Biomarkers of Cardiometabolic Risk in Children Treated With Antipsychotics: A Preliminary Study of Direct Measures
Condition: Mental Disorders
MeSH terms: Mental Disorders; Psychotic Disorders
Study type: Observational

Summary: 
      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.
    

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.
    

Intervention name(s): Testing (MRS, US, DEXA, blood tests)
Intervention type(s): Procedure
Intervention description(s): 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.
Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Children ages 6-18 who are currently being treated for a psychiatric condition with an
        antipsychotic medication, and age- and gender-matched healthy controls who are not treated
        with an antipsychotic medication.
      
Biospecimen description: 
      Some routine blood tests to assess glucose and lipid control and liver function, as well as
      an additional hepatitis screen if subjects have a history of hepatitis. Approximately 42 ml
      (3 tablespoons) of blood will be obtained.
    
Keywords: pediatric; mental illness; antipsychotic; cardiometabolic risk; Antipsychotic agents; Mental disorders diagnosed in childhood