Clinical Practice Pathways for Evaluation and Medication ... - Beacon Health Options · 2020. 7. 7. · symptoms”) occur in 41% to 78% of children with autism spectrum disorders

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)

PEDIATRICS Volume 130, Supplement 2, November 2012 S125

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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


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



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


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


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

SUPPLEMENT ARTICLE



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


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


Akhondzadeh

etal,20104

7

RCTcategory

I

Adjunctive

topiramate


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.



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


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


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


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


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


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


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


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


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


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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


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


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


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.



FIGURE 1ADHD symptom evaluation practice pathway.

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FIGURE 2ADHD symptom medication choice practice pathway.



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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Attention-Deficit/Hyperactivity Disorder Symptoms in Autism Spectrum Clinical Practice Pathways for Evaluation and Medication Choice for


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