Metabolic Effects of Antipsychotics in Children

Study Overview
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Brief Summary
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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
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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.

Official Title
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Metabolic Effects of Antipsychotics in Children

Conditions
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Aggression, Attention Deficit-Hyperactivity, Oppositional Defiant Disorder, Pervasive Development Disorders, Bipolar Disorder

Intervention / Treatment
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* Drug: risperidone
* Drug: olanzapine
* Drug: aripiprazole


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: aripiprazole<br>Participants in this group will be randomized to flexibly-dosed treatment with aripiprazole. | Drug: aripiprazole<br>* randomized to 12 week trial of aripiprazole<br>* Other names: Abilify;|
| Active Comparator: olanzapine<br>Participants in this group will be randomized to flexibly-dosed treatment with olanzapine. | Drug: olanzapine<br>* randomized to begin 12 week trial of olanzapine<br>* Other names: Zyprexa;|
| Active Comparator: risperidone<br>Participants in this group will be randomized to flexibly-dosed treatment with risperidone. | Drug: risperidone<br>* randomized to begin 12 week trial of risperidone<br>* Other names: Risperdal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 12 weeks | 
| 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. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 12 weeks | 
| 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. | 12 weeks | 
| 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. | 12 weeks | 
| 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. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antipsychotic treatment, Insulin action/secretion, Abdominal fat mass, total body fat, Aggression, Resting metabolic rates