Nili E. Major, M.D. Instructor, Developmental-Behavioral Pediatrics

1. MEDICATIONS AND ALTERNATIVE THERAPIES IN THE TREATMENT OF AUTISMCT CHAPTER OF AAP: CRITICAL ISSUES IN SCHOOL HEALTHMAY 20, 2010 Nili E. Major, M.D. Instructor, Developmental-Behavioral Pediatrics Yale University School of Medicine

2. Disclosure • Dr. Major has no conflicts of interest to disclose • The off label use of medication will be discussed

3. Outline of Presentation • Introduction to Autism Spectrum Disorders • Clinical approach to behavioral symptoms • Overview of medications commonly used in ASD • Clinical use • Evidence for efficacy • Side effects and monitoring • Complementary and alternative therapies • Role of the school health professional

4. Autism Spectrum Disorders • Autism Spectrum Disorders (ASD) are a collection of developmental disorders that are characterized by impairments in social interaction and communication, as well as the presence of restricted and repetitive behaviors and interests

5. Autism Spectrum Disorders • DSM-IV-TR diagnostic categories under “Pervasive Developmental Disorders”: • Autistic Disorder • Asperger’s Disorder • PDD-NOS • Rett Syndrome • Childhood Disintegrative Disorder

6. DSM Criteria: Social Impairment • Impairment in use of non-verbal behaviors to regulate social interaction • Eye contact, facial expressions, gestures • Failure to develop developmentally-appropriate peer relationships • Lack of spontaneous seeking to share enjoyment with others • Lack of showing or pointing out objects of interest • Lack of social or emotional reciprocity

7. DSM Criteria: Communication Impairment • Delay in, or total lack of development of spoken language • Failure to compensate with non-verbal gestures • In those with adequate speech, marked impairment in ability to initiate or sustain conversation • Stereotyped, repetitive or idiosyncratic language • Echolalia, scripting, unusual prosody • Lack of spontaneous, varied, make believe play

8. DSM Criteria: Repetitive and Stereotyped Behaviors and Interests • Stereotyped or restricted patterns of interest of abnormal intensity or focus • Inflexible adherence to non-functional routines or rituals • Stereotyped and repetitive motor mannerisms • Spinning, hand flapping, rocking • Persistent preoccupation with parts of objects

9. Epidemiology of ASD • Most recent studies report best estimate of current prevalence in US is ~ 1/110 (CDC, 12/2009) • Ongoing debate regarding increasing numbers • Increased male to female ratio (~4.5:1) • Seen across all races, ethnic groups, socioeconomic strata • Mean age of diagnosis ranged from 3 ½ - 5 yrs • More than 1/2 of children had developmental concerns recorded in chart prior to age 3

10. Etiology of ASD • Complex, biologically based neurodevelopmental disorders • Great phenotypic variation • Likely involve many genes • Environmental factors may modulate expression • Concordance rate of 60-90% in identical twins • Recurrence risk of 2-8% in sibs of affected individuals • ~ 10% of cases associated with a known genetic syndrome or medical condition (e.g., Fragile X syndrome, tuberous sclerosis)

11. Screening and Diagnosis • Current AAP recommendations (Myers and Johnson, 2007) • ASD surveillance at all well child visits • ASD specific screening (e.g., M-CHAT) at 18 and 24 month visits or when surveillance raises concern • Diagnosis is made clinically by a professional with experience in evaluating children for ASD • Evaluation may include multi-disciplinary assessment • Diagnostic instruments commonly used: ADOS, ADIR, CARS, GARS

12. Medical Evaluation • Purpose • Rule-out other conditions (e.g., hearing impairment) • Evaluate for co-morbid conditions (e.g., seizures) • Search for underlying etiology (e.g., genetic syndrome) • Components • Medical history (birth, current health, family history) • Physical exam (growth, dysmorphic features, neuro, skin) • Testing • Audiologic evaluation • Genetic testing (chromosomes, fragile x, microarray) • Other: EEG, brain imaging, metabolic testing

13. Approaches to Treatment • Behavioral/Educational Interventions • Early Intervention programs • Specialized school programs • Applied Behavior Analysis • Developmental models: DIR, Floortime, Denver • Speech and language therapy • Occupational therapy • Social skills instruction

14. Approaches to Treatment • Family support and training • Medical management • Routine well-child care • Co-occurring conditions • Seizure disorders • Sleep disturbances • Gastrointestinal problems • Challenging behaviors • Complementary and alternative therapies

15. Challenging Behavioral Symptoms • Hyperactivity • Impulsivity • Poor attention • Irritability: • Temper tantrums • Mood lability • Aggression • Self-injurious behavior • Anxiety • Depression • Sleep disturbances • Repetitive behaviors: • Stereotypic movements • Repetitive play • Inflexible routines • Perseverative speech

16. Clinical Approach to Challenging Behaviors • Careful assessment of target behaviors • Timing, intensity, triggers, response to interventions • Use of behavioral scales • Obtain input from multiple sources (home, school) • Assess existing and available supports • Behavioral services • Educational program • Family supports (Myers and Johnson, Pediatrics, 2007)

17. Clinical Approach to Challenging Behaviors • Search for medical factors that may be causing or exacerbating symptoms • Consider psychotropic medication use if • Symptoms are causing significant impairment • Suboptimal response to behavioral modifications • Choose medication based on • Likely efficacy for target symptoms • Potential adverse effects • Practical considerations (dosing, monitoring, cost)

18. Clinical Approach to Challenging Behaviors • Establish plan for monitoring effects • Identify desired outcomes and assessment measures • Discuss time course of expected effects • Arrange follow-up: visits, telephone • Outline plan for alternative options if medication is not effective • Obtain baseline lab data and plan follow-up monitoring • Consider withdrawal of medication after 6-12 months of therapy

19. Psychopharmacology in ASD • Goal is to reduce challenging behaviors and improve response to behavioral and educational interventions • Psychotropic medication use in ASD is common • 5,181 children < 18 yrs enrolled in web based registry • 35% used at least 1 psychotropic medication • Increased use with older age, presence of ID or psychiatric co-morbidity, residing in poorer county, South or Midwest US • Stimulants, anti-psychotics, and SSRI’s most common (Rosenberg et al, 2010)

20. Stimulants: Clinical Use • Most commonly used in the treatment of ADHD • Two classes exist: • Methylphenidate • Ritalin, Metadate, Concerta, Focalin, Daytrana patch • Amphetamines • Adderall, Dexedrine, Vyvanse • Work by increasing concentrations of dopamine and norepinephrine in the brain

21. Stimulants: Clinical Use • Preparations: Pills, sprinkle capsules, liquid (short acting only), transdermal patch • Varied durations of action: • Short acting (3-6 hours) • Ritalin, Focalin, Adderall • Intermediate acting (4-8 hours) • Ritalin SR, Metadate ER, Dexedrine Spansule • Long acting (8-12 hours) • Ritalin LA, Metadate CD, Adderall XR, Focalin XR, Concerta, Vyvanse, Daytrana • All with short half-lives; rebound effect may be seen

22. Stimulants: Evidence of Effect • Research Unit on Pediatric Psychopharmacology (RUPP) Autism Network trial of Methylphenidate (2005) • Design: • Double-blind, placebo-controlled crossover trial • 1 week each of placebo, low, medium, and high dose MPH in random order • Primary outcome of interest: Reduction of Hyperactivity subscale score on ABC (Aberrant Behavior Checklist) • Sample: • 72 children with ASD ages 5 to 14 years • Autistic Disorder (71%), PDD-NOS (21%), Asperger (7%) • 89% were male • Mean IQ of 63 (range 16-135)

23. Stimulants: Evidence of Effect • RUPP trial of Methylphenidate (2005) • Results • ABC Hyperactivity scores lower at all MPH dosage levels compared to placebo • 49% were “responders” to MPH vs. 13% to placebo • Compared with 70-80% response rate in ADHD trials • Adverse effects led to discontinuation in 18% of subjects • 1.4% discontinued due to adverse effects in ADHD MTA study • Irritability, decreased appetite, difficulty falling asleep, emotional outbursts

24. Stimulants: Evidence of Effect • Conclusions • Methylphenidate treatment may show benefit in some patients with ASD and ADHD-like symptoms • Rate and magnitude of response is lower than seen in children with ADHD alone • Rate of adverse effects is higher than in children with ADHD alone

25. Stimulants: Side Effects & Monitoring Potential Side Effects Recommended Monitoring • Headaches • Stomachaches • Decreased appetite • Slowed wt gain/growth • Sleep difficulty • Tics • Psychiatric symptoms • Cardiac effects • Baseline medical Hx & PE • Thorough cardiac history • EKG, cardiac evaluation if indicated • Weight gain/growth • Heart rate, blood pressure • Other side effects

26. Anti-Psychotics: Clinical Use • Primarily used in treatment of psychotic disorders • 1st generation anti-psychotics • Chlorpromazine, thioridazine, haloperidol • Work by blocking dopamine receptors • Risk of extrapyramidal symptoms (EPS) • 2nd generation anti-psychotics • Gained popularity due to decreased risk of EPS • Clozapine, risperidone, quetiapine, aripiprazole • Block dopamine and serotonin receptors

27. Anti-Psychotics: Clinical Use • 2006: Risperidone was first medication to be FDA approved for treatment of irritability in children aged 5-16 with ASD • 2009: Aripiprazole approved for same indication in children aged 6-17 • Both available in liquid preparations

28. Anti-Psychotics: Evidence of Effect • RUPP trial of Risperidone (2002) • Design: • Phase I: 8 week double-blind, placebo controlled study • Phase II: 4 months of open label treatment • Primary outcome of interest: Score at 8 weeks on ABC Irritability subscale and CGI-I rating • Sample: • 101 children with Autistic Disorder and significant irritability • ABC Irritability score >18, CGI-S >moderate • 5-17 years of age (mean age 8.8) • ~75% with mental retardation

29. Anti-Psychotics: Evidence of Effect • RUPP trial of Risperidone (2002) • Results (at 8 weeks): • Risperidone group had 57% decrease in Irritability score vs. 14% decrease in placebo group • 69% of risperidone group were “responders” vs. 12% of placebo group • Improvements also seen on Hyperactivity and Stereotypy subscales (no diff in Social Withdrawal and Inappropriate Speech scales)

30. Anti-Psychotics: Evidence of Effect • Results (at 8 weeks) • Adverse Effects: • Increased weight gain (2.7 kg in risp vs. 0.8 kg in placebo) • Drowsiness (49% in risp vs. 12% in placebo) • In most this was mild, and typically resolved by week 4 • Other effects: Fatigue, drooling, constipation, dizziness, tremor, tachycardia • No serious adverse events in risperidone group or withdrawal from study due to adverse effects

31. Anti-Psychotics: Evidence of Effect • Results (at 6 months): • 63 subjects entered the 4 month open label phase • 82.5% of patients continued to be rated as “much improved” or “very much improved” on CGI-I • 6 month weight gain of 5.1 kg (0.85 kg/month) • One subject withdrew due to constipation • 6 subjects reported to have abnormal movements (none confirmed on exam)

32. Anti-Psychotics: Evidence of Effect • Conclusions: • Risperidone was safe and effective for short-term treatment of tantrums, aggression, and self-injurious behavior in children with autistic disorder • Improvements also seen in hyperactivity and stereotypic behavior • Short period limits inferences about long-term efficacy and side effects

33. Anti-Psychotics: Evidence of Effect • Additional risperidone studies: • Shea et al, 2004: • 79 children ages 5-12 with ASD, risp or placebo for 8 weeks • 64% reduction in ABC Irritability score in risp group vs. 18% in placebo • RUPP, 2009: • 124 children ages 4-13 with PDD • Risperidone + parent training superior to risperidone alone • Aripiprazole • Owen et al, 2009: • 98 children ages 6-17 with Autistic Disorder, 8 weeks • 52% responders in aripiprazole group vs. 14% in placebo • Adverse effects: Fatigue, somnolence, weight gain, tremor

34. Anti-Psychotics: Side Effects & Monitoring Potential Side Effects Recommended Monitoring • Increased appetite and weight gain • Dyslipidemia • Diabetes • Increased liver enzymes • Sedation • Constipation • Extrapyramidal symptoms • Prolactin elevation • Baseline history, PE • Baseline labs • Fasting glucose and lipids • Liver function tests • Prolactin? • Repeat labs at 12 weeks, then every 3-6 months • Monitor weight/BMI • Monitor for side effects

35. SSRI’s: Clinical Use • Selective Serotonin Reuptake Inhibitor’s (SSRI’s) primarily used in the treatment of depression and anxiety • Similarity between repetitive behaviors of ASD and symptoms of OCD • Evidence of serotonin system abnormalities in ASD • Prevent reuptake of serotonin in the brain • Fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine • Liquid preparations available

36. SSRI’s: Evidence of Effect • Fluvoxamine (Posey & McDougle, 2000) • Double-blind, placebo controlled study • 34 children with ASD ages 5-18, 12 weeks • Only 1 of 18 patients responded to treatment • 14 of 18 patients experienced adverse effects (hyperactivity, insomnia, agitation, and aggression) • Fluoxetine (Hollander, 2005) • Double-blind, placebo controlled crossover study • 44 children with ASD ages 5-17, 16 weeks • Fluoxetine superior to placebo in reducing repetitive behaviors • No difference in adverse effects between fluoxetine and placebo

37. SSRI’s: Evidence of Effect • Citalopram (STAART Network, 2009) • 149 children with ASD ages 5-17 • Randomized to citalopram or placebo for 12 weeks • No difference between groups on CGI-I (33% tx vs. 34% pbo), CYBOCS-PDD, or repetitive behavior scale • Adverse effects: Increased energy level, impulsiveness, decreased concentration, stereotypy, diarrhea, insomnia, dry skin, and nightmares • Are repetitive behaviors in ASD fundamentally different from behaviors in OCD?

38. SSRI’s: Evidence of Effect • Conclusions: • Small, open-label studies with various SSRI’s have shown some benefits • Placebo controlled studies to date show mixed results • Largest study performed failed to show improvement of repetitive behaviors with citalopram • Side effects are common

39. SSRI’s: Side Effects & Monitoring Potential Side Effects Recommended Monitoring • Nausea and vomiting • Sedation • Weight gain • Dry mouth • Behavioral activation • Induction of mania • Insomnia • Suicidal ideation (FDA black box warning) • Baseline Hx & PE • No routine baseline labs/studies needed • Careful monitoring, especially for psychiatric side effects

40. Other Medications used in ASD • Alpha-2 adrenergic agonists (clonidine, guanfacine) • Hyperactivity, inattention • Sedation, dry mouth, decreased BP, dizziness, constipation, irritability • Atomoxetine • Anti-epileptics (topiramate, valproate) • Donepezil • Memantine

41. Complementary & Alternative Therapies • CAM is defined by the National Center for Complementary and Alternative Medicine as “a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine.”

42. Complementary & Alternative Therapies • CAM use is common in children with ASD • In recent studies, 50-75% of children with ASD were being treated with CAM (Wong et al, 2006, Hanson et al, 2007) • Almost 1/3 of children referred for ASD evaluation were being treated with dietary therapies (Levy et al, 2003) • Parents may be reluctant to share information regarding CAM use with their child’s doctor (Wong et al, 2006) • Concern about physician disapproval • No need for disclosure • Physician did not ask • Physician not knowledgeable about CAM

43. Complementary & Alternative Therapies Biological Treatments Non-Biological Treatments • Dietarymodifications • Vitamins/supplements • Chelation therapy • Melatonin • Antibiotics/Antifungals • Immunoglobulins • Hyperbaric oxygen • Auditory integration therapy • Behavioral optometry • Craniosacral manipulation • Music therapy • Yoga

44. Gluten/Casein Free Diet • Background • Gluten - protein found in wheat, rye, barley • Casein - protein found in dairy products • Based on hypothesis that: • Gluten and casein break down into opioid-like peptides • Diffuse across an abnormally permeable GI lining (“leaky gut theory”) • Excess opiate activity in CNS results in symptoms of autism

45. Gluten/Casein Free Diet • Evidence of effect • Knivsberg et al, 2002 • 20 children, assigned to GFCF or typical diet for 1 year • GFCF group showed improvements in attention, social/emotional factors, cognition, motor skills • Limitations: Small sample, lack of strict dietary control, single blinded • Elder et al, 2006 • Double-blind, placebo controlled study of 13 children • 12 week duration, crossover design • No differences between groups on outcome measures • Limitations: Small sample, no wash-out period

46. Gluten/Casein Free Diet • Conclusions: • Cochrane review, 2009: Insufficient evidence at this time to support the use of gluten/casein free diets • Further study needed with well-designed trials • Further information needed regarding potential risks • Recent data: • Whiteley et al, 2010, Nutritional Neuroscience • 72 children, diet vs. no diet, improvements in tx group • Awaiting results of NIMH trial

47. Gluten/Casein Free Diet • Clinical Considerations • Feasibility of implementing diet • Child’s current eating habits • Added time, effort and expense • Plans to ensure compliance in and out of home • Nutritional considerations • Monitor weight gain • Maintaining adequate intake of protein, calcium, vitamin D • Consultation with nutritionist • Plan for evaluating response to intervention

48. Vitamins and Supplements • Vitamin B6 and Magnesium • Cochrane review of 3 small controlled studies, insufficient evidence to support use • Generally safe, but toxicity may occur at elevated doses • Tolerable upper limits in children: • Vitamin B6 (30-80 mg/day) • Magnesium (65-350 mg/day) • NIH Office of Dietary Supplements: http://ods.od.nih.gov

49. Vitamins and Supplements • Omega 3 Fatty Acids • Polyunsaturated fatty acids • ALA from nuts, seeds; EPA and DHA from fatty fish • High concentrations of DHA in neural tissues • Some studies show decreased levels of omega 3 in ASD children • 1 placebo controlled trial in 13 children (Amminger et al, 2007) • Hyperactivity and stereotypy scales on ABC trended towards significance • 1 child withdrew due to GI complaints & lack of benefit • Remaining studies uncontrolled, some showing benefit • Main side effects related to GI upset

50. Chelation Therapy • Agents used to bind and remove heavy metals from body (e.g., lead poisoning) • Hypothesis that children with ASD have mercury toxicity • No evidence to support link between thimerosal and ASD • No controlled studies examining chelation • Trial initiated by NIMH in 2006 but halted due to concern over risk-benefit ratio • Can be associated with severe side effects • Arrhythmia, kidney failure, bone marrow suppression • 2005: 5 yo boy with ASD died from hypocalcemia related to EDTA use • Oral preparations available without prescription