Is methylphenidate effective in reducing symptoms of attention deficit hyperactivity disorder in school-aged children?

In the present column the authors respond to a concern that was raised by a member of the Canadian Paediatric Society who had become alarmed with the number of grade school referrals he was receiving for behavioural difficulties and possible attention deficit hyperactivity disorder (ADHD). He also raised concerns regarding the perceived increase in the general incidence of stimulant use as a means to treat this population. This topic invokes discussion around many related issues such as how one goes about establishing a diagnosis of ADHD, what the treatment options are for ADHD and when these should be explored. While there are many issues around the diagnosis and management of ADHD, the authors developed a specific question according to the population, intervention, comparison and outcome (PICO) framework that could be addressed within the present column, keeping with its objective of providing evidence for clinical decisions. The evidence-based librarian at the Alberta Research Centre for Child Health Evidence conducted a search of PubMed (1966 to April 2002) by using the following search strategy: “Child” [MESH] and “attention deficit disorder with hyperactivity/drug therapy” [MESH] and “methylphenidate” [MESH] and symptom* The results were screened and the evidence was graded (1). A summary of the most rigorous evidence and a clinical commentary are presented. Selective publication of studies based on the nature and direction of the study's findings (4). Evidence has demonstrated that studies with positive results are more likely to be published than those with negative findings, and that the larger the treatment effect is, the more likely a study will be published (5–8). If publication bias exists, the results may overestimate the benefit of the treatment under consideration. The extent to which the design and conduct of a study are likely to have prevented systematic errors or bias (4). Evidence has demonstrated that the quality of reporting is associated with estimates of treatment effects; that is, poor quality reports tend to have larger estimates of treatment effect and may overestimate the benefit of treatment by as much as 40% (9,10). There is good evidence (1) to suggest that methylphenidate (MPH) reduces some of the symptoms of ADHD in school-aged children (2,3). The direction of findings is consistent across many studies; however, the magnitude of the benefit may be exaggerated due to methodological flaws and the existence of publication bias. ADHD is one of the most commonly diagnosed childhood-onset behavioural disorders in North America (11,12). It occurs in 3% to 8% of school-aged children and accounts for 10% of general paediatric visits (13). This disorder is characterized by a combination of developmentally inappropriate and maladaptive levels of inattention, hyperactivity and impulsivity. To be diagnosed, some of these symptoms must be present before the child is seven years old, persist for at least six months, cause clinically significant impairment in social and/or academic functioning and be present in two or more settings (eg, in school and at home) (14). Children may exhibit symptoms of inattention without meeting the diagnostic criteria for ADHD. Several treatments are available for ADHD, including, but not limited to, medication management, behaviour modification and cognitive behavioural therapy. Of these treatments, stimulant medications have been the major foci of research (15). The behavioural effects of stimulants were discovered more than 60 years ago by Bradley (16) who found that dl-amphetamine produced a dramatic calming effect in children while simultaneously increasing compliance and academic performance. In the following years, numerous short term treatment studies (ie, up to three months) revealed similar results (17). They showed that stimulants decreased fidgeting, interrupting and finger tapping, and increased on-task behaviour, compliance and academic performance in hyperkinetic children. Stimulants have since become the most frequently prescribed medications for the management of ADHD in children due to their perceived effectiveness and relative safety (18). Side effects are generally mild and short-lived, as they often only occur early in treatment. Common side effects include headache, insomnia, loss of appetite and jitteriness. Rare side effects consist of movement control problems, angina and anorexia. Generally, side effects can be addressed by lowering the dose. Several stimulants are available and have been used to treat ADHD, including MPH and dextroamphetamine. The literature suggests that few, if any, differences exist between the effectiveness of these two stimulants, because each equally improves core symptoms (19). However, children may have unique responses to each of these drugs. MPH is the medication most often investigated for treating ADHD and, thus, is the most frequently prescribed stimulant (15). Although studies of the short term benefits of stimulants for treating ADHD report improvements in the behavioural symptoms, Schachter et al (3) critiqued the internal and external validity of these results in a recently completed systematic review. In the most rigorous synthesis of the evidence to date, Schachter et al combined the results of 62 randomized controlled trials, published between 1981 and 1999, that investigated the safety and efficacy of short acting MPH compared with placebo. The reviewed trials included 2897 participants. MPH interventions lasted, on average, 3.3 weeks, with the longest trial lasting 28 weeks. The authors found that the majority of trials evaluated had small sample sizes, were of poor methodological quality, were conducted over short periods of time and used inappropriate measures of primary ADHD symptoms. In addition, the authors found a bias toward the publication of trials showing MPH to be more effective than placebo. Thus, despite finding that short acting MPH safely and efficaciously reduced clinical manifestations of ADHD in children younger than 18 years of age, the authors warn that the benefit of MPH may be over-estimated and that the results of primary studies are neither robust nor completely valid. The methodologically strong Multimodal Treatment Study of Children with ADHD (MTA) (2) addresses some of Schachter et al's (3) criticisms regarding sample size, long-term treatment and choice of primary outcome measures. This study was not included in the meta-analysis by Schachter et al because it did not include a placebo group. In this prospective 14 month randomized controlled trial, 579 children aged seven to 10 years with ADHD were randomly assigned to one of four treatment groups: optimized medication management, behavioural treatment, optimized medication and behavioural treatment combined or standard community care. The optimized medication management groups followed systematic titration protocols for determining MPH dosage; for the routine community care group, dosage was based on the clinician's best judgement. During the trial, the children in the optimized medication groups exhibited a significantly larger decrease in parent-and teacher-reported ADHD symptoms (inattention and hyperactivity-impulsivity) than children in the other groups. Thus, the result suggests that treatment with an optimized dose of MPH is superior to behavioural treatment and routine community care that includes medication. However, many of the children who received an optimized dose of MPH failed to demonstrate fully normal behaviour (38% reached normal range at one year). Although the MTA study provides evidence for the effectiveness of MPH up to at least 14 months and as long as the medication is taken, the longer term effects are unclear. Thus, conclusive recommendations concerning long term treatment cannot be extrapolated and further research is required. For clinicians to make rational treatment decisions, they must identify the ultimate objectives of treatment, select an appropriate treatment and specify treatment targets (20). Selection of a specific treatment requires clinicians to be aware of the benefits and risks of various options. Effective treatment also requires clinicians to implement the treatment regime properly, assist patients to adhere to it and monitor progress and outcome over time. In making treatment decisions for children and youth with ADHD, clinicians can turn to a vast literature of trials of stimulant drugs, and an ever-increasing number of systematic and meta-analytic reviews (3,19,21,22). Reviews converge in concluding that stimulant drugs are efficacious in reducing core symptoms of ADHD, and ameliorating a number of associated problems in the short term. So, what else does the clinician need to know or do to provide effective management for a child presenting with symptoms of ADHD? Quite a few things, based on deficiencies that have been identified in the existing research literature, evidence emerging from the MTA study (2) and points of consensus among recently published practice parameters and treatment guidelines. In their recent meta-analysis of randomized trials of MPH, Schachter et al (3) point to methodological weaknesses and incomplete reporting of adverse effects. Without discounting these criticisms, clinicians need to remember that the existing literature includes both poor and reasonably good quality studies and that reviewers will differ in the significance they attach to adverse effects, such as appetite suppression and insomnia. Schachter et al (3) also point out some limitations of the existing literature in terms of generalizability of findings, that clinicians need to consider further. First, the efficacy of MPH is based on studies in which subjects are predominantly boys. A few studies have reported comparable levels of efficacy in girls (23,24), but clinicians should be aware that the evidence base for medication decisions involving girls remains scanty. Second, conclusions about efficacy of stimulants in systematic reviews are largely derived from studies that measured improvement in core symptoms of ADHD, and often other disruptive behaviours. However, these may not always be the targets of therapeutic intervention. The primary goal of treatment in ADHD should be to maximize function (25). Clinicians need to work with parents and teachers to clarify the domains in which functional improvement is most sought, thereby identifying the overall objectives and specific targets of treatment. They then need to consider the evidence that stimulants will be efficacious in addressing these agreed upon therapeutic goals. Stimulant effects appear to be most robust for measures of core ADHD symptoms and associated disruptive behaviours, but more limited for areas impacted by academic and social skills deficiencies (26). However, clinicians will likely diagnose ADHD in an increasing number of children who present with mainly academic difficulties since the revisions to diagnostic criteria for ADHD that appeared in the 1994 Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (14). The recognition of a primarily inattentive subtype of ADHD (ADHD-IA) in DSM-IV has been associated with an increase in prevalence of ADHD among school-aged children of up to 60% (27). At the present time, though, there is very little evidence on the utility of stimulants in ADHD-IA to guide clinicians in making treatment recommendations for these children. If improvement in academic performance, peer-relationships or self-esteem are goals of intervention, clinicians will not find much evidence to support stimulant monotherapy. At the same time, they will encounter a growing consensus among published practice parameters and clinical guidelines on the need for comprehensive assessment of children presenting with ADHD, and the importance of including school, family and other factors in a comprehensive management plan (25,28,29). Though some commentators have interpreted the MTA's findings as showing the supremacy and sufficiency of medication therapy, others have argued against such a conclusion (30), and subsequent analyses have shown that a combination of medication with psychological-behavioural interventions is usually superior to medication used alone (31). The MTA trial also highlighted the importance of proper implementation of the medication intervention. Titration procedures were meticulous and patients were seen regularly and fairly frequently for monitoring and support. This combination of factors probably accounts, at least in part, for the better outcomes of patients who received medication through the trial than those randomly assigned to routine community care, even though about two thirds of the latter received medication treatment (2,32). These same factors also presumably contributed to the high rates of persistence with therapy observed during the 14-month trial. Of those patients assigned who received medication, 87% were successfully maintained on the therapy to the conclusion of the study. However, in a general population study, just over 60% of children prescribed MPH received a total of five or fewer prescriptions within a seven-year time window (33). Failure to remain on medication has been implicated as a factor in the current lack of evidence that stimulant treatment alters long term prognosis of children with ADHD. Lack of evidence of changes in overall outcome or prognosis presents one final dilemma for clinicians who would like to address this issue with parents. The limited evidence that does exist suggests some degree of long term benefit in at least two domains. Young adults who had been treated with stimulants for ADHD as youths experienced less social ostracism and subsequently felt more positively about themselves and other people than those not treated (34). Also, a lower risk of substance abuse disorder during adolescence was observed among boys treated with stimulants during childhood, than those who were not treated (35). There are formidable methodological challenges in trying to construct a satisfactory evidence base for long term benefits and safety of stimulant drugs, but this remains an important need. The MTA experience suggests that this task may be facilitated if clinicians are able to provide care to this clinical population in a way that approximates the ideals laid out in recently published guidelines, with their emphasis on comprehensiveness and diligence in all phases of the assessment and treatment process.

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