Treatment of ADHD Chapter 4 Only Conclusions



Treatment of ADHD Literature Review with Medical Perspectives

Course Description:

This course is based on an abridged version of an extensive literature review of evidence-based treatment for ADHD. It includes the abstract, summary and conclusions of our longer more in-depth course on this topic. It is a course designed for an advanced practitioner. It reports on the findings of 78 studies on the treatment of ADHD and includes both pharmacological and non-pharmacological (therapy) interventions with children, adolescents and adults. Long term and short term effectiveness is evaluated as is combination approaches. The Agency for Healthcare Research and Quality (AHRQ), through its Evidence based Practice Centers (EPCs), sponsors the development of evidence reports to improve the quality of health care in the United States. The reports and assessments provide practioners with comprehensive, science-based information on common and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

Learning Objectives:

This course will provide a professional with in information about the treatment of ADHD that can be utilized in professional practice. Specifically, a professional will learn:

• The long-term and short-term effectiveness and safety of pharmacological interventions for attention-deficit/hyperactivity disorder (ADHD) in children and adults

• The most effective pharmacological intervention for ADHD according to current research

• The effectiveness of nonpharmacological interventions for attention-deficit/hyperactivity disorder (ADHD) in children and adults

• Whether combined interventions are more effective than individual interventions.

Treatment of Attention-Deficit/Hyperactivity Disorder

Evidence Report/Technology Assessment

Number 11

Prepared for:

Agency for Healthcare Research and Quality

U.S. Department of Health and Human Services

2101 East Jefferson Street

Rockville, MD 20852



Contract No. 290-97-0017

Prepared by:

McMaster University, Hamilton, Ontario, Canada

Alejandro R. Jadad M.D., D.Phil.

Project Director

Michael Boyle, Ph.D.

Charles Cunningham, Ph.D.

Marie Kim, M.D.

Russell Schachar, M.D.

Investigators

AHRQ Publication No. 00-E005

November 1999

Preface

The Agency for Healthcare Research and Quality (AHRQ), formerly the Agency for Health Care Policy and Research, through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

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|John M. Eisenberg, M.D. |Douglas B. Kamerow, M.D. |

|Director |Director, Center for Practice and Technology Assessment |

|Agency for Healthcare Research and Quality |Agency for Healthcare Research and Quality |

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|The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for |

|Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical |

|service. |

Acknowledgments

This report was funded by the Agency for Healthcare Research and Quality (AHRQ) and developed with the help of many dedicated contributors. We are especially grateful for the input received from our partner organizations, the American Academy of Pediatrics (AAP) and the American Psychiatric Association. The members of the AAP Subcommittee on ADHD were especially helpful during the formulation of the research questions and the development of the data extraction forms. The support and commitment from our contacts at AHRQ were invaluable: Dr. David Atkins, the AHRQ Task Order Officer; Jacqueline Besteman; Al Deal; and the late Therese Dick, the AHRQ Contract Officer for this Task Order. It was with great sadness that we learned of Therese's untimely passing in the fall of 1998.

Thanks go to the San Franciso Cochrane Center for coordinating the peer review process, to the peer reviewers, and to Dr. Patricia Huston for her development of a coherent and constructive synthesis of the peer review commentaries. Several people provided us with information that was otherwise unavailable to us, including Drs. G. DuPaul, P. Jensen, and J. Swanson and members of the MTA Cooperative Group and the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) research team. Special thanks to our colleagues at McMaster University for their enthusiasm, vision, and continued support.

Structured Abstract

Treatment of Attention-Deficit/Hyperactivity Disorder

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.

Suggested Citation:

Jadad AR, Boyle M, Cunningham C, et al. Treatment of Attention-Deficit/Hyperactivity Disorder. Evidence Report/Technology Assessment No. 11 (Prepared by McMaster University under Contract No. 290-97-0017). AHRQ Publication No. 00-E005. Rockville, MD: Agency for Healthcare Research and Quality. November 1999

Summary

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.[pic]

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.[pic]

Methodology

Inclusion and Exclusion Criteria

In preparing the Report, we followed current standards for assessing and distilling research evidence. Citations of individual studies were regarded as potentially eligible and selected for further evaluation if they were randomized controlled trials (RCTs) that focused on the treatment of ADHD in humans and if they were published in peer-reviewed journals, in any language, as a full report. If the studies included conditions other than ADHD, they were included only if they provided separate analyses for patients with ADHD. We acknowledge that randomized controlled trials are imperfect tools, but so far they are our best probe to evaluate health care interventions. Non-RCTs were included if they provided data on adverse effects of interest collected over more than 16 weeks. More refined inclusion and exclusion criteria defined within each of the seven categories of research studies are described in the body of the report.

Inclusion of a study in the evidence report was decided by two members of the research team, by consensus, and on the basis of the information available in the full published articles.[pic]

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 below. The searches were completed in November of 1997 using the terms behavioral symptoms, attention-deficit disorder with hyperactivity, attention-deficit, hyperactivity, cognition disorders, minimal brain damage, minimal brain dysfunction, hyperkinetic syndrome, hyperkinetic reaction, impulsivity or inattention, and random, clinical trial, comparative, case control, or cohort.

• 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.

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Data Extraction

Data extraction forms were especially developed and tested for this project. The local research team, partner organizations, and the Task Order Officer (TOO) were consulted and the forms approved for content. More than 41 different variables describing the general characteristics of the study were recorded. In addition, detailed information on interventions, outcomes, and tests were extracted from each of the full reports, independently by two reviewers, with differences resolved by consensus or by a third member of the research team.

Data Synthesis

Descriptive statistics were calculated for all the variables. Evidence tables were constructed to summarize, globally and question by question, all the information extracted from the study reports. 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 and decided that meta-analysis would be inappropriate to summarize the evidence on each of the research questions and 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). Therefore, this report represents a systematic qualitative review of the existing evidence, emphasizing the implications for clinical practice and the opportunities for future research to fill existing knowledge gaps.

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.

|Chapter 4. Conclusions and Implications for Future Research |

| |

|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 ( [pic]Freiman, Chalmers, Smith et al., 1978; [pic]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 ( [pic]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 ( [pic]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. |

|Drug vs. Drug Comparisons |

|The small group of studies comparing different chemical structures and formulations of the same stimulants suggests that the different compounds are |

|more effective than placebo but very similar to each other. |

|In agreement with the AMA and AACAP reports, it seems that few, if any, differences occur among MPH, DEX, and pemoline. In addition, the studies |

|comparing stimulants with tricyclic antidepressants had many limitations and presented conflicting results. More rigorous studies are clearly needed |

|to establish the relative effectiveness of stimulants and tricyclic antidepressants. |

|Studies are also required to compare the effects of stimulants with clonidine, buproprion, or selective serotonin-reuptake inhibitors. |

|Drug vs. Nondrug Studies |

|The studies available indicate consistently that stimulants (particularly MPH) may be more effective than nonpharmacological interventions when |

|compared head to head. The use of nondrug interventions as adjunct to treatment with stimulant awaits more definitive studies. |

|Combination Therapies |

|Evidence is lacking that supports the superiority of combination therapy over stimulant alone or superiority of combination therapy over nondrug |

|interventions alone. Thus, 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 study and represents an important contribution to knowledge in this area. |

|Tricyclic Antidepressants vs. Placebo |

|The studies on desipramine, regardless of their heterogeneous designs, small sample sizes, and variable quality, suggest that desipramine is more |

|effective than placebo. The studies evaluating imipramine show inconsistent results. Given that this group of drugs may be considered by clinicians |

|as the second line of treatment after stimulants, more rigorous research is needed to establish their role in the treatment of ADHD. |

|Long-Term Therapy |

|Despite the fact that most patients diagnosed with ADHD receive treatment for long periods of time, the research efforts made to date are of little |

|value to guide most clinical decisions. More studies are needed in this area because of the persistence of the disorder (NIH Consensus Statement |

|Online, 1998). Practically all the evidence available concentrates on school-age children. Even in this age group, few data are available on adverse |

|effects, on academic achievement, or on situation-specific outcomes (e.g., at home and at school). This is compounded by frequent crossover from one |

|treatment arm to another within studies with parallel design, high attrition rates, and poor description of the reasons for discontinuation of |

|treatments. |

|When adverse drug reactions do occur, they are usually related to dose and there is no evidence that concludes long-term effects of therapeutic use |

|of psychostimulants are harmful. Long-term therapy studies supply evidence that MPH reduces behavioral disturbance in ADHD children as long as it is |

|taken. Lithium does not appear to be an effective alternative in subjects who do not respond to stimulants. The MTA confirmed the findings of |

|previous studies demonstrating short-term benefits do continue during longer term treatment (MTA Cooperative Group, 1999). There is no information on|

|the long-term outcomes of medication-treated ADHD individuals in terms of educational and occupational achievements, involvement with law enforcement|

|agencies or other areas of social functioning (NIH Consensus Statement Online, 1998). |

|Treatment of ADHD in Adults |

|The studies available in this category are few, and most have incomplete reports and small sample sizes and are of short duration. Given the dearth |

|of research evidence in this area, more studies are needed to establish the effectiveness and adverse effects of different interventions for the |

|treatment of ADHD in adults. In the meantime, clinicians should be aware that the few studies evaluating MPH compared with placebo show contradictory|

|results, that antidepressants may be effective in adults, and that the studies available do not support the use of pemoline, nicotine, or |

|phenylalanine. Studies were not found that evaluated the effectiveness of nonpharmacological interventions for adults with diagnosis of ADHD. |

|Adverse Effects |

|The findings in this report agree with those in the AMA report in relation to the evidence available on adverse effects. Many of the side effects |

|associated with stimulant use appear to be relatively "mild, short lived and responsive to dosing or timing adjustments" ( [pic]Goldman, Genel, |

|Bezman et al., 1998). However, data are inadequate on the long-term effects and severity of the adverse effects of most interventions. Timing is an |

|additional element that should be taken into account in future studies (e.g., the effects of stimulants administered during puberty and/or |

|concomitant growth spurts). It appears from the available commentaries in many of the studies that desirable changes in behavior brought about by |

|stimulant medication far outweigh reported side effects. Although this may be true, no attempts have been made to evaluate the tradeoff explicitly |

|(i.e., examine the differential utility) between behavioral changes and side effects. The risks and benefits of treatment with psychostimulants must |

|also be measured (NIH Consensus Statement Online, 1998). However, this is only worth doing if the perspectives of all interested parties (parents, |

|teachers, and patients ) are included in the exercise. |

|In addition, it is important to highlight the following issues/concerns: |

|No comparative studies were identified with data on addiction in relation to the treatment of ADHD with stimulants, liver toxicity resulting from |

|pemoline administration, or major arrhythmia resulting from administration of tricyclic antidepressants. |

|Reports of 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 adverse side effects in order |

|to make an intelligible assessment of their importance from the patients' perspective. |

|A better understanding of the distinctions between "adverse effects" 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 problem behaviors. Including such behaviors distorts the |

|context for evaluating the importance of side effects. |

|Few girls and women have been studied. It is possible that effectiveness and adverse effects vary by sex. This issue needs to be examined or at least|

|discussed. |

|RCTs are limited 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 also provided limited information. More observational studies are required (particularly case-control or cohort |

|studies) to gain a better understanding of adverse effects associated with different treatments for ADHD. Knowledge of adverse effects may also |

|improve through more creative use of existing drug databases. |

| |

|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 ( |

|[pic]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. |

|References |

| |

|Ahmann PA, Waltonen SJ, Olson KA, Theye FW, Van Erem AJ, LaPlant RJ. . Placebo-controlled evaluation of Ritalin side effects. Pediatrics 1993 Jun. |

|91(6):1101-6. (PubMed) (Full Text in PMC) |

| |

|American Academy of Child and Adolescent Psychiatry. . Practice parameters for the assessment and treatment of children, adolescents and adults with |

|attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1997a. 36(Suppl 10):85S-121S. (PubMed) |

| |

|American Academy of Child and Adolescent Psychiatry. . Summary of practice parameters for the assessment and treatment of children, adolescents and |

|adults with ADHD. J Am Acad Child Adolesc Psychiatry 1997b. 36:1311-7. (PubMed) |

| |

|American Psychiatric Association.. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, D.C.: American Psychiatric Association;|

|1994. |

| |

|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. Arch Gen Psychiatry 1978 Apr. 35(4):463-73. (PubMed) |

| |

|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. Arch Gen Psychiatry 1976 Mar. 33(3):292-301. (PubMed) |

| |

|Arnold LE, Kleykamp D, Votolato NA, Taylor WA, Kontras SB, Tobin K. . Gamma-linolenic acid for attention-deficit hyperactivity disorder: |

|Placebo-controlled comparison to d-amphetamine. Biol Psychiatry 1989. 25:222-8. (PubMed) |

| |

|Barkley, RA.. Attention-deficit/hyperactivity disorder. In: Mash EJ and Barkley RA, editors. Child psychopathology. New York: Guildford; 1996. p. |

|63-112. |

| |

|Barkley RA, McMurray MB, Edelbrock CS, Robbins K. . The response of aggressive and nonaggressive ADHD children to two doses of methylphenidate. J Am |

|Acad Child Adolesc Psychiatry 1989. 28 (6):873-81. (PubMed) |

| |

|Barkley RA, McMurray MB, Edelbrock CS, Robbins K. . Side effects of methylphenidate in children with attention deficit hyperactivity disorder: A |

|systemic, placebo-controlled evaluation. Pediatrics 1990 Aug. 86(2):184-92. (PubMed) |

| |

|Barrickman LL, Perry PJ, Allen AJ, Kuperman S, Arndt SV, Herrmann KJ, Schumacher E. . Bupropion versus methylphenidate in the treatment of |

|attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1995 May. 34(5):649-57. (PubMed) |

| |

|Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, Pitkin R, Rennie D, Schulz KF, Simel D, Stroup DF. . Improving the quality of reporting of |

|randomized controlled trials. The CONSORT statement. JAMA 1996. 276(8):637-9. (PubMed) |

| |

|Berlin JA. . Does blinding of readers affect the results of meta-analyses? University of Pennsylvania meta-analysis blinding study group. Lancet |

|1997. 350(9072):185-6. (PubMed) |

| |

|Berman BM, Ezzo J, Hadhazy VA, Jadad AR, Lao L, Singh B.. Penetrating the methodological issues in randomized controlled trials of acupuncture and |

|chronic pain: A systematic review. Forthcoming. |

| |

|Bero LA, Rennie D. . Influences on the quality of published drug studies. Int J Technol Assess Health Care 1996. 12:209-37. (PubMed) |

| |

|Biederman J, Faraone SV, Keenan K. . Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Arch Gen |

|Psychiatry 1992. 49:728-38. (PubMed) |

| |

|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. J Am Acad Child Adolesc Psychiatry 1989a Nov. 28(6):903-11. (PubMed) |

| |

|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. J Am Acad Child Adolesc Psychiatry 1989b Sep. 28(5):777-84. (PubMed) |

| |

|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. J Am Acad Child Adolesc Psychiatry 1993 Jan. 32(1):199-204. (PubMed) |

| |

|Biederman J, Milberger S, Faraone S, Kiely K, Guite J, Mick E, Ablon S, Warburton R, Reed E. . Family-environment risk factors for attention-deficit |

|hyperactivity disorder. Arch Gen Psychiatry 1995. 52:464-70. (PubMed) |

| |

|Borcherding BG, Keysor CS, Cooper TB, Rapoport JL. . Differential effects of methylphenidate and dextroamphetamine on the motor activity level of |

|hyperactive children. Neuropsychopharmacology 1989 Dec. 2(4):255-63. (PubMed) |

| |

|Borden, KA, Brown, RT. . Attributional outcomes: The subtle messages of treatments for attention deficit disorder. Cognitive Ther Res 1989 Apr. |

|13(2):147-60. |

| |

|Brown RT, Wynne ME, Medenis R. . Methylphenidate and cognitive therapy: A comparison of treatment approaches with hyperactive boys. J Abnorm Child |

|Psychol 1985 Mar. 13(1):69-87. (PubMed) |

| |

|Brown RT, Borden KA, Wynne ME, Schleser R, Clingerman SR. . Methylphenidate and cognitive therapy with ADD children: A methodological |

|reconsideration. J Abnorm Child Psychol 1986 Dec. 14(4):481-97. (PubMed) |

| |

|Brown RT, Borden KA, Wynne ME, Spunt AL. . Patterns of compliance in a treatment program for children with attention deficit disorder. J Compliance |

|Health Care 1988. 3(1):23-39. |

| |

|Buitelaar JK, van der Gaag RJ, Swaab-Barneveld H, Kuiper M. . Pindolol and methylphenidate in children with attention-deficit hyperactivity disorder.|

|Clinical efficacy and side-effects. J Child Psychol Psychiatry 1996 Jul. 37(5):587-95. (PubMed) |

| |

|Cadoret RJ, Stewart MA. . An adoption study of attention deficit/hyperactivity/aggression and their relationship to adult antisocial personality. |

|Compr Psychiatry 1991. 32:73-82. (PubMed) |

| |

|Carlson CL, Pelham WEJ, Milich R, Dixon J. . Single and combined effects of methylphenidate and behavior therapy on the classroom performance of |

|children with attention-deficit hyperactivity disorder. J Abnorm Child Psychol 1992. 20(2):213-32. (PubMed) |

| |

|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. J Am Acad Child Adolesc Psychiatry 1997 May. 36(5):589-96. (PubMed) |

| |

|Cho MK, Bero LA. . The quality of drug studies published in symposium proceedings. Ann Intern Med 1996. 124:485-9. (PubMed) |

| |

|Christensen DE. . Effects of combining methylphenidate and a classroom token system in modifying hyperactive behavior. Am J Ment Defic 1975 Nov. |

|80(3):266-76. (PubMed) |

| |

|Conners CK, Taylor E. . Pemoline, methylphenidate, and placebo in children with minimal brain dysfunction. Arch Gen Psychiatry 1980 Aug. |

|37(8):922-30. (PubMed) |

| |

|Conners CK, Levin ED, Sparrow E, Hinton SC, Erhardt D, Meck WH, Rose JE, March J. . Nicotine and attention in adult attention deficit hyperactivity |

|disorder (ADHD). Psychopharmacol Bull 1996. 32(1):67-73. (PubMed) |

| |

|Conners CK, Taylor E, Meo G, Kurtz MA, Fournier M. . Magnesium pemoline and dextroamphetamine: A controlled study in children with minimal brain |

|dysfunction. Psychopharmacologia 1972. 26(4):321-36. (PubMed) |

| |

|Conrad WG, Dworkin ES, Shai A, Tobiessen JE. . Effects of amphetamine therapy and prescriptive tutoring on the behavior and achievement of lower |

|class hyperactive children. J Learn Disabil 1971. 4:509-17. |

| |

|DeVeaugh-Geiss J, Joseph A. . Paradoxical response to amphetamine in a hyperkinetic adult. Psychosomatics 1980. 21(3):247-52. (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. Clin Pharmacol Ther |

|1986 Jan. 39(1):72-81. (PubMed) |

| |

|Efron D, Jarman F, Barker M. . Methylphenidate versus dexamphetamine in children with attention deficit hyperactivity disorder: A double-blind, |

|crossover trial. Paediatrics 1997. 100(6):-. |

| |

|Elia J, Ambrosini, PJ, Rapoport JL. . Treatment of attention-deficit/hyperactivity disorder. N Engl J Med 1999 Mar. 340(10):780-8. (PubMed) |

| |

|Elia J, Borcherding BG, Rapoport JL, Keysor CS. . Methylphenidate and dextroamphetamine treatments of hyperactivity: Are there true nonresponders? |

|Psychiatry Res 1991 Feb. 36(2):141-55. (PubMed) |

| |

|Ernst M, Liebenauer LL, Jons PH, Tebeka D, Cohen RM, Zametkin AJ. . Selegiline in adults with attention deficit hyperactivity disorder: Clinical |

|efficacy and safety. Psychopharmacol Bull 1996. 32(3):327-34. (PubMed) |

| |

|Ernst M, Liebenauer LL, Tebeka D, Jons PH, Eisenhofer G, Murphy DL, Zametkin AJ. . Selegiline in ADHD adults: Plasma monoamines and monoamine |

|metabolites. Neuropsychopharmacology 1997 Apr. 16(4):276-84. (Same study as Ernst, Liebenauer, Jons et al., 1996). (PubMed) |

| |

|Evans SW, Vallano G, Pelham W. . Treatment of parenting behavior with a psychostimulant: A case study of an adult with attention-deficit |

|hyperactivity disorder. J Child Adolesc Psychopharmacol 1994. 4(1):63-9. |

| |

|Fehlings DL, Roberts W, Humphries T, Dawe G. . Attention deficit hyperactivity disorder: Does cognitive behavioral therapy improve home behavior? J |

|Dev Behav Pediatrics 1991 Aug. 12(4):223-8. |

| |

|Fine S, Johnston C. . Drug and placebo side effects in methylphenidate-placebo trial for attention deficit hyperactivity disorder. Child Psychiatry |

|Hum Dev 1993. 4(1):25-30. |

| |

|Firestone P, Crowe D, Goodman JT, McGrath P. . Vicissitudes of follow-up studies: Differential effects of parent training and stimulant medication |

|with hyperactives. Am J Orthopsychiatry 1986 Apr. 56(2):184-94. (PubMed) |

| |

|Fitzpatrick PA, Klorman R, Brumaghim JT, Borgstedt AD. . Effects of sustained-release and standard preparations of methylphenidate on attention |

|deficit disorder. J Am Acad Child Adolesc Psychiatry 1992. 31:226-3. (PubMed) |

| |

|Freiman JA, Chalmers TC, Smith H, Kuebler R. . The importance of beta, the type II error and sample size in the design and interpretation of the |

|randomized control trial. Survey of 71 "negative" trials. N Engl J Med 1978 Sep. 299(13):690-4. (PubMed) |

| |

|Gadow KD, Sverd J, Sprafkin J, Nolan EE, Ezor SN. . Efficacy of methylphenidate for attention-deficit hyperactivity disorder in children with tic |

|disorder [published erratum appears in Arch Gen Psychiatry 1995 Oct;52(10):836]. Arch Gen Psychiatry 1995 Jun. 52(6):444-55. (PubMed) |

| |

|Garfinkel BD, Webster CD, Sloman L. . Responses to methylphenidate and varied doses of caffeine in children with attention deficit disorder. Can J |

|Psychiatry 1981 Oct. 26(6):395-401. (PubMed) |

| |

|Gillberg C, Melander H, von Knorring AL, Janols LO, Thernlund G, Hagglof B, Eidevall-Wallin L, Gustafsson P, Kopp S. . Long-term stimulant treatment |

|of children with attention-deficit hyperactivity disorder symptoms. A randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 1997 |

|Sep. 54(9):857-64. (PubMed) |

| |

|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. 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. Arch Gen Psychiatry 1976 Oct. 33(10):1217-31. (PubMed) |

| |

|Gittelman-Klein R, Landa B, Mattes JA, Klein DF. . Methylphenidate and growth in hyperactive children. Arch Gen Psychiatry 1988. 45:1127-30. (PubMed)|

| |

| |

|Goldman LS, Genel M, Bezman RJ, Slanetz PJ. . Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. JAMA |

|1998. 279(14):1100-7. (PubMed) |

| |

|Greenberg LM, Deem MA, McMahon S. . Effects of dextroamphetamine, chlorpromazine, and hydroxyzine on behavior and performance in hyperactive |

|children. Am J Psychiatry 1972 Nov. 129(5):532-9. (PubMed) |

| |

|Greenhill LL, Rieder RO, Wender PH, Buchsbaum M, Zhan TP. . Lithium carbonate in the treatment of hyperactive children. Arch Gen Psychiatry 1973 May.|

|28(5):636-40. (PubMed) |

| |

|Gross MD.. A comparison of dextro-amphetamine and racemic-amphetamine in the treatment of the hyperkinetic syndrome or minimal brain dysfunction. Dis|

|Nerv Syst 1976 Jan. 37(1):14-6. (PubMed) |

| |

|Gualtieri CT, Evans RW. . Motor performance in hyperactive children treated with imipramine. Percept Mot Skills 1988 Jun. 66(3):763-9. (PubMed) |

| |

|Gualtieri CT, Keenan PA, Chandler M. . Clinical and neuropsychological effects of desipramine in children with attention deficit hyperactivity |

|disorder. J Clin Psychopharmacol 1991 Jun. 11(3):155-9. (PubMed) |

| |

|Handen BL, Feldman H, Gosling A, Breaux AM, McAuliffe S. . Adverse side effects of methylphenidate among mentally retarded children with ADHD. J Am |

|Acad Child Adolesc Psychiatry 1991 Mar. 30(2):241-5. (PubMed) |

| |

|Hinshaw SP, Buhrmester D, Heller T. . Anger control in response to verbal provocation: Effects of stimulant medication for boys with ADHD. J Abnorm |

|Child Psychol 1989 Aug. 17(4):393-407. (PubMed) |

| |

|Hinshaw SP, Henker B, Whalen CK. . Cognitive-behavioral and pharmacologic interventions for hyperactive boys: Comparative and combined effects. J |

|Consult Clin Psychol 1984 Oct. 52(5):739-49. (PubMed) |

| |

|. library/books/ullman/chap3.htm. |

| |

|Ioannidis JPA, Cappelleri JC, Lau J. . Issues in comparisons between meta-analyses and large trials. JAMA 1998. 279:1089-93. (PubMed) |

| |

|Jadad AR, Rennie D. . The randomized controlled trial gets a middle-aged checkup. (Editorial). JAMA 1998. 279(4):319-20. (PubMed) |

| |

|Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ. . Assessing the quality of reports of randomized clinical trials: |

|Is blinding necessary? Controlled Clin Trials 1996. 17:1-12. (PubMed) |

| |

|Jensen P, Martin D, Cantwell D. . Comorbidity in ADHD: Implications for research, practice, and DSM-V. J Am Acad Child Adolesc Psychiatry 1997. |

|36(8):1065-79. (PubMed) |

| |

|Kahn KS, Daya S, Jadad AR. . The importance of quality of primary studies in producing unbiased systematic reviews. Arch Intern Med 1996 Mar 25. |

|156:661-6. (PubMed) |

| |

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

| |

|Kavale K. . The efficacy of stimulant drug treatment for hyperactivity: A meta-analysis. J Learn Disabil 1982 May. 15(5):280-9. (PubMed) |

| |

|Kewley GD. . Personal paper: Attention deficit hyperactivity disorder is underdiagnosed and undertreated in Britain. BMJ 1998. 316:1594-6. (PubMed) |

| |

|Klein RG, Abikoff H. . Behavior therapy and methylphenidate in the treatment of children with ADHD. J Attention Dis 1997. 2(2):89-114. (Same study as|

|Gittelman-Klein, Klein, Abikoff et al., 1976). |

| |

|Klorman R, Coons HW, Borgstedt AD. . Effects of methylphenidate on adolescents with a childhood history of attention deficit disorder: I. Clinical |

|findings [published erratum appears in J Am Acad Child Adolesc Psychiatry 1987 Sep; 26(5): 820]. J Am Acad Child Adolesc Psychiatry 1987. |

|26(3):363-7. (PubMed) |

| |

|Klorman R, Brumaghim JT, Fitzpatrick PA, Borgstedt AD. . Clinical effects of a controlled trial of methylphenidate on adolescents with attention |

|deficit disorder. J Am Acad Child Adolesc Psychiatry 1990 Sep. 29(5):702-9. (PubMed) |

| |

|Kupietz SS, Winsberg BG, Richardson E, Maitinsky S. . Effects of methylphenidate dosage in hyperactive reading-disabled children: I. Behavior and |

|cognitive performance effects. J Am Acad Child Adolesc Psychiatry 1988 Jan. 27(1):70-7. (PubMed) |

| |

|Levine M, Walter S, Lee H, Haines T, Holbrook A, Moyer V. . Users' guide to the medical literature IV: How to use an article about harm. JAMA 1994. |

|271(20):1615-9. (PubMed) |

| |

|Levy F, Hobbes G. . Does haloperidol block methylphenidate? Motivation or attention? Psychopharmacology 1996 Jul. 126(1):70-4. (PubMed) |

| |

|Linden M, Habib T, Radojevic V.. A controlled study of the effects of EEG biofeedback on cognition and behavior of children with attention deficit |

|disorder and learning disabilities. Biofeedback Self Regul 1996 Mar. 21(1):35-49. (PubMed) |

| |

|Long N, Rickert VI, Ashcraft EW. . Bibliotherapy as an adjunct to stimulant medication in the treatment of attention-deficit hyperactivity disorder. |

|J Pediatr Health Care 1993 Mar. 7(2):82-8. (PubMed) |

| |

|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. Am J Psychiatry 1994. 151(5):658-64. (PubMed) |

| |

|Mattes JA, Boswell L, Oliver H. . Methylphenidate effects on symptoms of attention deficit disorder in adults. Arch Gen Psychiatry 1984 Nov. |

|41(11):1059-63. (PubMed) |

| |

|Miller A, Lee SK, Raina P, Klassen A, Zupancic J, Olsen L.. A review of therapies for attention-deficit/hyperactivity disorder. Ottawa: Canadian |

|Coordinating Office for Health Technology Assessment (CCOHTA); 1998. RFP #ADHD-1196 . |

| |

|Moher D, Dulberg CS, Wells GA. . Statistical power, sample size, and their reporting in randomized controlled trials. JAMA 1994 Jul. 272(2):122-4. |

|(PubMed) |

| |

|Moher D, Pham B, Jones A, Cook D, Jadad A, Moher M, Tugwell P, Klassen T. . Does quality of reports of randomised trials affect estimates of |

|intervention efficacy reported in meta-analyses? Lancet 1998. 352:609-13. (PubMed) |

| |

|MTA Cooperative Group.. 14-month randomized clinical trial of treatment strategies for attention deficit hyperactivity disorder. 1999. Submitted for |

|publication. |

| |

|NIH Consensus Statement Online.. Diagnosis and treatment of attention deficit hyperactivity disorder. 1998 Nov 16-18;16(2): |

|. |

| |

|Orford E. . Commentary: Diagnosis needs tightening. BMJ 1998. 316:1594-6. (PubMed) |

| |

|Ottenbacher KJ, Cooper HM. . Drug treatment of hyperactivity in children. Dev Med Child Neurol 1983 Jun. 25(3):358-66. (PubMed) |

| |

|Oxman AD, Guyatt GH. . Validation of an index of the quality of review articles. J Clin Epidemiol 1991. 44:1271-8. (PubMed) |

| |

|Pelham WEJ, Carlson C, Sams SE, Vallano G, Dixon MJ, Hoza B. . Separate and combined effects of methylphenidate and behavior modification on boys |

|with attention deficit-hyperactivity disorder in the classroom. J Consult Clin Psychol 1993. 61(3):506-15. (PubMed) |

| |

|Pelham WEJ, 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. Pediatrics 1990 Aug. 86(2):226-37. (PubMed) |

| |

|Pelham WEJ, 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. Pediatrics 1987 Oct. 80(4):491-501. (PubMed) (Full Text in PMC) |

| |

|Pliszka SR. . Comorbidity of attention-deficit hyperactivity disorder and overanxious disorder. J Am Acad Child Adolesc Psychiatry 1992. 31:197-203. |

|(PubMed) |

| |

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

|(PubMed) |

| |

|Rapport MD, Carlson GA, Kelly KL, Pataki C. . Methylphenidate and desipramine in hospitalized children: I. Separate and combined effects on cognitive|

|function. J Am Acad Child Adolesc Psychiatry 1993 Mar. 32(2):333-42. (PubMed) |

| |

|Reimherr FW, Wender PH, Ebert MH, Wood DR. . Cerebrospinal fluid homovanillic acid and 5-hydroxy-indoleacetic acid in adults with attention deficit |

|disorder, residual type. Psychiatry Res 1984 Jan. 11(1):71-8. (PubMed) |

| |

|Richardson E, Kupietz SS, Winsberg BG, Maitinsky S, Mendell N. . Effects of methylphenidate dosage in hyperactive reading-disabled children: II. |

|Reading achievement. J Am Acad Child Adolesc Psychiatry 1988. 27(1):78-87. (PubMed) |

| |

|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. J Am Acad Child Adolesc Psychiatry 1995 Aug. 34(8):987-1000. (PubMed) |

| |

|Sackett DL, Richardson WS, Rosenberg W, Haynes RB.. Evidence-based medicine: How to practice and teach EBM. New York: Churchill Livingstone; 1997. |

| |

|Schachar RJ, Tannock R, Cunningham C, Corkum PV. . Behavioral, situational, and temporal effects of treatment of ADHD with methylphenidate. J Am Acad|

|Child Adolesc Psychiatry 1997 Jun. 36(6):754-63. (PubMed) |

| |

|Schechter MD, Timmons GD. . Objectively measured hyperactivity -- II. Caffeine and amphetamine effects. J Clin Pharmacology 1985 May. 25(4):276-80. |

| |

|Schulz KF, Chalmers I, Hayes RJ, Altman DG. . Empirical evidence of bias: Dimensions of methodological quality associated with estimates of treatment|

|effects in controlled trials. JAMA 1995. 273(5):408-12. (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. Pediatrics 1995 Jan. 95(1):74-81. (PubMed) (Full Text in PMC) |

| |

|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. J Child Adolesc Psychopharmacol 1997. 7(2):123-36. (PubMed) |

| |

|Spencer T, Wilens T, Biederman J, Faraone SV, Ablon JS, Lapey K. . A double-blind, crossover comparison of methylphenidate and placebo in adults with|

|childhood-onset attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1995 Jun. 52(6):434-43. (PubMed) |

| |

|Spring C, Yellin AM, Greenberg L. . Effects of imipramine and methylphenidate on perceptual-motor performance of hyperactive children. Percept Mot |

|Skills 1976 Oct. 42(43):459-70. (PubMed) |

| |

|Srinivas NR, Hubbard JW, Quinn D, Midha KK. . Enantioselective pharmacokinetics and pharmacodynamics of dl-threo-methylphenidate in children with |

|attention deficit hyperactivity disorder. Clin Pharmacol Ther 1992 Nov. 52(5):561-8. (PubMed) |

| |

|Stein MA, Blondis TA, Schnitzler ER, O'Brien T, Fishkin J, Blackwell B, Szumowski E, Roizen NJ. . Methylphenidate dosing: Twice daily versus three |

|times daily. Pediatrics 1996 Oct. 98(4 Pt 1):748-56. (PubMed) |

| |

|Stephens RS, Pelham WE, Skinner R. . State-dependent and main effects of methylphenidate and pemoline on paired-associate learning and spelling in |

|hyperactive children. J Consult Clin Psychol 1984. 52(1):104-13. (PubMed) |

| |

|Szatmari P, Offord DR, Boyle MH. . Ontario Child Health Study: Prevalence of attention deficit disorder with hyperactivity. J Child Psychol |

|Psychiatry 1989. 30:219-30. (PubMed) |

| |

|Thurber S, Walker CE. . Medication and hyperactivity: A meta-analysis. J Gen Psychology 1983 Jan. 108(1st half):79-86. |

| |

|Weinberg WA, Brumback RA. . The myth of attention-deficit-hyperactivity disorder: Symptoms resulting from multiple causes. J Child Neurology 1992. |

|7:431-45. |

| |

|Wender PH, Reimherr FW, Wood DR. . Attention deficit disorder ("minimal brain dysfunction") in adults. A replication study of diagnosis and drug |

|treatment. Arch Gen Psychiatry 1981 Apr. 38(4):449-56. (PubMed) |

| |

|Wender PH, Reimherr FW, Wood D, Ward M. . A controlled study of methylphenidate in the treatment of attention deficit disorder, residual type, in |

|adults. Am J Psychiatry 1985 May. 142(5):547-52. (PubMed) |

| |

|Werry JS, Aman MG, Diamond E. . Imipramine and methylphenidate in hyperactive children. J Child Psychol Psychiatry 1980 Jan. 21(1):27-35. (PubMed) |

| |

|Whitehouse D, Shah U, Palmer FB. . Comparison of sustained-release and standard methylphenidate in the treatment of minimal brain dysfunction. J Clin|

|Psychiatry 1980 Aug. 41(8):282-5. (PubMed) |

| |

|Wilens TE, Biederman J, Prince J, Spencer TJ, Faraone SV, Warburton R, Schleifer D, Harding M, Linehan C, Geller D. . Six-week, double-blind, |

|placebo-controlled study of desipramine for adult attention deficit hyperactivity disorder. Am J Psychiatry 1996. 153(9):1147-53. (PubMed) |

| |

|Winsberg BG, Kupietz SS, Yepes LE, Goldstein S. . Ineffectiveness of imipramine in children who fail to respond to methylphenidate. J Autism Dev |

|Disord 1980 Jun. 10(2):129-37. (PubMed) |

| |

|Winsberg BG, Press M, Bialer I, Kupietz S.. Dextroamphetamine and methylphenidate in the treatment of hyperactive-aggressive children. Pediatrics |

|1974 Feb. 53(2):236-41. (PubMed) (Full Text in PMC) |

| |

|Wolraich ML, Hannah JN, Pinnock TY, Baumgaertel A, Brown J. . Comparison of diagnostic criteria for attention-deficit hyperactivity disorder in a |

|county-wide sample. J Am Acad Child Adolesc Psychiatry 1996. 35:319-24. (PubMed) |

| |

|Wood DR, Reimherr FW, Wender PH. . Treatment of attention deficit disorder with dl-phenylalanine. Psychiatry Res 1985 Sep. 16(1):21-6. (PubMed) |

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