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
• I have no financial or research interests in
any of the medications
• 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
• Case presentations
• ASD are a heterogeneous
group of disorders
– Clinical manifestations vary
in presentation & intensity
• Treatments must be
– Weigh potential risks &
• 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
• Medications available do not directly treat core
features of autism
– i.e. social-communication impairments
• Treat behavioral manifestations of the underlying
brain pathology
• 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
• 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
•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
•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
Aggression, Irritability & Self-Injury
•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
• 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
• Weight gain mediates treatment response
• Socioeconomic advantage, low baseline prolactin
and absence of anxiety, bi-polar symptoms, ODD,
stereotopy & hyperactivity correlates with positive
• Intensive behavioral intervention in addition to
risperidone resulted in the best outcome in autism
with aggression
Aggression, Irritability & Self-Injury
•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
•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
•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
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
• 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
•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
•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)
Hyperactivity & Inattention
Other Agents
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
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
•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
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: Antipsychotics
Neuroleptic malignant syndrome
Extra-pyramidal symptoms
Cardiovascular changes
Weight gain & metabolic disorder
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
Appetite supression
Sleep disturbance
Dullness/social withdrawal
Cardiovascular symptoms
Side-effects: Alpha-Agonists
Sedation (especially clonidine)
Dry mouth
Nocturnal enuresis
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
• 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
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Choosing a Medication
• Likelihood of improvement in target
• 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