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pharmacologic interventions for autism spectrum disorders
jane ripperger-suhler, MDchild and adolescent psychiatry
university of texas southwestern residency programs at seton family of hospitals/texas child study center
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
why do we need to intervene?
what is the problem that requires intervention? i.e. what do we want to treat?
what approach should we take?
how do we decide what treatment to use?
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
all treatments should be subjected to rigorous testing regardless if
they are traditional or CAM
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
irritability and aggression
• antipsychotics• alpha-agonists• mood stabilizers• others
antipsychotics - risperidoneRUPP 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.
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, 2004Nagaraj R et al J Child Neurol 21:450-455, 2006Luby J et al J Child Adolesc Psychopharmacol 16:575-587, 2006
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
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, 2008Stigler KA, et al: J Child Adolesc Psychopharmacol 20:75-78, 2010
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
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
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
summary: treatments for irritability/aggression
• risperidone• aripiprazole• other antipsychotics
(quetiapine?)• alpha-agonists?
• mood stabilizers and others – evidence does not support use
strength of evidence
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
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, 1988Quintana H, et al J Autism Dev Disord 25:283-294, 1995Handen BL, et al J Autism Dev Disord 30:245-255, 2000Di Martino A,et al J Child Adolesc Psychopharmacol 14:207-218, 2004Santosh PJ, et al Child Care Hlth Dev 32:575-583, 2006
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, 2005Posey DJ, et al Biol Psychiatry 61:538-544, 2007Nickels KC, et al J Dev Behav Pediatr 29:75-81, 2008
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?
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
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
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
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, 2008Scahill L et al J Child Adolesc Psychopharmacol 16:589-598, 2006
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
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
othersAEDs
• 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, 2008Hollander E, Anagnostou E: Clinical manual for the treatment of autism, APPI. Wash DC, 2007.
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, 2008Millward C, et al Cochrane Dat Syst Rev 2, CD003498, 2008.Whiteley P, et al Nutr Neurosci 13:87-100, 2010.
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
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
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
why SSRIs
• hyperserotonemia in autism• differences in serotonin synthesis in
autism• serotonin modulates synaptogenesis
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
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
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
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
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
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 groupSoorya L, et al Ch Adol Clinic N Amer 17:753-772, 2008King BH et al Arch Gen Psychiatry 66:583-590, 2009
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, 2008Hollander E, Anagnostou E: Clinical manual for the treatment of autism, APPI. Wash DC, 2007.
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
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, 2008Hollander E, Anagnostou E: Clinical manual for the treatment of autism, APPI. Wash DC, 2007.
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, 2008Millward C, et al Cochrane Dat Syst Rev 2, CD003498, 2008
• 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
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
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
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
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
problemsJohnson KP, et al Ch Adol Clinic N Amer 17:773-786, 2008Wirojanan, J, et al J Clin Sleep Med 5:145-150, 2009.
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)
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
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
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
tasksPosey DJ, et al Ch Adol Clinic N Amer 17:787-802, 2008Jahromi LB, et al J Autism Dev Disord 39:395-404, 2009
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 CGIPosey DJ, et al Ch Adol Clinic N Amer 17:787-802, 2008
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
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, 2008Andari E, et al PNAS 107:4389-4394, 2010
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
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
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
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
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, 2008Hollander E, Anagnostou E: Clinical manual for the treatment of autism, APPI. Wash DC, 2007.
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.
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.
summary: treatment of core symptoms
serotonin-dopamine agonistsoxytocinvitamin CL-carnitineSSRIscholinesterase inhibitorsd-cycloserineNMDA antagonistsvit B6GFCF diet
othersamino acids
naltrexone
chelation therapyfenfluramine
secretin
strength of evidence for effectiveness
strength of evidence for ineffectiveness
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
finding reliable information about CAM therapies
• AltMedDex (Thomson Micromedex)• http://nccam.nih.gov/camonpubmed• http://nccam.nih.gov
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
help families monitor alternative therapies
1. “n of 1” experiment2. set time period for “study”3. one treatment at a time4. help families choose target symptoms5. provide standardized rating forms to assess
target symptoms6. gather information from sources outside the
family as well7. follow up regularly8. document process
“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
the end
