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pharmacologic interventions for autism spectrum disorders

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. objectives.

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pharmacologic interventions for autism spectrum disorders

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  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?

  7. 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

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

  9. 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

  10. irritability and aggression • antipsychotics • alpha-agonists • mood stabilizers • others

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

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

  19. 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

  20. 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

  21. 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

  22. 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?

  23. 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

  24. 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

  25. 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

  26. 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

  27. cholinesterase inhibitors • hacetylcholine • 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

  28. NMDA antagonists • amantadine (hdopamine) • 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

  29. 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.

  30. 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.

  31. 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

  32. 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

  33. 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

  34. why SSRIs • hyperserotonemia in autism • differences in serotonin synthesis in autism • serotonin modulates synaptogenesis

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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.

  42. 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

  43. 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.

  44. 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

  45. summary: treatment of anxiety • 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 strength of evidence for effectiveness strength of evidence for ineffectiveness

  46. 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

  47. 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

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