1. pharmacologic interventions for autism spectrum disorders jane ripperger-suhler, MD child and adolescent psychiatry university of texas southwestern residency programs at seton family of hospitals/texas child study center jarippergersuhler@seton.org

2. objectives use evidence to choose appropriate treatments for symptoms associated with autism spectrum disorders or for core symptoms use evidence to discuss CAM treatments with patients/families

3. why do we need to intervene?

4. what is the problem that requires intervention? i.e. what do we want to treat?

5. what approach should we take?

6. how do we decide what treatment to use?

8. evidence based treatment “using best evidence available to decide, along with patients, on options for care” a number of systems to rate quality of evidence generally must be: rational hypothesis randomized double blinded placebo controlled ▪ placebo response higher in children - 30-50% clear and reliable outcome measures

9. all treatments should be subjected to rigorous testing regardless if they are traditional or CAM

11. problems that are frequently the focus of pharmacological intervention irritability/aggression ADHD symptoms anxiety/ repetitive behaviors and intense interests sleep problems poor social interaction and communication

12. irritability and aggression antipsychotics alpha-agonists mood stabilizers others

13. antipsychotics - risperidone RUPP trial 101 subjects; 5-17y; ABC irritability scale >/ 18 double blind, placebo controlled, 8 weeks average dose 1.8 mg/d 69% showed improvement (12% placebo) weight gain, sedation; no EPS 16 week continuation phase: no worsening of target symptoms 3 week randomized assignment to continue or placebo substitution: 62.5% relapse in placebo group (12.5% in continuation group) Research Units on Pediatric Psychopharmacology Autism Network (RUPP) N Engl J Med 347:314-321, 2002. RUPP: Am J Psychiatry 162:1361-1369, 2005.

14. antipsychotics - risperidone multicenter RCT in Canada – similar results FDA approved 5y – 17 y for irritability in autism two RCTs in 2-9y/<6y children – similar results (0.5-1.5 mg/d) Shea S et al Pediatrics 114:E634-E641, 2004 Nagaraj R et al J Child Neurol 21:450-455, 2006 Luby J et al J Child Adolesc Psychopharmacol 16:575-587, 2006

15. antipsychotics - aripiprazole 218 subjects; 6-17y; ABC irritability scale >/ 18 double blind, placebo controlled, 8 weeks fixed doses of 5,10, and 15 mg/d 43-50% improvement (30% placebo) sedation; EPS FDA approved 6-17 y for psychomotor agitation in autism Owen R, et al: Pediatrics 124:1533-1540, 2009

16. antipsychotics – others olanzapine one small RCT: 50% showed improvement compared to 20% on placebo (weight gain) quetiapine four open label studies: mixed results with less response on smaller doses (sedation, weight gain) ziprasidone small open label studies: 50-75% showed improvement (sedation, dystonia, increased QTc interval) palperidone two case studies in 20 and 16 y/o’s: improvement in irritabilty, aggression, SIB over 42 and 50 weeks (no EPS, no weight gain) Stigler KA, McDougle CJ Ch Adol Clinic N Amer 17:739-752, 2008 Stigler KA, et al: J Child Adolesc Psychopharmacol 20:75-78, 2010

17. alpha-agonists clonidine ▪ two small RCTs: improvement in irritability/impulsivity (sedation) guanfacine ▪ retrospective analysis: 14% less aggression (sedation) Stigler KA, McDougle CJ Ch Adol Clinic N Amer 17:739-752, 2008

18. mood stabilizers valproate open label study showed improvement; RCT showed no difference from placebo (sedation, weight gain, and others) lamotrigine RCT: no difference from placebo (insomnia and hyperactivity) topiramate case series: no notable improvement (decrease in BMI) levetiracetam RCT: no difference from placebo (agitation and aggression) Stigler KA, McDougle CJ Ch Adol Clinic N Amer 17:739-752, 2008

19. others hyperbaric oxygen therapy open label trial with non-random assignment and subjective parental report on ABC: improvement vancomycin case series: short term behavioral improvement (ototoxicity, rash) Levy SE, Hyman SL: Ch Adol Clinic N Amer 17:803-820, 2008

20. summary: treatments for irritability/aggression risperidone aripiprazole other antipsychotics (quetiapine?) alpha-agonists? mood stabilizers and others – evidence does not support use strength of evidence

21. ADHD symptoms: inattention, hyperactivity, impulsivity 30-60% of ASD kids in one school sample had one or more ADHD symptoms stimulants atomoxetine risperidone alpha agonists others

22. stimulants Several early studies of varying degrees of rigor, small numbers of subjects 46-62% response rates* variety of SEs reported (irritability, self injury, insomnia, social withdrawal) Santosh (2006, 113 children retrospective/52 prospective, ?HFA, methylphenidate) similar rates of response in ADHD w/o ASD and ADHD + ASD (51-66% on CGI) *65-85% general response rate in adhd w/o asd Birmaher B, et al J AM Acad Child Adolesc Psychiatry 27:248-251, 1988 Quintana H, et al J Autism Dev Disord 25:283-294, 1995 Handen BL, et al J Autism Dev Disord 30:245-255, 2000 Di Martino A,et al J Child Adolesc Psychopharmacol 14:207-218, 2004 Santosh PJ, et al Child Care Hlth Dev 32:575-583, 2006

23. stimulants RUPP* (2005, 72 children, ABC, methylphenidate) decreased hyperactivity with low, medium, high doses compared to placebo social withdrawal worsened with high dose compared to placebo Posey (2007, 66 RUPP children, SNAP, methylphenidate) decreased hyperactivity with low, medium, high doses compared to placebo age, IQ, type of ASD did not moderate outcome Nickels (2008, epidemiologic study, 80% mph, chart review) response rate of 69.4% response rate not affected by gender or type of prep RUPP Arch Gen Psychiatry 62:1266-1274, 2005 Posey DJ, et al Biol Psychiatry 61:538-544, 2007 Nickels KC, et al J Dev Behav Pediatr 29:75-81, 2008

24. stimulants - bottom line what we know: variable effectiveness among individuals some likelihood of positive response but less than in ADHD w/o ASD elevated risk of adverse events irritability insomnia social withdrawal sib amphetamines?

25. stimulants – bottom line what to do: methylphenidate first? low initial doses small dose increments monitor closely be prepared to stop the trial if unacceptable adverse effects

26. atomoxetine three open label studies and one placebo controlled small study all showed reduction of ADHD symptoms on one or more measure 56% response rate in controlled study* low rate of adverse effects *56-70% response rate in ADHD w/o ASD Aman MG, et al Ch Adol Clinic N Amer 17:713-738, 2008

27. antipsychotics 4 controlled studies with risperidone targeting hyperactivity and inattentiveness three showed significant decrease in hyperactivity small uncontrolled studies with others (quetiapine, ziprasidone, aripiprazole) significant decreases in hyperactivity Aman MG, et al Ch Adol Clinic N Amer 17:713-738, 2008

28. alpha-agonists clonidine two RCTs: mixed results with only some measures on both studies showing improvement in hyperactivity (sedation) guanfacine retrospective review: significant improvement in interfering behaviors including ADHD symptoms RUPP open trial: significant decrease in hyperactivity no studies on extended release guanfacine Aman MG, et al Ch Adol Clinic N Amer 17:713-738, 2008 Scahill L et al J Child Adolesc Psychopharmacol 16:589-598, 2006

29. cholinesterase inhibitors  acetylcholine galantamine one RCT: decreased hyperactivity open label study: no improvement in hyperactivity donepezil retrospective study: improvement in hyperactivity rivastigmine – unclear Aman MG, et al Ch Adol Clinic N Amer 17:713-738, 2008

30. NMDA antagonists amantadine (  dopamine) one RCT showed improved hyperactivity on investigator ratings, not on parent ratings need 200mg dose? memantine (blocks glutamate) open label study showed decreased hyperactivity chart review showed decreased hyperactivity hyperactivity reported as side effect Aman MG, et al Ch Adol Clinic N Amer 17:713-738, 2008

31. others AEDs topiramate ▪ open label, retrospective study showed decreased hyperactivity lamotrigine ▪ RCT showed no improvement in hyperactivity opiate blockers naltrexone ▪ open label studies: decreased hyperactivity ▪ several RCTs: marginal effects on hyperactivity Aman MG, et al Ch Adol Clinic N Amer 17:713-738, 2008 Hollander E, Anagnostou E: Clinical manual for the treatment of autism, APPI. Wash DC, 2007.

32. others dimethylglycine case series suggested improvement in attention omega 3 fatty acids pilot RCT showed improved behavior gluten free-casein-free diet multiple case reports, uncontrolled studies three small RCTs; one included ADHD sx as outcome measure and showed improvement need for replication ongoing studies Levy SE, et al Ch Adol Clinic N Amer 17:803-820, 2008 Millward C, et al Cochrane Dat Syst Rev 2, CD003498, 2008. Whiteley P, et al Nutr Neurosci 13:87-100, 2010.

33. summary: treatments for ADHD symptoms methylphenidate possibly other stimulants atomoxetine risperidone possibly other antipsychotics alpha-agonists other treatments are experimental or not useful strength of evidence

34. anxiety characterized by physical, cognitive, and behavioral symptoms can manifest as repetitive behaviors (compulsions) perseveration (obsessions) resistance to change restricted, repetitive, and stereotyped pattern of behaviors, interests, and activities

35. why SSRIs some FDA approved for use in children for OCD good evidence for effectiveness for anxiety in children most FDA approved for various anxiety disorders in adults similarities between repetitive behaviors, need for sameness and OCD

36. why SSRIs hyperserotonemia in autism differences in serotonin synthesis in autism serotonin modulates synaptogenesis

37. clomipramine tricyclic antidepressant with significant serotonin reuptake inhibition activity FDA approved for OCD 10y and up two small RCTs in older children and adults : improvement in repetitive behaviors open label studies in very young children: no improvement in repetitive behaviors significant side effects limit use (lowered seizure threshold, prolonged QTc, urinary retention, serotonin syndrome) Soorya L, et al Ch Adol Clinic N Amer 17:753-772, 2008

38. fluvoxamine FDA approved for OCD 8 y and up one RCT in adults: improvement in repetitive thoughts and behaviors (nausea and sedation) one RCT in children: only one child showed improvement in target symptoms (behavioral activation) Soorya L, et al Ch Adol Clinic N Amer 17:753-772, 2008

39. sertraline FDA approved for OCD age 6y and up open label study in adults: 57% improved on measures of repetitive behaviors (agitation, anxiety) open label study in 6-12 y/olds: 89% had positive response in the treatment of “transition-associated anxiety and agitation” Soorya L, et al Ch Adol Clinic N Amer 17:753-772, 2008

40. fluoxetine FDA approved for OCD ages 7y and up two case reports: increased tolerance of routine changes several open label studies: improvement in measures of repetitive, stereotyped behaviors and restricted interests and in perseverative behaviors Soorya L, et al Ch Adol Clinic N Amer 17:753-772, 2008

41. fluoxetine RCT in adults: improvement in all subjects on obsessive scale of YBOCS and on hamilton anxiety scale 20 week cross over RCT with 45 subjects (5-16y) significant reduction in repetitive behaviors diarrhea, weight gain, insomnia, anxiety – no difference from placebo group behavioral activation Hollander E et al: Neuropsychopharmacology 30:582-589, 2005. Soorya L, et al Ch Adol Clinic N Amer 17:753-772, 2008

42. citalopram chart review: improvement in repetitive behaviors and anxiety with increased response over time (average 31 weeks) STAART 149 subjects; 5-17y; research diagnosis double blind, placebo controlled, 12 weeks average maximum dose 16.5 mg/d 32.9% showed improvement in repetitive behaviors (34.2% placebo) behavioral activation significantly more than in placebo group Soorya L, et al Ch Adol Clinic N Amer 17:753-772, 2008 King BH et al Arch Gen Psychiatry 66:583-590, 2009

43. other SSRIs paroxetine two case reports: improvement in sib, anxiety, irritability, preoccupations (agitation, insomnia) escitalopram open label study: improvement in global severity and irritability Soorya L, et al Ch Adol Clinic N Amer 17:753-772, 2008 Hollander E, Anagnostou E: Clinical manual for the treatment of autism, APPI. Wash DC, 2007.

44. others venlafaxine (SNRI) retrospective open label study: improved repetitive behaviors and restricted interests mirtazapine open label study: no significant improvement in any measure risperidone one RCT in adults: reduction in repetitive behaviors (sedation) followup analysis of RUPP data: reduction in repetitive behaviors Soorya L, et al Ch Adol Clinic N Amer 17:753-772, 2008

45. others naltrexone open label studies: decreased stereotyped and compulsive behaviors valproate RCT: reduced hours spent on repetitive behaviors adjunct to SSRIs to reduce activation? oxytocin open study in adults: reduced severity, frequency, and number of repetitive behaviors Soorya L, et al Ch Adol Clinic N Amer 17:753-772, 2008 Hollander E, Anagnostou E: Clinical manual for the treatment of autism, APPI. Wash DC, 2007.

46. others gluten-free/casein-free diet case series with milk elimination: improvement in autism symptoms small single blind, RCT with gluten and casein elimination: improvement in global symptoms double blinded RCT with GFCF diet: no group differences on any measure vitamin C one RCT: decreased stereotyped behavior Levy SE, et al Ch Adol Clinic N Amer 17:803-820, 2008 Millward C, et al Cochrane Dat Syst Rev 2, CD003498, 2008

47. for anxiety symptoms: SSRIs/SNRIs cautiously with low doses for perseveration and resistance to change: few studies have addressed directly but evidence supports fluoxetine and sertraline for repetitive behaviors: fluoxetine sertraline risperidone valproate, vitamin C, venlafaxine, naltrexone, GFCF diet citalopram summary: treatment of anxiety strength of evidence for effectiveness strength of evidence for ineffectiveness

49. sleep disturbance 44-86% of children with ASD have sleep problems insomnia - most common irregular sleep-wake patterns early morning awakenings poor sleep routines Johnson KP, et al Ch Adol Clinic N Amer 17:773-786, 2008

50. causes of insomnia in ASD neurobiological abnormal GABA (active in hypothalamic sleep promoting system) abnormal melatonin regulation behavioral co-morbid neurologic (seizures), medical (GERD), or psychiatric (anxiety) condition medications other

51. melatonin neurohormone that promotes sleep produced in pineal gland from serotonin nutritional supplement not regulated by FDA mechanism of action may align circadian clock may supplement deficient endogenous melatonin may act as anxiolytic or hypnotic

52. melatonin retrospective study of 100 children with ASD: 85% with improved sleep (minimal adverse effects) two open label studies: decreased sleep latency and improvement on sleep diaries (fatigue, daytime sleepiness, dizziness) RCT: longer sleep duration and shorter time to onset start with 1 mg and titrate to 3 mg (max dose 6 mg) use same formulation d/t wide variations extended release for sleep maintenance problems Johnson KP, et al Ch Adol Clinic N Amer 17:773-786, 2008 Wirojanan, J, et al J Clin Sleep Med 5:145-150, 2009.

53. others use sedating medications that treat other present conditions as well AEDs risperidone clonidine trazodone amitriptyline very little data on use for sleep in kids clonazepam lorazepam (FDA approved >/ 12y) hydroxyzine (FDA approved)

54. core social and communication impairment difficulties in addressing with pharmacology neurobiology not yet clearly established symptoms improve over time diagnostic heterogeneity lack of agreement on best outcome measure

55. proposed neurobiological models impaired NT/peptide function altered networks altered number or functioning of receptors altered amount of NT/peptide gastrointestinal dysfunction impaired immunity impaired heavy metal detoxification

56. impaired NT/peptide function SSRIs do not seem to improve language acquisition of social interaction in groups may be effective in girls studies ongoing to determine factors relevant to time of interventions serotonin-dopamine antagonists effect of risperidone on social relatedness mixed in two well designed studies and in others other atypicals mixed results in small open label studies methylphenidate RUPP data RCT: increased response to and initiation of joint attention tasks Posey DJ, et al Ch Adol Clinic N Amer 17:787-802, 2008 Jahromi LB, et al J Autism Dev Disord 39:395-404, 2009

57. impaired NT/peptide function cholinesterase inhibitors donepezil one RCT: improvement in language compared to placebo but placebo group had more improvement in CARS scores rivastigmine open label study: improvement in CARS and expressive language galantamine open label study: 62% responders on CGI Posey DJ, et al Ch Adol Clinic N Amer 17:787-802, 2008

58. impaired NT/peptide function glutamatergic drugs glutamate – primary excitatory NT in brain support from animal models lamotrigine RCT: no different from placebo on any measure d-cycloserine antibiotic for tuberculosis pilot, single blind RCT: improvement in social withdrawal larger study underway NMDA antagonists mixed data Posey DJ, et al Ch Adol Clinic N Amer 17:787-802, 2008

59. impaired NT/peptide function naltrexone RCTs have failed to demonstrate benefit other than decreasing hyperactivity fenfluramine several studies failed to find benefit oxytocin RCT: promotion of social behavior in HFA (not yet available in USA) Posey DJ, et al Ch Adol Clinic N Amer 17:787-802, 2008 Andari E, et al PNAS 107:4389-4394, 2010

60. impaired NT/peptide function amino acids/dipeptides act as NTs are precursors to NTs commonly supplemented: ▪ tryptophan ▪ L-carnosine ▪ taurine ▪ GABA ▪ cystine ▪ lysine + methionine  carnitine

61. impaired NT/peptide function tryptophan (precursor of serotonin) decreased plasma levels in ASD depletion caused exacerbation of ASD symptoms in adults vitamin C (cofactor for tryptophan  serotonin) one RCT: positive effects; awaiting replication L-carnosine (modulates GABA?) one RCT showed improvement on GARS and PPVT no other peer reviewed published trials involving amino acid supplementation in children with ASD Levy SE, et al Ch Adol Clinic N Amer 17:803-820, 2008

62. impaired NT/peptide function cofactors for methionine metabolism vitamin B6 open label studies: improvement in social quotient blinded RCTs: no treatment effects but one very small and the other used small doses peripheral neuropathy > 100mg/d vitamin B12 one open trial: normalized methionine metabolism markers, no clinical correlation Levy SE, et al Ch Adol Clinic N Amer 17:803-820, 2008

63. gastrointestinal dysfunction secretin multiple RCTs have shown no benefit gluten-free/casein-free diet (addressed above) (nutritional deficiencies) probiotics several studies have shown usefulness for other conditions open label trial (with digestive enzymes) in ASD: some behavioral improvements; 22 of 46 completed study flatulence, constipation digestive enzymes (see above) Levy SE, et al Ch Adol Clinic N Amer 17:803-820, 2008

64. impaired immunity antifungals no published studies (hepatotoxicity with chronic use) IVIG three case series: two with clinical improvement, one with none (expensive, limited supply, flushing, hypotension, chills, fever, low back pain, HA) dimethylglycine (no proven immunologic effect) two small RCTs: no improvement compared to placebo antibiotics one study – vancomycin (see above) hyperbaric oxygen therapy (  inflammation of gut?) see above Levy SE, et al Ch Adol Clinic N Amer 17:803-820, 2008 Hollander E, Anagnostou E: Clinical manual for the treatment of autism, APPI. Wash DC, 2007.

65. impaired heavy metal detoxification metallothionein dysfunction cellular protein which neutralizes effects of toxic metals reported to be deficient in ASD one negative study, otherwise, no peer reviewed data published to support this hypothesis supplementation with amino acids, selenium and glutathione is recommended no peer reviewed, published trials of this treatment Hollander E, Anagnostou E: Clinical manual for the treatment of autism, APPI. Wash DC, 2007.

66. impaired heavy metal detoxification chelation therapy dimercaptosuccinic acid and edetate calcium disodium - chelating agents for acute exposure to heavy metals chelation ineffective once neurological damage occurs no evidence for effectiveness in children with ASD hematological, renal, liver toxicity and death with iv administration Hollander E, Anagnostou E: Clinical manual for the treatment of autism, APPI. Wash DC, 2007.

67. summary: treatment of core symptoms serotonin-dopamine agonists oxytocin vitamin C L-carnitine SSRIs cholinesterase inhibitors d-cycloserine NMDA antagonists vit B6 GFCF diet others amino acids naltrexone chelation therapy fenfluramine secretin strength of evidence for effectiveness strength of evidence for ineffectiveness

69. integrative medicine 33-50% of children with ASD are using some form of CAM families need help assessing options families do not always volunteer CAM uses to physicians physicians do not always ask

70. finding reliable information about CAM therapies AltMedDex (Thomson Micromedex) http://nccam.nih.gov/camonpubmed http://nccam.nih.gov

71. helping families who want to pursue CAM offer families lists of clinical trials (http://clinicaltrials.gov)http://clinicaltrials.gov offer information on how to choose a CAM provider (http://nccam.nih.gov)http://nccam.nih.gov discuss CAM provider recommendations and lab results at follow-up visit help families monitor therapies

72. help families monitor alternative therapies 1.“n of 1” experiment 2.set time period for “study” 3.one treatment at a time 4.help families choose target symptoms 5.provide standardized rating forms to assess target symptoms 6.gather information from sources outside the family as well 7.follow up regularly 8.document process

73. “We must never lose sight of the long term goal of treatment … to improve outcome for persons with autism,… that is, empowerment to live, work, learn, be mobile, and have fun… in natural settings with family, friends, and coworkers.” Freeman, BJ, J Autism and Developmental Disorders, 1997

74. the end

75. World Cup Fever!!!