Adhd Through Lyfe

Anthony L. Rostain, M.D., M.A. Attention DecitHyperactivity Disorder

Through The Life CycleAbstract: It is estimated that 5%8% of school-aged children and 4% of adults in the United States suffer from some

form of attention decit disorder and that the incidence of the disorder is increasing in the population. Although it is the

most widely studied behavior disorder of childhood, its etiology remains unclear, its outcome is variable, and its treatment

is both complex and moderately successful. Advances in neuroscience have provided new insights into the pathophysiology

of ADHD, pointing to key neural circuits involved in attention, behavioral control, learning, and reward maintenance that

appear to be underperforming in patients with the disorder. Moreover, the etiology of this heterogeneous disorder points to the

key role of genetic x environment interactions during prenatal and perinatal periods. Clinical assessment of ADHD requires

a comprehensive approach, including gathering a detailed developmental history, obtaining data from scales and structured

interviews, screening for comorbid conditions, and obtaining psychological testing where indicated. The mainstay of treatment

is a multimodal approach combining medications and psychosocial interventions that are tailored to the patient and familys

priorities. Optimal clinical care necessitates ongoing monitoring of treatment response and adverse reactions in a longitudinal

framework that is commonly used in managing chronic disorders.

DEFINITION

The most widely used denition of attentiondecit hyperactivity disorder is provided by theAmerican Psychiatric Associations Diagnostic andStatistical Manual, Fourth Edition (DSM-IV) (1),which outlines two major dimensions for the dis-order (see Table 1). Several changes being consid-ered for DSM-5 include raising the age at onset to12 years old, adding new criteria for impulsivity (e.g.acting without thinking, impatience, difcultyresisting temptations or opportunities), revisingthe number of criteria for adolescents and adults(e.g., 2-3 from each of the three categories) andremoving the exclusion for autism spectrum dis-orders.While the core 18 criteria will be unchanged,

descriptions will be added to contextualize them fordifferent age groups. There are also likely to bechanges in the subtypes of ADHD emphasizing thepresenting pattern of symptoms (2).

EPIDEMIOLOGY AND NATURAL HISTORY

It is now known that ADHD is a common neu-ropsychiatric disorder associatedwith awide range offunctional impairments throughout the lifespan (3,4). Between 5%8% of school-aged children (5)and 4% of adults (6) suffer from some form of at-tention decit disorder depending upon the methodof assessment. There are marked cross-national dif-ferences in prevalence rates due to variations in thecriteria used to make the diagnosis (7). A survey byKessler et al. (8) revealed that 36.3% of childrenmeeting the criteria for ADHD continued to meetfull diagnostic criteria for the disorder as adults andabout two thirds of all children with ADHD con-tinue to have residual symptoms into adolescenceand adulthood (9).Inattention is a prominent featurein more than 90% of adults (10). ADHD is associ-ated with impairments in educational, occupational,

Author Information and CME DisclosureAnthony L. Rostain, M.D., M.A. University of Pennsylvania Perelman School of Medicine

Dr. Rostain reports the following: Consultant and Advisor: Shire Development.

Address correspondence to Anthony L. Rostain, M.D., M.A., Director of Education, Department ofPsychiatry, University of Pennsylvania Health System, 3535Market Street, Room 2007, Philadelphia,PA 19104; e-mail: [email protected]

266 Summer 2012, Vol. X, No. 3 F O C U S THE JOURNAL OF L I F E LONG LEARN ING IN P SYCH I ATRY

neuropsychological, and social functioning in adults(11). Adults with ADHD tend to have more fre-quent job changes and work difculties; lower so-cioeconomic status; higher rates of marital problemsand divorce; and more speeding violations, driverslicense suspensions, and automobile accidents thanthose without ADHD. Therefore, the successfuldiagnosis and management of the disorder in adultsis of great importance.

ETIOLOGY

ADHD is a heterogeneous neurobehavioral dis-order with multiple likely causes. Approximately

65%75% of cases are thought to be due to ge-netics, with another 10%15% caused by CNSinsults from prenatal, perinatal, and postnatalsources (12, 13). Prenatal causes include maternalcigarette smoking (which increases the odds by 2.5times), maternal alcohol drinking (2.5 odds ratio),premature birth (with an incidence of 45% whenintracerebral hemorrhage occurs), maternal re-spiratory infections, maternal anxiety, and highmaternal phenylalanine levels. Perinatal asphyxia oranoxia also increases risk of ADHD. Contrary topopular myth, cocaine or crack exposure does notadd risk when other variables are controlled. Post-natal factors associated with ADHD include head

Table 1. DSM-IV Diagnostic Criteria for Attention-Deficit / Hyperactivity Disorder

A. Either (1) or (2)

1. six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistentwith developmental level:

Inattention

a. often fails to give close attention to details or make careless mistakes in schoolwork, work or other activities

b. often has difficulty sustaining attention in tasks or play activities

c. often does not seem to listen when spoken to directly

d. often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositionalbehavior or failure to understand instructions)

e. often has difficulty organizing tasks and activities

f. often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework)

g. often loses things necessary for tasks or activities (e.g. toys, school assignments, pencils, books, or tools)

h. is often easily distracted by extraneous stimuli

i. is often forgetful in daily activities

2. six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for at least 6months to a degree that is maladaptive andinconsistent with development level

Hyperactivity

a. often fidgets with hands or feet or squirms in seat

b. often leaves seat in classroom or in other situations in which remaining seated is expected

c. often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjectivefeelings of restlessness

d. often has difficulty playing or engaging in leisure activities quietly

e. is often on the go or often acts as if driven by a motor

f. often talks excessively

Impulsivity

g. often blurts out answers before questions have been completed

h. often has difficulty awaiting turn

i. often interrupts or intrudes on others (e.g. butts into conversations or games)

B. Some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7 years

C. Some impairment from the symptoms is present in two or more settings (e.g. at school [or work] and at home)

D. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning

E. Symptoms do not occur exclusively during the course of a psychotic disorder and are not better accounted for by another mental disorder

F. Types of ADHD

1. Combined - if both criteria A1 and A2 are met for past 6 months

2. Predominantly Inattentive Type - if only Criterion A1 is met for past 6 months

3. Predominantly Hyperactive-Impulsive Type - if only criterion A2 is met for past 6 months

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trauma, brain hypoxia, CNS tumors, CNS in-fection, febrile seizures, lead poisoning, pediatricacute lymphoblastic leukemia (ALL), streptococcalinfection, and elevated phenylalanine levels.There is a large and growing body of literature on

the genetic basis of ADHD dating back over 30 years.Early family, twin, and adoption studies have con-verged on a mean heritability of 0.75, which placesADHDjustbelowautistic-like traits (0.82-0.87)andschizophrenia (0.80-0.85). Recent family-based andcase-control studies of candidate genes have showna statistically signicant correlation betweenADHDand variants of seven genes: serotonin HTR1Breceptor, serotonin transporter, synaptosomal-associated protein 25 (SNAP 25), dopamineb-hydroxylase, dopamine transporter, dopamineD5 receptor, and the dopamine D4 receptor. Oneparticular common variant of the dopamine D4receptor (7-repeat) has been highly studied andfound to increase risk for ADHD when coupledwith both dopamine transporter (SLC6A3 10 re-peat) and maternal exposure to smoking (14). Thepresence of each of these along with maternalsmoking increases the risk of ADHD by 2.5 3.0times. The presence of both of them along withsmoking increases the risk to 9 times (15, 16).

NEUROANATOMY / PATHOPHYSIOLOGY

Studies over the past several decades suggest thatADHDresults fromdisruptions in several keyneuralcircuits involving the frontal lobe, anterior andmedial to the precentral motor cortex. The motorcircuit includes a subcortical feedback loop fromthe motor and somatosensory areas of the cortex,through restricted portions of the basal ganglia andthalamus, and back to the premotor cortex, sup-plementary motor area, and motor cortex. In addi-tion, the locus ceruleus appears to play a major rolein the initiation and maintenance of attention, par-ticularly in response to novel stimuli. Two majorsubsystems are involved in attention regulation:a posterior system which disengages from currentenvironmental stimuli in order to orient to newstimuli, and an anterior system which works to in-tegrate the various executive functions of the frontallobe. Imbalances in these pathways have also beenimplicated in ADHD.Pliszka et al. (17) proposed an interesting model

in which ADHD is hypothesized to be caused byimbalances in catecholamine functioning through-out several brain regions. The central norepinephrinesystem (via the locus coeruleus) may be hypoactive,causing insufcient response of the posterior at-tention system to novel stimuli. The dopaminergi-cally mediated anterior attention system (governing

executive function) may also be underactive, leadingto poor planning, faulty working memory, lack of at-tention to details, and inefcient problem-solving.The peripheral epinephrine system is also hypothe-sized to play a role in mediating the individuals re-sponse to psychostimulant medication. The beautyof this multistage model is that it integrates neuro-chemistry, neuroanatomy and neurophysiology. Italso helps to explain why neurotransmitter studieshave failed to show a specic deciency pattern inpatients with ADHD.Several reviews of the neuroanatomy of ADHD

(1821) suggest three related circuits that may bedysregulated in this disorder. The fronto-striatalcircuit is associated with decits in response sup-pression, freedom from distraction, working mem-ory, organization, and planning. The fronto-limbiccircuit is associated with symptoms of emotionaldyscontrol, motivation decits, hyperactivity-impulsivity, and proneness to aggression. And thefronto-striatal-cerebellar circuit is associated withmotor coordination decits, and problems with thetiming and timeliness of behavior (see Figure 1).Neuropsychologicaldecits seen inADHDsuggest

the involvement of the prefrontal cortex (especiallyin the right hemisphere) where classical studies ofpatientswithdamage to this area showpatterns of lossof working memory, forgetfulness, increased sus-ceptibility to interference, distractibility, poor con-centration, impulsivity, and poor organization. Thishas led to a growing recognition of ADHD as a de-velopmental disorder of executive functioning (EF)(22, 23) although there is as yet no consensus onthis point (24). EFs are a wide range of central con-trol processes previously referred to as frontal lobefunctions that connect, prioritize, and integratecognitive functions on a moment-by-moment basis.Brain structures and interconnections subserving EFare immature at birth and undergo continuous de-velopment into early adulthood. This maturationprocess depends upon mylenization, synaptic prun-ing, elaboration of DA & NE systems, and otherdevelopmental processes. Thus, EF can become im-paired developmentally, traumatically, and/or sec-ondary to disease processes.Structural and functional neuroimaging studies

over the past two decades have shown smaller, lessactive, and less developed brain regions in three areas:the orbital prefrontal cortex (primarily right side), thebasalganglia (mainly the striatumandglobuspallidus)and the cerebellum (central vermis area, more onright side). In addition, the anterior cingulate gyrushas been shown to be under-activated in ADHDpatients who are performing an error detection task.The size of the attentional network is correlated withdegree of ADHD symptoms, particularly inhibition.


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Interestingly, there appears to be a 3 year lag in braindevelopment with patients achieving typical brainvolumes by age 16. Moreover, these results are notdue to taking stimulant medication (15).The neurochemical evidence for ADHD is con-

tradictory at best. Urine, serum, and cerebrospinaluid metabolites of serotonin, norepinephrine, anddopamine are not consistently different in ADHDpatients as compared with matched controls. Do-pamine beta hydroxylase, monoamine oxidase, andcatechol-O-methyl transferase are also similar inthese two groups. There is some evidence for a de-creased turnover of dopamine (DA) and for a super-sensitivity to released DA in ADHD patients. Morerecently, researchers have demonstrated a reductionof DA synaptic markers in the DA reward pathways(mesoaccumbens) of ADHD individuals, whichmayexplicate the chronically diminished motivationalstate that many patients experience (25). Pharma-cologic studies with dopamine agonists, however, failto demonstrate a primary deciency of dopamine.The most signicant pharmacologic effects onADHD symptoms have been found with stimulants

such as methylphenidate and dextroamphetamine,both of which work on catecholamine metabolism,lending strong support to some role for both nor-epinephrine and dopamine in this disorder.

DIFFERENTIAL DIAGNOSIS

ADHD is associated with a variety of otherpsychiatric problems, and numerous psychiatricconditions can present as attention difculties.Comorbidity has become an important area of re-search in recent years, as studies reveal that highpercentages of children and adolescentswithADHDexperience other disturbances such as oppositionaldeant behavior, conduct disorder, and aggressivebehaviors; mood disorders (particularly depressionand bipolar affective disorder); anxiety disorders;learning disabilities and language disorders; and,among adolescents and young adults, substanceabuse and personality disorders. Special patientpopulations have high rates of ADHD in-cluding those with Tourette syndrome, obsessive-compulsive disorder, autistic spectrum disorders,

Figure 1.

PREFRONTAL LOOP

Dorsolateralprefrontal cortex

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Anteriorcingulate cortex

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Motor cortex

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Putamen

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anterior nuclei

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Attention responsesBehavioral organization

ReinforcementExtinction

Response coordinationNondeclarative habit learning

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fetal alcohol syndrome, and posttraumatic stressdisorder (3, 26) [See Table 2]. In adults, comorbidconditions are also the rule rather than the excep-tion, with even higher rates of alcohol and substanceabuse and dependence, mood disorders and anxietydisorders reported (6).Seizure disorders, including petit mal (absence) or

partial complex seizuresmay bemistaken forADHD.Sensory deciencies, particularly deafness and partialhearing impairment, can also mimic ADHD. Ap-proximately 40%50% of ADHD children sufferfrom a learning disability of sufcient magnitudethat school performance is negatively affected. Inadults, a number of medication conditions can ei-ther cause or worsen ADHD symptoms includinghead injury (TBI), sleep apnea, COPD, anoxic

encephalopathy, dementia, delirium, hypothyroidism,hyperthyroidism, renal insufciency, hepatic insuf-ciency, vitamin decient states, and medication-induced cognitive impairments (see Table 3).

ASSESSMENT

CHILDREN AND ADOLESCENTS

The diagnosis of ADHD is made by a compre-hensive clinical evaluation that should include in-terviews of parent(s) and patient, and the gatheringof collateral information from teachers and schoolrecords. Assessment beginswith a careful descriptionof the child or adolescents problem behaviors.When interviewing parents, it is important that theygive examples of situations in which the child orteen is having difculty. Terms like hyperactive,disruptive, and impulsive should be dened asprecisely as possible. When parents report that thepatient wont sit still, wont pay attention, andwont follow instructions, it is helpful to nd outwhen they rst became aware of these difculties. Italso helps to clarify if the problems occur both athome and at school. Parents should describe theirstrategies for handling these behaviors, and sharetheir insights into what works and what doesnt.Additionally, the clinician should review all 18symptoms of ADHD and ask the parent to describethe presence or absence of these symptoms, giveexamples, and clarify their onset and course.In addition to the cardinal signs of inattention,

impulsivity, and hyperactivity, the clinician shouldinquire about the degree of oppositional behavior,aggressiveness, moodiness, and temper outbursts thatthe child or teen is manifesting. Whenever possible,parents should be observed interacting with theirchild. The clinician should note how the child ad-dresses the parents, and whether s/he listens to theirinstructions and commands. If the patient begins tomisbehave in the ofce, this is an opportunity to learnhow parents handle challenging behaviors.After the problem description, a comprehensive

history should be obtained including pregnancy;perinatal period; medical history; developmentalmilestones; speech and language function; sleeppattern; presence of pica, enuresis or encopresis;early temperament; and diet and medications. Socialand family history should include an inquiry into thepresence of ADHD, learning disabilities, and otherdevelopmental/or psychiatric disturbances in theparents or siblings. Finally, the patients schoolhistory should be traced, especially regarding be-havior and achievement in the early grades. Copiesof old report cards and of teachers descriptions of

Table 2. Conditions Seen With ADHD

Oppositional Defiant Disorder

Conduct Disorder

Anxiety Disorders

Mood Disorders

Bipolar Disorder

Major Depression

Dysthymia

Learning Disorders

Language Disorders

Tourette Syndrome

Obsessive Compulsive Disorder

Autistic Spectrum Disorders

Fetal Alcohol Syndrome

Sleep Disorders

Substance Use Disorders

Post-Traumatic Stress Disorder

Table 3. Medical Conditions ComplicatingADHD in Adults

Head injury (TBI)

Sleep apnea

COPD

Anoxic encephalopathy

Dementia

Delirium

Hypothyroidism

Hyperthyroidism

Renal insufficiency

Hepatic insufficiency

Vitamin deficient states

Medication induced


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the child are extremely valuable. It is also importantto speak directly to the current teacher to learnabout the patients typical behavior in class, and tounderstand how the teacher views and handles thechild or teen.Parent and teacher rating scales are extremely

useful as adjuncts to the diagnostic interview. Thereare numerous instruments available (27); however,no single scale is perfect, nor can any scale makea diagnosis of ADHD. Scales offer a relatively quickmeasure of the youths behaviors as compared withthose of age- and sex-matched peers. They can alsobe used to measure change in targeted areas fol-lowing the initiation of treatment (3).Minor congenital anomalies, general neurologic

status, speech and language functioning, and overallmental status are important to evaluate. Signs offetal alcohol effects should be noted, and thepresence of unusual physical stigmata is an in-dication to order chromosome analysis. Thepatients speech and receptive language abilitiesare important to screen insofar as communicationdisorders and learning disabilities can be present inchildren and adolescents with ADHD. In additionto hyperactivity, inattentiveness, and impulsivity,the mental status examination should note signsof affective disturbance (i.e., anxiety, depression,irritability), autism and other developmental dis-orders, and general intellectual functioning.Standard grade-level screening tests (e.g., SlossonOral Reading Test) and perceptual motor tasks(including drawings and the Bender-Gestalt) canprovide additional information regarding the pa-tients cognitive abilities. These steps can help theclinician assess the child as well as help to rule inor rule out co-occurring conditions or conditionsthat may mask themselves as ADHD.For the most part, medical laboratory tests are of

little value in making the diagnosis of ADHD. Sincepatientswithmildly elevated lead levels (i.e., 10mg/dl)may show signs of ADHD, plasma lead level, freeerythrocyte protoporphyrin, and a complete bloodcount should be obtained at the initial visit in orderto rule out lead poisoning and iron deciency anemia.If there is suspicion of absence seizures or other neu-ropathology, an EEG is indicated. Evidence of alteredmetabolism (e.g., elevated resting heart rate, palpita-tions, tremors, agitation) suggests that a thyroid paneland a urine screen for VMA should be obtained.Psychoeducational testing of intellectual ability

and of scholastic achievement can pinpoint cogni-tive difculties which may be interfering with thepatients school performance. Speech and langu-age assessment is indicated for patients who seemto have communication problems. And whilecomputerizedmeasures of attention and impulsivity

are not required to make a diagnosis, they may behelpful in quantifying the symptom prole and inevaluating the effects of intervention.

ADULTS

Diagnosing ADHD in adults necessitates a com-plete evaluation, focusing on the core ADHDsymptoms starting in childhood (28) especially asthey may have affected academic achievement, so-cial relationships, and self management skills. It isimportant to elicit details of early school experiencesand to track these throughout the patients academiccareer. It can be useful to explore the degree of as-sistance and support provided by key adults (e.g.,parents, teachers), the patients changing symptompatterns and responses to these, and the impactof these on academic achievement, occupationalchoices, job performance, intimacy, and self-esteem. Rating scales such as the Wender UtahRating Scale (29), the Brown Attention-DecitDisorder Scale for Adults (30), the Conners AdultADHD Rating Scale (CAARS) (31), and the AdultSelf-Report Scale (32) are extremely important inthe assessment of past and current ADHD symp-toms in adults with suspected ADHD (33)[See (34)for an excellent comparative review]. Measures ofintellectual ability and academic skills may behelpful in gauging the likely success of occupationalaspirations and job performance. Object measuresof attention and impulsivity may help to clarify thepatients symptom severity but are not required forgeneral clinical practice.Given the very high rate of comorbidities seen in

this patient group, a thorough medical history is ofcritical importance in determiningwhether there areany medical conditions that could confound thediagnosis of ADHD (27). Equally important, a de-tailed history of drug and alcohol use and of otherpsychiatric disorders should be taken. Throughoutthe entire procedure, collateral observational in-formation should be obtained from spouse, signi-cant other, parent, or friend. This is important toverify the patients story (hence reducing the chanceof missing factitious disorder) and to corroborateand/or add important clinical data that the patientmay have missed or forgotten.

TREATMENT

CHILDREN AND ADOLESCENTS

Practice guidelines for the treatment of ADHDhavebeendevelopedbyanumberofworkinggroups,including the American Academy of Child and


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Adolescent Psychiatry (27), the American Academyof Pediatrics (35), the British Association for Psy-chopharmacology (36), the Canadian ADHD Re-source Alliance (37), the European Network forHyperkinetic Disorders (38), the National Institutefor Health and Clinical Excellence (39), and theNational Institutes of Health (40). All of thesepractice parameters stress the importance of amultimodal treatment approach to patients withADHD.Multimodal treatment of children and adolescents

with ADHD includes careful treatment planning,psychoeducation, medication, behavior manage-ment, school-based interventions, family therapy,and social competence training. While the precisecombination of these interventions will vary de-pending upon the needs of the patient and family, itis clear that no single treatment approach is sufcient,and that in order to be effective, treatment mustextend over long periods of timeTreatment planning needs to incorporate patient/

family priorities and available resources and identifypotential obstacles to successful treatment adher-ence. In addition, systems issues must be taken intoconsideration so that professional helpers can formconstructive relationships with patient/family, schoolpersonnel, key community supports, and with oneanother in order to maximize chances for successfultreatment.The goal of psychoeducation and counseling is

to help parents and youth cope better with the con-sequences of having ADHD. Patients/families need

reliable information and supportive guidance whenconfronted with the diagnosis of ADHD. It is im-portant that the clinician offer the patient and familysufcient time to discuss their concerns and answertheir questions. Factual information should beprovided in a comprehensible fashion so as to clarifyany misunderstandings or confusion about the dis-order. The clinician should emphasize the childspositive traits and the parents strengths in order toalleviate feelings of guilt, confusion, and anger.While parents are likely to be relieved to hear thattheir childs problems are not the result of inad-equate parenting, they are also likely to experiencegrief reactions as they learn more about the impli-cations of the diagnosis. While children may bepleased to hear their problems are not their fault,they are also likely to feel ashamed and resentfulabout having something wrong with them, andthey may resist taking their medication or partici-pating in behavioral treatment. It is important forthe physician to monitor the emotional reactions ofparents and children, and to be supportive of theirefforts to pursue treatment. There are numerousreferences written for parents that are very helpful inexplaining the diagnosis and treatment of ADHD,which are available on websites sponsored by theCenters for Disease Control, National Instituteof Mental Health, and CHADD (Children andAdults with Attention Decit/Hyperactivity Dis-order. These include resources like the ParentsMedication Guide for ADHD, coauthored by theAPA and the AACAP [see website listings inReference section]. Support groups for parents ofchildren with ADHD have proliferated in recentyears. These groups holdmeetings, sponsor lectures,publish newsletters, and offer emotional assistanceto families. Clinicians should be familiar with localchapters of CHADD and similar organizationsand should have their contact information readilyavailable for patients and families.Pharmacotherapy. At present, there are numer-

ous FDA-approved medical treatments for ADHD(Table 4). While medications have been shownto provide short-term benets for children andadolescents with ADHD, longitudinal studies in-dicate that pharmacotherapy is only one aspectof treatment and that without behavioral inter-ventions, the childs difculties at home and atschool are likely to persist. The decision to usemedication is mediated by several factors, includingthe childs age, severity and prole of the childssymptoms, comorbidity, and parental attitudes.Children under 5 years of age are less likely torespond to medications and are at greater risk ofhaving adverse side effects, suggesting that behav-ioral interventions are an important rst step with

Table 4. FDA Approved Medications forADHD

Medication Duration of effect

Methylphenidate-based formulations

Concerta (methylphenidate) 12 hoursRitalin (methylphenidate) 3-4 hours

Metadate CD (methylphenidate) 8-10 hours

Ritalin LA (methylphenidate) 8 hoursFocalin (XR) (dexmethylphenidate) 3-4 (8-10) hours

Daytrana (methylphenidate) 12 hours (worn for 9)Amphetamine-based treatments

Adderall XR (mixed amphetamine salts) 12 hoursAdderall (mixed amphetamine salts) 4-6 hours

Dexedrine Spansule (dextroamphetamine) 6-8 hours

Vyvanse (lisdexamfetamine) 12 hoursNonstimulants

Strattera (atomoxetine) Up to 24 hours

Intuniv (guanfacine) Up to 24 hours

Kapvay (clonidine) Up to 24 hours


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this age group (41). School-aged children withmoderate to severe symptoms of inattention anddistractibility (with or without impulsivity andhyperactivity) are extremely likely to benet frommedication. Children with mild symptoms are alsolikely to benet, although it is usually preferableto initiate behavioral treatment prior to startingmedication with this group. The presence of otherdisturbances such as tics, anxiety, aggression, ordepression tends to inuence the choice of phar-macologic agent. Finally, parental attitudes areextremely important to consider when recom-mending medication. Most parents are ambivalentabout starting their child on medication, so it is bestto give them ample time to consider the decisioncarefully. The following guidelines are suggestedwhen instituting a medication regimen:

1. Specify the target behaviors that the medi-cations are intended to ameliorate. Wherepossible, measure the behaviors; otherwise, useparent and teacher rating scales.

2. Obtain baseline laboratory measures such asCBC, serum electrolytes, and liver functiontests.

3. Begin with low doses, increase gradually, andaim for the lowest effective dose possible.

4. Follow side effects closely, and discontinue themedication if no positive effects are seen or ifside effects become severe.

5. Discuss the child reactions to and parentsfeelings about the medication. Give supportand encouragement if initial results are not asgood as expected.

6. Document benecial and adverse effects on aregular basis.

Algorithms have been developed to guide the se-lection of medication regimens according to bestavailable evidence (42), most of which suggest thatclinicians initiate treatment with a stimulant med-ication and only if there is insufcient responseshould alternative medications be introduced (Fig-ure 2).Psychostimulants. Psychostimulants have direct

and indirect agonist effects on -adrenergic andb-adrenergic receptors as well as on dopaminergicreceptors via three mechanisms: release of storedcatecholamines (dopamine and norepinephrine);agonist effects on postsynaptic receptors; and in-hibition of presynaptic reuptake of released cate-cholamine (note: methylphenidate works primarilyvia mechanism 3, whereas amphetamine works viaall three mechanisms [see Figure 3]).Over 80% of patients with ADHD demonstrate

a positive response to psychostimulants, although it

is impossible to predict in advancewhichmedicationwill produce the best results for any given patient.Clinical effects include reduced hyperactivity andimpulsivity, improved attention and concentration,improved ne motor skills (including handwriting),and improved social interactions (e.g., reducedoppositional behaviors). Behavioral measures ofcognitive performance with psychostimulantsdemonstrate improvements in attention span, im-pulse control, short-term memory, and problemsolving. These results are seen in both patients withADHD and controls, so a positive response cannotbe used to diagnose ADHD. In general, whilecognition of ADHD patients can be optimized bythe medication, this improvement can be eradicatedwith improper dosing.Up to 5% of patients will experience adverse effects

serious enough to warrant discontinuation of themedication. Adverse effects include appetite sup-pression, gastrointestinal discomfort, sleep distur-bance, increased heart rate and blood pressure(clinically insignicant), tics, and minor physicalcomplaints (e.g., headaches, stomach-aches). Irri-tability, dysphoria, heightened anxiety, lack ofspontaneity andover-sedationmaybe seen,but theseare often due to overmedication. It appears thata subgroup of patients who respond with intensemood lability and dysphoria may be expressing earlysigns of a mood disorder rather than ADHD. Thisshould prompt a change in medication and closemonitoring (43, 44).Extremely serious side effects such as delusions,

paranoia, and frank psychosis are rare but can be seenwith over-dosage and abuse of the medication.Concerns have been raised about cardiovascular sideeffects of stimulants, although recent reports seem toindicate that there are few, if any, serious adversecardiac events due to stimulant use (45, 46). Currentrecommendations include careful screening for car-diac symptoms in the patient (e.g., dyspnea, pa-lpitations, and exercise intolerance), for abnormalphysical ndings, and for family history of prematuredeaths or signicant morbidity from heart disease.Clinical and biochemical predictors of nonre-

sponse or adverse effects have not yet been identi-ed, although there is some evidence of diminishedefcacy of stimulants in ADHD children withsymptoms of anxiety (42). On the other hand, itappears that stimulants are helpful in reducingthe aggressive behavior of conduct disorderedADHD children. There are also studies suggest-ing that stimulant treatment in childhood andadolescence reduces the risk of later alcohol orsubstance abuse.Discussions with parents and teachers are helpful

to identify any incipient problems with stimulant


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Figure 2. ADHD Treatment Algorithm

Stage 0

Stage 1

Diagnostic Assessment andFamily Consultation Regarding

Treatment Alternatives

Methylphenidate or Amphetamine

Any stage(s) can be skippeddepending on the clinical picture.

Non-MedicationTreatment Alternatives

Stimulant not used in Stage 1

AMP formulationnot used in Stage 1

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Atomoxetine

AMP formulationnot used in Stage 2

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Bupropion or TCA

Combine stimulantand atomoxetine

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in Stage 2)

Response

Response



Stage 4

Agent not used in Stage 4

Alpha Agonist

ClinicalConsultation



Stage 5

Stage 6

Response

Response

Maintenance

AMP = AmphetamineDEX = DextroamphetamineMSA= Mixed salts amphetamineTCA= Tricyclic antidepressant

Continuation

Continuation

Continuation

Continuation

Continuation

Reprinted with permission from: The Texas Children's Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder.Pliszka SR, Crismon ML, Hughes CW, Corners CK, Emslie GJ, Jensen PS, McCracken JT, Swanson JM, Lopez M; Texas Consensus Conference Panel on Pharmacotherapy ofChildhood Attention Deficit Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2006 Jun;45(6):642-57.


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medication. It is also important to decide upon thetype and frequency of medication use. For example,most long-acting medications are sufcient to im-prove concentration during the school day, but anadditional dose of a short-acting preparation is oftenprescribed to help the child complete homeworkassignments in the late afternoon and early evening.Weekend dosing assists ADHD children with par-ticipation in team sports, social events, church ac-tivities, and instructional programs. It also enablesthem to complete homework assignments and studyfor examinations. For teenagers who drive, weekenddosing is essential to minimize the risk of hazardousdriving and accidents.After several weeks on a steady dose and schedule,

it may be necessary to increase the dose slightly. Thegoal of treatment should be symptom remission,which often necessitates steadily titrating the doseupwarduntil either symptoms improveor signicantadverse effects emerge. If there is no clear positiveresponse to the initial stimulant chosen, or if sideeffects emerge thatmight interfere with adherence asthedose is increased, it is advisable to introduce otherstimulant preparations before additional pharma-ceutical agents are introduced. Using parent- andteacher-report rating scales to track symptom re-sponse tomedicationcanbeveryhelpful.Aboveall, itis important to continuously monitor progress to-ward target goals and to adjust the medication reg-imen accordingly.

For the most part, children can be maintainedon the same dose for up to 6 to 12 months. It isimportant to monitor clinical and adverse effects ona regular basis. Height, weight and blood pressuremeasurements and a brief physical examinationshould be conducted approximately every 2 monthsif things are going smoothly. If the childbegins losingweight, the dose and schedule should be revisedin order to optimize appetite around mealtimes.Growth delay, although rarely seen with currentdosage recommendations, is an indication for stop-ping themedication for several weeks to allow catchup growth to take place.One of the most common problems seen with

stimulants is referred to as rebound. This is gen-erally seen in the late afternoon as the medicationwears off. Typically, the child becomes restless,hyperactive, inattentive, irritable, and prone totemper tantrums and emotional outbursts. It is of-ten helpful to add an additional slightly lower dosewhen the child returns from school. Parents shouldbe advised to allow the child to do something en-joyable and to avoid making too many demands onthe child during this time. If the rebound periodbecomes extremely difcult for the child and familyto handle, it may be necessary to switch medicationsor introduce longer acting preparations.Atomoxetine. Atomoxetine is the rst non-

stimulant medication to be FDA approved forthe treatment of ADHD. A norepinephrine (NE)

Figure 3. Mechanism of Action of Stimulant Medications

NEURON (Presynaptic)

SYNAPSE

AMPH

MPH and AMPHInhibit

Cytoplasmic DA

DA TransporterProtein

AMPH diffuses intovesicle causing DArelease into cytoplasm

AMPH is taken upinto cell causing DArelease into synapse

AMPH blocksuptake into vesicle

Storagevesicle


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reuptake inhibitor, it has been shown to have amoderate effect size (0.4 0.6) in numerous studiesinvolving children, adolescents and adults withADHD (47, 48). The advantages of atomoxetineare its milder side effects prole (compared withstimulants), and the absence of potential for abuseor misuse. Increased CNS NE levels resulting fromthis medication are associated with downstreamincreases in dopamine (DA) levels in the frontalcortex without concomitant changes in levels foundin the nucleus accumbens or the basal ganglia (49,50). Recent studies suggest that atomoxetinemay behelpful in patients with comorbid anxiety (51), and/or tic disorders (52). An open trial of atomoxetine inchildren and adolescents with dyslexia showedimproved reading task performance (53). Sideeffects include: dizziness, high blood pressure,headache, irritability, nervousness, abdominal pain,nausea, vomiting, loss of appetite, weight loss, drymouth, constipation, urinary hesitancy, decreasedsexual desire and a very slight chance of reversiblehepatic insufciency.Alpha-adrenergic agents (Clonidine,

Guanfacine). Alpha2 adrenergic agonists wererst introduced as antihypertensive agents over 40years ago but were supplanted by other medications(e.g., calcium channel blockers) with fewer sideeffects.Their effects on theCNSincludemodulationof the tonic and phasic activity of the locus coeruleus(major source of NE in the brain) and enhancedadrenergic activity in the prefrontal cortex. Theireffects on NE neurotransmission occur via up-regulation of intracellular cyclic adenosinemonophosphate (cAMP) which, in turn, improvessignal conduction along the axon (54, 55).Clonidine works on alpha2A, 2B, and 2C re-ceptors (which are located throughout the CNS,including the brain stem), leading to its producingmore hypotensive and sedative effects thanguanfacine, which is selective for the alpha2Areceptors. Extended release clonidine has beenfound to help ADHD symptoms either alone (56)or in conjunction with psychostimulants (57).Clinical trials of extended-release guanfacine haveshown it to be effective as monotherapy forADHD in children and adolescents (5860).Recent studies have shown guanfacine can becombined with stimulants to produce enhancedclinical effects in children and adolescents withsuboptimal response to stimulants alone (61, 62).Clinical experience with these agents suggests that

they are especially useful in reducing irritability,overarousal, emotional lability, and explosivenessin patients with ADHD. They are also helpful incontrolling tics and managing high blood pressure.The most common side effects seen with alpha2

adrenergic agonists are sedation, fatigue, dizziness,syncope, cardiac rhythm disturbances, dry mouth,indigestion, nausea, nightmares, insomnia, anxiety,dysphoria, and depression. In addition, hypertensivecrises can be induced by sudden discontinuation ofthese medications.Psychosocial Interventions. Whereas youth with

ADHD have trouble controlling their impulses,focusing their attention and following rules, parentsneed to learn basic methods of managing thesechallenging behaviors. Using techniques such aspositive reinforcement, rewards, response cost, pun-ishments, contracts, token economies, extinctionprocedures, environmental manipulation and stim-ulus controls, parents can be taught to exert a positiveinuence on behavior.The rst step in developing a behavior manage-

ment program is to specify which behaviors are ac-ceptable and which ones need to be modied. It isimportant that parents learn to focus more of theirattention on the childs positive behaviors, and tocatch them being good as often as possible. Byshifting more energy and attention to the childsgood behaviors, parents and teachers will in-evitably spend less time harping on the bad.Next,parents choose a specic behavior (or behavior se-quence) that they would like to change. Theyshould describe the behavior in ways they can ob-serve and measure. It is generally best for parents tobegin by focusing on a relatively simple behaviorwhich is easy for the child to perform and for theparents to observe and quantify. Behaviors likegetting ready in the morning, doing homework,putting toys away, completing chores, temper tan-trums, and getting ready for bed are good forstarters. It is also important for them to considerfactors that prevent the child from successfullycompleting tasks.Once a target behavior is chosen, parents will need

to identify ways to increase the childs motivation tocooperate. Rewards should be given for successfulefforts, and penalties should be given for overt re-sistance or major oppositional behavior. An ac-counting system must be set up to keep track of thechilds performance and to distribute the rewardsand penalties in an impartial fashion. It is importantthat parents not get angry or upset with the childwhen they are administering a penalty. After parentshave decided upon the rewards and penalties, it isadvisable for them to draw up a contract. Thecontract should include the date on which theagreement begins, the specic behaviors that arebeing targeted for change, the types of rewards andpenalties that will be used to enforce the contract,the accounting system that will be used to keeptrack of rewards and penalties, the time and


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frequency of rewards, the start and duration ofpenalties, and the schedule for reviewing the con-tract. The contract should be written in a languagethat the child can understand, and should be postedin a prominent place in the home. Once it has beendiscussed and reviewed, the contract should besigned by everyone who will be involved in its en-forcement (including other adults).After the contract becomes operational, its efcacy

will need to be closely monitored, and its terms willneed to be rened and corrected in order to ensurethat it is helping the child to achieve desired behaviorchanges. The child should succeed at the desiredbehaviors 80%of the time. If s/he is succeedingmoreoften, the task shouldbemademoredifcult; if less, itshould be made easier.It should always be kept in mind that the purpose

of any behavior management system is to help thechild learn to follow rules and to complete importanttasks.This is amajor challenge formost childrenwithADHD,andparentswill need toworkverydiligentlyto keep a behavior management program running.Although it takes a great deal of patience, re-sourcefulness and perseverance, parents can lookforward to modest rewards for the child and thefamily. If the program succeeds in improving thechilds ability to care for him/herself and in in-creasing his/her self-control, it will have the addedbenets of reducing stress and improving the emo-tional climate of the family.Classroom behavioral interventions have been

developed to improve both classroom deportmentand academic performance. The best studied havebeen daily report cards and contingency manage-ment programs with effect sizes in the range of 1.44(63). Classroom academic interventions seem tohave moderate benecial effects, although these arenot as well studied and sample sizes are small. Themost common interventions include task and in-structional modication, homework assistance, peertutoring, computer-assisted instruction, and strat-egy training (for an excellent review, see (64)).More

recent innovations include family-school inter-ventions that promote close collaboration betweenparents and teachers in order to achieve improvedacademic performance and classroom behavior (65).Recently, computer-assisted programs have been

introduced to enhance cognitive functioning inchildren and adolescents with ADHD. The beststudied of these, CogMed, is a software programdeveloped by Klingberg and colleagues at the Kar-olinska Institute. It entails web-based training ona series of rotating exercises designed to enhancevisuospatial and verbal working memory, ve timesper week for 30-40 minutes. Initial results of ran-domized controlled trials show modest improve-ments in these domains (66, 67).

TREATMENT CONSIDERATIONS FOR ADULTS WITHADHD

Treatment guidelines for adults with ADHD arestill evolving, but there is a growing consensus thatmultimodal approaches similar to those used withchildren and adolescents are the most likely to ad-dress the multiplicity of issues that these patientspresent to clinicians.Pharmacotherapy. The most important step

before startingpharmacotherapy forADHDadults isthorough education. To begin with, the objectivesfor using medications need to be claried by de-lineating the target symptoms that are the focus oftreatment (e.g., inattention, distractibility, restless-ness, and impulsivity).Next, amethod formeasuringand keeping track of symptom improvement needsto be agreed upon. It is best to have the patient keepa log that is user friendly and likely to be imple-mented (Table 5). Once a medication is selected,both written and oral information is provided to thepatient, and specic plans are discussed for startingthe medication. Typically this means starting at arelatively low dose, observing initial clinical effects,noting side effects, and setting a schedule for in-creasing the dosage to appropriate levels. Frequent

Table 5. Sample Patient Self-Report ADHD Medication Response Form

Medication response form Patient name

Medication Dose, schedule

Instructions to patient: Rate concentration, task completion, and mood on a scale of 1 to 10,

where 1 = poor, 5 = average, and 10 = excellent. Write comments in the appropriate column.

Day Time Dose Concentration Task Completion Mood Comments

Patients are to fill out the form once or twice daily, usually in the morning and the afternoon.


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follow-up visits are scheduled at rst to ensure thatthe patient has ample opportunity to discuss thepositive and negative effects observed and to addressany questions or concerns. Further adjustments to theregimen are made in accordance with patient reports,although it is a good idea to get input from signicantothers in the patients life.Pharmacotherapy for ADHD in adults is not as

well-studied as in children and adolescents, but theAmerican Academy of Child and Adolescent Psy-chiatry guidelines and others (4, 68) endorse the useof both stimulant and nonstimulant medicationsdepending upon patient variables. Initial treatmentchoice should consider the patients clinical pro-le (including risk factors and comorbid con-ditions), treatment goals, past history of medicationuse, preferences for medication effects and dosingpatterns (once-daily versus multiple times), and po-tential side effects. For relatively uncomplicated pa-tients, stimulants or atomoxetine are rst-line agents.Stimulants work quickly and are generally effective

(80%90% response rate, effect size = 0.9) andwell-tolerated, although long-term adverse effects havenot been studied. While short-acting stimulants arethe most widely prescribed medications, there issome evidence that longer-acting preparations arebetter tolerated, have less abuse potential, and areeasier for patients to remember to take consistently.It is important to monitor blood pressure and heartrate at each visit, and to inquire about treatmentemergent cardiovascular symptoms.Atomoxetine is FDA-approved for ADHD in

adults (6971).It has a long duration of action (half-life.12 hours) but works with gradual onset (4 to 6weeks), so that positive effects emerge over a longertime period than with stimulants. The response rate

to atomoxetine is 60% and the effect size is 0.4(moderate). It is most helpful with patients who donot tolerate stimulants, who are highly anxious, orwho express a preference for a medication thatworks around the clock. It has also shown to beeffective in ADHD patients with comorbid socialanxiety disorder (72). The most common sideeffects from atomoxetine are nausea, GI upset,headache, sedation, fatigue, reduced sexual drive,and difculty with urination.Mild increases in heartrate and blood pressure have also been reported, butrarely are these signicant enough to require dis-continuation.There is some evidence that the alpha2 agonists

can improve symptoms in adults with ADHD. Adouble-blind placebo-controlled study comparingguanfacine to dextroamphetamine in adults withADHD found that each were comparable in theirclinical effects as well as their impact on neuro-psychological measures (73).Bupropion is a medication with proven efcacy for

treatment of depression, smoking cessation, and adultADHD (74, 75). It is a potent DA reuptake inhibitorwith less potent inhibition of NE reuptake. Theregular-release preparation has a half-life of approxi-mately 14 hours, while the extended-release form hasa half-life of 24 hours. Although bupropion is acti-vating (even stimulating for some patients) and oc-casionally worsens anxiety symptoms, it produces lesssexual dysfunction than other antidepressants. Themost signicant side effect of bupropion is an in-creased incidence of seizures, reported in 0.4% ofpatients taking the immediate-release preparation.Seizures remit with discontinuation of the medica-tion. Other adverse effects include dry mouth, con-stipation, nausea, vomiting, anorexia, weight loss,headache, dizziness, fainting spells, insomnia, tremor,restlessness, excitability,mood swings, and irritability.Combining SSRIs with stimulants can be used

safely for adults with ADHD and comorbid anxietyor depression. The more sedating agents (e.g., par-oxetine or sertraline) might be preferable whenpatients report difculty with insomnia or over-activation, and the less sedating compounds (e.g.,uoxetine or citalopram) when they complain ofbeing too tired or underactive. Since there isno signicant interaction between stimulants andSSRIs, both typesofmedications canbeprescribedatusual dosage strengths.Psychosocial Interventions. There is a growing

body of research indicating that psychosocial treat-ments are effective for adult patients with ADHD,even those that are already taking medications. Incontrast to the large literature on children andadolescents, there are about 20 published psycho-social treatment studies to date using a variety of

Table 6. Published Psychosocial TreatmentStudies

Ratey et al. (1992) treatment failures

Wiggins et al. (1999) educational gp (TFA)

Wilens et al. (1999) chart review CBT/meds

Hesslinger et al. (2002) DBT group

Philipsen et al (2007) DBT-group, multisite replication

Stevenson et al. (2002, 2003) CRP group treatment & self-directed CRP

Safren et al. (2005, 2010) CBT/meds v. meds only; CBT v. relaxation

Weiss et al. (2006) PST & meds

Rostain & Ramsay (2006) CBT & meds

Ramsay & Rostain (2011) CBT only

Solanto et al. (2008, 2010) CBT gp focused on EFs

Virta et al. (2008, 2010); Salakari et al. (2010) CBT gp rehabilitation/6 mo. fu

Bramham et al. (2009) CBT group


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manualized approaches to improving symptoms andfunctioning in this population (76) (See Table 6).Several investigators have adapted CBT either forindividual patients (7782) or using a group ap-proach (8387). While the emphasis of each ap-proach is somewhat different, they share certainimportant features: psychoeducation about ADHDand its impact on daily functioning, redesigning theenvironment to improve task completion and reducedistractions, modifying distorted beliefs, practicalproblem-solving skills, and affect regulation. What isimpressive about these interventions is that they allseem to work equally well with patients who aremedicated or nonmedicated.

OUTCOMES

While it was once believed that hyperactive chil-dren outgrew their condition, evidence is accu-mulating that ADHD persists into adolescence andadulthood. It appears that over 50% of childrenwith ADHD will continue to exhibit some symp-toms of the disorder (e.g., inattention, impulsivity)into later life. Associated difculties for adolescentsinclude school failure, aggression, antisocial behav-ior, poor social skills, emotional immaturity, lowself-esteem and interpersonal conicts. Adults havean increased incidence of anxiety, low self-esteem,personality disorders (especially antisocial person-ality disorder), alcohol and substance abuse, in-terpersonal difculties, and occupational changes.For instance, Kessler et al. (6) found that 4.4% ofadults surveyed in the National Comorbidity Sur-vey Replication study met criteria for ADHD, anda substantial proportion of these individuals alsomet criteria for other psychiatric disorders. Negativeoutcomes are associated with factors such as ag-gression and antisocial behavior, severity of hyper-activity and impulsivity, lower intelligence, lowersocioeconomic status, and the presence of addi-tional individual and family psychopathology (e.g.,alcohol or substance abuse).Although follow-up studies raise serious concerns

about the long-term outcomes of ADHD children, itshould be kept in mind that individual outcomescannot be predicted from group-derived statistics.Given that ADHD is a heterogeneous condition, andthat the poorest outcomes are associated with aggres-sion and antisocial behavior rather than with the coresymptoms of ADHD, it is best to regard the prog-nosis as uncertain and mediated by factors other thanADHD.Professionals andparents need to take a longview of ADHD as a chronic condition in order toavoid a sense of failure or frustration if the course oftreatment is long and arduous. There are no simplesolutions to this complex biopsychosocial disorder.

FUTURE DIRECTIONS

In the future, clinicians will undoubtedly usegenetic testing to aid in the diagnosis of ADHD, aswell as to assist in selecting appropriate treatmentmodalities. The role of gene 3 environment inter-actions in the unfolding of ADHD and relateddisorders will be much better understood allowingfor preventive interventions to be targeted at highestrisk individuals. Pharmacogenomics holds thepromise of better prediction of treatment response(both pharmacologic and psychosocial). It is alsolikely that new medications targeting differentgenotypes will be available in the near future, as willagents that work at the epigenetic level, modu-lating the gene products that fundamentally in-uence key neurodevelopmental processes seen inADHD. Finally, advances in computer technology,particularly portable devices such as smart phonesand microcomputers, will offer patients new toolsfor improving executive functioning and self man-agement, and will enable clinicians to obtain bettermeasures of patient functioning and adaptation aswell as symptom severity.

WebsitesPatient/Parent Information about ADHDwww.add.org/www.cdc.gov/ncbddd/adhd/www.chadd.org/www.help4adhd.org/www.ncbi.nlm.nih.govhttp://www.nimh.nih.gov/health/publications/attention-decit-hyperactivity-disorder/adhd_booklet.pdfwww.ParentsMedGuide.org

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