pharmacologic interventions for autism spectrum disorders

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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_at_seton.org

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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

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why do we need to intervene?
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what is the problem that requires intervention?
i.e. what do we want to treat?
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what approach should we take?
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how do we decide what treatment to use?
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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

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

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irritability and aggression

• antipsychotics
• alpha-agonists
• mood stabilizers
• others

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antipsychotics - risperidone

• RUPP trial
• 101 subjects 5-17y ABC irritability scale gt/ 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 347314-321,
  2002.
• RUPP Am J Psychiatry 1621361-1369, 2005.

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antipsychotics - risperidone

• multicenter RCT in Canada similar results
• FDA approved 5y 17 y for irritability in
  autism
• two RCTs in 2-9y/lt6y children similar results
  (0.5-1.5 mg/d)
• Shea S et al Pediatrics 114E634-E641, 2004
• Nagaraj R et al J Child Neurol 21450-455, 2006
• Luby J et al J Child Adolesc Psychopharmacol
  16575-587, 2006

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antipsychotics - aripiprazole

• 218 subjects 6-17y ABC irritability scale gt/ 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 1241533-1540, 2009

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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/os improvement
  in irritabilty, aggression, SIB over 42 and 50
  weeks (no EPS, no weight gain)
• Stigler KA, McDougle CJ Ch Adol Clinic N Amer
  17739-752, 2008
• Stigler KA, et al J Child Adolesc
  Psychopharmacol 2075-78, 2010

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alpha-agonists

• clonidine
• two small RCTs improvement in irritability/impuls
  ivity (sedation)
• guanfacine
• retrospective analysis 14 less aggression
  (sedation)
• Stigler KA, McDougle CJ Ch Adol Clinic N Amer
  17739-752, 2008

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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
  17739-752, 2008

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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
  17803-820, 2008

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summary treatments for irritability/aggression

• risperidone
• aripiprazole
• other antipsychotics (quetiapine?)
• alpha-agonists?
• mood stabilizers and others evidence does not
  support use

strength of evidence
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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

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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 27248-251, 1988
• Quintana H, et al J Autism Dev Disord 25283-294,
  1995
• Handen BL, et al J Autism Dev Disord 30245-255,
  2000
• Di Martino A,et al J Child Adolesc
  Psychopharmacol 14207-218, 2004
• Santosh PJ, et al Child Care Hlth Dev 32575-583,
  2006

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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 621266-1274, 2005
• Posey DJ, et al Biol Psychiatry 61538-544, 2007
• Nickels KC, et al J Dev Behav Pediatr 2975-81,
  2008

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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?

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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

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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 17713-738,
  2008

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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 17713-738,
  2008

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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 17713-738,
  2008
• Scahill L et al J Child Adolesc Psychopharmacol
  16589-598, 2006

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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 17713-738,
  2008

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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 17713-738,
  2008

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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 17713-738,
  2008
• Hollander E, Anagnostou E Clinical manual for
  the treatment of autism, APPI. Wash DC, 2007.

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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 17803-820,
  2008
• Millward C, et al Cochrane Dat Syst Rev 2,
  CD003498, 2008.
• Whiteley P, et al Nutr Neurosci 1387-100, 2010.

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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
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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

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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

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why SSRIs

• hyperserotonemia in autism
• differences in serotonin synthesis in autism
• serotonin modulates synaptogenesis

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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 17753-772,
  2008

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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 17753-772,
  2008

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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 17753-772,
  2008

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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 17753-772,
  2008

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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
  30582-589, 2005.
• Soorya L, et al Ch Adol Clinic N Amer 17753-772,
  2008

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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 17753-772,
  2008
• King BH et al Arch Gen Psychiatry 66583-590, 2009

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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 17753-772,
  2008
• Hollander E, Anagnostou E Clinical manual for
  the treatment of autism, APPI. Wash DC, 2007.

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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 17753-772,
  2008

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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 17753-772,
  2008
• Hollander E, Anagnostou E Clinical manual for
  the treatment of autism, APPI. Wash DC, 2007.

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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 17803-820,
  2008
• Millward C, et al Cochrane Dat Syst Rev 2,
  CD003498, 2008

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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
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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
  17773-786, 2008

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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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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

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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
  17773-786, 2008
• Wirojanan, J, et al J Clin Sleep Med 5145-150,
  2009.

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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 gt/ 12y)
• hydroxyzine (FDA approved)

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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

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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

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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 17787-802,
  2008
• Jahromi LB, et al J Autism Dev Disord 39395-404,
  2009

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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 17787-802,
  2008

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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 17787-802,
  2008

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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 17787-802,
  2008
• Andari E, et al PNAS 1074389-4394, 2010

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impaired NT/peptide function

• amino acids/dipeptides
• act as NTs
• are precursors to NTs
• commonly supplemented
• tryptophan
• L-carnosine
• taurine
• GABA
• cystine
• lysine methionine g carnitine

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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 g 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 17803-820,
  2008

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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 gt 100mg/d
• vitamin B12
• one open trial normalized methionine metabolism
  markers, no clinical correlation
• Levy SE, et al Ch Adol Clinic N Amer 17803-820,
  2008

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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 17803-820,
  2008

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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 (i inflammation of
  gut?)
• see above
• Levy SE, et al Ch Adol Clinic N Amer 17803-820,
  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.

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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.

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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
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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

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finding reliable information about CAM therapies

• AltMedDex (Thomson Micromedex)
• http//nccam.nih.gov/camonpubmed
• http//nccam.nih.gov

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helping families who want to pursue CAM

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

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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

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• 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

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the end
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