MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 8: 162170 (2002)

THE EPIDEMIOLOGY OF ATTENTION-DEFICIT/ HYPERACTIVITY DISORDER (ADHD): A PUBLIC HEALTH VIEW

Andrew S. Rowland,*,1 Catherine A. Lesesne,2 and Ann J. Abramowitz3
1

MPH Program, Department of Family and Community Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia

Department of Psychology and Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia

Attention-decit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood. However, basic information about how the prevalence of ADHD varies by race/ethnicity, sex, age, and socio-economic status remains poorly described. One reason is that difculties in the diagnosis of ADHD have translated into difculties developing an adequate case denition for epidemiologic studies. Diagnosis depends heavily on parent and teacher reports; no laboratory tests reliably predict ADHD. Prevalence estimates of ADHD are sensitive to who is asked what, and how information is combined. Consequently, recent systematic reviews report ADHD prevalence estimates as wide as 2%18%. The diagnosis of ADHD is complicated by the frequent occurrence of comorbid conditions such as learning disability, conduct disorder, and anxiety disorder. Symptoms of these conditions may also mimic ADHD. Nevertheless, we suggest that developing an adequate epidemiologic case denition based on current diagnostic criteria is possible and is a prerequisite for further developing the epidemiology of ADHD. The etiology of ADHD is not known but recent studies suggest both a strong genetic link as well as environmental factors such as history of preterm delivery and perhaps, maternal smoking during pregnancy. Children and teenagers with ADHD use health and mental health services more often than their peers and engage in more health threatening behaviors such as smoking, and alcohol and substance abuse. Better methods are needed for monitoring the prevalence and understanding the public health implications of ADHD. Stimulant medication is the treatment of choice for treating ADHD but psychosocial interventions may also be warranted if comordid disorders are present. The treatment of ADHD is controversial because of the high prevalence of medication treatment. Epidemiologic studies could clarify whether the patterns of ADHD diagnosis and treatment in community settings is appropriate. Populationbased epidemiologic studies may shed important new light on how we understand ADHD, its natural history, its treatment and its consequences.

little attention. Basic epidemiologic information about the distribution of ADHD across the population by age, sex, race, and socio-economic status remains inadequately described. The origins of ADHD are poorly understood and few studies have looked for preventable risk factors. In this review, we discuss some of the underlying issues that have impeded epidemiologic research including difculties in reliably diagnosing and creating a case denition for ADHD. We will summarize the epidemiologic data about prevalence, natural history, and risk factors, identify key gaps in that literature, and end with some suggestions for future epidemiologic research. HISTORY OF ADHD NOMENCLATURE AND PRESUMED ETIOLOGY In 1902, George Still, M.D., delivered a series of lectures in which he described the lack of moral control among children without noted physical impairments [Barkley, 1998]. Historically, a series of different names, including minimal brain damage syndrome, minimal brain dysfunction, hyperkinetic reaction of childhood, and attention decit disorder have been used to describe the disorder now known as attention-decit/hyperactivity disorder [American Psychiatric Association, 1994]. The earlier pathology-oriented nomenclature (e.g., minimal brain damage syndrome) reected scientists perception of the disorders etiology. Early attempts to link attention decits and behavioral disturbances to brain dysfunction were shaped by the experience of the encephalitis epidemic of 19171918 [Sandberg and Barton, 1996]. Children who survived the infection experienced subsequent problems including hyperactivity, per*Correspondence to: Andrew S. Rowland, Ph.D., MPH Program, Department of Family and Community Medicine, 2400 Tucker NE, University of New Mexico, Albuquerque, NM 87131. E-mail: arowland@salud.unm.edu Received 21 May 2002; Accepted 23 May 2002 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrdd.10036

2002 Wiley-Liss, Inc.

MRDD Research Reviews 2002;8:162170.

Key Words: Attention Decit Disorder with Hyperactivity; diagnosis; comorbidity; risk factors; conduct disorder; anxiety disorders; drug therapy

INTRODUCTION ttention-Decit/Hyperactivity Disorder (ADHD) is not only the most common neurodevelopmental disorder of childhood but also the most studied. Nevertheless, the public health dimensions of ADHD have received relatively

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Table 1.

DSM-IV Criteria for ADHD

1. Either (A) or (B): (A) six or more of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Inattention: 1) often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities 2) often has difculty sustaining attention in tasks or play activities 3) often does not seem to listen when spoken to directly 4) often does not follow through on instructions and fails to nish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions) 5) often has difculty organizing tasks and activities 6) often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework) 7) often loses things necessary for tasks and activities (e.g., toys, school assignments, pencils, books, or tools) 8) is often easily distracted by extraneous stimuli 9) is often forgetful in daily activities (B) six or more of the following symptoms of hyperactivity-impulsivity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Hyperactivity: 1) often dgets with hands or feet or squirms in seat 2) often leaves seat in classroom or in other situations in which remaining in seat is expected 3) often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, it may be limited to subjective feelings of restlessness) 4) often has difculty playing or engaging in leisure activities quietly 5) is often on the go or often acts as if driven by a motor 6) often talks excessively Impulsivity 7) often blurts out answers before questions have been completed 8) often has difculty awaiting turn 9) often interrupts or intrudes on others (e.g., butts into conversations or games) 2. Some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7 years. 3. Some impairment from the symptoms is present in two or more settings (e.g., at school [or work] and at home). 4. There must be clear evidence of clinically signicant impairment in social, academic, or occupational functioning. 5. The symptoms do not occur exclusively during the course of Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for by another mental disorder (e.g., Mood disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder). Based on these criteria, three specic subtypes of ADHD are identied: 1. ADHD, Combined Type: if both criteria 1A and 1B are met for the past 6 months 2. ADHD, Predominately Inattentive Type: if criterion 1A is met but criterion 1B is not met for the past six months 3. ADHD, Predominately Hyperactive-Impulsive Type: if Criterion 1B is met but Criterion 1A is not met for the past six months

evidence implicating a single set of decits shared by all individuals with ADHD. From a classication perspective, it would enormously simplify our understanding of the disorder if a measurable core decit were identied. Nevertheless, because ADHD is so heterogeneous, it seems unlikely that a single, unifying decit will emerge. DIAGNOSIS Epidemiologic research about ADHD has been hampered by the difculties involved in diagnosing ADHD and because of the numerous changes in the denition of the disorder over the past 20 years. A few researchers question whether ADHD exists [Weinberg and Brumback, 1992]; they consider ADHD to be a poorly dened catch-all diagnosis. Most researchers consider this position extreme but agree that as currently dened, children diagnosed with ADHD comprise a heterogeneous population sharing a cluster of symptoms [Denckla, 1992]. The ADHD sections in the 1987 and 1994 Diagnostic and Statistical Manual for Mental Disorders (DSM-III-R and DSM-IV) acknowledge this heterogeneity. DSM-III-R differentiated between attention decit disorder with and without hyperactivity. This represented an important step forward and set the stage for better epidemiologic studies that no longer classied all ADHD cases as a single group. DSM-IV created separate subtypes for children who are primarily inattentive, those who are primarily hyperactive and impulsive, and a combined category for those who are both inattentive and impulsive/hyperactive (Table 1). Earlier versions of the DSM allowed ADHD to be present in one setting. DSM-IV, in contrast, requires that both symptoms and impairment from those symptoms are pervasive and therefore present in at least two settings, e.g., at school and at home. This criterion reduces the chance that a child who does not get along with a particular teacher or parent will be diagnosed with ADHD. In addition, symptoms must have been present for at least 6 months, and accompanied by clinically signicant impairment [American Psychiatric Association, 1994]. DSM-IV requires that symptoms and impairment were present before age 7 years. However, data from the DSM-IV eld trials suggested that for many children (particularly inattentive children) symptoms do not become apparent until older ages, when schoolwork becomes more difcult. Consequently, researchers have sug163

sonality changes, and learning difculties. However, despite many years of research attempting to identify specic etiologic correlates of the disorder, no single cause has been identied. ADHD is best understood as a group of behavioral symptoms that reect excessive impulsivity, hyperactivity, or inattention. Since 1980, the term attention has been incorporated into the name of the disorder (e.g., attention decit disorder with/without hyperactivity or attention-decit/hyperactivity disorder). While current diagnostic criteria do not require that attention difculties or distractibility are central to the disorder, the nomenclature suggests otherwise. Several researchers have attempted to identify core
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decits or measurable neuropsychological markers that underlie ADHD, with a focus on executive functions [Barkley, 2000; Tannock in Paule et al., 2000]. Barkley postulates a primary decit in response inhibition that impacts all other executive functions, and ultimately results in impaired social intelligence. His theoretical model is based on research involving executive functions but the applicability of this model still needs to be explored [Barkley, 2000]. Tannock has suggested three areas as potential core decits: executive functions including decits in working memory, visual-spatial orienting, and energetic state, particularly activation [Tannock in Paule et al., 2000]. To date, there is not experimental
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gested that the current age criteria be relaxed [Barkley and Biederman, 1997]. Clinicians and researchers rely heavily on parent and teacher reports about a childs behavior when identifying ADHD because these adults usually have the best sense of a childs behavior on a daily basis and over time. Teachers are particularly valuable informants because they usually have a good sense of developmentally appropriate behavior [Barkley, 1998]. The diagnosis of ADHD should be made in a developmental context. Symptoms are considered to be present and meaningful only if they are in excess of what would be expected of a child of the same age and cognitive level [Cantwell, 1996]. ADHD symptoms are not always apparent in highly structured or novel settings, which make observations of the child during an ofce visit or interview less valuable than histories obtained from the parent and teacher [Zametkin and Ernst, 1999]. Childrens (particularly preteens) reports of their own behavioral symptoms tend not to be reliable and consequently are of limited value in assessing ADHD [American Psychiatric Association, 1997; Barkley, 1998]. ADHD is often diagnosed by pediatricians or other primary care providers, not by psychologists or psychiatrists [Bussing et al., 1998]. Primary care physicians often do not use the DSM criteria when evaluating ADHD. A study from the Pediatric Research in Ofce Settings (PROS) network reported that the American Psychiatric Associations DSM criteria were only used by 38% of the 3900 clinicians surveyed [Wasserman et al., 1999]. Presumably, the other 62% based their diagnosis on clinical intuition or some other nonstandardized form of assessment. A possible explanation for this is that the health care system does not adequately compensate primary care providers for doing extensive mental health evaluations, the links between primary care providers and mental health specialists are often tenuous, and there are few incentives for providing systematic follow-up after assessment [Bussing et al., 1998; Goldman et al., 1998]. The rapid increase in the number of children being prescribed stimulant medication to treat ADHD has raised concern about whether the diagnosis is being made properly (see Public Health section below). In 2000, the American Academy of Pediatrics published practice guidelines suggesting that pediatricians should use DSM-IV based instruments and DSM-IV criteria when they conduct ADHD eval164

uations [American Academy of Pediatrics, 2000]. Even when DSM-IV criteria are used to make the diagnosis, there are subtle problems that epidemiologists need to consider. For example, DSM-IV does not specify how reports from different informants should be combined. Lack of standardization in this process dramatically shifts who is considered a case. It also shifts the diagnostic subtypes. In a study that examined the concordance of parent-teacher reports, Mitsis et al. [2000] found that diagnoses based only on parent report or teacher report frequently yielded a diagnosis of either inattentive or hyperactive subtype of ADHD but not the combined subtype. However, if the two sets of reports were combined, most children fell into the combined subtype and the inattentive and hyperactive subtypes became less common. The issue of how to combine

Epidemiologic studies can only approximate clinical diagnostic processes. Developing an effective case denition is a critical step for conducting epidemiologic studies of ADHD
reports from different respondents has important implications for treatment, as well as for epidemiologic research trying to establish an ADHD phenotype or case denition. EPIDEMIOLOGIC CASE DEFINITION Epidemiologic studies can only approximate clinical diagnostic processes. Developing an effective case denition is a critical step for conducting epidemiologic studies of ADHD. ADHD, like many other psychiatric and medical conditions, is a clinical diagnosis without objective laboratory tests. Although continuous performance tests (computerized measures of attention and impulsivity) are often used as part of the clinical assessment of ADHD, they lack adequate sensitivity or specicity [American Psychiatric Association, 1997]. Some researchers have tried to quantify ADHD behaviors
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by systematic observation of off task behavior or by using mechanical devices to measure leg movements or restlessness. Measurement of catecholamines or metabolites in plasma and urine has been implemented with mixed success [Halperin et al., 1993; Pliszka et al., 1994]. The current consensus (as stated in DSM-IV) is that no laboratory tests reliably predict ADHD. Therefore, teacher and parent rating scales or interviews about the childrens behavior over the past 6 months continue to be the most important diagnostic procedures available. Attentional and behavioral problems are often seen in children who are bored, who have been abused, or who have various forms of psychopathology other than ADHD. The diagnosis of ADHD depends on a having a well-dened history of behavioral symptoms of hyperactivity, impulsivity, or inattention as well as impairment from those symptoms. ADHD often does not present in isolation, but rather with another disorder (co-morbidity). Common comorbid conditions include learning disabilities, oppositional deant disorder, conduct disorder, Tourette syndrome, depression, anxiety disorders, and bipolar disorder [Biederman et al., 1991; Cantwell, 1996; Barkley, 1998]. Rough estimates of rates of co-morbidity are about 10% for reading disabilities [Shaywitz and Shaywitz, 1991], 27% for anxiety disorders [Biederman et al., 1991] and 25% 40% for oppositional deant disorder/ conduct disorder [Szatmari et al., 1989; American Academy of Pediatrics, 2000]. As with ADHD itself, estimates of the prevalence of comorbid conditions are highly susceptible to methodologic choices and denitions [Shaywitz and Shaywitz, 1991]. Many of these conditions can resemble ADHD. Further, other disorders may arise after an individual has been diagnosed with ADHD. Differentiating between comorbid conditions and underlying conditions that mimic ADHD is a problem for epidemiologic studies. In general, epidemiologic studies can document the presence or absence of symptoms and impairment that would justify a diagnosis of ADHD, and can follow a similar procedure for comorbid diagnoses. However, for studies that use rating scales or structured diagnostic interviews (rather than clinician-based semi-structured interviews), there is rarely a provision for making the sort of judgment that typically enters into the process of rendering a diagnosis following a good clinical assessment. In the absence of the type of clinical judgment and thoroughness in collecting data from
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all relevant respondents (e.g., the child, both parents, many teachers) that characterizes a state-of-the-art evaluation, there is often little basis for deciding whether an individuals reported ADHD symptoms may be better accounted for by an anxiety disorder or an untreated learning disability. What appears as ADHD may be symptoms of another disorder [American Psychiatric Association, 1994; Zametkin and Ernst, 1999]. This problem probably inates prevalence estimates of ADHD reported by many epidemiologic studies. Confounding of ADHD symptoms is another potential problem. Abikoff et al. [1993] found that respondents have more difculty accurately assessing ADHD symptoms if conduct problems are also present. Social researchers have suggested that teacher reports may be inuenced by factors such as class size, teacher training and experience, or disciplinary attitudes and practices. This may be conceptualized as the goodness of t between the child and the teacher, the environment and the family [Greene, 1996]. More research is needed on factors that cause a child to be referred for evaluation and treatment and on factors that inuence how teachers and parents respond to items on behavior rating scales and psychiatric interviews. Most of the ADHD literature is based on clinic samples of children. These samples often have the advantage of extensive evaluation but the disadvantage of not representing most children in the community, even those with ADHD. Children in clinic-based samples tend to show more psychiatric symptoms and more impairment. In contrast, population-based samples of children generally receive less thorough evaluations but ndings can be used to make inferences about the general population. The challenge facing epidemiologic researchers using population-based samples is how to screen large numbers of children and still assess psychopathology well. The present review focuses on DSM-based studies because this is the clinical standard for dening ADHD in the United States. Nevertheless, the power of population-based epidemiologic samples for studying ADHD was rst demonstrated by studies that did not use DSM-based instruments [Boyle et al., 1987; Taylor et al., 1991; August et al., 1996]. It is difcult to compare studies that used different assessment strategies. Although dimensional ratings scales have been widely used to select epidemiologic samples, we propose that screening
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should be based on DSM-IV rating scales and criteria. This would help generate more empirical data for the current classication system being used by clinicians, and reduce some of the differences between samples in the literature. However, creating screening criteria based on DSM-IV criteria is not straightforward. While it would ensure symptom coverage, methods for combining symptom reports from different respondents or dening impairment would still need to be addressed. Developing standardized case denitions is a critical step in harnessing the power of an epidemiologic approach to understanding ADHD. Genetic researchers interested in ADHD have made some progress in developing standardized approaches to

Although there is considerable value in conceptualizing symptoms and impairment both as dimensional measures and as categorical measures [ Jensen et al 1999], for epidemiologic purposes, it is circular to use cutpoints of the normal distribution to estimate prevalence.
identifying a common phenotype. Through an ambitious international collaborative effort, researchers have proposed a method (called a hypescheme) for combining data from different studies by requiring that each study collect a specic set of minimal information [Curran et al., 2000; ADHD Molecular Genetics Network, 2000]. Depending on how the hypescheme is implemented, this (or similar methods), could be a rst step in deriving a standardized case denition for epidemiologic studies on ADHD. PREVALENCE OF ADHD The obstacles to reliable diagnosis have made reported prevalence estimates difcult to interpret. Prevalence estimates
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are particularly sensitive to who was asked what, and how that information is combined [Gordon et al., 1988; Boyle et al., 1996]. Consequently, even systematic literature reviews report very different prevalence estimates. For example, three reviews published in major journals over a four year period reported the prevalence of ADHD as 1.7%17.8%, 3% 6% and 4%12% [Goldman et al., 1998; Elia et al., 1999; Brown et al., 2001]. Nevertheless, if standardized diagnostic criteria and methodology are applied, some of the variability in reported prevalence disappears, even in studies of populations as different as the United States, Great Britain, China, Thailand, and Kenya [Anderson, 1996]. The DSM-IV states that the prevalence of ADHD is about 35% among school-age children [American Psychiatric Association, 1994]. This estimate, although frequently cited, is poorly documented. While it is unclear where this estimate comes from, it is close to the cutoffs for clinical signicance in two of the most widely used behavior or symptom checklists used to assess ADHD, the Child Behavior Checklist (CBCL) and the Conners Parent and Teacher ratings scales. These scales have dened clinically important cutpoints as the extremes of a bell curve (typically 1.5 to 2 standard deviations above the mean or about the top 93%98% of the distribution). Although there is considerable value in conceptualizing symptoms and impairment both as dimensional measures and as categorical measures [Jensen et al., 1999], for epidemiologic purposes, it is circular to use cutpoints of the normal distribution to estimate prevalence. Epidemiologic studies that have simply applied the DSM-IV criteria to school populations have usually come up with estimates between 11 and 16% [Cantwell, 1996]. Without additional populationbased data, it is difcult to interpret the existing prevalence literature or to summarize what we know. However, the available data suggest some general patterns. For example, boys are identied with ADHD at least four times as often as girls [Cantwell, 1996]. The male predominance probably reects both referral bias because boys tend to display more disruptive behavior than girls do as well as a true sex difference in prevalence. Reliable information on the demographic distribution of ADHD, particularly for socio-economic variables, is not available. Higher prevalence rates have been reported among urban compared to rural children [Offord et al., 1987]. 165

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However, it is unclear whether this simply reects differences in access to medical care. Differences in prevalence between different racial and ethnic groups have not been adequately examined in population-based studies; additional research is needed. Preliminary data from a North Carolina study suggest little difference in the history of ADHD diagnosis between African-American and white children but more substantial racial differences in medication treatment patterns [Rowland et al., 2001; 2002]. In that study, 8% of white elementary school children were being treated for ADHD with medication compared to 5% of African-American children and 2% of Hispanic children [Rowland et al., 2002]. EVIDENCE SUGGESTING A BIOLOGICAL BASIS FOR ADHD It is beyond the scope of this review to summarize the etiologic risk factors for ADHD but we would like to direct the reader to some of the evidence that suggests there is a biologic basis for ADHD. Three areas of evidence are pertinent; neuroimaging studies, genetic studies, and other etiologic studies. The 1990s saw a proliferation of neuroimaging investigations of ADHD. At this point, preliminary ndings generally converge on dysfunction and dysregulation of cerebellar-striatal/adrenergic-prefrontal circuitry [Castellanos, 2001]. Abnormal right prefrontal anatomy and function have been suggested by several studies. Neuroimaging ndings must be considered preliminary, for several reasons. First, brain regions that have not been implicated in ADHD to date have not been studied; second, small sample sizes and inadequate statistical power characterize the majority of neuroimaging studies of ADHD; third, interpretation of ndings is limited by lack of information about normal, age-related developmental changes; and fourth, neuroimaging technologies are in their infancy and in a state of ux. A genetic component to ADHD is strongly suggested because ADHD clusters in families [Waldman and Rhee, 2002]. For example, in a clinic-referred sample, 34 40% of the subjects with ADHD reported a family history of ADHD compared to 8% of controls [Biederman et al., 1992]. Twin studies suggest that concordance for hyperactivity is greater among monozygotic twins than dizygotic twins. For example, one study reported concordance for clinically diagnosed hyperactivity in 51% of monozygotic and 33% of dizygotic pairs [Goodman and Stevenson, 1989]. 166

Recent molecular genetic studies have identied two polymorphisms in the dopamine transporter and the dopamine receptor genes that inuence risk of ADHD [Swanson et al., 2001]. These polymorphisms were selected as possible targets because stimulant medications, which are effective in treating ADHD, impact dopamine transmission. There is preliminary evidence that the dopamine transporter polymorphism is more closely linked to impulsivity and the dopamine receptor gene is more closely linked to inattention [Waldman et al., 1998; Rowe et al., 1998]. The genetic links involving these two polymorphisms have been replicated many times but the general consensus is that many genes are probably involved in the transmission of ADHD [Swanson et al., 2001]. More research is needed to understand how nongenetic risk factors interact with genetic predisposition in determining risk of developing ADHD. REPRODUCTIVE AND ENVIRONMENTAL RISK FACTORS Since the 1950s many studies have looked at the relationship between low birthweight and risk of ADHD. Perhaps the most convincing data about the relationship between low birthweight and ADHD come from follow-up studies of several longitudinal cohorts of low birthweight children. For example, Botting et al. [1997] found over a three fold increase in the risk of ADHD at age 12 among a cohort of children born weighing less than 1500 grams compared to age matched classroom controls. Breslau et al. [1996] reported a 23.5 fold increased risk of ADHD among low birthweight children assessed at age 6 compared to controls. The literature suggests low birthweight babies born between 1,500 and 2,500 grams are at increased risk of ADHD but more data is needed [Breslau, 1995]. Because it has not been adequately studied, more research is needed on whether risk of ADHD varies by gestational age (the number of weeks a baby is born preterm). A Danish neurologist has hypothesized that ADHD is caused by preterm related hypoxia (Lou, 1996). Because the brain is still developing rapidly during the third trimester, preterm delivery is plausibly an important risk factor for ADHD. Mothers of ADHD children are reported to have increased rates of pregnancy complications. Nevertheless, this literature is difcult to interpret because few studies have used standard reproductive epidemiologic methods for collectMRDD RESEARCH REVIEWS

ing or analyzing the data. More comprehensive epidemiologic studies of pregnancy history as risk factors for ADHD are warranted. The most suggestive evidence that an environmental toxicant might be an etiologic risk factor for ADHD is for lead. Animals dosed with lead are more aggressive and agitated, more distracted by irrelevant stimuli, and less able to inhibit inappropriate responses [Rice et al., 1996]. Needleman et al. [1979] reported a dose-response relationship between tooth lead levels and teacher ratings of disorganized, hyperactive, and inattentive behaviors among children without overt poisoning. Subsequent research, including a number of prospective studies, has generally corroborated Needlemans ndings using teacher and parent questionnaires [Fergusson et al., 1988; Bellinger et al., 1994] but has been less successful when using more specic neuropsychological measures of inattention [Bellinger, 1995]. Lead levels in the United States have dropped sharply since lead was removed from gasoline [Pirkle et al., 1994]. Therefore, it is unlikely that lead is a strong risk factor for ADHD for most American children, even if an etiologic link was present in the past. However, epidemiologists studying ADHD should not overlook a possible etiologic role for lead in areas where childhood blood lead levels are high. The literature on lead is important because it creates a paradigm for understanding how an environmental toxicant might increase the risk of ADHD. Few studies have been done on the possible relationship between ADHD and fetal exposure to toxicants like solvents, pesticides, or metals like mercury that cross the placenta and are excreted in breast milk. Cigarette smoking during pregnancy has been reported to increase the risk of ADHD. One case-control study reported an increased odds ratio of 2.7 for ADHD among children of women who smoked at least one pack of cigarettes per day during their pregnancy after adjusting for parental history of ADHD [Millberger et al., 1996]. Many other studies have reported increases in externalizing disorders and other psychiatric conditions among the children of women who smoked. However, the evidence may be partially artifactual. Nicotine acts as a stimulant and young adults with ADHD sometimes self-medicate by smoking. Therefore, maternal smoking status could be acting as a marker for ADHD status. Even with a detailed family history of ADHD, subtle bias may be difcult to detect. Prospective, population-based
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studies are needed to sort out the etiologic relationship between maternal smoking and risk of ADHD. Even though genetic risk factors are probably responsible for a substantial portion of the etiologic fraction of ADHD, nongenetic risk factors still deserve particular attention. Environmental (nongenetic) factors are more likely to be preventable and to be appropriate targets for intervention. Understanding the interaction between genetic and environmental risk factors may help identify susceptible sub-populations where interventions might be warranted. ADHD AS A DEVELOPMENTAL DISORDER Castellanos [1997] has proposed the hypothesis that ADHD represents a neurodevelopmental lag. Levels of dopamine metabolites in spinal uid in children tend to peak at age 2 and decline over the next dozen years. Castellanos hypothesizes that this may be why hyperactive symptoms decline in ADHD children as they age. Children with ADHD also tend to trail about 2 years behind their age-peers in social development as measured by instruments like the Vineland Social Maturity Scale. The excess male to female ratio (about 4:1 cited above) seen for ADHD is consistent with the sex ratio of many other developmental disorders [Verloove-Vanhorick et al., 1994]. In addition, the developmental delay hypothesis is consistent with the etiologic data suggesting a link between preterm delivery and ADHD. Because ADHD symptoms tend to change as children age, one ADHD researcher has proposed that the number of symptoms required for a diagnosis be age-normed so older children and adults would not be required to exhibit as many symptoms as young children to receive a diagnosis [Barkley, 1998]. While the concept of age-norming is attractive, it is problematic from an epidemiologic perspective if it implies creating an age-specic bell curve of symptoms and then dening the upper tail as abnormal. Nevertheless, the dilemma of how to dene and conceptualize ADHD in teenagers and adults and how to develop developmentally sensitive diagnostic criteria remains an important issue. A promising alternative approach might be to pay more attention to the nature of a persons impairment than to the number of symptoms reported. For example, if a teenager or adult who had ADHD as a child continues to suffer impairment from ADHD symptoms, then he or she would be reMRDD RESEARCH REVIEWS

garded as a case regardless of number of symptoms. In contrast, if that person were being evaluated, and he or she had similar types of impairment that were not related to specic ADHD symptoms and there was no childhood history of ADHD, he or she would not meet criteria for diagnosis. Nevertheless, diagnostic decisions for teenagers and adults presenting for the rst time, with impairment but fewer than the required number of symptoms, would continue to be difcult. Implementing this strategy in epidemiologic studies would require developing methods to collect reliable childhood histories. ADHD AS A LIFETIME DISORDER ADHD was once believed to disappear after childhood but longitudinal studies suggest the symptoms and resulting impairment often persist into adult

ADHD was once believed to disappear after childhood but longitudinal studies suggest the symptoms and resulting impairment often persist into adult life.
life [Shaffer, 1994]. The longest follow-up studies have been based on highly selected clinic-based samples, which probably included children with more co-morbidity and impairment than children with ADHD in the general population. In addition, when these studies began, case denitions were used that do not reect current diagnostic criteria for ADHD. Nevertheless, they provide some important insight into the lifetime impairments of those with ADHD symptomatology. For example, one prospective longitudinal study that followed 140 children with ADHD and 120 controls reported marked increases in behavioral, mood, and anxiety disorders as well as increased impairment in cognitive, family, school, and psychosocial function at the end of four years of follow-up [Biederman et al., 1996]. Most studies also have reported attenuation of ADHD symptoms over long periods of follow-up
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but have noted similar increases in rates of other types of impairment. For example, a prospective study of 100 hyperactive boys ages 6 12 found 43% met full criteria for ADHD about ten years later although after 16 years of follow-up, the rate of ADHD had dropped to 8% [Manuzza et al., 1991]. Nevertheless, when compared to a group of similar controls, the original hyperactive group had lower educational attainment, lower occupational status, substantially more antisocial personality disorder and more substance abuse [Manuzza et al., 1993]. Some researchers see the decline in cardinal ADHD symptoms (particularly hyperactive behavior) and the increase in co-morbidity and impairment as part of the natural history of ADHD. From this perspective, children with ADHD are at high risk for a wide range of learning problems, substance abuse, psychopathology, and difculties in their social relationships, work, and marriages. However, risk varies. Understanding which children with ADHD are at high risk becomes a crucial task for clinicians and epidemiologists because it suggests a direction for understanding the heterogeneity of ADHD and for designing effective treatments. For example, children with ADHD and early signs of aggressive behavior are at much higher risk than other children with ADHD for later developing poor outcomes including school failure, contacts with the criminal justice system, and severe psychopathology including antisocial personality disorder [American Psychiatric Association, 1997]. Similarly, children with ADHD and early signs of anxiety are at higher risk for later depression or other internalizing disorders [Jensen et al., 1997]. Therefore, some researchers have proposed that two new subtypes be added for children with ADHD and early signs of aggression and for children with ADHD who are highly anxious [Jensen et al., 1997]. TREATMENT Given the chronic and complicated nature of ADHD, the efcacy, availability and cost of different types of treatment are of extreme importance. For children who have ADHD symptoms without other comorbid conditions, converging evidence strongly supports stimulant medication as the primary treatment. The evidence in support of other treatments specically targeting ADHD symptoms is weak. However, comorbid conditions, which are the rule rather than the exception, typically warrant additional treatment, including psy167

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chosocial interventions. A recent, significant addition to our knowledge is the Multimodal Treatment Study of ADHD [MTA Cooperative Group, 1999a]. MTA is a multi-site, clinical trial designed to determine the relative benets of three treatment modalities: pharmacotherapy, psycho-social treatment, and the combination of the two. MTA indicated that pharmacotherapy alone or pharmacotherapy in combination with behavioral treatments can signicantly reduce ADHD symptoms and impairment. However, children with ADHD and internalizing problems like anxiety, or externalizing problems like aggression are more likely to benet from behavioral treatments compared to children with ADHD alone [MTA Cooperative Group, 1999b]. This has been demonstrated not only with the MTA sample, but also with a large body of smaller studies supporting the use of behavioral strategies in the treatment of disruptive behavior and anxiety disorders [Wells et al., 2000]. Although stimulant medication treatment is generally required for the duration of the disorder, psychosocial treatment may or may not be required for long periods of time. This is because, unlike ADHD itself, comorbid conditions may respond to short-term interventions, or treatments that are delivered sporadically, as needed. Yet failure to treat these comorbid problems may prevent medication from reaping its full benet in reducing the core ADHD problems. In the MTA, the group treated with behavior therapy plus medication had the same decrement in ADHD symptoms as the group treated with medication alone but was able to achieve this benet with doses of medication that were, on average, 20% lower. Clinically, this might be important because some stimulant side effects are related to dose [Elia et al. 1999]. In addition to the issue of comorbid problems requiring non-pharmacologic intervention, there are several reasons that research demonstrating efcacy only for medication must be interpreted cautiously. First, the MTA, and most treatment studies, have examined only the DSM-IV combined subtype of ADHD, or in DSM-III, attention decit disorder with hyperactivity. The efcacy of medication and psychosocial treatment with the inattentive subtype is largely unknown. Second, the MTA was a clinical trial where medication was titrated and maintained utilizing data obtained on a regular basis from multiple informants with close monitoring of compliance [MTA Cooperative Group, 1999a]. 168

These practices are vastly different from the way medication is typically prescribed and monitored in the real world, where suboptimal doses and inconsistent administration are common; consequently, it may be necessary to have additional interventions in place. Third, stimulant medication causes problematic side effects such as sleep disturbances and loss of appetite in a signicant minority of children, increases anxiety in some children; and is unsuitable for, or ineffective in treating, another group. Overall, approximately 20% of youngsters with ADHD cannot benet from stimulant medication for one of these reasons. Some of these children might benet from other medications but psychosocial treatments may also be benecial and are often overlooked. For example, an analysis of the 1995 national ambulatory medical care survey found that less than 50% of pediatric visits for psychiatric reasons involving stimulant medication included any form of psychosocial intervention and in 21% of these visits, no recommendations were made for follow-up [Hoagwood et al. 2000]. ADHD AS A PUBLIC HEALTH CONCERN The large number of children being identied and treated for ADHD is of concern to both the general public and public health ofcials. Over 1.5 million children are now taking methylphenidate (Ritalin) to treat ADHD and there was a 2.5 fold increase in the number of children treated between 1990 and 1995 [Safer et al., 1996]. Moreover, two community-based studies have reported that in some parts of the U.S., over 15% of all white boys in the upper elementary school grades are being treated with stimulant medication [LeFever et al., 1999; Rowland et al., 2002]. Because there has never been a long-term (more than 3 years) follow-up study of children taking stimulant medication, it is not known whether there might be any risks associated with taking the medication over many years. In clinical trials, stimulant medication is efcacious in about 70 75% of children being treated, and if another stimulant is substituted when response is initially poor, a positive response can eventually be found about 8590% of the time [Cantwell, 1996]. Because the prevalence of ADHD medication treatment is high, the 10 15% of individuals who respond poorly to pharmacological interventions constitute a signicant public health concern. This may represent only part of the problem because medication treatment is usually
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less effective in real world settings than it is in clinical trials where compliance and side-effects are carefully monitored. For example, a North Carolina study reported that over a third of the children receiving ADHD medication treatment showed six or more symptoms of ADHD and impairment at school [Rowland et al., 2001]. Further, medication alone often does not normalize behavior. Understanding the dynamics and lifecourse of ADHD in children who respond poorly to medication treatment or who experience signicant side-effects is important so that other treatment approaches can be developed. Youngsters with ADHD are at increased risk of engaging in health-threatening behaviors including smoking [Lambert and Hartsough, 1998], risky sexual behavior including multiple partners and nonuse of contraceptives [Barkley, 1998], and alcohol and substance abuse [Barkley, 1998]. A study of driving behavior among individuals with ADHD reported they had about 50% more moving violations and three times more accidents involving severe damage to vehicles compared to controls [Barkley et al., 1996]. Although early intervention with medication treatment should, theoretically, reduce high-risk behaviors and their adverse consequences, we are unaware of studies demonstrating this. Children with ADHD use medical and mental health services more often than other children. For example, one study reported that children with ADHD have over 10 times the risk of self-inicted injury and over twice the risk of serious injury as other children without ADHD [Discala et al., 1998]. Guevara et al. [2001] conducted a retrospective cohort study in a large health maintenance organization and found that children with ADHD had twice the mean medical costs as children without ADHD. In that study, children with ADHD had ten times the outpatient mental health services costs as controls. Garland et al. [2001] found 54% (n 1,618) of youths active in one or more of ve social service sectors (substance use, child welfare, juvenile justice, mental health, or public school care for emotional disturbances) met criteria for at least one psychiatric disorder. Of these, half met criteria for ADHD, which was the most common diagnosis. The data suggesting that children with ADHD disproportionately use the health care and mental health systems are complicated by the issue of comorbidity. Some researchers have argued that the bulk of the impairment is found in children with co-morbid conditions and
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Table 2.

Questions About ADHD That Epidemiologic Studies Might Help Address

1) What is the prevalence of ADHD and how does it vary by socio-economic status, by race, by gender, and by age? 2) How effective are current treatments for ADHD as they are being administered in the community? Are there particular sub-groups for whom current treatments are not working well? 3) What are the long-term risks and benets of stimulant medication treatment? 4) What is the natural history of ADHD? Can we understand and better subtype the disorder? Can we use epidemiologic studies to develop a complex developmental picture of the disorder that accounts for the different trajectories of children who have ADHD? 5) Are there preventable (nongenetic) risk factors for the disorder? If so, how do these factors interact with genetic risk factors in modifying risk of ADHD and impairment from symptoms? 6) What is the extent of impairment among children and adults with ADHD and what are the factors that tend to reduce or increase impairment? 7) Are there ways to identify and help children with ADHD at risk for developing co-morbid conditions that may impact their lives? 8) What is the spectrum of health risk behaviors for children, adolescents, and adults with ADHD? How do these behaviors effect long-term health outcomes? Can prevention efforts be developed to reduce risk and to improve the health of children, adolescents and adults with ADHD?

it is the children with ADHD and other comorbid conditions who are at greatest risk [Fergusson et al., 1997]. Regardless of the developmental path, ADHD by itself or in combination with other disorders has signicant health implications. To date, public health agencies have not initiated signicant efforts to address the magnitude of ADHD in the population, the consequences of the disorder and the comorbid conditions that often accompany it, or directions for prevention. National monitoring of ADHD as well as studies of long-term outcomes are important steps needed to formulate a public health response to ADHD and for implementing prevention strategies to reduce health risk behaviors. Given the large numbers of children receiving medication treatment, community-based studies are needed to assess the effectiveness of stimulant treatment and to assess what, if anything, might be the risks of long-term treatment. Only then will health professionals and parents be able to make informed decisions and adequately weigh the benets and risks of treatment. CONCLUSION Epidemiology has been an underutilized methodology in ADHD research. Denitional and assessment issues, which we have summarized in this paper, have discouraged epidemiologists from studying the disorder. This is true even though there is strong evidence suggesting a biological basis for ADHD. The dearth of population-based epidemiologic studies has limited our understanding of ADHD. Developing a standardized case denition for ADHD is an important rst
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step. Starting points for developing this have been proposed [Curran et al., 2000; Rowland et al., 2001]. Without a national surveillance system to monitor prevalence and epidemiologic studies using similar case denitions, we will be unable to properly estimate the prevalence of ADHD and to detect whether prevalence is changing. Similarly, without standardized assessment methods, we cannot answer whether ADHD is being appropriately diagnosed and treated. If standardized methods of assessment are developed, epidemiologic studies of ADHD can answer these questions. Epidemiology can also promise much more (see Table 2). We suggest that population-based epidemiologic studies may shed important new light on how we understand ADHD, its natural history, its treatment, and its consequences. ACKNOWLEDGMENTS We would like to thank Kathleen Wayland, PhD, Lewis P. Rowland, MD, as well as the editor and two reviewers of this paper for their critical comments on earlier drafts of this manuscript. f REFERENCES
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