clinical practice pathways for evaluation and medication ......children with autism spectrum...
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Clinical Practice Pathways for Evaluation andMedication Choice for Attention-Deficit/HyperactivityDisorder Symptoms in Autism Spectrum Disorders
abstractBACKGROUND AND OBJECTIVE: Hyperactivity, impulsivity, and inatten-tion (referred to as “ADHD [attention-deficit/hyperactivity disorder]symptoms”) occur in 41% to 78% of children with autism spectrumdisorders (ASDs). These symptoms often affect quality of life,interfering with learning or interventions that target primary ASDsymptoms. This practice pathway describes the guidelines forevaluation and treatment of children and adolescents with ASD andcomorbid ADHD symptoms.
METHODS: Current research in this area is limited, and, therefore,these recommendations are based on a systematic literature reviewand expert consensus in the Autism Speaks Autism Treatment NetworkPsychopharmacology Committee.
RESULTS: The recommended practice pathway includes the SymptomEvaluation Pathway for systematic assessment of ADHD symptomsacross settings; examination for comorbid sleep, medical, or psychi-atric comorbidities that may contribute to symptoms; and evaluationof behavioral interventions that may ameliorate these symptoms. Forchildren for whom medication is being considered to target the ADHDsymptoms, the medication choice pathway provides guidance on theselection of the appropriate agent based on a review of available re-search, assessment of specific advantages and disadvantages of eachagent, and dosing considerations.
CONCLUSIONS: These recommendations provide a framework for pri-mary care providers treating children who have ASD and ADHD symp-toms. Our systematic review of the current evidence indicates the needfor more randomized controlled trials of the medications for ADHDsymptoms in ASD. There will also be a need for studies of the effec-tiveness of these practice pathways in the future. Pediatrics 2012;130:S125–S138
AUTHORS: Rajneesh Mahajan, MD,a Maria Pilar Bernal,MD,b Rebecca Panzer, MA, RD, LD,c Agnes Whitaker, MD,d
Wendy Roberts, MD,e Benjamin Handen, PhD,f AntonioHardan, MD,g Evdokia Anagnostou, MD, FRCPC,h JeremyVeenstra-VanderWeele, MDi
aDepartment of Psychiatry, Kennedy Krieger Institute and JohnsHopkins University School of Medicine, Baltimore, Maryland;bDepartment of Psychiatry, Kaiser Permanente NorthernCalifornia, San Jose, California; cDepartment of Pediatrics,MassGeneral Hospital for Children, Boston, Massachusetts;dDepartment of Psychiatry, Columbia University Medical Centerand New York State Psychiatric Institute, New York, New York;eDepartment of Pediatrics, Hospital for Sick Children, Universityof Toronto, Toronto, Ontario, Canada; fDepartment of Psychiatry,University of Pittsburgh School of Medicine and Medical Center,Pittsburgh, Pennsylvania; gDepartment of Psychiatry andBehavioral Sciences, Stanford University Medical School,Stanford, California; hDepartment of Pediatrics, HollandBloorview Kids Rehabilitation Hospital and University of Toronto,Toronto, Ontario, Canada; iDepartments of Psychiatry, Pediatricsand Pharmacology, Vanderbilt University Medical Center,Nashville, Tennessee
KEY WORDSADHD symptoms, autism spectrum disorders, hyperactivity,impulsivity, inattention
ABBREVIATIONSADHD—attention-deficit/hyperactivity disorderASD—autism spectrum disorderATN-PC—Autism Treatment Network Psychopharmacology Com-mitteeDSM-IV—Diagnostic and Statistical Manual of Mental Disorders,Fourth EditionRCT—randomized controlled trial
This Manuscript has been read and approved by all authors.This paper is unique and not under consideration by any otherpublication and has not been published elsewhere.
www.pediatrics.org/cgi/doi/10.1542/peds.2012-0900J
doi:10.1542/peds.2012-0900J
Accepted for publication Aug 8, 2012
Address correspondence to Rajneesh Mahajan, MD, KennedyKrieger Institute, Center for Autism and Related Disorders, 3901Green Spring Ave, Baltimore, MD 21211. E-mail:[email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2012 by the American Academy of Pediatrics
(Continued on last page)
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Children with autism spectrum dis-orders (ASDs) frequently experiencemedical or neurologic comorbidities,including gastrointestinal symptoms,sleep difficulties, and seizures.1–3 Simi-larly, co-occurring behavioral or mentalhealth symptoms occur in themajority ofchildren who have ASD,4 with individualchildren often showing symptoms of$2comorbid disorders.5–7 Recent system-atic analyses of comorbidity in ASD in-dicate that behavioral or mental healthconditions increase the need formultipleresources, extra assistance in schools,and therapeutic interventions.8–10
Symptoms of hyperactivity and impulsiv-ity, with or without inattention (attention-deficit/hyperactivity disorder [ADHD]symptoms), are common in childrenwho have ASD. Rates vary from 41% to78% in large samples.11 These symp-toms often lead parents and care-givers to seek medical evaluation andtreatment.12 Conversely, autistic fea-tures have been reported in childrenwho have ADHD, especially in thosewith the combined type.13,14 Medicalproviders often prescribe medicationstargeting ADHD symptoms in ASD, rec-ognizing the significant impairmentthat results if these symptoms are leftuntreated.15,16
Children may manifest all ADHD symp-toms as outlined in the Diagnostic andStatistical Manual of Mental Disorders,Fourth Edition (DSM-IV)17 criteria forADHD; however, the DSM-IV does notallow the concurrent diagnosis of ADHDand ASD. The fifth edition of the DSM isanticipated to allow a concurrent di-agnosis of the 2 conditions.18 In theinterim, we refer to hyperactivity, im-pulsivity, and inattention in ASD as“ADHD symptoms” to reflect the DSM-IVcriteria. Although guidelines exist forevaluating and treating ADHD symp-toms in typically developing children,19–22
there are no such guidelines forchildren with ASD whomay have thesesymptoms. In addition, the evaluation
and treatment, although based onguidelines and evidence for the typicallydeveloping children, are not alwayssuccessful because of the multidimen-sional difficulties that children who haveASD experience. Psychotropic medica-tions, although used commonly for thesesymptoms, may not be as effective forchildren who have ASD as in typicallydeveloping children. Moreover, childrenwho have ASD are more sensitive to theside effects of these medications. Withthese considerations, clinicians oftenseek specialist opinion, which may notbe readily available, given the variabilityin such access regionally. The presenteffort provides an attempt to addressthe need for a clinical pathway forpractitioners, specifically for evaluatingand treating symptoms of ADHD in chil-dren who have ASD.
Within the behavioral symptomdomains,the Autism Speaks Autism TreatmentNetwork Psychopharmacology Commit-tee (ATN-PC) Medication Choice Sub-committee, composed of specialists inthe treatment of children with ASD andcomorbid conditions, was charged withthe task of developing practice pathwaysfor the symptom evaluation and use ofpsychotropic medications for targetsymptoms in children who have ASD.The current practice pathways provideclinicianswith critical steps in evaluationof ADHD symptoms andwith guidance onthe choice of appropriate medications.
METHODS
Becauseof the limitedevidencebase forevaluation and treatment of ADHDsymptoms in children who have ASD,we were forced to rely primarily oncollective clinical experience, com-plemented, where possible, with suchevidence as does exist, as well as pre-viously available guidelines inADHDandASD. Based primarily on group con-sensus, the ATN-PC Medication ChoiceSubcommittee developed 2 practicepathways related to ADHD: 1 for the
evaluation of ADHD symptoms and 1 forthe choice of medication for individualswhose symptoms merit a medicationtrial. After refinement of the practicepathways, accompanying narrativeswere composed for each step in thepathway. Individual members draftednarrative subsections correspondingto single steps in the pathway. Thesedrafts underwent further reviewby 1 or2 other members of the subcommittee.The entire ATN-PC Medication ChoiceSubcommittee then discussed and re-vised each step in detail before the in-tegration forfinal reviewbymembersofthe larger ATN-PC.
Systematic Literature Review
To ensure there were no omissions ofrelevant evidence from the pathway, weconducted a systematic literature re-view to identify evidence for thebenefitsand adverse effects of stimulants,atomoxetine, a-agonists, antipsychoticagents, and othermedications on ADHDsymptoms in ASD. The searches wereconducted in Ovid, CINAHL, Embase,Database of Abstracts and Review, andthe Cochrane Database of Systematicreviews (Tables 1 and 2) and werelimited to research conducted withhumans, published in the English lan-guage, involving children aged 0 to 18years, and published between January2000 and July 2010. The year 2000was used as a cutoff because thestandard diagnostic instruments forASD (Autism Diagnostic Interview-R23
and Autism Diagnostic ObservationSchedule24) were rarely applied beforethis time. Four primary reviewersgraded the research by using a systemadapted from GRADE.25 The systemsystematically assigned numerical val-ues (26 points possible across 16questions) based on the quality, con-sistency, directness, and effect sizedemonstrated (Table 3). Those scoring,40%were removed from the evidencebase.23
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RESULTS
Results of the Literature Review
The search identified 1255 articles. Afterremoving review articles, commen-taries, studies including ,10 subjects,nonintervention trials, and articles that
did not measure ADHD symptoms, 31articles remained. These were orga-nized into 2 tables (Tables 4 and 5), 1 forthe randomized controlled trials (RCTs)and another for the non-RCT studies(non-RCTs). Based on the review, atypi-cal antipsychotic agents (primarily ris-peridone) had the most RCTs, althoughADHD symptoms were not the primaryend points in these studies. Thesemedications were being studied for ir-ritability and behavioral symptoms; thebenefit for ADHD was a secondary out-come, with improvement reported pri-marily in hyperactivity. Surprisingly,there were fewer RCTs for the ADHD-focused studies, with medicationscommonly used in clinical practice totarget these symptoms (eg, stimulantmedications, atomoxetine, a2-agonists).Among these medications, most evi-dence was available for stimulant med-ications (only methylphenidate), with 3RCTs, including 1 study of preschool-aged children.24 Non-RCTs includedstudies of stimulant medications (onlymethylphenidate), atomoxetine, a2-ago-nists (primarily guanfacine), atypicalantipsychotic agents (risperidone, ari-piprazole, ziprasidone, and olanzapine),and others (memantine and levetir-acetam).
Results of Guideline Development
Figures 1 and 2 present the recom-mended ADHD symptom evaluation andmedication choice practice pathwaysfor children with ASD. An overview ofthe accompanying narrative and thesystematic review describes the func-tion and flow of evaluation througheach step of the 2 practice pathways.*
Pathway 1: Symptom Evaluation
Routine screening for ADHD symptomsbyprimarycarecliniciansshould followthe American Academy of Pediatrics’2011 guideline.25 When a child presentsto a clinician with significant ADHDsymptoms, along with a suspicion ofASD by the caregivers, an accurate di-agnosis of ASD should be made usingexisting ASD diagnostic guidelines.20,26,27
Language and cognitive testing shouldbe conducted as part of the evaluationfor ASD. Educational, speech and lan-guage, and behavioral supports shouldbe optimized to target the core ASDsymptoms, as well as language or cog-nitive impairment.
If the child continues to display ADHDsymptoms despite these initial steps,a clinical interview focused on ADHDshould be conducted, supplemented bycommonly used ADHD-focused ques-tionnaires such as the Conners Scale28
and the Vanderbilt ADHD DiagnosticScales.29,30 (Figure 1, Boxes 1 and 2)Often, children may not exhibit ADHDsymptoms on 1 or more clinical visits.Therefore, information about thesesymptoms in school, home, and com-munity may serve to establish thatADHD symptoms are pervasive and nottriggered by a specific environmentalcontext.
Childrenshouldalsoundergoasystemicmedical evaluation to rule out any un-diagnosed medical problem† that maycontribute to the ADHD symptoms, es-pecially if the child has limited ability tocommunicate (Figure 1, Box 3). Forsomemedical problems, correspondingATN practice pathways may provideguidance (eg, sleep, constipation). Othercomorbid conditions, such as mood oranxiety symptoms, may contribute tothe ADHD symptoms (Figure 1, Box 4)andmerit assessment and treatment bya mental health provider.
TABLE 1 Literature Review Questions
• What are the indications for the following medicines in treating ADHD symptoms in ASD/PDD?• What are the side effects of the following medicines in treating ADHD symptoms in ASD/PDD?
PDD, pervasive developmental disorder.
TABLE 2 Medication Medical SubjectHeadings and Key Words
• StimulantsAmphetamineLisdexamfetamine dimesylateDextroamphetamineMethylphenidateDexmethylphenidate
• a-AgonistsClonidineGuanfacine
• Antipsychotic/neuroleptic agentsRisperidoneAripiprazole
• Atomoxetine• AntidepressantNortriptyline
TABLE 3 Summary of Grading Criteria
Quality Measures the quality of the studydesign, such as blinding, randomassignment, patient selection, andmeasures used
Consistency Measures the quality of patientselection, such as ASD diagnosis/definition, homogenous populationin terms of disease andprogression, and adjustment forconfounders.
Directness Measures the external validity of thestudy, suchas representative of thegender distribution, loss to follow-up due to treatment demands, andapplicability to “real life”
Effect size Measures the study’s use of statisticsto report outcomes/findings.Follows use of confidenceintervals, relative risk/odds ratio,and/or P values. Studies were notgraded on basis of the value of thestatistic presented but instead onpresence. Presence of statisticswas weighted by a factor of 3 asthe absence denotes the paper asmore qualitative than quantitative
*Full versions of the narrative and practice path-ways are available at www.autismspeaks.org/atn. †Narrative available at www.autismspeaks.org/atn.
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TABLE4
System
aticLiterature
Review
Results
(RCTs)
StudyMedication/
StudyType/Grade
Population
Intervention
Measures
Results
Conclusion
Stimulants
MPH
Included:72childrenaged
5to14
ywith
ASD(DSM
-IV)
MPH
inrandom
ized,controlled
crossoverdesign.Aftertest
dosing
toestablish
tolerability,subjects
underw
ent1
weekateach
ofthreeTIDdoses(0.125,0.25,
and0.5mg/kg
perdose)
versus
placebo
ABC-H,CGI-I,SNAP-IV
AllM
PHdosesimproved
both
teacherand
parentratings
ontheABC-H:low(parent,P=.03;
teacher,P=.03),m
edium
(parent,P,
.001;teacher,P
=.008),andhigh
(parent,P=
.003;teacher
P=.002)with
bestsignalforthe“optimal
dose”(parent,P,
.001;
teacher,P,
.001).Effectsizes
ranged
from
0.20
to0.89
MPH
was
oftenefficaciousin
treatinghyperactivity
inchildrenwith
ASD,butthe
effectsizeissm
allerthan
that
seen
inpure
ADHD
,and
adverseeventsaremore
common
Poseyetal,
2005
32
RCTcategory
II
MPH
Included:20preschool-aged
childrenaged
3to5yw
ithPDD
orID
MPH
inrandom
ized,controlled
crossoverdesign.Doserange
from
1.25
mgBIDto10
mgBID.
Single-blindtitrationfollowed
byarandom
ized,double-blind
phaseof2wkofplacebowith
2wkatchild’sbestdose
Parent
ratingofDSM-IV-ADH
Dsymptom
s,CPRS-R,N-H
MPH
improved
parentratings
onCPRS-RandDSM-IV-ADH
D(P
=.005
forthePDDsubgroup).
Estim
ated
effectsizesranged
from
0.5to0.95.Only14
childrencompleted
the
crossoverphase
MPH
was
oftenefficaciousin
treatingADHD
symptom
sin
preschool-agedchildrenwith
PDD,although
theresponse
was
smallerthan
inolder,
typically
developing
children
andadverseeventsaremore
common
Ghum
anetal,
2009
24
RCTcategory
II
MPH
Included:13childrenwith
autistic
disorder
orPDD-NO
SMPH
incontrolled,crossover
design
with
MPH
dosesof0.3
and0.6mg/kg
BIDor
TIDfor1
weekversus
placebo.Lower
MPH
preceded
higher
dose
orinterspacedwith
placebo
ConnersTeacherScale;IOWA
ConnersTeacherScale;ABC-H;
CARS;Childhood
Autism
RatingScaleside
effects
checklist
8of13
childrenwereMPH
responders
(minimum
50%
decrease
onConnersscale
betweenoneMPH
dose
and
placebo)Significant
decreasesbetweenplacebo
andoneor
both
oftheMPH
dosesforConners(P
=.000),
IOWAConners(P
=.004),ABC-
H(P
=.003)
MPH
was
oftenefficaciousin
treatingADHD
symptom
sin
childrenwith
ASD
Handen
etal,
2000
41
RCTcategory
II
ATX ATX
Included:16children/
adolescentsaged5to15yw
ithASD
ATXinrandom
ized,controlled,
cross-overdesign.Splitdoses,
startingat0.25
mg/kg
perd
ayandincreasedevery4to5
days
byincrem
entsof0.3to
0.4to
maximum
dose
of1.4
mg/kg
perdayor
100mg/day
total
DSM-IV-ADH
D;ABC-H;CGI-S
ATXwas
superior
toplaceboon
DSM-IV
ADHD
hyperactive/
impulsivesymptom
s(P=.005,
d=1.27),with
atrendon
inattentivesymptom
s(P
=.053,d
=0.89)
Inthissm
allpilotstudy,ATX
was
oftenefficaciousintreating
ADHD
symptom
sinchildren
with
ASD,with
infrequent
intolerableadverseevents
Arnoldetal,
2006
34
RCTcategory
I
a-Agonist
Guanfacine
Included:11childrenaged
5to9y
with
ASD
Guanfacine
inrandom
ized,
controlled,crossoverdesign
over
6wk.Titrated
toamaximum
of3mg/day(1mg
TID)
Parentandteacher-ratedABC-H;
CGI-S
Guanfacine
was
superior
toplaceboon
parent
and
teacherABC-H(P
=.025,P
=.005,respectively)
Guanfacine
was
efficaciousand
welltolerated
for
hyperactivity
symptom
sin
thissm
allpilotstudy
Handen
etal,
2008
38
RCTcategory
II
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TABLE4
Continued
StudyMedication/
StudyType/Grade
Population
Intervention
Measures
Results
Conclusion
Antipsychoticagenta
Risperidone
Included:101
children(82boys
and19
girls)(m
eanage,8.86
2.7y)with
autistic
disorder
andirritability/aggression
symptom
s
Risperidoneinrandom
ized
controlleddesign
compared
with
placebofor8wk(dose
range,0.5–
3.5.5mg/d)
ABC-H;variousscales
forother
symptom
sRisperidonewas
superior
toplaceboon
theparent
ABC-H
(P,
.001;effectsize,1.0)
Risperidoneimproved
multiple
symptom
s,including
hyperactivity,inchildrenwith
autismdisorder
and
irritability/agitation
McCracken
etal,
2002
39
RCTcategory
I
Risperidone
Included:38children,aged
5to
17ywith
ASDandsevere
behavioraldisturbance
Risperidoneinrandom
ized,
controlleddesign,0.25or
0.5
mgto2.5or
3.5mg/day,
comparedwith
placebo
CancellationTask
(for
attention
span)andClassroomAnalog
Task
(timed
mathtask)
Nodeclines
ineither
measure
ofattentionwerenotedatweeks
4and8.ANOVAindicated
significant
improvem
enton
CancellationTask
(P=.05)
Risperidonedoes
notseemto
have
adetrimentaleffecton
cognitive
performance
Aman
etal,
2008
42
RCTcategory
I
Risperidone
Included:24children(22males;2
females)aged
5to17
y,with
ASD
Risperidone24-wkopen-label
treatm
entw
ithup
to2.5or
3.5
mg,followed
byarandom
ized
placebosubstitution,with
3wkoftaperand5wkof
placeboonlyor
continuing
useofrisperidone
ABC-H;variousscales
forother
symptom
sNonsignificant
increase
inparent
ABC-H(P
=.118
but
largeeffectssize,z
=–1.56)
Noconclusion
ispossible,
perhapsduetolowpower
Troostetal,
2005
43
RCTcategory
I
Risperidone
Included:79children(61males,
18females),aged
5to
12y,
with
ASDandirritability/
agitation
Risperidoneinarandom
ized,
controlleddesign,beginning
at0.01
mg/kg
perdaytitrated
uptoamaximum
of0.06
mg/
kgperday,comparedwith
placebo
ABC-H;N-H;variousscales
for
othersymptom
sRisperidonewas
superior
toplaceboforABC-H(P
,.001)
andN-H(P
,.05)
Risperidoneimproved
multiple
symptom
s,including
hyperactivity,inchildrenwith
ASDandirritability/agitation
Shea
etal,
2004
44
RCTcategory
II
Risperidone
Included:40childrenwith
autism,aged2to
9y
Risperidoneinarandom
ized,
controlleddesign,beginning
at0.5mgdaily
andincreased
to1mgdailyfora
totalof6mo,
comparedwith
placebo
Parent
Questionnaire/Report
Risperidonewas
superior
toplaceboforhyperactivity
(7of
19responders;P
=.002)
Risperidonereduced
hyperactivity
inchildrenwith
ASD
Nagarajetal,
2006
45
RCTcategory
II
Aripiprazole
Included:98patientsaged
6to17
y(86males,12females)with
autistic
disorder
and
irritability/aggression
symptom
s
Aripiprazoleinarandom
ized,
controlleddesign,doserange
of5to15
mg/day,compared
with
placebo
ABC-H;variousscales
forother
symptom
sAripiprazolewas
superior
toplaceboon
theparent
ABC-H
(P,
.01)
Aripiprazoleimproved
multiple
symptom
s,including
hyperactivity,inchildrenwith
autismandirritability/
agitation
Owen
etal,
2009
40
RCTcategory
I
Aripiprazole
Included:218
childrenaged
6to
17y(50%
males)w
ithautistic
disorder
andirritability/
aggression
symptom
s
Aripiprazoleinarandom
ized,
placebo-controlled,fixed-
dose
design
with
dosesof5,
10,or15
mg/dayfor8wk
ABC-H;variousscales
forother
symptom
sAlldoses
show
edimprovem
ent
comparedwith
placeboon
ABC-H(5mg,P#.005;10mg,
P#.05;15
mg,P#.001)
Aripiprazoleimproved
multiple
symptom
s,including
hyperactivity
inchildrenwith
autistic
disorder
and
irritabilityandagitation
Marcusetal,
2009
46
RCTcategory
I
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For children who have ASD and symp-toms of ADHD who show a discrepancyin symptoms across settings, educa-tional or behavioral interventions maybe beneficial (Figure 1, Box 5). Somechildren may have a decrease in theiroverall ADHD symptoms with a morestructured environment and schedulein school, whereas others may havemore difficulty due to excessively de-manding school routines. ADHD symp-toms occurring only at home mightrespond to behavioral or family-ori-ented interventions.
When ADHD symptomsoccur primarilyin school, parents should request in-corporation of a behavioral inter-vention plan into a Section 504 plan orIndividualized Educational Program.Successful behavioral interventionsmay include functional behavioral as-sessment, identification of successfulteaching styles, accommodations forlearning disorders, tailored curricu-lum to the developmental and adaptivelevelof thechild,orprovisionof relatedservices (eg, speech and languagetherapy, occupational therapy). Com-prehensive psychoeducational test-ing and/or neuropsychological testinghelp to evaluate the child’s cogni-tive strengths/weaknesses, which, inturn, will aid in designing an app-ropriate individualized educationalplan.
Once medical, mental health, andeducational/behavioral interventionshave been optimized, the symptoms ofADHDcanbereevaluated toassess thenecessity of a medication trial forADHD as a target symptom domain,depending on the severity of thesymptoms and their effect on dailyfunctioning.
Importantly, some children who haveASD and severe ADHD symptoms mayrequire simultaneous evaluation andtreatment across multiple steps inthe symptom evaluation pathway. Theprocess for implementing the pathwayTA
BLE4
Continued
StudyMedication/
StudyType/Grade
Population
Intervention
Measures
Results
Conclusion
Otherb
Adjunctive
pentoxifylline
Included:40children(29boys,11
girls)aged
4to12
ywith
autistic
disorder
and
irritability/agitation
Pentoxifylline
versus
placebo
addedtorisperidonein
random
ized,controlled
design.Risperidone
was
titratedup
to2or3mg/dayfor
thefirst3w
k.Pentoxiphylline
was
startedat200mgand
titratedto
amaximum
of400
or600mg/day,dependingon
weight
ABC-H;variousscales
forother
symptom
sAdjunctivepentoxifylline
was
superior
toplaceboon
ABC-H
(P,
.0001)
whenaddedto
risperidone
Adjunctivepentoxifylline
may
improvehyperactivity
symptom
swhenaddedto
risperidoneinchildrenwith
autistic
disorder
and
irritability/agitation
Akhondzadeh
etal,20104
7
RCTcategory
I
Adjunctive
topiramate
Included:40childrenaged
4to12
ywith
ASDandirritability/
agitation
Topiramateversus
placebo
addedtorisperidonein
random
ized,controlled
design.Risperidone
was
titratedup
to2or3mg/dayfor
thefirst3
wk.Topiramatewas
then
titratedup
to100or
200
mg/day,dependingon
weight
ABC-H;variousscales
forother
symptom
sAdjunctivetopiramatewas
superior
toplaceboon
ABC-H
(P,
.0001)
whenaddedto
risperidone
Adjunctivetopiramatemay
improvehyperactivity
symptom
swhenaddedto
risperidoneinchildrenwith
ASDandirritability/agitation
Rezaeietal,
2010
48
RCTcategory
I
Tianeptine
Included:12boys
with
autistic
disorder
(ages4–14
y)Tianeptineinrandom
ized,
controlledcrossoverstudy,
37.5mgdaily
for12
wk
comparedwith
placebo
ABC-C;variousmeasuresof
othersymptom
sTianeptinewas
superior
toplaceboforABC-H(P
=.035)
Tianeptinemay
behelpfulfor
hyperactivity
inASD
Niederhofer
etal,20034
9
RCTcategory
II
GradeCategories:categoryI,80%to100%
ofidealm
ethodology
met;categoryII,60%to79.99%
ofidealm
ethodology
met;categoryIII,40%
to59.99%
ofidealm
ethodology
met;and
categoryIV,,
39.99%
ofidealm
ethodology
met.ABC-H,AberrantBehavior
ChecklistHyperactivity
Subscale;ATX,atomoxetine;BID,twicedaily;CARS,Childhood
Autism
RatingScale;CGI-I,ClinicalGlobalImpression
ofImprovem
ent;CGI-S,ClinicalGlobalIndexof
Severity;CPRS-R,ConnersParent
RatingScale–Revised;MPH,
methylphenidate;ID,intellectualdisability;N-H,NisongerChild
Behavior
RatingForm
-Parent-H
yperactiveSubscale;PDD
,pervasive
developm
entaldisorder.SNAP-IV,Teacher-and
parent-rated
Swanson,Nolan,andPelham
Questionnaire;TID,3
times
daily.
aHyperactivity
was
notaprimaryendpoint
inanyRCTofan
antipsychotic,and
findings
arenotcorrectedformultiplecomparisons.
bHyperactivity
was
notaprimaryendpoint
inanyRCTandfindings
arenotcorrectedformultiplecomparisons.
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TABLE 5 Nonrandomized Studies of Medications for Hyperactivity/Impulsivity/Inattention Symptoms in ASD
Study Medication/Reference/StudyType and Category
Population Intervention Results/Conclusionsa
MPH Included: 13childrenandadolescentswithASD aged 5 to 17 y
Open-label administration of MPH 0.5 60.2 mg/kg single dose and ongoingtreatment over 3 mo
Some childrenwith ASD showed improvedADHD symptoms with MPH. Five of 13subjectshadadverse eventswith singledose
Di Martino et al, 200450
Pre/post without control,category III
MPH or DEX Included: 88 total patients with DSM-IVdiagnosed ASD + ADHD compared with138 patients with ADHD alone
Mixed retrospective and prospective dataon MPH 10 to 50 mg/day or DEX 5 to 30mg/day
Children with ASD + ADHD showeda similar pattern of response andadverse events compared with thosediagnosed with ADHD alone
Santosh et al, 200651
Case series, category III
ATX Included: 16 children and adolescentsaged 6 to 14 y with ASD
Prospective open-label study of ATXincreasing from0.5 to 1.2mg/kgperdayfor 6 wk
Some children and adolescents with ASDshowed improved ADHD symptoms onopen-label ATX
Posey et al, 200652
Pre/post without control,category III
ATX Included: 14 boys aged 7 to 17 y with ASD(DSM-IV)
Open-label ATX starting at 0.5 to 1.4 mg/kgper day for 10 wk
Some children and adolescents with ASDshowed improved ADHD symptoms onopen-label ATX, which was welltolerated
Zeiner et al, 201153
Pre/post without control,category III
Guanfacine Included: 25 children aged 5 to 14 y withASD who did not improve with MPH
Open-label guanfacine starting at 0.25 to0.5mg qhs titrated up to 3.5 to 5mg/dayin divided TID doses
Some childrenwith ASD showed improvedhyperactivity symptoms withguanfacine
Scahill et al, 200654
Pre/post without control,category III
Clonidine Included: 19 children aged 4 to 16 y withASD (DSM-IV)
Clonidine starting at 0.5 mg qhs andtitrated further based on clinicianjudgment
Some childrenwith ASD showed improvedsleep with clonidine, with fewerchildren showing benefit for ADHDsymptoms
Ming et al, 200855
Case series, category IV
Risperidone Included:124children, aged4 through13 y,with ASD and irritability/agitation
Risperidone open-label treatment with 0.5to 3.5 mg/day. Randomized parent-training behavioral treatment
Some childrenwith ASD showed improvedhyperactivity with risperidone, withlarger improvements seen in the groupthat also received behavioral therapy(d = 0.55; P = .04)
Aman et al, 201056
Pre/post without control,category I
Risperidone Included: 22 children, aged 2 to 16 y, withautistic disorder
Risperidone open-label treatmentbeginning at 0.5 mg/day and titrated tomaximum of 6 mg/day. Continued for 6mo followed by 1 mo discontinuation
Some childrenwith ASD showed improvedhyperactivity with risperidoneMalone et al, 200257
Pre/post without control,category III
Risperidone Included: 21 boys and 3 girls, aged 3 to 6 ywith autistic disorder or PDD-NOS
Risperidone open-label treatmentbeginningat 0.25mgqhsand titratedupto a maximum dose of 0.04 mg/kg or0.75 mg/day
Some young children with ASD showeddecreased hyperactivity withrisperidone
Masi et al, 200158
Pre/post without control,category III
Risperidone Included: 63 childrenaged5 to 17 ywith forautistic disorder and irritability/agitation
Risperidone open-label extension afterRCTwith risperidoneup to 3.5 or 4.5mg/day, depending on weight, followed byrandomized, controlleddiscontinuation, but hyperactivitymeasures not reported fordiscontinuation
Some children and adolescents withautism showed persistentimprovement in hyperactivity withrisperidone
RUPP, 200559
Pre/post without control,category III
Risperidone Included: 20 children aged 3 to 10 ydiagnosed with autistic disorder
Risperidone open-label treatment with0.75 to 2 mg/day. A 12-wk phase first,followed by continuation phase
Some children with autism showedpersistent improvement inhyperactivity with risperidone
Gagliano et al, 200460
Pre/post without control,category III
Aripiprazole Included: 14 children and adolescents,aged 7 to 17 y, with ASD
Aripiprazole retrospective chart reviewwith dose range of 5 to 15 mg/dayextendingoveranaverageof183daysoftreatment
Some children showed improvement inmultiple poorly defined symptomdomains, including hyperactivity
Kim et al, 201061
Case series, category III
Olanzapine Included: 23 children aged 6 to 16 y withASD and irritability/agitation
Olanzapine open-label treatmentbeginning at 2.5 mg every other day,titrated to a maximum dose of 15 or 20mg/day, depending on weight
Some children with ASD showeddecreased hyperactivity witholanzapine
Kemner et al, 200262
Pre/post without control,category III
Ziprasidone Included:15 adolescents (mean age, 14.56 1.8 y) with autistic disorder andirritability/agitation
Ziprasidone open-label treatmentbeginning at 20 mg every other day,titrated to amaximum dose of 40 to 160mg/day, depending on weight
Somechildrenwithautismand irritability/agitation showed decreasedhyperactivity with ziprasidone
Malone et al, 200763
Pre/post without control,category III
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may be sequential or simultaneousacross multiple steps for different chil-dren, as determined by severity ofsymptoms and/or availability of re-sources. Our intention is to provideguidance on the comprehensive medi-cal, psychiatric, and behavioral domainsthat should be considered when evalu-ating and treating a child who has ADHDsymptoms.
Pathway 2: Medication Choice
As indicated in the systematic review,most of the medications used to treatADHDsymptomshavenotbeenstudied insufficient depth in ASD to allow for ac-curate assessment of the treatmenteffects. Therefore, this pathway (Fig-ure 2) represents consensus expertclinician opinion and is based on (1)existing research in ASD; (2) treatmentof ADHD in the non-ASD population forwhich there have been considerablymore research studies; and (3) clinicalexperience. These opinions serve asbroad recommendations, and the clini-cian should continue to use judgment inselecting medications. These are nota substitute for medication handouts ordesk references and do not list all theprecautions, potential adverse effects,or risks of using a particular medi-cation. For detailed recommendations,
including those for initial evaluation andfor initiation of individual medications,monitoring for side effects and adverseevents, and maintenance on these me-dications, please see the narrative.†Pathway 2 assumes that the child hasbeen determined to need a medicationtrial for the ADHD symptoms (Figure 2,Box 1).
Stimulant medications (Figure 2, Box 2)include methylphenidate and amphet-amine preparations. They enhance do-paminergic transmission by inhibitingor reversing dopamine reuptake andact, to a lesser degree, on the norad-renergic system.31 Generally, methyl-phenidate preparations are the firstchoice for treating ADHD symptoms inASD because (1) there is extensiveclinical experience with them over thepast several decades; and (2) they havea relatively well- documented safetyrecord and side effect profile. Com-pared with typically developing chil-dren with ADHD, children who have ASD,as in other developmental disabilities(including intellectual disabilities, Frag-ile X syndrome, and head trauma), seemto have lower effect sizes with thesemedications and are more sensitive toside effects, including emotionality andagitation. Although best studied in typi-cally developing children with ADHD,19
there is 1 large RCT of methylphenidatein children with ASD.32,33 Only 49% ofchildren in this study displayed a thera-peutic response compared with 69% inthe Multimodal Treatment Study ofChildren with ADHD (MTA) study. In ad-dition, 18% of the children discontinuedparticipation due to adverse events,especially irritability, compared with1.4% in children with ADHD.
We recommend beginning stimulanttreatment with a methylphenidate for-mulation because of greater evidence inboth ASD and ADHD.32 It is often prefer-able to start with a short-acting for-mulation to gauge side effects beforeswitching to the corresponding long-acting formulation. Amphetamine saltsare an option for children who do notbenefit sufficiently from methylpheni-date or who experience dose-limitingside effects. We recommend followingthe American Academy of Pediatrics’guidelines for screening for cardiacproblems before initiating treatmentwith stimulant medications.21,22
Atomoxetine (Figure 2, Box 3) is a se-lective norepinephrine reuptake in-hibitor. There is limited evidence of itseffectiveness in treating ADHD symp-toms in ASD, with 1 small, randomizedcrossover pilot study34; this studyproduced a 50% response rate with
TABLE 5 Continued
Study Medication/Reference/StudyType and Category
Population Intervention Results/Conclusionsa
Olanzapine Included: 40 male children, aged 7–17 y,with autistic disorder
Olanzapine open-label treatmentbeginning at 2.5 mg BID, titrated up toa maximum dose of 10 mg/day
Some children with autism showeddecreased hyperactivity witholanzapine
Fido et al, 200864
Pre/post without control,category III
Memantine Included: 18 children and adolescents,aged 6 to 19 y, with ASD
Memantine open-label treatmentbeginning at 2.5 or 5 mg daily,depending on weight, titrated up tomaximum dose of 20 mg/day
Some children showed improvement inhyperactivity with memantineErickson et al, 200765
Pre/post without control,category III
Levetiracetam Included: 12 children, aged 4 to 10 y, withASD and irritability/agitation
Levetiracetam open-label treatment at 13mg/kg divided twice daily
Some children showed improvement inhyperactivity and impulsivity withlevetiracetam
Rugino and Samsock, 200266
Pre/post without control,category III
Grade Categories: category I, 80% to 100% of ideal methodology met; category II, 60% to 79.99% of ideal methodology met; category III, 40% to 59.99% of ideal methodology met; and category IV,,39.99% of ideal methodology met. ATX, atomoxetine; BID, twice daily; DEX, dexamphetamine; MPH, methylphenidate; qhs, every night; RUPP, Research Units on Pediatric Psychopharmacology.Pre/post refers to pre-intervention and post-intervention - in non randomized studies.a Non-RCTs cannot demonstrate treatment-specific effects.
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FIGURE 1ADHD symptom evaluation practice pathway.
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FIGURE 2ADHD symptom medication choice practice pathway.
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atomoxetine compared with 25% withplacebo. One treatment study in typi-cally developing children who haveADHD found that atomoxetine is effec-tive in children with comorbid anxietysymptoms,36 although this agent hasnot been evaluated in those with ASD.
Guanfacine and clonidine are 2 avail-able a2-agonists (Figure 2, Box 4).Originally developed as antihyperten-sive agents, they primarily target hy-peractivity and impulsivity, and areused as adjuncts to stimulant medi-cations, although they are also pre-scribed as singlemedications for thesesymptoms. They are frequently used inthe treatment of ADHD symptoms inASD.36 Guanfacine has the benefit ofbeing relatively longer-acting and lesssedating compared with clonidine.Most studies of these agents have beenopen-label (Tables 4 and 5).37 RCTs ofthese medications have included verysmall sample sizes.38 Although thesemedications have been studied in typ-ically developing children who haveADHD, leading to the recent approval bythe US Food and Drug Administration oftheir extended-release preparations asadjunct agents in the treatment ofADHD, there is currently limited em-pirical evidence for their effectivenessfor ADHD in ASD.
Risperidone and aripiprazole are 2atypical antipsychotic medications (Fig-ure 2, Box 5) that have received ap-proval by the US Food and DrugAdministration for the treatment of ir-ritability and agitation in children whohave ASD. These studies have alsodemonstrated reduction in ADHD symp-toms in children with ASD who have co-occurring irritability and agitation.39,40
Among all the medications used totreat ADHD symptoms, these antipsy-chotic agents have the most empiricalevidence (including most RCTs). How-ever, children who have ASD are moresensitive than typically developingchildren to the side effects and adverse
events of these medications; their useis limited by the risk of weight gain/metabolic syndrome and movementdisorders, including tardive dyskine-sia. Therefore, these medicationsshould be reserved only for childrenwho have severe impulsivity leading tosafety concerns (eg, dangerous andimpulsive running or jumping) orthose with comorbid irritability,40 agi-tation, or aggression.
Consultation or referral to an autism ormental health specialist should be con-sidered when risperidone, aripiprazole,or another antipsychotic medication isbeing considered for a child who hasADHD symptoms in ASD. Choice of thesemedications depends primarily on theside effect profile, with risperidonemore likely to lead to weight gain andaripiprazole more likely to lead toa movement disorder.39,40
DISCUSSION
Assumingan accurate ASDdiagnosis, inmost cases, the symptom evaluationpathway (Fig 1) may be completed in 1or 2 visits that begin with a clinicalevaluation, obtaining a description ofADHD symptoms in different settings,extend to identifying possible causesor triggers for the ADHD symptoms,and finish with developing a treatmentplan. If medication is part of thattreatment plan, the practitioner shouldfollow the medication choice pathway(Fig 2), involving the family in thedecision-making process so that theycan understand the evidence, the tar-get symptoms that may improve, andthe potential side effects or adverseevents. Because initiating a medicationis a significant choice by the family,.1visit may be necessary to discuss thepros and cons of a given treatmentplan. This action may also allow timefor medical, behavioral, or educationalinterventions to be implemented, pro-viding further evidence for or againstthe need for a medication trial. As part
of the discussion, the clinician shouldexplore the caregivers’ beliefs andvalues related to using medicationsfor ADHD symptoms and provide anevidence-based, realistic appraisal ofthe risks and benefits of the use ofthese medications.
Included in any discussion of medica-tion should also be the definition oftarget symptoms and the time frameduring which they can be expected toimprove. To prevent potentially benefi-cial medications from being stoppedprematurely at low doses, or inade-quate duration of treatment, cliniciansshould explain that identification of aneffective medication usually takes timeand careful evaluation. This will alsohelp prevent disappointment with in-adequate or lack of response to themedication. Even more concerning,however, are situations in which sideeffects and adverse events of medi-cations are not recognized or areallowed to continue too long betweenclinic visits. Familiesshouldbecarefullyeducated about potential side effectsandadverseeventsbefore theyemerge,emphasizing both the ones that aremost likely and those that are severeand should prompt a call to the clini-cian’s office. Monitoring for effective-ness and safety of these medicationsshould be done at each visit to gaugetheir usefulness.
CONCLUSIONS
Children who have ASD and co-occurring ADHD symptoms should un-dergo careful symptom evaluation and,if indicated, trials of medications, fol-lowing the recommended practicepathways as outlined in this article. Atall steps, clinical judgment should beused in evaluating ADHD symptoms andchoosing an appropriate medication. ‡Stimulant medications are considered
‡Detailed narrative at www.autismspeaks.org/atnfor reference.
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first, although they have fewer RCTs anda response rate of ∼50%, with higherrates of side effects. As shown in oursystematic review, atypical antipsy-chotic medications currently have themost evidence for efficacy in the treat-ment of ADHD symptoms in ASD. Thesebenefits, however, have only beenstudied in the context of irritability and
agitation and are accompanied by sig-nificant adverse effects that shouldlimit their use. This review highlightsthe need for more RCTs to evaluatemedications for ADHD symptoms inchildren who have ASD, especially asnew medications and preparations ofthe existing medications are added tothe available formulary. Future re-
search could also focus on the effec-tiveness of the recommended practicepathway in clinical practice.
ACKNOWLEDGMENTSThe authors gratefully acknowledge thevaluable assistance of the members oftheATN, especially theATN-PC, in review-ing this document.
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FINANCIAL DISCLOSURE: Dr Veenstra-VanderWeele has received research funding from Seaside Therapeutics, Roche Pharmaceuticals, Forest Pharmaceuticalsand Novartis Pharmaceuticals. Dr Anagnostou has consulted without fees for Neuropharm Group, Proximagen Group, and Novartis Pharmaceuticals; she hasreceived consultation fees from Seaside Therapeutics. Dr Handen has received research support from Bristol-Myers Squibb Company, Curemark, Eli Lilly andCompany and Autism Speaks. Dr Hardan has also received research funding from Forest Pharmaceuticals and Bristol-Myers Squibb Company and has consultedfor IntegraGen and Forest Pharmaceuticals. The other authors have indicated they have no financial relationships relevant to this article to disclose.
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DOI: 10.1542/peds.2012-0900J2012;130;S125Pediatrics
Veenstra-VanderWeeleRoberts, Benjamin Handen, Antonio Hardan, Evdokia Anagnostou and Jeremy
Rajneesh Mahajan, Maria Pilar Bernal, Rebecca Panzer, Agnes Whitaker, WendyDisorders
Attention-Deficit/Hyperactivity Disorder Symptoms in Autism Spectrum Clinical Practice Pathways for Evaluation and Medication Choice for
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DOI: 10.1542/peds.2012-0900J2012;130;S125Pediatrics
Veenstra-VanderWeeleRoberts, Benjamin Handen, Antonio Hardan, Evdokia Anagnostou and Jeremy
Rajneesh Mahajan, Maria Pilar Bernal, Rebecca Panzer, Agnes Whitaker, WendyDisorders
Attention-Deficit/Hyperactivity Disorder Symptoms in Autism Spectrum Clinical Practice Pathways for Evaluation and Medication Choice for
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