Mental Disorders
Conditions
Keywords
pediatric, mental illness, antipsychotic, cardiometabolic risk, Antipsychotic agents, Mental disorders diagnosed in childhood
Brief 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.
Interventions
PROCEDURETesting (MRS, US, DEXA, blood tests)
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.
Sponsors
Washington University School of Medicine
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
6 Years to 18 Years
Healthy volunteers
Yes
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Carotid Artery Intima-media Thickness Measured by Ultrasonography. | Week 1 |
| Intrahepatic Triglyceride Content (IHTG) Measure by Liver Magnetic Resonance Spectroscopy. | Week 1 |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORGinger E Nicol, MD
Washington University School of Medicine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Antipsychotic-Treated Children with psychiatric diagnoses who are currently treated with antipsychotic medications. | 25 |
| Healthy Control Age- and gender-matched children who do not have a psychiatric diagnosis, are not taking antipsychotic medications, and are otherwise healthy. | 19 |
| Total | 44 |
Baseline characteristics
| Characteristic | Antipsychotic-Treated | Healthy Control | Total |
|---|---|---|---|
| Age, Continuous Post-pubertal status, age 12-19 | 14.7 years STANDARD_DEVIATION 1.7 | 15.3 years STANDARD_DEVIATION 1 | 15.0 years STANDARD_DEVIATION 1.4 |
| Age, Continuous Pre-pubertal status, ages 6-11 | 10.3 years STANDARD_DEVIATION 1.5 | 9.5 years STANDARD_DEVIATION 1.6 | 9.9 years STANDARD_DEVIATION 1.6 |
| Alanine Aminotransferase (ALT) | 20.5 IU/L STANDARD_DEVIATION 7.1 | 18.9 IU/L STANDARD_DEVIATION 6.6 | 19.8 IU/L STANDARD_DEVIATION 6.8 |
| Albumin | 4.4 g/dL STANDARD_DEVIATION 0.3 | 4.4 g/dL STANDARD_DEVIATION 0.2 | 4.4 g/dL STANDARD_DEVIATION 0.3 |
| Alkaline Phosphatase | 220.3 IU/L STANDARD_DEVIATION 67.8 | 234.1 IU/L STANDARD_DEVIATION 106.5 | 226.3 IU/L STANDARD_DEVIATION 86.2 |
| Aspartate Aminotransferase (AST) | 29.0 IU/L STANDARD_DEVIATION 6 | 31.4 IU/L STANDARD_DEVIATION 10.5 | 30.0 IU/L STANDARD_DEVIATION 8.3 |
| Blood Pressure Diastolic | 69 mm Hg STANDARD_DEVIATION 6 | 67 mm Hg STANDARD_DEVIATION 8 | 68 mm Hg STANDARD_DEVIATION 7 |
| Blood Pressure Systolic | 111 mm Hg STANDARD_DEVIATION 9 | 112 mm Hg STANDARD_DEVIATION 13 | 111 mm Hg STANDARD_DEVIATION 11 |
| Body Mass Index (BMI) Percentile | 67.5 Percentile STANDARD_DEVIATION 28.4 | 58.9 Percentile STANDARD_DEVIATION 30.2 | 63.8 Percentile STANDARD_DEVIATION 29.2 |
| Carotid Intima Media Thickness (CIMT) | 0.51 mm STANDARD_DEVIATION 0.05 | 0.52 mm STANDARD_DEVIATION 0.05 | 0.51 mm STANDARD_DEVIATION 0.05 |
| Dual Energy X-ray Absorptiometry (DEXA) Total Percent Fat | 26.3 percent of total body fat STANDARD_DEVIATION 11.1 | 24.1 percent of total body fat STANDARD_DEVIATION 11.4 | 25.3 percent of total body fat STANDARD_DEVIATION 11.2 |
| Fasting Glucose | 88.0 mg/dL STANDARD_DEVIATION 8.1 | 87.2 mg/dL STANDARD_DEVIATION 7.3 | 87.7 mg/dL STANDARD_DEVIATION 7.7 |
| Fasting Insulin | 15.5 uIU/mL STANDARD_DEVIATION 16.8 | 11.0 uIU/mL STANDARD_DEVIATION 5.8 | 13.5 uIU/mL STANDARD_DEVIATION 13.3 |
| Fasting Lipids High Density Lipoprotein (HDL) Cholesterol | 57.1 mg/dL STANDARD_DEVIATION 12.7 | 54.1 mg/dL STANDARD_DEVIATION 15.2 | 55.8 mg/dL STANDARD_DEVIATION 13.7 |
| Fasting Lipids Low Density Lipoprotein (LDL) Cholesterol | 93.4 mg/dL STANDARD_DEVIATION 19.1 | 81.7 mg/dL STANDARD_DEVIATION 20.1 | 88.3 mg/dL STANDARD_DEVIATION 20.1 |
| Fasting Lipids Total Cholesterol | 164.2 mg/dL STANDARD_DEVIATION 24.9 | 149.7 mg/dL STANDARD_DEVIATION 25.5 | 158.0 mg/dL STANDARD_DEVIATION 25.9 |
| Fasting Lipids Triglycerides | 68.6 mg/dL STANDARD_DEVIATION 40.7 | 68.8 mg/dL STANDARD_DEVIATION 24.7 | 68.7 mg/dL STANDARD_DEVIATION 34.3 |
| Fibrinogen | 301.3 mg/dL STANDARD_DEVIATION 72.7 | 269.0 mg/dL STANDARD_DEVIATION 45 | 287.8 mg/dL STANDARD_DEVIATION 64 |
| High Sensitivity C-Reactive Protein (hsCRP) | 1.52 mg/L STANDARD_DEVIATION 3.2 | 0.77 mg/L STANDARD_DEVIATION 1.02 | 1.19 mg/L STANDARD_DEVIATION 2.49 |
| Intrahepatic Triglyceride Content (IHTG) | 2.5 percent of liver fat STANDARD_DEVIATION 3 | 1.6 percent of liver fat STANDARD_DEVIATION 1.4 | 2.1 percent of liver fat STANDARD_DEVIATION 2.5 |
| Race/Ethnicity, Customized Not White | 16 Participants | 6 Participants | 22 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 13 Participants | 22 Participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 19 Participants | 15 Participants | 34 Participants |
| Total Bilirubin | 0.35 mg/dL STANDARD_DEVIATION 0.16 | 0.50 mg/dL STANDARD_DEVIATION 0.52 | 0.41 mg/dL STANDARD_DEVIATION 0.37 |
| Total Protein | 7.4 g/dL STANDARD_DEVIATION 0.5 | 7.1 g/dL STANDARD_DEVIATION 0.5 | 7.2 g/dL STANDARD_DEVIATION 0.5 |
| Vitamin D Level | 18.4 ng/mL STANDARD_DEVIATION 5.4 | 22.1 ng/mL STANDARD_DEVIATION 7.1 | 20.0 ng/mL STANDARD_DEVIATION 6.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Carotid Artery Intima-media Thickness Measured by Ultrasonography.
Time frame: Week 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antipsychotic-Treated | Carotid Artery Intima-media Thickness Measured by Ultrasonography. | 0.508 millimeters | Standard Deviation 0.053 |
| Healthy Control | Carotid Artery Intima-media Thickness Measured by Ultrasonography. | 0.519 millimeters | Standard Deviation 0.048 |
Comparison: The null hypothesis is that mean DEXA total percent fat is similar between the two groups of interest. The primary statistical model consisted of treatment group as a 2-level factor (AP-Treated Vs Non-AP Treated) and DEXA total percent fat as a covariate. Carotid intima-media thickness (CIMT) was the dependent variable.p-value: 0.49ANCOVA
Primary
Intrahepatic Triglyceride Content (IHTG) Measure by Liver Magnetic Resonance Spectroscopy.
Time frame: Week 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antipsychotic-Treated | Intrahepatic Triglyceride Content (IHTG) Measure by Liver Magnetic Resonance Spectroscopy. | 2.48 percent | Standard Deviation 3.03 |
| Healthy Control | Intrahepatic Triglyceride Content (IHTG) Measure by Liver Magnetic Resonance Spectroscopy. | 1.57 percent | Standard Deviation 1.37 |
Comparison: The statistical analysis consisted of treatment group as a 2-level factor variable and DEXA total percent fat as a covariate. An interaction term between treatment group and DEXA total percent fat was also generated. Hepatic triglyceride content was the dependent variable. DEXA total percent fat was found to be significant while treatment group and the interaction between treatment group and DEXA total percent fat were not significant.p-value: <0.0001ANCOVA