Chapter  11:  Treatment of Attention-Deficit/Hyperactivity Disorder: Evidence Report/Technology Assessment Number 11

Objectives

To determine (a) the long-term and short-term effectiveness and safety of pharmacological and nonpharmacological interventions for attention-deficit/hyperactivity disorder (ADHD) in children and adults and (b) whether combined interventions are more effective than individual interventions.

Search Strategy

MEDLINE (from 1966), CINAHL (from 1982), HEALTHStar (from 1975), PsycINFO (from 1984), EMBASE (from 1984), and the Cochrane Library searches were completed in November 1997. Reference lists of eligible studies and files of members of the research team and partner organizations were also searched.

Selection Criteria

Studies were selected if they focused on the treatment of ADHD in humans and were published in any language as a full report in peer-reviewed journals. Studies including conditions other than ADHD were reported if separate subgroup analyses for patients with ADHD were provided.

Data Collection and Analysis

3 Two reviewers independently extracted data for 41 variables on general characteristics, along with detailed information on interventions, outcomes, and tests. Differences were resolved by consensus or by a third researcher. Studies were not combined quantitatively because the quality of reporting was low and heterogeneity existed across outcome measures and tests.

Main Results

• Seventy-eight studies (77 randomized controlled trials) met the inclusion criteria.

• Twenty-three studies compared drugs and showed few, if any, differences among methylphenidate (MPH), dextroamphetamine (DEX), and pemoline; studies comparing stimulants with tricyclic antidepressants (2) were inconclusive.

• Six studies compared drugs with nondrug interventions and showed consistently that stimulants, particularly MPH, may be more effective than nonpharmacological interventions.

• Twenty studies compared combination therapies with a stimulant or a nondrug intervention alone; no additional beneficial effects for combination therapies were shown.

• Nine studies compared tricyclic antidepressants with placebo and showed that desipramine may be more effective than placebo; no consistent effect was shown for imipramine.

• Fourteen studies (13 in school children and 1 in adults) evaluated long-term therapy (>12 weeks) and showed a trend to general improvement regardless of treatment, but the length of followup was inadequate. MPH may reduce behavioral disturbance in children with ADHD while it is taken. Academic performance does not appear to be improved with stimulants.

• Twelve studies evaluated treatment in adults with ADHD. For MPH vs. placebo, the results were contradictory. Antidepressants may be effective in adults, but no beneficial effect was seen with pemoline, nicotine, or phenylalanine compared with placebo.

• Thirty-two reports (29 studies) evaluated adverse effects of drug therapy; many of the side effects associated with stimulant use appear to be relatively mild and of short duration and to respond to dosing or timing adjustments. Data are inadequate on the long-term effects and severity of adverse effects of most interventions.

Conclusions

This report describes rigorous systematic reviews on the treatment of ADHD, 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. Studies on ADHD have low reporting quality, methodological flaws, and heterogeneity across outcome measures and tests. A detailed description is included of the many limitations of the available evidence plus recommendations to fill existing knowledge gaps. Fulfilling such knowledge gaps will not be easy and will require genuine collaboration among decisionmakers.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of the copyright holders.

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.

Commissioning of This Report

Since 1997, the Agency for Healthcare Research and Quality (AHRQ) has been supporting initiatives that could facilitate the production of clinical practice guidelines and quality improvement tools and inform consensus conferences. One of these efforts is a joint initiative involving the AAP and Technical Resources International, Inc., to gather and analyze evidence on the prevalence and diagnostic screening of ADHD.

In June 1997, the U.S. Department of Health and Human Services announced the start of a new program through which the AHRQ would award contracts to institutions in the United States and Canada to serve as Evidence-based Practice Centers (EPCs). The mission of these EPCs, of which McMaster University is one, is to review all the relevant scientific literature on health care topics assigned to them by AHRQ. The main task of the EPCs is to produce "evidence reports" that will serve as the scientific foundation for public and private sector organizations to develop tools and strategies for improving the quality of the health care services. The first set of topics was nominated by a group of public and private sector organizations in response to a solicitation published by AHRQ in November 1996. On August 21, 1997, the McMaster University EPC (MU-EPC) was invited to submit a proposal for the development of an evidence report on the treatment of ADHD. This topic had been nominated by the AAP and the APA. Dr. David Atkins was identified by AHRQ as the Task Order Officer (TOO) for this Task Order.

The MU-EPC was notified on September 30, 1997, that it was successful in its bid to undertake the development of an evidence report on the treatment of ADHD, which is described in this document. The objectives of this Task Order were to conduct a comprehensive systematic review of the literature on the treatment of ADHD and to support guideline development initiatives by the nominating organizations, while building on existing work and focusing on answerable, clinically relevant questions.

Concurrent Work

During the period in which this Task Order was in development, two professional organizations, the American Medical Association (AMA) and AACAP produced important reports on the treatment of ADHD (American Academy of Child and Adolescent Psychiatry, 1997a; Goldman, Genel, Bezman et al., 1998).

The report by the AMA was produced by the Council of Scientific Affairs. It had some elements of a systematic review, as it included a clear description of the research questions and provided a description of the search strategy used to identify the relevant literature. The report, however, did not describe the inclusion or exclusion criteria for articles, the methods to assess the validity of the information, or the strategies used for data synthesis. The report by the AMA addressed six questions to inform current professional and public concern about ADHD. Two of the questions relate to issues addressed by this Task Order:

• What constitutes optimal treatment for ADHD, and how do stimulants fit into it?

• What are the adverse consequences of using stimulants, and, in particular, what is known about the risks of abuse and diversion?

The report by the AACAP was produced by the Work Group on Quality Issues and approved by the AACAP Council in February 1997. It also included a description of the search strategy used to identify literature on the assessment and treatment of children, adolescents, and adults with ADHD. The report did not present the issues of interest as questions but was structured following clear sections by topics of interest. As in the AMA report, no description of the inclusion and exclusion criteria, the criteria to assess the validity of the information, or the strategies used to synthesize the information was included. Because reports were published in peer-reviewed journals, it is possible that the information was not provided because of space limitations.

The National Institutes of Health (NIH) held a consensus planning conference on ADHD in November 1998. The NIH has also funded a long-term, collaborative Multimodal Treatment Study of Children with ADHD (the MTA Collaborative Group study) to address issues emphasized by the Institute of Medicine study Research on Children and Adolescents with Mental, Behavioral, and Developmental Disorders, the National Institute of Mental Health (NIMH) National Plan for Research on Child and Adolescent Mental Disorders, the Healthy People 2000, and Healthy Children 2000. This study examined long-term (14 months with a 24-month followup) effectiveness of medication for treatment of ADHD vs. behavioral treatment vs. both and compared state-of-the-art treatment with routine community care. In a parallel-groups design, 576 children (age 7 to 9 years) with ADHD were thoroughly assessed and randomized to 4 conditions: (1) medication alone, (2) psychosocial treatment alone, (3) the combination of both, or (4) community comparison (Richters, Arnold, Jensen et al., 1995). The results of this study became available to us in early 1999 and have been incorporated into this report.

The research team for this report was also aware that a systematic review that included placebo-controlled studies evaluating the effect of stimulants had been commissioned by the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) to a group of researchers at the University of British Columbia in Canada. Relevant results from that effort have also been incorporated into this Task Order Report.

Research Questions and Scope of Work

A multidisciplinary research team was assembled, with participation of members of the nominating organizations (the subcommittee of the AAP on ADHD and the Deputy Medical Director of the APA), consumer groups, local experts, and research staff (Appendix B). The local experts and research staff constituted a "local research team." All others were regarded as partners. To identify the research questions for this Task Order, the group engaged in multiple consultations and considered the findings of a systematic review of published systematic reviews and meta-analyses (Appendix C). This process led to the identification of the following questions to be addressed by 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?

An extensive period of time at the outset of the report process was spent consulting with members of the nominating partner groups, AHRQ, and the research team in order to refine the general questions. To answer these questions and avoid duplication of work, make efficient use of the resources available, and ensure maximum added clinical 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.

The above categories will be described in detail in the Methodology chapter. A separate category of studies comparing the short-term effect (<3 months) of stimulants with placebos was not included in the scope of work for this Task Order. Individual studies comparing stimulants with placebo were included in this report only if they met the inclusion criteria for any of the other categories. The main reason behind this decision was that, as mentioned above, another group had been commissioned to cover this issue. Most of the members of the research team considered that even if an additional review was conducted, the conclusions would not be different from those obtained by the researchers at University of British Columbia, given that most studies to date have shown consistently that stimulant medication improves core symptoms, at least in the short term (Kavale, 1982; Ottenbacher and Cooper, 1983; Thurber and Walker, 1983). Therefore, it was concluded that a new systematic review on this topic would have added little to the current state of knowledge and would have consumed all the resources available to answer other questions. Instead, the team decided to focus attention on studies comparing the long-term effects (>12 weeks) of stimulants with placebo and complement the findings with those of previous systematic reviews and the concurrent work conducted at the University of British Columbia. In summary, focusing the scope of work on the seven categories of studies described above was the strategy used by the research team to ensure maximum added value, avoid duplication of work, and present the unique contributions of this Task Order to current knowledge on the treatment of ADHD in children and adults.

Inclusion and Exclusion Criteria

Citations of individual studies were regarded as potentially eligible and selected for further evaluation if they met the following generic criteria:

• They focused on the treatment of ADHD in humans.

• They were published, in any language, in peer-reviewed journals as a full report.

Hard copies were obtained for all potentially eligible studies. They were independently assessed by two members of the research team who then decided, by consensus, whether to include the study in one or more of the categories covered in the evidence report. If the studies included conditions other than ADHD, they were included if separate analyses for patients with ADHD were provided.

With the exception of the systematic review of adverse effects, the focus was placed on evidence provided by randomized controlled trials (RCTs), the simplest and more powerful research design to evaluate the efficacy and effectiveness of interventions. The specific inclusion criteria for each of the categories listed below were agreed to by all the members of the research team.

Literature Search

Citations of potentially eligible studies were identified through a systematic search of:

• MEDLINE (from 1966), CINAHL (from 1982) and HEALTHStar (from 1975), PsycINFO (from 1984), and EMBASE (from 1984) using the search strategy described in Appendix D. All databases were searched from the date of their release to November of 1997. The strategy was designed for search of MEDLINE and was modified to meet the specific features of CINAHL, EMBASE and PsycINFO.

• The Cochrane Library (issue 4, 1997).

• The reference lists any eligible article identified in any of the above sources.

• Web sites of organizations funding research on the treatment of ADHD.

• Files of members of the research team and partner organizations.

Data Extraction

Data extraction forms were especially developed and tested for this project (Appendix E). After consultation with all the members of the local research team, the partners, and the TOO, the forms were approved for content. Two reviewers extracted data independently from each of the full reports. Any differences were resolved by consensus and by referring to the information in the original report. Any differences that could not be resolved by the two reviewers who extracted the data were resolved by the Task Order Leader or by a member of the local research team designated by him.

The original reports were not masked because an empirical methodological study showed results indicating that masking was time consuming and did not have an important impact on the results of systematic reviews (Berlin, 1997).

The information extracted addressed 41 different aspects (Appendix E, pages 1 to 5) of the studies, which were selected by the team members a priori. Of these, 25 elements were regarded as essential to judge the validity of each of the studies. The selection of five of these elements (questions 37 to 41 in Appendix E) was supported by empirical methodological evidence from studies that showed a direct relationship between these elements and the likelihood of bias in RCTs. The remaining 20 elements were selected by consensus among all the research team members as clinically important but are not based on empirical methodological research.

Data Synthesis

Descriptive statistics were calculated for all the fields of the database. Evidence tables were constructed to describe the most salient characteristics of the eligible studies. These tables, which can be found after the References in this report, summarize, globally and category by category, all the information that was extracted.

Within each of the categories, four sets of tables were produced. The first three sets were regarded as the main evidence tables to support the information included in the Findings chapter, whereas the fourth was regarded as a separate source of information for readers interested in the data extracted in a very detailed fashion. The sets of tables have the following general structure:

• The first set contains a summary of the key characteristics of the studies reviewed, including the name of the first author, the year of publication of the study, the type of study design, the number of patients randomized (or the number of patients analyzed, if the number of patients randomized was not available), the diagnosis model, the interventions studied, the duration of exposure to each of the interventions, the quality scores, the number of elements extracted from the articles among those regarded as essential to judge the validity of each of the studies but that were not supported by empirical evidence (20 in total), the outcomes of interest measured (following the list provided above), and the key results for the outcomes of interest (expressed in terms of statistical significance set at p<0.05). Data on outcomes other than those identified a priori as being of interest were not reported in these tables. They were mentioned in the text of the report when they had clinical significance.

• The second set of tables includes a summary of the presence or absence in each of the studies of each of the 20 elements extracted from the articles that were regarded as essential to judge the validity of each of the studies but that were not supported by empirical evidence. The last column of these tables provides a count of these elements by article. This count should not be regarded as a quality score because no evidence exists on the relative weights of each of these elements. The counts were included to provide the reader with additional information to guide his or her decisions. The cells of all the other columns only include 1 and 0, representing whether the element was present or not in the articles, respectively.

• The third set of tables has the same structure as the second set, but instead of 1 and 0, the cells include the actual information provided in the study reports and extracted as part of the review.

• The fourth set of tables focuses on the actual results of the studies. It contains the name of the first author, the year of publication, the interventions, the tests used to measure the outcomes, data on each of the outcomes of interest measured with each of the tests, and the statistical significance (p<0.05) of the results on the outcomes of interest across the study groups. This table, which was requested by the AAP subcommittee, was subdivided by group of outcomes to help establish whether the effect of the interventions varies by outcome (e.g., intervention A may improve core symptoms but not academic achievement). One limitation for the production and interpretation of this set of tables derives from the fact that many tests were used to measure the outcomes and that even when the same test was used, the authors often made modifications that were not clearly described in the reports. Because of the magnitude and complementary nature of the tables, they are included in the report as a separate section. To make the data extracted easier to understand, the information on the studies was organized in the tables following an alphabetical order. The studies are also presented in alphabetical order within the text. In addition, every effort was made to describe the studies according to their methodological quality, taking into account both the evidence-based criteria and the count of the elements that were not supported by empirical evidence.

The local research team, in consultation with members of the partner organizations and the TOO, evaluated the overall quantity and quality of the data available. This evaluation led to the conclusion that meta-analysis would be inappropriate to summarize the evidence on each of the research questions or for each of the main categories of interest. The main reasons for this decision were substantial clinical heterogeneity across the studies (e.g., therapies evaluated, patient populations, duration), inconsistency in outcome measurements, low methodological quality, and incomplete data reporting (see detailed descriptions within each category). The use of meta-analysis to synthesize this type of data has been associated with a greater chance of obtaining imprecise and potentially misleading results (Ioannidis, Cappelleri, and Lau, 1998). Therefore, this report represents a systematic qualitative review of the existing evidence, emphasizing the implications for clinical practice and the directions that future researchers could take to fill existing knowledge gaps.

Every effort was made to present the information obtained in each of the categories following a uniform format. Overall, each section begins with a general description of the most salient characteristics of the studies and ends with a summary of the main findings of the studies. The way in which the results from the individual studies are presented varies substantially across sections. This reflects the different perspectives that the questions provide on the treatment of ADHD. For instance, two of the sections focus on pharmacological interventions (e.g., drug-to-drug comparisons, and antidepressants vs. placebo), whereas others focus on combined interventions, length of therapy, specific populations (e.g., adults), and outcomes (e.g., adverse effects). The tables complementing the text in each of the sections, as mentioned above, follow the same format.

Consultation With Partners

The production of the evidence report involved continuous communication among members of the local research team, the TOO, and representatives of the partner organizations.Three face-to-face meetings were held; and communication by telephone, fax, and electronic mail was frequent. The partner organizations provided input during each of the steps of the process, from the formulation of the questions through the literature search and data extraction, to data synthesis.

Peer-Review Process

Potential peer-reviewers were identified in April 1998. Thirty-eight individuals were approached by the San Francisco Cochrane Center and asked if they would be willing to review this evidence report. Twenty of these people responded positively to this request, and the report was sent out to them in early July. The potential reviewers included 14 content experts (practicing physicians, psychologists, researchers, representatives of organizations interested in the treatment of ADHD), 3 consumer representatives, and 3 methodologists. All reviewers were sent a "Structured Format for Referee's Comments" (Appendix G) and encouraged to provide comments on the text. The comments were returned to our Criticism Editor, Dr. Patricia Huston, who synthesized them for the McMaster EPC. All comments were shared with the Task Order Officer. All comments were reviewed and, where feasible, incorporated into the final report. Comments were received from 15 of the 20 reviewers who were invited to comment (Appendix G).

Yield of the Literature Search

Figure 1. Yield of Literature Search

Click on image to enlarge 

   Figure 1. Yield of Literature Search

Figure 1

The subset of RCTs was screened to determine the number of articles with evidence to answer the research questions of interest. The following is the number of reports found in each category (in parentheses, the number of trials described in the reports):

• Drug vs. drug 22 (22)

• Drug vs. nondrug 12 (6)

• Combination therapies (stimulants plus others) 27 (20)

• Tricyclic antidepressants vs. placebo 12 (9)

• Long-term therapies (>12 weeks) 19 (14)

• Treatment of ADHD in adults (>18 years of age) 13 (12)

• Adverse effects of interest 32 (29) (one non-RCT)

A total of 92 reports were included in this project. Numerous overlaps exist among the categories. In addition, multiple reports of the same studies were found. Information from multiple reports of the same studies was combined and considered as a single data set. Once this was accounted for, 78 different studies were included. The evidence tables in this document are based on information from these 78 studies. The remaining articles were not included because they did not provide data on any of the categories or questions of interest for this project.

The evidence identified within each of the categories of interest will be described separately (see below).

An unpublished copy was obtained of the Canadian Coordinating Officer for Health Technology Assessment (CCOHTA)-funded report on the treatment of ADHD prepared by researchers at the University of British Columbia (Miller, Lee, Raina et al., 1998). As planned, its methodological quality was assessed and information on RCTs comparing stimulants with placebo was extracted.

General Characteristics of All Studies Included

The most salient characteristics of all the studies included (Evidence Tables A1 through A34) were the following:

• Sixty-five of the 78 studies were identified in MEDLINE first. Other sources contributed little.

• Most of the studies (48 of the 78) had a crossover design.

• Most of the studies reported funding by a government agency (48 studies). The second source of funding was industry (22 studies). Charities and consumer groups funded few studies (seven studies).

• The first study identified was published in 1971 and the last in 1999. One-half of the studies (34/78) were published since 1990.

• All but six studies were published in North America.

• More than one-half the studies had 3 to 5 authors (49 studies).

• The lead author was typically a pediatrician or a psychiatrist.

• All the studies but two described a single research center.

• Seventy-five studies included men or boy patients, and 51 included women or girl patients.

• DSM-IIIR and -IV criteria were used almost as often (28 studies) as DSM-I and -III (30 studies) for the diagnosis of ADHD.

• The number of arms in the studies varied from 2 to 6; 54 studies had 2 or 3 arms.

• Thirty-two different interventions were studied. Apart from placebo (64 studies), the most frequently evaluated intervention was MPH (55 studies), followed by DEX (18 studies), and cognitive/behavioral therapy (8 studies). Intervention with pemoline was evaluated in five studies.

• No studies provided an analysis stratified by treatment setting.

• Forty-eight different outcomes were measured in the 78 studies. The most frequently measured outcomes were inattention (29 studies) and hyperactivity (30 studies). Impulsivity was measured in 13 trials. Global assessment of symptoms was provided in 22 studies and combined scores for core symptoms, in 20.

• Sixty-nine different tests were used to measure the outcomes. Conners was the most frequently used test, followed by spontaneous reports.

The reports of the studies included in the review had deficiencies that increase the likelihood of bias in their results:

• One study (MTA Cooperative Group, 1999) was given the maximum quality score with the validated scale (Jadad, Moore, Carroll et al., 1996). The average quality score was 2 out of 5 points. Only five trials were given 4 points. Only 18 of the 77 randomized trials were given scores > 3 points. As mentioned above, it has been shown consistently that trials that receive < 2 points are more likely to exaggerate treatment effects (Berman, Ezzo, Hadhazy et al., forthcoming; Khan, Daya, and Jadad, 1996; Moher, Pham, Jones et al., 1998). The main reasons for the low scores were lack of description of the method of randomization (73/77 trials), lack of description of methods to achieve double blinding (59 trials), and poor description of withdrawals and dropouts (66 trials).

• Seventy-three trials did not mention concealment of allocation to study groups.

• An association with industry was reported in 27 studies. Ciba-Geigy was associated with 16 studies.

• Most studies had one or more factors that limited their external validity or generalizability. Only one of the studies (MTA Cooperative Group, 1999) included information on all of the 20 clinically relevant elements selected a priori for extraction from the articles.

The following is a brief summary of the main problems found in the studies:

• The total duration (including the time required to administer the interventions and assess their outcomes) was 12 weeks or less in 64 studies. Results obtained in short-term studies may not apply to the long treatment periods that are often required.

• Overall, the description of the interventions evaluated in the studies, particularly nonpharmacological ones, was poor.

• Fewer than one-third of the trials mentioned ethnic groups. The most frequently considered group was white, followed by African American (35 studies).

• Twenty of the studies did not report the inclusion criteria or reported them unclearly. One-half of the trials did not report the exclusion criteria. Insufficient information on inclusion or exclusion criteria limits the ability of clinicians to compare their patients with those reported in published studies.

• The primary outcome of interest to the researchers was not described in 61 of the studies. As mentioned above, the identification of the primary outcome, especially when it is done a priori, provides the basic elements for the calculation of the sample size required by the researchers to identify clinically important differences and minimize the risk of finding false-negative results. In addition, this is likely to reduce the tendency of researchers to give more prominence to secondary outcomes when the interventions do not produce the expected effects on the primary outcome of interest.

• Most of the studies (64) included patients between the ages of 5 and 12 years.

• Forty-three studies did not report information on comorbid disorders, which are frequently present in patients with diagnosis of ADHD. The presence of comorbid disorders may increase or reduce the effectiveness of interventions targeted to ADHD. In addition, these comorbid disorders could be improved or exacerbated by the same treatments.

• Family characteristics were not mentioned in 45 studies.

• The fidelity of treatments was not described in 52 studies, and compliance was not measured in 44 of the 78 studies. Knowing the adequacy with which treatments are administered by health care providers (fidelity) or the adherence of patients to the treatments (compliance) are two essential components to determine the generalizability of the results of any study.

• Baseline measurements of ADHD symptoms were provided in 54 studies. The most frequently used test to generate baseline measurements was Conners (37 studies), followed by Weschler (23 studies). Information on baseline characteristics enables readers to compare their cases with those included in the studies.

The following seven sections provide a detailed description of the evidence and main findings within each of the categories of interest. Within each section, studies are discussed in detail when they provide information that could increase the understanding of the interventions under evaluation.

Main Findings by Category

Full references for the studies cited can be found in the References chapter. The Bibliography contains all sources that were considered, including those used and not used.

Effect of Stimulants Compared With Placebo: What Did We Learn?

Overall Conclusions

The main overall conclusions from studies included in the Task Order are the following:

• Extensive research has been done on the treatment of ADHD for more than 25 years. However, few studies compare different pharmacological interventions head to head or with nonpharmacological treatments or evaluate the efficacy of antidepressants or combination therapies, the implications of long-term therapy, the treatment of ADHD in adults, or the adverse effects associated with the most frequently prescribed medications.

• 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.

• The reports of the studies available have numerous deficiencies that limit the assessment of their validity, relevance, precision, and, therefore, their clinical application. It was surprising, for instance, to find that most studies did not describe clearly important information such as the presence of comorbid disorders, the characteristics of the patients' families, the fidelity of treatments, compliance with treatment, or baseline measurement of outcomes of interest. Little information is available on the treatment of adult patients who belong to minority ethnic groups. In addition, the reporting of other important aspects of the studies was deficient.

• Most of the studies available had small sample sizes and did not provide information on the primary outcome of interest to the researchers. Therefore, it was unclear on most occasions whether statistically nonsignificant results reflected a true lack of difference among interventions or false-negative results from underpowered studies. Research during the past 20 years on this issue in other areas indicates that the latter is the most plausible situation in most cases (Freiman, Chalmers, Smith et al., 1978; Moher, Dulberg, and Wells, 1994).

• One of the most important challenges faced by researchers interested in ADHD and its treatment is to select a core set of uniform outcome measures to be used across studies in addition to those preferred by individual research groups. Standardized methods to obtain and report each of the outcomes, and the identification of clinically meaningful changes in the outcomes in response to treatment, would facilitate the interpretation of individual studies and the synthesis of data across studies.

• More research is needed to understand the relative value of the different aspects of a study. For instance, it is unclear whether having information on family characteristics is more or less important than having information on comorbid disorders. More efforts should be made to understand the implications that different diagnostic models for ADHD and comorbid disorders could have on the outcomes of treatment. This area provides a fertile ground of research on these clinically and methodologically important issues. Any future research efforts may also benefit from more communication among clinicians, providers, and consumers.

• Most reports lacked description of basic generic methodological aspects that increase their likelihood of bias. For instance, 97 percent of the articles did not describe the method of randomization, 95 percent did not provide information on concealment of allocation, and 87 percent did not describe the number of, or reasons for, withdrawals and dropouts in each of the groups. It is important to acknowledge that the studies may have included most of the elements in their protocols throughout the execution of the study but did not describe them in their report. Journal editors and peer reviewers should recognize the importance of these elements and encourage authors to include them in their reports. Most of the current problems that were encountered could be easily corrected if journal editors adopted evidence-based reporting recommendations such as the Consolidation of the Standards of Reporting Trials (CONSORT) statement (Begg, Cho, Eastwood et al., 1996) and kept track of new methodological developments that could increase the validity and applicability of research. The CONSORT statement was produced and published by an international group of clinical epidemiologists, biostatisticians, and journal editors in 1996. Its aim is to improve the standards of written reports of RCTs and to ensure that readers find all the information they require in the reports to interpret the trial results with confidence. This statement includes a checklist of 21 items and a flow diagram that authors can use to provide necessary information on the progress of patients through a study. The statement has already been adopted by over 70 major biomedical journals (Jadad and Rennie, 1998).

• The approach used in this review for the assessment of the quality of the studies by no means represents the only or most appropriate way to assess trial quality. However, the authors of this Task Order report included the only validated tool available that also appears to produce robust and valid results in an increasing number of empirical methodological studies. In addition, the scale was not used in isolation. Instead, it was complemented with separate assessments of other components for which empirical evidence of a direct relationship with bias exists. In addition, separate assessments of 20 other components were added to provide readers with a much wider and more clinically relevant picture. Any future decision on the assessment of trial validity should be made in the light of new empirical methodological evidence.

• The large number and heterogeneity of outcome measures and tests used in the studies limited efforts to compare and synthesize data across the studies included in this report.

• Researchers often use modified versions of the same tests (e.g., Conners) across studies but provide little information on their modified versions. The field would benefit by the selection of 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. Few studies have been supported financially by sources other than governments or pharmaceutical companies. A great opportunity exists 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.

• Future research efforts in the areas reviewed in this Task Order report will require collaboration and commitment among different groups of stakeholders. The MTA study funded by NIMH is an example of this type of collaboration.

The following is a description of the main implications for clinical practice and future research efforts from each of the seven categories of interest.

Limitations of This Evidence Report

The findings and conclusions of this evidence report are based on the information that was available in the published reports of the studies included. Additional information obtained directly from the authors could have overcome many of the reporting limitations described above. Contact with authors could have also led to reduction in the likelihood of publication bias through the identification of unpublished studies. The budget and time lines available, however, were insufficient to allow this.

The interpretability of these data included in most of the tables of this evidence report is limited. These data were obtained by the authors of the studies with many different instruments that were poorly described in most reports.

Another limitation of this report is that it does not include quantitative estimates of the relative effects of the interventions evaluated. However, meta-analysis was deemed inappropriate given the amount, heterogeneity, and quality of the data available. As mentioned above, the use of meta-analysis to synthesize this type of data has been associated with a greater chance of obtaining imprecise and potentially misleading results (Ioannidis, Cappelleri, and Lau, 1998). It is unclear, however, whether the problems found in this data set are greater or smaller than those in other areas. It is important, however, to recognize that qualitative systematic reviews can introduce other problems such as biased narrative description of the characteristics and findings of the studies included. By including detailed evidence tables in this report, it is hoped that readers will be able to replicate the findings, when appropriate.

It could also be argued that another limitation of this report is that it did not include a separate section for studies comparing the short-term effects of stimulants with placebo. This decision was motivated by the need to make efficient use of the resources available while ensuring the maximum added value from the Task Order report. Given the consistency of the findings of the individual studies included in this review, the three published systematic reviews, and the most recent unpublished review, as well as the limitations of the studies available, it is the belief of the authors that the decision to focus attention on the other seven categories resulted in the most efficient use of the resources available.

It could be argued that systematic reviews of behavioral interventions could benefit substantially by the inclusion of nonrandom within-subject and single-subject research designs. However, we regarded these study designs as too vulnerable to bias and of limited value for direct head-to-head comparisons between psychosocial therapies and interventions.

In many instances, it was concluded that there was a lack of evidence on the effectiveness of clinically important interventions. It is important to recognize that this is different from the lack of effectiveness of the same interventions.

Closing Remarks

This report represents a collective effort by representatives of different groups of stakeholders, including government agencies (AHRQ), professional organizations (AAP and APA), consumer groups (Children and Adults with Attention-Deficit Disorders [CHADD]), clinicians, and researchers with content and methodological expertise. Emphasis was placed on ensuring the relevance of the research questions, on building on existing knowledge, and on supporting future clinical practice guideline development or research efforts.

The report includes seven systematic reviews that incorporated state-of-the-art methodology and data that are ready for incorporation into evidence-based clinical practice guidelines or performance measures.

This report would best be used as a tool to guide future research priorities and as a platform from which to develop programs, guidelines, and policies rather than as a guideline for clinical practice. Our hope is that this report will be used to stimulate discussion, advance knowledge, and provide constructive challenge in an area of public concern: ADHD.

Appendix A. DSM-IV Criteria for Attention-Deficit/Hyperactivity Disorder from the American Psychiatric Association

Appendix B. Members of the Multidisciplinary Research Team: McMaster University Evidence-based Practice Center (MU-EPC)

Appendix C. Results of the Systematic Review and Meta-Analyses

[This appendix includes a summary of the main findings and the list of the articles that were included. The full document is available upon request]

Appendix D. Computerized Database Library Search Strategy

Database: Medline <1966 -- 28-Nov-97>
Set Search

• 001 exp "Behavioral Symptoms (Non MeSH)"/

• 002 hyperactiv:.tw,sh.

• 003 exp Cognition Disorders/

• 004 1 and 2

• 005 2 and 3

• 006 exp attention deficit disorder with hyperactivity/

• 007 attention deficit:.tw,sh.

• 008 6 or 7

• 009 4 or 5

• 010 8 or 9

• 011 minimal brain damage:.tw,sh.

• 012 minimal brain dysfunction:.tw,sh.

• 013 hyperkinetic syndrome:.tw,sh.

• 014 hyperkinetic reaction:.tw,sh.

• 015 impulsivity:.tw,sh.

• 016 inattent:.tw,sh.

• 017 10 or 11 or 12 or 13 or 14 or 15 or 16

• 018 random:.tw,sh,pt.

• 019 clinical trial:.tw,sh,pt.

• 020 comparative:.tw,sh.

• 021 case-control:.tw,sh.

• 022 cohort:.tw,sh.

• 023 18 or 19 or 20 or 21 or 22

• 024 17 and 23

• 025 17 and 18

• 026 17 and 19

• 027 17 and 20

• 028 17 and 21

• 029 17 and 22

• 030 29

Appendix E: Data Extraction Form for ADHD Studies

Appendix F. Quality Assessment Scale

Jadad, Moore, Carroll et al. Controlled Clin Trials 1996;17:1-12.

Appendix G: Peer Review Process

The San Francisco Cochrane Center helped coordinate the peer review of this report. Our thanks go to Dr. Lisa Bero, Dr. Drummond Rennie and Ms. Andrea Clark.

Appendix H: Reference List of All Included Articles by Categories

Drug vs. Drug studies RCTs only (n=22)

Arnold LE, Christopher J, Huestis R, Smeltzer DJ. Methylphenidate vs dextroamphetamine vs caffeine in minimal brain dysfunction: controlled comparison by placebo washout design with Bayes' analysis. Source Database: Medline. Arch Gen Psychiatry. 1978 Apr; 35(4): 463–73.

Arnold LE, Huestis RD, Smeltzer DJ, Scheib J, Wemmer D, Colner G. Levoamphetamine vs dextroamphetamine in minimal brain dysfunction. Replication, time response, and differential effect by diagnostic group and family rating. Source Database: Medline. Arch Gen Psychiatry. 1976 Mar; 33(3): 292–301.

Borcherding BG, Keysor CS, Cooper TB, Rapoport JL. Differential effects of methylphenidate and dextroamphetamine on the motor activity level of hyperactive children. Source Database: Medline. Neuropsychopharmacology. 1989 Dec; 2(4): 255–63.

Castellanos FX, Giedd JN, Elia J, Marsh WL, Ritchie GF, Hamburger SD, Rapoport JL. Controlled stimulant treatment of ADHD and comorbid Tourette's syndrome: Effects of stimulant and dose. Source Database: Medline. J Am Acad Child Adolesc Psychiatry. 1997 May; 36(5): 589–96.

Conners CK, Taylor E. Pemoline, methylphenidate, and placebo in children with minimal brain dysfunction. Source Database: Medline. Arch Gen Psychiatry. 1980 Aug; 37(8): 922–30.

Conners CK, Taylor E, Meo G, Kurtz MA, Fournier M. Magnesium pemoline and dextroamphetamine: A controlled study in children with minimal brain dysfunction. Source Database: Medline. Psychopharmacologia. 1972; 26(4): 321–36. [PubMed]

Efron D, Jarman F, Barker M. Methylphenidate versus Dexamphetamine in children with Attention Deficit Hyperactivity Disorder: A double-blind, crossover trial. Source Database: Consultant. Paediatrics. 1997; 100(6): –.

Elia J, Borcherding BG, Rapoport JL, Keysor CS. Methylphenidate and dextroamphetamine treatments of hyperactivity: Are there true nonresponders? Source Database: Medline. Psychiatry Res. 1991 Feb; 36(2): 141–55.

Fitzpatrick PA, Klorman R, Brumaghim JT, Borgstedt AD. Effects of sustained-release and standard preparations of methylphenidate on attention deficit disorder. Source Database: Medline. J Am Acad Child Adolesc Psychiatry. 1992; 31(2): 226–34. [PubMed]

Gross MD. A comparison of dextro-amphetamine and racemic-amphetamine in the treatment of the hyperkinetic syndrome or minimal brain dysfunction. Source Database: Medline. Dis Nerv Syst. 1976 Jan; 37(1): 14–6. [PubMed]

Kauffman RE, Smith-Wright D, Reese CA, Simpson R, Jones F. Medication compliance in hyperactive children. Source Database: Medline. Pediatr Pharmacol. 1981; 1(3): 231–7.

Matochik JA, Liebenauer LL, King C, Szymanski HV, Cohen RM, Zametkin AJ. Cerebral glucose metabolism in adults with attention deficit hyperactivity disorder after chronic stimulant treatment. Source Database: Embase. Am J Psychiatry. 1994; 151(5): 658–64. [PubMed]

Pelham WE J, Greenslade KE, Vodde-Hamilton M, Murphy DA, Greenstein JJ, Gnagy EM, Guthrie KJ, Hoover MD, Dahl RE. Relative efficacy of long-acting stimulants on children with attention deficit-hyperactivity disorder: A comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dextroamphetamine, and pemoline. Source Database: Medline. Pediatrics. 1990 Aug; 86(2): 226–37.

Pelham WE J, Sturges J, Hoza J, Schmidt C, Bijlsma JJ, Milich R, Moorer S. Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder. Source Database: Medline. Pediatrics. 1987 Oct; 80(4): 491–501. [Free Full text in PMC]

Quinn PO, Rapoport JL. One-year follow-up of hyperactive boys treated with imipramine or methylphenidate. Source Database: Medline. Am J Psychiatry. 1975 Mar; 132(3): 241–5.

Rapport MD, Carlson GA, Kelly KL, Pataki C. Methylphenidate and desipramine in hospitalized children: I. Separate and combined effects on cognitive function. Source Database: Medline. J Am Acad Child Adolesc Psychiatry. 1993 Mar; 32(2): 333–42.

Spring C, Yellin AM, Greenberg L. Effects of imipramine and methylphenidate on perceptual-motor performance of hyperactive children. Source Database: Medline. Percept Mot Skills. 1976 Oct; 42(43): 459–70.

Srinivas NR, Hubbard JW, Quinn D, Midha KK. Enantioselective pharmacokinetics and pharmacodynamics of dl-threo-methylphenidate in children with attention deficit hyperactivity disorder. Source Database: Medline. Clinical Pharmacology & Therapeutics. 1992 Nov; 52(5): 561–8.

Stephens RS, Pelham WE, Skinner R. State-dependent and main effects of methylphenidate and pemoline on paired-associate learning and spelling in hyperactive children. Source Database: Embase. J Consult Clin Psychol. 1984; 52(1): 104–13. [PubMed]

Werry JS, Aman MG, Diamond E. Imipramine and methylphenidate in hyperactive children. Source Database: Medline. J Child Psychol Psychiatry. 1980 Jan; 21(1): 27–35.

Whitehouse D, Shah U, Palmer FB. Comparison of sustained-release and standard methylphenidate in the treatment of minimal brain dysfunction. Source Database: Medline. J Clin Psychiatry. 1980 Aug; 41(8): 282–5.

Winsberg BG, Press M, Bialer I, Kupietz S. Dextroamphetamine and methylphenidate in the treatment of hyperactive-aggressive children. Source Database: Medline. Pediatrics. 1974 Feb; 53(2): 236–41. [Free Full text in PMC]

Combination Therapy Papers RCTs only (n=26)

Arnold LE, Abikoff HB, Cantwell DP, Conners CK, Elliott G, Greenhill LL, Hechtman L, Hinshaw SP, Hoza B, Jensen PS, Kraemer HC, March JS, Newcorn JH, Pelham WE, Richters JE, Schiller E, Severe JB, Swanson JM, Vereen D, Wells KC, for the MTA. National Institute of Mental Health Collaborative Multimodal Treatment Study of Children With ADHD (the MTA): Design challenges and choices. (same study as MTA Cooperative Study Group, 1999). Source Database: Medline. Arch Gen Psychiatry. 1997; 54(9): 865–70. [PubMed]

Borden, KA, Brown, RT. Attributional outcomes: The subtle messages of treatments for attention deficit disorder. Source Database: PsycINFO. Cognitive Ther Res. 1989 Apr; 13(2): 147–60.

Brown RT, Borden KA, Wynne ME, Schleser R, Clingerman SR. Methylphenidate and cognitive therapy with ADD children: A methodological reconsideration. Source Database: Medline. J Abnorm Child Psychol. 1986 Dec; 14(4): 481–97.

Brown RT, Borden KA, Wynne ME, Spunt AL. Patterns of compliance in a treatment program for children with attention deficit disorder. Source Database: PsycINFO. J Compliance Health Care. 1988; 3(1): 23–39.

Brown RT, Wynne ME, Medenis R. Methylphenidate and cognitive therapy: A comparison of treatment approaches with hyperactive boys. Source Database: Medline. J Abnorm Child Psychol. 1985 Mar; 13(1): 69–87.

Carlson CL, Pelham-WE J, Milich R, Dixon J. Single and combined effects of methylphenidate and behavior therapy on the classroom performance of children with attention-deficit hyperactivity disorder. Source Database: Embase. J Abnorm Child Psychol. 1992; 20(2): 213–32. [PubMed]

Christensen DE. Effects of combining methylphenidate and a classroom token system in modifying hyperactive behavior. Source Database: Medline. Am J Ment Defic. 1975 Nov; 80(3): 266–76. [PubMed]

Conrad WG, Dworkin ES, Shai A, Tobiessen JE. Effects of amphetamine tharapy and prescriptive tutoring on the behavior and achievement of lower class hyperactive children. Source Database: reference list Schachar review article. J Learn Disabil. 1971; 4: 509–17.

Firestone P, Crowe D, Goodman JT, McGrath P. Vicissitudes of follow-up studies: differential effects of parent training and stimulant medication with hyperactives. Source Database: Medline. Am J Orthopsychiatry. 1986 Apr; 56(2): 184–94.

Firestone P, Kelly MJ, Goodman JT, Davey J. Differential effects of parent training and stimulant medication with hyperactives: A progress report. (Same study as Firestone, Crowe, Goodman et al., 1986). Source Database: Medline. J Am Acad Child Psychiatry. 1981; 20(1): 135–47. [PubMed]

Garfinkel BD, Webster CD, Sloman L. Responses to methylphenidate and varied doses of caffeine in children with attention deficit disorder. Source Database: Medline. Can J Psychiatry. 1981 Oct; 26(6): 395–401.

Gittelman-Klein R, Klein DF, Abikoff H, Katz S, Gloisten, AC, Kates W. Relative efficacy of methylphenidate and behavior modification in hyperkinetic children: an interim report. Source Database: Medline. J Abnorm Child Psychol. 1976; 4(4): 361–79. [PubMed]

Gittelman-Klein R, Klein DF, Katz S, Saraf K, Pollack E. Comparative effects of methylphenidate and thioridazine in hyperkinetic children. I. Clinical results. Source Database: Medline. Arch Gen Psychiatry. 1976 Oct; 33(10): 1217–31.

Greenhill LL, Abikoff HB, Arnold LE, Cantwell DP, Conners CK, Elliott G, Hechtman L, Hinshaw SP, Hoza B, Jensen PS, March JS, Newcorn J, Pelham WE, Severe JB, Swanson JS, Vitiello B, Wells K. Medication treatment strategies in the MTA study: Relevance to clinicians and researchers. (same study as MTA Cooperative Group, 1999). Source Database: Medline. J Am Acad Child Adolesc Psychiatry. 1996; 34(10): 1304–13.

Hinshaw SP, Buhrmester D, Heller T. Anger control in response to verbal provocation: Effects of stimulant medication for boys with ADHD. Source Database: Medline. J Abnorm Child Psychol. 1989 Aug; 17(4): 393–407.

Hinshaw SP, Henker B, Whalen CK. Cognitive-behavioral and pharmacologic interventions for hyperactive boys: comparative and combined effects. Source Database: Medline. J Consult Clin Psychol. 1984 Oct; 52(5): 739–49.

Hinshaw SP, March JS, Abikoff H, Arnold LE, Cantwell DP, Conners CK, Elliott GR, Halperin J, Greenhill LL, Hechtman LT, Hoza B, Jensen PS, Newcorn JH, McBurnett K, Pelham WE, Richters JE, Severe JB, Schiller E, Swanson J, Vereen D, Wells K, Wigal T. Comprehensive assessment of childhood Attention-Deficit Hyperactivity Disorder in the context of a multisite, multimodal clinical trial. (same study as MTA Cooperative Group, 1999). Source Database: Medline. J Attention Dis. 1997; 1(4): 217–34.

Klein RG, Abikoff H. Behavior therapy and methylphenidate in the treatment of children with ADHD. (Same study as Gittelman-Klein, Klein, Abikoff et al., 1976). Source Database: Medline. J Attention Dis. 1997; 2(2): 89–114.

Levy F, Hobbes G. Does haloperidol block methylphenidate? Source Database: Medline. Motivation or attention? Psychopharmacology. 1996 Jul; 126(1): 70–4. [Free Full text in PMC]

Long N, Rickert VI, Ashcraft EW. Bibliotherapy as an adjunct to stimulant medication in the treatment of attention-deficit hyperactivity disorder. Source Database: Medline. J Pediatr Health Care. 1993 Mar; 7(2): 82–8.

MTA Cooperative Group. 14-month randomized clinical trial of treatment strategies for attention deficit hyperactivity disorder. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999 Dec; 56(12): 1073–86.

Pataki CS, Carlson GA, Kelly KL, Rapport MD, Biancaniello TM. Side effects of methylphenidate and desipramine alone and in combination in children. (Same study as Rapport, Carlson, Kelly et al., 1993). Source Database: Medline. J Am Acad Child Adolesc Psychiatry. 1993; 32(5): 1065–72. [PubMed]

Pelham WE, Carlson C, Sams SE, Vallano G, Dixon MJ, Hoza B. Separate and combined effects of methylphenidate and behavior modificationon boys with attention deficit-hyperactivity disorder in the classroom. Source Database: Embase. J Consult Clin Psychol. 1993; 61(3): 506–15. [PubMed]

Rapport MD, Carlson GA, Kelly KL, Pataki C. Methylphenidate and desipramine in hospitalized children: I. Separate and combined effects on cognitive function. Source Database: Medline. J Am Acad Child Adolesc Psychiatry. 1993 Mar; 32(2): 333–42.

Richters JE, Arnold IE, Jensen PS, Abikoff H, Conners CK, Greenhill LL, Hechtman L, Hinshaw SP, Pelham WE, Swanson JM. NIMH Collaborative Multisite Multimodal Treatment Study of children with ADHD: I. Background and rationale. (same study as MTA Cooperative Group, 1999). Source Database: Medline. J Am Acad Child Adolesc Psychiatry. 1995 Aug; 34(8): 987–1000.

Schechter MD, Timmons GD. Objectively measured hyperactivity-II. Caffeine and amphetamine effects. Source Database: Medline. J Clin Pharmacol. 1985 May; 25(4): 276–80.

Solanto MV, Wender EH, Bartell SS. Effects of methylphenidate and behavioral contingencies on sustained attention in attention-deficit hyperactivity disorder: A test of the reward dysfunction hypothesis. Source Database: Embase. J Child Adolesc Psychoparmacol. 1997; 7(2): 123–36.

Tricyclic Antidepressants vs. Placebo, n=12

Biederman J, Baldessarini RJ, Wright V, Keenan K, Faraone S. A double-blind placebo controlled study of desipramine in the treatment of ADD: III. Lack of impact of comorbidity and family history factors on clinical response. Source Database: Medline. J Am Acad Child Adolesc Psychiatry. 1993 Jan; 32(1): 199–204.

Biederman J, Baldessarini RJ, Wright V, Knee D, Harmatz JS, Goldblatt A. A double-blind placebo controlled study of desipramine in the treatment ADD: II. Serum drug levels and cardiovascular findings. Source Database: Medline. J Am Acad Child Adolesc Psychiatry. 1989 Nov; 28(6): 903–11.

Biederman J, Baldessarini RJ, Wright V, Knee D, Harmatz JS. A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy. Source Database: Medline. J Am Acad Child Adolesc Psychiatry. 1989 Sep; 28(5): 777–84.

Conners CK, Taylor E. Pemoline, methylphenidate, and placebo in children with minimal brain dysfunction. Source Database: Medline. Arch Gen Psychiatry. 1980; 37(8): 922–30. [PubMed]

Donnelly M, Zametkin AJ, Rapoport JL, Ismond DR, Weingartner H, Lane E, Oliver J, Linnoila M, Potter WZ. Treatment of childhood hyperactivity with desipramine: Plasma drug concentration, cardiovascular effects, plasma and urinary catecholamine levels, and clinical response. Source Database: Medline. Clin Pharmacol Ther. 1986 Jan; 39(1): 72–81.

Gualtieri CT, Evans RW. Motor performance in hyperactive children treated with imipramine. Source Database: Medline. Percept Mot Skills. 1988 Jun; 66(3): 763–9.

Gualtieri CT, Keenan PA, Chandler M. Clinical and neuropsychological effects of desipramine in children with attention deficit hyperactivity disorder. Source Database: Medline. J Clin Psychopharmacol. 1991 Jun; 11(3): 155–9.

Rapport MD, Carlson GA, Kelly KL, Pataki C. Methylphenidate and desipramine in hospitalized children: I. Separate and combined effects on cognitive function. Source Database: Medline. J Am Acad Child Adolesc Psychiatry. 1993; 32(2): 333–42. [PubMed]

Singer HS, Brown J, Quaskey S, Rosenberg LA, Mellits ED, Denckla MB. The treatment of attention-deficit hyperactivity disorder in Tourette's syndrome: A double-blind placebo-controlled study with clonidine and desipramine. Source Database: Medline. Pediatrics. 1995 Jan; 95(1): 74–81. [Free Full text in PMC]

Werry JS; Aman MG; Diamond E. Imipramine and methylphenidate in hyperactive children. Source Database: Medline. J Child Psychol Psychiatry. 1980; 21(1): 27–35. [PubMed]

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