Innovations in Attention-Deficit/Hyperactivity Disorder Pharmacotherapy: Long-acting Stimulant and Nonstimulant Treatments

This article reviews innovations in attention-deficit/hyperactivity disorder (ADHD) pharmacotherapyand describes research on the newer, long-actingstimulant and nonstimulant treatments for ADHD.Results from peer-reviewed articles comparing theefficacy and safety of longer-acting methylphenidateor amphetamine-based stimulants and the nonstimulantatomoxetine are described. Longer-acting stimulantsand nonstimulants provide increased clinicalutility compared with short-acting stimulants.Efficacy and safety are similar to 2- or 3-times-a-daytreatment with short-acting stimulants. Longer-actingstimulants and nonstimulants provide increased convenienceand flexibility for treating youth withADHD and show considerable promise. Direct head-to-head studies are needed to better inform clinicaldecision making and to identify moderators andmediators of differential response.

(Am J Manag Care. 2004;10:S89-S98)

Attention-deficit/hyperactivity disorder(ADHD) is one of the most commonand well characterized child andadolescent psychiatric disorders.^1,2 Longitudinalstudies of hyperactive children followedinto adulthood indicate that ADHDsymptoms continue into adulthood for mostindividuals, even for those with previousstimulant treatment.³ These findings, coupledwith several popular books on ADHD inadults,⁴ have increased awareness of ADHDfor all age groups. Individuals with ADHDalso exhibit increased psychiatric and psychosocialcomorbidity, chronic and acutehealth conditions, and medical care usewhen compared with non-ADHD individuals.⁵ Consequently, both specialists andprimary care physicians should be familiarwith the diagnosis of ADHD and innovationsin medical management of this disorder.

Stimulant medications have been used totreat the core ADHD symptoms of overactivity,impulsivity, and inattention since 1937.^6,7The safety and short- and immediate-termefficacy of stimulants have been demonstratedin some studies.^8,9 When given at appropriatedoses, a significant percentage ofpatients are able to obtain normal functioningas evidenced by less severe ADHD symptomswith little or no impairment.^10,11

ADHD Treatment Before 2000

Until recently, ADHD has been viewedprimarily as a childhood disorder. Generally,medication was used to improve schoolbehavior and academic performance. Themost common treatment options before 2000were either immediate-release, short-actingstimulants, such as methylphenidate (MPH)(Ritalin) or dextroamphetamine (Dexedrine)taken twice daily, or first-generation, extended-release (ER), intermediate-acting stimulants,such as mixed amphetamine salts(Adderall [MAS]), sustained-release (SR)MPH (Ritalin SR), dextroamphetamine spansules(Dex Span), or pemoline (Cylert). Theefficacy and duration of effects of MAS onbehavior and ADHD symptoms is similar toMPH taken twice daily.¹² The pharmacokineticand pharmacodynamic profile of SRMPH is highly variable and not clearly superiorto short-acting stimulants in efficacy.^13,14 Pemoline has a behavioral half-life of 6to 8 hours.¹⁵ However, its use declined significantlyafter concerns about hepatotoxicitywere reported.¹⁶ Consequently, until recently,immediate-release, short-acting stimulantswere the most commonly used pharmacologicaltreatment of ADHD.

Because of an increasing awareness thatimpairments associated with ADHD extendbeyond the school day, as well as concernsabout worsening of symptoms as stimulantconcentrations decline or rebound, manyclinicians had begun adding a third dose of ashort-acting stimulant in the late afternoon.¹⁷ Kent et al showed that adding a thirddose of MPH improved evening behavior.¹⁸Similarly, Stein et al conducted a study contrastingMPH given 3 times a day with MPHgiven 2 times a day and reported increasedefficacy and satisfaction with no significantincrease in stimulant side effects with the 3-dose regimen.¹⁹ Thus, longer durations oftreatment (ie, 10-12 hours) may be optimalfor many youth with ADHD.

The landmark National Institute of MentalHealth Multimodal Treatment Study ofADHD (MTA) demonstrated that a carefullytitrated stimulant medication managementregimen typically administered 3 times dailyfor core ADHD symptoms was superior tobehavior modification alone or community-basedinterventions.^20,21 However, a contrastgroup of community providers treating youthwith ADHD with stimulant medication werefound to use lower dosages and less effectivetreatment regimens than the MTA medicationmanagement strategy, which emphasizedrobust doses, individual titration untilsignificant benefit, and a duration of treatmentthat extended beyond the school dayand weekends.^20,22,23 Thus, despite impressiveefficacy data from controlled studiesof short-acting stimulants, there was littleevidence that empirically developed "bestpractices" for medication use were beingtranslated to real-life practice settings.

In addition to stimulants, nonstimulantmedications, such as the tricyclic antidepressants,have been extensively evaluatedfor ADHD.²⁴ However, because of an unfavorableside-effect profile and concernsabout cardiotoxicity, their use for ADHDtreatment has declined significantly despitetheir efficacy.²⁵ The clinical significance ofcardiac risk of these agents to ADHDpatients when properly monitored, however,remains controversial.²⁶

Development of Long-acting Medications

Within the past few years, several secondgeneration,extended-release, long-actingstimulants have been developed and evaluatedfor treating youth with ADHD. The longestacting MPH-based stimulant, osmotic releaseoral system (OROS) MPH (Concerta), wasdesigned to mimic MPH given 3 timesdaily.²⁷ Based on research by Swanson etal,²⁸ a unique osmotic delivery system withan overcoat of 22% immediate-release MPHwas developed to provide increasing MPHconcentrations over 6 to 8 hours with clinicaleffects up to 12 hours. Other long-actingstimulants were soon developed, includingMetadate CD (MCD), ER MPH (Ritalin LA),and ER formulation of MAS (Adderall XR).MCD and ER MPH were designed to be similarin duration of effect to twice-daily MPH.MCD contains 30% immediate-release MPHand 70% MPH beads coated with a controlled-release polymer to deliver MPH graduallywith clinical effects for a 6- to 8-hourperiod. Ritalin LA is composed of 50% immediate-release and 50% ER MPH beads to providea second bolus. Adderall XR, the longestacting amphetamine preparation, is an ERformulation of a racemic mixture of dextroandleve-isomers of amphetamine salts in acapsule containing microbeads released in 2pulses, approximately 4 hours apart.^28-30

Atomoxetine hydrochloride (Strattera) forADHD is the first nonstimulant to receive anindication for ADHD from the US Food andDrug Administration. Atomoxetine is a selectivenoradrenergic agent, which was initiallydeveloped as an antidepressant. Although efficacyfor treating adults with ADHD was firstdemonstrated in 1998,³¹ several short- andintermediate-term efficacy and safety studieswere subsequently conducted with childrenand adolescents with ADHD.³² Although atomoxetinehas a plasma half-life of approximately4 hours, its clinical effects have beenreported to last significantly longer whentaken either once or twice daily.³³

This review will describe what is knownabout these new agents, particularly thelong-acting stimulants and nonstimulants ascompared with short-acting stimulants orplacebo. This review searched for controlledstudies of efficacy and safety of long-actingstimulant and nonstimulant medications.Tables 1 through 3 contain summaries ofrecent studies with these medications.

Methylphenidate-based, Long-actingMedications

The efficacy of OROS MPH in reducingADHD symptoms has been demonstrated ina multisite study,^34,35 2 laboratory school settings,^25,28 and in a dose-response study.³⁶The effects of OROS MPH were comparableto MPH given 3 times per day on both parentand teacher ratings of ADHD and oppositionaldefiant disorder (ODD) symptoms, onpeer interaction, and on clinician-rated globalefficacy.²⁷ In the Pelham study,³⁵ therewas also a statistically significant differencebetween OROS MPH and MPH 3 times a dayon parent ratings of Inattention/Overactivityand the Abbreviated Conners' scale, favoringOROS MPH. Moreover, slightly more of theparents preferred the week on OROS MPHrelative to MPH 3 times a day (47% vs 31%).Because this study employed a "double-dummy"procedure, parent preference wasnot the result of increased convenience ofonce-a-day dosing. Further research is neededto identify the specific reasons for parentpreference of OROS MPH over MPH 3 timesa day (eg, increased or longer efficacy, fewerside effects, smoother wear-off effects).

The safety and efficacy of MCD was evaluatedin a multisite study of 321 childrenaged 6 to 16 who were treated for 3 weekswith either MCD (20-60 mg) or placebo.³⁷ Atthe end of the study, 64% of those receivingMCD were moderately or markedly improvedversus 27% of those receiving placebo usingsymptom ratings on the teacher version ofthe 10-item Conners' Global Index. Teacherratings for mornings were similar to afternoons.Effect sizes were moderate forteacher ratings, but small to moderate forparent ratings, which is consistent with theduration of effect of approximately 8 hours.Subjects with more severe ADHD requiringlonger duration of treatment were excluded.The most common adverse events in theMCD group were: appetite loss (47%), irritability(45%), trouble sleeping (32%), andlistlessness, tired (31%), however, onlydecreased appetite was rated higher in theMCD versus the placebo group.

Two studies have compared fixed dosagesof an intermediate- and long-acting MPHstimulant. A recent multisite study comparedMCD with OROS MPH and placebo in a sampleof 184 children who were previously takingMPH.²⁹ In general, the time course ofresponse was related to predicted plasmaconcentrations of MPH. Thus, MCD, whichdelivers more MPH earlier than OROS MPH,was superior to OROS MPH in the morningbut similar to OROS MPH in the afternoon.OROS MPH was associated with superior outcomes12 hours postdose. Both active medicationswere superior to placebo at all timeperiods except immediately after dosing.There were no statistically significant differencesin ratings of stimulant side effects andno severe adverse events. It is unclear howthese findings based on fixed doses wouldtranslate to broader outcome measures inreal-world settings, where the optimal doseis individually titrated until there is significantbenefit with reduction in impairment.

In another study of 36 stimulant responders,ER MPH, which was designed to mimictwice-daily MPH, was compared with startingdoses of OROS MPH (18 or 36 mg).³⁸Children taking 18 or 36 mg of OROS MPHor 20 mg of ER MPH displayed more improvementsin teacher ratings of sustainedattention and in completed math problemsthan children taking placebo. In addition,during the first 4 hours of treatment, statisticallysignificant differences favoring ERMPH over OROS MPH were reported indeportment, attention, and math problemscompleted correctly. Surprisingly, in thisstudy no dose-response differences werereported between 18 and 36 mg of OROSMPH. In addition, the external validity of thestudy is limited because children were nottitrated to optimal dose, and parent orteacher measures of ADHD symptoms,impairment, or satisfaction were not reported.Consequently, it is unclear how themeasures obtained during the first 4 hoursat fixed dosages generalize to clinical treatmentwhere dosages are titrated untilimprovement occurs on multiple measures,including reduction in impairment.

In a crossover study where 47 youth withADHD were given placebo and 3 differentOROS MPH dosages, Stein et al reported lineardose-response effects on ADHD symptomsand impairment with OROS MPH.³⁶There was a difference between ADHD subtypes,with children with ADHD inattentivetype responding better to lower doses thanchildren with combined type who requiredhigher dosage levels to achieve normalization.Normalization of ADHD symptomsoccurred in half to two thirds of subjects.Using a questionnaire, stimulant side effectswere found to be common, but generallymild. Of note, 70% of the sample was stimulantnaive. The most frequent significantside effects were insomnia (9%-25%),decreased appetite (5%-27%), and irritability(5%-17%). Decreased appetite and reports ofinsomnia were more common at the higherdose levels.

A recent trend in ADHD treatmentresearch is to identify more meaningful outcomesother than reductions in ADHDsymptoms, such as quality-of-life measuresor functional impairments, including familyfunctioning.³⁹ Another important outcomefor adolescents and young adults is developingdriving skills, as individuals with ADHDare at increased risk for involvement inmotor vehicle accidents and have poor drivingrecords relative to individuals withoutADHD.⁴⁰ A recent study of driving skills inadolescents with ADHD conducted on a drivingstimulator demonstrated significantdeterioration at 8:00 PM in 6 adolescents takingMPH 3 times a day versus OROS MPHtaken once in the morning. This study suggeststhat OROS MPH may have a prolongedbeneficial effect relative to MPH 3 timesdaily that extends well beyond the 12 hoursOROS MPH is presumed to be effective.⁴¹

Amphetamine-based Stimulants

The short-term efficacy and safety of theER formulation of MAS versus placebo wasevaluated in a multicenter home and laboratoryschool study of 509 children.⁴² Morethan 90% of the sample had ADHD combinedtype and 30% to 38% were treatment naive.Children were randomized to 3 weeks ofplacebo or 10, 20, or 30 mg of the ER formulationof MAS. Improvement was doserelated based on late afternoon parent ratingsof ADHD symptoms and morning andafternoon teacher ratings. Loss of appetite(reported in 21.9%) was also dose related.Other adverse events more common in theactive treatment group than the placebogroup were: insomnia (16.6% vs 1.9%),abdominal pain (14.4% vs 9.5%), vomiting(7.2% vs 3.8%), and nervousness (5.6% vs1.9%). Spontaneously reported adverseevents occurred in 70% of those taking theER formulation of MAS: 69% rated mild, 28%moderate, and 4% were rated severe.

In a laboratory school study of 51 children,3 doses of the ER formulation of MASwere compared with placebo and with 10 mgof MAS. More than 90% of the sample wasprevious stimulant responders. Efficacy inreducing ADHD symptoms relative to placebowas dose dependent. Duration of effectwas also related to dose, with 20- and 30-mgdoses of the ER preparation associated witheffects on classroom behavior and math testperformance 10 to 12 hours after administration.Parents commonly reported adverseevents, but were not judged to be serious andwere described as comparable with sideeffects seen with MAS. The most commonadverse events were nervousness (42%-56%),insomnia (12%-32%), anxiety (12%-27%),emotional lability (12%-27%), and loss ofappetite (27%-55%). In this 5-week study,duration of effect, efficacy in reducing ADHDsymptoms, and loss of appetite were dosedependent.

Nonstimulants

Several studies of atomoxetine clearlydemonstrate short-term efficacy relative toplacebo in reducing both inattentive andhyperactive/impulsive ADHD symptoms andimproving family and social functioning.^33,43,44 The effect sizes of atomoxetinetreatment versus placebo were similar fordosing once or twice daily.³² Controlledstudies suggest that atomoxetine is generallywell tolerated in youth with ADHD withfew spontaneously reported adverse events.In 2 studies of children and adolescents, lossof appetite occurred more often in thosetreated with atomoxetine versus those treatedwith placebo.⁴⁴

Only one published study was found comparingatomoxetine to a stimulant medication.A preliminary, 9-week, open-label study was reported by Kratochvil and colleagues.⁴⁵ Both atomoxetine and MPH wereassociated with reductions in ADHD symptomsand improved global ratings in childrenaged 7 to 15, according to parent and clinicianratings. Atomoxetine (administeredtwice daily) and MPH (administered either 2or 3 times daily) were both well tolerated,with vomiting, insomnia, and weight lossreported more often for the group receivingatomoxetine. Clinical implications of thestudy are quite limited, however, because ofthe open-label nature of the study, the lackof objective or blinded assessment of ADHDsymptoms, and differential attrition betweentreatment groups. In addition, it is unclear ifchildren in the MPH arm were receivingoptimal MPH treatment, as the dose and dosingregimen (eg, 2 vs 3 times daily) were notstandardized or reported.

Summary and Discussion

The landscape of ADHD treatment haschanged significantly over the past fewyears and since the MTA study. Long-acting,often once-a-day medications have largelyreplaced the short-acting stimulants as themost common pharmacological treatmentfor children and adolescents because oftheir significant clinical utility. For an oftenlong-term disorder such as ADHD, long-actingmedications provide increased convenience, less embarrassment because of homeversus school administration, and representan easier therapeutic regimen for individuals,schools, and families than treatmentsthat require multiple doses throughout theday. With administration and supervisionat home, there is also less concern aboutpotential diversion or stimulant abuse.

A variety of available medications providedifferent durations of effects and increasedflexibility in customizing the treatment to fitthe patient. Early studies have establishedthe duration of medication effects on ADHDsymptoms, short-term efficacy and safety,and dose-response effects. MPH-based treatmentsand atomoxetine have been the moststudied of the new treatments. In general,studies of long-acting stimulants in childhoodADHD uniformly demonstrated equivalencein efficacy and side effects toshort-acting stimulants administered 2 to 3times per day with increased preference andadherence. In addition to reducing ADHDsymptoms, stimulant medications alsoreduce symptoms of ODD.^23,35,46

Because of their safety record, stimulantshave few absolute contraindications for treatmentof ADHD, which presents with a widerange of comorbid psychiatric and neurologicaldisorders.⁴⁷ According to the AmericanAcademy of Child and Adolescent Psychiatrymost recent practice parameters,⁴⁸ contraindicationsfor stimulants include: individuals witha previous sensitivity to stimulant medications,glaucoma, symptomatic cardiovascular disease,hyperthyroidism, hypertension, or activepsychotic disorder. Recent studies suggestthat individuals with a variety of conditionspreviously assumed to be contraindicationscan be successfully treated with stimulants,including individuals with comorbid seizure disorders,⁴⁹ tics and Tourette's syndrome,^9,50,51and manic ⁵² or anxiety symptoms.⁴⁶ Use inindividuals or families with comorbid substancedisorders requires considerable cautionand safeguards and remains controversial.

Adverse events associated with long-actingMPH and amphetamine-based stimulantsappear to be comparable in severity andprevalence with that of short-acting MPHand amphetamine-based stimulants. However,it should be noted, that with the exceptionof the Stein et al study,³⁶ most studysamples have consisted primarily of stimulantresponders. Thus, the absolute rates ofadverse events or side effects may be anunderestimate when applied to nonselectedclinical populations. A second issue iswhether there are differences in specific sideeffects between MPH and amphetaminebasedstimulants. Stimulant side effects arehighly correlated with treatment adherence.⁵³ Although there is some anecdotal evidenceof differential response54 (eg, severaltreatment reviews),^55,56 well-controlled, adequatelypowered comparator studies usingclinically relevant dosages are needed toinform clinical practice, in addition to studiesof moderators and mediators of response,and longer-term safety studies. Nonetheless,it is reassuring that to date adverse eventshave been generally mild and no new sideeffects have been associated with the longer-acting stimulants. In the majority of cases,side effects associated with long-acting stimulants and atomoxetine are not severe andrespond to dose adjustments or alternative medications.

Atomoxetine, with its different mechanismof action, is associated with a slightly different side-effect profile than stimulant medications,particularly increased somnolence and gastrointestinal symptoms in children. Forindividuals at risk of stimulant abuse,⁵⁷ or who display stimulant-related side effects,which are not transitory, or insignificant (eg, severe stimulant-induced insomnia or tics),atomoxetine and other nonstimulants provide a welcome alternative. Ongoing researchis being conducted to determine if there are distinct clinical subgroups that respond optimallyto atomoxetine (eg, ADHD and tics, or ADHD and insomnia). It should be noted thatefficacy and safety data are not available for children under age 6.

Currently, the field is in great need of effectiveness studies using active comparatorswith state-of-the-art treatments to evaluate differential effects that would assistclinicians and families in making the best treatment decisions. The relevance of futuretreatment studies can be enhanced by measuring a range of functional outcomes relevantto the impairments displayed by individuals with ADHD in their daily living,social, educational, and vocational functioning. Although the studies reviewed to datesuggest considerable promise, more clinically relevant treatment studies are neededthat address the relative efficacy, safety, and palatability of these new agents. These studiesshould evaluate effects over longer time periods (vs acute effects), and should use unselectedor treatment-naive samples (rather than selecting responders). Treatmentsshould use clinically effective doses (rather than fixed or starter doses), and multiplemeasures of ADHD symptoms, associated problems, impairment, consumer satisfaction,and cost should be obtained.

The outlook for individuals with ADHD has never been better, in large part becauseof increased awareness of ADHD and the clinical utility of the long-acting medications.It is hoped that use of these agents will reduce the risk of cumulative social and academicimpairments associated with untreated or undertreated ADHD relative to theshort-acting treatments. Finally, there may be unique advantages to the longer-actingmedications that have not been identified yet, as suggested by increased parent satisfactionwith long-acting stimulants when double-dummy procedures are used.

Acknowledgment

The author would like to thank Joey Lerner, MD, who reviewed an earlier versionof the manuscript.

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