Transcript Slide 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
[email protected]
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:
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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
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antipsychotics
alpha-agonists
mood stabilizers
others
antipsychotics - risperidone
RUPP trial
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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, 2004
Nagaraj R et al J Child Neurol 21:450-455, 2006
Luby J et al J Child Adolesc Psychopharmacol 16:575-587, 2006
antipsychotics - aripiprazole
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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, 2008
Stigler 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, 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
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
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
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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, 2008
Scahill L et al J Child Adolesc Psychopharmacol 16:589-598, 2006
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
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
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.
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.
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
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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
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.
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, 2008
Hollander 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, 2008
Millward C, et al Cochrane Dat Syst Rev 2, CD003498, 2008
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
strength of
evidence for
effectiveness
• valproate, vitamin C, venlafaxine,
naltrexone, GFCF diet
• citalopram
strength of
evidence for
ineffectiveness
sleep disturbance
• 44-86% of children with ASD have sleep
problems
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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
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neurobiological
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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
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.
others
• use sedating medications that treat other
present conditions as well
• AEDs
• risperidone
• clonidine
• trazodone
• amitriptyline
• clonazepam
very little data on use for sleep in kids
• lorazepam (FDA approved >/ 12y)
• hydroxyzine (FDA approved)
core social and communication
impairment
difficulties in addressing with pharmacology
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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 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
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
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, 2008
Andari 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 g 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 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 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 (i 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.
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 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
ineffectiveness
strength of
evidence for
effectiveness
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.
2.
3.
4.
5.
“n of 1” experiment
set time period for “study”
one treatment at a time
help families choose target symptoms
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
“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