Introduction

Prior to initiating a pharmacologically based treatment approach for attention-deficit hyperactivity disorder (ADHD), one must ensure that an accurate diagnosis has been made. This includes ensuring that the diagnostic criteria described in the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) are met.^[1] It is important to obtain adequate and complete histories from family members, caregivers, and teachers to assist in providing an overall, comprehensive evaluation. Additionally, a baseline level of functioning should be established by using 1 or more of the numerous ADHD psychometric assessment scales that are available (eg, Conners scale).^[2]

Including family members or assigned caregivers in the initial discussions of initiating medication is also very important. Often children with ADHD will look to their caregiver for guidance and understanding. The caregiver's attitude toward medication is often the determining factor as to whether or not a child will accept and be compliant with medication. Discussing the potential benefits and risks of medication is vital to the eventual outcome of the medication trial. It is also important to not ignore the other facets of treatment for ADHD. Although cognitive behavioral therapy is largely unsuccessful, it is important to use other methods of behavioral therapy, including the use of a reward system for positive behavior.

Pharmacologic Treatments

The mainstay for years in the management of ADHD has been the use of stimulant therapy. Methylphenidate (Ritalin) is the stimulant with the most extensive database of clinical trials providing efficacy, safety, and tolerability data.^[3-8] There is also ample and growing evidence with dextroamphetamine (Dexedrine), the combination product of d- and l-amphetamine (Adderall), and pemoline (Cylert) (Table).^[3-8] Recently there have been some new advancements in the methods and rates of drug delivery for methylphenidate.

Table. Pharmacologic Treatments

Stimulant Medication	Brand Name	Dosage Form(s) Available
Methylphenidate	Ritalin	5-, 10-, and 20-mg tablets
Methylphenidate sustained release	Ritalin SR	20-mg tablet
Methylphenidate extended release (OROS delivery system)	Concerta	16-, 36-, and 54-mg caplets
Methylphenidate extended release	Metadate	10- and 20-mg tablets
Dextroamphetamine sulfate and saccharate/ amphetamine sulfate and aspartate	Adderall	5-, 10-, 20-, and 30-mg double-scored tablets
Dextroamphetamine	Dexedrine	5-, 10-, and 15-mg sustained release capsules 5 and 10 mg tablets 5 mg/ml elixir
Pemoline	Cylert	18.75-, 37.5-, and 75-mg tablets 37.5-mg chewable tablet

Recently released is the extended-release preparation of methylphenidate known as Concerta.^[9] Concerta uses the OROS drug delivery system, which is an oral osmotic delivery system formulation. The medication consists of a semipermeable rate controlling membrane that surrounds an osmotic core. The medication is coated with an immediate-release form of drug and contains a triple layer of drug inside the membrane. One of the inner layers is considered to be a "push" dose. Water enters the membrane and dissolves the drug, which is then released at a controlled rate through one of the laser-drilled holes in the membrane. Concerta is designed to have a 12-hour duration of action and is available in 18-mg, 36-mg, and 54-mg caplets. Concerta should be used with caution in cases of potential gastrointestinal obstruction, as the semipermeable membrane does not dissolve and passes through the gastrointestinal tract and is eliminated with different excipients inside the capsule. Pharmacokinetically, Concerta has been studied against sustained-release and immediate-release methylphenidate, and no significant differences have been found. Numerically, the C_max was lower and the T_max was slightly longer with essentially an equal area under the curve. To date, over 400 patients have been treated in blinded, placebo-controlled trials and Concerta has been found to be equally efficacious with immediate-release methylphenidate.

Additionally, another extended-release form of methylphenidate (Metadate ER) has become available in 10-mg and 20-mg tablets.^[10] Metadate ER is designed to have approximately an 8-hour duration of action with the goal to use once-daily dosing. Pharmacokinetic studies comparing both the sustained-release and immediate-release forms of methylphenidate have shown that Metadate ER was more slowly but just as extensively absorbed. The C_max, T_max, and AUC were found to be equivalent with sustained-release methylphenidate. Additionally, when taken with food, the C_max of Metadate ER was found to increase. Metadate ER is to be used in place of immediate-release methylphenidate when the 8-hour dose of Metadate ER corresponds to the titrated 8-hour dose of immediate-release tablets.

Pemoline (Cylert) continues to be a viable option, but is often considered as a later option for the treatment of ADHD in patients who have failed trials with methylphenidate and dextroamphetamine.^[7,8] The primary reasons for this include the possibility of hepatotoxicity, which requires twice monthly liver function test monitoring, and its delayed onset of effect, usually as long as 2 weeks. An advantage of Cylert is that it can be dosed once daily.

The dosing of stimulants has been an issue with clinicians over the years. The controversy has centered on a weight-based dosing model vs empiric dosing. According to recent clinical trials, efficacy has not been greatly associated with the weight-based model, and more clinicians prefer to use an empiric dosing approach.^[11] Typically, methylphenidate is initiated at 5-10 mg per day in divided doses, with increases of 5-10 mg per week to a maximum of 60 mg/day. Dextroamphetamine is typically dosed at 2.5-5.0 mg per day, with increases of 5 mg every week to a maximum dose of 40 mg/day. Adderall (dextroamphetamine/amphetamine) is typically initiated at 5-10 mg per day in children 6 years of age and older, and at 2.5 mg per day in children from the ages of 3-5 years. Pemoline is usually started at 37.5 mg per day and is increased by 18.75 mg on a weekly basis, depending on response, to a maximum of 112.5 mg per day.

Additional therapies that have been studied but that are not yet widely used include antidepressants (bupropion, tricyclic antidepressants [TCAs], monoamine oxidase inhibitors [MAOIs], selective serotonin reuptake inhibitors [SSRIs]), and the alpha agonists clonidine and guanfacine.^[5-8,12,13]

The side effects from stimulants are very similar among the different available agents. Those side effects include insomnia, anorexia, weight loss, nausea, hypertension, tachycardia, gastrointestinal distress, growth suppression, tic development, psychosis, mania, rash, headache, and a potential of lowering the seizure threshold.^[5-8]

Drug interactions are also a potential concern with stimulant medications. Stimulant use with MAOIs should be avoided concurrently and also within 2 weeks of using an MAOI. Additionally, there is concern about using other classes of antidepressant medications, including the TCAs, which have the potential for cardiac-related adverse events. Stimulants have also been associated with increasing clotting times in patients who are treated with warfarin. Additional precaution should be taken when stimulants are taken with over-the-counter cold preparations that contain systemic decongestants.

Predicting who will respond to stimulant therapy remains something that clinicians are not able to determine. Response is generally measured by a decrease in motor activity (eg, reduced activity to normal, improved fine motor control), improvement in social interactions (eg, decreased anger and increased ability to play with others), and improved cognitive functioning (eg, increased sustained attention, reduced distractibility).

The Texas Children's Medication Algorithm Project has attempted to provide a set of guidelines to assist the clinician with a standardized method to treat ADHD alone and when several comorbidities are present.^[7,8] The guidelines have been established from an extensive literature search and an assessment of the available data. For classic ADHD, inattentive or hyperactive-impulsive type, the stimulants methylphenidate or dextroamphetamine are recommended as first line.^[7,8] If no response is obtained after 2 weeks, it is recommended to switch to the other stimulant.^[7,8] For ADHD with comorbid anxiety or depression, a stimulant is used as the first-line therapy for a minimum of 2 weeks.^[7,8] If ADHD improves, but depression does not, then it is recommended that an antidepressant, preferably an SSRI, be added.^[7,8]

Clinical Trials

Until recently, a major area of ADHD research that was lacking was clinical data showing head-to-head efficacy comparisons between stimulants. The last 2 years have produced some clinical efficacy evidence comparing dextroamphetamine/amphetamine (Adderall) and methylphenidate (Ritalin).^{[14-17 ]} There continues to be no comparative trials of extended-release methylphenidate vs sustained-release methylphenidate, sustained-release methylphenidate vs dextroamphetamine/amphetamine, extended-release methylphenidate vs dextroamphetamine/amphetamine, or dextroamphetamine vs dextroamphetamine/amphetamine.

Methylphenidate and Adderall were tested in school-aged children (range, 5-17 years) with ADHD.^[14] Subjects participated in a 4-week, double-blinded, placebo-controlled trial in which the treating psychiatrist was allowed to determine which stimulant the child would be prescribed. One hundred fifty-nine subjects were referred for treatment, 117 of whom were placed on methylphenidate and 42 of whom were placed on Adderall. Subjects received a placebo dose, and varying doses of either methylphenidate (5 mg, 10 mg, or 15 mg by mouth twice daily) or Adderall (5 mg, 10 mg, or 15 mg by mouth every day). Subjects were then matched to the 42 Adderall subjects based on age, length of treatment, and gender. Results of this trial showed that the best dose of each agent was 19.5 mg per day of methylphenidate and 10.6 mg per day of Adderall. Both agents were considered to be more effective than placebo based on both parent and teacher ratings.

Side-effect reports were similar for both agents, with methylphenidate subjects reporting more anxiety and Adderall subjects reporting more insomnia and changes in mood. Notably, 15 subjects who received Adderall had been considered treatment failures on methylphenidate, 13 of whom responded. The findings of this study provide evidence that once daily dosed Adderall is at least as efficacious as twice-daily methylphenidate. The study was not without limitations, which included a nonrandom assignment of patients to treatment arms and the use of primarily middle-class subjects. Additionally, those who had not responded to methylphenidate may have benefited from the increased attention they received during the trial, thus increasing their likelihood of response.

Another comparative trial between Adderall and Ritalin studied the efficacy and time course to response in children with ADHD.^[15] The trial evaluated 25 subjects who were enrolled in a 6-week, within-subject, double-blind, placebo-controlled, crossover-designed trial. All subjects concurrently participated in an intensive behavioral treatment program. Subjects received placebo, Ritalin 10 mg or 17.5 mg by mouth twice daily, and Adderall 7.5 mg or 12.5 mg by mouth twice daily. Medications were changed daily at random so that each subject received an average of 5 days on each dose being evaluated. Ritalin and Adderall were considered to be more effective than placebo on all measures, including in the classroom and at recess. Adderall was found to significantly improve social behavior over Ritalin. Counselors and teachers felt that the higher dose of Ritalin and the low and high doses of Adderall were equally effective. Additionally, the authors concluded that using a reduced midday dose of stimulant would be effective for stimulants that require twice-daily dosing. Adderall was also reported to have a larger effect size during the fifth hour after the morning dose when compared with Ritalin. Adderall was reported to result in more side effects, which included gastrointestinal upset, loss of appetite, insomnia, changes in mood, and headache. Surprisingly, though, at the conclusion of the study more subjects were recommended to continue on the low dose of Adderall (n = 11) than on the high dose of Ritalin (n = 4). The primary limitation of this trial is that nonequivalent doses (3:4 ratio) of Adderall and Ritalin were used.

In a 3-week, double-blind, placebo-controlled study, Adderall was again compared to methylphenidate in children (mean age = 8.1 years) diagnosed with ADHD.^[16] Fifty-eight subjects were randomly assigned to receive placebo (n = 18), Adderall (n = 20), or methylphenidate (n = 20). Subjects were dosed according to specific dosing algorithms, with dosage adjustments made at the end of each week. Both stimulants were found to be superior to placebo according to psychiatrist and teacher ratings, while parents found no difference between stimulants in their evening assessments. Again, the side-effect profiles for both stimulants were similar, with more Adderall-treated subjects reporting changes in mood (sadness) and gastrointestinal upset. The mean doses during the trial were 25.2 mg per day for methylphenidate and 12.5 mg per day for Adderall. Again, this trial was potentially limited by restrictions on methylphenidate dosing according to the algorithm and the relatively short 3-week duration of the study.

Summary

The future study of ADHD looks very promising. With a new dosage formulation of methylphenidate coming to market, one can expect an increase in the number of comparative trials between once-daily dosed Adderall and once-daily dosed methylphenidate. Research for all stimulants to date shows a very robust response rate, estimated to be nearly 60% to 70%. Selection of therapy is often dependent on family history of response, physician familiarity, and comfort level with a particular medication, issues of compliance, and issues of cost. While methylphenidate continues to be commonly prescribed, in part due to its efficacy and in part due to the availability of a generic formulation, the newer agents are certainly a viable treatment option in cases where frequent dosing and intolerability are of concern.

References

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10. Metadate Package Insert, Medeva Pharmaceuticals, Inc., May 2000.
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17. Pelham WE, Gnagy EM, Chronis AM, et al. A comparison of morning-only and morning/late afternoon Adderall ^[TM] to morning-only, twice-daily, and three times-daily methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics. 1999;104:1300-1311.