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Innovations in Attention-Deficit/Hyperactivity Disorder Pharmacotherapy: Long-acting Stimulant and Nonstimulant Treatments
Mark A. Stein, PhD
New Options in the Pharmacological Management of Attention-Deficit/Hyperactivity Disorder
Mark Olfson, MD, MPH
Attention-Deficit/Hyperactivity Disorder: Medication Treatment-dosing and Duration of Action
Kenneth W. Steinhoff, MD
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Oscar G. Bukstein, MD, MPH

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

Mark A. Stein, PhD

This article reviews innovations in attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy and describes research on the newer, long-acting stimulant and nonstimulant treatments for ADHD. Results from peer-reviewed articles comparing the efficacy and safety of longer-acting methylphenidate or amphetamine-based stimulants and the nonstimulant atomoxetine are described. Longer-acting stimulants and nonstimulants provide increased clinical utility compared with short-acting stimulants. Efficacy and safety are similar to 2- or 3-times-a-day treatment with short-acting stimulants. Longer-acting stimulants and nonstimulants provide increased convenience and flexibility for treating youth with ADHD and show considerable promise. Direct head-to-head studies are needed to better inform clinical decision making and to identify moderators and mediators of differential response.

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

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common and well characterized child and adolescent psychiatric disorders.1,2 Longitudinal studies of hyperactive children followed into adulthood indicate that ADHD symptoms continue into adulthood for most individuals, even for those with previous stimulant treatment.3 These findings, coupled with several popular books on ADHD in adults,4 have increased awareness of ADHD for all age groups. Individuals with ADHD also exhibit increased psychiatric and psychosocial comorbidity, chronic and acute health conditions, and medical care use when compared with non-ADHD individuals.5 Consequently, both specialists and primary care physicians should be familiar with the diagnosis of ADHD and innovations in medical management of this disorder.

Stimulant medications have been used to treat the core ADHD symptoms of overactivity, impulsivity, and inattention since 1937.6,7 The safety and short- and immediate-term efficacy of stimulants have been demonstrated in some studies.8,9 When given at appropriate doses, a significant percentage of patients are able to obtain normal functioning as evidenced by less severe ADHD symptoms with little or no impairment.10,11

ADHD Treatment Before 2000

Until recently, ADHD has been viewed primarily as a childhood disorder. Generally, medication was used to improve school behavior and academic performance. The most common treatment options before 2000 were either immediate-release, short-acting stimulants, 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). The efficacy and duration of effects of MAS on behavior and ADHD symptoms is similar to MPH taken twice daily.12 The pharmacokinetic and pharmacodynamic profile of SR MPH is highly variable and not clearly superior to short-acting stimulants in efficacy.13,14 Pemoline has a behavioral half-life of 6 to 8 hours.15 However, its use declined significantly after concerns about hepatotoxicity were reported.16 Consequently, until recently, immediate-release, short-acting stimulants were the most commonly used pharmacological treatment of ADHD.

Because of an increasing awareness that impairments associated with ADHD extend beyond the school day, as well as concerns about worsening of symptoms as stimulant concentrations decline or rebound, many clinicians had begun adding a third dose of a short-acting stimulant in the late afternoon.17 Kent et al showed that adding a third dose of MPH improved evening behavior.18 Similarly, Stein et al conducted a study contrasting MPH given 3 times a day with MPH given 2 times a day and reported increased efficacy and satisfaction with no significant increase in stimulant side effects with the 3-dose regimen.19 Thus, longer durations of treatment (ie, 10-12 hours) may be optimal for many youth with ADHD.

The landmark National Institute of Mental Health Multimodal Treatment Study of ADHD (MTA) demonstrated that a carefully titrated stimulant medication management regimen typically administered 3 times daily for core ADHD symptoms was superior to behavior modification alone or community-based interventions.20,21 However, a contrast group of community providers treating youth with ADHD with stimulant medication were found to use lower dosages and less effective treatment regimens than the MTA medication management strategy, which emphasized robust doses, individual titration until significant benefit, and a duration of treatment that extended beyond the school day and weekends.20,22,23 Thus, despite impressive efficacy data from controlled studies of short-acting stimulants, there was little evidence that empirically developed "best practices" for medication use were being translated to real-life practice settings.

In addition to stimulants, nonstimulant medications, such as the tricyclic antidepressants, have been extensively evaluated for ADHD.24 However, because of an unfavorable side-effect profile and concerns about cardiotoxicity, their use for ADHD treatment has declined significantly despite their efficacy.25 The clinical significance of cardiac risk of these agents to ADHD patients when properly monitored, however, remains controversial.26

Development of Long-acting Medications

Within the past few years, several secondgeneration, extended-release, long-acting stimulants have been developed and evaluated for treating youth with ADHD. The longest acting MPH-based stimulant, osmotic release oral system (OROS) MPH (Concerta), was designed to mimic MPH given 3 times daily.27 Based on research by Swanson et al,28 a unique osmotic delivery system with an overcoat of 22% immediate-release MPH was developed to provide increasing MPH concentrations over 6 to 8 hours with clinical effects up to 12 hours. Other long-acting stimulants were soon developed, including Metadate CD (MCD), ER MPH (Ritalin LA), and ER formulation of MAS (Adderall XR). MCD and ER MPH were designed to be similar in duration of effect to twice-daily MPH. MCD contains 30% immediate-release MPH and 70% MPH beads coated with a controlled- release polymer to deliver MPH gradually with clinical effects for a 6- to 8-hour period. Ritalin LA is composed of 50% immediate-release and 50% ER MPH beads to provide a second bolus. Adderall XR, the longest acting amphetamine preparation, is an ER formulation of a racemic mixture of dextroand leve-isomers of amphetamine salts in a capsule containing microbeads released in 2 pulses, approximately 4 hours apart.28-30

Atomoxetine hydrochloride (Strattera) for ADHD is the first nonstimulant to receive an indication for ADHD from the US Food and Drug Administration. Atomoxetine is a selective noradrenergic agent, which was initially developed as an antidepressant. Although efficacy for treating adults with ADHD was first demonstrated in 1998,31 several short- and intermediate-term efficacy and safety studies were subsequently conducted with children and adolescents with ADHD.32 Although atomoxetine has a plasma half-life of approximately 4 hours, its clinical effects have been reported to last significantly longer when taken either once or twice daily.33

This review will describe what is known about these new agents, particularly the long-acting stimulants and nonstimulants as compared with short-acting stimulants or placebo. This review searched for controlled studies of efficacy and safety of long-acting stimulant and nonstimulant medications. Tables 1 through 3 contain summaries of recent studies with these medications.







Methylphenidate-based, Long-acting Medications

The efficacy of OROS MPH in reducing ADHD symptoms has been demonstrated in a multisite study,34,35 2 laboratory school settings,25,28 and in a dose-response study.36 The effects of OROS MPH were comparable to MPH given 3 times per day on both parent and teacher ratings of ADHD and oppositional defiant disorder (ODD) symptoms, on peer interaction, and on clinician-rated global efficacy.27 In the Pelham study,35 there was also a statistically significant difference between OROS MPH and MPH 3 times a day on parent ratings of Inattention/Overactivity and the Abbreviated Conners' scale, favoring OROS MPH. Moreover, slightly more of the parents preferred the week on OROS MPH relative to MPH 3 times a day (47% vs 31%). Because this study employed a "double-dummy" procedure, parent preference was not the result of increased convenience of once-a-day dosing. Further research is needed to identify the specific reasons for parent preference of OROS MPH over MPH 3 times a day (eg, increased or longer efficacy, fewer side effects, smoother wear-off effects).

The safety and efficacy of MCD was evaluated in a multisite study of 321 children aged 6 to 16 who were treated for 3 weeks with either MCD (20-60 mg) or placebo.37 At the end of the study, 64% of those receiving MCD were moderately or markedly improved versus 27% of those receiving placebo using symptom ratings on the teacher version of the 10-item Conners' Global Index. Teacher ratings for mornings were similar to afternoons. Effect sizes were moderate for teacher ratings, but small to moderate for parent ratings, which is consistent with the duration of effect of approximately 8 hours. Subjects with more severe ADHD requiring longer duration of treatment were excluded. The most common adverse events in the MCD group were: appetite loss (47%), irritability (45%), trouble sleeping (32%), and listlessness, tired (31%), however, only decreased appetite was rated higher in the MCD versus the placebo group.

Two studies have compared fixed dosages of an intermediate- and long-acting MPH stimulant. A recent multisite study compared MCD with OROS MPH and placebo in a sample of 184 children who were previously taking MPH.29 In general, the time course of response was related to predicted plasma concentrations of MPH. Thus, MCD, which delivers more MPH earlier than OROS MPH, was superior to OROS MPH in the morning but similar to OROS MPH in the afternoon. OROS MPH was associated with superior outcomes 12 hours postdose. Both active medications were superior to placebo at all time periods except immediately after dosing. There were no statistically significant differences in ratings of stimulant side effects and no severe adverse events. It is unclear how these findings based on fixed doses would translate to broader outcome measures in real-world settings, where the optimal dose is individually titrated until there is significant benefit with reduction in impairment.

 
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