1. Cardiometabolic Consequences of Risperidone in Children with Autism Cardiometabolic Consequences of Risperidone in Children with Autism Susan J. Boorin, MSN, APRN-BC PhD Candidate, 2012 Yale University School of Nursing

2. Promise of Atypical Antipsychotic Medications Clozapine – 1958* Risperidone – 1994 Olanzapine – 1996 Quetiapine – 1997 Ziprasidone – 2001 Aripiprazole - 2001 Asenapine – 2009 Not released in US until 1990 * Not released in US until 1990

3. Pediatric antipsychotic use in US 1993-2002 Six-fold increase in antipsychotic use in office-based practice ( National Ambulatory Care Survey and US Census, Olfson et al, 2006) 92% of visits: atypical antipsychotic prescription, with risperidone most common

4. “Core symptoms” of Pervasive Developmental Disorders “Core symptoms” of Pervasive Developmental Disorders Qualitative impairment in social interaction Qualitative impairment in communication Restrictive and stereotyped patterns of behavior and interests Autistic Disorder + + + Asperger’s Disorder + No evidence of a language delay + Pervasive developmental disorder not otherwise specified + Communication or Restrictive interests

5. *Aberrant Behavior Checklist subscale: Irritability *Mean Score Changes Risperidone versus placebo in children with autism and serious behavioral problems N=101, Ages 5-17 RUPP Autism Network, 2002 Target Symptoms*: tantrums, aggression, self-injury, irritability

6. RUPP Autism Network: Risperidone only vs. Risperidone + Parent Training RUPP Autism Network, JAm Acad Child Adoles Psychiatry, 2009

7. All Children Treated with Risperidone Design 124 subjects (Ages 4-13 years) Diagnosis: a Pervasive Developmental Disorder (Autism Spectrum Disorder) 6-month prospective study Risperidone Only versus Risperidone + Parent Training

8. Baseline Demographics  n = 124 Male: 85%  75% White / 14% African American / 7% Hispanic / 3% Asian / Other 1%  65% Autistic Disorder, 30% PDD-NOS, 6% Asperger’s Median Age: 6.0 years 50% 4-6 years old

9. Median Weight Percentiles Absolute Weight Gain mean: 11.7 ± 7.3 lbs range: – 2 to 36.4 lbs

10. Parent Report of Excessive Appetite

12. Change in metabolic indices from baseline to Week 16 Insulin (mean) (n=87) ↑p =.0086 Glucose (mean) (n=100) ↑p =.0065 Triglycerides (mean) (n=96) ↑ > 90 th percentile (standardized category) ↑ p =.001 p = 0.55 Selected Metabolic Indices Baseline to Week 16

13. Change in Adipocyte Hormones Baseline to Week 16 Adipocyte Tissue Dreamstime Adipocyte Hormones Baseline to Week 16 Leptin (n=90) mean (95% CL) ↑ p <.0001 Adiponectin (n=90) mean (95% CL) ↓ p <.0047

14. Waist : Height Ratio ≥.5 Dreamstime Visceral Fat

15. Central Adiposity Waist : Height ratio ≥.5 ↑ Baseline 31%

16. Weight Over Time Weight gain ≥ 15% n = 46%

17. Change in Weight z-Score

18. Consequences of > 15% Weight Gain Odds ratio (adjusted for baseline obesity) for adverse metabolic outcomes at Week 16 ↑ LDL cholesterol ↑ TriglycerideAdiponectin ≤ 12.2 Central adiposity* ≥ 15% weight gain 2.7 [1.0 -7.5]4.6 [1.7-12.7]5.2 [1.3 – 21]6.1 [2 – 18] * Waist to height ratio ≥ 0.5

19. Clinical Implications

20. Consensus Statement, 2004 American Diabetes Association: Consensus development conference on antipsychotic drugs and obesity and diabetes (Consensus Statement). Diabetes Care 27:596–601, 2004

21. Pediatric Modifications/Suggestions History Assess history of excessive appetite Younger age-group Maternal obesity, history of type II diabetes Weight Monitor BMI at every visit (using CDC growth charts adjusted for gender and age) Waist to Height Ratio Simple, but useful measure of central adiposity Blood pressure Use age and gender adjusted norms to screen for hypertension

22. Fasting Lipids Use age and gender adjusted norms More frequent monitoring for high risk children Fasting Glucose Important to Monitor Not an early marker for children Healthy children  insulin to manage  in glucose …. Pediatric Modifications/Suggestions

23. Insulin Resistance by HOMA-IR

24. Insulin Resistance at Week 16 (By HOMA-IR; n = 21) Insulin Resistance Positive 21% glucose ≥ 100 mg/dL 38% at-risk triglyceride (≥ 90 th percentile) 57% obese

25. In conclusion Metabolic changes were significant Only prescribe risperidone after a careful analysis of benefit and risk Due to early weight gain, healthy lifestyle choices should be emphasized prior to starting the medication

26. Thank You