identify medical risks, and guide regulatory decisions in this vulnerable population.
Oppositional Defiant Disorder
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Metabolic Effects of Antipsychotics in Children|
- To evaluate effects of selected antipsychotic treatments on insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (lipolysis). [ Time Frame: 12 weeks and 6 months ] [ Designated as safety issue: No ]
|Study Start Date:||October 2004|
|Study Completion Date:||July 2011|
|Primary Completion Date:||June 2011 (Final data collection date for primary outcome measure)|
|Active Comparator: randomized treatment||
randomized to begin 12 week trial of ziprasidone
Other Name: RisperdalDrug: olanzapine
randomized to begin 12 week trial of olanzapine
Other Name: ZyprexaDrug: aripiprazole
randomized to 12 week trial of aripiprazole
Other Name: Abilify
The proposed randomized clinical trial aims to assess both the safety and efficacy of atypical antipsychotic agents in antipsychotic-naive aggressive children with various childhood psychiatric disorders during 12 weeks of prospective, randomized treatment with olanzapine (Zyprexa), risperidone (Risperdal) or aripiprazole (Abilify).
Aim 1: To evaluate effects of selected antipsychotic treatments on insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (lipolysis).
Aim 2: To evaluate effects of selected antipsychotic treatments on insulin secretion.
Aim 3: To evaluate effects of selected antipsychotic treatments on abdominal fat mass, total body fat and total fat-free mass.
Aim 4: To evaluate effects of selected antipsychotic treatments on resting metabolic rates (carbohydrate and fat oxidation).
Aim 5: To evaluate effects of selected antipsychotic treatments on efficacy for symptoms of aggression.
Important secondary aims include the assessment of non-metabolic adverse events, and the assessment of each antipsychotic treatment condition in children with and without concomitant stimulant therapy. Reduced adverse metabolic effects are hypothesized during concomitant stimulant therapy. Children aged 7-18 will be studied, exploring age-related differences in vulnerability to treatment-induced adverse metabolic changes. Finally, treatment effects on regulatory hormones, including cortisol, glucagon, leptin, ghrelin and adiponectin will be explored. This will allow the assessment of possible confounds to the interpretation of the primary hypotheses. It will also permit the generation of additional hypotheses concerning mechanisms contributing to drug-induced changes in weight and fat mass. Relevant data on the primary and secondary aims are critically needed to assess the risks as well as benefits of clinical therapy in children, to identify needs for additional basic research, as well as to guide administrative and regulatory decision-making.
|United States, Missouri|
|Washington University School of Medicine, Psychiatry Dept.|
|St. Louis, Missouri, United States, 63110|
|Principal Investigator:||John W. Newcomer, M.D.||Univeristy of Miami|
|Principal Investigator:||Ginger Nicol, MD||Washington University School of Medicine|