New Options in the Pharmacological Management of Attention-Deficit/Hyperactivity Disorder

A brief review of the efficacy and common sideeffects of pharmacological treatments for attention-deficit/hyperactivity disorder (ADHD) is presented.Methylphenidate and amphetamine continue tohave the strongest base of empiric support. They areboth available in extended- and immediate-releasepreparations. Although most children with ADHDrespond favorably to either medication, many childrenwho do not respond to one medication willrespond to the other. Additional pharmacologicaloptions include the nonstimulant atomoxetine, thestimulant pemoline, the antidepressants bupropionand desipramine, and the antihypertensives clonidineand guanfacine. In selecting the appropriatepharmacological regimen, consideration should begiven to the child's daily school and after-schoolschedule, the presence of aggressive symptoms, andthe risk of diversion. Careful selection of an appropriatemedication regimen and active engagement ofthe child, parents, and teacher in daily managementmay help to ensure long-term adherence.

(Am J Manag Care. 2004;10:S117-S124)

Each year in the United States, an estimated3.0% of children aged 3 to 18years receive pharmacological treatmentfor attention-deficit/hyperactivity disorder(ADHD).¹ This overall rate of treatmentis at the lower end of the range of communityprevalence estimates for ADHD (3%-5%)among school-age children.^2-4 Across individualcommunities, however, there is probablysubstantial variation in the rate and qualityof pharmacological treatment of ADHD.Whereas 1 study of 4 communities foundthat one eighth of children diagnosed withADHD received adequate pharmacologicaltreatment,⁵ a second survey of a rural regionreported that a substantial proportion ofschool-age children who received pharmacologicaltreatments for ADHD did not meetclinical criteria for the disorder.⁶ In 2 communities,elementary school children werereported to be prescribed pharmacologicaltherapy for ADHD at 2 to 3 times the expectedbase rate prevalence of the disorder.⁷Such findings suggest that substantial variationexists in the extent and quality of pharmacologicaltreatment as well as thediagnosis of ADHD in the United States.

Stimulant medications are the mainstaypharmacological treatment for ADHD.Stimulants, which include methylphenidate(MPH), amphetamine (AMP), and pemoline,are prescribed to more than 80% of outpatientstreated for ADHD.¹ More experimentalevidence supports the safety, dosing, andefficacy of stimulants than any other psychopharmacologicaltreatment for children.⁸Among the stimulants, MPH is by far themost commonly prescribed medication.

There is a nearly 70-year history of treatmentof hyperactive children with stimulants.In the past several years, substantialprogress has been made in broadening therange of pharmacological choices to manageADHD. What follows is a brief review of theefficacy of drug treatments focusing on newstimulant preparations and other new pharmacologicaloptions.

Efficacy of Stimulants

Controlled clinical trials consistentlydemonstrate that treatment with stimulantssubstantially reduces the characteristicsymptoms and impairment of patients withADHD.^9-11 Stimulants result in a rapid improvementin the conduct, attentiveness,and academic performance of children andadolescents with ADHD.⁹ Approximately70% of ADHD patients respond to stimulantmedications in the short term ¹⁰ and overperiods up to 18 months.^11,12 In addition topharmacological treatments, which are thefocus of the current review, behavioralapproaches involving classroom behaviormodification and academic interventions,^13,14parent training,¹³ contingency managementprograms,¹⁵ and special education placement¹⁶ are also established treatments forchildren with ADHD. For some patients insome outcome domains, medications incombination with behavioral psychosocialinterventions may be more effective thaneither treatment alone. In the NationalInstitute of Mental Health (NIMH) MultimodalTreatment Study of ADHD (MTA), forexample, patients who received the combinedtreatment significantly improved on acomposite measure that combined ADHDsymptoms and other functioning domains,in relation to those who received eithermedication management or behavioral treatmentalone.¹⁷ However, the effect sizes weremodest. For ADHD symptom outcomes,patients receiving combination strategy andmedication management alone did notmeaningfully differ in improvement, andboth groups achieved significantly greatersymptom reduction than the behavioral-treatment-alone group.

Studies comparing the efficacy of MPH,AMP, and dextroamphetamine (DEX) havegenerally failed to show group differences inkey outcomes.¹⁸ Most young people respondwell to each medication. However, individualpatients may vary substantially in theirclinical response to the different medicationsand to different doses of the same medication.¹⁹ Unfortunately, there are no physiologicalor psychological measures that reliablypredict response to individual stimulants.However, controlled crossover studies indicatethat a substantial proportion of childrenwith ADHD who do not respond to MPH,respond favorably to AMP and conversely asubstantial proportion of AMP nonrespondersrespond to MPH.^20,21

Dexmethylphenidate (Focalin) is the pharmacologically active D-threoenantiomerof MPH. Although the L-isomer is more rapidly metabolized and degraded thanthe D-isomer following oral administration, the L-isomer has little or no clinical efficacy.In a randomized, double-blind, controlledtrial comparing twice-daily dexmethylphenidate, immediate-release MPH, andplacebo, both active drugs were significantly more efficacious than placebo, according toteacher and parent ratings of ADHD symptoms. There was also a trend favoringdexmethylphenidate, based on evening ratings.²² Dexmethylphenidate is typically prescribedat one half the dose of the usual racemic MPH mixtures. At present, dexmethylphenidateis only available as an immediate-release formulation.

Development of Long-acting Stimulants

Standard stimulants have a relativelybrief duration of action.²³ The clinical effectsof the immediate-release preparations ofMPH, DEX, and mixtures of AMP occur duringthe first 30 minutes following dosing,reach maximal effect over approximately 2hours, and are no longer clinically apparentat 5 hours.²⁴ The short duration of action ofimmediate-release preparations representan important limitation to their effectivenessin community practice.

The clinical effects of pemoline last for upto 6 hours. However, abnormal elevations inserum hepatic enzymes occur in 1% to 3% ofyouth receiving maintenance pemolinetreatment.²⁵ Together with rare reports ofpemoline-related fatal hepatic toxicity, thesefindings have led to a warning concerninghepatic toxicity in the medication's packageinsert.²⁵ As a result, pemoline is not generallyregarded as a first-line treatment forADHD.

For continuous coverage with immediate-releaseformulations of MPH throughout theday, school-age patients must receive at least1 dosage during school. A typical regimen ofimmediate-release preparations involves adose at breakfast (8:00 AM), another at lunch,and a third dose after school to provide coveragefor homework and other after-schoolactivities. The necessity for in-school dosingrisks embarrassing the student in front of hisor her peer group. A school nurse or otherschool staff member is also generallyrequired to dispense the midday stimulantdose. Because some schools may not reliablyadminister midday dosages and otherschools may prohibit administration of medicationsaltogether, immediate-release preparationsmay pose problems with long-termtreatment adherence. In addition, childrenmay simply forget to take their medication,especially the after-school dose. In one 12-month retrospective study of once-dailyosmotic release oral system (OROS) MPH(Concerta), patients were less likely toswitch to other medications when comparedto patients taking short- and intermediate-actingMPH treatments.²⁶ Further, a 9-monthhealthcare claims data study assessing persistencywith therapy suggests that patientsprescribed OROS MPH were 42% more likelyto persist on their medication than those prescribedER (extended-release) MPH.²⁷

Sustained-release formulations of MPHand DEX represent advances in the pharmacologicalmanagement of ADHD. Thesustained-release preparations provide continuousclinical effects throughout the traditional8-hour school day. This extendedcoverage eliminates the requirement of inschool—administered dosing.²⁸ Because earlytreatment termination is quite common inthe community care of ADHD ^29-31 andbecause less complex dosing regimens aregenerally associated with improved adherence,32 sustained-release formulations arebelieved to have facilitated stimulant medicationadherence in community practice.

MPH-20 (Ritalin-SR) was one of the earliestlong-acting stimulants. It relies on a waxmatrixvehicle to release the medicationslowly following ingestion. There are nowseveral slow-release racemic MPH genericpreparations that use a similar wax-matrixvehicle. However, clinicians and expertsreport that such extended-duration preparationsare less effective, especially by theafternoon, than standard 3-times-daily dosingof immediate-release MPH.³³ This may bebecause immediate-release MPH preparationsproduce higher peak plasma concentrationswith a steeper absorption slope thanthe slow-release, long-acting preparations.³⁴The performance of children may beenhanced by a rising rather than steadyplasma concentration of MPH.³⁵ Similarly,although long-acting DEX formulations havea typical duration of approximately 8 hours,these medications may not achieve prolongedbehavioral effects because of thesteady concentrations.³⁶

OROS MPH is a new single-daily-doseMPH preparation that retains the increasedefficacy associated with immediate-releaseMPH. Following ingestion of an OROS MPHtablet, there is an immediate release of MPHin the outer covering of the tablet. After thisinitial bolus, there is a slower controlledrelease of MPH over approximately 8 hours.As water permeates the semipermeabletablet covering, MPH is released into thebloodstream through a laser-drilled hole atone end of the capsule that acts as an osmoticpump.³⁷ In a large randomized controlledtrial, OROS MPH once per day was as effectiveas MPH immediate release given in thestandard 3-times-daily regimen.³⁸ A recentlypublished open-label study further suggeststhat clinical improvements achieved withOROS MPH are generally sustained over the12-month follow-up period of continuoustreatment.³⁹

MPH hydrochloride (Metadate CD) isanother sustained-release MPH formulation.The capsule combines 30% of immediate-releaseMPH and 70% ER MPH beads. Thisformulation typically results in a peak plasmaconcentration approximately 1.5 hoursafter dosing and a second peak approximately4.5 hours after dosing. Metadate CDhas the advantage that it can be given as asprinkle over food. This may be especiallyhelpful in the treatment of younger childrenwho are unable to swallow a pill.

Adderall (dextroamphetamine saccharate/dextroamphetamine sulfate/amphetamineaspartate/amphetamine sulfate) is amixture of 75% DEX and 25% levoamphetamine.The clinical duration varies from 5 to8 hours depending on dose, absorption, andmetabolism. A randomized, double-blind,controlled trial comparing ER DEX spansulesand immediate-release DEX revealedthat both immediate-release preparationshad earlier onset of effects, while the spansulepreparation had more sustained clinicaleffects.⁴⁰

Adderall XR, a recently marketed ERmixed amphetamine salts (MAS XR), uses abead technology to provide a double-pulseddelivery of immediate-release MAS. One halfof the active ingredient is released uponingestion and the other half is releasedapproximately 4 hours later. The clinicalduration of MAS XR is intended to replicatea 4-hour, twice-daily dosing of immediate-releaseAdderall (MAS). Some research suggeststhe effects of a single morning dose ofMAS XR extends beyond the 8-hour schoolday to 10 or 12 hours.

Adverse Effects, Contraindications, andLonger-term Risks of Stimulants

Most side effects experienced by childrentreated with stimulants for ADHD are relativelymild, time-limited, and resolve followingadjustment of the dose or daily regimen.The most common adverse events early inthe course of stimulant treatment of childrenwith ADHD include difficulty falling asleep,reduced appetite, stomachache, headache,and dizziness.⁴¹ Although pediatricians commonlyreduce or eliminate the after-schooldose of MPH to reduce insomnia, it is notclear that this dose of immediate-releaseMPH contributes to sleep difficulties.⁴²

The package insert for each stimulantmedication lists specific contraindications,warnings, and precautions. From a clinicalperspective, the most significant contraindicationsinclude concomitant treatment witha monoamine oxidase (MAO) inhibitor andstimulant treatment of patients with psychoticdisorders or glaucoma. Although MAOinhibitors are rarely used in contemporaryclinical practice, there is a contraindicationconcerning their use in patients treated withstimulants. MAO inhibitors taken with stimulantsmay trigger severe hypertension andincrease the risk of cerebrovascular accidents.Stimulants should also be avoided inpatients with a known history of schizophrenia,schizoaffective disorder, mania, or otherpsychotic disorders. In patients with psychoticdisorders, stimulants may triggerexacerbations of psychotic symptoms.Sympathomimetic agents, including stimulants,may increase intraocular pressure andshould be avoided in patients with glaucoma.

Patients with a history of stimulant abuseor dependence should also not be treatedwith stimulants. Because parents and otherfamily members may abuse stimulants prescribedfor someone else in the family, acareful family history of substance abuse iswarranted before a physician prescribesstimulant therapy. Although there is wideacceptance of the need to avoid stimulanttreatment in patients with a history of stimulantor polysubstance abuse, controversysurrounds the extent to which stimulant useleads to abuse or dependence in young peoplewithout a history of these disorders.Some investigators report that stimulants differin their ability to induce euphoria, withDEX having the highest liability, MPH anintermediate liability, and pemoline possessinglittle or no euphorigenic potential.^43,44

Stimulants may not be the only cause forincreased substance abuse for ADHDpatients. ADHD, by its nature, may have animpact on increasing the risk of substanceuse disorders. A recent and controversialmeta-analysis of 6 studies of adolescents andyoung adults suggests that contrary to theseconcerns, stimulant therapy in childhood isactually associated with a reduction in subsequentsubstance use disorder.⁴⁵ Oneexplanation for earlier reports linking stimulanttreatment to substance abuse is failureto control for the potentially confoundingeffects of comorbid conduct disorder thatincrease risk of substance abuse.^46,47 Continuedresearch in this important area iswarranted.

Some individuals with a history of intravenousdrug abuse may attempt to dissolvetablets of stimulants before injecting themintravenously. This practice poses risks ofpulmonary talc granulomatosis and pulmonaryhypertension.⁴⁸ Stimulant abuse alsosometimes involves crushing and intranasallyinhaling the drug. OROS MPH is less proneto these forms of abuse than immediate-releaseMPH preparations because it exists asa pasty substance that cannot be injected orsnorted.⁴⁹

Controversy surrounds the extent towhich long-term stimulant treatment ofchildren slows their height and weightgrowth. While some studies show significantattenuation of growth on stimulants,^50,51others show only small effects.^52,53 Catch-upin growth may be inferred from cross-sectionalstudies that demonstrate that theheights of adults treated as children withstimulants do not significantly differ fromcontrols.^54,55 Given the uncertainty regarding the effects of long-term stimulant treatmenton growth rates, it is prudent for cliniciansto monitor carefully the height andweight of treated children with regularmeasurements plotted on growth charts.

Nonstimulants

Atomoxetine (Straterra) is a nonstimulantfor the treatment of ADHD approved bythe US Food and Drug Administration. Itenhances noradrenergic function throughhighly selective and potent inhibition of thepresynaptic reuptake of norepinephrine.Low concentrations of norepinephrine inthe right dorsal and orbital sections of theprefrontal cortex are believed to contributeto many ADHD symptoms.⁵⁶ Controlled trialshave demonstrated that atomoxetine ismore efficacious than placebo in the treatmentof children and adults with ADHD.The adverse effects and discontinuationrates associated with atomoxetine appear toresemble those of MPH. However, atomoxetinemay not have the abuse potential ofMPH because it does not affect the nucleusaccumbuns or striatum, regions of the brainimplicated in addictive behaviors.⁵⁷ Althoughstimulants remain the first-linetreatment for ADHD, atomoxetine is an efficaciousalternative for patients who do notrespond to stimulants or do not toleratethem.

Several other medications have beenstudied for their efficacy in ADHD. Amongthe most extensively studied are the tricyclicantidepressants imipramine anddesipramine. These medications effectivelyinhibit norepinephrine reuptake and havebeen demonstrated to be more effective thanplacebo in controlled clinical trials of thetreatment of ADHD. However, becauseimipramine and desipramine affect cardiacconduction, and therefore require periodicelectrocardiograms and blood drug levelmonitoring, they are rarely used for thetreatment of pediatric ADHD.

The antidepressant bupropion (Wellbutrin)is also efficacious in the treatment ofpediatric ADHD.^58,59 Because improvementwith bupropion treatment is generally not asrobust as improvement with stimulants,⁶⁰ itis also seldom used as a primary treatmentfor ADHD, though it is used more commonlyas an adjunctive agent. There is also evidencethat the antihypertensives clonidine ⁶¹and guanfacine62 are effective in reducingsome ADHD symptoms in children.However, concerns about hypotension,rebound hypertension, and sedation havelimited their use in clinical practice.

Pharmacological Management of PatientsWith Comorbid Mental Disorders

Youth with ADHD commonly have cooccurringmental disorders. In the largeNIMH MTA study of ADHD, for example, 40%of the subjects had oppositional defiant disorder,39% had an anxiety disorder, 14% hadconduct disorder, 11% had a tic disorder,and 4% had a mood disorder.¹⁷ In addition,adolescent and adult ADHD may contributeto the development of substance use disorders.⁶³ The presence of comorbid mental disorderscomplicates the pharmacologicaltreatment of ADHD. Although a detailedexamination of this broad and complex topicis beyond the scope of the current review, abrief discussion is provided on pharmacologicaltreatment of ADHD with comorbidticdisorders and ADHD with aggressive behaviorcommon in oppositional defiant and conductdisorders.

Case reports have long fueled concernthat stimulants exacerbate tic disorders inchildren with ADHD. However, prospectivestudies indicate that stimulants are generallysafe and effective for the treatment of ADHDin most children with mild-to-moderatecomorbid tic disorders.^64,65 In children withboth disorders whose ADHD symptoms donot respond or whose tics worsen followingstimulant therapy, some evidence supportstreatment with desipramine66 or guanfacine.⁵⁶ One randomized, controlled trial ofchildren and adolescents with both disordersdemonstrated that, as compared with placebo,desipramine (3.4 mg/kg/day) significantlyreduced core ADHD symptoms and tic symptoms.⁶⁶ Similarly, a randomized, controlledtrial revealed that as compared with placebo,the α₂-adrenergic receptor agonist guanfacine(1.5-3.0 mg/day) significantly reducedtotal ADHD and tic symptom scores. In thisstudy, however, guanfacine was not associatedwith a significant decline in parent-ratedhyperactivity.⁶⁷

Stimulants are only modestly effective inreducing aggressive behavior in young peoplewith ADHD.⁶⁷ Some evidence suggeststhat clonidine augmentation of stimulanttherapy is a safe and effective treatment foraggression in young people with ADHD.^68,69In one randomized, controlled trial, childrentreated with a stimulant and clonidineas compared with stimulant alone exhibiteda significantly greater reduction in conductsymptoms, but not in hyperactivesymptoms. Children treated with clonidineand a stimulant generally experiencedfewer side effects than the stimulant-onlygroup, though they did experience a transientincrease in dizziness and drowsiness.Although concern has been expressedregarding adverse cardiovascular eventsincluding sudden death in children treatedwith clonidine and a stimulant,⁷⁰ no seriouscardiovascular events occurred in thisstudy.

Conclusion

Widespread variation exists in the rateand quality of pharmacological treatmentfor ADHD.^5,6,71 Extending the initial evaluationto include a thorough symptom andfunctional assessment of the child andsoliciting a detailed history from parentsand teachers may improve the accuracy ofthe diagnostic process.⁷² Once a diagnosisis established, appropriate selection ofpharmacotherapy requires a knowledge ofavailable pharmacological treatments andan understanding of daily coverage needsof the child.

Available stimulant preparations offer arange of pharmacokinetic profiles and durationsof action to help meet the diverse andchanging needs of ADHD patients over time.The long-acting medications may enhancemedication adherence by obviating the needfor a midday stimulant dose in school andreducing the need for a dose after school.Children who do not respond to one stimulantmedication may respond to anotherstimulant or to the nonstimulant atomoxetine.Long-acting preparations and atomoxetinemay also reduce the potential forrelated drug abuse.

Stimulant medications provide short-termbehavioral and academic improvement.To maintain these benefits, manychildren must remain on these medicationsover the long term. Simplifying the pharmacologicregimen and selecting the medicationregimen that best meets the child'sneeds may contribute to improved clinicaloutcomes. In addition, healthcare professionalsshould provide children, parents,and teachers with appropriate informationabout pharmacological therapy and treatmentresponse to increase their participationin the treatment process. Although theduration of treatment with stimulants isincreasing,⁹ early treatment discontinuationremains common.⁷³ Older patient age,comorbid oppositional defiant disorder, andfewer ADHD symptoms may place youngpeople with ADHD at particular risk of medicationnonadherence.⁷⁴

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