Attention deficit hyperactivity disorder


Historical note and nomenclature

  Still and Tredgold are credited with the first modern descriptions of what is today known as “attention deficit hyperactivity disorder,” or ADHD (Barkley 1990). They highlighted relevant features of ADHD and hypothesized a neurologic etiology. In the same era, other physicians were linking behavioral pathology to brain injuries.

  In the 1930s, Strauss and colleagues described hyperactivity, distractibility, emotional lability, and perseveration in a group of survivors of encephalitis lethargica (Strauss and Lehtinen 1947). These behaviors were posited to be de facto evidence of brain injury, and it was suggested that children who demonstrated these behaviors were brain damaged, even when there was no known injury (Strauss and Kephart 1955). The minimal brain damage concept persisted until the 1960s, despite the circularity of the reasoning that led to its existence. The minimal brain damage concept gave way to the minimal brain dysfunction concept.

  Ultimately, the focus shifted to the symptoms rather than etiology or mechanism. The hyperactive child syndrome was included in the Diagnostic and Statistical Manual of Mental Disorders as the hyperkinetic reaction of childhood. Inattention became the predominant feature in DSM-III; attention deficit disorder was said to exist with or without hyperactivity. The core symptoms of inattention, hyperactivity, and impulsivity were not considered 3 independent variables, and they were merged into a single syndrome that required inattention and hyperactivity-impulsivity in DSM-III-R. DSM-IV reflects the covariation of hyperactivity with impulsivity and independence of inattention (American Psychiatric Association 1994). Consequently, 3 major syndromes evolved: (1) inattention and hyperactivity-impulsivity, (2) inattention alone, and (3) hyperactivity-impulsivity alone.

  The understanding of ADHD is still evolving. The existence of the syndrome is still actively debated (Faraone 2005). Frazier and colleagues used latent class techniques to investigate whether ADHD was a categorical disorder or whether behavioral and performance indicators formed a continuum and found that ADHD may be best represented by a dimensional structure (Frazier et al 2007). Concerns also have been raised about the limits of the syndrome: that normal behavioral variation is being “medicalized” (Carey 1999; Anonymous 2004), that preschool children are increasingly being diagnosed and subjected to inconsistent pharmacological regimens (Rappley et al 1999; Zito et al 1999), and that ADHD is responsible for a greater portion of medical care (Robison et al 1999).

  Some people have questioned the specificity of inattention (Halperin et al 1992). Barkley presented a model of ADHD that posits poor behavioral inhibition as the central deficit (Barkley 1997a; 1997b); this results in the disturbance in 4 neuropsychologic functions: (1) nonverbal working memory, (2) internalized self-speech, (3) self-regulation of affect-motivation-arousal, and (4) behavioral analysis and synthesis (reconstitution). Other models of ADHD have been put forth: Executive Dysfunction, State Regulation, Delay Aversion, and Dynamic Developmental (Johnson et al 2009). Working memory deficits have received increased attention as a model for inattentive ADHD. The Scandinavians maintain a broader view of the disorder and combine deficits of attention, motor control, and perception as the acronym “DAMP” (Landgren et al 1996).

Clinical manifestations

  The core symptoms of ADHD disorder are developmentally inappropriate and maladaptive degrees of inattention, hyperactivity, and impulsivity, resulting in clinically significant impairment in social, academic, or occupational functioning. Symptoms begin before 7 years of age and persist for at least 6 months in 2 or more settings (eg, home, school, or play). The criteria for age of onset of symptoms have been questioned. Although hyperactivity is usually noted before 7 years of age, inattentiveness that impairs function may not (Applegate et al 1997). The requirement for multiple settings significantly decreases the prevalence of ADHD because parents and teachers show low agreement when reporting ADHD symptoms and performance (Wolraich et al 2004).

  Inattention. Inattention has been defined as the presence of 6 of the following 9 characteristics:

  (1) Often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities.

  (2) Often has difficulty 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 finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions).

  (5) Often has difficulty organizing tasks and activities.

  (6) Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (ie, schoolwork or homework).

  (7) Often loses things necessary for tasks or activities (eg, toys, school assignments, pencils, books, or tools).

  (8) Is often easily distracted by extraneous stimuli.

  (9) Is often forgetful in daily activities.

  Hyperactivity-impulsivity. Hyperactivity-impulsivity is defined by the presence of 6 of 9 behaviors, 6 of which relate to hyperactivity and 3 of which relate to impulsivity.


  (1) Often fidgets with hands or feet or squirms in seat.

  (2) Often leaves seat in classroom or in other situations in which remaining seated is expected.

  (3) Often runs about or climbs excessively in inappropriate situations (in adolescents or adults, this may be limited to subjective feelings of restlessness).

  (4) Often has difficulty 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.


  (7) Often blurts out answers before questions have been completed.

  (8) Often has difficulty waiting for his or her turn.

  (9) Often interrupts or intrudes on others (eg, butts into conversations or games).

  Four attention deficit hyperactivity syndromes have been defined in DSM-IV: (1) “attention deficit hyperactivity disorder combined type” if both inattention and hyperactivity-impulsivity criteria have been met for the past 6 months; (2) “attention deficit hyperactivity disorder predominantly inattentive type” if inattention is present, but the hyperactivity-impulsivity criterion has not been met for the past 6 months; (3) “attention deficit hyperactivity disorder predominantly hyperactive-impulsive type” if hyperactivity-impulsivity is present, but inattention criteria has not been met for the past 6 months; and (4) “attention deficit hyperactivity disorder not otherwise specified” if symptoms are present of inattention or hyperactivity-impulsivity that do not meet criteria for attention deficit hyperactivity disorder.

  The symptoms listed in DSM-IV are most applicable to the school-aged child (American Psychiatric Association 1994), but not all of the DSM-IV symptoms are equally discriminative or equally predictive of impairment. Mota and Schachar used semistructured interviews and impairment rating scales to assess the DSM-IV criteria in 218 children. They developed an algorithm based on ROC analysis that required at least 1 characteristic in each of 2 clusters (cluster 1: difficulty sustaining attention in tasks or avoiding tasks requiring sustained mental effort, or is often forgetful, or blurts out; cluster 2: not listening when spoken to directly, or does not follow through on instructions, or difficulty organizing tasks and activities, or talks excessively). The algorithms derived had similar ability to discern children with ADHD but were substantially better in not misclassifying children who were not impaired (Mota and Schachar 2000).

  Barkley reviewed the diagnosis of ADHD (Barkley 2003) and made the following points:

  (1) ADHD is a heterogeneous disorder.

  (2) Diagnostic thresholds may not be applicable to age groups outside the ones used in the field trials (ages 4 to 16).

  (3) ADHD is a developmental disorder in the sense that it must be compared to typical children of similar age.

  (4) Content of an item set may not apply equally well at different ages.

  (5) The requirement for a 6-month duration of symptoms is arbitrary and should be revisited.

  (6) Age of onset by 7 years is not justifiable.

  (7) Diagnosis should have a lower age limit. Hyperactive-impulsive subtype does not seem to emerge until 3 years of age.

  (8) Diagnostic “cut points” should be modified for gender.

  (9) The requirement for pervasive dysfunction is difficult, given the poor reliability of parents and teachers and across teachers.

  Symptoms of attention deficit vary as the child ages. The applicability of these criteria to preschool children, adolescents, and adults is yet to be determined. In a study of preschoolers, Byrne and colleagues found that some symptoms contained in DSM-IV were infrequently endorsed by parents of preschoolers with ADHD and would be of little clinical utility (Byrne et al 2000). Other symptoms frequently endorsed by parents of typically developing preschoolers might result in overidentification (Gimpel and Kuhn 2000). Others have found stability of the ADHD symptoms in preschoolers who were followed longitudinally, although the subtypes were not constant; hyperactive-impulsive preschoolers either “outgrew” their ADHD or became the combined type at follow-up (Lahey et al 2005).

  Cutoff scores of 4 for current symptoms of inattention and hyperactivity-impulsivity are sufficient to identify a college student as distinct from the norm (Heiligenstein et al 1998). Recently the WHO developed a 6-question screener to identify ADHD in adults in the general population. The sensitivity was 68.7%, specificity was 99.5%, and total classification accuracy was 97.9% (Kessler et al 2005).

  Girls with ADHD do not differ from boys in respect to impulsivity, academic performance, social functioning, fine motor skills, parental education, or parental depression. Girls showed greater intellectual impairment, lower levels of hyperactivity, and lower rates of externalizing behaviors. In nonreferred populations, girls with the disorder had lower levels of inattention, internalizing behaviors, and peer aggression than boys with the disorder (Gaub and Carlson 1997).

  Future formulations of ADHD will need to reconcile DSM and ICD classification systems, provide better criteria for diagnosis of adults and preschool children, reconsider the requirement for age of onset before 7 years, and address whether ADHD should be diagnosed in children with pervasive developmental disorders, intellectual disability, or genetic disorders (Deb et al 2008; Pelc and Dan 2008; Reiersen and Todd 2008; Rohde 2008). Dysfunction in areas other than activity level and attention may presage ADHD. Infants and preschool children who will develop the disorder, as a group, show more sleep disturbance (Thunstrom 2002), motor disorders (Hadders-Algra and Groothuis 1999; Kroes 2002), and language disorders.

  Frequently, children with ADHD have associated symptoms that are not essential to the diagnosis (Kadesjo and Gilberg 2001). These symptoms include fine neuromotor abnormalities (Pereira et al 2000), gross neuromotor abnormalities, clumsiness, tics, learning problems, speech and language delays, sleep disorders (Sung et al 2008), enuresis, encopresis, immaturity, disorganization, poor peer interactions, oppositionality, emotional distress, and antisocial behaviors. Mood instability (eg, mood changeability, volatility, irritability, hot temper, low frustration tolerance) is often seen in ADHD and may not be affective in origin (Skirrow et al 2009). They may be more troubling than the hyperactivity or inattention and may be the motivation for seeking assistance. Children with ADHD frequently have asthma, but the association is thought to be the coexistence of 2 common disorders and not the result of the asthma or its treatment (Biederman et al 1994).

  Academic difficulty often accompanies ADHD. Children with inattentive ADHD, diagnosed at 4 to 6 years of age, consistently had lower reading, spelling, and math scores than comparison children and children who met criteria for other types of ADHD, even after controlling for intelligence (Massetti et al 2008). Dysgraphia is common in children with ADHD and adversely affects academic performance (Racine et al 2008). One study found that spelling and writing problems in children with ADHD are associated with attentional problems, are nonlinguistic in nature, and reflect impairment in kinematic motor production (Adi-Japha et al 2007).

  ADHD is common in children with epilepsy. Hermann and colleagues found that prevalence of ADHD in new-onset epilepsy was 31% versus 6% in a control population (Hermann et al 2007). They also found that ADHD in childhood epilepsy is associated with lower global intelligence, significantly increased rates of academic underachievement, poorer executive function, and increased prevalence of oppositional disorders.

Clinical vignette

  JL, a 6.5-year-old, right-handed male, was referred for evaluation of inattention, increased activity, and declining school performance in first grade. JL had problems with school since the beginning; he had poor fine motor skills before even beginning kindergarten. JL was considered to be “high spirited” in kindergarten and had difficulty following instructions, following rules of games, and sitting for story time. The prior year had been more difficult; JL could not sit in his seat as well as other children, would shout out answers, and would “zone out.” He was not having trouble with reading but could not work independently. When working in a group, he was always “minding other people’s business.” Teachers and parents provided accommodations for JL’s difficulties, but he did not seem to be “closing the gap.” A conference was held to consider placement in a transitional first grade the following year.

  Past history and family history were unremarkable. History of developmental milestone attainment was notable for mild delays in fine motor achievement. He had delayed onset of handedness and delayed attainment of shoe-tying skills. Behavior had always been marked by high intensity, need for external structure, and immaturity. JL was beginning to call himself “stupid,” and his parents were concerned about his self-esteem. His mother endorsed 8 DSM-IV symptoms of inattention and 9 symptoms of hyperactivity-impulsivity. Convergent data were available from school reports. General physical examination was unremarkable. Neurologic examination was notable for silliness, excessive fidgetiness, distractibility, synkinesias, and diffuse, mild hypotonia. A diagnosis of “attention deficit hyperactivity disorder combined type” was made, and a diagnosis of developmental coordination disorder was entertained.

  JL undertook a therapeutic trial of stimulant medication. Accommodations were outlined for difficulties with handwriting. His parents were referred to a parent group for children with ADHD. JL started taking martial arts. When medication was started, JL was moody and evidenced decreased appetite for the first week. Over the next month, his dose was titrated, moodiness diminished, and appetite improved. Neither tics nor insomnia were observed. JL responded well to medication. His school performance and socialization improved. His pediatrician performed continued developmental surveillance.


  The cause of ADHD is unknown. ADHD is likely to be a “final common pathway” with multiple causes. It has been seen as a consequence of acquired brain disorders (infectious, traumatic, or toxic), in conjunction with seizure disorders, and as a result of fetal exposure to alcohol. The prevalence of ADHD is related to a number of prenatal “risk factors,” maternal smoking, and prenatal emotional distress (McIntosh et al 1995). Linnet and colleagues reviewed 24 studies of maternal smoking and found that they consistently supported a greater risk of ADHD-related disorders. In a Danish cohort, mothers who smoked while pregnant had a 1.9-fold risk of having children with hyperkinetic disorders (after controlling for maternal age, socioeconomic factors, and psychiatric history of parents and siblings). The relationship remained after controlling for parental age, exclusion of low birthweight children, preterm delivery, and Apgar scores of less than 7 at 5 minutes (Linnet et al 2005). ADHD is also increased in children who were of low birthweight (Linnet et al 2003).

  Disordered sleep has been reported by parents of children with ADHD, but the majority of these findings have not been supported by objective sleep data. Experimentally restricting sleep had a direct effect on classroom performance and attention, as rated by teachers, but did not result in hyperactivity (Fallone et al 2005). Support was voiced for increased nighttime activity, reduced rapid eye movements, and significant daytime somnolence in unmedicated children with ADHD when compared to controls. Data also suggested increased periodic limb movements but did not support sleep disordered breathing (Cohen-Zion and Ancoli-Israel 2004). A study that evaluated 40 children with ADHD found no patient with obstructive sleep apnea or periodic limb movement disorder/restless legs syndrome and concluded that obstructive sleep apnea or periodic leg movement disorder is not a common underlying disorder or etiologic factor in ADHD (Sangal et al 2005).

  Television watching has been reported to be associated with ADHD. Although statistically significant relationship was found between time of television watching in kindergarten and ADHD in first grade, the effect size was small and not thought to represent a meaningful relationship (Stevens and Mulsow 2006).

  Abnormal serum ferritin (less than 30 ng/ml) was more common in a French cohort of children with ADHD than controls and the mean serum ferritin was significantly lower in the children with ADHD (Konofal et al 2004). Iron supplementation improved the mean Clinical Global Impression-Severity significantly in nonanemic children with low-serum ferritin and ADHD (Konofal et al 2008).

Pathogenesis and pathophysiology

  A wide variety of genetic, neuroimaging, and neuropsychologic approaches have been employed to elucidate the pathogenesis and pathophysiology of ADHD. These studies are confounded by the heterogeneity of ADHD (etiology, expression, and limits); small population sizes; comorbid conditions; varying effects of family, age or gender; and difficulty determining whether the noted associations are causal or the result of ADHD or treatment.

  ADHD has been the subject of intensive genetic study. Familial studies, twin studies, latent class analysis, linkage analysis, genome-wide association studies, quantitative trait locus approaches, endophenotype analysis, and knockout models in animals have all been employed. Progress in these areas has been documented (Asherson and IMAGE Consortium 2004; Heiser et al 2004).

  ADHD has a high level of heritability (approximately 0.75) (Spencer et al 2002). Studies of twins, siblings, half-siblings, adoptees, and families all point to a strong genetic component in this condition (Faraone and Doyle 2001; Kuntsi et al 2005). Approximately 25% of first-degree relatives of attention deficit probands are thought to have attention deficits (Biederman et al 1990). Second-degree relatives are also at a significantly higher risk for ADHD than controls (Faraone et al 1994).

  Genome-wide linkage analysis has yielded positive results for a number of sites, but consistent findings have not been replicated across studies. Chromosome 5p13, which is proximal to the location for the candidate gene for the dopamine transporter, and 17p11 are the most consistent findings across studies (Smith et al 2009). This has lead to the conclusion that genes of moderately large effect are unlikely to exist (Faraone et al 2007; Mick and Faraone 2008).

  Studies of specific candidate genes have been more revealing. Even though statistically significant relationships exist, candidate genes account for only about 3% to 4% of the total phenotypic variance in ADHD. Mill and colleagues posited that the diagnosis of ADHD might be the extreme end of a set of traits that are quantitatively distributed in the general population (Mill et al 2005). They examined genes associated with ADHD and sought to evaluate whether these candidate loci also would act as a quantitative trait locus for ADHD. They found that DAT1 3′UTR VNTR was significantly associated and weak evidence for SNAP-25. There was little support for DRD4 VNTR, a 5HT1B SNP, or a microsatellite marker near DRD5. Curran and colleagues found that SLC6A4, the serotonin transporter gene, may be a quantitative trait locus for ADHD (Curran et al 2005). Bobb and colleagues provided a comprehensive overview of over 100 articles that have examined the genetics of ADHD and concluded that evidence for association exists for 4 genes in ADHD: D4 and D5 receptors and the dopamine and serotonin transporters (Bobb et al 2005). Seven genes for which the same variant has been studied in 3 or more case-control or family-based studies that show statistically significant associations with ADHD on the basis of the pooled odds ratios across studies include DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25 (Faraone et al 2005). Other promising leads that require further replication include the dopamine D2 and serotonin 2A receptors.

  The relationship with ADHD and the transporter gene was reported by Cook and colleagues (Cook et al 1995). The transporter gene is localized to chromosome 5p15.3. Sequence analysis yielded a variable number of tandem repeats polymorphism with a 40-bp unit repeat length (DiMaio et al 2003). Waldman and colleagues replicated this study; they used the transmission dysequilibrium test and found a relationship between dopamine transporter gene and hyperactivity-impulsivity, but not inattentiveness (Waldman et al 1998). A relatively strong relationship between ADHD combined type and dopamine transporter gene was noted for within family analyses. This relationship did not exist for ADHD inattentive type. The authors concluded that there was a reliable relationship between dopamine transporter gene and ADHD, but that the relationship was likely to be relatively small in magnitude (3.6% of the variance in hyperactive-impulsive type, 1.1% in inattentive type).

  A population-based twin study evaluated 2 polymorphisms, the VTNR and rs27072, and found no association between VTNR and ADHD symptoms but significant relationships between rs27072 and inattention and hyperactivity and impulsivity, leading the authors to confirm the association with the DAT1 gene but question whether the VTNR is the optimal polymorphism to study in all populations (Ouellet-Morin et al 2008).

  The relationship that has been postulated between the 40-bp repeat variable number of tandem repeats in the 3′-untranslated region of the gene and ADHD has been reviewed recently. A metaanalysis of 18 published transmission disequilibrium test studies that included 1373 informative meioses, 7 haplotype-based haplotype relative risk studies, and 6 case-controlled studies found support for a small but significant association between ADHD and the DAT1 gene in transmission disequilibrium test studies but not in the haplotype-based haplotype relative-risk studies or case-control studies (Yang et al 2007).

  These findings were not universally endorsed. No support for an association between the 10-repeat allele of DAT1 and ADHD was found when the Family-Based Association Test was used (Langley et al 2005). Others have found a DAT1 relationship but did not find any variation in the sequence for either the 10-or 9-repeat alleles in the probands screened, nor was the DraI (T/C) variation observed (Feng et al 2005). By contrast, the dopamine transporter (DAT1) 10/10-repeat genotype was studied in a general population using behavioral and neuropsychological measures (Cornish et al 2005). There was a significant association between teacher-reported ADHD symptoms and DAT1 10/10-repeat genotype. A hierarchical logistic regression was used to adjust for age, ADHD symptoms, and IQ and found a relationship between DAT1 and measures of selective attention and response inhibition but did not find a relationship with working memory. Selective attention was associated with DAT scores but not teacher report. A follow-up study found that people with ADHD who were heterozygous 9/10 repeat, when compared to those with 10/10 repeat pairs, evidenced greater symptoms of ADHD and externalizing symptoms across the age span, with family, educational, and occupational impairments extending into adulthood (Barkley et al 2006a).

  Environmental cofactors may influence the expression of DAT. An association was found between child hyperactivity-impulsivity and oppositional behaviors and the DAT polymorphism but only when the child also had exposure to maternal prenatal smoking (Kahn et al 2003). Smoking was also associated with a decrease in DAT density in a SPECT study of adults with ADHD (Krause et al 2005).

  Durston and coworkers investigated the link between genetic and neuroimaging studies and found that dopamine genes have been found to be expressed differentially in the brain (Durston et al 2005). DAT1 is expressed predominantly in the basal ganglia and preferentially influences the caudate volumes. DRD4 is expressed predominantly in the prefrontal cortex and preferentially influences prefrontal gray matter. In a preliminary study of 20 sibling pairs discordant for ADHD and 9 controls, Durston and colleagues evaluated the effects of DAT1 genotype in the striatum and cerebellum using an fMRI go/no go task (Durston et al 2008). She found that DAT1 genotype influenced MR for individuals at familial risk for ADHD (affected and unaffected siblings) but not controls in the striatum, but this effect was not seen in the vermis. The observation that the effect was also seen in unaffected siblings suggests that the 10R allele of the DAT1 gene is not sufficient to convey genetic risk in isolation and suggests moderating influences on the vulnerability to the DAT1 10R allele. By contrast, Rommelse and coworkers did not find an association between DAT1 and neuropsychological performance (Rommelse et al 2008a).

  The dopamine D4 receptor gene has also been associated with ADHD. It is located near the telomere of chromosome 11p. The DRD 4 polymorphism is the result of a 48 bp tandem repeat (VNTR) at exon 3, encoding the third intracellular loop with variant alleles containing 2-11 repeats. More than 67 DRD4 variable number tandem repeat alleles have been identified (Wang et al 2004). DRD4 has a high level of expression in the prefrontal cortex. The candidate gene DRD4*7 is found in 30% of the general population and 60% of the ADHD population. Multiple repeats are associated with a deficit in translating the dopaminergic signal to the second messenger system. In addition, epinephrine and norepinephrine are agonists at DRD4*7 (Spencer et al 2002). Smalley and colleagues have investigated the variable nucleotide random repeat polymorphisms and ADHD in affected sibling pair families and singleton families. They used a transmission disequilibrium test and a mean test of identity-by-descent sharing (Smalley et al 1998). Use of the transmission disequilibrium test showed that the 7-repeat allele is differentially transmitted to ADHD children, whereas the mean test revealed no evidence of increased identity-by-descent sharing among affected sibling pairs. Presence of the 7-repeat allele attributes a 1.5-fold risk for developing ADHD over noncarriers. Faraone and colleagues found an association with the 7-repeat allele, but noted that 58% of their sample had ADHD without the 7-repeat allele, and concluded that the 7-repeat allele cannot be viewed as a necessary cause of the disorder (Faraone et al 1999).

  The dopamine receptor gene, DRD 5, has also been associated with ADHD (Thapar et al 2007). The associated polymorphism is 18.5 kb away from the protein encoding region of the gene and how this influences the function of DRD 5 is not known. DRD 5 has been associated with earlier age of onset of ADHD (Lasky-Su et al 2007). Another study found the DRD 5 microsatellite marker but no association with DRD4 or DAT1 and concluded that DRD 5 may be associated with a transient form of ADHD that has a good prognosis in adulthood (Johansson et al 2008).

  Smith and colleagues studied 105 Caucasian subjects with ADHD and 68 ethnicity- and age-matched controls and found a significant association between the DBH TaqI A1 allele and ADHD (Smith et al 2003). They did not find an association with the DBH GT microsatellite repeat polymorphism nor with the DAT1 10 repeat or the DRD4*7 repeat alleles. Executive function measures have been associated with a functional polymorphism (–1021 C/T) in the promoter region of the DBH gene (Kieling et al 2008).

  Additional studies have found significant preferential transmission of the serotonergic 5-HT-1B allele 861G has been reported (Hawi et al 2002). Conflicting results have been noted for studies of ADRA2A (Xu et al 2001; Park et al 2004; da Silva et al 2008). Other studies have failed to show relationships with adrenergic receptors ADRA1C or ADRA2C (Barr et al 2001).

  Given that not all children with ADHD respond to stimulants equally and substantial variability in tolerability exists, there is interest in pharmacogenomic approaches to the treatment of ADHD (McGough 2005; Stein and McGough 2008).

  DAT1 allele status mediates medication-related changes in cognitive and neuropsychological measures among children with ADHD. The mechanism of action is not simple, and drug effects may be affected by the norepinephrine transporter’s ability to clear dopamine as well as DAT (Madras et al 2005). At present, studies show inconsistent results for the DAT1 10 repeat polymorphism. Both increased and decreased symptom reduction have been reported. Compared to those with 1 or more copies of the DAT1 9-repeat allele, children with 2 copies of the 10-repeat allele exhibited poorer performance on a continuous performance vigilance task and showed increased central and parietal beta power, decreased right frontal theta power, and lower theta and beta ratios, whereas those with the 9-repeat allele showed the opposite pattern (Loo et al 2003). Homozygosity for the 10-repeat allele at DAT1 was associated with increased DAT density on SPECT and a lower rate of good responses to methylphenidate (Cheon et al 2005). Some studies show that DRD4 7R requires increased dosage of methylphenidate.

  The full range of neuroimaging techniques has been used to define the neuronal substrate of ADHD. MRI (volumetric, fMRI, diffusion tensor imaging, spectroscopy), magnetoencephalography, emission tomography (PET, SPECT), EEG, and near infrared spectroscopy are some of the techniques that have been applied. These techniques are complementary but often yield inconsistent findings. Willis and Weiler have reviewed the MRI and EEG data. No study of brain structure or function has reached the level of diagnostic certainty (Willis and Weiler 2005). This has led some to caution about the reliability of the finding and, consequently, the strength of the association between attention deficit and the neuroimaging findings (Baumeister and Hawkins 2001). Varying results may be due to differences in technique, population selection criteria, associated and additional disorders, treatment, and familial variation. When children with ADHD were compared to their unaffected siblings, it was found that the volumetric reductions in cortical gray and white matter in subjects with ADHD were also present in their unaffected siblings (Durston et al 2004). Recent reviews of structural neuroimaging studies (Seidman et al 2005; Krain and Castellanos 2006; Makris et al 2009) reported that the most replicated alterations in ADHD in childhood include smaller volumes in the dorsolateral prefrontal cortex, caudate, pallidum, corpus callosum, and cerebellum and concluded that the brain is altered in a more widespread manner and that ADHD is not limited to frontal-subcortical etiology (Giedd et al 2001; Durston 2003). A metaanalysis encompassing 21 studies (565 subjects with ADHD and 583 controls) found that total cerebral volume was most studied followed by regions of the corpus callosum, caudate, and cerebellum. The standard mean differences were largest for the posterior inferior cerebellar vermis followed by the splenium, right and total cerebral volume, and the right caudate (Valera et al 2007). A model of cognitive control has been suggested wherein the basal ganglia are involved in inhibition of competing actions, and the frontal cortex is involved in representing the relevant thoughts and guiding the appropriate behaviors (Casey et al 2002).

  In a longitudinal study of the brain structure of children with ADHD, 152 children and 139 controls had serial MRI scans (Castellanos et al 2002). Children with ADHD had smaller total brain volumes and smaller cerebellar volumes. Previously unmedicated children with ADHD also demonstrated significantly smaller total cerebral volumes. Over time, the differences in total and regional cerebral volumes and in the cerebellum persisted. Differences in caudate volume that were seen in childhood diminished during adolescence. The authors also correlated anatomy with behavior; frontal and temporal gray matter, caudate, and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures. Children with dyslexia or ADHD were noted to have smaller right anterior width measurements on MRI, but 70% of the normals and children with ADHD had the expected left greater than right asymmetry, whereas only 10% of the dyslexics did (Hynd et al 1990).

  Another longitudinal study provided neuroanatomic evidence that supported the theory of delayed cortical maturation in ADHD (Shaw et al 2007a). Two hundred and twenty-three children with ADHD and 223 controls estimated cortical thickness over 2 to 3 years and found that the peak cortical thickness was delayed in children with ADHD for most of the cortical points by a time window of approximately 3 years. The differences in the frontal lobes showed a delay of 5 years in the middle frontal cortex and a delay of about 2 years for the posterior and medial prefrontal cortices. The second most delayed region was in the peak of cortical thickness in the bilateral middle and superior temporal cortex with a delay of about 4 years. A cross sectional study found decreased total cerebral volume of over 7% and decreased total cortical volume of 8%; with decreased cortical volume in all 4 lobes bilaterally (Wolosin et al 2009). The ADHD group also showed decreased surface area (over 7%) and a significant decrease in cortical folding bilaterally. The 7 repeat microsatellite in the DRD4 gene (but not DAT1 or DRD1) was associated with cortical thinning in regions important in attentional control and showed a distinct trajectory of cortical development that showed normalization of the right parietal cortex (Shaw et al 2007b).

  Overmeyer and colleagues noted that when compared to non-ADHD children, children with ADHD who also met ICD-10 criteria for hyperkinetic disorder demonstrated significant gray matter deficits in the right superior frontal gyrus, right posterior cingulate gyrus, and both basal ganglia (especially right globus pallidus and putamen) (Overmeyer et al 2001). Central white matter deficits in the left hemisphere anterior to the pyramidal tracts and superior to the basal ganglia were thought to be due to dysmyelination.

  Wolosin and colleagues confirmed and extended the findings of Overmeyer and colleagues (Wolosin et al 2009). They found decreased brain volume (7%), total cortical volume (8%), surface area (over 7%), and cortical folding bilaterally. High-resolution MRI and surface-based computational analytic techniques revealed region-specific anatomical abnormalities in cortical components of attentional systems: reduced regional brain size localized mainly to inferior portions of dorsal prefrontal cortices bifrontally, reduced brain size in anterior temporal cortices bilaterally, and prominent increases in grey matter in large portions of the posterior temporal and inferior parietal cortices bilaterally (Sowell et al 2003).

  Quantitative neuroanatomic imaging has not demonstrated consistent results in the corpus callosum. A metaanalysis that encompassed 13 studies found that the splenium was smaller in children with ADHD, but this was largely due to smaller splenia in girls (Hutchinson et al 2008). Boys exhibited a smaller rostral body. When comorbid conditions were included there were no significant differences in corpus callosum measurements.

  Quantitative morphology techniques applied to the basal ganglia have also revealed inconsistent findings. Castellanos and colleagues found absence of the normal asymmetry of the caudate nucleus (the right caudate was smaller than in the comparison group) and proposed frontal striatal abnormalities as a possible mechanism for ADHD (Castellanos et al 1994). A subsequent study confirmed loss of asymmetry but also found smaller right globus pallidus, smaller right anterior frontal region, smaller cerebellum, and reversal of normal lateral ventricular asymmetry (Castellanos et al 1996). Using volumetric approaches, Filipek and colleagues found smaller volumes of left total caudate and caudate head with reversed asymmetry, right anterior-superior (frontal) region en bloc and white matter, bilateral anterior-inferior region en bloc, and bilateral retrocallosal (parietal-occipital) white matter (Filipek et al 1997). In a carefully controlled study of 15 children with ADHD, Pineda and colleagues found the left caudate to be larger in subjects and controls, but caudate size was not different when children with ADHD were compared to controls (Pineda et al 2002). Age and pattern of associated deficits may be responsible for the observed differences. Mataro and colleagues found larger right caudate areas in children with the disorder when compared to a control group and also found that a larger caudate area (either left or right) correlated to poorer performance on tools of attention and higher scores on Conner’s Teacher Rating Scales (Mataro et al 1997). Casey and colleagues also related performance on 3 response inhibition tasks to MRI findings and found correlations predominantly in the right hemisphere and only with anatomical measures of frontostriatal circuitry observed to be abnormal in ADHD (Casey et al 1997).

  The inferior posterior lobe (lobules VIII-X) of the cerebellar vermis was noted to be significantly smaller in children with ADHD than in controls (Berquin et al 1998; Mostofsky et al 1998; Castellanos et al 2001). This led the authors to speculate that dysfunction in cerebello-thalamo-prefrontal circuits that underlie connections between cerebellum and prefrontal associative areas might subserve at least some of the symptoms of ADHD.

  Finally, drug therapy may affect volumetric findings. Semrud-Clikeman and colleagues compared children with ADHD combined type who were treated with stimulants to treatment-naïve children with ADHD combined type and typically developing children. They found that both ADHD groups had decreased caudate volume when compared to controls. They also found that the right anterior cingulate cortex was smaller for treatment-naïve children when compared to children who received stimulants or who were controls. Similar differences were noted for the left but did not achieve statistical significance (Semrud-Clikeman et al 2006).

  Diffusion tensor imaging studies by Silk and colleagues have shown greater fractional anisotropy in white matter regions underlying inferior parietal, occipito-parietal, inferior frontal, and inferior temporal cortex and suggest that the difference seen in ADHD may relate to a lesser degree of neural branching within key white matter pathways (Silk et al 2009). Tractography methods show these regions to form part of the white matter pathways connecting prefrontal and parieto-occipital areas with the striatum and the cerebellum.

  Functional studies have yielded varying results and must be viewed as preliminary. Despite the inability to use functional neuroimaging for diagnostic purposes, converging data from neuroimaging, neuropsychology, genetics, and neurochemical studies have implicated dysfunction in frontostriatal structures (lateral prefrontal cortex, dorsal anterior cingulate cortex, caudate, and putamen) as being involved in the pathophysiology of ADHD (Bush et al 2005). The most consistent evidence shows that patients with ADHD have reduced activation in the striatum, but dysfunction is also noted in the frontal lobes (on tasks that tap inhibitory control) and temporal and parietal areas (during tasks that examine attentional processes) (Paloyelis et al 2007). Baseline functional neuroimaging studies have indicated pronounced hypoperfusion and hypometabolism in prefrontal and caudate regions, and abnormal responses have been noted in these regions to cognitive challenges requiring attentional and executive functions (Hale et al 2000). Zametkin and colleagues, using PET scan studies, found global and regional reductions in glucose metabolism (particularly in premotor cortex and superior prefrontal cortex) in adults who had been hyperactive since childhood (Zametkin et al 1990). Xenon-133 inhalation and emission tomography showed decreased regional blood flow in striatal areas (Lou et al 1989); however, global or absolute measures of metabolism using PET scans and fludeoxyglucose F18 did not statistically differentiate normal adolescents from those with ADHD (Zametkin et al 1993). Girls with the disorder had significantly lower global metabolism, as measured by positron emission tomography, than did boys with the disorder, normal girls, or normal boys (Ernst et al 1994). In addition, PET scans did not show metabolic effects of chronic stimulant treatment even though behavioral data demonstrated effectiveness (Matochik et al 1994).

  A voxel-wise quantitative metaanalytic technique, activation likelihood estimation, was applied to 16 neuroimaging studies. Significant patterns of frontal hypoactivity were detected in patients with ADHD affecting anterior cingulated, dorsolateral prefrontal, and inferior prefrontal cortices, as well as related regions such as basal ganglia, thalamus, and portions of the parietal cortex. When focusing on studies of response inhibition, differences emerged in the inferior prefrontal cortex, medial wall regions, and the precentral gyrus. The authors concluded that the results failed to support dysfunction in any 1 frontal subregion. (Dickstein et al 2006).

  Functional imaging has given us insight into brain function in vivo. For example, on the Counting Stroop test, developed for MRI studies, adults with ADHD activated the frontostriatal-insular network but showed significantly less activation than controls of the anterior cingulate cognitive division (Bush et al 1999). Another study, using a go/no go task, found that adolescents with ADHD made significantly more errors of omission and commission and evidenced marked abnormalities of brain activation during response inhibition. The underactivation in frontal regions was felt to reflect the core deficit in response/task-switching abilities for the ADHD group (Tamm et al 2004). A third study, that assessed simple, sequential finger tapping, found that children with ADHD evidenced decreased contralateral motor cortex and right parietal cortex activation during both right and left handed sequencing, which suggests that children with ADHD have anomalous development of cortical systems needed for execution of patterned movements (Mostofsky et al 2006). Schweitzer and colleagues used PET scanning techniques to assess regional cerebral blood flow changes related to working memory in adults with attention deficit and a comparison group without attention deficit. They found that task-related changes in rCBF in men without ADHD were more prominent in the frontal and temporal regions. In men with ADHD, rCBF changes were more widespread and primarily located in the occipital regions. These findings led the authors to suggest that men with ADHD make use of compensatory neural and mental strategies to perform working memory tasks (Schweitzer et al 2000). Finally, when confronted with unsuccessful inhibition, children with ADHD did activate the same brain regions (anterior cingulated cortex and left ventrolateral prefrontal cortex) as controls (Pliszka et al 2006b).

  PET has been used to study dopamine transporter levels. Most studies show higher DAT availability in untreated patients with ADHD and note that methylphenidate lowers DAT availability in normals and patients with ADHD, but the relationship between DAT availability and a polymorphism of DAT1 is not clear (Krause 2008). Jucaite and colleagues found that there was lower binding potential for DAT in the midbrain of children with ADHD and that the dopamine D2 receptor binding in the right caudate nucleus correlated with increased motor activity (Jucaite et al 2005). In another study, treatment-naive adults with ADHD were found to have lower levels of dopamine transporter in the left caudate and nucleus accumbens. The transporter levels correlated with measures of attention in subjects and controls, leading the authors to conclude that additional factors are needed to explain the large attentional differences between controls and ADHD subjects (Volkow et al 2007). In another study, ADHD patients showed a dopamine dysfunction that might be partly due to compensatory mechanisms and that methylphenidate seems to downregulate dopamine turnover (Ludolph et al 2008).

  SPECT studies using I-123 IMP revealed greater hemispheric asymmetry with less activity in the left frontal and left parietal hemispheres in subjects with ADHD (Sieg et al 1995). High resolution SPECT imaging showed prefrontal hypoperfusion in 87% of a group of children and adolescents with the disorder (65% during an intellectual stress test and 22% at rest) (Amen and Carmichael 1997). Gustafsson and colleagues evaluated the same clinical sample of children with the disorder and found that SPECT imaging distinguished 2 different patterns of rCBF (Gustafsson et al 2000). One pattern had low rCBF in the temporal and cerebellar regions and high rCBF in the subcortical and thalamic regions, which was significantly associated with the degree of motor impairment and results on a cognitive test. The other pattern had high rCBF in frontal and parietal regions and a significant negative correlation with the degree of behavior symptoms. There was a negative correlation between the rCBF in the right frontal regions and the degree of behavior symptoms. They concluded that there were different types of brain dysfunction in children with the disorder (Gustafsson et al 2000). Using a different task and method of image analysis, Langleben and colleagues found that severe hyperactivity was associated with the most prefrontal asymmetry (left greater than right) and left greater than right occipitoparietal asymmetry (Langleben et al 2001).

  Kim and colleagues showed that children with ADHD who responded to methylphenidate therapy had robust perfusion increases over baseline in the caudate nuclei and frontal lobes (Kim et al 2001). Thalamus and temporal lobe perfusion also increased over pretreatment state, with the right hemisphere showing a greater increase than the left. When the population was expanded to include all subjects, significant increased perfusion was noted in both dorsolateral prefrontal cortices, primarily the right caudate and thalamus. In another study, 22 boys with ADHD were scanned 36 hours after their last dose of methylphenidate and, compared to controls, showed significant increases in motor, premotor, and anterior cingulate cortex blood flow (Langleben et al 2002). They concluded that methylphenidate may exert its effects by modulating motor and anterior cingulate cortical activity, directly or indirectly. Other investigators found that regional cerebral blood flow decreased in the left parietal region with methylphenidate therapy, leading the authors to posit a role for the posterior attentional system in ADHD (Szobot et al 2003). In another study that compared methylphenidate responders (n=24) and nonresponders (n=10), SPECT showed that methylphenidate nonresponders had higher rCBF in the left anterior cingulate cortex, left claustrum, the right anterior cingulate cortex, the right putamen, and lower rCBF in the right superior parietal lobule (Cho et al 2007).

  Szobot and colleagues sought to link neuroimaging and genetic studies and used SPECT to assess the association of DRD4 and DAT1 with differences in cerebral blood flow (Szobot et al 2005). They found significantly higher perfusion in the right middle temporal gyrus in the group with risk alleles at both DRD4 and DAT1. This relationship did not exist for either locus alone. The increased flow was posited to be a compensatory mechanism to offset the effects of these genes. Cheon and colleagues used [123I]IPT SPECT to investigate the dopamine transporter and found that drug-naive ADHD children showed an increased ratio of specific to nonspecific DAT in the basal ganglia, but severity scores on the DuPaul behavior scale did not correlate with DAT binding (Cheon et al 2003).

  Near infrared spectroscopy studies changes in the concentration of oxygenation and hemodynamic changes in the cerebral cortex by measuring the different absorbance of near infrared light at various wavelengths. It does not require radionuclides nor does it have the constrained environment of an MRI scanner. All children partaking in a number of attention tasks showed unlateralized increase in cerebral blood volume and oxygen supply, but tasks related to lateralization seemed to be confined to the controls. The authors concluded that this represented prefrontal dysfunction in the children with ADHD (Weber et al 2005).

  Recent reviews of work in norepinephrine, epinephrine, and dopamine neurotransmitter systems as they relate to ADHD conclude that the findings in this syndrome cannot be explained by abnormality in a single transmitter system, that a role exists for each of the systems, that the dysfunction seen in ADHD is likely to occur at multiple levels, and that drugs that work at a variety of receptor sites are the most effective therapeutic agents for ADHD (Mercugliano 1995; Pliszka et al 1996; Gonon 2009). A model based on anatomic neuroimaging studies suggests that relevant regulatory circuits include the prefrontal cortex and the basal ganglia, which are modulated by dopaminergic innervation from the midbrain and by stimulants (Castellanos 1997). Ernst and colleagues used positron emission tomography to quantify accumulation of [18F]Dopa in synaptic terminals as a measure of dopa decarboxylase activity. They assessed regions rich in dopaminergic innervation-caudate nucleus, putamen, frontal cortex, and midbrain (ie, substantia nigra and ventral tegmentum) and found that children with ADHD had 48% higher accumulation of [18F]Dopa than controls in the right midbrain. The authors concluded that the findings indicated dopaminergic dysfunction at the level of the dopaminergic nuclei in children with the disorder; however, they could not distinguish a primary from a secondary disorder of dopamine decarboxylase activity (Ernst et al 1999). Hesse and colleagues found that adults with ADHD have a reduced dopaminergic, but not serotonergic, reuptake function (Hesse et al 2009). Another study demonstrated depressed dopamine activity in the caudate and preliminary evidence in limbic regions in adults with ADHD that was associated with inattention and enhanced reinforcing responses to intravenous methylphenidate (Volkow et al 2007b). Iodobenzamide brain SPECT was used to estimate striatal dopamine (D2) receptor availability in non drug-treated children with ADHD before and after methylphenidate therapy. Specific D2 binding ratios, at baseline, were higher than those obtained in normal young adults, and D2 availability was reduced as a function of methylphenidate therapy with ADHD. The decrease in hyperactivity was related to the baseline D2 level, but this relationship was not seen for inattention (Ilgin et al 2001).

  A meta-analysis of 16 reports that used proton magnetic spectroscopy to study ADHD revealed that most studies have focused on the frontal lobe and the basal ganglia (Perlov et al 2008). Relative to creatine, choline compounds, N-acetyl-aspartate, and glutamate/glutamine were altered in ADHD. Meta-analytic techniques showed that children showed significant changes of choline compounds in left striatum and right frontal lobe.

  Magnetoencephalography was used to evaluate children with ADHD. Subjects were found to have significantly lower Lempel-Ziv complexity scores, with the maximum difference in the anterior region. Combining age and anterior complexity values yielded a sensitivity of 93% and specificity of 79% (Fernandez et al 2009). A simplified version of the Wisconsin Card Sorting Test was used in a study of magnetoencephalography that measured event-related brain activity. In control children, set-shifting cures evoked a higher degree of activation in the medial temporal lobe, with medial temporal lobe activation predicting later activity in the left anterior cingulate cortex. This was diminished in children with ADHD. Children with ADHD also showed early activity in regions barely activated in control children (eg, left inferior parietal lobe and posterior superior temporal gyrus). The data support theories of frontal dysfunction but also suggest that deficits in higher level functions might be secondary to disruptions in earlier limbic processes (Mulas et al 2006).

  EEGs provide a possible way of defining ADHD based on brain function and not behavior. In resting EEGs, elevated relative theta power, reduced relative alpha and beta, together with elevated theta/alpha and theta/beta ratios are most reliably related to ADHD. Theta/alpha and theta/beta ratios also discriminate diagnostic subgroups of ADHD (Barry et al 2003a). Quantitative EEG studies in adolescents showed increased anterior EEG absolute theta activity and reduced posterior relative beta activity when compared to controls (Lazzaro et al 1998).

  The role of Quantitative EEG in ADHD was reviewed and a metaanalysis was performed on 9 studies (Snyder and Hall 2006). The studies noted the Quantitative EEG traits of a theta power increase and a beta power decrease, summarized as the theta/beta ratio. Sensitivity ranged from 86% to 90% and specificity from 94% to 98%. The authors cautioned that theta/beta ratio trait may be seen in conditions other than ADHD.

  Quantitative EEG analysis has revealed 5 electrophysiologic subtypes within the DSM-IV subtypes: 3 in ADHD combined type and 2 in ADHD inattentive type. Electroencephalograms in children (184 children with ADHD combined subtype and 40 age-matched controls) were studied to determine whether their EEG profiles clustered into meaningful groups that could serve as a basis for subtyping ADHD. Cluster analysis revealed 3 main groups characterized by (a) increased slow wave activity and deficiencies of fast wave, (b) increased high-amplitude theta with deficiencies of beta activity, and (c) an excess beta group. The authors concluded that ADHD is not homogeneous with respect to EEG profiles and noted that the variability has important implications for other EEG studies of ADHD (Clarke et al 2001). A follow-up study used EEG to distinguish 2 distinctive groups of inattentive type ADHD–1 group with increased high-amplitude theta with deficiencies of delta and beta activities and 1 group with increased slow wave and deficiencies of fast wave activity. The authors concluded that 1 group represented a cortical hypoarousal and the other was characterized by a maturational lag in CNS development (Clarke et al 2002).

  A complex range of event-related potential deficits have been associated with ADHD. Barry and colleagues have reviewed the subject (Barry et al 2003b). They have noted that differences between subjects with ADHD and controls have been reported in the preparatory responses, auditory modality, and visual attention systems. In the auditory modality, ADHD-related differences are apparent in all components from the auditory brainstem response to the late slow wave. Results suggesting an inhibitory processing deficit have been reported. Studies of the frontal inhibitory system indicate difficulties in inhibitory regulation.

  A study of brainstem auditory-evoked responses reported that, compared to controls, subjects with ADHD had (1) prolonged latencies of wave III and wave V, (2) longer brainstem transmission of wave I to wave III and wave I to wave V, and (3) significant asymmetry of wave III latencies between ears (Lahat et al 1995). Comparing event-related potentials of children with ADHD to normal children in a series of auditory and visual selective attention tasks suggested a deficit in the activation of the P3b process, although this might be caused by other disturbances of the attention processes that precede P3b (Jonkman et al 1997a). Methylphenidate ameliorates some, but not all, deficits and improves processing where no differences with normal children are present (Jonkman et al 1997b). Ozdag and colleagues found indirect evidence that ADHD is associated with deficits in signal detection (inattention) and discrimination and information processing (Ozdag et al 2004). Methylphenidate normalized event related potential indices except FN2A and PN2A, and they concluded that methylphenidate may be effective on impaired information processing in ADHD but not on receiving information.

  In a subsequent event-related potential study, Jonkman and colleagues found that children without ADHD showed enhancement of the parietal P3 to task-relevant stimuli in harder visual tasks, whereas children with the disorder did not. Methylphenidate improved the number of correct responses and the task P3 amplitudes in both easy and hard tasks but did not influence the probe P3 amplitudes. The authors concluded that children with the disorder do not suffer from a shortage in attentional capacity, but from a problem with capacity allocation (Jonkman et al 2000).

  Questions have arisen about the best method for studying the pathogenesis and pathophysiology of this syndrome. Endophenotypes are heritable quantitative traits that index an individual’s ability to develop or manifest a certain disease. They are thought to be more directly related than dichotomous diagnostic categories to etiologic factors. Consequently, they may be a better means of understanding the brain-behavior interaction in ADHD (Castellanos and Tannock 2002). Neuropsychologic tasks have been used to define endophenotypes. Although endophenotypic function is moderately predictive of the ADHD diagnosis, there is substantial overlap in endophenotypic function between groups of affected children, nonaffected siblings, and controls (Rommelse et al 2008b).


  The prevalence of ADHD varies from a low of 2.0% to a high of 6.3% (Szatmari 1992; Scahill and Schwab-Stone 2000). In a population-based cohort followed from birth through 19 years, the cumulative incidence of ADHD was 16.0% using the most liberal definition, whereas the most restrictive estimate was 7.4% (Barbaresi et al 2002). A survey of a nationally representative sample of 8- to 15-year-old children revealed that 8.7% of the children met DSM IV criteria for ADHD but that less than half were diagnosed with ADHD or received regular medication treatment (Froehlich et al 2007). These results were similar to the estimated prevalence in the longitudinally studied Northern Finnish Birth Cohort (8.5%). Adolescents with ADHD showed substantially increased rates of anxiety (OR 2.4) as well as mood (OR2.9) or disruptive behavior disorders (OR 17.3) in the cohort (Smalley et al 2007).

  Using DSM-IV criteria increased the prevalence of ADHD in a community sample by approximately one third over simultaneously administered DSM-III-R. The prevalence of ADHD in a county-wide sampling of kindergarten through fifth-grade students was 7.3% using DSM-III-R and 11.4% using DSM-IV (Wolraich et al 1996). The change in classification had small changes on diagnosis when applied to a clinically referred population; 93% were classed as having ADHD using both systems (Biederman et al 1997). The prevalence is unknown in preschool children and adults. Males more commonly demonstrate ADHD than females; although, the prevalence of attention deficits without hyperactivity has an equal sex distribution (Szatmari et al 1989).

  Data from the National Ambulatory Medical Care Survey have shown an increase in office based visits from 1.1% of all office visits in 1990 to 2.8% of all office visits in 1995. Between these 2 times, there was a 2.3-fold increase in the population-adjusted rate of office-based visits documenting a diagnosis of ADHD, a 2.9-fold increase in the population-adjusted rate of ADHD patients prescribed stimulant pharmacotherapy, and a 2.6-fold increase in the population-adjusted case rate of ADHD patients prescribed methylphenidate (Robison et al 1999).

  Injured children with ADHD are more likely to sustain severe injuries than children without it. Review of charts submitted to the National Pediatric Trauma Registry between October 1988 and April 1996 showed that children with ADHD were significantly more likely than controls to be boys, to be injured as pedestrians, or on bicycles, or suffer self-inflicted injury. They were more likely to sustain injuries to multiple body regions, to sustain head injuries, and to be severely injured as measured by the Injury Severity Score and the Glasgow Coma Scale (DiScala et al 1998).

  In a population-based cohort study of children born in Rochester, Minnesota, people with attention deficit exhibited significantly greater use of medical care in multiple care delivery settings (Leibson et al 2001). Compared to those without the disorder, people with the disorder are more likely to have multiple diagnoses that require medical attention, have higher rates of inpatient, hospital outpatient, or emergency department admissions, and increased median health cost over a 9-year period. The authors note that the burden of ADHD extends beyond the recognized social, behavioral, and academic outcomes to include markedly increased use of medical care. In Seattle, a retrospective matched cohort study found that children with ADHD had over twice the per capita costs than children without ADHD; had more outpatient mental health visits, pharmacy fills, primary care visits, and coexisting mental health disorders; and the presence of coexisting mental health disorders substantially increased the cost of care (Guevara et al 2001).

  A retrospective review of 189 children who were evaluated for developmental dysfunction at a tertiary clinic revealed:

  (1) 43% of all subjects had a final diagnosis of ADHD.

  (2) 40% of those referred with a complaint of ADHD did not have it at final diagnosis.

  (3) More children over 5 years old were diagnosed with ADHD than those who were 5 years old or younger.

  (4) 41% of the referrals over 5 years old had specific learning disabilities.

  (5) Of those 5 years old or younger, 24% had ADHD, 35% had mental retardation, and 50% had language or other behavior disorders.

  (6) In subjects whose referral complaint of ADHD was confirmed, 48% were taking stimulants at the time of evaluation (Kube et al 2002).


  The prevention of ADHD is related to the prevention of the associated disorders. No information is available about preventive measures that specifically target ADHD.

Differential diagnosis

  The major point of differential diagnosis is to discern primary attention problems from those that are secondary to other disorders. Specific learning disabilities, unrecognized mental retardation, developmental language disorders, hearing impairment, or mental disorders (eg, mood disorder, anxiety disorder, dissociative disorder, or a personality disorder) may masquerade as attention disorders. Often these disorders coexist with ADHD and may not be distinguished. The presence of pervasive developmental disorder, schizophrenia, or other psychotic disorders precludes the diagnosis of ADHD.

  Distinguishing children with developmental language disorders from those with ADHD is difficult. McInnes and colleagues found that children with ADHD and those with developmental language disorders both had impairments in working memory and listening comprehension (McInnes et al 2003). They noted that children with ADHD but no language impairment comprehended factual information from spoken passages as well as typically developing children but were poorer at comprehending inferences and monitoring comprehension of instructions. Children with ADHD demonstrate better performance on measures of utterance formulation whereas children with developmental language disorders perform more poorly on measure of lexical diversity, average sentence length, and morphosyntactic development (Redmond 2004).

  The exclusivity of ADHD and the pervasive developmental disorders is being questioned. Children with ADHD scored at an intermediate level between children with pervasive developmental disorder and typically developing children on the Autism Spectrum Screening Questionnaire. Children with pervasive developmental disorder did not differ from children with ADHD in communication and restricted/repetitive domains. Children with pervasive developmental disorder scored at a level similar to children with ADHD on the ADHD rating scale (Hattori et al 2006). Yoshida and Uchiyama found that 36 of 53 children with high functioning pervasive developmental disorders also met criteria for ADHD (Yoshida and Uchiyama 2004). They noted a higher rate for the Asperger disorder/pervasive developmental disorder NOS (85%) than for the autistic disorder (57.6%). ADHD was more common in younger children.

  Forty-one percent of children who met criteria for autism spectrum disorders had suspected ADHD; 22% with suspected ADHD met criteria for an autism spectrum disorder. Significant correlations were found between autistic and ADHD traits in the general population, and bivariate models showed moderate overlap on autistic and ADHD traits both in the general population and at the quantitative extremes (Ronald et al 2008). Children with ADHD tend to confound different emotions, exhibit lower social skills, and have more trouble with facial expression recognition than age, socioeconomic status, class, and school environment matched controls (Kats-Gold et al 2007). A subgroup of ADHD has been defined that demonstrates poor social perception skills and deficits in complex visual perception and fluid reasoning (Schafer and Semrud-Clikeman 2008).

Diagnostic workup

  The diagnosis of ADHD rests on the demonstration of the neurobehavioral characteristics of developmentally inappropriate, functionally impairing inattention and hyperactivity-impulsivity. Four techniques may be employed to diagnose ADHD: (1) interviews (with child, parents, or teachers), (2) questionnaires, (3) direct observation, and (4) measurement. Practice parameters for the diagnosis and treatment of attention deficit have been updated (American Academy of Pediatrics 2000; Brown et al 2001; Nutt et al 2007; Pliszka 2007).

  Rating scales are helpful adjuncts to the diagnostic and management process, but they are not adequate for diagnosis when used alone (Snyder et al 2006). A recent study of the Conner’s Teacher Rating Scale-Revised showed that if a T-score of greater than 60 on the Total Score (N scale) was used as a cut point, a child had a 77% chance of having clinical ADHD; a child had a 44% chance of having clinical ADHD if the cut point was not reached (Charach et al 2009). Scales are limited by time frame of assessment, general versus specific behavioral targets, psychometric properties, time to administer, cost, and flooding (Madaan et al 2008). Parent evaluations and teacher evaluations are commonly discordant (Mitsis et al 2000). Despite the shortcomings in diagnosing ADHD, rating scales are useful in research and clinical work, aid treatment planning, and help to ensure accountability in practice (Collett et al 2003). Parents are good in perceiving preschool hyperactivity when their child was not hyperactive (89% accuracy), but were not better than chance (50% accuracy) when the child was hyperactive (Hutchinson et al 2001). Focusing on the ADHD symptoms (inattention, impulsivity, hyperactivity) alone is insufficient, and assessment should include inquiry about daily life function impairments and adaptive behavior deficits (eg, peer relations, parenting style, academic functioning) (Pelham et al 2005).

  A complete history, physical examination (with emphasis on minor physical anomalies), and assessment of soft neurologic signs are useful to discern associated disorders and define further evaluations. Symptoms of sensory modulation dysfunction (eg, tactile defensiveness, repetitive touching, auditory filtering, taste and smell sensitivity) typically associated with autistic spectrum commonly are noted in children with ADHD (Mangeot et al 2001).

  The motor examination is of particular interest in children with ADHD. Positive correlations have been established between overflow movements and measures of response inhibition (Mostofsky et al 2003). Denckla summarizes the import of the motor examination, “…If a child is seen between the ages of 5 and the onset of puberty, there is a maximum chance that the motor examination will serve as a ‘within-brain’ laboratory for the biological basis of the characteristics of ADHD; conversely, if a child appears to have all of the characteristics of ADHD…but lacks the colocalizing motor signs, it is highly likely that ADHD is not the diagnosis.” (Denckla 2003) The presence of motor dysfunction is a marker for more severe ADHD and other neurodevelopmental and behavioral problems, but it does not predict poorer response to treatment (Tervo et al 2002). In children with ADHD, gross and fine motor performance may be due to different behavioral processes (Tseng et al 2004).

  The PANESS was administered to children with ADHD or bipolar disorder and compared them to typically developing controls. Children with ADHD were impaired on repetitive task reaction time (eg, foot tapping, hand tapping and finger tapping) whereas those with bipolar disorder (with or without comorbid ADHD) were impaired on sequential task reaction time (foot rocking, hand flipping, and serial thumb to finger opposition). The authors concluded that the children with ADHD had deficits in inhibiting nonrelevant movements whereas the children with bipolar disorder evidenced patterns of motor performance that are consistent with impaired attentional set-shifting and reversal learning (Dickstein et al 2005).

  Schoemaker and coworkers evaluated the nature of the motor deficit relative to handwriting in children with ADHD. Motor planning (a sequence of abstract spatio-temporal goal trajectories that takes place either before a sequence of strokes begins or concurrent with the completion of a stroke pattern) was distinguished from parameter setting (eg, regulation of the force level, tempo, size of letters). The authors found no evidence for a motor planning deficit but noted that parameter setting seemed to be deficient when a group of children with ADHD was compared to normal controls on a series of copying tasks of increasing complexity (Schoemaker et al 2005).

  Children with ADHD subtypes that included inattentiveness showed significant difficulties with time and force output and greater variability in difficulty with force control on a finger-tapping test that targeted motor processing, preparation, and execution (Pereira et al 2000). Those with ADHD and developmental coordination disorder showed particular difficulty with force control (Pitcher et al 2002). Children with ADHD performed less well on a task that required them to move a cursor on a horizontal digitizing tablet between 2 points and did particularly poorly without visual feedback, leading Eliasson and colleagues to posit a primary motor deficit that was independent of inattention and hyperactivity (Eliasson et al 2004). Deficits in bimanual coordination also have been documented (Klimkeit et al 2004).

  Voice problems are also common in children with ADHD (Hamdan et al 2009). They have increased rates of hoarseness, breathiness, and straining in their voice and they were louder than controls.

  Psychological, educational, speech, and language evaluation assists in the diagnosis of cognitive dysfunctions but are not needed to make the diagnosis of ADHD. Psychiatric assessment may be warranted depending on the severity of findings. Routine use of neuroimaging, electroencephalography, evoked potential measurements, metabolic studies, or chromosome tests has low yields.

  Normal performance on neuropsychological tests does not rule out the diagnosis of ADHD, although impairments on multiple neuropsychological tests are predictive of the disorder (Doyle et al 2000). In a case-controlled study of 35 children with ADHD, Koschack and colleagues found that the children with ADHD did not show consistent patterns of deficit in attention or activity levels (Koschack et al 2003). Most ADHD subjects performed on attentional measures within the normal range. They reacted faster than controls on all attentional tests and significantly faster on the go/no go test and the divided attention test. They also performed with significantly fewer errors on the divided attention test. On the go/no go test, visual scanning test, and attentional-shift test, ADHD subjects made significantly more errors than controls. The researchers concluded that the data suggest that children with ADHD do less well in self-paced tasks and better in externally-paced attentional tasks. They also questioned the contribution of neuropsychological tests of attention to the clinical diagnosis of ADHD.

  Continuous performance tests do not have a high correlation with behavioral questionnaires in the diagnosis of ADHD (DuPaul et al 1992). They also have a high rate of false positives; 30% of control children test positive (Schatz et al 2001). Actigraphy must be interpreted in the context of situational and temporal factors (Dane et al 2000).

  Neuropsychological deficits were not predicted by ADHD subtype (Chhabildas et al 2001). Chhabildas and colleagues found that children with ADHD of the predominantly inattentive type had similar patterns of attentional impairment as those with ADHD of the combined subtype. Children with ADHD of the predominantly hyperactive and impulsive subtype did not show neuropsychological deficits after the subclinical measures of inattention were controlled. The authors concluded that symptoms of inattention, rather than hyperactivity and impulsivity, were associated with neuropsychological impairment. The Stroop Color and Word Test did not consistently discriminate ADHD groups from other groups across studies (Homack and Riccio 2004).

  Abnormal performance on psychological testing may not be exclusively due to ADHD. Langley and colleagues found that children with the DRD4 7-repeat allele demonstrated an inaccurate, impulsive response style on neuropsychological tasks that was not explained by the ADHD symptom severity (Langley et al 2004).

  Children with ADHD have deficits in some aspects of executive function, but the deficits are not consistent within ADHD samples and are not specific to ADHD (Sergeant et al 2002). Children with ADHD and substantial executive function deficits are at increased risk for grade retention and decreased academic achievement relative to (a) ADHD without executive function deficits, (b) controlled socioeconomic status, (c) learning disability, and (d) IQ (Biederman et al 2004). Executive function measures are related to IQ; for children with average IQ, executive function measures distinguished those with ADHD from those without. At high average and superior level IQ, there were no significant group differences on measures of executive function between children with ADHD and controls (Mahone et al 2002). A recent metaanalysis of executive function, encompassing 83 studies and 6705 subjects, found that the strongest and most consistent effects were obtained on measures of response inhibition, vigilance, working memory, and planning. However, the effects were only in the medium range (.46 to .69) and were not present universally, leading the authors to conclude that executive function deficits among individuals with ADHD are neither necessary nor sufficient to cause all cases of ADHD (Willcutt et al 2005).

  In a cohort of 7- to 11-year-old children with ADHD, executive functions were not related to ADHD symptoms but to comorbid syndromes of depression and autistic symptomatology. Language abilities, rather than executive functions, best predicted teacher ratings of inattention (Jonsdottir et al 2006). Preschool children with ADHD performed less well on neuropsychological measures, but after accounting for nonexecutive abilities, no deficits could be attributed to specific functions targeted by the tasks. Performance on executive measures was not related to objective indices of activity level or ratings of ADHD symptoms. These results cast doubt on the etiologic contribution of executive dysfunction to early behavioral manifestations of ADHD (Marks et al 2005).

  Working memory was assessed in 4 groups of children: a group with ADHD, a group with ADHD plus reading disability/language impairment, a group with reading disability/language impairment, and a group of typically developing children. Children with ADHD without comorbid language learning disorders exhibited deficits in visual-spatial storage and verbal and visual-spatial central executive function. Children with language learning disorders, regardless of ADHD status, exhibited impairments in both verbal and spatial storage as well as central executive domains of working memory. Inattention, but not hyperactivity/impulsivity, predicted performance on verbal and visual-spatial central executive measures independent of age, verbal cognitive ability, and reading and language performance (Martinussen and Tannock 2006).

  Children with ADHD have difficulty with time perception. They show poorer ability on time reproduction tasks (Meaux and Chelonis 2003) as well as significant impairment in time discrimination thresholds (Smith et al 2002). Children with ADHD evidence a generic motor timing deficit, and the impaired time perception does not seem to be related to motivational factors (Van Meel et al 2005). It was posited that these deficits might impact perceptual language skills and motor timing abilities. Specific tests of memory do not significantly improve the predictive accuracy of a diagnosis of ADHD, reading disability, or both over and above more standard diagnostic academic, intellectual, and behavioral measures (Dewey et al 2001). Poor visual habituation also has been documented in children with ADHD (Jansiewicz et al 2004).

  The assessment of adults is the same as children; however, they are less likely to show hyperactivity or impulsivity and more often complain of difficulties with organization and planning. Behaviors and difficulties may be underreported or overemphasized; thus, validation from another person is helpful. Neuropsychological deficits in adults with ADHD cross multiple domains of function, most notably in attention, behavioral inhibition, and memory, but show normal function in simple reaction time (Hervey et al 2004). In a review of 24 studies of 50 standard instruments, only moderate effect sizes were noted, and the authors concluded that executive functions were not generally reduced in adults with ADHD (Schoechlin and Engel 2005). Finally, the requirement to document the onset of symptoms before 7 years of age necessitates the practical archeology of reviewing old report cards, school notes, and other behavior data (Weiss 2003). Unfortunately, when most adults come to attention, such school files have usually been destroyed.

Prognosis and complications

  The prognosis of ADHD depends on the age at diagnosis, the associated disorders, the IQ, and such external characteristics as the length of follow-up, the referral or population cohort, and the discipline providing follow-up (eg, pediatrics or psychiatry) (Mannuzza and Klein 2000). In a population study, McGee and colleagues found that 75% of pervasively hyperactive preschoolers had continuing symptoms at 15 years of age, but half of the hyperactives who did not have preschool hyperactivity had resolution of their syndrome between 7 and 11 years of age (McGee et al 1991). By contrast, Weiss and Hechtman found that almost one third of patients with hyperactivity who were followed 15 years after diagnosis through a psychiatric clinic had at least a single symptom of restlessness, poor concentration, impulsivity, or explosiveness that was moderately or severely impairing (Weiss and Hechtman 1993). Almost one half of this cohort had no DSM-III diagnosis at follow-up, but almost one quarter had the diagnosis of antisocial personality disorder.

  A similar study of young adults (mean age 26 years) by Mannuzza and colleagues reported lower educational and occupational achievements, somewhat lower rates of ADHD symptoms (11%) and antisocial personality (18%), and higher rates of drug abuse disorder (16%) (Mannuzza et al 1993). A subsequent study confirmed these findings but did not find higher rates of anxiety or affective disorders at outcome (Mannuzza et al 1998). Another study found increased rates of arrest, conviction, and incarceration when compared to controls but noted no improvement in outcome for multimodality treatment over drug treatment only (Satterfield et al 2007). Adult criminality was predicted by socioeconomic status, IQ, and antisocial acts in childhood.

  A follow-up study of hyperactive (n=149) and control (n=72) children who were initially evaluated in 1978 to 1980 were interviewed in 1992 to 1996, at a mean age of 20 (Barkley et al 2006b). The hyperactive group did less well than the controls on all measures. They had lower educational attainment, higher rates of failing to complete high school, more firings from jobs, lower job performance, and greater employer-rated ADHD and oppositional defiant disorder symptoms. The hyperactive group had fewer close friends, more trouble keeping friends, and more social problems as rated by parents. Many more of the hyperactive group had become parents (38% vs. 4%). The authors concluded that ADHD is not a benign developmental disorder of childhood and that clinical interventions need to center on a wide range of adaptive impairments.

  A more optimistic review confirmed the clinical observation that hyperactivity wanes with age. It went on to note that 20% of children with persistent ADHD performed poorly in emotional, educational and social adjustment domains, but 20% did well in all 3 domains. Sixty percent had intermediate outcomes. The authors concluded that persistence of ADHD is not associated with a uniform functional outcome (Spencer et al 2007).

  Hechtman reviewed the long-term treatment of children and adolescents with ADHD. She noted that the longest controlled studies involved approximately 2 years of stimulant treatment and that there were an insufficient number of long-term studies of nonstimulant agents. She found that side effects were minimal and tolerance was not a problem. Treated ADHD patients functioned worse in academic, work, social, and emotional domains than matched controls without ADHD. However, a comparison of ADHD patients who were treated with stimulants with ADHD patients who were not treated with stimulants showed that the treated group appeared to have fewer car accidents, better social skills, and more self-esteem. Psychosocial treatments have lasting effects 10 months after cessation of the intervention but not at 22 months after. She concluded that there is a need to continue psychosocial treatments in order to maintain long-term gains (Hechtman 2006).

  ADHD is a risk factor for driving offenses. Drivers with ADHD are more likely to receive traffic citations, be involved in traffic accidents, and be cited for driving without a license (Jerome et al 2006; Barkley and Cox 2007). Stimulants may improve driving performance. Adolescents with ADHD showed improved performance in a driving simulator when they received mph-OROS than when they received immediate release methylphenidate 3 times a day (Cox et al 2004b). This has been replicated in a real-life driving test (Cox et al 2004a).

  In addition to studies that report the adult outcome of children who were previously diagnosed as ADHD, there has been substantial attention to adults who manifest attention deficit but were not previously diagnosed (Faraone et al 2000c). Adults with the disorder are impulsive, inattentive, and restless. They have similar comorbidity to children with the disorder and often have clinically significant impairments. Studies of biological features show correspondences between child and adult cases of ADHD.


  Protocols have been developed for the treatment of the disorder (American Academy of Pediatrics 2001; Hill and Taylor 2001; Greenhill et al 2002), and algorithms that guide use of medications for the disorder have been published (Pliszka et al 2006a). They do not, however, provide clear guidelines for instituting and ceasing the use of stimulants. Consequently, concern remains that stimulants may be overprescribed (Jensen et al 1999; Safer 2000). The National Survey of Children’s Health found approximately 7.8% of U.S. children aged 4 to 17 years had ever had ADHD diagnosed and 56.3% of those children were receiving medication at the time of the survey (Centers for Disease Control and Prevention 2005). Angold and colleagues studied a population in a community sample and found almost three quarters of children with the disorder received stimulant medicines but noted that children who did not meet DSM-III-R criteria for the disorder were receiving stimulants (Angold et al 2000). A population-based study in Rochester, MN, found that the prevalence of treatment with stimulant medications varied with the likelihood of the ADHD diagnosis: 86.5% of children with definite ADHD, 40.0% with probable ADHD, 6.6% with questionable ADHD, and 0.2% without ADHD (Barbaresi et al 2002). A study of public school students receiving stimulants in Maryland found that 45% of children received special education as well as stimulants and an additional 8% had Section 504 status. Males received stimulants more frequently than females, and African-American and Hispanic students received stimulants at approximately half the rate of their Caucasian counterparts (Safer and Malever 2000).

  Stimulants remain the mainstay of therapy for ADHD (Wilens and Spencer 2000; Brown et al 2005). Motor activity, aggressiveness, and impulsivity are decreased, whereas classroom behavior and relationships with peers and family members are improved. Irritability, anorexia, insomnia, and behavioral rebound are the most common short-term side effects. Stimulants also seem to improve executive function performance in children with the disorder (Kempton et al 1999) and affect event-related potentials (Sunohara et al 1999).

  There are 2 primary types of stimulants that are used to treat ADHD, amphetamine and methylphenidate. There are many different delivery systems for these agents (Anonymous 2006a). Short acting, intermediate acting, and long acting formulations are available. The clinical differences of the various formulations are minor. Amphetamine and methylphenidate have similar effectiveness and side-effect profiles, even though their mechanism of action may differ. Associated deficits in cognitive, emotional, educational, or social domains may need to be addressed to prevent adverse outcomes. Ialongo and colleagues were unable to find superior treatment effects of multimodal therapy over stimulant monotherapy in a short-term, double-blind study (Ialongo et al 1993).

  Methylphenidate is the most commonly prescribed stimulant. The pharmacology has been reviewed (Challman and Lipsky 2000; Wolraich and Doffing 2004). Oral methylphenidate significantly increases extracellular dopamine in the brain (Volkow et al 2001). In a study of motor persistence, immediate release (methylphenidate in a wax matrix) methylphenidate tablets exerted their maximum effects during the absorption phase; a U-shaped curve relationship that posits optimal cognitive and social effects of methylphenidate at different dosages was not found, and long-term tolerance was not noted (Greenhill et al 2001). Swanson and colleagues studied the purported decreased effectiveness of sustained release methylphenidate and noted increased efficacy with ascending dosing patterns when compared to flat dosing patterns and that efficacy of high concentrations of methylphenidate was reduced shortly after exposure. They concluded that “acute tolerance” to methylphenidate develops (Swanson et al 1999). Late afternoon dosage with short-acting stimulants decreases rebound and facilitates performance during homework and extracurricular activities without increasing side effects (Stein et al 1996).

  Pharmacokinetic delivery profiles and standard bioavailability measures were compared for dextroamphetamine and amphetamine and for methylphenidate (Auiler 2002). The results showed lower amphetamine levels after breakfast. Methylphenidate levels were unaffected by breakfast and showed consistent blood levels. Unfortunately, the authors did not report on behavioral responses.

  Age significantly affects the absorption and metabolism of methylphenidate. Pharmacokinetic studies were undertaken for immediate release methylphenidate in preschool and school-aged children with ADHD. The dose normalized C max was significantly higher and clearance was significantly slower in preschool children than in school-aged children (Wigal et al 2007).

  A transdermal system for delivery of methylphenidate has been developed (Anonymous 2006b). This provides long-acting treatment with methylphenidate for children who have difficulty swallowing pills and who have adverse responses to amphetamine. The side effects reported mirrored those of orally administered methylphenidate, but with transitory additional discomfort and redness at the local site. Allergic contact dermatitis and allergic contact urticaria were rarely reported when the transdermal system was used as prescribed. Theoretically, the transdermal delivery system may sensitize patients to methylphenidate, but no serious adverse events were described in 7 trials encompassing 695 patients and extending from 4 weeks to 12 months (Warshaw et al 2008).

  An osmotic release oral system (mph-OROS) has been shown to be as effective as thrice daily methylphenidate, is not associated with increased side effects, and eliminates the peaks and valleys encountered with immediate release methylphenidate (Pliszka 2001; Wolraich et al 2001). A long-term, open-label study reported good acceptance by patients and families and no clinically meaningful changes in blood pressure, pulse, or height at 12 months (Wilens et al 2003b).




Short acting



• Daily dosing schedule




– usually 2 to 3 times per day



• Duration




– 3 to 5 hours


Intermediate acting



• Daily dosing schedule




– once to twice per day



• Duration




– 3 to 8 hours


Extended release



• Daily dosing schedule




– daily



• Duration




– 8 to 12 hours




Short acting



• Daily dosing schedule




– usually 2 to 3 times per day



• Duration




– 4 to 6 hours


Intermediate acting



• Daily dosing schedule




– once to twice per day



• Duration




– 6 to 8 hours


Extended release



• Daily dosing schedule




– daily



• Duration




– 10 to 12 hours


  Methylphenidate does not address all aspects of ADHD equally; thus, determination of what constitutes an appropriate clinical response is a judgment decision. Intensity-dimension functions of attention (eg, alertness, sustained attention) are best influenced by higher doses, executive functions by moderate doses, and selectivity-dimension functions (eg, divided attention) by variable doses (Konrad et al 2004). This is consistent with the finding that children with ADHD predominantly inattentive type respond to lower doses but do not show the continuing benefit from higher doses that is seen in ADHD combined type (Stein et al 2003). Methylphenidate may also target other behaviors beyond the core inattention, hyperactivity, and impulsivity. Organization, time management, and planning behaviors may be improved but not normalized (Abikoff et al 2009). Children with ADHD and developmental coordination disorder showed improvement in manual dexterity and quality of handwriting (Flapper et al 2006). The strokes on a graphomotor task became less fluent but more accurate.

  The Multimodal Treatment Study for Children with Attention-Deficit Hyperactivity Disorder, a multisite, randomized, controlled, long-term clinical trial that compared medical management, behavioral therapy, and combined therapy to community-based therapy, found: (1) medical management was superior to behavioral therapy on parent and teacher ratings of inattention and teacher ratings of hyperactivity; (2) combined therapy and medical management did not differ on any dependent measure; (3) combined treatment was better than behavior therapy on parent and teacher ratings of inattention and parent ratings of hyperactivity-impulsivity, parent-rated oppositional behavior, and reading achievement; (4) both medical management and combined treatments were generally superior to community treatments on parent and teacher ADHD symptom ratings; and (5) behavioral therapy was generally equivalent to community treatments (MTA Cooperative Group 1999a; 1999b; Pelham 1999). Peer ratings failed to find support for the superiority of any of the interventions (Hoza et al 2004). Children from all groups remained significantly impaired in their peer relationships.

  A follow-up study at 24 months showed the continuing superiority of medication therapy over behavioral and community care approaches, although the effect sizes were not as large as at 14 months (MTA Cooperative Group 2004a). By 36 months, the earlier advantage of the medication algorithm was not longer apparent, possibly due to age-related declines in ADHD behaviors, starting or stopping medication altogether, or other factors not measured in the original study (Jensen et al 2007).

  A subsequent 8-year follow-up study noted that the originally randomized groups did not differ significantly on repeated measures or newly analyzed variables (eg, grades earned at school, arrests, psychiatric hospitalizations, other clinically relevant outcomes) (Molina et al 2009). Medication use declined by 62% after the initial 14-month study, but adjusting for this did not change the results. The MTA participants did worse than the local normative comparison group on 91% of the variables tested. The authors concluded that children with combined type ADHD exhibit significant impairment in adolescence and that the type or intensity of treatment for ADHD in childhood does not predict functioning 6 to 8 years later. Early ADHD symptom trajectory is prognostic.

  Socioeconomic status was found to moderate treatment outcomes in the MTA study (Rieppi et al 2002). Children from more educated families showed superior reduction of ADHD symptoms with combined therapy. Oppositional-aggressive symptoms were most improved with combined therapy in blue-collar, lower socioeconomic status households, whereas white-collar, higher socioeconomic status homes showed no differential treatment response.

  Another study of 103 children ages 7 to 9 years old with ADHD divided the children into 3 groups: medication alone, medication and intensive behavioral intervention (behavioral therapy, academic assistance, and parent training), and medication and “attention control” (play groups). All 3 groups improved equally on academic tests, behavior ratings, or the children’s own ratings. None of the psychosocial treatments were found to make a difference in the outcomes (Abikoff et al 2004a; 2004b; Hechtman et al 2004).

  No criteria exist that predict stimulant response. Approximately 70% of children respond to any single stimulant. Up to 90% of children will respond to at least 1 stimulant without major adverse events if drug titration is done carefully (Goldman et al 1998). Methylphenidate works in preschool children in a fashion that is similar to their school-aged counterparts (Musten et al 1997). Body mass failed to predict optimal dose or gains achieved at optimal dose and did not predict drug response (Rapoport and Denney 1997).

  Amphetamines have been used to treat attention deficit longer than any other stimulant. They are approved by the Food and Drug Administration for use in children younger than 6 years. Dextro-amphetamine has been shown to be effective in a randomized, double-blind, placebo-controlled trial in adults (Paterson et al 1999). Pelham and colleagues found that single morning dose of a racemic mixture of d- and l-amphetamine salts had behavioral effects equivalent to twice daily methylphenidate, and the behavioral effects lasted through the school day. They also noted that adding a late afternoon dose to an early morning dose did not improve behavior more than an early morning dose with a late afternoon placebo (Pelham et al 1999). The racemic mixture of d- and l-amphetamine salts may benefit children who fail to improve with methylphenidate management (Manos et al 1999). A meta-analytic study concluded that dextroamphetamine and amphetamine has a small but statistically significant advantage over standard release methylphenidate (Faraone et al 2002). The advantage was noted on symptom measures and global function ratings but was stronger on the latter. The effect of dextroamphetamine and amphetamine was significant for parents and clinicians but not teachers. It was present for fixed dose and best dose designs. Microtol technology has been used to develop a preparation of mixed amphetamine salts that has clinical effects up to 12 hours and can be used as sprinkles (McKeage and Scott 2003; Sallee and Smirnoff 2004).

  Because of concern about diversion and overdose toxicity, a prodrug form of amphetamine has been developed. Lisdexamfetamine dimesylate binds lysine to amphetamine. It is inactive until metabolized to amphetamine by the liver. It also shows clinical effect for 12 hours. The Medical Letter concluded that “There is no evidence that lisdexamfetamine dimesylate (Vyvanse) offers an advantage over any other formulation of amphetamine for the treatment of children with ADHD.” (Anonymous 2007).

  The mechanism through which stimulants achieve their effects is unknown. Methylphenidate downregulates the dopamine receptor and transporter system. Three months after initiation of treatment of ADHD, SPECT scans showed a downregulation of the postsynaptic dopamine receptor with a maximum of 20% and a downregulation of the dopamine transporter with a maximum of 74.7% in the striatal system that corresponded to clinical improvement (Vles et al 2003). Volkow and colleagues used PET to study the mechanisms of action of methylphenidate on the human brain (Volkow et al 2002). They made the following observations: (1) Oral methylphenidate reaches peak concentration in the brain 60 to 90 minutes after administration. (2) Methylphenidate binds to DAT and occupies more than 50% of the DAT. (3) Oral methylphenidate increases dopamine levels in the brain, which enhances ability to distinguish signal from noise and increases the saliency of stimuli. (4) Increases in dopamine by methylphenidate are due to the d-threo and not the l-threo enantiomer of methylphenidate. (5) Dopamine in the basal ganglia is increased by methylphenidate, appears to be modulated by the rate of DA release, and seems to be affected by age. (6) The variability in methylphenidate-induced increases in dopamine is accounted for not only by differences in DAT blockade but also by differences in dopamine release. (7) Effects of methylphenidate appear to be sensitive to the context in which the drug is administered. Solanto suggests that psychostimulants do not target the disease locus or deficits that are specific to ADHD but rather act in a compensatory manner via central nervous system mechanisms that are present in normal as well as disordered individuals (Solanto 1998).

  Brain activation and task performance when undergoing methylphenidate therapy have been studied and yield inconsistent results. In a study of adults with ADHD, methylphenidate improved executive functions, but task-related activity on PET scan was not normalized (Schweitzer et al 2004). A study of children with ADHD showed that improving the ADHD symptoms was associated with normalization of abnormally reduced orbitofrontal activity and abnormally increased somatosensory cortical activity on SPECT (Lee et al 2005). A study of adolescents found that methylphenidate led to an increase in activation as measured by fMRI in the left ventral basal ganglia but had no effect on task performance on a divided attention task (Shafritz et al 2004).

  Pemoline’s association with life-threatening hepatic failure has removed it from consideration as first-line drug therapy for ADHD, although assumptions about the risk of acute hepatic failure may be overestimated (Shevell and Schreiber 1997).

  Recently, the adverse effects of pharmacotherapies for ADHD have been reviewed (Graham and Coghill 2008) and the authors concluded, “that by far the majority of prescriptions for ADHD result in only temporary adverse effects in a minority of cases that are troublesome but that do not pose a significant risk to the child.”

  Mild growth suppression is associated with long-term stimulant use (MTA Cooperative Group 2004b). Decreased growth continued to the 36-month evaluation, and the authors found that the newly medicated subgroup showed an average growth of 2.0 cm and 2.7kg less than the nonmedicated group (Swanson et al 2007). Deficits in linear growth were seen in early adolescents with ADHD but were unrelated to psychotropic medication and were not present in late adolescence (Spencer et al 1996). This is consistent with a recent systematic review that found that although treatment with stimulants led to statistically significant delays in height and weight, the effects attenuated with time (Faraone et al 2008). Methylphenidate did not significantly affect standard deviations for height, weight, BMI, IGF-1, and IGFBP-3, but serum T4 and free T4 levels showed modest reductions (but remained in the normal range) in a time dependent manner (Bereket et al 2005).

  Tics are not a contraindication to stimulant usage; methylphenidate and clonidine are effective for ADHD in children with comorbid tics (The Tourette Syndrome Study Group 2002). Low doses of stimulants may exacerbate tics mildly, but the majority of children with comorbid tic disorders do not show significant tic worsening (Gadow et al 1995), even after prolonged use (Gadow et al 1999). Methylphenidate is effective in treating children with ADHD and epilepsy and is safe in children who are seizure free (Gross-Tsur et al 1997). A longitudinal study of children with ADHD and seizures and ADHD and EEG abnormalities found that seizure frequency did not increase from baseline; no patients with EEG abnormalities developed seizures; and the EEG improved in both groups (Gucuyener et al 2003).

  Concerns about the safety of stimulants have been raised. For a time, Health Canada suspended the marketing of Adderall XR based on 14 reports of death in children that were not linked to abuse or overdose. Five of the children had structural heart defects. The Food and Drug Administration added a warning against using the drug in children with heart defects (Anonymous 2005).

  The Drug Safety and Risk Management Advisory Committee of the Food and Drug Administration recommended a “black box” warning describing the cardiovascular risks of stimulant drugs used to treat ADHD. The committee noted that approximately 4 million people took stimulants for ADHD (1.5 million adults, 10% of whom are over 50 years of age). The concerns of the advisory committee reflected several considerations: (1) that stimulants were associated with a clinically significant increase in systolic blood pressure of about 5mm Hg in adults, (2) the similarity between stimulants and other sympathomimetic amines (eg, ephedra and phenylpropanolamine) that had a history of serious adverse effects that led to FDA action, and (3) a review of 25 cases of sudden death that were in the FDA’s Adverse Event Reporting System (Nissen 2006). Other members of the committee did not agree with action on procedural and factual grounds. They noted that the risk of sudden death associated with methylphenidate, amphetamine products, and atomoxetine was 0.2 to 0.5 per 100,000 patient-years, whereas the expectation of sudden death in those younger than 18 years was 1.3 to 8.5 per 100,000 patient-years (Rappley et al 2006).

  A study was done of 223 adults with combined type ADHD who were exposed to mixed amphetamine salts extended release (20 to 60 mg/day) for less than 24 months. The patients’ blood pressure was monitored at baseline, weekly, and then monthly. EKGs were obtained at baseline, weekly, and then at 3- and 6-month intervals. The authors found small, clinically insignificant changes in blood pressure (diastolic 1.3 + 9.2 mm Hg, systolic 2.3 + 12.5 mm Hg) and pulse (2.1 + 13.4 bpm). A clinically insignificant increase in QTcB interval was noted. However, 7 subjects discontinued due to hypertension or palpitation/tachycardia. They concluded that mixed amphetamine salts extended release was safe in otherwise healthy adults but that monitoring of blood pressure and heart rate were indicated (Weisler et al 2005).

  A study of 568 children who participated in an open-label extension study of mixed amphetamine salts extended release (10 to 30 mg/day) showed mean increases in blood pressure (diastolic 2.6 mm Hg, systolic 3.5 mm Hg) and pulse (3.4 bpm). There was no apparent dose-response relationship (Findling et al 2005). In another study, 2968 children 6 to 12 years of age also did not show clinically significant changes in blood pressure or pulse. Approximately 2.5% of subjects demonstrated 2 consecutive systolic blood pressure or diastolic blood pressure values higher than the 95th percentile, and 3.6% of subjects’ pulses increased by 25 or more beats per minute, for a total of 110 or more beats per minute (Donner et al 2007). Finally, almost 6000 children were administered EKGs, and the authors found that prior stimulant history was associated with a small but significant increase in QTc values and that the Bazett correction formula overestimated the prevalence of prolonged QTc interval in the population (Prasad et al 2007).

  The American Heart Association recommended that EKGs be obtained routinely before children with ADHD started on medication (Vetter et al 2008). The American Academy of Pediatrics and the American Academy of Child and Adolescent Psychiatry concluded that sudden cardiac death in persons taking medications for ADHD is a rare event and that there was no evidence that the routine use of ECG screening before beginning medication for ADHD would prevent sudden death (Perrin et al 2008). The American Heart Association and the American Academy of Pediatrics clarified their positions and recommended a careful assessment of all children using a targeted cardiac history and a careful cardiac examination and the EKG was left to the discretion of the treating physician (American Heart Association 2008).

  Therapeutic use of stimulants is associated with a reduction in the risk for subsequent drug and alcohol use disorder (Faraone and Wilens 2003; Wilens et al 2003a).

  Few long-term studies of the safety of stimulant use exist. Cardiovascular effects are not the only long-term safety concerns raised. A preliminary report of 12 children with ADHD treated with methylphenidate noted significant increase from baseline in chromosome aberrations, sister chromatid exchanges, and micronuclei frequencies after 3 months of treatment (El-Zein et al 2005); however, these findings could not be replicated (Walitza et al 2009).

  Concerns also have been raised about the effects of stimulants on the developing brain, but the links between preclinical studies and clinical use are not adequately established. Stimulants exert unique, short-term effects on the developing brain that may have long-term influences. Preclinical studies suggest that stimulants work by the same mechanism but have differing effects on the neural substrate at different ages (Andersen 2005).

  A more recent study addressed the effects of methylphenidate on the dopamine transporter in a group of children who were treated with methylphenidate for 9 to 20 months. Three months after initiation of treatment, a reduction of the dopamine transporter in the striatal system was observed. However, follow-up SPECT after withdrawal of methylphenidate showed return of the dopamine transporter activity to pretreatment levels. The authors concluded that the down regulation of dopamine transporter activity seen in association with methylphenidate treatment was not permanent and speculated that it did not cause permanent damage to the nigrostriatal dopaminergic pathways (Feron et al 2005).

  Nonstimulant medications have been shown to be useful for adults with ADHD. Atomoxetine, a selective norepinephrine reuptake inhibitor (Kratochvil et al 2004), was well tolerated and caused improvement on behavioral and psychologic measures in a double-blind, placebo-controlled crossover study in 22 adults with the disorder (Spencer et al 1998). In children, it has been shown to reduce ADHD symptoms and improve social and family functioning symptoms at a dose of 1.2 mg/kg daily (Michelson et al 2001). Atomoxetine does less well than osmotic release oral system methylphenidate (Newcorn et al 2008) or mixed amphetamine salts extended release (Wigal et al 2005) in direct comparisons, but about as well as immediate release methylphenidate (Wang et al 2007).

  Among the second line medications are tricyclic antidepressants, bupropion, MAO inhibitors, and clonidine and guanfacine. Carbamazepine, modafinil, and donepezil have also been used. Clonidine did not improve ADHD symptoms on the Conners’ Teachers Abbreviated Symptom Questionnaire, but they did improve on the Conners’ Abbreviated Symptom Questionnaire for Parents and the Global Assessment Scale (Palumbo et al 2008). Clonidine has been recommended to treat sleep disorders associated with ADHD (Wilens et al 1994). Cardiac arrhythmias have been reported in otherwise healthy children who were taking clonidine (Cantwell et al 1997). Guanfacine extended release has been shown to decrease ADHD symptoms (Sallee et al 2008). Combinations of tricyclic antidepressants and stimulants or clonidine and stimulants have been used effectively. Bupropion was shown to be effective in a controlled clinical trial (Wilens et al 2001).

  Modafinil, a wake-promoting agent used for narcolepsy, had similar effects and side effects to dextro-amphetamine in a randomized, double-blind, placebo-controlled study of 190 patients who showed significantly improved behavior at home and at school on the ADHD Rating Scale IV and the Clinical Global Impressions Improvement Scale (Swanson et al 2006). Insomnia, headache, and decreased appetite were the most common side effects. Abrupt discontinuation was not associated with withdrawal or rebound. A secondary analysis based on 638 patients (423 receiving modafinil and 215 placebo) showed that modafinil significantly improved (versus placebo) mean total scores for the ADHD Rating Scale IV, School and Home versions for inattentive and combined type ADHD (Biederman and Pliszka 2008). Greater improvement was also seen on the Conners’ Parent Rating Scale-Revised: Short form and the Clinical Global Impression of Improvement. The FDA has not approved modafinil for the treatment of ADHD.

  Cognitive training, either alone or in combination with stimulants, has been suggested to improve cognitive, academic, and behavioral function, but support is minimal for its utility with children with hyperactivity (Abikoff 1991). A meta-analysis of 174 studies found that effect sizes varied with the type of study, but there was strong and consistent evidence that supported the use of behavioral treatments for ADHD (Fabiano et al 2009). Organizational skills interventions are associated with significant improvement in the organization of materials, homework management, time management, and planning (Langberg et al 2008). By contrast, a behavioral training program for single mothers of children with ADHD resulted in increased engagement to treatment, but the behavioral training did not normalize behavior for most children, and the treatment gains were not maintained (Chacko et al 2009). White noise had a positive effect on the cognitive performance of children with ADHD whereas it deteriorated performance of controls, leading the authors to invoke stochastic resonance as the explanation for the improvement (Soderlund et al 2007).

  Vestibular stimulation using the Comprehensive Motion Apparatus was not found to be effective for a group of children with combined type ADHD without comorbid learning disorder (Clark et al 2008). A Cochrane review of homeopathy for ADHD or hyperkinetic disorder concluded that there was little evidence for the efficacy of homeopathy in ADHD (Coulter and Dean 2007). Shaywitz and colleagues found no support for an effect of aspartame on the urinary excretion of monoamines and metabolites or on the cognitive or behavioral status of children with ADHD (Shaywitz et al 1994). A metaanalysis encompassing 16 studies failed to show an effect of sugar on children’s behavior or cognition (Wolraich et al 1995). For food supplements, the evidence is best for zinc; mixed for carnitine, pycnogenol, and essential fatty acids; and insufficient for vitamins, magnesium, iron, SAM-e, tryptophan, and Ginkgo biloba with ginseng (Rucklidge et al 2009). A randomized, double blind, placebo-controlled trial of docosahexaenoic acid supplementation did not decrease symptoms of ADHD (Voigt et al 2001). Similar findings were reported for linoleic acid supplements (Raz et al 2009).

  Schachar and colleagues reviewed the literature to determine the effectiveness of long-term therapies for ADHD (Schachar et al 2002). Studies that were randomized and for which treatment extended 12 or more months were reviewed. They were too heterogeneous to permit metaanalysis. The authors found that pharmacologic interventions were studied more frequently than nonpharmacologic approaches. Six studies permitted the evaluation of the effects of combined drugs and behavioral intervention. Twenty-five different outcomes were measured with 26 different tests. Stimulant medication appears to reduce ADHD symptoms, dysfunctional social behavior, and internalizing symptoms. Available studies provide little evidence for improved academic performance with stimulants. Medications other than stimulants have not been studied extensively. Only 1 study showed that combination therapy adds to the effects of medication.

  Parental ADHD complicates the treatment of ADHD in children. Two studies conclude that treatment of parental ADHD may be a prerequisite to effective treatment of the child. Exposure to parental ADHD predicted higher levels of family conflict and lesser levels of family cohesion relative to families without parental ADHD, independent of other psychopathological conditions in the parents or ADHD status. Significant interactions were detected in which parental ADHD had a deleterious effect on measures of school performance in offspring without ADHD but not in those with ADHD. Parental ADHD did not increase the risk for ADHD in children beyond that conveyed by the liability associated with the diagnosis. However, because exposure to parental ADHD was associated with increased disruption in family environment, the identification and treatment of adults with ADHD may be an important component of the treatment plan of the children (Biederman et al 2002). Another study enrolled 83 preschoolers in an 8-week parent-training program and assessed the progress before the program, at the end of the program, and at follow-up 15 weeks later. Children of the mothers with the highest ADHD scores displayed no progress after parent training, whereas children of mothers with lower ADHD scores showed significant improvement over baseline (Sonuga-Barke et al 2002). Mothers with ADHD were found to be poorer at monitoring child behavior and less consistent disciplinarians compared to mothers without ADHD. There was some evidence that suggested that mothers with ADHD were less effective at problem solving about child-rearing issues than control mothers. These differences persisted after controlling for child behavior disorders (Murray and Johnston 2006).

  An approach to refractory cases has been published (Wagner 2002). A minimum of 2 psychostimulant trails should be instituted before a child’s symptoms of ADHD are considered treatment refractory. Diagnostic accuracy, comorbid disorders, psychosocial features, medication compliance, symptoms across settings, and behavioral treatment should be addressed before initiating alternative medication trials.


  No information is available.


  Fentanyl and midazolam were used for forearm-fracture reduction in the emergency department at a children’s hospital. Drug doses, vital signs, and sedation scores did not significantly differ between children with ADHD and controls. The mean emergency department visit duration and sedation duration were significantly longer for children with ADHD (Schmerler et al 2008).

Associated disorders

Anxiety disorders

Attention deficit hyperactivity disorder, combined type

Attention deficit hyperactivity disorder, not otherwise specified

Attention deficit hyperactivity disorder, predominantly hyperactive impulsive type

Attention deficit hyperactivity disorder, predominantly inattentive type

Bipolar disorder

Central auditory processing disorders

Communication disorder

Conduct disorders

Developmental coordination disorder

Developmental dysphasia

Developmental language disorders





Learning disorders

Minimal brain dysfunction

Mood disorders

Oppositional defiant disorders

Pervasive developmental disorders

Receptive expressive language disorders

Tic disorders

Related summaries


Mental retardation




Periodic limb movements

Sleep enuresis

Tourette syndrome

Differential diagnosis

learning disabilities

mental retardation

developmental language disorders

hearing impairment

mental disorders

mood disorder

anxiety disorder

dissociative disorder

personality disorder

pervasive developmental disorder


psychotic disorder


For more specific demographic information, see the Epidemiology, Etiology, and Pathogenesis and pathophysiology sections of this clinical summary.



01-23 months

02-05 years

06-12 years

13-18 years

19-44 years

45-64 years

65+ years



None selectively affected.



None selectively affected.



male>female, >1:1


Family history

family history may be obtained

family history typical



heredity may be a factor

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