Valentina Intagliata, MD Assistant Professor of Pediatrics UVa Children ’ s Hospital

1. Another Piece of the Puzzle:  the Role of Medication in the Care of Individuals on the Autism Spectrum Valentina Intagliata, MD Assistant Professor of Pediatrics UVa Children’s Hospital

2. Disclaimer • I have no financial or research interests in any of the medications

3. Objectives • Recognize target symptoms in children with ASD which can be treated with medications • Be familiar with medications used commonly in children with ASD • Be aware of the possible side-effects of these medications • Case presentations

4. Introduction • ASD are a heterogeneous group of disorders • Clinical manifestations vary in presentation & intensity • Treatments must be individualized • Weigh potential risks & benefits

5. Introduction • Behavioral & educational approaches are the cornerstone of comprehensive treatment for core symptoms • Medications may be a useful adjunct to treat common comorbid symptoms – after behavioral & environmental interventions have been maximized

6. Introduction • Medications available do not directly treat core features of autism • i.e. social-communication impairments • Treat behavioral manifestations of the underlying brain pathology

7. Introduction • Most existing evidence on medication use is extrapolated from studies on comorbid conditions (e.g. ADHD, OCD, anxiety) in children without ASD • Studies in children with ASD are generally small, retrospective & unblinded • Also, lack of diagnostic tools standardized in the ASD population

8. Introduction • Most medications are not FDA-approved for use in children with ASD • Exceptions: • Risperidone & Aripiprazole • Methylphenidate • Many other medications are used off-label • Parents/caregivers should be informed of this

9. Target Symptoms

10. Target Symptoms • Behaviors that interfere with learning, health, safety, socialization, quality of life, and/or overall functioning • Aggression, irritability & self-injury • Repetitive behaviors & rigidity • Hyperactivity & inattention • Anxiety & depression • Sleep disturbance

11. Aggression, Irritability & Self-Injury • Aggression & related disruptive behavior generally elicit the most concern in ASD • These behaviors can lead to injury & isolation • High prevalence of these symptoms (Kanneet al, 2011) • 68% to caregivers • 49% to non-caregivers

12. Aggression, Irritability & Self-Injury Antipsychotics • Efficacy of antipsychotics in autistic children was first documented in the 1970s • Now commonly used for ASD • Risperidone & Aripiprazole are the only 2 FDA-approved agents for aggression

13. Aggression, Irritability & Self-Injury Antipsychotics • Anderson LT & Campbell M et al, 1984 • RCT of Haloperidol (~1.7 mg/d) • Significant improvement in aggression (negativism, angry affect & mood lability) • However… • Sedation common • 1/3 children developed dystonia & withdrawal dyskinesias

14. Aggression, Irritability & Self-Injury Antipsychotics • Risperidone was first “atypical antipsychotic” • RUPP, 2005 • RCT of Risperidone (~2.08 mg/d) • Effective in decreasing moderate-severe tantrums, aggression & self-injurious behavior • Effects stable over time w/o dose increase, but relapse w/ medication withdrawal at 6 mos

15. Aggression, Irritability & Self-Injury Antipsychotics • Risperidone quickly became first-line treatment • FDA approved Risperidone in 2006 for autism • Ages 5-16 yo with max dose 3 mg/d

16. Moderators and Mediators of Risperidone Effect • Higher symptom severity associated with greater improvement • Weight gain mediates treatment response negatively • Socioeconomic advantage, low baseline prolactin and absence of anxiety, bi-polar symptoms, ODD, stereotopy & hyperactivity correlates with positive outcome • Intensive behavioral intervention in addition to risperidone resulted in the best outcome in autism with aggression

17. Aggression, Irritability & Self-Injury Antipsychotics • Aripiprazole is another “atypical antipsychotic” • Marcus RN et al, 2009 • RCT of Aripiprazole (5, 10, 15 mg/d) • All doses superior to placebo • Extrapyramidal symptoms but which rarely led to discontinuation

18. Aggression, Irritability & Self-Injury Antipsychotics • FDA approved Aripiprazole in 2009 for autism • Ages 6-17 yo with max dose 15 mg/d • Other antipsychotics lack large-scale RCTs • Variable benefits of Olanzapine & Ziprasidebased on small open-label studies • Quetiapinedoes not appear to be beneficial

19. Aggression, Irritability & Self-Injury Stimulants • Methylphenidate (MPH) has been examined for Tx of aggression in ASD ages 5-11 yo • Quintana H et al, 1995; Handen BL et al, 2000 • RCTs, but small & short duration • Superiority over placebo • High rate of side-effects

20. Aggression, Irritability & Self-Injury Other Agents • Valproate showed modest superiority & min side-effects in RCT (Hollander E, et al, 2010) • Naltrexone & Clonidine showed superiority in RCT (Parikh MS et al, 2008) • Not considered first-line agents

21. Aggression, Irritability & Self-Injury Other Antiepileptics • Carbamazepine(Tegretol) • Gabapentin (Neurontin) • Lamotrigine (Lamictal) • Topiramate (Topamax) • Oxcarbazepine(Trileptal) • Levetiracetam(Keppra)

22. Aggression, Irritability & Self-Injury • No clinical algorithm exists for • Clinicians generally start with lower risk alternatives • However, poor response & serious symptoms, these agents are often replaced by one of two FDA-approved antipsychotics

23. Repetitive Behaviors & Rigidity • Restricted, repetitive & stereotyped behaviors (RRBs), interests & activities (“rigidity”) are characteristic of ASDs • Lower-level motor behaviors (e.g. rocking) • Higher-level routines/rituals (e.g. insistence on sameness)

24. Repetitive Behaviors & Rigidity Selective Serotonin Reuptake Inhibitors • Initial use based on reports on serotoninergic dysfunction in ASD & shared symptomatology with OCD which responds to SSRIs • Most common class of psychotropics for individuals with ASD • Evidence is marginal from RCTs

25. Repetitive Behaviors & Rigidity • Hollander et al, 2005 • RCT of Fluoxetine (~10 mg/d) • Better than placebo • 39 children 5-16 yo • SOFIA, 2011 • RCT of Fluoxetine • No benefit over placebo over 14-wks • 158 children 5-17 yo

26. Repetitive Behaviors & Rigidity • King BH et al, 2009 • Large RCT of Citalopram (2.5-20 mg/d) • No significant difference b/w Tx & control • 149 children ages 5-17 yo • 1/3 experienced serotoninergic activation (increased activity, mood changes, insomnia) • Owley T et al, 2005 • Open-label RCT of Escitalopram • More positive effects on irritability

27. Repetitive Behaviors & Rigidity Atypical Antipsychotics • RRBs were examined as secondary outcomes in studies discussed previously • Risperidone significantly greater reduction vs. placebo (RUPP, 2005) • Aripiprazole significantly improved RRBs vs. placebo (Marcus RN et al, 2009)

28. Repetitive Behaviors & Rigidity Other Agents • Hollander E, et al, 2006 • Small RCT (13 individuals) of Valproate • Showed significant improvement of RRBs/rigidity vs. placebo

29. Repetitive Behaviors & Rigidity • RRBs/rigidity constitute frequent problematic behavior in children with ASD • Tx choices are difficult given relative lack of support of efficacy & side-effects can be difficult to tolerate • Clinicians advised to recognize Tx limitations & reserve medication to those with severe RRBs

30. Hyperactivity & Inattention • High prevalence of hyperactivity & inattention in children with ASD • Between 30-80% meeting criteria for ADHD • These children have more severe difficulties vs. ASD alone • Multiple agents have been investigated to treat these symptoms

31. Hyperactivity & Inattention Stimulants • Role of stimulantsin typical children is well-documented • Third most common class of medications used in ASD • Methylphenidate (MPH) is used preferentially • Studies on amphetamines are lacking

32. Hyperactivity & Inattention Stimulants • RUPP, 2005 • RCT of MPH (0.15mg/kg, 0.25mg/kg, 0.5mg/kg) • All doses superior to placebo • Even highest effect size was much lower vs. typical children • 18% discontinued medication due to side-effects

33. Adverse Effects of Stimulants in Children with ASD • Can increase perseveration, repetitive behaviors & irritability • May increase anxiety • May lead to increased sensory processing difficulties • Often better tolerated & more useful in mild range of ASD • Less effective in the presence of significant intellectual disability

34. Hyperactivity & Inattention Atypical Antipsychotics • RUPP, 2002 • RCT of Risperidone • Secondary analysis showed large reduction in hyperactivity in children with ASD • Owen et al, 2009 • RCT of Aripiprazole • Significant improvement over placebo

35. Hyperactivity & Inattention Other Agents • Arnold LE et al, 2006 • Small, pilot placebo-controlled crossover study of Atomoxetine(1.2-1.4 mg/kg) • Significant improvement vs. placebo • Effects comparable to MPH in ASD • Tolerable side-effects • Concomitant use of other psychotropics

36. Hyperactivity & Inattention Other Agents • Small, controlled trial of Clonidine showed superior reduction in disruptive behaviors (Jaselskis CA et al, 1992) • Small, open-label prospective study of Guanfacine showed moderate benefit (47% response) for high levels of hyperactivity & inattention (Scahill L et al, 2006) • Well-tolerated

37. Hyperactivity & Inattention Other Agents • Valproate • Topiramate • Lamotrigine

38. Hyperactivity & Inattention • None of the highly effective Tx for ADHD (i.e. stimulants) in typically developing children have same robust response in ASD • High rate of side-effects even a low doses • Alpha-agonists deserve more research and often form a solid second-line Tx choice • Antipsychotics can be effective for hyperactivity, but less favored

39. Anxiety & Depression • Research is lacking in effects of psychotropics for depression & anxiety in children with ASD • Strong empirical support exists for SSRIs in typical children; uncertain whether this translates to those with ASD • Some support exists for use of these medications in adults with ASD • High rate of significant adverse effects (“activation”) in children greatly tempers enthusiasm

40. Sleep Disturbance • Children w/ ASD experience sleep disturbance at much higher rates • Chronic sleep disturbance is disruptive to overall functioning & quality of family life • Lack of FDA-approved medications for this problem

41. Sleep Disturbance Melatonin • RCTs of Melatonin (Sanchez-Barcelo EJ, 2011) • Up to 6 mg/d was found to be effective • No significant side-effects • Long-term Tx has not been studied

42. Sleep Disturbance Other Agents • Risperidone • Clonidine

43. Social Deficits • Medications that may improve social deficits in children with ASD include: • Atypical antipsychotic, SSRIs • Oxyctocin • Memantine, Amantadine • Lamotrigine, D-cycloserine • Galantamine, Rivastigmine, Donepezil • Tetrahydrobiopterin

44. Side-effects

45. Side-effects: Antipsychotics • Neuroleptic malignant syndrome • Extra-pyramidal symptoms • Agranulocytosis • Cardiovascular changes • Galactorrhea • Weight gain & metabolic disorder • Sedation

46. Side-effects: SSRIs • Neuropsychiatric (10-30%) • Especially activation (agitation, disinhibition, hyperkinesia), may be more common in younger patients • Initial worsening of anxiety & OCD • GI upset (10%) • Suicidal thinking & behavior ???

47. Side-effects: Stimulants • Appetite supression • Irritability • Sleep disturbance • Dullness/social withdrawal • Headaches • Tremors/tics • Cardiovascular symptoms

48. Side-effects: Alpha-Agonists • Sedation (especially clonidine) • Aggression/irritability • Dry mouth • Constipation • Nocturnal enuresis • Dizziness • Hypotension & bradycardia

49. General Guidelines

50. “Rules of Thumb” • Identify specific problematic behaviors • Address environmental issues that may be exacerbating the behaviors • Start low and go slow • Address sleep difficulties early • Change one variable at a time