jurnal reading adhd

CLINICIAN’S CORNERCONTEMPO UPDATESLINKING EVIDENCE AND EXPERIENCE

Attention-Deficit/Hyperactivity Disorderin AdultsTimothy E. Wilens, MDStephen V. Faraone, PhDJoseph Biederman, MD

ATTENTION-DEFICIT/HYPER-activity disorder (ADHD) isa prevalent disorder esti-mated to affect 3% to 9% of

school-aged children and approxi-mately 4% of adults worldwide.1-3 Al-though in the past it was thought thatADHD did not continue beyond ado-lescence, long-term controlled fol-low-up studies have shown that the dis-order persists in a sizable number ofadults who had been diagnosed as hav-ing ADHD in childhood.4

Longitudinal studies in ADHD youthshow that symptoms of hyperactivityand impulsivity may decay, but inat-tention tends to persist.5 Studies of clini-cally referred adults with ADHD showthat about half have clinically impor-tant levels of hyperactivity and impul-sivity and up to 90% have prominentattentional symptoms.6 Like some youthwith ADHD, adults with ADHD tend tohave additional cognitive deficits, spe-cifically executive function deficits,which include problems encoding andmanipulating information and difficul-ties with organization and time man-agement.7

Adults with ADHD typically havechildhood histories reflecting schooldysfunction, including deficits in edu-cational performance, discipline prob-lems, and high rates of repeatedgrades, tutoring, placement in specialclasses, and reading disabilities.8

School problems faced by children

with ADHD often continue or worsenin college, resulting in academicunderachievement, low grade pointaverages, lower completion rates, andmore time to complete degrees.2

Adults with ADHD tend to have lowersocioeconomic status, lower rates ofprofessional employment, more fre-quent job changes, more work diffi-culties, and high rates of spousal sepa-ration and divorce.9 Similarly, adultswith ADHD have more speeding viola-tions, driver’s license suspensions, andautomobile collisions, and they per-form poorly in driving simulators.3,10

Adults with addictions (eg, alcohol orother drug abuse, tobacco, gambling),repeated traffic violations (speeding,failure to renew license), and recur-rent life failures (occupational, finan-cial, academic)—especially in the con-text of a family history of ADHD—should be screened for ADHD.

Diagnosis of ADHD in AdultsAttention-deficit/hyperactivity disor-der can be diagnosed reliably in adultswho currently have symptoms of ADHD(as defined in the Diagnostic and Sta-tistical Manual of Mental Disorders,Fourth Edition (DSM-IV)11 and who, oncareful questioning, give a history ofsuch symptoms since childhood.

According to the DSM-IV defini-tions, a diagnosis of ADHD requires thatpatients must meet all criteria in estab-lished sections B through E and musthave a minimum of 6 symptoms listedin sections A1 (inattention) or A2 (hy-peractivity and impulsivity). Thesesymptoms not only must have per-sisted for at least 6 months but theymust also be “to a degree that [they are]maladaptive and inconsistent with de-velopmental level.”11

For inattention, those symptomsare

a. Often fails to give close attention todetails or makes careless mistakes in school-work, work, or other activities;

b. Often has difficulty sustaining atten-tion in tasks or play activities;

c. Often does not seem to listen whenspoken to directly;

d. Often does not follow through on in-structions and fails to finish schoolwork,chores, or duties in the workplace (not dueto oppositional behavior or failure to un-derstand instructions);

e. Often has difficulty organizing tasksand activities;

f. Often avoids, dislikes, or is reluctantto engage in tasks that require sustainedmental effort (such as schoolwork or home-work);

g. Often loses things necessary for tasksor activities (eg, toys, school assignments,pencils, books, or tools);

Author Affiliations: Clinical Research Program in Pe-diatric Psychopharmacology, Massachusetts GeneralHospital and Harvard Medical School, Boston, Mass(Drs Wilens, Faraone, and Biederman), Departmentof Epidemiology, Harvard School of Public Health, Bos-ton, Mass (Dr Faraone).Financial Disclosure: Dr Wilkens has received sup-port from the National Institute on Drug Abuse, Na-tional Institute of Mental Health, McNeil Consumerand Specialty Pharmaceutical, Shire Laboratories Inc,CellTech, Eli Lilly & Co, GlaxoSmithKlineBeecham, andNovartis Pharmaceuticals. Dr Biederman receives re-search support from Shire Laboratories, Eli Lilly, Wy-eth Ayerst, Pfizer Pharmaceutical, Cephalon Pharma-ceutical, Novartis, Janssen Pharmaceutical, StanleyMedical Foundation, the National Institute of MentalHealth; serves on the speaker’s bureau for Eli Lilly,Pfizer, Novartis, Wyeth Ayerst, Shire, McNeil, andCephalon; and is on the advisory boards of Eli Lilly,CellTech, Shire, Novartis, Janssen, Johnson & Johnson,Pfizer, and Cephalon. Dr Faraone receives research sup-port from McNeil, Shire, Eli Lilly, the National Insti-tute of Mental Health, the National Institute of ChildHealth and Development, and the National Instituteof Neurological Diseases and Stroke; is a on the speak-er’s bureau for Eli Lilly, McNeil, and Shire; and has hadan advisory or consulting relationship with McNeil, No-ven Pharmaceuticals, Shire, and Eli Lilly.Corresponding Author: Timothy E. Wilens, MD, Pe-diatric Psychopharmacology Unit (ACC 725), Massa-chusetts General Hospital, 15 Parkman St, Boston, MA02114-3139 ([email protected]).Contempo Updates Section Editor: Catherine Meyer,MD, Fishbein Fellow.

CME available online atwww.jama.com

©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, August 4, 2004—Vol 292, No. 5 619

h. Is often easily distracted by extrane-ous stimuli;

i. Is often forgetful in daily activities.

For hyperactivity, those symptomsare

a. Often fidgets with hands or feet orsquirms in seat;

b. Often leaves seat in classroom or inother situations in which remaining seatedis expected;

c. Often runs about or climbs exces-sively in situations in which it is inappro-priate (in adolescents or adults, may be lim-ited to subjective feelings of restlessness);

d. Often has difficulty playing or engag-ing in leisure activities quietly;

e. Is often “on the go” or acts as if “drivenby a motor”;

f. Often talks excessively.

For impulsivity, those symptomsare

a. Often blurts out answers before ques-tions have been completed;

b. Often has difficulty awaiting one’sturn;

c. Often interrupts or intrudes on oth-ers (eg, butts into conversations or games).

The final 4 criteria B through E areB. Some hyperactive-impulsive or inat-

tentive symptoms that caused impairmentwere present before age 7 years;

C. Some impairment from the symp-toms is present in �2 settings (eg, school,work, home);

D. There must be clear evidence of clini-cally significant impairment in social, aca-demic, or occupational functioning;

E. The symptoms do not occur exclu-sively during the course of a pervasive de-velopmental disorder, schizophrenia, or otherpsychotic disorder and are not better ac-counted for by another mental disorder (eg,mood disorder, anxiety disorder, dissocia-tive disorder, or a personality disorder).

Research shows that diagnosingADHD based on the retrospective self-reports of adults is a valid method ofdiagnosing the disorder. Murphy andSchachar12 reported that the consis-tent reporting of childhood ADHDsymptoms by both adults and their par-ents is highly correlated (R�0.75). Theyalso found strong agreement betweenthe self-reports of adults and of theirpartners regarding ADHD symptoms.However, to ensure accuracy, clini-cians should corroborate these self-reports and familial reports with a clini-cal interview because the use of written

adult self-report scales—such as theADHD rating scale and the Conners rat-ing scale, which incorporate the DSM-IVcriteria for ADHD—are highly valid andreliable instruments).13,14 The Brown at-tention-deficit disorder and Wender-Reimherr scales are also used com-monly to diagnose ADHD (andcomorbidity) in adults.14

Psychiatric and learning problemsexist simultaneously in a majority ofadults with ADHD, who also manifesthigher rates of anxiety disorders, de-pression, cigarette smoking, and sub-stance use disorders than adults with-out ADHD.9 Conversely, approximately15% to 20% of adults with substanceabuse disorders, anxiety, depressive dis-orders, and bipolar disorders haveADHD.15-17 Since attentional dysfunc-tion may be evident in a host of otherdisorders (eg, depression, anxiety,dementia), careful attention to the exis-tence of longitudinal symptoms and im-pairments of ADHD coupled with thepossibility that the manifest cognitivedeficits may be related to another dis-order are necessary for an accurate di-agnosis. Adults presenting with diag-nostic dilemmas or clinically significantco-occurring disorders such as de-pression, bipolar disorder, panic dis-order, and substance abuse should bereferred to a practitioner with experi-ence in treating ADHD.

Genetic Susceptibilityto ADHD in AdultsFamily, twin, adoption, and molecu-lar genetic studies show that genes in-fluence the etiology of ADHD. The heri-tability of the disorder, about 70%, isamong the highest for psychiatric dis-orders.18 Family studies show thatADHD is more prevalent among therelatives of children with ADHD, andthe biological children of adults withADHD are at high risk of having ADHDthemselves.19 This high familial load-ing of adult ADHD suggests that bio-logical factors may be stronger in adultsthan in pediatric ADHD.20

Studies of children and adults havefound evidence for the involvement ofseveral genes in the etiology of ADHD:

the D2 dopamine-receptor gene, the do-pamine-beta-hydroxylase gene, the do-pamine transporter gene, the SNAP 25,and the D4 dopamine-receptor gene,and others.21 The data for the D4 recep-tor are especially compelling becausethe gene variant associated with ADHDis known to mediate a blunted re-sponse to the neurotransmitters nor-epinephrine and dopamine,22 impor-tant neurotransmitters associated withthe pathophysiology of ADHD.

Brain Anomalies in AdultsWith ADHDA substantial body of literature impli-cates abnormalities of brain structureand function in the pathophysiology ofboth childhood and adult ADHD.23-25

We have known for decades that ADHDyouth show impaired performance ontasks requiring vigilance, motoric in-hibition, organization, planning, com-plex problem-solving ability, verballearning, and memory. A recent meta-analysis has demonstrated that a smallerbut substantial literature shows simi-lar problems in adults with ADHD.23

Age, learning disabilities, psychiat-ric comorbidity, and gender do not ac-count for these impairments.23 Al-though neuropsychological testing isnot used for diagnosing ADHD inadults, such testing can help identifyother problems, including disabilities,subaverage intelligence, and specific in-formation processing deficits.

As recently reviewed,26 current think-ing suggests that a network of interre-lated brain areas are involved in the at-tentional-executive impairments ofchildren with ADHD. The cingulate cor-tex plays a role in motivational as-pects of attention and in response se-lection and inhibition. A system mainlyinvolving the right prefrontal and pa-rietal cortex is activated during sus-tained and directed attention across sen-sory modalities.26,27 The inferior parietallobe and superior temporal sulcus arepolymodal sensory convergence areasthat provide a representation of ex-trapersonal space, which plays an im-portant role in focusing on and select-ing a target stimulus. The brain-stem

ADULT ATTENTION-DEFICIT/HYPERACTIVITY DISORDER

620 JAMA, August 4, 2004—Vol 292, No. 5 (Reprinted) ©2004 American Medical Association. All rights reserved.

reticular activating system and the re-ticular thalamic nuclei regulate atten-tional tone and filter interference. Ab-normalities involving multiple areas ofthe brain, including the anterior hip-pocampus, ventral anterior and dorso-lateral thalamus, anterior cingulate, pa-rietal cortex, and dorsolateral prefrontalcortex may play a part in problems withmemory.26,27

Neuroimaging StudiesIn the neuroimaging literature, nearlyall studies using either computed to-mography or magnetic resonance im-aging show evidence of structural brainabnormalities in those with ADHD.28

The most common findings are smallervolumes in frontal cortex, cerebellum,and subcortical structures.28

Functional imaging studies are con-sistent with the structural studies inimplicating frontosubcortical systemsin the pathophysiology of ADHD.29 Forexample, in a positron emission tomog-raphy study of adult ADHD, Zametkinet al30 found reduced global and regionalglucose metabolism in the premotorcortex and the superior prefrontal cor-tex. Neuroimaging studies suggest that3 subcortical structures—caudate, puta-men, and globus pallidus—are part ofthe neural circuitry that underlies motorcontrol, executive functions, inhibi-tion of behavior, and modulation ofreward pathways. These frontal-striatal-pallidal-thalamic circuits provide feed-back to the cortex for the regulation ofbehavior. Adults with ADHD also dem-onstrate less activation of the anteriorcingulate than adults without ADHD.28

Of interest, functional imaging studiesof children with ADHD show thatstimulant medications do not affectbrain growth adversely.31

Attention-deficit/hyperactivity dis-order is thought to be mediated by cat-echolaminergic dysregulation of dopa-mine and norepinephrine. Althoughthere is some disagreement about this,some studies have shown increased do-pamine transporter density in the stria-tum.32 This is particularly importantgiven that the dopamine transporter inthe striatum is the site of action of

stimulant medications used to treatADHD.33

TreatmentFormal guidelines on the treatmentof adults with ADHD are lacking.Support groups, such as Childrenand Adults With Attention-Deficit/Hyperactivity Disorder (informationabout which can be found athttp://www.chadd.org), assist newly di-agnosed adults by providing informa-tion about ADHD and available re-sources, including peer support groups.Coaching and training in organiza-tional skills appear useful but remainunstudied. Although the efficacy of vari-ous psychotherapeutic interventions re-main to be established, limited data sug-gest that cognitive-behavioral therapies

may be useful for adults with ADHD.34

The benefit of pharmacotherapy forthe treatment of ADHD in children hasbeen established, but the usefulness ofmedication as a treatment for adultswith ADHD is not well established. Themedications used to treat ADHD mainlyaffect neurotransmission of catechol-amines, including dopamine and nor-epinephrine. A recent review of the lit-erature35 identified 15 studies (N=482participants) of stimulants, and 28 stud-ies of nonstimulant medications(N=1179 participants) including nor-adrenergic reuptake inhibitors, antide-pressants, and cholinergic agents thatmay be useful for the treatment ofADHD in adults (TABLE).

To date, the US Food and DrugAdministration approved the follow-

Table. Medications Used in Adults With Attention-Deficit/Hyperactivity Disorder

MedicationDaily

Dose, mg*Daily Dosage

Schedule Common Adverse Effects

StimulantsMethylphenidate 20-100 Twice to 4 times Insomnia

Decreased appetite/weight lossHeadachesEdginess

AmphetamineDextroamphetamine

and mixedamphetamine salts†

10-60 Twice to 3 times InsomniaDecreased appetite/weight lossHeadachesEdginessMild increases in pulse/bloodpressure

Magnesium pemoline 75-150 Once or twice InsomniaDecreased appetite/weight lossHeadachesEdginessAbnormal liver function test results

Noradrenergic agentsAtomoxetine 40-120 Once or twice Sleep disturbance

Gastrointestinal tract distress,nausea

HeadacheMild increases in pulse/blood

pressure

AntidepressantsTricyclics

Desipramine;imipramine

100-300 Once or twice Dry mouthConstipationVital sign and electrocardiographic

changes

Nortriptyline 50-200 Once or twice Dry mouthConstipationVital sign and electrocardiographic

changes

Bupropion 150-450 Once or twice InsomniaRisk of seizures (in doses

�6 mg/kg)Contraindicated in bulimia

*Denotes typical daily doses, which may exceed US Food and Drug Administration–approved dosing.†US Food and Drug Administration approved for adults with attention-deficit/hyperactivity disorder.



ing agents for adult-use only: mixedamphetamine compounds and thenoradrenergic specific reuptake inhibi-tor, atomoxetine. The stimulantmedications—amphetamine, methyl-phenidate, and pemoline—block thepresynaptic reuptake of dopamine andnorepinephrine resulting in accumula-tion of norepinephrine and dopaminein the synaptic cleft.36 Amphetaminealso releases dopamine and norepi-nephrine directly. Atomoxetine spe-cifically inhibits presynaptic norepi-nephrine reuptake resulting similarlyin increased synaptic norepineph-rine.37 Placebo-controlled clinical trialswith stimulants,38-40 atomoxetine,37

and the catecholaminergic antidepres-sants41 have demonstrated significantshort-term improvement in ADHDsymptoms.35 The stimulants methyl-phenidate and amphetamine are themost commonly used and are highlyeffective in a dose-dependent mannerfor adults with ADHD.36-38 The stimu-lants have an immediate onset ofaction and may last from 4 to 12 hoursdepending on the formulation of theagent ( immediate vs extendedrelease). Longer-term trials of methyl-phenidate use by adults support theongoing effectiveness and tolerabilityof stimulants.35 The most commonadverse effects with stimulants includeedginess, insomnia, headache, andmild increases in heart rate and bloodpressure necessitating monitoring.38-40

Atomoxetine may be particularly use-ful when anxiety, mood, or tics occurwith ADHD. Atomoxetine should bestarted slowly (0.5 mg/kg per day) andincreased to therapeutic dosing (40-120 mg/d) over 1 month. Commonadverse effects include gastrointestinalupset, mild increases in heart rate andblood pressure, and sexual dysfunc-tion in men.37 Other available medica-tions shown to be effective for adultswith ADHD include bupropion, desi-pramine, and pemoline, the latter 2requiring serum level (desipramine)or frequent liver function test (pemo-line) monitoring.35 A limited amountof data suggests that pharmaco-therapy may improve the driving skills

of adults with ADHD42 and may pre-vent the onset of substance abuse.43

Although taking medication is life-long, periodic reappraisals of the needto continue therapy are recom-mended. The lack of current symp-toms or impairments of ADHD in theunmedicated status is one signal, forexample, that medication may not benecessary any longer.

SummaryAttention-deficit/hyperactivity disor-der in adults can be validly and reliablydiagnosed. The clinical features arehighly reminiscent of the pediatric formof the disorder. Diagnosis is based onclinical assessment using the DSM-IVcriteria. Many adults with ADHD expe-rience co-occurring disorders and haveimpaired success in academic achieve-ment, career development, automobiledriving, and interpersonal relation-ships. Studies of biological features sup-port a genetic etiology for the disorderwith associated neuropsychologicaldeficits and catecholaminergic dysregu-lation. Emerging treatment strategies in-clude structured psychotherapies, stimu-lant, and nonstimulant medications.

Funding/Support: This work was supported by grantsR01 DA14419 (Dr Wilens) and R01MH57934 (Dr Fara-one) from the National Institutes of Health.

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I once had a sparrow land upon my shoulder for a mo-ment, while I was hoeing in a village garden, and I feltthat I was more distinguished by that circumstancethan I should have been by any epaulet I could haveworn.

—Henry David Thoreau (1817-1862)



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