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McDonagh MS, Peterson K, Thakurta S, et al. Drug Class Review: Pharmacologic Treatments for Attention Deficit Hyperactivity Disorder: Final Update 4 Report [Internet]. Portland (OR): Oregon Health & Science University; 2011 Dec.

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Drug Class Review: Pharmacologic Treatments for Attention Deficit Hyperactivity Disorder: Final Update 4 Report [Internet].

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Introduction

According to the most recent National Institutes of Health Consensus Statement (1998), “attention deficit hyperactivity disorder is the most commonly diagnosed childhood behavioral disorder.”1 Classification of hyperactivity and defects in attention emerged in the 1960's as Minimal Brain Dysfunction and Hyperkinetic Syndrome, and has continued to evolve over time.2

A number of community-based studies have reported attention deficit hyperactivity disorder (ADHD) prevalence rates that range from 1.7% to 16%.3 This is broader than the range of 3% to 5% that was estimated by the expert panelists that participated in the National Institutes of Health Consensus Development Conference on Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder in 1998.1 The estimated prevalence cited in the most recent (1997) version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) is 3% to 7%.4 Differences in prevalence estimates may be due to variation in methods of ascertainment and diagnostic criteria.5 While no independent diagnostic test exists for ADHD, the DSM-IV provides standardized criteria that can be used as a foundation for clinical diagnosis.1, 4 According to the DSM-IV, essential features of ADHD include persistent levels of inattention, impulsivity, and/or hyperactivity that exceed usual developmental patterns.4 In order to qualify for a DSM-IV diagnosis of ADHD, symptoms must date back to before age 7, persist for at least 6 months, and cause impairment that interferes with functional capacity in at least 2 performance settings (social, academic, or employment).4 The DSM-IV specifies 3 distinct subtypes of ADHD that are characterized by predominantly inattentive, hyperactive-impulsive, or mixed symptoms.4

ADHD is diagnosed more frequently in males than in females.6 Comorbidities such as mood, anxiety, and/or conduct disorders, tics or Tourette syndrome, learning disorders, and mental retardation may be found in up to 65% of individuals with ADHD.3 With regard to the course of ADHD, symptoms can persist into adolescence in 80% of cases and into adulthood in 65% of cases.6 Comorbid DSM-IV mood, anxiety, substance use, and/or impulse disorders also commonly occur in combination with ADHD in adults.7

Historically, drug therapy for ADHD has consisted primarily of stimulant medications. More recently, nonstimulant medication treatment alternatives have been identified. These include atomoxetine, atypical antipsychotics, bupropion, clonidine, and guanfacine. Nonstimulant treatment options may offer advantages for individuals (1) seeking medications that have not been identified as having potential for abuse; (2) with concern over the potential long-term effects of stimulants on growing children; (3) with a history of nonresponse to or poor tolerance of stimulants; and/or (4) in whom stimulants are contraindicated due to coexisting medical and/or behavioral disorders and/or concomitant medications.

Purpose and Limitations of Systematic Reviews

Systematic reviews, also called evidence reviews, are the foundation of evidence-based practice. A systematic review focuses on the strength and limits of evidence from studies about the effectiveness of a clinical intervention. Systematic reviews begin with a careful formulation of research questions. The goal is to select questions that are important to patients and clinicians, then to examine how well the scientific literature answers those questions. Terms commonly used in systematic reviews, such as statistical terms, are provided in Appendix A and are defined as they apply to reports produced by the Drug Effectiveness Review Project.

Systematic reviews emphasize the patient's perspective in the choice of outcome measures used to answer research questions. Studies that measure health outcomes (events or conditions that the patient can feel, such as fractures, functional status, and quality of life) are emphasized over studies of intermediate outcomes (such as change in bone density). Reviews also emphasize measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions depends on the number of events in both groups, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant across groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than the absolute risk reduction. Another useful measure is the number needed to treat (or harm). The number needed to treat, often referred to as the NNT, is the number of patients who would have to be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the number needed to treat.

Systematic reviews weigh the quality of the evidence, allowing a greater contribution from studies that meet high methodological standards that reduce the likelihood of biased results. In general, for questions about the relative benefit of a drug, the results of well-executed, randomized, controlled trials are considered better evidence than results of cohort, case-control, or cross-sectional studies. In turn, these studies provide better evidence than uncontrolled trials and case series. For questions about tolerability and harms, observational study designs may provide important information that is not available from controlled trials. Within the hierarchy of observational studies, cohort designs are preferred when conducted well and for assessing a common outcome. Case-control studies are preferred only when the outcome measure is rare and the study is well conducted.

Systematic reviews pay particular attention to the generalizability of efficacy studies performed in controlled or academic settings. Efficacy studies provide the best information about how a drug performs in a controlled setting. These studies attempt to tightly control potential confounding factors and bias; however, for this reason the results of efficacy studies may not be applicable to many, and sometimes to most, patients seen in everyday practice. Most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, adherence to treatment, or severity of illness. For many drug classes, including the antipsychotics, unstable or severely impaired patients are often excluded from trials. In addition, efficacy studies frequently exclude patients who have comorbid diseases, meaning diseases other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that may be impractical in typical practice settings. And these studies often restrict options that are of value in actual practice, such as combination therapies or switching to other drugs. Efficacy studies also often examine the short-term effects of drugs that in practice are used for much longer periods of time. Finally, efficacy studies tend to assess effects by using objective measures that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families.

Systematic reviews highlight studies that reflect actual clinical effectiveness in unselected patients and community practice settings. Effectiveness studies conducted in primary care or office-based settings use less stringent eligibility criteria, more often assess health outcomes, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the “average” patient than results from the highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, frequency or duration of hospitalizations, social function, and the ability to work. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures, such as scores based on psychometric scales.

Efficacy and effectiveness studies overlap. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. For these reasons, it was neither possible nor desirable to exclude evidence based on these characteristics. Labeling each study as either an efficacy or an effectiveness study, while convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one's practice or to a particular patient.

Studies anywhere on the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard for determining whether characteristics of different drugs are related to their effects on disease. Systematic reviews thoroughly cover the efficacy data in order to ensure that decision-makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how much of it there is, may have limited applicability to practice. Clinicians can judge the relevance of the study results to their practice and should note where there are gaps in the available scientific information.

Unfortunately, for many drugs there exist few or no effectiveness studies and many efficacy studies. Yet clinicians must decide on treatment for many patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in various subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment.

In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on strong evidence from clinical studies. By themselves, they do not say what to do. Judgment, reasoning, and applying one's values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice.

Scope and Key Questions

The purpose of this review is to compare the benefits and harms of different pharmacologic treatments for ADHD. The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project. The participating organizations of the Drug Effectiveness Review Project are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review:

  1. Evidence on Effectiveness and Efficacy
    1. What is the comparative or noncomparative evidence that pharmacologic treatments for attention deficit disorders improve effectiveness outcomes?
      1. Comparisons include individual drugs, as well as between stimulants and nonstimulants, and immediate-release compared with intermediate-release compared with long-acting formulations.
      2. Noncomparative evidence will be considered for drugs with no comparative evidence.
    2. What is the comparative efficacy between any included pharmacologic treatment, between stimulants and nonstimulants, and between immediate-release compared with intermediate-release compared with long-acting formulations, for attention deficit disorders?
  2. Tolerability, Serious Adverse Events, Misuse, and Diversion
    1. What is the evidence of comparative tolerability of different pharmacologic treatments, between stimulants and nonstimulants, and between immediate-release compared with intermediate-release compared with long-acting formulations, for attention deficit disorders?
    2. What is the evidence of serious adverse events or long-term adverse events associated with use of pharmacologic treatments for attention deficit disorders?
    3. What is the comparative or noncomparative evidence that pharmacologic treatments for attention deficit disorders impact the risk of misuse or illicit diversion in patients with no history of misuse or diversion?
      1. Comparisons include individual drugs, as well as between stimulants and nonstimulants, and immediate-release compared with intermediate-release compared with long-acting formulations.
      2. Noncomparative evidence will be considered for drugs with no comparative evidence.
  3. Evidence in Subgroups of Patients
    1. What is the evidence of benefits and harms of pharmacologic treatments, between stimulants and nonstimulants, and between immediate-release compared with intermediate-release compared with long-acting formulations, for attention deficit disorders in subgroups of patients based on demographics (age, racial groups, gender), socioeconomic status, other medications or therapy, or comorbidities (e.g. tics, anxiety, substance use disorders, disruptive behavior disorders)?
    2. What is the comparative or noncomparative evidence of misuse or illicit diversion of pharmacologic treatments for attention deficit disorders in patients with current or past substance use disorder comorbidities?
      1. Comparisons include individual drugs, as well as between stimulants and nonstimulants, and immediate-release compared with intermediate-release compared with long-acting formulations.
      2. Noncomparative evidence will be considered for drugs with no comparative evidence.

Inclusion Criteria

Populations

Pediatric (age <3, <6, and 6-17 years), and adult (age ≥18 years) outpatients with attention deficit disorders

  • Attention deficit disorder
  • Attention deficit hyperactivity disorder

Interventions

Included drugs are described in Table 1. Black box warnings for the included interventions are listed in Appendix B.

Table 1. Attention deficit hyperactivity disorder drugs and indication.

Table 1

Attention deficit hyperactivity disorder drugs and indication.

Benefits

Effectiveness outcomes

  1. Functional capacity (social, academic, and occupational productivity)
  2. Caregiver satisfaction (parent, teacher, other)
  3. Quality of life (patient, family members, caregivers, teachers)
  4. Time to onset of effectiveness
  5. Duration of effectiveness (length of therapy)

Efficacy outcomes

  1. Symptom response (inattention, hyperactivity-impulsivity, aggression, global ratings, etc.)

Harms

Tolerability

  1. Overall adverse effect reports
  2. Withdrawals due to adverse effects and overall withdrawal
  3. Specific adverse events (insomnia, anorexia, abuse potential, tics, anxiety, and sexual dysfunction)

Serious adverse effects

  1. Hepatotoxicity
  2. Cardiovascular events
  3. Growth effects

Misuse/diversion

  1. Trading, selling
  2. Compliance, overdose
  3. Development of substance abuse disorders

Scales and tests used to measure outcomes

Numerous ADHD-specific and other psychiatric rating scales, as well as neuropsychological testing methods, are used to measure symptoms of ADHD. We limited our analyses to rating scales/tests for which we found published evidence of good reliability and validity. Our primary sources for documentation of the psychometric properties of rating scales included the Agency for Healthcare Research and Quality Technical Review #3 (Diagnosis of Attention-Deficit/Hyperactivity Disorder)8 and Mental Measurements Yearbooks.9-16 The Agency for Healthcare Research and Quality Technical Review #3 provided qualitative information on many of the rating scales cited in our report, including subscales included in each test, comorbid conditions addressed by each checklist, time required to administer, number of items, ages for which norms are available, computer scoring availability, and ordering information, including cost and reliability and validity. Appendix C provides a listing of commonly used scales and tests and associated acronyms.

Study designs

The benefit of the randomized controlled trial design is the reliably unbiased estimate of treatment effects in a controlled setting by randomizing patients, the best method of producing comparable groups based on both known and unknown prognostic factors.17, 18 However, randomized controlled trials can vary in quality and often suffer from limitations in generalizability to the larger patient population. Observational study designs are thought to have greater risk of introducing bias, although they typically represent effects in a broader section of the overall patient population. While it has been shown that some observational studies and randomized controlled trials of the same treatments have similar findings, there are also multiple examples of situations where this has not been true and the question of what type of evidence is best has not been resolved.19, 20 While randomized controlled trials also provide good evidence on short-term adverse events, observational designs are useful in identifying rare, serious adverse events, which to be identified often require large numbers of patients exposed to a treatment over longer periods of time.

For this review, the following study designs were included:

  • Effectiveness: Controlled clinical trials, good-quality systematic reviews, and comparative observational studies (cohort studies including database studies and case-control studies).
  • Efficacy and general adverse events: Controlled clinical trials and good-quality systematic reviews.
  • Serious adverse events: Controlled clinical trials, good-quality systematic reviews, and comparative observational studies (cohort studies including database studies and case-control studies).
  • Misuse/diversion: Controlled clinical trials, good-quality systematic reviews, comparative observational studies (cohort studies including database studies and case-control studies), and noncomparative observational studies (before-after, time-series).
  • Subgroups: Controlled clinical trials, good-quality systematic reviews, and comparative observational studies (cohort studies including database studies and case-control studies)
Copyright © 2011 by Oregon Health & Science University.
Bookshelf ID: NBK84415
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