Another Piece of the Puzzle:
the Role of Medication in the Care of
Individuals on the Autism Spectrum
Valentina Intagliata, MD
Assistant Professor of Pediatrics
UVa Children’s Hospital
Disclaimer
• I have no financial or research interests in
any of the medications
Objectives
• Recognize target symptoms in children with
ASD which can be treated with medications
• Be familiar with medications used commonly
in children with ASD
• Be aware of the possible side-effects of these
medications
• Case presentations
Introduction
• ASD are a heterogeneous
group of disorders
– Clinical manifestations vary
in presentation & intensity
• Treatments must be
individualized
– Weigh potential risks &
benefits
Introduction
• Behavioral & educational approaches are the
cornerstone of comprehensive treatment for
core symptoms
• Medications may be a useful
adjunct to treat common
comorbid symptoms – after
behavioral & environmental
interventions have been
maximized
Introduction
• Medications available do not directly treat core
features of autism
– i.e. social-communication impairments
• Treat behavioral manifestations of the underlying
brain pathology
Introduction
• Most existing evidence on medication use is
extrapolated from studies on comorbid
conditions (e.g. ADHD, OCD, anxiety) in children
without ASD
• Studies in children with ASD are generally small,
retrospective & unblinded
– Also, lack of diagnostic tools standardized in
the ASD population
Introduction
• Most medications are not FDA-approved for use
in children with ASD
– Exceptions:
• Risperidone & Aripiprazole
• Methylphenidate
• Many other medications are used off-label
– Parents/caregivers should be informed of this
Target Symptoms
Target Symptoms
• Behaviors that interfere with learning, health,
safety, socialization, quality of life, and/or
overall functioning
– Aggression, irritability & self-injury
– Repetitive behaviors & rigidity
– Hyperactivity & inattention
– Anxiety & depression
– Sleep disturbance
Aggression, Irritability & Self-Injury
• Aggression & related disruptive behavior
generally elicit the most concern in ASD
• These behaviors can lead to injury & isolation
• High prevalence of these
symptoms (Kanne et al, 2011)
• 68% to caregivers
• 49% to non-caregivers
Aggression, Irritability & Self-Injury
Antipsychotics
•Efficacy of antipsychotics in autistic children was
first documented in the 1970s
• Now commonly used for ASD
– Risperidone & Aripiprazole are the only 2
FDA-approved agents for aggression
Aggression, Irritability & Self-Injury
Antipsychotics
•Anderson LT & Campbell M et al, 1984
– RCT of Haloperidol (~1.7 mg/d)
– Significant improvement in aggression
(negativism, angry affect & mood lability)
– However…
• Sedation common
• 1/3 children developed dystonia & withdrawal
dyskinesias
Aggression, Irritability & Self-Injury
Antipsychotics
•Risperidone was first “atypical antipsychotic”
•RUPP, 2005
– RCT of Risperidone (~2.08 mg/d)
– Effective in decreasing moderate-severe
tantrums, aggression & self-injurious behavior
– Effects stable over time w/o dose increase,
but relapse w/ medication withdrawal at 6 mos
Aggression, Irritability & Self-Injury
Antipsychotics
• Risperidone quickly
became first-line treatment
• FDA approved Risperidone in 2006 for autism
– Ages 5-16 yo with max dose 3 mg/d
Moderators and Mediators of
Risperidone Effect
• Higher symptom severity associated with greater
improvement
• Weight gain mediates treatment response
negatively
• Socioeconomic advantage, low baseline prolactin
and absence of anxiety, bi-polar symptoms, ODD,
stereotopy & hyperactivity correlates with positive
outcome
• Intensive behavioral intervention in addition to
risperidone resulted in the best outcome in autism
with aggression
Aggression, Irritability & Self-Injury
Antipsychotics
•Aripiprazole is another “atypical antipsychotic”
•Marcus RN et al, 2009
– RCT of Aripiprazole (5, 10, 15 mg/d)
– All doses superior to placebo
– Extrapyramidal symptoms but which rarely led
to discontinuation
Aggression, Irritability & Self-Injury
Antipsychotics
•FDA approved Aripiprazole
in 2009 for autism
– Ages 6-17 yo with max dose 15 mg/d
•Other antipsychotics lack large-scale RCTs
– Variable benefits of Olanzapine & Zipraside
based on small open-label studies
– Quetiapine does not appear to be beneficial
Aggression, Irritability & Self-Injury
Stimulants
•Methylphenidate (MPH) has been examined for Tx
of aggression in ASD ages 5-11 yo
•Quintana H et al, 1995; Handen BL et al, 2000
– RCTs, but small & short duration
– Superiority over placebo
– High rate of side-effects
Aggression, Irritability & Self-Injury
Other Agents
• Valproate showed modest superiority & min sideeffects in RCT (Hollander E, et al, 2010)
• Naltrexone & Clonidine showed superiority in
RCT (Parikh MS et al, 2008)
• Not considered first-line agents
Aggression, Irritability & Self-Injury
Other Antiepileptics
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Carbamazepine (Tegretol)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Topiramate (Topamax)
Oxcarbazepine (Trileptal)
Levetiracetam (Keppra)
Aggression, Irritability & Self-Injury
• No clinical algorithm exists for
• Clinicians generally start with
lower risk alternatives
• However, poor response &
serious symptoms, these agents
are often replaced by one of two
FDA-approved antipsychotics
Repetitive Behaviors & Rigidity
• Restricted, repetitive & stereotyped behaviors
(RRBs), interests & activities (“rigidity”) are
characteristic of ASDs
– Lower-level motor behaviors (e.g. rocking)
– Higher-level routines/rituals (e.g. insistence
on sameness)
Repetitive Behaviors & Rigidity
Selective Serotonin Reuptake Inhibitors
•Initial use based on reports on serotoninergic
dysfunction in ASD & shared symptomatology with
OCD which responds to SSRIs
•Most common class of psychotropics
for individuals with ASD
– Evidence is marginal from RCTs
Repetitive Behaviors & Rigidity
• Hollander et al, 2005
– RCT of Fluoxetine (~10 mg/d)
– Better than placebo
– 39 children 5-16 yo
• SOFIA, 2011
– RCT of Fluoxetine
– No benefit over placebo over 14-wks
– 158 children 5-17 yo
Repetitive Behaviors & Rigidity
• King BH et al, 2009
– Large RCT of Citalopram (2.5-20 mg/d)
– No significant difference b/w Tx & control
– 149 children ages 5-17 yo
– 1/3 experienced serotoninergic activation
(increased activity, mood changes, insomnia)
• Owley T et al, 2005
– Open-label RCT of Escitalopram
– More positive effects on irritability
Repetitive Behaviors & Rigidity
Atypical Antipsychotics
• RRBs were examined as secondary outcomes in
studies discussed previously
– Risperidone significantly greater reduction
vs. placebo (RUPP, 2005)
– Aripiprazole significantly improved RRBs vs.
placebo (Marcus RN et al, 2009)
Repetitive Behaviors & Rigidity
Other Agents
• Hollander E, et al, 2006
– Small RCT (13 individuals) of Valproate
– Showed significant improvement of
RRBs/rigidity vs. placebo
Repetitive Behaviors & Rigidity
• RRBs/rigidity constitute frequent
problematic behavior in children with
ASD
• Tx choices are difficult given relative
lack of support of efficacy & sideeffects can be difficult to tolerate
• Clinicians advised to recognize Tx
limitations & reserve medication to
those with severe RRBs
Hyperactivity & Inattention
• High prevalence of hyperactivity & inattention in
children with ASD
– Between 30-80% meeting criteria for ADHD
• These children have more severe difficulties vs.
ASD alone
• Multiple agents have been investigated to treat
these symptoms
Hyperactivity & Inattention
Stimulants
•Role of stimulants in typical children is welldocumented
•Third most common class of medications
used in ASD
– Methylphenidate (MPH)
is used preferentially
– Studies on amphetamines are lacking
Hyperactivity & Inattention
Stimulants
•RUPP, 2005
– RCT of MPH (0.15mg/kg, 0.25mg/kg, 0.5mg/kg)
– All doses superior to placebo
– Even highest effect size was much lower vs.
typical children
– 18% discontinued medication due to side-effects
Adverse Effects of Stimulants in
Children with ASD
• Can increase perseveration,
repetitive behaviors & irritability
• May increase anxiety
• May lead to increased sensory
processing difficulties
• Often better tolerated & more useful
in mild range of ASD
• Less effective in the presence of
significant intellectual disability
Hyperactivity & Inattention
Atypical Antipsychotics
•RUPP, 2002
– RCT of Risperidone
– Secondary analysis showed large reduction in
hyperactivity in children with ASD
•Owen et al, 2009
– RCT of Aripiprazole
– Significant improvement over placebo
Hyperactivity & Inattention
Other Agents
•Arnold LE et al, 2006
– Small, pilot placebo-controlled crossover study
of Atomoxetine (1.2-1.4 mg/kg)
– Significant improvement vs. placebo
– Effects comparable to MPH in ASD
– Tolerable side-effects
– Concomitant use of other psychotropics
Hyperactivity & Inattention
Other Agents
•Small, controlled trial of Clonidine showed
superior reduction in disruptive behaviors
(Jaselskis CA et al, 1992)
•Small, open-label prospective study of
Guanfacine showed moderate benefit (47%
response) for high levels of hyperactivity &
inattention (Scahill L et al, 2006)
–Well-tolerated
Hyperactivity & Inattention
Other Agents
•Valproate
•Topiramate
•Lamotrigine
Hyperactivity & Inattention
• None of the highly effective Tx for ADHD (i.e.
stimulants) in typically developing children have
same robust response in ASD
– High rate of side-effects even a low doses
• Alpha-agonists deserve more research and often
form a solid second-line Tx choice
• Antipsychotics can be effective for hyperactivity,
but less favored
Anxiety & Depression
• Research is lacking in effects of psychotropics for
depression & anxiety in children with ASD
• Strong empirical support exists for SSRIs in
typical children; uncertain whether this translates
to those with ASD
• Some support exists for use of these medications
in adults with ASD
– High rate of significant adverse effects
(“activation”) in children greatly tempers
enthusiasm
Sleep Disturbance
• Children w/ ASD experience sleep disturbance at
much higher rates
• Chronic sleep disturbance is disruptive to overall
functioning & quality of family life
• Lack of FDA-approved medications for this problem
Sleep Disturbance
Melatonin
•RCTs of Melatonin (Sanchez-Barcelo EJ, 2011)
•Up to 6 mg/d was found to be effective
•No significant side-effects
•Long-term Tx has not been studied
Sleep Disturbance
Other Agents
•Risperidone
•Clonidine
Social Deficits
• Medications that may improve social deficits in
children with ASD include:
– Atypical antipsychotic, SSRIs
– Oxyctocin
– Memantine, Amantadine
– Lamotrigine, D-cycloserine
– Galantamine, Rivastigmine, Donepezil
– Tetrahydrobiopterin
Side-effects
Side-effects: Antipsychotics
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Neuroleptic malignant syndrome
Extra-pyramidal symptoms
Agranulocytosis
Cardiovascular changes
Galactorrhea
Weight gain & metabolic disorder
Sedation
Side-effects: SSRIs
• Neuropsychiatric (10-30%)
• Especially activation (agitation,
disinhibition, hyperkinesia), may be
more common in younger patients
• Initial worsening of anxiety & OCD
• GI upset (10%)
• Suicidal thinking & behavior ???
Side-effects: Stimulants
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Appetite supression
Irritability
Sleep disturbance
Dullness/social withdrawal
Headaches
Tremors/tics
Cardiovascular symptoms
Side-effects: Alpha-Agonists
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Sedation (especially clonidine)
Aggression/irritability
Dry mouth
Constipation
Nocturnal enuresis
Dizziness
Hypotension & bradycardia
General Guidelines
“Rules of Thumb”
• Identify specific problematic behaviors
• Address environmental issues that may be
exacerbating the behaviors
• Start low and go slow
• Address sleep difficulties early
• Change one variable at a time
“Rules of Thumb”
• Children with ASD are more sensitive to
psychotropic medications – thus more
likely to have adverse effects
• It is often difficult (due to limited
communication and difficulty identifying
emotions) to determine the predominant
target symptom & thus the best medication
Case 1
• 3 yo male with ASD
• Up all night, hyperactive, aggressive,
constantly in dangerous situations
• Attends a special education pre-school
program where similar behaviors are
occurring
• Family is exhausted
Case 2
• 8 yo male with ASD
• Anxious, constant repetitive behaviors,
inattentive at school, many sensory
processing issues
• Prior trials of Adderall & Concerta made
the situation worse
Case 3
• 14 yo female with ASD and severe
intellectual disability
• Frequent aggression & self-injury
• Prior trials of Adderall, Concerta & Zoloft
worsened behaviors
References
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Anderson LT, Campgell M, et al. Haloperidol in the treatment of infatile autism: effects on learning
& behavioral symptoms. Am J Psychiatry 1984; 141(10):1195-202.
Handen Bl et al. Efficacy of mehtylphenidate among children with autism and symptoms of ADHD.
J Autism Dev Disord 2000;30:245-55.
Hollander E, et al. A placebo-controlled crossover trial of liquid fluoxetine on repetitive behaviors
in childhood and adolescent autism. Neuropsychopharmacology 2005;30:582-9.
Hollander E, et al. Divalproex sodium vs. placebo in the treatment of repetiitve behaviors in autism
spectrum disorder. Int J Neuropsychopharmacol 2006;9(2):209-13.
Hollander E, et al. Divalproex sodium vs. placebo for the treatment of irritability in cildren and
adolescents with autism specrum disorders. Neuropsychopharmacology 2010;35:990-8.
Kanne SM, Mazurek MO. Aggression in children and adolescents with ASD: prevalence and risk
factors. J Autism Dev Disord 2011;41(7):926-37.
Kaplan G & McCracken JT. Psychopharmacology of Autism Spectrum Disorders. Pediatr Clin N
Am 2012;59:175-187.
Marcus RN et al. A placebo-controlled, fixed-dose study of apriprazole in children & adolescents
with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry
2009;48(11):1110-9.
References
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Owen R, et al. Aripiprazole in the treatment of irritability of children & adolescents with autistic
disorder. Pediatrics 2009;124:1533-40.
Owley T, et al. An open-label trial of escitalopram in PDD. J Am Acad Child Adolesc Psychiatry
2005;44(4):343-8.
Parikh MS et al. Psychopharmacology of aggression in children and adolescents with autsim: a
critical review of efficacy & tolerability. J Child Adolesc Psychopharmacol 2008;18(2):157-78.
Quintana H et al. Use of methylphenidate in the treatment of children with autistic disorder. J
Autism Dev Disord 1995;25:283-94.
RUPP. Risperidone in children with autism and serious behavioral problems. Research Units on
Pediatric Psychopharmacology (RUPP) Autism Network. N Engl J Med 2002;347:314-21.
RUPP. Randomized, controlled, crossover trial of methylphenidate in PDD with hyperativity.
Research nits on Pediatric Psychopharmacology (RUPP) Autism Network. Arch Gen Psychiatry
2005;62(11):1266-74.
Sanchez-Barcelo EJ et al. Clinical uses of melatonin in pediatrics. Int J Pediatr 2011;89:24-26.
SOFIA. Available at:http://wwww.autismspeaks.org/about-us/press-releases/autism-speaksannounces-results-reported-study-fluoxetine-autism-sofia.
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Arnold LE, et al.: Moderators, mediators, and other predictors of risperidone response in children
with autistic disorder and irritability. Journal of Child & Adolescent Psychopharmacology. 20(2):8393, 2010 Apr.
Erickson CA, et al.: A retrospective study of memantine in children and adolescents with
pervasive developmental disorders. Psychopharmacology (2007) 191:141-147
Findling RL: Pharmacologic treatment of behavioral symptoms in autism and pervasive
developmental disorders. J Clin Psychiatry 2005;66(suppl 10):26-31
Frazier TW, et al.: Effectiveness of medication combined with intensive behavioral intervention for
reducing aggression in youth with autism spectrum disorder. Journal of Child & Adolescent
Psychopharmacology. 20(3):167-77, 2010 Jun.
Grant P, et al.: An open-label trial of riluzole, a glutamate antagonist, in children with treatmentresistant obsessive-compulsive disorder. J Child Adolescent Psychopharmacology (2007)
17(6):761-767
King BH, et al.: Lack of efficacy of citalopram in children with autism spectrum disorders and high
levels of repetitive behavior: citalopram ineffective in children with autism. Archives of general
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Mandell DS, et al.: Psychotropic medication use among Medicaid-enrolled children with autism
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Choosing a Medication
• Likelihood of improvement in target
symptoms
• Potential adverse effects
• Practical considerations
– Formulations
– Dosing schedule
– Lab monitoring
Stimulant or SSRI?
• External versus internal distractibility
• External distractibility is seen in ADHD
• Many children with ASD have a prominent
ADHD component (dual diagnosis)
• Internal distractibility is a result of the
anxiety and behavioral rigidity that is a part
of ASDs
Combining Medications
• Consider a phone call or referral to a subspecialist; be willing to continue with
management and monitoring
• Be wary of increased drug interactions
with 3 or more medications
• Low doses of 2 medications may be better
than a high dose of one