Attention-deficit/Hyperactivity Disorder in the Contextof Autism Spectrum Disorders

Michael J. Murray

Published online: 7 August 2010# Springer Science+Business Media, LLC 2010

Abstract Autism spectrum disorders (ASD) are frequentlymarked by symptoms consistent with attention-deficit/hyperactivity disorder (ADHD), namely inattention,hyperactivity, and impulsivity. Recent work has estab-lished that about half of the ASD population also meetsdiagnostic criteria for ADHD, although the comorbiddiagnoses are precluded by the DSM-IV-TR. Individualswith co-occurring ASD and ADHD symptoms are moreseverely impaired, with significant deficits seen in socialprocessing, adaptive functioning, and executive control.Children with ASD and ADHD symptoms are also proneto motor problems, which lead to especially poor out-comes. Recent work has also demonstrated high rates ofASD symptoms in a subset of children with ADHD.Medication studies have demonstrated the efficacy ofmethylphenidate, atomoxetine, and guanfacine, amongothers, in treating ADHD symptoms co-occurring withASD. However, these effects were not as great as thoseseen when treating primary ADHD, and they are less well-tolerated in the ASD population.

Keywords Autism . ASD . Attention deficit . ADHD .

Comorbidity . Co-occurrence . Executive control .

Adaptive functioning .Motor coordination .

Psychopharmacology . Psychostimulants .

Adrenergic agonists

Introduction

The diagnoses of autism spectrum disorders (ASD) andattention-deficit/hyperactivity disorder (ADHD) are basedon behavioral symptoms [1]. ASD is characterized byimpairments in social functioning and communication, andrestricted, repetitive behaviors and interests. (For thepurposes of this article, ASD refers to the common pervasivedevelopmental disorders [PDD]: autism, PDD not otherwisespecified [PDD-NOS], and Asperger’s syndrome.) ADHD ischaracterized by difficulties in maintaining attention andpatterns of impulsive and/or hyperactive behavior. TheDSM-IV-TR precludes a comorbid diagnosis of ASD andADHD, arguing that because ASD is the more severedisorder within the diagnostic hierarchy, any inattention,hyperactivity, or impulsivity observed can be thought of asstemming from the primary diagnosis of autism. Thisexclusion fails to account for the many individuals withASD who also meet full criteria for ADHD; theseindividuals typically have more severe overall impairment[2]. Furthermore, many individuals with milder forms ofASD, such as Asperger’s syndrome, may present clinicallywith initial concerns of ADHD symptoms.

This article examines the literature covering the co-occurrence of ADHD and ASD symptoms. Next, theliterature concerning the executive control (EC) issues andmotor coordination problems encountered in ASD and

M. J. MurrayDivision of Autism Services,Penn State Milton S. Hershey Medical Center,Mail Code HO73, 500 University Drive,Hershey, PA 17033-0850, USA

M. J. Murray (*)Department of Psychiatry,Penn State College of Medicine,Mail Code HO73, 500 University Drive,Hershey, PA 17033-0850, USAe-mail: mmurray2@psu.edu

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ADHD is discussed. A brief review of the literatureregarding the effectiveness of medications for ADHDsymptoms in the ASD population is offered, and the articleconcludes with recommendations for future diagnosticstrategies and areas needing additional research.

Co-occurrence of ASD and ADHD

Individuals with ASD may exhibit such a high preferencefor their idiosyncratic interests or inanimate objects thatthey may fail to attend to social stimuli. This type ofinattentiveness by itself would not lead to a consideration ofco-occurring ADHD. Hyperactivity in ASD may be seen inhighly repetitive motor stereotypies or result from anxiety/agitation when the individual is in highly demanding socialor sensory environments. These limited and causal episodessimilarly would not lead to a consideration of co-occurringADHD in an individual with ASD.

However, several studies have supported the co-occurrence of ASD and ADHD. In recent studies basedon large samples of clinically evaluated children, 41–78% of children with ASD also met criteria for ADHD[3–6]. In another clinic-based population, more than 40%of preschoolers and more than 50% of school-age childrenwith ASD met criteria for a DSM-IV subtype of ADHD [7,8]. The severity of these symptoms was similar acrossASD subtypes (autism, PDD-NOS, Asperger’s syndrome).In another study, children with ASD who also met criteriafor a subtype of ADHD experienced more clinicaldifficulties than children who did not. Additionally, thesubtype of ADHD that was co-occurring correlated withthe severity of these difficulties [6]. Children with thecombined (C) subtype of ADHD and ASD generally hadmore severe symptoms than those with the other twosubtypes. Children with the hyperactive (H) subtype ofADHD had the least severe symptoms compared withthose with the other two subtypes; this was also the leastprevalent subgroup. The inattentive (I) subtype of ADHDcorrelated with more language and social impairment inpreschoolers with ASD. Aggressive and oppositionalbehaviors were more problematic for individuals with theC and H subtypes. The greater impairment in ASDsymptoms of the C and I subtypes might be resultantfrom the primal role of attention in language and socialdevelopment.

Social impairment has long been recognized as a featureof ADHD [9]. This may be due to the direct effects ofADHD symptoms such as impulsive speech and intrusive-ness. The social impairment also may result from theexecutive functioning and working memory deficits fre-quently encountered in ADHD. There is evidence toindicate that these social impairments can be characterized

into two types: relationship difficulty and social communi-cation deficits [10]. Relationship difficulty is closelyassociated with conduct problems, mood symptoms, andenvironmental stressors, whereas social communicationdeficits are closely associated with developmental delays,including repetitive/stereotyped behaviors and languagedelays.

Recent work has demonstrated that autistic traits arecommon in children with ADHD. Children with the socialcommunication deficits type of social impairment are thoughtto be at risk of developing ASD symptoms. In a study ofchildren with ADHD, clinically significant autistic traits weremeasured on the Social Responsiveness Scale (SRS); nearlyone third of the boys had a SRS score indicating probableASD [11]. The level of autistic symptomatology corre-sponded to severity of ADHD subtype, with children withthe C subtype of ADHD demonstrating the most autisticsymptoms, and children with the H subtype demonstratingfewer symptoms. These findings mirror the findings of ASDseverity among the subtypes of ADHD in children with aprimary diagnosis of ASD.

EC and Adaptive Functioning

EC refers to the mental processes that enable physical,cognitive, and emotional self-control. They are key tomaintaining effective goal-directed behavior [12]. Theyinclude skills such as response inhibition, working memory,cognitive flexibility, planning, and fluency. Deficits in EChave been widely observed in ADHD and ASD. Findingsare inconsistent as to which deficits may be intrinsic or keyto the larger difficulties experienced by individuals withADHD and ASD, and very limited work has examined theEC deficits observed in individuals with co-occurringADHD and ASD.

In a recent study examining the EC profiles of childrenwith ASD, children with ADHD, and typically developingchildren, co-occurring ADHD symptoms in ASD was notan exclusion criterion, as has been the case in most studiesof EC in this population to date [13••]. As predicted,children with ASD demonstrated more extensive and severeEC deficits than children with ADHD and typical develop-ment. They demonstrated significant deficits in inhibition,working memory, and flexibility compared with the othertwo groups. This was in contrast to previous work thatdemonstrated children with ASD as having less severe ECdeficits compared with children with ADHD [14]. Theauthors speculate that different compositions of the ASDgroup between the two studies may account for the differentfindings. In the earlier study, most of those in the ASDgroup had Asperger’s syndrome, whereas in the later study,which demonstrated more EC impairment in the ASD

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group, most individuals had autism, with few participantshaving Asperger’s syndrome. This points to two potentialcauses of variance in the level of EC impairment within thespectrum: co-occurring ADHD symptoms and developmen-tal level.

Adaptive functioning is impaired in both ASD andADHD. Individuals with ASD show more severe impair-ments [15, 16]. Individuals with ASD tend to demonstrateinternalizing behavior problems, whereas individuals withADHD demonstrate externalizing behavior problems.Individuals with co-occurring ASD and ADHD demon-strate a mixture of externalizing and internalizing behaviorproblems, indicating that the presence of ADHD symp-toms exacerbates behavior problems in ASD. Global ECdeficits are more severe in this group; the combination oftwo disorders with EC deficits seems to have an additiveeffect on the difficulties experienced with planning andorganization, which are necessary for establishing dailyroutines [17••].

Motor Coordination Problems

Motor coordination abnormalities and elevated neurologicalsoft signs are well-documented in children with ADHD andASD [18–22], but the form of these motor issues seems todiffer between the disorders. Children with ASD typicallydisplay problems with motor planning, while children withADHD typically display deficient motor response inhibi-tion. Children with both ADHD and ASD show abnormal-ities of motor persistence in addition to motor planning andresponse inhibition issues [19].

A syndrome of deficits in attention, motor control,and perception (DAMP) was described in Scandinavianpopulations long before the first descriptions of ADHDin the DSM. Children with DAMP have high rates oflearning disorders, and more than two thirds of childrenwith severe DAMP meet criteria for ASD [23]. Morerecently, DAMP has been thought of as the co-occurrenceof ADHD and developmental coordination disorder(DCD). Although the concept of DAMP is controversial,it is well-established that children with ADHD plus otherdevelopmental concerns (eg, DCD) have worse psychoso-cial prognoses than children with ADHD alone [24].Reiersen and colleagues [25••] demonstrated that childrenwith ADHD plus motor problems were more likely to haveclinically significant autistic traits than those with ADHDalone as measured by the SRS. Children with thecombined form of ADHD and motor coordination prob-lems were particularly vulnerable to these clinicallysignificant autistic symptoms. These children may be asubset of those with ADHD in need of more intensivemonitoring and treatment interventions.

Kaplan and colleagues [26, 27] described a model forco-occurring multiple developmental problems as “atypicalbrain development.” This concept emphasizes the interre-latedness of developmental disorders and highlights thepossibility of multiple developmental concerns (eg, ADHD,motor coordination problems, and/or autistic features)stemming from a common dysfunction in a brain systemsubsequently affecting multiple brain processes, rather thanco-occurring problems resulting from multiple etiologies.

This concept of atypical brain development is supportedby recent studies that suggest that some genes may increasethe risk of ASD and ADHD, as well as evidence for theoverlap between ADHD and DCD. Smalley and colleagues[28] found evidence of a statistically significant overlap oflinkage peaks in genome-wide scans of ADHD and autism.Two of the four ADHD–ASD linkage overlap regions alsoshow evidence of linkage for atypical cerebral laterality.This suggests that cerebral laterality may influence bothASD and ADHD, particularly in individuals manifestingmore severe motor coordination issues.

The dopaminergic system has been implicated in motordysfunction, ADHD, and autism [29]. This neurotransmittersystem may serve as a potential etiology when these issuesco-occur. The prefrontal cortex and basal ganglia are highlyinnervated by the dopaminergic system, making thisneurotransmitter particularly relevant when these problemsco-occur.

Psychopharmacology and Treatment Considerations

Psychostimulants

In addition to sharing dopaminergic system dysregulation,both ASD and ADHD demonstrate frontal lobe dysfunc-tion. Psychostimulant medications may be expected to offerbenefit to children suffering from both ASD and ADHD.However, early case studies and open-label trials suggestedthat they were ineffective and associated with high rates ofadverse events. For instance, one early, retrospective chartreview demonstrated that 25% of participants had afavorable response to treatment, while 60% demonstratedadverse events, the most common of which was agitation[30]. However, community surveys suggest a steady rise inthe use of these agents in children with ASD [31].

The Research Units on Pediatric Psychopharmacology(RUPP) Autistic Disorder Network conducted a largerandomized controlled trial with methylphenidate to attemptto demonstrate its efficacy and tolerability in the individualswith ASD who also exhibited ADHD symptoms [32].Participants were 72 children aged 5–14 years with ASDand significant ADHD symptoms as measured on theSwanson, Nolan, and Pelham-Version IV (SNAP-IV)

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ADHD scale. The study consisted of a 1-week test-dosephase to assess tolerability. The next phase involved acrossover trial of 1 week each of placebo, methylphenidate(0.125, 0.25, or 0.5 mg/kg per dose) administered threetimes daily. The study concluded with an 8-week, open-label continuation for responders.

Children were considered responders if they were rated asmuch improved or very much improved on the ClinicalGlobal Impressions Global Improvement Scale and theydemonstrated either a 30% reduction in their parent- orteacher-rated Aberrant Behavior Checklist Hyperactivity(ABC-H) scale score or a 25% reduction on both the parentand teacher ratings. Other scales and measures were obtainedto perform secondary analyses of efficacy and tolerability.

A total of 35 (49%) of the 72 children respondedbest to one of the three doses of methylphenidate.Parent ratings indicated the best treatment response wasseen with the 0.25-mg/kg dose, while the teacher ratingsindicated the better outcome with the 0.50-mg/kg dose.The effect sizes ranged from 0.20 to 0.54, suggestingsmall to medium responses. Thirty-one of the 35participants completed the open-label phase of the study,with benefits sustained for the majority. Hyperactivity/impulsivity symptoms improved more than inattention,and no exacerbations of stereotypies or other repetitivebehaviors were observed [33]. Additionally, positiveeffects of methylphenidate were noted in social commu-nication skills and self-regulation, including initiating jointattention and improved affective states [34].

Adverse events were reported in many of the partic-ipants, with 18% discontinuing due to the severity of theseeffects. Irritability was the most frequent reason fordiscontinuation. Of note, in a similar large randomizedcontrolled study of children with ADHD alone (theMultimodal Treatment Study of Children with ADHDstudy), 69% of the 289 participants were deemed methyl-phenidate responders. Improvement in irritability was notedto improve significantly with methylphenidate treatment,and only 1.4% of participants discontinued secondary toadverse events [35]. Methylphenidate is less efficacious andyields more adverse events in children with ASD than intypically developing children with ADHD.

It is important to note that all the placebo-controlled studiesto date have involved immediate-release methylphenidate.Generalizing these findings to other stimulants or tosustained-release methylphenidate products may not translate.For instance, some small, open-label studies of dexamphet-amine have demonstrated worsening of symptoms [36].

α-2 Adrenergic Agonists

Clonidine is an α-2 agonist that has been used to treatoveractivity and impulsivity in children for more than

20 years. The main drawback of clonidine is sedation.Guanfacine is a newer α-2 agonist that appears to be lesssedating than clonidine and therefore may be bettertolerated. Additionally, it has a longer plasma half-life(10–30 h in adults) than clonidine (4–10 h), which may leadto the need for less frequent dosing. Guanfacine’s longerplasma half-life might also be protective from the reboundhypertension sometimes experienced with missed doses orthe abrupt discontinuation of clonidine. Animal studieshave offered preliminary evidence of improved prefrontalcortical functioning with guanfacine [37]. For thesereasons, recent studies examining the efficacy and tolera-bility of α-2 agonists in children with ASD and ADHDsymptoms have used guanfacine.

A large retrospective study of guanfacine demonstrated amodest effect on ADHD symptoms, although it washampered by its retrospective design and lack of specificityfor target symptoms [38]. More recently, RUPP conducteda prospective open trial of guanfacine in 25 children withASD and ADHD symptoms; the participants were pooledfrom the nonresponders to the methylphenidate studydescribed previously [39]. Doses ranged from 1 to 3 mg/din two or three divided doses.

After 8 weeks, guanfacine was associated with a 39%improvement over baseline on the parent-rated ABC-Hsubscale and SNAP-IV scale. Improvements were alsonoted on teacher report, although to a lesser degree. Gainswere largest in the areas of hyperactivity and impulsive-ness, similar to what is seen in typically developingchildren with ADHD. Improvements were also noted onparent report in irritability and explosive behavior, stereo-typies, and social interaction.

Sedation, sleep disturbances, and irritability were the mainadverse effects that required dose reduction or discontinuationin three cases. The irritability observed as an adverse effectwas described as poor frustration tolerance with tearfulnessrather than explosive outbursts. This finding has not beenreported in studies of typically developing children withADHD or tic disorders, which suggests that children withASD may be particularly vulnerable to the observed irritabil-ity. Guanfacine was well-tolerated from a cardiovascularstandpoint; blood pressure and pulse changes were minimaland diminished over time.

Selective Noradrenergic Reuptake Inhibitors

Because psychostimulant treatment demonstrated less effi-cacy and led to more adverse events in children with ASDand ADHD symptoms, alternative strategies for targetingthese symptoms have been explored, with atomoxetinereceiving considerable interest. Atomoxetine exerts itseffect via the selective inhibition of the presynapticnorepinephrine transporter. In the frontal lobe, in contrast

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to the basal ganglia, norepinephrine transporters also takeup dopamine, which allows atomoxetine to exert a selectivedopamine effect. Researchers have been interested indetermining whether this may lead to better tolerabilityand efficacy in the ASD population. Early open-labelstudies demonstrated some promising preliminary findingsregarding atomoxetine’s tolerability and efficacy in thispopulation [40, 41].

A recent randomized, placebo-controlled, crossover pilottrial of atomoxetine was conducted [42]. A total of 16participants with ASD and significant ADHD symptomswere randomly assigned in this double-blind study, witheach condition lasting 6 weeks. The primary outcomemeasure was improvement on the ABC-H subscale. Sevenof the 16 participants demonstrated significant enoughdifferences in the ABC-H scores to be classified as atom-oxetine responders. The 43% response rate is similar to the49% response rate to methylphenidate in the RUPP study(the two studies used the same response definition). Threeof the children terminated the study early. Two did so duringthe placebo phase secondary to lack of improvement. Onlyone participant terminated early during the atomoxetinephase (after 4 weeks of atomoxetine) secondary to adverseevents (increased irritability). Based on this limited informa-tion, atomoxetine may be a better tolerated medication forchildren with ASD and ADHD symptoms. An importantcaveat to consider is that children in this study werepermitted to take concomitant medications (including fourwho were taking atypical antipsychotics), whereas childrenin the methylphenidate study were not. However, the oneparticipant who terminated early while taking atomoxetinewas one of the four taking an antipsychotic.

Cholinergic Drugs

Cholinergic pathways have been implicated in the patho-physiology of ASD [43]. Anticholinesterase inhibitors havebeen studied primarily in children with ASD to determinethe potential effects on learning and memory [44]. Oneretrospective chart review of eight children with ASD andADHD treated with donepezil revealed seven demonstrat-ing improvement in their ADHD symptoms, as well as insome of the core symptoms of ASD (communication,socialization, and behavior rigidity). Improvement wasmeasured with the Clinical Global Impressions Scale [45].Of note, all patients in this study were taking multipleconcomitant medications and had ASD symptoms that wererated as moderate or severe.

Atypical Antipsychotics

In the RUPP studies examining the efficacy and tolerabilityof risperidone in targeting aggression and irritability among

children with ASD, the mean ABC-H subscale scores weresignificantly lower for risperidone than placebo. Of note,the children in this study did not necessarily exhibithyperactivity [46]. Adverse events included sedation andweight gain. Open-label studies of quetiapine [47] andaripiprazole [48] have demonstrated similar reductions inhyperactivity.

Conclusions

According to the current DSM-IV-TR criteria, a diagnosis ofASD precludes a comorbid diagnosis of ADHD. However,little doubt exists as to the frequent presence of (oftensevere) ADHD symptoms in the ASD population. Thesesymptoms frequently are of such number and severity tomeet the current full DSM-IV-TR diagnostic criteria forADHD separate from the primary diagnosis of ASD.Researchers have established evidence that children withASD possessing ADHD features have different clinicalprofiles and outcomes than children with ASD alone. Thesedifferences are seen in a variety of contexts, including socialprocessing, EC, and adaptive functioning. Pennington [49]outlined six criteria for identifying a distinct clinicalphenotype. There must be differences in 1) treatmentresponse, 2) clinical profiles, 3) performance measuresindependent from measures defining the diagnosis, 4)etiology, 5) pathogenesis, and 6) developmental trajectories.At this time, good evidence exists to fulfill the second andthird criteria for individuals presenting with ASD andADHD symptoms. Additional work is needed to assessdevelopmental trajectories, treatment response, and potentialpathogenesis.

However, despite not having the evidence to fulfill thecriteria for a distinct ASD–ADHD phenotype, the earlywork of researchers in this area needs to inform currentclinical practice. There is good evidence suggesting that asmany as 50% of children with ASD exhibit significant co-occurring ADHD symptoms. Children with co-occurringconditions demonstrate more severe social impairmentsand worse outcomes. Careful evaluation for the potentialpresence of ADHD symptoms is warranted for allindividuals with ASD. Standardized rating scales thatallow for reporting of potential impairment in a variety ofsettings are beneficial to obtain in addition to a carefulhistory and review of symptoms. Likewise, early work hasestablished the frequent presence of significant ASDsymptoms in individuals with ADHD. Screening for thesesymptoms in this population, preferably with a standard-ized instrument, is equally important to consider. Individ-uals with social communication symptoms may haveimportant unmet clinical needs, such as for structuredsocial skills instruction.

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In future work examining the co-occurrence of ADHDand ASD, objective measures of motor coordinationproblems and neurological soft signs will be helpful togain further understanding of the potential relationshipbetween these disorders. This seems particularly importantgiven the early work establishing children with clinicalfeatures of ADHD, ASD, and motor coordination problemsas having particularly poor outcomes.

Cognitive testing examining executive functioning alsomay be useful in furthering our understanding of brainmechanisms responsible for this combination of symptoms.Better description of co-occurring conditions will lead tomore meaningful treatment and outcome studies; thecombination of these conditions may have differentetiologies and prognoses compared with uncomplicatedADHD or ASD. The possible effects of the ADHD subtypein children with ASD on treatment response are justbeginning to be recognized. Diagnosing co-occurringsymptoms prior to treatment also may be helpful indifferentiating suspected treatment-induced symptom exac-erbation from baseline clinical status.

The importance of recognizing the co-occurrence ofASD and ADHD symptoms is gaining support. Atpresent, the Neurodevelopmental Disorders Work Groupfor the DSM-V is proposing that the criteria for ADHD bemodified to allow for the co-occurrence of ASD andADHD. The ADHD and Disruptive Behavior DisordersWork Group is agreeable to considering this possibility[50]. Revision of current DSM criteria to allow for theseconcurrent diagnoses may encourage clinicians to morefully assess and treat these co-occurring symptoms whenthey occur. This will not only further our understanding ofthese disorders but will lead to better clinical and researchoutcomes.

Disclosure No potential conflict of interest relevant to this articlewas reported.

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