Clinical trial NCT00205699: Metabolic Effects of Antipsychotics in Children
Official title: Metabolic Effects of Antipsychotics in Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: 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
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2005-09-20
Enrollment: 144
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change in DEXA % Body Fat
timeFrame: 12 weeks
measure: Change in Insulin-stimulated Glucose Rate of Disappearance (Glucose Rd)
timeFrame: 12 weeks
Secondary outcomes:
measure: Change in Insulin-stimulated Glycerol Rate of Appearance (Glycerol Ra)
timeFrame: 12 weeks
measure: Change in Insulin-stimulated Glucose Rate of Appearance (Glucose Ra)
timeFrame: 12 weeks
measure: Change in MRI-measured Visceral Abdominal Fat
timeFrame: 12 weeks
measure: Change in MRI-measured Subcutaneous Abdominal Fat
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine, Psychiatry Dept.
state: Missouri
Study officials:
affiliation: Florida Atlantic University and Washington University School of Medicine
name: John W. Newcomer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Washington University School of Medicine
name: Ginger Nicol, MD
role: STUDY_DIRECTOR
References:
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.