Effects of treatment

Most children with attention deficit hyperactivity disorder (ADHD) have a robust response to stimulants, and most clinicians agree that one of the stimulants should be the first pharmacologic treatment of choice. Currently available stimulants and the dose ranges approved by the U.S. Food and Drug Administration are summarized in Table: Stimulants Used to Treat ADHD.

Successful treatment improves the core symptoms of ADHD. In addition, improvements in fine motor control, decreased aggression, improvements in social relationships, reductions in oppositional and rule-breaking behaviors, and improved accuracy in schoolwork are seen.

The effective use of stimulant medication is not specific to ADHD but can extend to other disorders of attention and behavior. In patients with ADHD and conduct disorder, methylphenidate (MPH) markedly reduced not only aggressive symptoms but also covert symptoms such as cheating and stealing.

The use of stimulants has a long history, starting in the 1930s with Charles Bradley,66 who reported on the successful use of benzedrine (a racemic mixture of d- and l-isomers of amphetamine) in 30 school-age children with behavioral problems. His keen clinical observations on the first use of a stimulant in children remain relevant today.

Pharmacokinetics

The therapeutic effects of the stimulants are related to their ability to enhance catecholaminergic transmission.67 All stimulants are rapidly absorbed and metabolized and demonstrate low plasma protein binding.

The immediate-release preparations generally begin to act 30 minutes after ingestion, and their effects last 3 to 5 hours. The effects of Focalin, an isomer of the MPH molecule, last 3 to 5 hours. There are some reports that adverse effects are somewhat less with this preparation, but that has not been proven.

Although the original sustained-release preparations were longer-acting, they rarely covered a child for the entire school day. For example, the traditional sustained-release version of MPH is erratically absorbed and performs poorly.

Pharmaceutical companies, using essentially the same active ingredient, recently have developed true, longer-acting stimulants. The newest additions to the stimulants are Concerta, Metadate CD, and Ritalin LA. These are MPH products in unique, controlled-release delivery systems. These systems appear to give a steady release of MPH throughout the day, resulting in 7 to 12 hours of efficacy. One company is working to develop MPH in a patch delivery system, with the aim of having the effects last until bedtime.

Adderall consists of equal portions of four salts: dl-amphetamine sulfate, dl-amphetamine aspartate, dextroamphetamine sulfate, and dextroamphetamine saccharate. Several studies have shown that Adderall is as effective as MPH, that the duration of action is slightly longer than immediate-release MPH, and that the duration of action increases as the dose increases.

Adderall XR is an amphetamine product that (like the long-acting MPH products) has a controlled delivery system that allows it to last for 8 to 10 hours.

Metadate CD, Ritalin LA, and Adderall XR are in a capsule form that can be opened and sprinkled on food for youngsters who have trouble swallowing capsules or pills.

Pemoline is used infrequently, in part because it was less extensively studied but also because it appeared to take 3 to 4 weeks to become effective and periodic liver function testing was required. More recent studies indicate that pemoline is as effective as MPH and has the advantage of a longer half-life. In addition, it can be titrated much more quickly than MPH, resulting in clinical efficacy within a short period.68 However, liver toxicity, liver failure, and deaths were associated with pemoline treatment,69 resulting in newly revised guidelines for its use by the manufacturer. These guidelines include obtaining serum alanine aminotransferase levels every 2 weeks during pemoline therapy and obtaining written consent for use of this agent.

Choosing a stimulant

The choice of stimulant is dictated by such issues as duration of action and slight differences in adverse effects. All the stimulants have similar effects on target symptoms. One study testing the efficacy of MPH and dextroamphetamine (DEX) in boys found that 75% of subjects improved on one of the stimulants. Most of those who failed to respond to one stimulant responded to the other. As a result, 96% of the subjects showed improvement.70

Dosage and titration

The stimulants have often been titrated on the basis of a youngster’s body mass. Rapport and Denney,71 in their study of 76 children treated with MPH under double-blind crossover conditions, found no evidence that body mass predicted the appropriate medication dose or distinguished between responders and nonresponders. It appears that this practice should be abandoned. For most children, U.S. Food and Drug Administration guidelines for maximum daily dose of a particular stimulant can be followed. A subgroup of children requires higher dosages or more frequent doses to bring symptoms under effective control.

No evidence exists for the development of tolerance with these medications.

Side effects

All stimulants have similar side effects, which tend to be mild and short-lived. They occasionally cause decreased appetite, mild stomachache, headaches, and initial insomnia in susceptible individuals. Patients on high dosages have rarely exhibited perseverative behaviors or hallucinatory phenomena. Generally, no additional sleep delays are seen with an afternoon dose of MPH.72 Many side effects are time-limited and can often be reduced or eliminated by manipulating the timing, dose, form, or kind of stimulant.

Growth suppression

The effects of stimulants on the rate of growth and final height have been controversial. Approximately one-third of the studies found no evidence of growth suppression. In cases in which growth suppression did occur, studies have generally identified modest deficits of 1 to 3 centimeters over a several-year period. Follow-up studies of adults treated for ADHD in childhood found no difference in the height of these adults as compared to controls.73 A study by Spencer et al.74 of 124 subjects with ADHD found that, whether or not the subjects were treated with stimulants, their rate of growth during childhood was slower than that of non-ADHD children, and their rate of growth normalized by late adolescence.

Tics

Whether the development or exacerbation of tics is related to MPH and other stimulants is a long-standing and controversial issue. A concern persists that stimulants can precipitate tics in individuals without tics,75 worsen tics in individuals with preexisting tics, and precipitate the full picture of Gilles de la Tourette’s syndrome in susceptible individuals.76–78 The current data indicate, however, that for patients with Gilles de la Tourette’s syndrome or tic disorder and ADHD, MPH is an appropriate medication.79–81

Gadow et al.81 studied boys with ADHD and moderately severe tics who were taking MPH and found no worsening of tics at doses of 0.1–0.5 mg/ kg twice daily. Castellanos et al.82 examined 20 children with ADHD and Gilles de la Tourette’s syndrome in a 9-week, placebo-controlled, double-blind crossover trial involving MPH and DEX. Doses ranged from 15 to 45 mg twice daily for MPH (means of 0.43–1.20 mg/kg per dose) and from 7.5 to 22.5 mg twice daily for DEX (means of 0.20–0.64 mg/kg per dose). At the lowest doses, no significant effects on tic severity were observed, but with increasing doses, tic exacerbation became evident. In most patients on MPH, these exacerbations were only temporary. However, for most of the patients on DEX, tic severity did not decrease while subjects remained on the medication. During follow-up, clear-cut advantages for MPH over DEX remained. Two-thirds of the patients remained on stimulant medication at the 4-year follow-up, whereas a subgroup was unable to tolerate such treatment. Interestingly, transient obsessive-compulsive symptoms were noted in five subjects on MPH and in one subject on DEX. In a long-term follow-up by Gadow et al.,83 subjects demonstrated high acceptance for continued use of MPH.

Law and Schacher84 studied 91 children with ADHD who had received no previous medical treatment. The children, who had a mean age of 8 years, participated in a 1-year, randomized, placebo-controlled trial of MPH titrated to an effective dose. Thirty percent of the subjects had preexisting tics. The mean MPH dose was 0.5 mg/ kg twice daily. Over the course of the study, 60% of the placebo-treated subjects were switched to active medication because of lack of improvement of their ADHD. The results indicated that, regardless of whether they were on active medication or placebo, approximately 19% of the children without preexisting tics developed tics. Of children with preexisting tics, 67% experienced no change in or improvement of their tics. Most of those whose preexisting tics worsened were managed with a reduction in dose.

Stimulants and seizures

The Physician’s Desk Reference entry for Ritalin (MPH) states: “There is some clinical evidence that Ritalin may lower the convulsive threshold in patients with prior history of seizures, with prior EEG abnormalities in absence of seizures and, very rarely, in absence of history of seizures and no prior EEG evidence of seizures.”88 This caution appears to be largely unsubstantiated.

Gross-Tsur et al.89 studied 30 children with epilepsy and ADHD who were taking antiepileptic drugs (AEDs). All children were monitored for a 2-month period and then given a morning dose of MPH of 0.3 mg/kg for 2 months. All children who were seizure-free on AEDs alone remained seizure-free. Of the five subjects whose seizure activity was incompletely controlled by the AEDs, three showed an increase in seizures, one showed no change, and one was seizure-free. These investigators also found no significant changes in AED levels or EEG findings. On parent reports, 70% of all the subjects showed a positive response to MPH.

Feldman et al.,90 in a double-blind crossover study, evaluated 10 children having a variety of seizure disorders. All were taking AEDs and were seizure-free. The addition of MPH twice daily (0.3 mg/kg per dose) in a double-blind, placebo-controlled manner did not result in significant changes in EEG findings. While taking MPH, none of the children had seizures and 70% showed improvement of their ADHD symptoms.

A single case report describes two children who developed dyskinesia and bruxism when MPH was added to a maintenance dose of valproic acid.91

Stimulants and preschoolers

The use of stimulant medication for preschool children has been controversial. Making the diagnosis of ADHD in this age group is difficult, and the public has concerns about administering medication to very young children.85 Musten et al.86 studied 31 children (ages 4 to 6 years) in whom ADHD had been diagnosed, and found that preschoolers' symptoms responded to both 0.3 mg/kg and 0.5 mg/kg in a fashion similar to that in school-age children. Side effects were relatively mild.87 (See more on preschoolers below.)

Stimulants in mental retardation and pervasive developmental disorders

Several studies have evaluated the use of stimulants in school-age children who have mental retardation (MR).92,93 Generally, these studies reported some improvement in core symptoms, but most subjects continued to have a significant level of symptoms and a greater level of adverse effects than subjects without MR.

Studies of stimulant use in preschoolers with MR have tended to be complicated because of the difficulty in determining the appropriateness of these youngsters’ behavior as it relates to their mental age. Small studies and case reports have generally revealed improvement of some symptoms, but almost half the subjects experience significant side effects. Handen et al.94 treated 11 preschool-age children who were mentally retarded. The study was a double-blind crossover design using placebo and two doses of MPH (0.3 mg/kg and 0.6 mg/kg). The study found that 73% of subjects responded positively. Although the positive response was greater at the 0.6-mg dose, adverse events also increased with the higher dose. Adverse events were reported in 45% of the sample. The most commonly reported side effect was social withdrawal.

A double-blind study of patients with fragile X syndrome found that subjects improved while taking stimulants.95 Birmaher et al.96 found significant improvement of all ADHD symptoms with use of MPH in a group of autistic children. Given their ease of use, stimulants should be the first line of treatment for ADHD symptoms in these children.

Adapted from: Hirsch GS and Koplewicz HS. Attention-deficit hyperactivity disorder. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;187–204.
With permission from Elsevier (www.elsevier.com).
Reviewed and revised June 2004 by Glenn S. Hirsch MD, NYU Child Study Center, New York.

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