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Kooij, J J., Bejerot, S., Asherson, P. (2019)
Updated European Consensus Statement on diagnosis and treatment of adult ADHD
European psychiatry, 56: 14-34
https://doi.org/10.1016/j.eurpsy.2018.11.001
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Original
article
Updated
European
Consensus
Statement
on
diagnosis
and
treatment
of
adult
ADHD
J.J.S.
Kooij
a,b,*
,
D.
Bijlenga
a,b,
L.
Salerno
a,b,
R.
Jaeschke
a,b,
I.
Bitter
a,b,
J.
Balázs
a,b,
J.
Thome
a,b,
G.
Dom
a,b,
S.
Kasper
a,b,
C.
Nunes
Filipe
a,b,
S.
Stes
a,b,
P.
Mohr
a,b,
S.
Leppämäki
a,b,
M.
Casas
Brugué
a,b,
J.
Bobes
a,b,
J.M.
Mccarthy
a,b,
V.
Richarte
a,b,
A.
Kjems
Philipsen
a,b,
A.
Pehlivanidis
a,b,
A.
Niemela
a,b,
B.
Styr
a,b,
B.
Semerci
a,b,
B.
Bolea-Alamanac
a,b,
D.
Edvinsson
a,b,
D.
Baeyens
a,b,
D.
Wynchank
a,b,
E.
Sobanski
a,b,
A.
Philipsen
a,b,
F.
McNicholas
a,b,
H.
Caci
a,b,
I.
Mihailescu
a,b,
I.
Manor
a,b,
I.
Dobrescu
a,b,
J.
Krause
a,b,
J.
Fayyad
a,b,
J.A.
Ramos-Quiroga
a,b,
K.
Foeken
a,b,
F.
Rad
a,b,
M.
Adamou
a,b,
M.
Ohlmeier
a,b,
M.
Fitzgerald
a,b,
M.
Gill
a,b,
M.
Lensing
a,b,
N.
Motavalli
Mukaddes
a,b,
P.
Brudkiewicz
a,b,
P.
Gustafsson
a,b,
P.
Tani
a,b,
P.
Oswald
a,b,
P.J.
Carpentier
a,b,
P.
De
Rossi
a,b,
R.
Delorme
a,b,
S.
Markovska
Simoska
a,b,
S.
Pallanti
a,b,
S.
Young
a,b,
S.
Bejerot
a,b,
T.
Lehtonen
a,b,
J.
Kustow
a,b,
U.
Müller-Sedgwick
a,b,
T.
Hirvikoski
a,b,
V.
Pironti
a,b,
Y.
Ginsberg
a,b,
Z.
Félegeházy
a,b,
M.P.
Garcia-Portilla
a,b,
P.
Asherson
a,ba
PsyQPsycho-MedicalPrograms,ExpertiseCenterAdultADHD,CarelReinierszkade197,2593HR,TheHague,TheNetherlands
b
AmsterdamUMC,LocationVUMc,Dept.ofPsychiatry,Amsterdam,theNetherlands
ARTICLE INFO Articlehistory: Received9July2018
Receivedinrevisedform2November2018 Accepted3November2018
Availableonlinexxx Keywords: AdultADHD
UpdatedEuropeanConsensusStatement Diagnosis
Treatment
EuropeanNetworkAdultADHD EPA
ABSTRACT
BackgroundAttention-deficit/hyperactivitydisorder(ADHD)isamongthemostcommonpsychiatric disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently underdiagnosedandundertreatedinmanyEuropeancountries,leadingtochronicityofsymptomsand impairment,duetolackof,orineffectivetreatment,andhighercostsofillness.
MethodsTheEuropeanNetworkAdult ADHDandtheSectionforNeurodevelopmentalDisorders AcrosstheLifespan(NDAL)oftheEuropeanPsychiatricAssociation(EPA),aimtoincreaseawarenessand knowledgeofadultADHDinandoutsideEurope.ThisUpdatedEuropeanConsensusStatementaimsto supportclinicianswithresearchevidenceandclinicalexperiencefrom63expertsofEuropeanandother countriesinwhichADHDinadultsisrecognizedandtreated.
ResultsBesidesreviewingthelatestresearchonprevalence,persistence,geneticsandneurobiologyof ADHD,threemajorquestionsareaddressed:(1)WhatistheclinicalpictureofADHDinadults?(2)How shouldADHDbeproperlydiagnosedinadults?(3)HowshouldadultADHDbeeffectivelytreated?
ConclusionsADHDoftenpresentsasalifelongimpairingcondition.ThestigmasurroundingADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective,diagnosticassessment,andtreatmentofADHDmustincreaseforstudentsofgeneraland mentalhealth,andforpsychiatryprofessionals.InstrumentsforscreeninganddiagnosisofADHDin adultsareavailable,asareeffectiveevidence-basedtreatmentsforADHDanditsnegativeoutcomes. Moreresearchisneededongenderdifferences,andinolderadultswithADHD.
©2018TheAuthor(s).PublishedbyElsevierMassonSAS.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
1.Introduction:theEuropeanNetworkAdultADHD
The EuropeanNetworkAdult ADHD(ENAA) was foundedin 2003 tohelpimprovethediagnosis andtreatmentof ADHDin adultsinEuropeandbeyond.ENAArepresentsmentalhealthcare professionalsandresearchersfrom28countrieswithexpertiseon
*Correspondingauthorat:EuropeanNetworkAdultADHD,VUMc,Amsterdam, EPA,TheNetherlands.
E-mailaddress:s.kooij@psyq.nl(J.J.S. Kooij).
http://dx.doi.org/10.1016/j.eurpsy.2018.11.001
0924-9338/©2018TheAuthor(s).PublishedbyElsevierMassonSAS.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).
ContentslistsavailableatScienceDirect
European
Psychiatry
ADHD in adults (http://www.eunetworkadultadhd.eu). The SectionNeurodevelopmentalDisordersAcrosstheLifespan(NDAL) oftheEuropeanPsychiatricAssociation(EPA)joinedoureffortto provide this update of our first Consensus Statement on adult ADHDpublishedin2010[1].
1.1.Objectivesoftheupdatedconsensusstatementforclinicians Despitestrongevidenceontheclinicalpresentation,genetics, neurobiology,theburdenofthedisorder,andonsafeandeffective treatment for ADHD in adults, many people are still under-diagnosedandundertreated.Specializedclinicalservicesremain scarceinmostpartsoftheworld,includingEurope[2,3].Ouraimis toprovideanupdateoftheliteratureonassessmentandtreatment ofadultADHDto[1]increaseawarenessonADHDasanimpairing life-longneurodevelopmentalconditionuptooldage[2];update theassessmentprocedurefordiagnosingADHDinadults;and[3] giveupdatedrecommendationsforappropriatetreatments. 1.2.Methodology
Creating a Consensus Statement does not follow the same procedureasrequiredforthedevelopmentofaguideline,suchas systematicreviewsusingformalratingsoftheevidence.Mostof theauthorsparticipatedinthedevelopmentofafirstConsensus StatementonadultADHDin2010,andwereaskedtoprovidean updateoftheprevioustextbasedonnewfindingsintheliterature since thetime of publication.Subgroupsdealing withdifferent subjectswereformed.Thesubgroupsreached consensusonthe textamongthemselvesbeforesendingittothefirstauthor.The firstauthorputallparagraphstogetherandeditedthetextwiththe helpofafewothercoauthors(DW,SY,PA,DB).Thisdraftofthe manuscriptwassendtoallauthorsfortheircomments.Thefirst authorcheckedthecommentsandimplementedadjustmentsinto thetext,andsendthefinalversiontoallauthorsforagreement.All authorsagreedwiththefinalversion.
2.Heritabilityandenvironment
Family,twinandadoptionstudiesfromthelast20yearsshow thatADHDisafamilialdisorderwithhighheritability,indicating that a significant genetic component influences risk for the disorder[4–12].Environmentalfactorssuchassevereinstitutional deprivationare alsolikely toplaya role, either asmain causal factorsin a fewcases[13] orby interactionwithgeneticrisks. Familystudiesindicatearisktofirst-degreerelativesof4–5fold thepopulationrateorhigher,withprevalenceratesaround20% amongfirstdegreerelatives[14].DataonADHDinchildrenand adolescentsfindaverageheritabilityofaround76%[12].Studiesin adulttwinsusingself-ratedADHDsymptomsconsistentlyreport lowerestimatesofheritability,around30–40%[15–17].Onereason forlowerheritabilityofadultself-reportedADHDsymptomsmay befromtheuseofself-ratings.Theseleadtolowerestimatesof heritability compared to informant ratings regardless of age, perhapsdue tovariablelevels of awarenessamong individuals ratingtheirownADHDsymptoms[18,19].Studiescombiningdata acrossinformants [20], or using clinicaldiagnostic information [21]findheritabilityestimatesforadultADHDinthesamerange (70–80%)asforchildren[22].
2.1.Candidategenes
EarlymoleculargeneticstudiesofADHDinchildrenreported geneticassociationswithseveralcandidategenes.Geneticvariants withinorneartheD4andD5dopaminereceptorgenesprovided the most consistent findings supported by meta-analysis [23].
Otherspecificcandidategeneswereimplicatedintheearlystudies [12,24,25], butnonehaveprovided consistentevidenceorbeen replicated in more recent large-scale genome wide association studies. Takentogetherthetraditionalneurotransmitter system genesappeartoexplainonlyasmallamountof thevariance in ADHD[26].Thereisalsosomeconvergingevidencefortheroleof genes that fit into a neurodevelopmental network involved in directedneuriteoutgrowth[27].
2.2.Genomewideassociationstudies(GWAS)
More recent findings have emerged from genome-wide associationstudies[28].Themostrecentdatasetreportedincluded over20,000ADHDcasesand35,000controls.Thesedatawereused to estimate that around 30% of the heritability of ADHD is explained by common genetic variation. In total, twelve loci achieved genome-wide significance, including FOXP2; notable becausepriorworkhadimplicateditinadultADHD[29].These findings placeADHD firmlyonthepath todetectingverylarge numbersofassociatedcommongeneticvariantsasmoresamples areaccrued.
LD regression analyses that estimate genetic correlations betweendisordersfindstronggeneticlinksbetweenADHD and arangeofoutcomesincludingeducationalperformance, depres-sion,obesity,smokingandlungcancer[28].Afurtherfindingisthe verystronggeneticcorrelationbetweenthediagnosisofADHD, andtraitscoresingeneralpopulationsamples,demonstratingthat ADHDrepresenttheextremeofacontinuouslydistributedtraitin thegeneralpopulation[30].Thesefindingconfirmthepolygenic natureofgeneticliabilitytoADHD.
Rarecopynumbervariants(CNVs)occurringonlessthan1%of chromosomes are also known to play a role in a subset of individualswithADHD[31,32].CNVswerefoundtobe2-foldmore commoninchildrenwithADHDwithinthenormalIQrange,and 6-fold higher in those with IQs below 70 [32]. Specific genes suggestedasCNVslinkedtoADHDincludethenicotinicalpha-7 acetylcholinereceptorgene(e.g.,[33]),severalglutamatereceptor genes [34] and neuropeptide-Y [35], although these findings remaininconsistentandhardtoverifyduetolowfrequencyinthe population.
2.3.MoleculargeneticstudiesofadultADHD
MoleculargeneticstudiesofadultADHDarelessadvanced,but are expectedtoconfirm somegeneticassociations identifiedin childhood and findothergenetic associationsrelated to persis-tenceorremissionofADHDinadultlife[20].Apreliminaryreport attheInternationalNeuropsychologymeeting(Washington,2018) foundthegeneticcorrelationbetweenchildandadultADHDtobe greater than 80%. Most of the current research has been coordinatedin Europe byBarbara Franke fromtheNetherlands for theInternationalMulticentre PersistentADHD Collaboration (IMPACT) group.Thiscollaborationhassuccessfullygenerateda multi-site sampleof morethan 3500patientsand continuesto grow.Todateseveralpublicationshighlightpotentialassociations withadultADHD,somebutnotallofwhicharesharedwithgenetic associationfindingsinchildren[36–42].
2.4.Environmentalfactors
Ithasbeenknownforalongtimethatenvironmentalfactors areassociatedwithADHD[43],particularlyprenatalriskfactors suchasexposuretoalcoholanddrugs,valproicacid,highblood pressure, maternalstress duringpregnancy, as wellaspreterm birthandlowbirthweight[44–46].Howeversophisticatedstudy designs are needed toclarify whetherthese association reflect
directeffectsoftheenvironmentalexposureorreflectgenetically correlatedriskmeasures.Forexample,althoughsmokingduring pregnancy is clearly associated with offspring ADHD, this associationappearstobeentirely accountedfor bythe genetic correlationbetweenmaternalsmokingandoffspringADHD[47]. Incontrast,evidencefromRomanianadopteessuggeststhatsevere earlydeprivationiscausallyrelatedtoADHDinadosedependent way[13]. Gene byenvironment interactions(G x E)havebeen proposedandmayexplainsomeofthemissingheritabilityseen between heritability estimates derived from twin (0.76) and moleculargenetic(0.22)data.However,todatenoGxEeffects havebeen clearly identified. The findings todate indicate that muchmoreworkisneededtounderstandtheinterplaybetween geneticandenvironmentalrisks.
3.NeurobiologyofADHD
3.1.Neuro-imaging:evidenceforatypicalgrayandwhitematterareas StructuralbrainscansofadultswithADHDshowedgreymatter abnormalitiesinseveralbrainareas,includingtherightfrontaland prefrontal areas [48,49], anterior cingulate [50–52], the basal ganglia and the cerebellum [53–56] with some preliminary research also showing abnormalities of the visual cortex [57]. Additionally,corticalthicknesswasfoundtobereducedinadult ADHD [56,58,59]. Some evidence suggests that grey matter abnormalities,insomesubcorticalregions,aremorepronounced in children than adults. This might reflect the effects of age, medication,intrinsicheterogeneityoftheADHDsyndrome,ora combinationthereof[51,60–64].
Despite these reported findings the latest mega-analysis conducted by the Enigma consortium found no significant differencesinbrainstructurebetweenadultADHDandcontrols; although,smallbutsignificantdifferenceswerefoundinchildren for subcortical regions including the accumbens, amygdala, caudate, hippocampus, putamen and intracranial volume with effectsrangingfromd=.10–.15[65].Thesefindingsindicatethat whiletherearestructuralchangesinsubcorticalbrainregionsin ADHDinchildren,thesearerelativelysubtleeffectsthatdissipate withincreasingage.
Diffusion tensorimaging(DTI)highlightedthat whitematter tracts, including fronto-occipital, fronto-striatal, temporal and temporo-occipitalfasciculiandpartofthecorpuscallosum,bear microstructural abnormalities [66–71]. Additionally, some find-ingsalsolinkedmicrostructurevariabilitytosymptomatologysuch that greater inattention but not hyperactivity-impulsivity was associatedwithsignificantlylowerfractionalanisotropy(thatis lowermicrostructuralintegrity)intheleftuncinateandinferior fronto-occipitalfasciculicomparedtocontrols[70].Theseresults indicatethatstructuraldeficitsinADHDarenotjustconfinedto specificregions butinvolveinterconnections among largescale brainnetworks[68,71–73].
3.2.Functionalneuroimaging
Regarding functional MRI (fMRI) studies, task-based and resting-statefindings converge.Meta-analysesshowthat ADHD isassociatedwithdysfunctionsinseveraldomain-specific fronto-striatal and fronto-cerebellar neural networks. Thus a meta-analysisof39childand16adultADHDfMRIstudiesconcludedthat inADHDtherearesignificant dysfunctionsinmultipleneuronal systemsinvolvedinhigher-levelcognitive functions[74]. These include hypoactivations in the frontoparietal executive control network, putamen, and ventral attention network, which is consistent with the classical model of ADHD as a disorder of deficientfronto-striatalactivation.
Hyperactivationsarealsoseeninregionsofthedefaultmode andvisualnetworks,whichsupportthecontemporaryviewthat ADHDisassociatedwithfaultyregulationofrelationshipsbetween defaultmodeandtaskpositivenetworks.Similarfindings come from meta-analyses, which show consistent underactivation in inferior fronto-striatalnetworks during cognitive tasks [75], in dorsolateral fronto-striato-parietal networks during attention tasks[75],andinfronto-cerebellarnetworksfortimingfunctions [76]; in addition to abnormally enhanced activation in default moderegions[76].
The recent focus on resting state fMRI (RS-fMRI) identified multipleintrinsicneuralcircuits,reflectingfunctionalconnectivity withinandbetweenregionswhichiscontinuouslyencodedinthe spontaneousactivityofthebrain[77].Theintrinsicfronto-parietal, dorsal attentional,visual,motor anddefault modenetworksall overlapwithregionsshowingdifferentialtaskactivationsduring inhibition,attention,orworkingmemorytasksinADHDcompared tocontrols[78].Despitethewealthofestablishedfindingsfrom fMRIandRS-fMRIstudiesofADHD,cross-sectionalneuroimaging dataiscorrelationalinnatureandcausalinferencescannotyetbe made.
More recently outcome studies of children diagnosed with ADHDhasbeenabletocomparefunctionalbrainchangeinadults withpersistentand remittedADHD and comparetheseto age-matchedcontrols.Thelargestsuchfollow-upstudytodate,of205 children with ADHD, found that persistence of ADHD was associated with loss of the balance of connections within the defaultmodenetwork,andconnectionsbetweenthedefaultmode andthosesupportingattentionandcognitivecontrol.Incontrast therewerenodifferencesinthesenetworksbetweenthosewhose ADHDhadremittedandnon-ADHDcontrols[79].
Overall,despitethewealthofestablishedfindingsfromfMRI andRS-fMRIstudiesofADHD,cross-sectionalneuroimagingdatais correlationalinnatureandcausalinferencescannotyetbemade. Thefindingthatcertainfunctionalbrainchangesareseentodiffer between persistent compared to remitted cases of childhood ADHD sheds somelight on likely causalprocesses, but further longitudinaldataisstillrequiredbeforefirmconclusionscanbe drawn.
3.3.Neuropsychologicalandelectrophysiologicaltests
Asagroup,individualswithADHDarecharacterizedbyaltered neuropsychological functioning across a variety of executive function (EF) measures. However, thus far there is neither a neurobiologicalnoraneuropsychologicaltest(battery)forADHD with sufficient positive predictive power to establish the diagnosis at the individual level [80]. In one study, the vast majority of neuropsychological instruments showed poor dis-criminative ability compared to clinical assessment measures such as the ASRS Screener v1.1 and the DIVA 2.0 Diagnostic Interview for ADHD in adults, with an overall classification accuracyrangingfrom53%to66%[81].Nevertheless,whenused in combination with the DIVA 2.0, objective cognitive perfor-mance tests measuring omission and commission errors, and physicalactivity,werefoundtoincreasethecorrectclassification of adultADHD [81].Thereis currentlyinsufficientevidenceto warranttheuseofneuropsychologicaltestingtodeterminethe diagnosis ofADHD[82] ortopredict impairmentin majorlife domains[83].
Moreover,cliniciansshouldalsobeawareofthepossibilitythat a few individuals may feignADHD symptoms togain external incentives,likestimulantmedicationorspecialacademic accom-modations.Thereissomeevidencesupportingtheeffectivenessof performance validity tests (PVTs) in differentiating between genuineandfeignedADHDcomparedtoratingscales[84].
Electrophysiologicalstudiessuggestthatbraindysfunctionsare involvedinthecentralcomponentsofADHDinbothchildrenand adults [85–89], although the finding of increased DAT density remainscontroversial[90,91].
DatafromElectroEncephalography(EEG)isrelativelyscarcein adultADHD.Generally,EEGstudiesofADHDfindsimilardeficitsin adults and children, while some findings changewith ageand mightbesensitivetodevelopmentalchanges[92].DespiteUSFood andDrug AdministrationapprovalofanEEGdevice(2013)that assistsinthediagnosisofADHDsubtypes[93–95],thisremains controversial[96].EEGtestsarenotsufficientlyaccuratebutcould beusefultoincreasediagnosticcertainty.
4.ICDandDSMcriteriaforADHD
TherearetwodiagnosticmanualsusedtodiagnoseADHD:The DiagnosticandStatisticalManualofMentalDisorders(DSM)and theInternationalStatisticalClassificationofDiseasesandRelated HealthProblems(ICD).AsADHDhasbeenrecognizedasadisorder affectingindividualsacrossthelifespan,thediagnosticcriteriafor adolescents and adults have been adjusted in the DSM-5, publishedinMay2013:
1)ADHD isnow in thechapterNeurodevelopmental Disorders, whichincludesconditionsassociatedwithfactorsaffectingthe braindevelopment.
2)Diagnosticcriteriahavebeenadaptedbyaddingsomeexamples describing how ADHD symptoms are expressed across the lifespan.
3)Theageofonset criteriahasbeenchangedrequiringseveral symptomstobepresentbeforeageof12years,insteadofsome symptomsandimpairmentbyage7.
4)The term “subtype” has been replaced by “presentation”, reflectingthevariation ofADHD symptomswithinthesame individualduringthelifespan.
5)The symptom threshold required has been reduced to 5 symptoms instead of six for older adolescents and adults (>17years)ineithertheinattentionorhyperactive/impulsive domain.
6)Criteriarequiringsignificantimpairmenthasbeenmodifiedto “clear evidencethat symptomsinterferewith or reduce the qualityofsocial,academicandoccupationalfunctioning”,with specifiersregardingseveritylevel.
7)ThepresenceofAutismSpectrumDisorder(ASD)isnolongeran exclusion criterion, consistent with evidence showing their frequentco-occurrence.
8)ADHDNotOtherwiseSpecified(NOS)hasbeenchanged into OtherSpecifiedADHDandUnspecifiedADHD.
TherevisionofICD-10,ICD-11hasbeenpublishedinJune2018. ICD-11,developedbytheWorldHealthOrganizationnowrefersto ADHD as Attention Deficit Hyperactivity Disorder, instead of previouslyHyperkineticDisorder(HKD)[97].Itnowusessimilar requirementsastheDSM-5regardingageofonset,andthesame3 presentation types. In Europe, ICD codes are often used for statisticsonmortality, morbidityand byinsuranceagenciesfor health-relatedreimbursements [98], whereas DSM is primarily usedin clinicalpractice bylicensedmental health care profes-sionals[99].
Thediagnosticassessmentstartsbyevaluationofself-reported symptomatology.Theclinicalinterviewisessentialfordiagnosing ADHDinadults,whichinvestigatesthecharacteristicsymptoms andimpairmentsofADHD inbothchildhood andadulthood.In childrenandadolescents,informants’ratingsarehighercorrelated withheritabilityandcognitiveandEEGfindingsthanself-ratings [19].Alsoprevalenceandpersistenceratesincreasewhenparent
reportsareused[19].Inadultsthismaybeslightlydifferent,as someresearchshowsthattheadultpatientisthebestinformant [100].Thepresenceofafamilymemberhowever(aparentand/or the partner) during the assessment can still provide valuable additional information, e.g. onseverity and its translation into dailyactivities.
There is compelling evidence that a cut-off of four current symptomsisthemostappropriateforanadultdiagnosis[101,102]. However, due to concern about the possibility of an artificial increase in the prevalence of the disorder, DSM-5 loweredthe thresholdfordiagnosingADHDfromsixtofivesymptomsforthose olderthan17yearsofage.Severalitemshavebeenexpandedby some illustrative examples to facilitate the recognition of the disorder throughout development. Although not included in thecriteria as such, behaviors reflecting executive dysfunction usually appear clearly during the assessment, when patients describeproblemswithorganization,facingdailyresponsibilities, solvingproblems,managingtimeandself-regulating(inhibiting) behaviors.
DSM-5 also highlights the importance of mood lability and emotionaldysregulationas“anassociatedfeaturethatsupportthe diagnosis”.Althoughemotionaldysregulationmaydominatethe clinicalpresentation[103–105],itisnotacriterionforclassifying individualsasitlacksspecificity,occurringinmanyothermental healthconditions.
DSM-IVrequiredthatsymptomsandimpairmentwerepresent beforeage7,butasresearchdemonstratednodifferencesbetween children withan ageofonset before andafterage7 [106]this criterion was changed toseveral symptoms byage 12. Similar findingshavealsobeenreportedregardingadultsreporting later-onset of symptoms [107,108], and there is disagreement both within and across sources concerningrecall of symptom onset [109]. The fact that adults with ADHD frequently fail to recall childhoodbehaviorledtothesuggestionthatclinicianstakenote that the onset of the disorder was during the developmental period,ortheyshoulduseage16yearsastheupperagelimit.Using thiscriteriacapturedallcasesofchildhoodADHDand99%ofadults withthedisorder[110].ThedecisionofDSM-5toextendtheageof onsetto12insteadof16mayhaveanegativeimpactonadultswith ADHDwhohavedifficultieswithretrospectiverecallofchildhood behaviors,andmaynotreceivethediagnosisforthisreason.This maybeparticularlytrueforthosewhohad somecompensation due to high intelligence, or lived in a highly structured or supported environment, orpresented predominantlywith inat-tentive symptoms. In such cases, the presence of a collateral informant(generallyaparentorspouse)isofgreatvalue.Many adultswithADHDthatareusedtotheirlifelongsymptoms,have limitedawarenessofhowADHDsymptomsadverselyimpacttheir interpersonalrelationshipsand affecttheirlife;somereporting highersymptomsbutlowerimpairmentsorviceversa.
Suchinconsistencyhasbeenattributedtoalackof introspec-tionandanincoherentself-view[111,112],andsupportstheutility of a collateral informant.If a significant otheris not available, schoolreportsorsocialcarereportsmaybehelpful.
4.1.Clinicalpicture
4.1.1.Inattentionandhyperfocus
Patients withmainlyinattentionproblems areoftenslowto thinkandformulateduetodistractions.Theymayformulatethings in a long-winded and tangential way, losing themselves in irrelevant details and having difficulty making decisions. A difficultyfortheclinicianisthatthis mayhinderthediagnostic assessment. Patients mayalsoover-concentrate or ‘hyperfocus’. This phenomenon most commonly occurs when engaged in activities that the patientfinds very interesting and/orprovide
instantgratification,suchascomputergamesoronlinechatting. Forsuchactivities,concentrationmaylastforhoursonend,ina veryfocusedmanner.
4.1.2.Hyperactivity
Withrespecttohyperactivity,adultsdonotpresentinthesame wayaschildren.Theirhyperactivityusuallymanifestsinamore subtleway.Cliniciansneedtoassesstheirfeelingsofrestlessness.A firstimpressionofmobilityisnotdefinitive;sittingcalmlyduring thediagnosticassessmentdoesnotexcludeanyADHD. Hyperac-tivityinadultsoftenmanifestsitselfasfeelingsofcontinuousinner restlessness or agitation, talking too much, ceaseless mental activity,not beingable torelaxproperlyor needing alcohol or drugstorelaxand/orsleep.Hyperactivityand/orrestlessnessmay betemporarilyrelievedbythepatientengaginginexcessivesport activities, and in such cases the person may suffer physical ailmentsasthebodymayhaveinsufficienttimetorecoverand/or duetosustainedinjuries.
4.1.3.Impulsivity
Impulsivebehaviorandassociatedinterpersonalconflictsoften have consequences for relationships with family, friends, col-leaguesandemployers.Itmayalsoseriouslyimpactonpersonal financewhen impulsive spending causes debt. Impulsive binge behaviorsmayalsobepresent(e.g.bingeeating),oftentocombat restlessnessorduetoaneedforimmediategratification.Closely related to impulsivity are ‘sensation seeking’ behaviors when patientsmayseekoutexcitementfromnovelandthrillingstimuli. Theseofteninvolverisktakingbehaviorssuchasplayingwithfire, recklessdriving,sexualrisks,andprovocativebehaviorleadingto fights.
4.1.4.Emotionaldysregulation
EmotionaldysregulationislistedbyDSM-5asacharacteristic feature of ADHD, supporting the diagnosis [113]. The type of emotionaldysregulationseeninADHDhasbeencharacterizedas deficientself-regulationofemotionalsymptomssuchas irritabili-ty, frustration and anger [114], and low frustration tolerance, temperoutbursts,emotionalimpulsivity,andmoodlability[115]. Emotional dysregulation in ADHD is different from episodic symptomssuchasmarkedsustainedirritabilityoccurringwithin the context of altered mood states, such as an episode of depression or mania. In ADHD, emotional symptoms tend to reflectshortlivedexaggeratedchanges,ofteninresponsetodaily events,withrapid return tobaselinewithin afew hours[114]. Whether the type of emotional instability seen in ADHD is qualitativelydifferenttothatseeninotherchronicconditionssuch asborderlinepersonalitydisorderorpost-traumaticstressremains unclear.
4.1.5.Excessivemindwandering
Another common feature of adult ADHD is excessive mind wandering,alsoreferred toas mentalrestlessness[116–118]. In DSM-5mindwanderingisbrieflymentionedastheoccurrenceof unrelated thoughts. Although mind wandering is a universal experience, some forms of mind wandering are detrimental becausetheyinterferewithtaskperformance.AdultswithADHD frequently report a distractible mental state with multiple unrelatedthoughtsthatareconstantlyonthegoandjumpfrom onetopictoanother[119,120].Mindwanderingisalsoafeatureof other mental health disorders suchas depressive or obsessive disorders.However,inADHDmindwanderingischaracterizedby unfocused,short lived distractiblethoughts withno pattern of repeatedthoughtsorabnormalityofcontent.Researchfoundthat excessive mind wandering was strongly correlated with ADHD symptoms,wasastrongpredictorofthediagnosis(sensitivityand
specificityaround90%forcase-controldifferences),co-variedwith ADHD symptoms over a 6-month period, and was a better predictorofADHD-relatedimpairmentsthantheinattentiveand hyperactive-impulsivesymptomsofADHD[120].InADHDitcan be measured using the Mind Excessively Wandering Scale [116,118,120](Table1).
4.1.6.Behavioralself-regulation(executivefunctiondeficits) ADHDhasbeendescribedasadisorderofexecutivefunctions suchasinhibitionandworkingmemory.Theseincludeproblems organizing,prioritizingandinitiating work;focusing,sustaining and shifting attention totasks; regulating alertness, sustaining effortandprocessingspeed;managingfrustrationandregulating emotions; utilizing working memory and accessing recall; and monitoring and self-regulation of behavior [121,122]. Although clinicallythesearegooddescriptions ofthetypesofdifficulties experienced byadults withADHD, behavioralmeasuresdo not
Table1
ExamplesofADHD-relatedsymptoms. Inattention Forgetfulness
Distractibility Chaoticpresentation
Difficultyorganizing&planning Difficultylistening
Difficultywithpunctuality(arrivingeithertoolateortoo early)
Temporaryhyperfocusforhighlysalienttasks,butno controlofattentionwhenrequiredorformanyessential activitiesofdailylife
Gettinglostindetails
Doubtfulness–unabletomakedecisionsorsolve problems
Needingtoomuchtimetocompletetasks Difficultystartingandfinishingtasks MindWandering:
Mentalrestlessness
Unrelatedspontaneousthoughts,constantlyonthego, jumpingandflitting,multiplethoughtsatthesame time
Associativethinking
Hyperactivity (Inner)Restlessness Difficultyrelaxing Pacingupanddown Talkingtoomuchandtooloud Fidgeting,rockingortapping
Notbeingabletobearanofficejobbecauseof restlessness
Knockingthingsoverbecauseofexcessivemobility Beingabletositstillbutthiscomeswithmusclestrain Restlesssleep
Impulsivity Actingwithoutthinking
Difficultywaitingturn–linkedtofeelingsofirritability Blurtingthingsoutthatcausedistresstoothers Interruptingothers
Impatienceanddifficultywaitingturn Spendingtoomuch
Walkingoutofjobs Startingrelationshipsquickly Notbeingabletopostponegratification Sensationseekingandrisktakingbehaviors Bingeeating
Emotional dysregulation
Moodlability
Lowfrustrationtolerance Emotionalimpulsivity Irritability
Angeroutbursts
correlate well with cognitive or neuropsychological tests of executive control [121–123]. A distinction needs to be made between rating scale measures of behaviours reflecting self-regulationofbehaviorreferredtoasEF(behavioral)deficits,and theresultsofneurocognitivetestsofEFssuchasworkingmemory andinhibition.Neuropsychologicaltestscoresreflectingexecutive functioninglackecologicalvalidityinthattheyhavenosignificant relationshiptobehaviouralratingscalemeasuresofEF[124].The EFtest scoresalsoarevery poorat predictingimpairmentin a variety of domains of major life activities, compared to EF behaviouralratingscales[125].
4.1.7.BurdenofADHD
TheimpairmentsassociatedwithADHDacrossthelifespanare impressive.ADHDisassociatedwithlearningdifficulties,school dropout,underachievementatwork[126],frequentjobchanges [127],chronic fatigue [128], financial problems,gambling and internet use [129,130], home and traffic accidents leading to increasedmortalityrates[131–133],relationshipdifficultiesand intimate partner violence [134,135], early onset of addiction [136], teenage pregnancies and sexual transmitted diseases [137,138],atwo-foldincreasedsmokingrate[139],anincreased number of suicide attempts and self-harm in adolescents [140,141],andincreasedcriminality[142,143].Moreover,physical disordersandailmentsmaybecomechronicduetoforgetfulness, healthproblemsinducedbyanegativelifestyle,pooreatingand sleeping habits, and lack of health care follow-up [144–147]. ADHDhasfurtherbeen associatedwithauto-immunediseases [148],obesity[149],andphysicalmulti-morbidity.Inone large study,individualswithmorethan4diseaseshadovermorethan 3-foldhigheroddsofpossibleADHD[146].Theriskofdiabetes, hypertension,cardiovasculardiseaseandcancer,thatarerelated toobesity,maybe increased aswell. Anadditional burdenon familylife may bethe presenceof one or more children with ADHD,whichhappensfrequentlyduetothehighfamilialrisksof thedisorder.
Clinicians shouldalsobeawarethat highfunctioningadults withADHDmaynotpresentwithatypicalpatternoffunctional impairmentsintheirdailylife.Adaptiveorcompensatoryskillscan developthatmaskthemoreovertbehavioralproblemsrelatedto ADHD [150]. Somemay find work that is well suited to their symptom profile. Furthermore,in ADHD neurocognitive perfor-manceandinattentivesymptomsaresensitivetothesalienceof taskactivities [151,152]. Such people withADHD mayexcel in certainaspectsoftheirlives,butstillbeimpairedinothers,suchas moreroutineandmundanetaskssuchaspayingbills,lookingafter thehouse,ordevelopingstablesocialrelationships.Problemscan include subjectivedistress fromsymptomssuchas mental and physicalrestlessness,sleepproblems,andemotionalinstability; andtheuseofdrugssuchascannabisoralcoholtoreducethese symptoms.
5.PrevalenceofADHDacrossthelifespan
Inchildhood, ADHD isamong themostcommonpsychiatric disorderswithaprevalencerateof3–5%[153].Forthisagegroup, wellestablisheddiagnosticand treatmentservicesareavailable throughoutmostofEurope.Inthelastfourdecades,alargebodyof evidencehasaccumulated,showinghowinthemajorityofcases ADHD isa lifespan disorder,persistingaseither thefullblown disorder, or in ‘partial remission’ with persistence of some symptomsand continuedclinicalandpsychosocialimpairments [154–161]. The prevalence of ADHD in adults across twenty countrieswasrecentlyestimatedat2.8%,witharangebetween 1.4-3.6%[3].ADHDwasalsofoundinaDutchpopulationstudyto persistintooldage(>60 years)witha prevalenceof 2.8–4.2%
dependingoncut-off(6or4currentsymptomsrespectively),and associated withimpairment [162–166]. ADHDinolderadults is accompaniedbyincreasedratesofmoodandanxietysymptoms, generalhealthproblems,conflicts,divorce,loneliness,andalower income,showingasimilarpatternofproblemsasinyoungerage groups.Researchexploringtheneedsfortreatmentofolderadults withADHDhascommenced,andthefirsttreatmentprotocolof olderadultswithADHDhasbeenpublished[167].
5.1.Sexissues
SexdifferencesinADHDdiagnosisarewelldocumented,withgirls beinglesslikelytobediagnosed,andsexratios rangingbetween1:5to 1:9[168].Suchdiscrepancyislessevidentinepidemiologicalresearch inchildrenwherethesexratiois1:3,suggestingunderrecognitionof ADHDingirlsintheclinic.Inbothepidemiologicalandclinicalstudies ofadultADHDthesexratioiscloserto1:1[169].Severalfactorsmay explainthesexdisparityduringthelifespan.GirlswithADHDmay have lesshyperactive/impulsive symptoms than boys;because of higherdisruptiveness,boysaremorelikelytobereferredbyparents and teachers, whereas girls remain undiagnosed [170]. Missed diagnosis maybedueto a lackof knowledgeandrecognition of ADHDingirlsbyhealthcareprofessionals,andto thepresenceofother conditions:lowself-esteem,anxietyaswellaffectivedisordersoccur frequently in females with ADHD, and it is possible that ADHD symptoms may be mistakenly attributed to such comorbidities [171,172]. Females with ADHD appear to develop better coping strategiesthanmales,andarebetterabletomasksymptomsofADHD throughoutchildhood.However,thismaynolongerworkwellwhen theyface salientlife challenges,suchasleavingschool, attending collegeoruniversity,commencingemployment,managingintimate relationships,andtakingresponsibilityfortheirownlifedecisions [173]. Different genetic liability between the sexes[174], aswell neuroendocrinefactorsaffectingthedopaminergicsystem,suchas thyroidandestrogenhormones[172,175],haveallbeen alsosuggested toplayaroleinthemaskingofADHDingirlsandwomen.Inaddition, girlsandwomenwithADHDarelesswellstudiedthanmales.
Women with ADHD are particularly vulnerable to early adversities, health and mental health problems compared to controls [176]. A higher prevalence of insomnia, chronic pain, suicidalideation,generalizedanxietydisorder,depressive disor-ders,agreatervulnerabilitytonicotinedependence[176,177]and anincreasedlikelihoodofriskysexualbehaviors[138]hasbeen reportedinwomenwithADHDincomparisonwithcontrols. 5.2.Transitionofadolescentstoadultmentalhealthservices
Astwo-thirdsormoreofchildrenwithADHDcontinuetohave impairmentintoadulthood[178],manyrequirethetransitionfrom childtoadultmentalhealthservices.However,transitionbetween servicesisgenerallydifficult,placingyouthswithADHDinaneven morevulnerableposition[179].Researchshowsthatdisruptionof careduringtransitionadverselyaffectsclinicaloutcome[180,181]. Clear recommendationshavebeenformulated,mostlybasedon clinicalexperience, tofacilitatesuccessful transitionofpatients withADHDfromchildtoadultmentalhealthservices[1,182–185]. Thesearea)transitionshouldideallybecompletedbytheageof18 years,b)transitionshouldbeplannedinadvancebybothchildand adultmentalhealthservices,c)youngpeoplewithADHDandtheir parentsshouldhavesufficientinformationregardingthetransition process (e.g. psychoeducational material including available services), d) both continued parental care and child’s growing autonomyshouldbeconsidered,e)ifnecessaryaformalmeeting involving child and adult mental health services (with specific knowledgeonthisagegroup)andpatientsandparentsshouldbe considered.Allthesecanhelptopreventthedrop-outofyoung
peoplewithADHD from services.However, thereality is quite different,asindicatedbytworeviews[186,187].Comparedtoother diagnosticgroups,youthwithADHDweresignificantlylesslikely tobe referred, they weremore likely to refuse referral, and a significantnumberremainedinchildserviceswellbeyondtheir 18th year. Studies also have found transition policy deficits
[186,188],suboptimalexperienceoftransitionwhenitdoesoccur [186,189], a dearthof adultADHDservices[190], and a lackof expertiseonADHDamongstadultclinicians[3,191].Thissuggests thereis anurgentneedfor a multifacetedapproachcombining transitionspecificclinicalguidelines,andfundingforthetraining thetrainingofclinicians,toensurethatthoseinneedofongoing interventionmaysuccessfullytransitiontoadultservices. 5.3.Late-onsetADHD?
Recent longitudinalstudies haveindicated thatbesidestypical childhoodonsetADHD,withthefulldiagnosticcriteriabeingmet beforetheageof12years,theremaybelater-onsetcaseswithonsetof the full diagnostic criteria beyond this age [104,189,190]. These findingshave proven controversial due to severemethodological limitations[192,193],howeverthelargemajorityoflateronsetcases appeartomeet theDSM-5ageofonsetcriteria ofseveralsymptomsby theageof12[113].Lateonsetofsymptomswasevaluatedinthe controlarmofthelong-termfollow-upoftheMultimodalTreatment studyofADHD(MTA).Inmostcases,otherfactorswerepresentthat coulddiscountthelateonsetofADHDsymptomsandexcludethe diagnosis of ADHD [194], such as symptoms representing non-impairingcognitivefluctuations,acomorbiddisorder,orthecognitive effectsofsubstanceuse[192].However,thereremainedaverysmall sampleofadolescentonsetcases.Anotherpopulationcohortstudy foundthatthemajorityofthosewithapparentlate-onsetADHDhad highADHDscoresatleastonepointinchildhood,suggestingthatthey mayhavebeenmisclassifiedonthebasisoftheirscoreatage12years [195].Thesecaseswithhighscorebeforetheageof12yearsmightnot havemetfullcriteriabeforetheageof12years,butwouldmeetthe current DSM-5 criteria for several symptoms in childhood. One conclusion is that clinicians should be aware that subthreshold cases of ADHD during childhood might go on to meet the full diagnostic criteria as older adolescents. Clinicians should take care to fully assess impairment,psychiatrichistory,andsubstanceusewhendiagnosing andtreatingcaseswithapparentlater-onsetADHD[192].
6.Screeninganddiagnosticassessment 6.1.Screening
Several screeningtoolsareavailable forADHDinadults.The validatedtoolrecognizedbytheWorldHealthOrganization(WHO) and updated for DSM-5 criteria is the Adult ADHD Self report RatingScale(ASRS).ThisrevisedASRSwasstudiedin managed
care,thegeneralpopulationandinaclinicalgroup.Thesensitivity was 91.4%; specificity 96.0%; AUC, 0.94; PPV, 67.3% [196]. The previous version of the ASRS has been translated into many languages (see http://www.hcp.med.harvard.edu/ncs/asrs.php). TheWenderUtahRatingScaleassessesbesidesADHDabroader spectrum of symptoms that often accompany ADHD or are comorbid. Several other scales that ask about the 18 items as definedintheDSM-5toclassifyADHDareavailable,seeTable2. AkeyquestioniswhoshouldbescreenedforADHD.Ingeneral, sincethehallmarkofadultADHDisachronictrait-likecondition that emerges out of childhood or early adolescence, anyone presentingwithsuchaclinicalpictureshouldbescreened[2].This shouldincludethosewithchronichistoriesofinattentive,restless orimpulsivebehaviors,aswellasthosewithemotionalinstability. TargetedgroupswhereratesofADHDaresignificantlyincreased and should therefore be screened include family members of people with ADHD, and those with a history of behavioral problems,anychronicmentalhealth disorderincludinganxiety, depression, cyclothymia, personality disorder, bipolar disorder, substance use disorders, those withmultiple physical diseases [146],andthosewithinthecriminaljusticesystem[197]. 6.2.Diagnosticassessment
For diagnostic assessment, the use of a semi-structured diagnosticinterviewisadvised,suchastheDiagnosticInterview forADHDinadults,secondedition(DIVA2.0)[198],basedonthe DSM-IV-TRcriteria.DIVA 2.0isavailable onlinewithoutcharge, currentlyin19languages(www.divacenter.eu).TheConner’sAdult ADHD Diagnostic Interview for DSM-IV (CAADID) has been validatedinEnglishandSpanish[199].DIVA2.0hasbeenvalidated intwoEuropeanpopulations[81,199],andisincreasinglyusedin internationalresearch.ADIVA2.0appisavailableintheAppand GooglePlaystores.TheupdateofDIVA2.0forDSM-5criteriainto ‘DIVA-5’in alllanguages isongoing.DIVA-5-ID,for peoplewith Intellectual Disability (ID) and Young DIVA, for children and adolescents,arenewversionsofDIVA-5. AnalternativeisACE+ (http://www.psychology-services.uk.com/resources.htm),a semi-structured diagnosticinterview to assess ADHD in adults (>16 years). ACE+assesses the core symptoms of ADHD in both adulthood and childhood, the extent to which they impair functioning,and thepresenceofco-existing conditions.ACE+is currentlyonlineavailablein7languages,withmoretranslations underway.Fortheseandotherdiagnostictools,seeTable2. 6.3.TheassessmentprocessofADHDandcomorbidity
DiagnosisofADHDisbasedon acarefulandsystematicassessment ofalifetimehistoryofsymptomsandimpairment.Centraltothis process is the assessment of childhood-onset and current symptoms of ADHD,andthepresenceofsymptomsandimpairmentinatleasttwo
Table2
OpenaccessScalesandInterviewsforDiagnosticAssessmentofADHDinadulthood. Scalesa
AdultADHDSelf-ReportScale DevelopedbyWHO;6-itemversion,basedon DSM-5(ASRS),inmanylanguages
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470397/
WenderUtahRatingScale https://www.thecalculator.co/health/Wender-Utah-ADHD-Rating-Scale-Calculator-858.html
DiagnosticInterviewsb
DIVA-5 StructuredDiagnosticInterviewforADHDinadults;accordingtoDSM-5;in19languageswww.divacenter.eu
ACE+ Semi-structuredInterviewforADHDinadultshttps://www.psychology-services.uk.com/adhd.htm
a
Otherscaleswithoutopenaccessare:ConnersAdultADHDRatingScale(CAARS),andtheAdultADHDInvestigatorRatingScale(AISRS).
b
domains (school, work, home, interpersonal contacts). For this lifetime assessment,collateralinformationfromfamilymembersandspouse areuseful.Itisimportanttotakeafullmedicalhistoryofpsychiatric andsomaticconditions,aswellasafamilyhistoryofpsychiatricand neurologicalproblems.Highintelligenceshouldbetakenintoaccount asapotentialmoderatorinthediagnosticassessment,asADHDis underdiagnosedinpatientswithhighintelligencebecausetheyuse morecompensatorystrategies[200].Cliniciansshouldalsobeaware thathighfunctioning adults with ADHD may not presentwitha typical patternof functional impairments in theirdaily life. Adaptiveor compensatoryskillscandevelopthatmaskthemoreovertbehavioral problemsrelatedtoADHD[150].Somemayfindworkthatiswell suited to their symptom profile.Furthermore,inADHDneurocognitive performanceandinattentivesymptomsaresensitivetothesalienceof taskactivities[151,152].SuchpeoplewithADHDmayexcelincertain aspectsoftheirlives,butstillbeimpairedinothers,suchasmore routineandmundanetaskssuchaspayingbills,lookingafterthe house,ordevelopingstablesocialrelationships.Problemscaninclude subjective distress from symptoms such as mental and physical restlessness,sleepproblems,andemotionalinstability;andtheuseof drugssuchascannabisoralcoholtoreducethesesymptoms.
Adultdiagnosesmaybemissedinclinicalpracticeduetolack ofknowledgeaboutADHDinadulthoodamongpractitionersand due tothe high frequencyof comorbid psychiatricconditions [201].Thelifetimeco-morbidityrateis60–80%.Havingthreeor more disorders wasassociated witha ten-fold increaseof the chanceofhavingADHDinapopulationstudyin20countries[3]. Beforetreatmentstart,allcomorbiditiesmustbeestablishedso thatthebestorderoftreatmentcanbedeterminedtogetherwith the patient. In the study by Fayyad et al, data on ADHD and comorbidities was collected on 26,744 respondents [202]. In adultswithADHD havingonecomorbiditywasfoundin23%of cases,twoin14%ofcasesandthreein14%ofcases.Rateswere particulary high for any mood disorder (22%), any anxiety disorder(34%),substanceusedisorders(11%)andanybehavioural disorder(15%).
Psychiatriccomorbidityisthusaclinically important dimen-sionofADHDheterogeneityanda factorthatcontributestothe persistenceofADHDinadulthood[203,204].Itisimportantforthe diagnosisofADHD,aswellasthecorrecttargetingoftreatments,to identifymood,anxiety,eating,sleep,somaticandsubstanceuse disorders, in addition to personality, tic and autistic spectrum disorders[205].BecauseadultswithADHDoftenexhibitlow self-esteem,lowmood,moodlabilityandirritability,thesesymptoms maysometimesbeconfusedwithdysthymia,cyclothymia,bipolar disorder or borderline personality disorder. Furthermore, daily moodchangesinADHDareverycommon,andrepresentapoorly regulatedbutessentiallynormalrangeofmoods,ratherthanthe moresevereextremesofdepressionandelationasseeninbipolar disorder.Ithasbeenarguedthatchronicmoodinstabilityshould beconsideredpartofthecoresyndromeofADHD[206,207].ADHD andborderlinepersonalitydisordersharesymptomsof impulsivi-ty, mood instability, anger outbursts and feelings of boredom [158,208,209]. In the ADHD patient, impulsivity and anger are usuallyshort-livedandthoughtlessratherthandriven.Conflictsin relationships, suicidal preoccupation, self-mutilation, identity disturbancesandfeelingsofabandonmentareusuallylessintense thaninborderlinepersonalitydisorder.However,thedifferences maynot beclear-cut becausethese symptomsare chronicand trait-likeinbothconditions[210].
ADHD in childrenis alsoassociated with increasedrates of neurodevelopmental disorders like autism spectrum disorder, dyslexiaand impairedmotorcoordinationwhich arethoughtto arise from overlapping genetic influences [211]. Such neuro-developmentalcomorbiditiesarelesswellstudiedinadults,but theyarecommonlyobservedinclinicalpracticeandmayleadto
continuedimpairments.Astheorderoftreatmentwilldependon thepresenceandseverityofcomorbidities,evaluationofcomorbid disorders isa keycomponentoftheADHDassessment process, usingappropriateclinicaldiagnosticapproaches.
6.4.ADHDandcriminality
Theprevalenceof ADHDisincreasedinforensicpopulations compared to the general population [212], and the risk of criminalityis increasedin individualswithADHD, especially in those with comorbid oppositional defiant disorder, conduct disorder, substance misuse and antisocial personality disorder [213]. Ameta-analysiscomprising 42 studiesfrom15countries reporteda 5-foldincreasedprevalenceofADHDinyouthprison populations (30%) and a 10-fold increased prevalence in adult prisonpopulations(26%)ascomparedtothegeneralpopulation [214]. Whenusing diagnosticclinical interviews, theestimated ADHD prevalence in prisoners was 25.5%, without significant differencesforgenderandage[214].Further,inmateswithADHD comparedtothosewithoutarereportedtohavehigherratesof psychiatricmorbidityincludingsubstancemisuse,anearlieronset ofoffending,moreviolentoffences,criminalrecidivismandmore frequentandsevereinstitutionalaggression[215,216].
7.Treatment
7.1.Effectivetreatments
ThetreatmentofadultswithADHDshouldfollowamultimodal andmultidisciplinaryapproach,whichincludespsychoeducation, pharmacotherapy,cognitivebehaviortherapy(CBT)andcoaching forADHD,whicharealldiscussedinthisarticle.
Ideally, thetreatment plan alsoinvolves theadult’s partner, familyorcloserelationships,andinsomecasessystemic(family) therapy may be required when gross disruption to family relationshipsandfunctioningispresent.
7.2.TreatmentfocusincomorbidADHD
In the most recent report of 20 nationally or regionally representativeWorldMentalHealthsurveys,dataonADHDand comorbiditieswascollectedon26,744respondents[202].Inadults withADHDhavingonecomorbiditywasfoundin23%ofcases,two in14%ofcaseandthreein14%ofcases.Rateswereparticularyhigh foranymooddisorder(22%),anyanxietydisorder(34%),substance usedisorders(11%)andanybehaviouraldisorder(15%).Treatment of ADHD is therefore mostoften in the contextof co-occuring disorders.
Beforetreatmentstarts,allcomorbiditiesmustbeestablished sothatthebestorderof treatmentcanbedeterminedtogether withthepatient.Ingeneral,themostseveredisorderisprioritized. Forinstance,psychosis,bipolardisorder,substanceabuse,severe depression and severe anxiety are usually treated first. Milder moodoranxietydisorders,andemotionalinstability,mayrespond totreatment of ADHD and canbe treatedat thesame time as ADHD. Drugand alcohol abuse shouldbestabilizedbut canbe treatedatthesametimeasADHD.
7.3.PsychoeducationonADHD
Accordingtoconsensusbasedongoodclinicalpracticeandthe needtoworkonaninformedconsentbasiswithinamultimodal treatmentapproach,psychoeducationshouldbethefirststepasa standard of care[217]. First evidencefrom anopentrial anda randomized clinical trial shows, that patients and significant otherswhoattendastructuredpsychoeducationprogramincrease
theirknowledge aboutADHD, andimprove thequalityof their relationshipsandpsychologicalwell-being[218,219].
7.4.PharmacotherapyforADHD 7.4.1.Introductiononpharmacotherapy
In thefirst EuropeanConsensusStatement[1] psychostimu-lants (methylphenidate and dexamphetamine) were recom-mended as the first-line pharmacotherapy for adult ADHD [1,184,220],astheyexertmoderate-to-highclinicaleffects, with average effects higher than atomoxetine (ATX) and other non-stimulantmedications[2].Therewere,however,nohead-to-head studiesprovidingrobustcomparative analysisof efficacy differ-ences[221].AcrossmostofEurope,lisdexamfetamine(LDX)has been introduced as a slow release formulation of dexamphet-amine.Therecentsystematicreviewandnetworkmeta-analysis onthe comparative efficacy and tolerability of medications for ADHDinchildren, adolescentsandadultsbySamCorteseetal. showed,thatthefirstpharmacologicalchoiceforADHDinchildren andadolescentsismethylphenidate,andamphetaminesinadults [222]. In fact inadults, amphetamines werenot onlythemost efficaciouscompounds,asratedbycliniciansandbyself-report, but also as well tolerated as methylphenidate and the only compoundswithbetteracceptabilitythanplacebo.
7.4.2.Licensing
LicensingofADHDmedicationsforadultsismorediversethan in2009[1],reflectinggreaterunderstandingofADHD,andefforts to market ADHD medications in Europe. In Denmark, Ireland, Norway, Sweden, Switzerland, the Netherlands and the United Kingdom,mostADHDmedicationscanbeprescribed,eitherwitha fulllicense(e.g.Medikinet1,Strattera1,Elvanse1)ortransitional licenses(e.g.ConcertaXL1)andoff-labelprescribingisendorsed by national guidelines and formularies. Dexmethylphenidate (FocalinXR1)islicensedinSwitzerlandonly.Inothercountries, onlyalimitedselectionofmedicationsisavailableforfundingby thestatesector,but offlabelprescribingispossible.Inanother groupofcountries(e.g.Greece,Slovenia,Poland),onlyveryfew ADHDmedicationsareavailable,withoff-labelprescribingmostly in the private sector. The European Network on Adult ADHD (ENAA)andtheNeurodevelopmentalDisordersAcrosstheLifespan (NDAL)sectionatEPAstronglyrecommendthatevidence-based treatmentsforadultADHDaremademoreavailableandlicensed acrossEuropeancountries.
7.4.3.Efficacyandadverseeffectsofstimulants
Meta-analysesofrandomizedcontrolledtrials(RCTs) demon-stratetheefficacyofstimulantsandATXinthereductionofADHD symptoms in adults [223–227]. Standardized mean differences (SMDs)range from0.4 to0.7, withstimulantsshowinggreater efficacy than ATX [224]. The longest RCT in adults still found significanteffectsofMPHafteroneyear[228].Nationalregistry dataalsosuggestlongtermbenefits.Althoughthesestudiesarenot definitive due to lack of randomization and controls, they demonstrate ‘real-world’ societal benefits associated with the useofADHDmedications.Thesestudiesshowthatduringperiods ofreceivingmedicationsforADHDtherearemarkedreductionsin transport accidents and mortality rates [132,229], criminal convictions [230], suicidal behavior [231], violent reoffending [230], depression [232] and substance misuse [233]. Similar analyses with antidepressants find no effects, suggesting the effectsarespecifictoADHDmedications.
A 2011 meta-analysis [225] revealed that MPH (mean dose 41.2–82mg/day)exerteda moderateeffectonADHDsymptoms, withlargeeffectsobservedatdosesof>77.4mg/day.Immediate release(IR)MPHhasashortdurationofactionofmaximum4h.
Due to difficulties with compliance when needing to take medicationuptoseveraltimesaday,long-actingMPH prepara-tions have been developed, with durations of action ranging between6–12h.
Therecommendeddoserangeof ImmediateRelease dexam-phetamine(IR)is5–60mg/day[220].Lisdexamfetamine(LDX)has aslowreleaseprofilegivingthedrugarelativelylowabuseprofile [234].LDXistakenoncedailywithamodeofactionofupto14h [235].ThreeRCTsinadultsindicatemoderatetolargeeffectson ADHD symptoms [236–238] (SMD=0.97) [239], comparable to MPH. The safety and tolerability profile is similar to other stimulants[240,241].
Themainadverseeffectsofstimulantsareincreasedheartrate and bloodpressure, and reducedappetite andsleep [242–245]. Heart rate, blood pressure, sleep problems and weight are therefore assessed before, and monitored at leasttwice a year during treatment. Serious cardiac complications are rare [243,246,247] with reported risks for myocardial infarction, suddencardiacdeath,ventriculararrhythmiasorstrokenomore than 0.2-0.4% higher in one study [248]. MPH might trigger arrhythmiasinpatientswithcongenitalheartdiseases[249].The consensusiscautioninpatientswithknowncardiacdefects,but risksaresmall.
7.4.4.Atomoxetine
ATX yields moderate efficacy in reducing ADHD symptoms (SMD:–0.33to–0.40)[227].Onsetofactionis1–2weeks,andfull effectsmaytakeupto6monthstodevelop[250].Ifrapidonsetof effect isnot essential, ATX maybea good choicefor highrisk patientswhoneedstablecontrolofADHDsymptoms[251].
Theuseof ATXasfirst lineindrugabusers continuestobe debated with other experts preferring stimulants due to rapid onsetandpotentiallygreatereffects [252].Althoughinthepast there were concerns that stimulants may increase the risk of substance use disorders (SUD), there is now a wealth of data demonstratingreductionsinSUDduringperiodsoftreatmentof ADHDwithstimulants[233,253].
ATXmaybeagoodchoicewithco-occurringanxietythatmight beexacerbatedbystimulants,asaRCTofadultswithcomorbid ADHD andsocial anxietydisorderfoundimprovements inboth ADHDandsocialanxiety[254].ATXdoesnotappeartobeeffective inthetreatmentofcomorbiddepressioninadolescents[255]. 7.4.5.Guanfacineandclonidine
In Europe, guanfacine extended-release (GXR), an alfa-2 adrenergicagonist,islicensedforthetreatmentofchildrenand adolescentswithADHDforwhomstimulantsarenotsuitable,not toleratedorwhereshowntobeineffective[256,257],whereasin theUS,IRguanfacineisapprovedforuseinchildrenandadults with ADHD (both as monotherapy and in combination with stimulants).Notably,therearecurrentlynoRCTsinadultpatients tosupporttheuseofGXRinthisagegroup,onlyastudyusingGXR or placebo as an adjunct to stimulant treatment that had insufficienteffect.Bothtreatmentsdidnotdifferinefficacy[258]. Extended-release (ER) clonidine is approved in the US for treatment of ADHD in 6–17- year olds as monotherapy or an adjunct to stimulants. There are RCTs on both ER clonidine [259,260]andIRclonidine[261,262]inchildrenandadolescents withADHD,butnoequivalentstudiesinadults.
7.4.6.Bupropion
There are conflicting findings for bupropion from a small numberofadultstudies.Positiveresultswerereportedwithhigher doses(400–450mgperday)[263,264].Duetoalimitedevidence base, bupropion useshould be restricted to cases who do not tolerateotherADHDmedications.
7.4.7.Othermedications
Selectivenoradrenalinereuptakeinhibitorssuchasreboxetine maybeanalternativetoATX[265,266].Thereislimitedevidence fortricyclicantidepressants[267,268]. Selectiveserotonin reup-takeinhibitors(SSRIs)arenoteffectiveforthetreatmentofADHD [229,230,269].Modafinil,awakefulness-promotingagentusedin thetreatment of narcolepsy, hasnot been demonstrated asan effectivetreatmentforadultADHDinaphase3trialthathadhigh ratesofsideeffects(86%) anddrop-out(47%)possiblyresulting fromexcessivedoses(210–510mg/day)[270].
7.4.8.Long-termsafetyconcerns
Currentlythere is noevidenceof significant long-termrisks usingstimulants.Tomographyscansfindhigherstriataldopamine transporteravailabilityinADHDpatientstreatedwithstimulants [271].Theclinicalimplicationsofthisup-regulationarenotclear. Potentialtoxicityonheartvalvesofmedicationswithanagonist effecton5-HT2Breceptorshavebeendiscussed[272], including
MPHandguanfacine.Somearguethatechocardiographyshouldbe routinely performed prior to treatment with potential valvulo-pathicdrugs[273].Thisriskisnothoweverestablished,andwe and others do not recommend routine echocardiograms [184,252,274],exceptinolderadults(>age50)[167].
7.4.9.Combinedpsychopharmacology
The high rate of psychiatric comorbidity in adult ADHD frequently necessitates combined psychopharmacology [275]. Accordingly, the risk of possible drug-drug interactions when treatingadultswithADHDmustbeconsidered.Theseincludethe following:
–Monoamine oxidase inhibitors are generally contraindicated duetotheriskofhypertensivecrisis.
–Although MPH is mainly metabolized in the liver, drug interactionsviaCYPenzymesareuncommon.Amphetamines, however,aremetabolized primarilyviatheCYP 2D6enzyme system makingdruginteractions possible(with inhibitorsor inducersofthisenzymesystem,e.g.fluoxetineandparoxetine) [276].
–Treatment with medications that act on the noradrenaline system, including certain antidepressants (e.g. duloxetine, venlafaxine), will have an additive effect and may increase the risk of hypertension and other adverse cardiovascular events.
–Due toitsmetabolism bythe CYP 2D6 enzymesystem, ATX levelscanincreaseincombinationwithenzyme-inhibitingSSRIs (e.g.fluoxetineandparoxetine)[277].
7.5.Considerationswhentreatingspecialgroupswith pharmacotherapy
7.5.1.ADHDwithcomorbidbipolardisorder
A pharmaco-epidemiological study found that MPH mono-therapy in patients withbipolar disorderincreased the risk of switch to a manic episode (hazard ratio 6.7). However, when combinedwithamoodstabilizer,MPHreducedtheriskofmania (hazardratio0.6)[278].Thissupportsthecurrent recommenda-tiontotreatADHDinbipolardisorderpatientswithstimulants,so longastheyarealsotakingmoodstabilizers.
7.5.2.ADHDwithcomorbidsubstanceuse
Meta-analysis of RCTs in adults found that most ADHD medicationsreducethecoresymptomseverityofADHD,buthave limitedeffectoncomorbidsubstanceuse[279].However,alarge DanishRegistrystudyshowedadecreaseofsubstanceuseinADHD
patientswhenusingMPH[280].RecentRCTsusinghigherdosesof ER Mixed Amphetamine Salts (Adderall XR1) or OROS MPH (Concerta1), combined with CBT found bettereffects on both ADHDandsubstanceuse,comparedtostudiesusinglowerdosages [281,282]. The relevance of higher doses is supported by a pharmaco-epidemiological study from Sweden showing that higher MPH dose was associated with long-term treatment adherence inpatients withADHD and substanceuse disorders (SUD)[283].Immediate-releasestimulantsshouldbeavoidedin patientswithADHDandSUD,whereasOROS-MPHandLDXhave lowerabusepotential[284].Furtherrecommendationsfortreating comorbidsubstanceusedisorderscanbefoundinBolea-Alamanac etal.[184],andintherecentlypublishedinternationalConsensus Statementondiagnosisandtreatmentofsubstanceusedisorders withcomorbidADHD[285].ThisConsensusStatementmentions thattheuseofstimulanttreatmentforADHDdoesnotprecipitate theonsetofSUDinadultswithoutpreviousSUD[286];alsothatin SUDpatients,treatmentofADHDcanbeusefultoreduceADHD symptomswithoutworseningtheSUD,andshouldnotbeavoided [287].
7.5.3.Cognitiveenhancementinstudents
AnothergroupwherescreeningforADHDisappropriateisthe studentpopulation.ThisisbecauseweknowthatADHDspecially interferes with educational attainment. Further, this has been highlightedbethefindingthatgeneticrisksforADHDoverlapwith those for educational outcomes [28]. Student groups with particularly highrates of ADHD include those presenting with specific learning difficulties [288] and mental health problems [202].Relatedtothis,thereareconcerns,particularlyincountries withahigherrateofstimulantprescriptions,thatstudentsmay seekthe diagnosisof ADHD toreceivestimulants forcognitive enhancement.Somestudiesshowthatalthoughmoststudentsuse theirADHDmedicationasprescribed,misuseanddiversionisnot uncommon[289]. Caremust thereforebe takentoensure that studentsarediagnosedandtreatedforADHDwhenappropriate, whileminimisingrisksofdiversion.
7.5.4.Pregnancyandbreastfeeding
There is only limited information on the effects of ADHD medication onthe fetus and new-born [290]. As suggested by population-basedstudies,MPHoramphetamineexposureduring pregnancy is not related to higher rates of any congenital malformations [291–293]. For cardiac malformations, MPH use was associated with a small increased risk (RR 1.28 (95% CI, 0.94–1.74),whereamphetamineswerenot.Thereissomeevidence suggestingthattreatmentwithMPHorATXmightincreasetherisk ofmiscarriage[294,295],althoughtherewereseveralconfounding factorssuchasyoungerageandsocial disadvantage,thatcould explaintheassociation[296].Anotherstudyfoundthattheuseof stimulant medication during pregnancy is associated with miscarriagetothesamedegreeashavingADHDitself[295],these findingsneedfurtherinvestigation.Potentialadverseeffectsonthe fetus fromintraplacental exposuretomedicationinpregnancy should be considered against the possible adverse effects of interrupting treatment abruptly in women with ADHD [184,297,298]. Each caseshould beassessedindividually taking into account possible risks of both treating and interrupting treatment.
Amphetamines maybegiven preferenceover other medica-tions.SomeauthorsdonotconsiderAtomoxetinebecauseoflackof safetydata[299,300].MPHseemstobesafeduringbreastfeeding. Theamountsofmedicationexcretedinbreastmilk,andconsumed bytheinfant,areverysmall(withtheRelativeInfantDose(RID) (<1%)[290,299],andnodrug-relatedsideeffectshavebeenwere reported. The impact of ATX, guanfacine, and clonidine on
breastfeeding-related outcomes is largely unknown [301–303], andtheyarenotrecommended[299].
Untilnownoadversereactionswerereportedamonginfantsof mothersreceivingLDXordexamphetamine(RID:4–10.6%).There aresome preliminaryreports suggesting that dexamphetamine treatmentmay lead to a suppression of prolactin secretion in postpartum women, though with unclear clinical implications [304]. Bupropion was found to produce low levels in milk, suggestingrelativesafety.Ofnote,therearetwoknowncasesof seizures developed by children breastfed by women receiving bupropion[305].
7.5.5.ADHDandsleepproblems
In the majority of cases, ADHD in children and adults is associatedwithacircadianrhythmdisorderwithdelayedsleep onset[306–308].Meta-analysisofninestudiesinvestigatingthe effects of stimulant medication on sleep in children and adolescentsfoundthatstimulantscanleadtolongersleeplatency, worsesleepefficiency,andshortersleepduration[309].Similar findingshavebeenreportedin adults[310].Carefultitration of stimulantsand psychoeducationaround sleepoptimizationcan improvethequalityofsleep,possiblydue toimproveddaytime structure, the maintenance of regular physical activity and improvedmood[198,309,311].InchildrenwithADHDandchronic insomnia,melatoninhasbeenshowntoadvancethesleeponset, andincrease sleepduration [312]. Atrialtargetinginsomnia in adultswithADHDisongoing,andclinicalexperiencepointsinthe samedirectionofpossibleefficacyoftreatmentwithmelatoninat night,andalsooflighttherapyinthemorning[308].Treatmentof insomniashouldalways startwithsleephygieneeducationand optimizing thestimulant or non-stimulant treatment of ADHD [311].AlowdoseofIRMPH(usually5mg)takenatnighttimecan reduceceaselessmentalactivitytoadegreethatallowssleepin somecases.
7.6.Cognitivebehaviortherapy(CBT)andcoachingforADHD AlthoughpharmacologicaltreatmentofADHDisveryeffective, manypatientscontinuetoexperiencesignificantsymptomsand functional impairment in dailyliving. Empiricalevidence from numerous uncontrolled studies, more than ten randomized controlledtrials (RCTs) and a meta-analysishas shown that in grouporindividualsettings,cognitive behavioral therapy(CBT) reduces ADHD-core symptoms, associated symptoms such as emotion dysregulation, anxiety and depression, and functional impairments across different areas of daily living in adults [228,313–315].CBTisbestusedwithinamulti-modaltreatment approachandasanadjuncttomedicationascurrentresearchdoes notfullysupporttheefficacyofCBTasasoletreatmentforadult ADHD [274,316–318]. Most controlled studies have been con-ductedinpatientstakingADHDmedicationanddemonstratean additionalsignificanttreatmenteffect[313,318–322].Thelargest controlledmulti-centerCBT-studytodatehasdemonstratedthat psychological interventions result in better outcomes when combinedwithMPHascomparedtopsychologicalinterventions in unmedicated patients [228]. In a systematic review of 51 pharmacological and non-pharmacological interventions [316], the highest proportion of improved outcomes (83%) was for patientsreceivingcombinationtreatment.However,notalladults withADHDdesireortoleratepharmacologicaltreatment.Inthese casesCBTmaybethebestoption.
Acrossallstudiestherearesomeconsistentcharacteristicsof CBTtreatment,bothinformandcontent.Allapproachesarehighly structured.Mostaremanualized,andestablishpsychoeducationas the first step. Most programs are skills-based and focus on organizationalandtimemanagementskills,emotionalregulation/
control,problemsolvingskills,prosocialcompetenceand strate-giestoimproveattentionandimpulsivitymanagement.Inaddition tobehavioral interventionsthatrequire patientstotryoutand rehearseindailylifetechniquessuggestedinthetherapysession, programsincludecognitivestrategies,suchastheidentificationof negativeautomaticthoughts,methodstoaddress‘thinkingerrors’ andtheintroductionofcognitiverestructuringtechniques[323]. There is emerging evidence that cognitive distortions and dysfunctionalcognitiveschemesrelatedtoabiographic accumu-lationofnegativeexperiencesassociatedwithADHD-symptoms contributetonegativefunctionaloutcomesandleadtoavoidance behavior, failure-orientation, reduced self-efficacy, procrastina-tion,depressivesymptomsandanxiety[324–326].Furthermore, mostprogramshighlighttheimportanceofincludingsignificant others in the treatment process to reduce dysfunctional inter-actionsandstigmatizationassociatedwithADHDsymptoms.
Coaching or mentoring is a derivative of the cognitive behavioralparadigminvolvingthedevelopmentofacollaborative mentoring partnership. Coaching aims to provide structure, supportandfeedbackforbuildinglifeskillsandchangingnegative outcomesrelatedtoADHDindailyliving[217,327,328].However, thereisnostandardmethodologyandthecoachingprocessvaries considerably,includingface-to-facecontact,telephonecallsand/or emailcontact.Todate,therearenocontrolledstudiesassessingthe efficacyofcoachingasatherapeuticmeansinthetreatmentof adultswithADHD.Neverthelessthereissomepreliminarysupport for positive outcomes from uncontrolled studies [327,328]. Similarlythereissomesupportfortheeffectivenessof mindful-nessbasedcognitivetherapy(MBCT)foradultswithADHD[329– 331].
8.Costandcosteffectiveness
BecauseofthebroadimpactofADHDongeneralfunctioning, thedisorderis likelytohaveseriouseconomic implicationsfor children,families,andsociety.Thestudieswhichcalculatecosts however areso farlimited as they typically examine onlyone aspectofthecosts,forexample“fromtheperspectiveofamajor Germanhealthinsurancefund”[332].Particularlyforadultswith ADHD,estimatesshouldincludenotonlydirectcosts(thecostsof labor, supplies, and equipment to provide direct patient care services) but also indirect costs (mainly related to the loss of productivity)suchascoststofamily,costsduetoimpairmentin employment,costsduetoaccidents[333],smokingandsubstance misuse, andcostsdue toinvolvementwiththecriminaljustice system.
Directcostshave beenexamined [334–336], but are heavily dependingonthehealthcaresystemfromwhichtheyarederived andthetypeofpathway/carepackageprovided.Theseestimates therefore, althoughpotentially useful forcomparisons between disorders within the same healthcare system, should not be generalized to different contexts. The most comprehensive approach to calculate the total costs of ADHD in the Danish Psychiatric Central Register, showed that there is an economic burden of ADHD which is considerable and falls both on the individualandthestate[337].
Apartfromthecosts(eitherdirectorindirect)ofADHD,thereis alsothequestionofcostbenefitfortreatingADHD.Thisfirstasks whetheratreatmentofadisorderisworthwhilewhencompared againstalternativesintermsofallocationofhealthcarefunds,and secondwhichADHDinterventionbringsthemostbenefitatthe lowestcost.Fortheformer,anargumentcanbemadethatadult ADHD is a condition which is cost effective totreat from the societalperspectivebecauseoftheefficacyandrelativelylowcost ofthemedicinesusedforitstreatment[224,338].Forthelatter, amongchildrenand adolescentswithADHD,thereisconsistent
