Cardiometabolic Side Effects of Risperidone in Children with Autism Susan J. Boorin, MSN, PMHNP-BC PhD Candidate Yale School of Nursing 1 This speaker has no conflicts of interest to disclose. 2 Boorin 1
Promise of Atypical Antipsychotic Medications Clozapine 1958* Risperidone 1994 Olanzapine 1996 Quetiapine 1997 Ziprasidone 2001 Aripiprazole 2001 Dramatic in antipsychotic use in the pediatric population *Not released in US until 1990 3 Proportion Outpatient Visits for Children diagnosed with an autism spectrum disorder and prescribed a psychotropic Significant Increase in Psychotropics Prescribed 80% 79% 60% 40% 20% 0% 39% 1996 2000 2001 2005 psychotropic prescribed (Tobias, Chavez, Olfson & Crystal, 2009) 4 Boorin 2
Atypical Antipsychotics Clozapine 1958* Risperidone 1994 Olanzapine 1996 Quetiapine 1997 Ziprasidone 2001 Aripiprazole 2001 Report Card Motor Adverse Effects Benefit for negative symptoms less clear Metabolic problems emerging as major health concern *Not released in US until 1990 5 RUPP Autism Network: Risperidone only vs. Risperidone + Parent Training RUPP Autism Network, JAm Acad Child Adoles Psychiatry, 2009 6 Boorin 3
Baseline Demographics Male: 85% 75% White / 14% African American / 7% Hispanic / 3% Asian / Other 1% 65% Autistic Disorder, 30% PDD NOS, 6% Asperger s Age of sample: Mean age= 6.9 years, SD 2.4, N = 124 range 4 to 13 years Mean Age: 6.9 years 50% 4 6 years old 7 Medication Target Symptoms: Tantrums, Self Injury, Aggression, Irritability 35 30 Rapid Decrease in Mean Irritability Score 25 Irritability Score 20 15 Irritability Score 10 5 0 0 2 4 6 8 12 16 20 24 Week of Clinical Trial 8 Boorin 4
Weight Gain 9 Associated Behavioral Factors 70 Ac ctual Score (number) 60 50 40 30 20 10 Appetite Week 12 24 (mean) Adaptive Communication (mean) Adaptive Functioning Daily Living Skills (mean) Impairment in Social Interaction: Autism Sx (mean) 0 < 15% weightgain 15% weightgain 10 Boorin 5
Mild and Moderate Excessive Appetite 100 80 Percent Children 60 40 20 Excessive Appetite at Baseline No Report of Excessive Appetite at Baseline 0 Baseline 1 2 3 4 5 6 7 8 12 16 20 24 WEEKS 11 Does rapid weight gain carry risk independent of weight status? Excessive Weight Gain Group at Week 16 BMI < 1.645 Not Obese BMI 1.645 Obese 12 Boorin 6
Percen nt BMI Categories Adjusted for Age and Gender 70 60 50 40 30 20 10 0 Baseline Week k8 Week 24 Baseline Week 8 Week 24 Target BMI 61 44 30 Overweight 20 22 28 Obese 19 34 42 13 Adiposity: Bogalusa Heart Study Webber et al, (1995). Obesity studies in Bogalusa. The American Journal of Medical Sciences* Long term epidemiological study over a period of 20 years Examined cardiovascular risk factors in children, adolescents and young adults Biracial population Sebastian Kaulitzki Dreamstime.com Clustering of childhood obesity with: Blood pressure Serum lipids A predictor for adult obesity *One of many articles using this dataset 14 Boorin 7
Calorie consumption /inactivity Lipocentric Framework Obesity Ectopic Free fatty acid pancreatic islets liver heart skeletal muscle 15 Relationship between BMI and Body fat: Pediatric Rosetta Project N = 1196 Age: 5 18 year olds DEXA estimated body fatness BMI for age < 85 th BMI for age 85 th to 94 th percentile (n=200)* BMI for age 95 th percentile * 20% of the children had body fatness comparable to those with higher BMIs, 30% had body fatness comparable with children with BMIs < 85 th percentile (Freedman & Sherry, 2009,Pediatrics ) 16 Boorin 8
Can you see risk? This girl is 4 years old and weighs 38.6 lbs Height = 39.2 inches http://www.cdc.gov/growthcharts/ Photo from UC Berkeley Longitudinal Study, 1973 17 Plotted BMI For Age BMI BMI Girls: 2 to 20 years BMI BMI 18 http://www.cdc.gov/growthcharts/ Boorin 9
Insulin Resistance Insulin Resistance/Obesity (Kahn, Hull & Utzschneider (2006) Nature ) Increased β cell function Impaired β cell function Compensatory Hyperinsulinemia Impaired Glucose Tolerance Alila07 Dreamstime.com Normal glucose tolerance 19 Insulin Resistance: Clinical Monitoring HOMA IR Normal age related changes Partner with Primary Care or Endocrinology Note: Fasting plasma glucose may be within normal range despite the presence of hyperinsulinemia 20 Boorin 10
At Risk Criteria: Lipids Pediatric Considerations Children in Trial no.,(%) Baseline Week 16 LDL 75 th percentile for age and gender 25 (26%) 23 (27%) HDL 10 th percentile for age and gender 26 (21%) 30 (31%) Triglyceride 75 th percentile for age and gender 41 (37%) 44 (45%) REFERENCE: PEDIATRIC TABLE of Age and Gender Adjusted Lipid Categories : Daniels, S.R., Greer, F.R. & the Committee on Nutrition (2008). Lipid Screening and Cardiovascular Health in Childhood, Pediatrics, 122(1),198 208 21 Cultural differences? Six year old boy BMI : > 95 th percentile for age and gender Waist/Height ratio >.5 (considered a risk factor) Fasting Glucose = 95 mg/dl Lucian Coman Dreamstime.com Triglyceride level in 25 th percentile category for gender and age 22 Boorin 11
Fatty Liver: relationship with childhood obesity Healthy Liver Over accumulation of Fat in Liver Large multiethnic group of obese youth: n= 392 Liver fat measured by MRI technology Markers: Increased visceral fat Alanine Aminotransferase (ALT) Plasma triglycerides Insulin resistance (Burgert et al. (2009) The Journal of Clinical Endocrinology & Metabolism) 23 What other information would be valuable? Five year old girl Began treatment with risperidone last October October 2010 Fasting glucose = 77 mg/dl Lab work returns this week: October 2011 Fasting glucose = 91 mg/dl ALT = 40 Units/liter 24 Boorin 12
Pediatric Blood Pressure National High Blood Pressure Education Program Working Group on Children and Adolescents (2005). The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure In Children and Adolescents. US Dept of Health and Human Services * Normal BP in children = SBP and DBP that is < the 90 th percentile for gender, age and height Hypertension in children = average SBP or DBP that is the 95 th percentile for gender, age and height (noted on at least 3 different occasions) *Excellent reference 25 Change from baseline to Week 16 of TX Insulin (n=87) p=.0086 Glucose (n=100) p=.0065 HOMA IR p<.0002 Leptin (n=90) p<.0001 Adiponectin (n=90) p=.0047 Triglycerides (n=96) p=.001 Waist Circumference p<.0001 ALT (liver enzyme) p= 0.0015 Diastolic BP p= 0.0153 Appetite OR= 5.02 26 Boorin 13
ADA Consensus on Antipsychotic Drugs and Obesity and Diabetes: Monitoring Protocol for Adults* Start 4 wks 8 wks 12 wks Qtrly. 12 mos. Personal/family Hx X X 5 yrs. Weight (BMI) X X X X X Waist circumference X X Blood pressure X X X Fasting glucose X X X Fasting lipid profile X X X *More frequent assessments may be warranted based on clinical status American Diabetic Association (2004) Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care, 27, 596 601 27 Preliminary Pediatric Modifications/Suggestions History Assess hx of excessive appetite, and potential for appetite Weight Monitor BMI using CDC growth charts adjusted for gender and age at every visit Waist Circumference Not enough evidence, not recommended at present Blood pressure Use age and gender adjusted norms to screen for hypertension Fasting Glucose High risk ikchildren may need to be referred for further evaluation: collaborate with primary care Fasting Lipids Use age and gender adjusted norms Consider more frequent monitoring for high risk children 28 Boorin 14
The influence of location: Visceral and intramyocellular Adiposity SUBJECTS : N=14 insulin sensitive adolescents paired with 14 insulin resistant adolescentsmatchedfor age, gender, and body composition. RESULTS: Insulin sensitive adolescents had intramyocellular fat stores (p=0.017) and visceral lipid deposition (p=0.04) CONCLUSION: Location of lipid deposition may influence insulin sensitivity (Weiss et al, 2005 The Journal of Clinical Endocrinology & Metabolism) 29 Expert pediatric recommendation: Supports use of BMI in clinical setting August, G. et al (2010). Prevention and treatment of pediatric obesity: an endocrine society clinical practice guideline based on expert opinion. J Clin Endocrinol Metab., December 2008, 93(12) 4576 4599. 4599 Barlow, S.E. (2007). Expert Committee Recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: Summary report. Pediatrics, 120,supplement 4. Daniels, S.R. (2009). The use of BMI in the clinical setting. Pediatrics, 124, S35 41 Correll, C. (2008). Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. J. Am. Acad. Child Adolesc. Psychiatry, 47 (1) 9 20. 30 Boorin 15