Overview

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common disorders diagnosed in children and adolescents. The American Psychiatric Association (APA) describes the essential feature as "a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development." Terms that have been used to describe children with "distractability, impulsivity, and usually overactivity" include minimal brain dysfunction/damage (MBD), hyperkinetic reaction, and hyperkinesis.

ADHD has been surrounded by great controversy involving clinicians, teachers, policymakers, parents, and the media. The range of opinion regarding the validity of ADHD extends from those who do not believe it exists and regard it as a myth, to those who believe that there is genetic and physiological evidence supporting its existence.

Prevalence estimates of ADHD vary according to the methods of ascertainment, diagnostic criteria, informants, and population sampled. According to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV), the prevalence of ADHD in school-age children is 3 to 5 percent. However, prevalence studies using the two previous versions of the DSM (DSM-III and DSM-III-R) in the United States, Canada, United Kingdom, Germany, and New Zealand have shown rates that vary from 1.7 to 16.1 percent. Although it was previously thought that ADHD remitted before or during adolescence, it has been estimated that more than 70 percent of hyperactive children continue to meet criteria for ADHD as adolescents and up to 65 percent as adults.

Problems with the diagnosis and treatment of this condition can also arise because approximately 65 percent of ADHD patients may have at least one comorbid disorder in the form of anxiety, communication, mood, conduct, oppositional defiant, and learning disorders; Tourette's syndrome; and subnormal intelligence. ADHD has been associated with impaired academic achievement, rejection by peers, and family resentment and antagonism. The rich terminology may reflect the broad spectrum and the high frequency with which it is described with other comorbid conditions.

There is also variation and controversy around the treatment of ADHD, which often includes stimulant medication. To reduce inappropriate variation in treatment, major organizations in North America have developed, or are in the process of developing, practice parameters or clinical practice guidelines to guide treatment decisions.

In 1997, the Agency for Healthcare Research and Quality (AHRQ) charged the McMaster University Evidence-based Practice Centre (MU-EPC) with producing an evidence report on the treatment of ADHD. The objectives of this work were to conduct a comprehensive systematic review of the literature on the treatment of ADHD, with input from different groups of stakeholders, and to support guideline development initiatives, while building on existing work and focusing on answerable, clinically relevant questions.

Reporting the Evidence

A multidisciplinary research team was assembled, with participation of members of the nominating organizations, the American Academy of Pediatrics (AAP) and the APA, local experts, and research staff. After multiple consultations and the evaluation of published systematic reviews and meta-analyses, the following general questions were selected as the focus of the evidence report:

• What is the evidence from comparative studies on the effectiveness and safety, both short and long term, of pharmacological and nonpharmacological interventions for ADHD in children and adults?
• Are combined interventions more effective than individual interventions?

To answer these questions, while avoiding the duplication of work, making efficient use of the resources available, and ensuring maximum added value, the scope of the evidence report focused on the following seven categories of research studies:

• Studies with drug-to-drug comparisons of pharmacological interventions.
• Placebo-controlled studies evaluating the effect of tricyclic antidepressants.
• Studies comparing pharmacological with nonpharmacological interventions (drug vs. nondrug studies).
• Studies evaluating the effect of long-term therapies (>12 weeks).
• Studies evaluating therapies for ADHD in adults (>18 years of age).
• Studies evaluating therapies given in combination.
• Studies evaluating adverse effects of pharmacological interventions.

Numerous systematic reviews and meta-analyses have examined placebo-controlled trials of stimulant medication and have established consistently the short-term efficacy of these agents for core symptoms. Consequently, placebo-controlled trials evaluating stimulant medication were reviewed in this report only if they met the criteria for inclusion in any of the other six categories. In addition, the report focuses on head-to-head comparisons of pharmacological interventions and on head-to-head comparisons of pharmacological and nonpharmacological interventions. This was identified as the area of prime interest to clinicians rather than effectiveness of stand-alone interventions-either pharmacological or nonpharmacological.

Methodology

Findings

• A total of 2,405 citations were identified by the search strategies. Ninety-two reports, describing 78 different studies, met all the inclusion criteria.
• Overall, numerous deficiencies in the reporting of available RCTs limit the assessment of their validity, relevance, precision, and, therefore, their clinical application. Most studies did not clearly describe clinically important information such as the primary outcomes of interest, the presence of comorbid disorders, the characteristics of the patients' families, compliance with treatment, and baseline measurement of outcomes of interest. There was little information on the treatment of ADHD in minority groups.
• The small sample size of most studies limited their power to detect meaningful clinically important differences among the interventions.
• Ninety-seven percent of the reports of RCTs did not describe the method of randomization. Ninety-five percent did not describe efforts to conceal allocation from the investigators who recruited the patients into the study (e.g., allocation codes were obtained by telephone after a patient accepted to enter the study). Eighty-seven percent did not describe the number of withdrawals and dropouts and the reasons for such in each of the groups. These limitations increased the likelihood of biased results.
• Comparison or synthesis of data across studies was limited by the low quality of reporting and by the large number and heterogeneity of outcome measures and tests used in the studies. Researchers often used modified versions of the same tests (e.g., Conners) across studies but did not provide enough information on the modifications. This led to the conclusion in many instances that there is a lack of evidence on the effectiveness of clinically important interventions. It is important to recognize that this is different from finding evidence of the lack of effectiveness of the same interventions.

The following is a description of the main conclusions from each of the seven categories of interest:

• Drug vs. drug comparisons: The limited evidence available from studies comparing different stimulants suggests that there are few, if any, short-term differences in effectiveness among methylphenidate (MPH), dextroamphetamine, and pemoline. The studies comparing stimulants to tricyclic antidepressants had many limitations and presented conflicting results.
• Drug vs. nondrug comparisons: Despite the limitations in the individual studies, the results indicate consistently that stimulants are more effective than nonpharmacological interventions when compared head-to-head.
• Combination therapies: Evidence is lacking to support the superiority of combination therapy over stimulant alone or superiority of combination therapy over nondrug intervention alone. A recent large trial found that combined treatment offers modest additional benefits over single-component treatments for non-ADHD areas of functioning.
• Tricyclic antidepressants vs. placebo: The studies on desipramine, despite their heterogeneous designs, small sample sizes, and variable quality, suggest that desipramine is more effective than placebo. The studies evaluating imipramine show inconsistent results.
• Long-term therapy: All but one of the studies available were restricted to school-age children. Few studies followed children for a period of time equivalent to the length of time children typically remain on these treatments or reported side effects or used outcome measures that are situation specific (e.g., measure outcomes at home and at school). These studies show a trend to general improvement over time regardless of treatment and support the need for long-term placebo-controlled studies. MPH appears to reduce behavioral disturbance in ADHD children as long as it is taken. However, there is no information on the reasons so many children discontinue medication. The studies available provide little evidence for improvement in academic performance with stimulants, even though MPH treatment appears to produce consistent behavior improvement. The largest and most comprehensive study to date (Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder-the MTA Cooperative Group study) indicates that intensive behavior therapy, comprising child, family, and school-based interventions, adds little to the effects of long-term stimulant therapy. The MTA study also identified that the quality of supervision of medication may be an important factor in optimizing long-term therapeutic benefit. Lithium does not appear to be an effective alternative in patients who do not respond to stimulants.
• Treatment of ADHD in adults: The few studies evaluating MPH vs. placebo show contradictory results. The study with the highest methodological scores suggests that MPH may be effective for the treatment of ADHD in adults. Antidepressants may be effective in adults. Studies (one each) comparing pemoline, nicotine, or phenylalanine with placebo did not produce evidence in favor of these medications. There were no studies designed to determine the proportion of adults with ADHD who will use and benefit from other interventions.
• Adverse effects: Many of the side effects associated with stimulant use appear to be relatively mild and of short duration and respond to dosing or timing adjustments. However, data are inadequate on the long-term effects and severity of the adverse effects of most interventions. No comparative studies were identified with data on important adverse effects of interest, including potential for abuse of stimulants, liver toxicity due to pemoline, or major arrhythmia with tricyclic antidepressants in patients with ADHD.

Future Research

Areas needing further research include the following:

• Effective strategies are needed to improve the quality of the study designs and reports. Journals that publish articles on the treatment of ADHD could benefit by the endorsement of criteria such as those included in the Consolidation of the Standards of Reporting Trials (CONSORT) statement, which has been adopted by over 70 leading peer-reviewed journals.
• Larger studies with more rigorous design and longer term followup are needed to establish the effectiveness and adverse effects of most interventions in both children and adults.
• The field would benefit from empirical methodological research evidence indicating the added value of nonrandomized within-subject and single-subject research designs for direct head-to-head comparisons between psychosocial interventions and other treatments.
• Research groups should make efforts to select a core set of validated and clinically relevant outcomes to be measured in all the studies in addition to any other outcomes of interest to the specific groups of researchers.
• More rigorous studies are clearly needed to establish the relative effectiveness of stimulants and tricyclic antidepressants and to compare the effects of stimulants with clonidine, buproprion, or selective serotonin-reuptake inhibitors.
• More definitive studies are needed to determine the added value of nondrug interventions when patients are already receiving stimulants, as well as the value of adding stimulants when nondrug interventions fail to achieve the desired outcomes. These studies, however, will require complex designs, substantial amounts of resources, and efficient collaboration among research groups. The MTA study is an example of this type of collaborative effort.
• Studies are also needed to determine whether comorbid factors (e.g., anxiety and depressive disorders) influence response to treatment.
• Studies are required to assess the severity of most adverse effects associated with stimulant medication and to evaluate, explicitly, the tradeoff between improvement in ADHD symptoms and signs and adverse effects. However, such a study is only worthwhile if the perspectives of all interested parties (parents, teachers, and patients) are included in the exercise.
• Reports of effectiveness and adverse effects almost always come from parents and/or teachers. One study (of adolescents) showed some important differences between parents and adolescents in the side-effects profile reported by each group. Data need to be collected from children on effectiveness and adverse side effects in order to gain a better understanding of the implications of treatment from the patients' perspective.
• A better understanding of the distinctions between "adverse effects" of therapy and concomitant characteristics of ADHD is needed. A number of reports discuss the high prevalence of "side effects" reported on placebo. Many of these may be associated with problem behaviors. Including such behaviors distorts the context for evaluating the importance of side effects.
• There were very few female patients in the available studies. A possibility exists that effectiveness and adverse effects vary by gender. This is an issue that needs to be examined or at least discussed.
• RCTs are of limited power to evaluate adverse effects, particularly rare ones or those that appear during long-term therapy. Only one comparative non-RCT with adequate data was found and it provided limited information. More observational studies are required (particularly case-control or cohort studies). Knowledge of adverse effects may also improve through more creative use of existing drug databases.
• Few studies have been supported financially by sources other than the Government or pharmaceutical companies. There is a great opportunity for consumer groups to support more research activities, given the number of important questions that remain unanswered and the implications of the results of research on the public.
• Conducting research on the treatment of ADHD is not easy, given the complexity of the disorder, the frequent presence of comorbidity, and the variety of interventions and outcomes available. Future research efforts will require commitment among different groups of stakeholders.

In summary, this report includes seven systematic reviews that incorporate state-of-the-art methodology, represent the most rigorous systematic review conducted to date, and are ready for incorporation into evidence-based clinical practice guidelines or performance measures. The report also provides a detailed description of the many limitations of the evidence available and provides recommendations to fill existing knowledge gaps. Filling such gaps will not be easy and will require highly innovative efforts and collaboration among different groups of decisionmakers. The MTA study confirms that large-scale, long-term collaboration among researchers is possible. If this field continues to produce small, incompletely reported studies with heterogeneous designs, instead of the high-quality collaborative efforts required, research in this area will continue to be abundant but will be of little value to guide most clinically relevant decisions.