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Metabolic Effects of Antipsychotics in Children (MEAC)

Primary Purpose

Aggression, Attention Deficit-Hyperactivity, Oppositional Defiant Disorder

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
risperidone
olanzapine
aripiprazole
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Aggression focused on measuring Antipsychotic treatment, Insulin action/secretion, Abdominal fat mass, total body fat, Aggression, Resting metabolic rates

Eligibility Criteria

6 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Washington University School of Medicine, Psychiatry Dept.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

aripiprazole

olanzapine

risperidone

Arm Description

Participants in this group will be randomized to flexibly-dosed treatment with aripiprazole.

Participants in this group will be randomized to flexibly-dosed treatment with olanzapine.

Participants in this group will be randomized to flexibly-dosed treatment with risperidone.

Outcomes

Primary Outcome Measures

Change in DEXA % Body Fat
This study hypothesized that antipsychotic treatment would increase percent total body fat, as measured by whole body dual energy x-ray absorptiometry (DEXA), with larger adverse effects for olanzapine.
Change in Insulin-stimulated Glucose Rate of Disappearance (Glucose Rd)
This study hypothesized that antipsychotic treatment would decrease insulin sensitivity at muscle, as measured by the insulin-stimulated rate of disappearance of glucose (glucose Rd), with larger adverse effects for olanzapine.

Secondary Outcome Measures

Change in Insulin-stimulated Glycerol Rate of Appearance (Glycerol Ra)
This study hypothesized that antipsychotic treatment would decrease insulin sensitivity at adipose tissue, as measured by the insulin-stimulated rate of disappearance of glycerol (glycerol Ra), with larger adverse effects for olanzapine.
Change in Insulin-stimulated Glucose Rate of Appearance (Glucose Ra)
This study hypothesized that antipsychotic treatment would decrease hepatic insulin sensitivity, as measured by the rate of appearance of glucose (glucose Ra), with larger adverse effects for olanzapine.
Change in MRI-measured Visceral Abdominal Fat
This study hypothesized that antipsychotic treatment would increase visceral abdominal fat, as measured by abdominal magnetic resonance imaging (MRI), with larger adverse effects for olanzapine.
Change in MRI-measured Subcutaneous Abdominal Fat
This study hypothesized that antipsychotic treatment would increase subcutaneous abdominal fat, as measured by abdominal magnetic resonance imaging (MRI), with larger adverse effects for olanzapine.

Full Information

First Posted
September 13, 2005
Last Updated
June 13, 2018
Sponsor
Washington University School of Medicine
Collaborators
National Institute of Mental Health (NIMH)
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1. Study Identification

Unique Protocol Identification Number
NCT00205699
Brief Title
Metabolic Effects of Antipsychotics in Children
Acronym
MEAC
Official Title
Metabolic Effects of Antipsychotics in Children
Study Type
Interventional

2. Study Status

Record Verification Date
June 2018
Overall Recruitment Status
Completed
Study Start Date
April 2006 (Actual)
Primary Completion Date
March 2011 (Actual)
Study Completion Date
July 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
National Institute of Mental Health (NIMH)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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, abdominal fat mass, total body and fat-free mass, 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, body composition with dual energy x-ray absorptiometry and magnetic resonance imaging (MRI), and standardized assessments of efficacy and adverse events. Relevant data are critically needed to target clinical therapy and basic research, identify medical risks, and guide regulatory decisions in this vulnerable population.
Detailed Description
This randomized clinical trial assesses 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, risperidone or aripiprazole. Aim 1: To evaluate effects of selected antipsychotic treatments on insulin action in muscle (glucose disposal), liver (glucose production) and adipose tissue (lipolysis). Aim 2: To evaluate effects of selected antipsychotic treatments on abdominal fat mass, total body fat and total fat-free mass.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aggression, Attention Deficit-Hyperactivity, Oppositional Defiant Disorder, Pervasive Development Disorders, Bipolar Disorder
Keywords
Antipsychotic treatment, Insulin action/secretion, Abdominal fat mass, total body fat, Aggression, Resting metabolic rates

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
144 (Actual)

8. Arms, Groups, and Interventions

Arm Title
aripiprazole
Arm Type
Active Comparator
Arm Description
Participants in this group will be randomized to flexibly-dosed treatment with aripiprazole.
Arm Title
olanzapine
Arm Type
Active Comparator
Arm Description
Participants in this group will be randomized to flexibly-dosed treatment with olanzapine.
Arm Title
risperidone
Arm Type
Active Comparator
Arm Description
Participants in this group will be randomized to flexibly-dosed treatment with risperidone.
Intervention Type
Drug
Intervention Name(s)
risperidone
Other Intervention Name(s)
Risperdal
Intervention Description
randomized to begin 12 week trial of risperidone
Intervention Type
Drug
Intervention Name(s)
olanzapine
Other Intervention Name(s)
Zyprexa
Intervention Description
randomized to begin 12 week trial of olanzapine
Intervention Type
Drug
Intervention Name(s)
aripiprazole
Other Intervention Name(s)
Abilify
Intervention Description
randomized to 12 week trial of aripiprazole
Primary Outcome Measure Information:
Title
Change in DEXA % Body Fat
Description
This study hypothesized that antipsychotic treatment would increase percent total body fat, as measured by whole body dual energy x-ray absorptiometry (DEXA), with larger adverse effects for olanzapine.
Time Frame
12 weeks
Title
Change in Insulin-stimulated Glucose Rate of Disappearance (Glucose Rd)
Description
This study hypothesized that antipsychotic treatment would decrease insulin sensitivity at muscle, as measured by the insulin-stimulated rate of disappearance of glucose (glucose Rd), with larger adverse effects for olanzapine.
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Change in Insulin-stimulated Glycerol Rate of Appearance (Glycerol Ra)
Description
This study hypothesized that antipsychotic treatment would decrease insulin sensitivity at adipose tissue, as measured by the insulin-stimulated rate of disappearance of glycerol (glycerol Ra), with larger adverse effects for olanzapine.
Time Frame
12 weeks
Title
Change in Insulin-stimulated Glucose Rate of Appearance (Glucose Ra)
Description
This study hypothesized that antipsychotic treatment would decrease hepatic insulin sensitivity, as measured by the rate of appearance of glucose (glucose Ra), with larger adverse effects for olanzapine.
Time Frame
12 weeks
Title
Change in MRI-measured Visceral Abdominal Fat
Description
This study hypothesized that antipsychotic treatment would increase visceral abdominal fat, as measured by abdominal magnetic resonance imaging (MRI), with larger adverse effects for olanzapine.
Time Frame
12 weeks
Title
Change in MRI-measured Subcutaneous Abdominal Fat
Description
This study hypothesized that antipsychotic treatment would increase subcutaneous abdominal fat, as measured by abdominal magnetic resonance imaging (MRI), with larger adverse effects for olanzapine.
Time Frame
12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John W. Newcomer, MD
Organizational Affiliation
Florida Atlantic University and Washington University School of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ginger Nicol, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Study Director
Facility Information:
Facility Name
Washington University School of Medicine, Psychiatry Dept.
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
29898210
Citation
Nicol GE, Yingling MD, Flavin KS, Schweiger JA, Patterson BW, Schechtman KB, Newcomer JW. Metabolic Effects of Antipsychotics on Adiposity and Insulin Sensitivity in Youths: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Aug 1;75(8):788-796. doi: 10.1001/jamapsychiatry.2018.1088.
Results Reference
derived

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Metabolic Effects of Antipsychotics in Children

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