According to a recent review, “Stimulants are among the most effective psychotropic medications in clinical use today.”

Currently, the most commonly prescribed medication for ADHD is osmotic-release methylphenidate (OROS MPH), a long-acting stimulant designed to release gradually increasing concentrations of MPH over 10–12 hours.The effectiveness of OROS MPH is supported by two studies conducted in laboratory settings and a multisite efficacy study. In these studies, OROS MPH was shown generally to mimic the efficacy and side effect profile of three-times-a-day (tid) MPH in treating childhood ADHD. Recently, a one-year open follow-up study indicated that OROS MPH is well tolerated, with few clinically significant adverse effects. Dosage varied from 18 to 54mg in these studies, with the most common dose being 36mg. However, none of the aforementioned studies systematically examined the relationship between OROS MPH dose and behavioral and cognitive symptoms of ADHD.

As defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),ADHD is a heterogeneous disorder with considerable variation within individuals in their degree of cognitive (i.e. inattention) and behavioral (i.e. hyperactivity) symptoms. Studying inter-individual differences within and across different domains of functioning can increase understanding of the pathophysiology of the disorder and facilitate understanding of pharmacotherapy. Stimulant medications are usually titrated until there is optimal symptom reduction or until significant stimulant side effects occur. Mild side effects are commonly reported in children who take stimulant medications, and changes in timing and dosage often result in improvement.The two most frequent untoward effects of immediate-release stimulant medications are sleep disturbance and decreased appetite; slightly less common side effects include negative mood changes (e.g. irritability, sadness, anxiety), headaches, tics, and stomach-aches. Stimulant side effects are often presumed to be dose related, with higher doses yielding more severe side effects. However, with the exception of decreased appetite, this has not been demonstrated within the mild to moderate dose ranges (i.e. 0.3–0.5mg/kg/dose) in studies of short-acting stimulants with school-age children. The relationship between dose and stimulant side effects has not been evaluated systematically using long-acting stimulants.

In 1937, Bradley first noted that children vary significantly in their response to stimulant medication and stressed the importance of identifying correlates of treatment response to further our understanding and improve clinical decision making. Moderators, or subgroups defined by baseline characteristics, may respond differentially to stimulant treatment. For example, the landmark Multimodal Treatment Study of Children with ADHD (MTA) examined several potential moderators, such as previous medication use,demographic characteristics, and comorbidity, but one of the most common ADHD subgroups, individuals with ADHD predominantly inattentive type (ADHD-PI), was not included in the MTA sample.Thus, it is unclear whether stimulant medication response is moderated by ADHD subtype. In an earlier study conducted before DSM-IV, Barkley and colleagues examined the efficacy of 5, 10,and 15mg of MPH administered twice per day, in children with DSM-III-defined attention-deficit disorder (ADD) with and without hyperactivity. The subgroup of children with ADD without hyperactivity responded to lower doses than children with ADD with hyperactivity. Extrapolating to DSM -IV, Stein et al. hypothesized that ADHD subtype will moderate dose-response relationships to OROS MPH and conducted a study to investigate. The goals were to examine the relationship between OROS MPH dose and ADHD symptoms, impairment, and side effects and evaluate the potential moderating effects of ADHD subtype.