Biomarkers of Cardiometabolic Risk in Children Treated With Antipsychotics: A Preliminary Study of Direct Measures

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT00894738
First received: May 4, 2009
Last updated: July 19, 2012
Last verified: July 2012
  Purpose

The proposed study aims to begin the multi-step process of establishing the reliability and validity of hepatic triglyceride content (HTGC) and carotid artery intima-media thickness (IMT) as biomarkers of cardiometablic risk in children treated for mental illness. The distribution of HTGC and carotid IMT—proximate indicators of cardiometabolic risk—across a range of dual-energy X-ray absorptiometry (DEXA)-measured adiposity in children treated with antipsychotic agents will be characterized in comparison to healthy, untreated, non-psychiatric controls, in order to estimate effect sizes for future studies incorporating these markers. The ability of HTGC and IMT to predict cardiometabolic risk as measured by commonly-used laboratory tests, such as fasting lipids, liver function tests, C-reactive protein and serum fibrinogen, will be assessed.


Condition Intervention
Mental Disorders
Procedure: Testing (MRS, US, DEXA)

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Biomarkers of Cardiometabolic Risk in Children Treated With Antipsychotics: A Preliminary Study of Direct Measures

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Carotid artery intima-media thickness measured by ultrasonography. [ Time Frame: Week 1 ] [ Designated as safety issue: Yes ]
  • Hepatic triglyceride content measure by liver magnetic resonance spectroscopy. [ Time Frame: Week 1 ] [ Designated as safety issue: Yes ]
  • Adiposity measured by dual energy X-ray absorptiometry. [ Time Frame: Week 1 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Blood tests, including lipids, liver enzymes, C-reactive protein and fibrinogen levels. [ Time Frame: Week 1 ] [ Designated as safety issue: Yes ]

Enrollment: 45
Study Start Date: January 2010
Study Completion Date: January 2012
Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: antipsychotic treated
Children with psychiatric diagnoses who are currently treated with antipsychotic medications.
Procedure: Testing (MRS, US, DEXA)
Magnetic Resonance Spectroscopy (MRS) of the liver to determine hepatic triglyceride content; ultrasound (US) of the carotid artery to determine intima-media thickness; dual energy X-ray absorptiometry (DEXA) to determine body composition; fasting lipids, fasting insulin, C-reactive protein, liver enzymes and fibrinogen levels.
Placebo Comparator: healthy control
Age- and gender-matched children who do not have a psychiatric diagnosis, are not taking antipsychotic medications, and are otherwise healthy.
Procedure: Testing (MRS, US, DEXA)
Magnetic Resonance Spectroscopy (MRS) of the liver to determine hepatic triglyceride content; ultrasound (US) of the carotid artery to determine intima-media thickness; dual energy X-ray absorptiometry (DEXA) to determine body composition; fasting lipids, fasting insulin, C-reactive protein, liver enzymes and fibrinogen levels.

Detailed Description:

Carotid artery intima media wall thickness (IMT) is one of the most developed biomarkers of cardiometabolic risk, with established reliability and predictive validity, and has been utilized as a surrogate endpoint for cardiovascular disease progression in FDA-reviewed registration studies. This technique has also been used in children and adolescents without psychiatric disorders, indicating that changes in IMT are positively correlated with metabolic syndrome criteria. Magnetic Resonance Spectroscopy (1H MRS) to quantify hepatic triglyceride content (HTGC) is a promising new marker of cardiometabolic risk, especially given the importance of nocturnal circulating free fatty acids in the development of insulin resistance leading to type 2 diabetes. Fatty liver, related in part to obesity, is the most common liver abnormality found in children ages 2-19, with one in ten children manifesting signs of macrovascular steatohepatitis. 1H MRS is a well-established methodology used to measure HTGC that correlates well with liver biopsy results. This technique has been studied in obese children without psychiatric disorders, and is widely considered to be the optimal noninvasive means by which to measure HTGC. Unfortunately, neither of these promising methods have been applied to the study of cardiometabolic risk in children with psychiatric disorders.

It is important to now study these biomarkers in psychiatric populations, where individuals are subject to treatments that can increase risk. Our group is experienced in the application of sophisticated, gold standard techniques for measuring cardiometabolic risk in psychiatric populations, and is—to our knowledge—the only group in the US using sensitive methodologies like stable isotopomer euglycemic clamps to study the pathophysiology leading to diabetes and cardiovascular disease in the mentally ill. An important goal of studying these biomarkers is to ultimately determine which of the more commonly available conventional risk measures (e.g., lipid profiles, adiposity measures) can be used alone or in combination to accurately identify children at highest risk, to aid in the development and targeting of effective interventions.

  Eligibility

Ages Eligible for Study:   6 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

The inclusion criteria for the treatment group participants are: i) aged approximately 6-18 years; ii) BMI percentile between approximately 25 and 99; iii) otherwise healthy and meets DSM-IV criteria for one or more childhood onset psychiatric disorder, any type (determined by semi-structured Missouri Assessment of Genetics Interview for Children or MAGIC—described below and at the discretion of the PI), treated with an antipsychotic > approximately 12 weeks; iv) able to give assent and have a guardian that can provide informed consent; and v) no antipsychotic medication dose changes for approximately 1 month, and no other medication changes for 1 month prior to study enrollment.

The inclusion criteria for healthy controls are: i) aged 6-18 years; ii) BMI percentile between approximately 25 and 99 iii) otherwise healthy and at the PI's discretion do not meet DSM-IV criteria for any Axis I psychiatric illness; iv) not currently taking any medications; and v) able to give assent, and have a guardian that can provide informed consent.

The exclusion criteria are: i) active suicidality or a primary diagnosis of major depressive disorder; ii) any lifetime use of antipsychotics; individual subjects with a remote, brief prior antipsychotic exposure may be considered for enrollment on a case by case basis by the PI; iii) the presence of any serious medical disorder 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; all based on PI discretion; iv) subjects regularly taking within the last 3 months 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 nasal spray and inhalers are permitted), 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); v) IQ < 70 (based on school records and/or evaluation by clinician); vi) current substance abuse; vii) past history of, or current dyskinesia; viii) stimulant dosage significantly higher (per PI judgment) than the equivalent of approximately 2 mg/kg/day methylphenidate equivalent dose.

  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00894738

Locations
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Ginger E Nicol, MD Washington University School of Medicine
  More Information

No publications provided

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00894738     History of Changes
Other Study ID Numbers: 56790
Study First Received: May 4, 2009
Last Updated: July 19, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Washington University School of Medicine:
pediatric
mental illness
antipsychotic
cardiometabolic risk
Antipsychotic agents
Mental disorders diagnosed in childhood

Additional relevant MeSH terms:
Mental Disorders
Psychotic Disorders
Schizophrenia and Disorders with Psychotic Features
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Psychotropic Drugs

ClinicalTrials.gov processed this record on July 10, 2014