hyperactivity disorder: identifying high priority future research needs.

Attention-Deficit/Hyperactivity Disorder: Identifying High Priority Future Research Needs

With onset often occurring before 6 years of age, attention-deficit/hyperactivity disorder (ADHD) involves attention problems, impulsivity, overactivity, and sometimes disruptive behavior. Impairment usually persists into adulthood, with an estimated worldwide prevalence in adults of 2.5%. Existing gaps in evidence concerning ADHD hinder decision-making about treatment. This article describes and prioritizes future research needs for ADHD in three areas: treatment effectiveness for at-risk preschoolers; long-term treatment effectiveness; and variability in prevalence, diagnosis, and treatment. Using a recent systematic review concerning ADHD completed by a different evidence-based practice center as a foundation, we worked with a diverse group of 12 stakeholders, who represented researchers, funders, healthcare providers, patients, and families, to identify and prioritize research needs. From an initial list of 29 evidence gaps, we enumerated 8 high-priority research needs: a) accurate, brief standardized diagnosis and assessment; b) comparative effectiveness and safety of pharmacologic treatments for children under 6 years of age; c) comparative effectiveness of different combinations of psychosocial and pharmacologic treatments for children under 6 years of age; d) case identification and measurement of prevalence and outcomes; e) comparative effectiveness of psychosocial treatment alone versus pharmacologic and combination treatments for children under 6 years of age; f) comparative long-term treatment effectiveness for people 6 years of age and older; g) relative efficacy of specific psychosocial program components for children under 6 years of age; and h) identification of person-level effect modifiers for people 6 years of age and older. In this article, we describe these future research needs in detail and discuss study

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BRADLEY N. GAYNES, MD, MPH ROBERT CHRISTIAN, MD LISSETTE M. SAAVEDRA, PhD ROBERTA WINES, MPH DANIEL E. JONAS, MD, MPH MEERA VISWANATHAN, PhD ALAN R. ELLIS, PhD, MSW CAROL WOODELL TIMOTHY S. CAREY, MD, MPH

designs that could be used to address them. (Journal of Psychiatric Practice 2014;20:104–117) KEY WORDS: attention-deficit/hyperactivity disorder (ADHD), future research needs, treatment, effectiveness, psychopharmacology, psychosocial interventions

Attention-deficit/hyperactivity disorder (ADHD) is often associated with concurrent oppositional and aggressive behaviors, anxiety, low self-esteem, and learning disabilities. Symptoms generally interfere with behavior in multiple settings, including school and academic functioning, and they may also disrupt family and peer relationships. ADHD is usually first identified and treated in primary school, when children are between 7 and 9 years of age, but onset often occurs before children enter school.1 In the preschool age group, ADHD is frequently characterized GAYNES, WINES, JONAS, ELLIS, and CAREY: University of North Carolina at Chapel Hill and the Cecil G. Sheps Center for Health Services Research, RTI-UNC Evidence-based Practice Center, Chapel Hill, NC; CHRISTIAN: University of North Carolina at Chapel Hill and the Carolina Institute for Developmental Disabilities, Chapel Hill, NC; SAAVEDRA, VISWANATHAN, and WOODELL: Research Triangle Institute International, RTI-UNC Evidence-based Practice Center, Research Triangle Park, NC. Copyright ©2014 Lippincott Williams & Wilkins Inc. Please send correspondence to: Bradley N. Gaynes, MD, MPH, Department of Psychiatry, CB #7160, University of North Carolina School of Medicine, 100 Manning Drive, Chapel Hill, NC 27599. [email protected] The authors declare no conflicts of interest. Funding for this project was provided by the Agency for Healthcare Research and Quality (AHRQ) through the American Recovery and Reinvestment Act (ARRA) (Contract No. 290 2007 10056 I). The views expressed in this manuscript do not represent and should not be construed to represent a determination or policy of AHRQ or the U.S. Department of Health and Human Services. DOI: 10.1097/01.pra.0000445245.46424.25

Journal of Psychiatric Practice Vol. 20, No. 2

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

IDENTIFYING HIGH PRIORITY FUTURE RESEARCH NEEDS FOR ADHD

not only by impairment in attention span, excessive impulsivity, and overactivity, but also by additional disruptive behavior symptoms, including severe temper tantrums; demanding, uncooperative behavior; and aggressiveness.2 In the absence of an ADHD diagnosis, these disruptive behaviors are seen as markers of risk for ADHD.2 Although symptom levels decrease with age, the majority of children with ADHD continue to show impairment relative to same-age peers throughout adolescence and into adulthood. Among adults, the estimated prevalence of ADHD worldwide is 2.5%.3 Treatment often includes medication with a psychostimulant, such as methylphenidate, dextroamphetamine, or mixed amphetamine salts, or, more recently, a non-stimulant such as an alpha-adrenergic agent or atomoxetine. Because ADHD is a chronic disorder, many children, teenagers, and adults stay on medications for years at a time, but little information is available to patients and physicians regarding long-term effects or the natural history of the disorder as children mature into adulthood. The psychostimulants used to treat older children and adults with ADHD are not approved for use in children younger than 6 years of age; therefore, based on general clinical consensus, treatments for this population emphasize nonpharmaceutical interventions such as parenting programs. Little information is available concerning the effectiveness of either medication or nonmedication interventions for ADHD in this age group.4 In 2010, the Agency for Healthcare Research and Quality (AHRQ) provided funding to the McMaster University Evidence-based Practice Center to complete a comparative effectiveness review titled, “Attention Deficit Hyperactivity Disorder: Effectiveness of Treatment in At-risk Preschoolers; LongTerm Effectiveness in All Ages; and Variability in Prevalence, Diagnosis, and Treatment.”4 Tables 1–3 describe the key questions that were addressed in this review and summarize the conclusions.4 The AHRQ review also included the authors’ recommendations for future research on each key question. The purpose of our work was to build on the AHRQ review by defining and prioritizing future research needs (FRNs) in a comprehensive, systematic way. We gathered and synthesized the opinions of an informed and involved stakeholder group by asking them to help identify evidence gaps in the systematic review and to prioritize specific future research


needs. We then developed strategies to address the highest priority needs.

METHODS Because the AHRQ review was produced by another Evidence-Based Practice Center, and the final report was not yet published when our study began, we used the draft review to compile an initial list of evidence gaps—topics for which the review authors rated the strength of evidence20 as “low” or “insufficient” to support conclusions. Once the final review was published, we verified that our list of evidence gaps was consistent with the limitations described in the final version. We then scanned clinicaltrials.gov, HSRProj, NIH RePORTER, and the International Clinical Trials Registry Project to find relevant ongoing or recently completed research that might address any of the gaps. A description of the search strategy and results is available in our full report which can be accessed online.21 We convened a 12-member national stakeholder panel of individuals with expertise in many facets of childhood ADHD, drawn from family and advocacy groups, researchers, providers of care, funders, and professional organizations. Our stakeholder group (for a list of participants, see Acknowledgments p. 115) included 9 non-federal participants and 3 representatives from federal agencies that commonly fund ADHD research. Each potential stakeholder completed a disclosure form, which was reviewed by both the project team and AHRQ for potential conflicts of interest. Had a substantial conflict of interest been discovered, the stakeholder involved would have been eliminated from consideration and another stakeholder would have been approached as a replacement. A complete description of our methods is provided in the full report available online.21 We engaged stakeholders through two teleconferences, electronic mail, and two Web-based prioritization exercises. During the first teleconference, we asked the stakeholders to refine the initial list of evidence gaps based on their expertise. After the call, we revised the list of gaps and asked each stakeholder to complete an online prioritization exercise21 using the following elements from the AHRQ Effective Health Care Program topic selection criteria: importance, desirability of new research/duplication, and potential impact.22 The online exercise used a forced prioritization method in which each person

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Table 1. Key question 1: level of evidence and conclusions4 Key Question 1: Among children < 6 years of age with ADHD or disruptive behavior disorder, what are the effectiveness and adverse event outcomes following treatment? Intervention

Level of evidence

Conclusions

Parent behavior training

SOE: High

Parent behavioral interventions are an efficacious treatment option for preschoolers with disruptive behavior disorder and show benefit for ADHD symptoms. Studies support the long-term effectiveness of parent interventions for preschoolers with disruptive behavior disorder, including ADHD symptoms, with evidence that benefits are maintained for up to 2 years. There also appears to be a dose-response effect.

SMD: –0.68 (95% CI, –0.88 to –0.47) Multi-component home and school or daycare based interventions

SOE: Insufficient

When there is no socioeconomic burden, multicomponent interventions work as well as a structured parent education program in several domains. When there is socioeconomic burden, the treatment classroom appears to be the primary beneficial intervention, and this appears to be related to lack of parent engagement and attendance at PBT sessions. Relative benefits of the school-based intervention diminished over 2 years.

Medication (MPH Only)

SOE: Low SMD: –0.83 (95% CI, –1.21 to –0.44)

With evidence drawn primarily from the PATS,5 MPH (e.g., shortacting, immediate-release MPH) is both efficacious and generally safe for treatment of ADHD symptoms, but there has been no long-term follow-up in preschoolers.

Abbreviations: ADD = attention deficit disorder; ADHD = attention deficit hyperactivity disorder; ATX = atomoxetine; CI = confidence interval; MPH = methylphenidate; PATS = Preschool ADHD Treatment Study; PBT = parent behavior training; RCT = randomized controlled trial; S-DDD = standardized defined daily dose; SOE = strength of evidence; SMD = standard mean difference

could distribute a limited number of votes among the evidence gaps. We reviewed the results of this exercise with the stakeholders on the second conference call. Then, in a second round of the same online exercise, the stakeholders assigned priorities among the evidence gaps that had been ranked the highest in the first round. We used the results of the second round to determine the final list of high-priority research needs. Consistent with AHRQ methods for refining topics for systematic reviews, the study team described each of the eight high-priority needs in more detail by developing PICOTS (populations, interventions, comparators, outcomes, timeframe, and settings) elements.23 We considered potential study designs using specific criteria, including ability to produce a valid result, resource requirements, availability of data or ability to recruit subjects, and ethical and legal considerations.24 Drawing on the priorities expressed by the stakeholder group, study design options were generated and refined by the multidisciplinary study

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team, which included methodologists, analysts, and mental health services researchers. For topics without previous systematic reviews, we considered whether researchers should examine the current literature to avoid duplicating prior work. Several future research needs could be addressed by more than one study design; we anticipated that the study design implemented would depend on study setting, administrative feasibility, and availability of funding. Choice of clinical and organizational outcome was derived from the team’s knowledge of the literature, experience with similar studies, and judgment as to the most efficient way of addressing the research need. A timeframe for each study was selected based on the team’s research experience and knowledge of organizational change in practices. We determined trial feasibility by conducting power analyses and examining the practicalities of randomization, contamination, setting, and timeframe. We conducted power analyses based on several hypothetical designs for randomized trials that




Table 2. Key question 2: level of evidence and conclusions4 Key Question 2: Among people 6 years of age or older with ADHD, what are the effectiveness and adverse event outcomes following 12 months or more of any combination of follow-up or treatment, including, but not limited to, 12 months or more of continuous treatment? Intervention

Level of evidence

Conclusions

Medication treatment: MPH and ATX

SOE: Low

Very few studies included untreated controls, and studies were largely funded by industry.

MPH: SMD: –0.54 (95% CI, –0.79 to –0.29) ATX: SMD: –0.40 (95% CI, –0.61 to –0.18)

Medication treatment: GXR

SOE: Insufficient

Combined SOE: Low psychostimulant medication and SMD: –0.70 behavioral (95% CI, –0.95 treatment to –0.46)

Psychostimulants continue to provide control of ADHD symptoms and are generally well tolerated for months to years at a time. MPH use in the context of careful medication monitoring shows good evidence for benefits for symptoms for 14 months.4 ATX is effective for ADHD symptoms and well tolerated over 12 months.4 . Only one study of GXR monotherapy6 is available. It reported reduced ADHD symptoms and global improvement, although fewer than a fifth of participants completed 12 months. Monitoring of cardiac status may be indicated since approximately 1% of participants showed ECG changes that were judged clinically significant.

Results from two cohorts indicated both medication (MPH) and combined medication and behavioral treatment are effective in treating ADHD plus oppositional defiant disorder symptoms in children, primarily boys 7–9 years of age of normal intelligence with combined type of ADHD (as defined in DSM-IV-TR), especially during the first 2 years of treatment.4 Several reports from one high-quality study7–9 suggest that combined medication and behavioral treatment improves outcomes more than medication alone for some subgroups of children with ADHD combined type and for some outcomes.

Behavioral/ psychosocial

SOE: Insufficient

There is not enough evidence to draw conclusions for persons 6 years of age and older with a diagnosis of ADHD.

Parent behavior training

SOE: Insufficient

There is not enough evidence to draw conclusions for persons 6 years of age and older with a diagnosis of ADHD.

Academic interventions

SOE: Insufficient

One good-quality study and its extension10–13 showed that classroom-based programs to enhance academic skills are effective in improving achievement scores in multiple domains, but, following discontinuation, the benefits for sustained growth in academic skills are limited to the domain of reading fluency. All other domains show skill maintenance but not continued growth.

Abbreviations: ADHD = attention deficit hyperactivity disorder; ATX = atomoxetine; CI = confidence interval; ECG = electrocardiogram; GXR = guanfacine extended release; MPH = methylphenidate; SOE = strength of evidence; SMD = standard mean difference


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Table 3. Key question 3: Conclusions4 Key Question 3: How do a) underlying prevalence of ADHD, and b) rates of diagnosis (clinical identification) and treatment for ADHD vary by geography, time period, provider type, and sociodemographic characteristics? Issue

Factor

Conclusions

Prevalence

Geography

Context and cultural overlay influence how ADHD is understood from country to country and thus how it is treated. Underlying prevalence does not appear to vary much between nations and regions after differences in methodologies for ascertainment are taken into account.

Time period

Since identified as a clinical entity in 1902 in the context of mandatory education, prevalence of cases identified has increased. Some proportion of this secular trend is due to refinement of the state of knowledge, changes in the definitions of acceptable informants and uses of screening tests, and changes in classification systems and diagnostic categories over time. In addition, patterns of access and location of service have been used to document prevalence.

SES

Some studies suggest that those of lower SES have a higher prevalence of ADHD, although those of higher SES are more likely to be treated.14,15

Sex

Most studies illustrate a sex difference in the prevalence of ADHD (males > females).

Age

Children approximately 5–10 years of age appear to experience the highest prevalence. ADHD research detailing prevalence in adults is lacking.

Service Clinical identification provider

Appreciation of the combined neurodevelopmental and environmental etiologies and magnitude of impairment due to the condition has increased over the past 4 decades.4 Providers vary in level of expertise in diagnosis of ADHD, as well as in familiarity with screening instruments and classification systems.

Location

Rates of diagnosis vary considerably due to cultural context, access to health care services, and provider type. Significant regional variations are noted in the United States. Prevalence is reported to average 7.8%, with variability from 5.0% in Colorado to 11.1% in Alabama.16 In special populations, such as the incarcerated, rates as high as 25.5% have been noted.17

Informant

Parent and teacher observations have been accepted by some researchers in population studies in lieu of clinician diagnosis. The National Survey of Children’s Health18 accepted a positive response from the primary caretaker to the question, “Has a doctor or health professional ever told you that [child name] has … ADD or ADHD?” to estimate ADHD prevalence in 2003. Rates of diagnosis vary considerably due to cultural context. Some ethnicities are more likely to seek help or accept the diagnosis than others.

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Sex

Boys are identified as having ADHD more frequently than girls.

Age

Primary school-age children are more frequently identified as having ADHD than older children. ADHD was formerly thought to disappear in adulthood, but it is now recognized that it may persist throughout the lifespan.

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Table 3. Key question 3, continued Issue

Factor

Conclusions

Treatment

Location

Rates of treatment vary considerably due to location and access to providers of healthcare services, internationally as well as regionally or even within the same community, dependent on provider type and availability, provider remuneration, and insurance status of patient.

Provider

Family practitioners in many jurisdictions, particularly those with limited access to specialists, report significant pressure from parents and teachers to prescribe stimulant medications.

Informant

The sociocultural experience of the parent or teacher informant may influence interpretation and reporting of behaviors, willingness and persistence in seeking professional help, and/or the acceptance of treatment. Accuracy and completeness of data influence prevalence estimates, with health insurance and prescription administrative databases suggesting a greater increase in medication treatment over time than repeated community surveys.

Time

The rate of use of psychostimulant medication has increased over the past 3 decades. More recent statistics from the International Narcotics Control Board, using a denominator of standardized defined daily doses, report that medical use of MPH in the United States has increased from 7.14 S-DDDs per 1,000 inhabitants per day in 2004 to 12.03 S-DDDs per 1,000 inhabitants per day in 2008.19

SES

Children of lower SES are identified as having ADHD more often than children of higher SES; however, the latter are more likely to receive stimulant medications. Lower SES and minority ethnicity are associated with shorter duration of medication use. Insurance status may influence access to specialist providers in the United States.

Sex

Only sparse comparative data are available examining rates of treatment by sex once ADHD is diagnosed.

Age

Medication treatment prevalence is higher for primary school-age children than for adolescents or adults.

Abbreviations: ADHD = attention deficit hyperactivity disorder; MPH = methylphenidate; SES = socioeconomic status; ECG = electrocardiogram; S-DDD = standardized defined daily dose, SOE = strength of evidence

would fit one or more of the research needs outlined in this report. For example, for factorial designs involving two treatments, we considered cross-sectional studies as well as longitudinal studies with varying numbers of repeated measures. The objective was to determine the approximate numbers of patients and measurement occasions needed in order to have power of 0.80 to detect a clinically meaningful difference in outcomes with a two-tailed test at a significance level of 0.05. The power analysis results are reflected in the study designs suggested below; details appear in the full report.21


RESULTS Ten of the 12 stakeholders (83%) completed the first round of the online prioritization exercise. For the 29 initial evidence gaps (listed in the full report online21), the number of votes allocated ranged from 1 to 10. Based on the distribution of votes, we proposed retaining the 15 gaps that received 5 or more votes for the second round. After reviewing the results, the stakeholders requested that one additional gap be carried forward to the second round. This additional gap was one of two that had received

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Table 4. Final eight highest priority research needs 1. For people of all ages diagnosed with ADHD, what are the most accurate, brief standardized tools for diagnosis and outcome measurement that can be administered in generalizable practice settings, used on a repeated basis, and integrated into clinical care? 2. For children younger than 6 years of age with disruptive behavior disorder or ADHD, what is the comparative efficacy, effectiveness, and harmfulness of the available pharmacological treatments, used alone or in combination with other pharmacologic interventions? 3. For children younger than 6 years of age with disruptive behavior disorder or ADHD, what is the comparative efficacy and effectiveness for patient outcomes of differing combinations of psychosocial and pharmacological treatments for those who are either initiating treatment with psychosocial therapies or who have not improved on their current therapy? Are there discrete patient-level predictors that favor a particular treatment strategy? 4. For people of all ages diagnosed with ADHD (and especially adolescents and adults), what methods provide the most useful data collection, assessment of prevalence, case identification, and outcomes measurements for studies involving epidemiologic surveys and administrative databases? 5. For children younger than 6 years of age with disruptive behavior disorder or ADHD, what is the comparative efficacy and effectiveness of specific psychosocial treatments alone compared with pharmacological treatments alone or in combination with psychosocial treatments for patient outcomes? 6. For people 6 years of age or older with ADHD, what are the comparative long-term outcomes for the available psychosocial and pharmacological treatments? 7. Among children younger than 6 years of age with disruptive behavior disorder or ADHD, what is the relative/comparative efficacy of key components of psychosocial treatment programs? These might include the relative efficacy of specific parent training compared with treatment components targeting the child, or the efficacy of variants in psychosocial treatment service delivery that allow flexibility for parental preferences compared with those that do not. 8. For people 6 years of age or older with ADHD, which specific sociodemographic and baseline clinical characteristics and neurobiological features predict a positive treatment response with respect to patient outcomes? 4 votes. Its inclusion resulted in a list of 16 evidence gaps for the second round of prioritization. Between the first and second rounds of prioritization, the project team applied a PICOTS framework23 to the evidence gaps and transformed each gap into a research need presented in the form of a question. Results from the second round of prioritization were based on responses from 9 of the 12 stakeholders (75%). The number of votes allocated to each research need ranged from 0 to 11. Eight of the 16 research needs received 5 or more votes, indicating the stakeholders’ highest priority research needs and representing roughly the top quarter (28%) of the original 29 evidence gaps (Table 4). The following sections provide background on each of the top eight future research needs (FRNs) and

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review PICOTS associated with each as well as potential study designs. The research needs are not ranked in any order of importance—they are all seen as high priority. A complete discussion of study design considerations can be found in the full report available online.21

Research Need 1 For people of all ages diagnosed with ADHD, what are the most accurate, brief standardized tools for diagnosis and outcome measurement that can be administered in generalizable practice settings, used on a repeated basis, and integrated into clinical care?




Population: All ages diagnosed with ADHD Intervention: Not applicable (N/A) Comparator: Feasible tools for diagnosis and measuring outcomes would be compared with reference standards. Outcome: Validation of instrument in comparison with reference standard Time frame: N/A Setting: Potential settings include: a) Epidemiologic and naturalistic research settings b) Clinical trials (efficacy) c) Practice-based research settings (effectiveness) Study design considerations: Both the AHRQ review and our group of stakeholders emphasized the need for validated, brief identification and management tools that are feasible to use in real-world clinical settings. One stakeholder specifically emphasized the need for validated brief social functioning and peer interaction measures. A limitation is that a clear reference standard does not exist for social functioning measures. Potential study designs to address this research need include: Rigorous psychometric testing using a reference standard for comparison. This type of rigorous evaluation would be appropriate for developing feasible and practical tools for use in diverse realworld clinical settings (clinical trials, practicebased research settings), in particular for collecting adequate data on social functioning and peer interaction. The preparation for such testing might require multiple steps, some qualitative and some quantitative, before some of the relevant tools are ready for validation in clinical trials or practice-based settings.

Research Need 2 For children younger than 6 years of age with disruptive behavior disorder or ADHD, what is the comparative efficacy, effectiveness, and harmfulness of the available pharmacological treatments, used alone or in combination with other pharmacologic interventions? Population: Age < 6 years and diagnosed with ADHD or a disruptive behavior disorder Intervention: Pharmacologic treatments, used alone (as a single agent) and/or in a medication combination


Comparator: Other single or combined pharmacologic treatments (e.g., stimulants vs. nonstimulants) Outcome: Outcomes for children and parents. These include change in ADHD symptoms, social functioning, emotional regulation, executive functioning, treatment adherence, behavior problems, global functioning, academics, and parent competence, and harms, such as behavioral side effects, sleep difficulties, appetite/metabolic concerns, and cardiovascular changes. Time frame: Months/years Setting: Private clinic, community clinic, school, home Study design considerations: This need focuses on pharmacologic interventions, including monotherapy and combination therapy, and broadly considers both the potential benefits and harms of interventions as key outcomes. ADHD outcomes are multifaceted. As noted above, we identified key clinical and adverse events outcomes that were reported in the draft review, which were limited by the variables reported in published trials. Stakeholders expressed the need for greater information on each of these outcomes, and in particular noted a dearth of information regarding social functioning. Future studies might consider different or additional outcomes. Potential study designs to address this research need include: Randomized controlled trials (RCTs): The strongest study design is the randomized trial with comparison between agents or, where the strength of evidence is low, comparison to placebo. Retrospective cohort studies: Given the large sample size needed to detect relatively rare harms, prospective or retrospective cohort studies would be more feasible than RCTs in assessing those outcomes. Meta-analysis of individual participant data (MIPD): If appropriate data are available, metaanalysis of individual participant data could generate information about comparative efficacy or effectiveness.

Research Need 3 For children younger than 6 years of age with disruptive behavior disorder or ADHD, what is the comparative efficacy and effectiveness for patient outcomes of differing combinations of

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psychosocial and pharmacological treatments for those who are either initiating treatment with psychosocial therapies or who have not improved on their current therapy? Are there discrete patient-level predictors that favor a particular treatment strategy? Population: Age < 6 years and diagnosed with ADHD or at risk for ADHD or diagnosed with a disruptive behavior disorder, including oppositional defiant disorder (ODD) or conduct disorder (CD), according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) Intervention: Initial treatment with psychosocial and/or pharmacologic treatments or addition of a psychosocial and/or pharmacologic treatment to an existing treatment after treatment failure. Comparator: In evaluating initial intervention with psychosocial and/or pharmacologic treatments, the comparator would be other initial psychosocial and/or pharmacologic treatments. In evaluating the addition of a psychosocial and/or pharmacologic treatment to an existing treatment after treatment failure, the comparator would be continuation of the existing treatment without the addition of any other treatment. Outcome: Outcomes for children and parents. These include change in ADHD symptoms, behavior problems, social functioning, emotional regulation, executive functioning, treatment adherence, global functioning, academics, and parent competence. Time frame: Months/years Setting: Private clinic, community clinic, school, home Study design considerations: Currently the standard of practice for patients with ADHD who are younger than 6 years of age is to begin with psychosocial treatment.25 This research need involves identifying the most effective combination of pharmacologic and psychosocial interventions, either as the initial line of treatment or as an option following failure of the current treatment. Initial combination treatments would be compared with initial monotherapy, and combinations after treatment failure would be compared with other combinations after treatment failure or continuation of the existing treatment. This research need involves a complex question concerning a variety of potential treatment combinations. Study designs to address this research need could include:

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RCTs to provide information on comparative efficacy and effectiveness of different combinations of psychosocial and pharmacologic treatments for patient outcomes. Research Need 4 For people of all ages diagnosed with ADHD (and especially adolescents and adults), what methods provide the most useful data collection, assessment of prevalence, case identification, and outcomes measurements for studies involving epidemiologic surveys and administrative databases? Population: Subjects of all ages diagnosed with ADHD Intervention: N/A Comparator: a) Education system, b) Health insurance, and c) Care providers, for example, pediatricians, family physicians, internists Outcome: Evidence-based performance measures, (e.g., fidelity to evidence-based guidelines for care) Time frame: N/A Setting: Population-based surveys Study design considerations: This methods question highlights the need for tools to facilitate the efficient study of large-scale datasets as well as primary data collection through surveys. Intervention and time frame considerations are not a direct focus of this research need; rather, they are key in how to apply the findings that might result from acquiring these tools. The setting consideration should maximize generalizability and reflect the population of children and young adults. Although a variety of data collection instruments are available, stakeholders indicated a concern that the datasets available may not contain the necessary data to capture information such as diagnosis or clinical status. This need highlights the absence of validated brief instruments for use in epidemiologic surveys and for secondary analyses of administrative or clinical datasets. Potential approaches include: Secondary analyses of epidemiologic and treatment studies. Formulating an expert panel: An expert panel could assist in improving administrative databases for research purposes. The panel could examine data sources such as third-party payer (e.g., private health insurance and state Medicaid) databases,




electronic medical records, school records, and large epidemiologic studies of children’s health. Such a panel should include experts with knowledge of diagnostic codes, variables in databases, and access issues for school and medical records; epidemiologists and other researchers with knowledge of how to standardize data and use multiple data sources; and diagnosticians who specialize in screening and diagnosing ADHD in people of all ages. Consultation with privacy and information technology experts would also be helpful. Research Need 5 For children younger than 6 years of age with disruptive behavior disorder or ADHD, what is the comparative efficacy and effectiveness of specific psychosocial treatments alone compared with pharmacological treatments alone or in combination with psychosocial treatments for patient outcomes? Population: Age < 6 years; diagnosed with ADHD, at risk for ADHD, or diagnosed with a disruptive behavior disorder, including ODD or CD, according to the DSM Intervention: Psychosocial interventions alone (including parent training and school-based interventions) Comparator: Pharmacologic treatments, alone or in combination with psychosocial treatments Outcome: Outcomes for children and parents, including change in ADHD symptoms, social functioning, emotional regulation, executive functioning, treatment adherence, behavior problems, global functioning, academics, and parent competence Time frame: 6 months/1 year Setting: Private clinic, community clinic Study design considerations: Both monotherapy and combinations of pharmacologic and psychosocial interventions are relatively common in the treatment of ADHD. Although significant literature exists on the efficacy of psychosocial treatments, we currently know little regarding the benefits of such behavioral and educational interventions compared to either medication alone or a combination of the two treatment types. Potential study designs to address this research need include: RCTs: For this research need, RCTs could be designed to compare various components and vari-


ants of psychosocial treatments (e.g., parent training, school-based intervention) used alone with either pharmacologic treatments used alone or a combination of pharmacologic and psychosocial treatments. Research Need 6 For people 6 years of age or older with ADHD, what are the comparative long-term outcomes for the available psychosocial and pharmacological treatments? Population: Age ⭓ 6 years diagnosed with ADHD Intervention: Psychosocial and pharmacological treatments Comparator: Other psychosocial and pharmacological treatments Outcome: Outcomes for children and parents, including change in ADHD symptoms, social functioning, emotional regulation, executive functioning, treatment adherence, behavior problems, global functioning, academics, parent competence, and adverse events/harms Time frame: Months/years Setting: Private clinic, community clinic, school, home Study design considerations: This need highlights the current lack of longer term outcome data to guide decision-making, an issue that was raised both in the AHRQ review and by our stakeholders. Outcomes of interest would involve both benefits, including academic outcomes, and harms. The definition of “long-term” is not clear, but would likely be multiple years. Potential study designs to address this research need include: Extensions of RCTs: This research design could be applied to current or future RCTs by adding extension phases in which treatments are continued for some or all of the trial participants beyond the original timeline of the trial. Retrospective cohort study. Research Need 7 Among children younger than 6 years of age with disruptive behavior disorder or ADHD, what is the relative/comparative efficacy of key components of psychosocial treatment programs? These might include the relative effica-

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Population: Age < 6 years; diagnosed with ADHD, at risk for ADHD, or diagnosed with a disruptive behavior disorder, including ODD or CD, according to the DSM Intervention: Variety of components as part of a psychosocial treatment program Comparator: A different collection of components of a psychosocial treatment program in order to allow isolation of the effects of specific components Outcome: Outcomes for children and parents including change in ADHD symptoms, social functioning, emotional regulation, executive functioning, treatment adherence, behavior problems, global functioning, academics, and parent competence Time frame: Months/years Setting: Private clinic, community clinic, school, home Study design considerations: In discussing this research need, stakeholders emphasized the importance of identifying which key parts of the psychosocial intervention were associated with improved outcomes, since these interventions currently contain a number of “bundled” components. They also described dropout as a substantial concern and highlighted the need for a better understanding of the relationship between adherence and outcomes. In particular, they indicated that parental preference may be an influential factor. Given the complexity of the study design, we recommend a randomized trial; other study types would suffer from selection bias and the challenges of accurately describing the different intervention components, hence threatening the validity of results. Potential study designs to address this research need include RCTs.

Population: Age ⭓ 6 years diagnosed with ADHD Intervention: Any treatment for ADHD Comparator: a) Inter-subgroup comparisons (e.g., male versus female) b) Subgroup versus all ADHD subjects (e.g., comorbidity versus no comorbidity, inattentive subtype versus combined subtype) c) Correlation with quantitative traits (e.g., neuropsychological dysfunction) Outcome: Outcomes for children and parents including change in ADHD symptoms, behavior problems, social functioning, emotional regulation, executive functioning, treatment adherence, global functioning, academics, and parent competence Time frame: Months/years Setting: Private clinic, community clinic, school, home Study design considerations: Relevant sociodemographic and clinical characteristics include gender; socioeconomic status; race; ADHD subtypes; and comorbid psychiatric disorders, developmental disorders, learning disabilities, language impairments, reading disorders, and mathematics disorders. Neurobiological features include genetic variants and neuroimaging abnormalities. In contrast to several other research needs, this need does not involve measuring treatment effectiveness, but rather involves identifying predictors of treatment response. This need reflects stakeholders’ interest in finding variables that might be helpful in tailoring treatment recommendations for individuals. Analyses would involve consideration of moderators and mediators. Potential study designs to address this research need include: Secondary analysis of data from cohort studies and randomized trials Consensus conference (i.e., researchers’ consensus regarding the routine collection of patient baseline clinical characteristics for future studies, which would greatly facilitate progression toward more patient-centered and personalized care for ADHD).

Research Need 8

CONCLUSIONS

For people 6 years of age or older with ADHD, which specific sociodemographic and baseline clinical characteristics and neurobiological features predict a positive treatment response with respect to patient outcomes?

The purpose of this project was to utilize a structured approach to further refine and prioritize specific areas of future research that were necessary to sufficiently address previously identified key questions regarding the management of ADHD.4 This

cy of specific parent training compared with treatment components targeting the child, or the efficacy of variants in psychosocial treatment service delivery that allow flexibility for parental preferences compared with those that do not.

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project worked to clearly identify evidence gaps described in the report, collaborate with stakeholders to prioritize this list of gaps and transform them into research needs, further prioritize these needs, and consider PICOTs and potential future study designs for the highest prioritized needs. The final list of research needs incorporated a broad spectrum of issues ranging from epidemiologic considerations to more clinically oriented topics and identified the need for more information about patients with ADHD in all age groups. Specifically, it included two epidemiologic needs involving all ages, four clinically oriented needs for children younger than 6 years old, and two clinically oriented needs for those 6 years of age and older. For the younger group, the stakeholders identified research needs that would guide the selection of the most efficacious and effective medication and psychosocial interventions. For the older group, stakeholders identified a need for studies to evaluate the relations between patientlevel characteristics and treatment response and a need for comparative evaluation of long-term outcomes. We proposed RCTs as the optimal study design for many questions. However, trials designed to compare components of different interventions or those designed to evaluate the role of patient-level predictors on treatment response would require substantial sample sizes, on the order of 500–600 participants. For comparison, the major longitudinal study of ADHD to date, the Multimodal Treatment Study of Children with ADHD (MTA),26 had a sample size of 579. In examining these small intervention and interaction effects, it may be appropriate to include observational studies of secondary data with advanced techniques such as propensity scoring and instrumental variable analysis. The nature of the stakeholder process comes with certain limitations. First, the process created tension between the need to create a list of clear, concise gaps and the need to remain faithful to the language and intent of the findings of the original AHRQ review, which was completed by a different Evidence-Based Practice Center. Indeed, there might be other high priority needs that were not identified in the original comparative effectiveness review, but we would not be able to consider those. At the same time, while this balance was difficult to strike, it may represent a strength of the process in that neither the findings of the systematic review nor the views of the stakeholder panel fully dominated the final product. Second,


participation by stakeholders in each exercise was not complete, which might unfairly favor a research need that was preferred by those who did participate. However, we had at least 75% participation in each exercise. Further, the broad spectrum of the high priority research needs, cutting across age ranges and involving both epidemiologic and clinical areas, suggests that no one view was over-represented. We worked with a group of stakeholders to identify and refine 29 evidence gaps and to distill from them eight high-priority research needs in the field of ADHD. These high priority needs included a broad range of issues cutting across age range (above and below 6 years of age), key clinical issues, and epidemiologic and measurement concerns. Within this group of eight, clear themes emerged: the need for improved measurement tools, more generalizable study populations and settings, longer follow-up periods, more understanding of patient-level predictors of response, and more comparative evaluation of psychopharmacologic, psychosocial, and combination interventions across age ranges. We used PICOTS construction to aid our consideration of study design issues and example power analyses (not shown) to identify pragmatic barriers presented by many of the potential designs. Observational studies with advanced methods may allow some of these questions to be addressed in a more cost-effective manner but cannot substitute for new large, long-term trials to evaluate these complex research needs in ADHD.

Acknowledgements We wish to thank our Task Order Officer at the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care Program, Sonia Tyutyulkova, MD, and the members of our stakeholder panel for their contributions of time and expertise. The stakeholder panel members were Ann Abramowitz, PhD, Emory University, Atlanta, GA; Anne Chelminski, MD, MPH, University of North Carolina, Chapel Hill, NC; Lisa Clements, PhD, Missouri HealthNet, Missouri Department of Social Services, Jefferson City, MO; Tammy Davis, EdD, American School Counselor Association, Alexandria, VA; Tiffany Farchione, MD, U.S. Food and Drug Administration, Division of Psychiatry Products, Silver Spring, MD; Stephen Faraone, MD, State University of New York (SUNY) Upstate Medical University, Syracuse, NY; Laurence Greenhill, MD, New York State Psychiatric

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Institute, New York, NY; Penelope Knapp, MD, University of California at Davis M.I.N.D. Institute, Sacramento, CA; Sarah Mulligan, MEd, Division for Early Childhood (DEC), Council for Exceptional Children, Missoula, MT; Sue Visser, PhD, Centers for Disease Control and Prevention, National Center for Birth Defects and Developmental Disabilities, Atlanta, GA; Benedetto Vitiello, MD, National Institutes of Health, National Institute of Mental Health, Rockville, MD; and Julie Zito, PhD , University of Maryland, Baltimore, MD.

11.

12.

13.

14.

References 1.

Pliszka S, AACP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Can Acad Child Adolesc Psychiatry 2007;46: 894–921. 2. Greenhill LL, Posner K, Vaughan BS, et al. Attention deficit hyperactivity disorder in preschool children. Child Adolesc Psychiatr Clin North Am 2008;17:347–66, ix. 3. Simon V, Czobor P, Balint S, et al. Prevalence and correlates of adult attention-deficit hyperactivity disorder: Meta-analysis. Br J Psychiatry 2009;194:204–11. 4. Charach A, Dashti B, Carson P, et al. Attention deficit hyperactivity disorder: Effectiveness of treatment in atrisk preschoolers; long-term effectiveness in all ages; and variability in prevalence, diagnosis, and treatment. Rockville, MD: Agency for Healthcare Research and Quality Comparative Effectiveness Review No. 44; 2011 (available at www.effectivehealthcare.ahrq.gov/search-forguides-reviews-and-reports/?pageaction=displayproduct&productID=818, accessed February 3, 2014). 5. Greenhill L, Kollins S, Abikoff H, et al. Efficacy and safety of immediate-release methylphenidate treatment for preschoolers with ADHD. J Am Acad Child Adolesc Psychiatry 2006;45:1284–93. 6. Sallee FR, Lyne A, Wigal T, et al. Longterm safety and efficacy of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2009;19:215–26. 7. Swanson JM, Kraemer HC, Hinshaw SP, et al. Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment. J Am Acad Child Adolesc Psychiatry. 2001;40:168–79. 8. Conners CK, Epstein JN, March JS, et al. Multimodal treatment of ADHD in the MTA: An alternative outcome analysis. J Am Acad Child Adolesc Psychiatry 2001;40: 159–67. 9. Jensen PS, Hinshaw SP, Kraemer HC, et al. ADHD comorbidity findings from the MTA study:Comparing comorbid subgroups. J Am Acad Child Adolesc Psychiatry 2001;40: 147–58. 10. MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up:

116

March 2014

15.

16.

17.

18.

19.

20.

21.

22.

23.

24-month outcomes of treatment strategies for attentiondeficit/hyperactivity disorder. Pediatrics 2004;113:754–61. Jensen PS, Arnold LE, Swanson JM, et al. 3-year follow-up of the NIMH MTA study. J Am Acad Child Adolesc Psychiatry 2007;46:989–1002. Molina BS, Hinshaw SP, Swanson JM, et al., The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009;48:484–500. MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: Changes in effectiveness and growth after the end of treatment. Pediatrics 2004;113:762–9. Froehlich TE, Lanphear BP, Epstein JN, et al. Prevalence, recognition, and treatment of attention-deficit/hyperactivity disorder in a national sample of US children. Arch Pediatr Adolesc Med 2007;161:857–64. Bokhari F, Mayes R, Scheffler RM. An analysis of the significant variation in psychostimulant use across the U.S. Pharmacoepidemiol Drug Saf 2005;14:267–75. Fulton BD, Scheffler RM, Hinshaw SP, et al. National variation of ADHD diagnostic prevalence and medication use: Health care providers and education policies. Psychiatr Serv 2009;60:1075–83. Eyestone LL, Howell RJ. An epidemiological study of attention-deficit hyperactivity disorder and major depression in a male prison population. Bull Am Acad Psychiatry Law 1994;22:181–93. Centers for Disease Control and Prevention. Mental health in the United States. Prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder—United States, 2003. MMWR Morb Mortal Wkly Rep 2005;54:842–7. Report of the International Narcotics Control Board for 2009. Psychotropic Substances–-Technical Report, 2009 (available at www.incb.org/documents/Psychotropics/technical-publications/2009/Psychotropic_Report_2009.pdf, accessed February 24, 2014) Owens DK, Lohr KN, Atkins D, et al. AHRQ series paper 5: Grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the Effective Health-Care Program. J Clin Epidemiol 2010;63:513–23. Gaynes B, Christian R, Saavedra L, et al. Future research needs for attention deficit hyperactivity disorder: Effectiveness of treatment in at-risk preschoolers, longterm effectiveness in all ages, and variability in prevalence, diagnosis, and treatment. Future research needs No. 9 (prepared by RTI-UNC Evidence-based Practice Center under Contract No. 290-2007-10056-I) Rockville, MD: Agency for Healthcare Research and Quality; 2012. AHRQ Publication No. 12-EHC008-EF (available at www.ncbi.nlm.nih.gov/books/NBK83972, accessed February 3, 2014). Agency for Healthcare Research and Quality Effective Health Care Program. How are research topics chosen? (available at www.effectivehealthcare.ahrq.gov/index .cfm/submit-a-suggestion-for-research/how-are-researchtopics-chosen, accessed February 3, 2014). Whitlock EP, Lopez SA, Chang S, et al. AHRQ series paper



IDENTIFYING HIGH PRIORITY FUTURE RESEARCH NEEDS FOR ADHD 3: Identifying, selecting, and refining topics for comparative effectiveness systematic reviews: AHRQ and the effective health-care program. J Clin Epidemiol 2010;63: 491–501. 24. Carey TS, Sanders GD, Viswanathan M, et al. Framework for considering study designs for future research needs. Methods future research needs paper no. 8 [Internet]. Rockville, MD: Agency for Healthcare Research and Quality; 2012 (prepared by the RTI–UNC Evidence-based Practice Center under Contract No. 290-2007-10056-I) (available at www.ncbi.nlm.nih.gov/books/NBK95273, accessed February 3, 2014). 25. Subcommittee on Attention-Deficit/Hyperactivity Disorder, Steering Committee on Quality Improvement


and Management. ADHD: Clinical practice guideline for the diagnosis, evaluation, and treatment of attentiondeficit/hyperactivity disorder in children and adolescents. Pediatrics 2011;128;1007; originally published online October 16, 2011; DOI: 10.1542/peds.2011-2654. The online version of this article, along with updated information and services, is available at http://pediatrics.aappublications.org/content/128/5/1007.full.html, accessed March 3, 2014. 26. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attentiondeficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry 1999;56:1073–86.

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Future directions and research needs.

High-priority research needs for insulin delivery and glucose monitoring methods.

Hyperactivity Disorder.

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Herbicide-resistant weeds: from research and knowledge to future needs.

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hyperactivity disorder (ADHD) and high risk behaviors.

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Practices in pelvic organ prolapse operations among surgeons: an international survey identifying needs for further research.

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Urban Health Research in Africa: Themes and Priority Research Questions.

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Education research: priority designs and common misperceptions.