Metabolic Effects of Antipsychotics in Children (MEAC)

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT00205699
First received: September 13, 2005
Last updated: March 12, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Aggression
ADHD
Oppositional Defiant Disorder
PDD
Bipolar Disorder
Drug: risperidone
Drug: olanzapine
Drug: aripiprazole
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Metabolic Effects of Antipsychotics in Children

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • 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 ]

Enrollment: 240
Study Start Date: October 2004
Study Completion Date: July 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: randomized treatment Drug: risperidone
randomized to begin 12 week trial of ziprasidone
Other Name: Risperdal
Drug: olanzapine
randomized to begin 12 week trial of olanzapine
Other Name: Zyprexa
Drug: aripiprazole
randomized to 12 week trial of aripiprazole
Other Name: Abilify

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   6 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Aged 6-18 years
  • Generally healthy and a score of ≥ 18 on the Aberrant Behavior Checklist in the context of one or more Axis I Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) childhood psychiatric disorders, including conduct disorder, oppositional defiant disorder, disruptive behavior disorder, autism, pervasive developmental disorder, attention deficit disorder, schizophrenia and bipolar affective disorders
  • Children's Global Assessment Scale (CGAS) score ≤ 60
  • Not previously treated with an antipsychotic; individual subjects with remote, brief prior antipsychotic exposure may be considered for enrollment by the PI on a case by case basis
  • Patient assent and informed consent obtained from the parent or guardian
  • No clinically significant (based on PI determination) changes in permitted medications (e.g., stimulants and selective serotonin reuptake inhibitors [SSRIs]) for approximately 1 month prior to Baseline evaluations

Exclusion Criteria:

  • Active suicidality or primary dx of major depressive disorder
  • Any lifetime use of antipsychotics or non-serotonin selective reuptake inhibitor (non-SSRI) anti-depressants
  • The presence of any serious medical disorder, based on PI determination, that may confound the assessment of relevant biologic measures or diagnoses, including:

    • significant organ system dysfunction;
    • endocrine disease, including type 1 or type 2 diabetes mellitus;
    • coagulopathy;
    • anemia;
    • or acute infection.
  • Subjects regularly taking any glucose lowering agent, lipid lowering agent, exogenous testosterone, recombinant human growth hormone, or any other endocrine agent that might confound substrate metabolism, oral glucocorticoids (glucocorticoid inhalants and nasal sprays are permitted), antihistamines, sedating antihistamines (non-sedating antihistamines such as but not limited to Claritin (loratadine) and Zyrtec (cetirizine) are permitted), and certain mood stabilizing agents, as some medications may themselves worsen or otherwise alter weight gain, glucose and lipid regulation or otherwise make it difficult to assess the effects of the antipsychotic alone; (note that exposure to many psychotropic agents including stimulants and SSRI's is permitted in order to maintain the generalizability of the sample);
  • Intelligence quotient (IQ) < 70 (based on school records and/or evaluation by clinician)
  • current substance abuse
  • Past history or currently has dyskinesia
  • Stimulant dosage significantly higher (per PI judgment)than the equivalent of approximately 2mg/kg/day methylphenidate equivalent dose.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00205699

Locations
United States, Missouri
Washington University School of Medicine, Psychiatry Dept.
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: John W. Newcomer, M.D. Washington University School of Medicine and Florida Atlantic University
Principal Investigator: Ginger Nicol, MD Washington University School of Medicine
  More Information

Additional Information:
No publications provided

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00205699     History of Changes
Other Study ID Numbers: NIMH, R01 MH72912
Study First Received: September 13, 2005
Last Updated: March 12, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Washington University School of Medicine:
Antipsychotic treatment
Insulin action/secretion
Abdominal fat mass, total body fat
Aggression
Resting metabolic rates

Additional relevant MeSH terms:
Aggression
Bipolar Disorder
Attention Deficit and Disruptive Behavior Disorders
Behavioral Symptoms
Affective Disorders, Psychotic
Mood Disorders
Mental Disorders
Mental Disorders Diagnosed in Childhood
Antipsychotic Agents
Risperidone
Olanzapine
Aripiprazole
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Psychotropic Drugs
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Dopamine Antagonists
Dopamine Agents
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on April 22, 2014