Contents

1 Use of Methylphenidate in the Treatment of
Attention-Deficit/Hyperactivity Disorder

For near 50 years, the most widely used pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD) is the racemic (50:50) mixture of d-threo-(R,R)-methylphenidate and l-threo-(S,S)-methylphenidate isomers. The clinical effectiveness of racemic methylphenidate (MPH) appears to reside primarily in the d-isomer, the l-MPH isomer of racemic MPH formulations has long been regarded as an inactive component [11]; because of stereospecific pre-systemic metabolism of oral MPH, l-MPH does not reach effective levels in plasma. However, more direct administration of the l-MPH isomer has been shown to inhibit the locomotor stimulation by d-MPH and other stimulants in rats in a dose-dependent fashion [1].

Stimulants have been prescribed to treat restlessness and ADHD symptoms in children since the 1930s, mostly mixed amphetamine (AMPH) salts until the synthesis of MPH in 1944, and the marketing of MPH as Ritalin^®; in 1954 [2, 10]. Although newer drugs have been developed, including pure d-MPH, a transdermal patch, osmotic and slow release formulatins, racemic-MPH immediate release is still one of the most highly prescribed drugs for the treatment of ADHD [3]. Non-stimulant drugs have also been used to treat ADHD, however the average effect size for stimulants is greater than for non-stimulants, so non-stimulants are primarily used after stimulants have induced unwanted side-effects in individuals [6].

Though it was once assumed that the beneficial effects of stimulant medications on individuals with ADHD were paradoxical, studies have demonstrated that the direction of response is often the same in healthy individuals without ADHD [15]. Stimulant medications elicit a biphasic action in humans; low doses reduce locomotor activity and distractibility; high doses lead to nervousness, sleeplessness, and anorexia; overdoses show signs of excessive central nervous system stimulation including excessive agitation and anxiety as well as dizziness, nausea, palpitations, increased heart rate, and psychosis [16]. At some doses and on some tasks [5], stimulant drugs may have the same direction of effect (cognitive enhancement) in some individuals without ADHD [4] as well as in those with ADHD.

In Europe, where the prescription of stimulants has been restricted by custom and by law, clinical guidelines recommend an initial rigorous trial of multiple psychosocial interventions such as behaviour modification, cognitive therapy, family therapy and teacher consultation. In North America, where the prescription of stimulants has been accepted for decades and some restrictions have been relaxed, clinical guidelines recommend an initial rigorous pharmacological trial [20]. Over the past decade, the prescriptions for these stimulants (MPH and AMPH) have increased from less that 2 million in 1991 to over 10 million in 2001, and now it is estimated that approximately 6 % of school-age children are identified and treated with these drugs (about 3 million/year in the US) [21].

In the The Multimodal Treatment Study of Children with ADHD Cooperative Group (MTA) [14], the largest and longest study of children with ADHD combined type, aged 7 years to 9.9 years, were randomly assigned to 14 months of treatment in four groups: rigorous medication management; intensive behavioral treatment; the two combined; or standard community care (2∕3 treated with medication). All groups in the study showed reduction of symptoms over time [14]. However, the children in the combined treatment and the medication management groups showed further reduction in core ADHD symptoms than those in behavioral alone, or community care groups [14]. This validates the clinical experience that children who largely adhere to a well-titrated regimen of stimulants continue to benefit significantly for at least 14 months [9]. After the MTA study completed, the caregivers/children determined their continued treatment. Interestingly, most children who were treated with stimulants did not continue this treatment. After 8 years, only 32.5 % of ADHD cases were being treated with stimulant medications [19]. By the 3 year follow-up assessment point, the initial relative benefits of assignment to the medication conditions and of current medication use were no longer significant [8, 12, 17]. In an 8 year follow-up [13], treatment-related improvements during the study were generally maintained, but differential treatment efficacy was lost. There were no differences between the four initially assigned treatment groups on repeated measures of psychiatric symptoms, academic function, and social functioning [13]. There was also no difference between groups for long-term outcomes, e.g. substance use or delinquency [12, 13]. This suggests that the relative benefits of childhood treatment with stimulant medication, compared with non-pharmacological treatments—improvement in cognitive deficits as well as reductions in symptom severity—may dissipate after a 2 year to 3 year period, whether or not the medication component of treatment is continued or withdrawn [13, 17, 18].

In a different long-term study, where subjects had self-selected medication status for 9 years, groups separated into medicated > 1 year (average 5.3 years) or no treatment/short-term treatment, differed on 3 measures of academic achievement and on grade point average, with the medicated group outperforming the non-medicated group regardless of current medication status [19]. Compared with non-ADHD controls, the subgroup of ADHD adolescents not taking medication at follow-up had a more pervasive pattern of significant deficits than the subgroup of ADHD adolescents taking medication. The ADHD subgroup on medication had better performance on sustained attention and verbal learning tests [19].

1.0.1 Failures of Stimulant Drugs

A meta-analysis found that stimulants have a three-fold greater benefit on behaviour ratings than on attention as measured by performance on academic tests [20].

The effect of stimulant drugs can sometimes fade over time. This return of symptoms is usually attributed to drug tachyphylaxis or placebo relapse, and in the case of MPH and other reuptake inhibitors, Hinz et al. [7] suggests that this reduction of drug effect is due to systemic depletion of monoamines and a moderate relative nutritional deficit. When the diet was adjusted to include more of the monoamine precursors l-tryptophan and l-tyrosine and monoamine levels had returned to the normal reference range of the population the problem was corrected and the drug effects returned to previous levels. 97 % of subjects who experienced waning of initial drug effects were suffering from monoamine depletion and monoamine electrical dysfunction secondary to developing a relative nutritional deficit [7].

Acronyms

ADHD

attention-deficit/hyperactivity disorder

AMPH

amphetamine

MPH

methylphenidate

MTA

The Multimodal Treatment Study of Children with ADHD Cooperative Group

References