Attention deficit hyperactivity disorder (ADHD) …

David E Mandelbaum MD PhD

Neurobehavioral & Cognitive Disorders

Updated 02.13.2024
Released 11.28.1994
Expires For CME 02.13.2027

Attention deficit hyperactivity disorder

Author: David E Mandelbaum MD PhD

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Editor: Ann Tilton MD

Attention deficit hyperactivity disorder

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Introduction

Overview

Attention deficit hyperactivity disorder (ADHD) is one of the most common conditions seen by child neurologists and psychiatrists. It is a neurobehavioral syndrome that is defined by its behavioral phenotype and frequently coexists with other cognitive and behavioral disorders. ADHD is a lifelong disorder. Although the diagnosis of ADHD is independent of any specific etiology, a strong familial component to ADHD exists. Genetic studies show a number of statistically significant relationships that are of small effect size. Converging data from a number of sources implicate frontal-striatal-cerebellar dysfunction as a possible mechanism for ADHD. These sources, however, fail to identify a single explanation for ADHD. Psychostimulant medications remain the mainstay of therapy, but several nonstimulant medications have been shown to be effective agents. An improvement in function in response to psychostimulants is not diagnostic of ADHD. Psychostimulants can have a beneficial effect on performance in children with no underlying attentional problems (coffee is as popular as it is for a reason).

Key points

	• ADHD is a neurologic disorder that is defined by its behavioral characteristics.
	• ADHD is frequently associated with comorbidities, such as disorders in motor, language, or academic functions.
	• ADHD may persist into adulthood, and although the hyperactivity becomes attenuated, distractibility, impulsivity, and pathological disorganization may persist.
	• Stimulants are the mainstay of therapy and have a wide therapeutic margin.

Historical note and terminology

Still and Tredgold are credited with the first modern descriptions of what is today known as "attention deficit hyperactivity disorder," or ADHD (17). 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 (283). 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 in the absence of any history of injury (282). 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 three 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. Consequently, three major syndromes evolved: (1) inattention and hyperactivity-impulsivity, (2) inattention alone, and (3) hyperactivity-impulsivity alone.

DSM-5 modified the diagnostic criteria when applied to older adolescents and adults, recognizing that symptoms of inattention and hyperactivity may be less prominent in older adolescents and adults, and decreased the number of symptoms that define inattention or hyperactivity from six to five. However, cutoff scores of 4 for current symptoms of inattention and hyperactivity-impulsivity are sufficient to identify a college student as distinct from the norm (124).

Some people have questioned the specificity of inattention (118). Barkley presented a model of ADHD that posits poor behavioral inhibition as the central deficit (18; 19); this results in the disturbance in four 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 (139). Working memory deficits have received increased attention as a model for inattentive ADHD (05). Impulsivity has been related to deficits in temporal processing (243). The Scandinavians maintain a broader view of the disorder and combine deficits of attention, motor control, and perception as the acronym "DAMP" (164).

It has been argued that the underlying deficit in ADHD with hyperactivity is distinct from attention deficit without hyperactivity (73), with the former representing a primary deficit in response inhibition and the latter representing a core deficit in working memory. This would have implications for the expected comorbidities as well as the type of intervention in the two groups.

Clinical manifestations

Presentation and course

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 12 years of age, are present in two or more settings (eg, home, school, or at work; with friends or relatives; in other activities), and persist for at least 6 months. Most children present in the early years of school but initial diagnosis in adults or preschoolers is not uncommon. Preschool presentations show a predominance of hyperactivity whereas adult presentations are more associated with inattention. Byrne and colleagues found that some symptoms contained in DSM-4 were infrequently endorsed by parents of preschoolers with ADHD and would be of little clinical utility (44). Other symptoms frequently endorsed by parents of typically developing preschoolers might result in overidentification (105). 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 (162).

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% (151).

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 (101).

Criteria for the diagnosis of ADHD are codified in the DSM. Although DSM-5 did not change the DSM-4 symptoms that constituted inattention or hyperactivity, the new classification included examples that modified the symptoms (eg, symptom of inattention). The effect of these expanded examples on the diagnosis will have to be determined. The DSM-5 incorporates a number of changes over the previous edition:

(1) The age of onset of impairing symptoms was raised from 7 to 12 years.

(2) Subtypes are replaced by presentations, in recognition that subtypes were not stable longitudinal constructs.

(3) The number of symptoms required for a diagnosis was reduced from six to five for older adolescents and adults.

(4) Multiple informants are required for the diagnosis.

(5) Pervasive developmental disorder has been removed from the exclusion criteria.

ADHD is diagnosed based on the following symptoms:

(1) Inattention: six (or more) of the following symptoms (five or more for older adolescents, over the age of 17 years, and adults)

	(a) Often fails to give close attention to details or makes careless mistakes in schoolwork, at work, or during other activities (eg, overlooks or misses details, work is inaccurate).
	(b) Often has difficulty sustaining attention in tasks or play activities (eg, has difficulty remaining focused during lectures, conversations, or lengthy reading).
	(c) Often does not seem to listen when spoken to directly (eg, mind seems elsewhere, even in the absence of obvious distraction).
	(d) Often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (eg, starts tasks but quickly loses focus and is easily sidetracked).
	(e) Often has difficulty organizing tasks and activities (eg, difficulty managing sequential tasks; difficulty keeping materials and belongings in order; messy, disorganized work; has poor time management; fails to meet deadlines).
	(f) Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (eg, schoolwork or homework; for older adolescents and adults, preparing reports, completing forms, reviewing lengthy papers).
	(g) Often loses things necessary for tasks or activities (eg, school materials, pencils, books, tools, wallets, keys, paperwork, eyeglasses, mobile telephones).
	(h) Is often easily distracted by extraneous stimuli (for older adolescents and adults may include unrelated thoughts).
	(i) Is often forgetful in daily activities (eg, doing chores, running errands; for older adolescents and adults returning calls, paying bills, keeping appointments).

(2) Hyperactivity and impulsivity: six (or more) of the following symptoms (five or more for older adolescents, over the age of 17 years, and adults)

	(a) Often fidgets with or taps hands or feet or squirms in seat.
	(b) Often leaves seat in situations when remaining seated is expected. (eg, leaves his or her place in the classroom, in the office or other workplace, or in other situations that require remaining in place).
	(c) Often runs about or climbs in situations where it is inappropriate. (In adolescents or adults may be limited to feeling restless).
	(d) Often unable to play or engage in leisure activities quietly.
	(e) Is often "on the go," acting as if "driven by a motor" (eg, is unable to be, or uncomfortable being still for extended time as in restaurants, meetings; may be experienced by others as being restless or difficult to keep up with).
	(f) Often talks excessively.
	(g) Often blurts out an answer before a question has been completed (eg, completes people's sentences, cannot wait for turn in conversation).
	(h) Often has difficulty waiting his or her turn (eg, while waiting in line).
	(i) Often interrupts or intrudes on others (eg, butts into conversations, games, or activities; may start using other people's things without asking or receiving permission; for adolescents and adults, they may intrude into or take over what others are doing) (08).

The symptoms of ADHD are not solely a manifestation of oppositional behavior, defiance, hostility, or a failure to understand tasks or instructions. The symptoms do not occur exclusively during the course of schizophrenia or another psychotic disorder and are not better explained by another mental disorder (eg, mood disorder, anxiety disorder, dissociative disorder, personality disorder, substance intoxication, or withdrawal).

One of the difficulties in making the diagnosis of ADHD is how to integrate the data that come from the multiple sources. Disparate reporting is not uncommon between parents, between parents and teachers, or among teachers (when there are multiple informants). Some investigators have scored a symptom present if it is reported by any of the informants. Others have opted to score a symptom present if there is agreement by the reporters. A study proposed summing symptoms at the domain level or overall diagnostic category and averaging across reporters as a means of decreasing variability due to rating bias and standardizing diagnostic practice (184). A study suggested that a teacher rating was not necessarily essential if the parent rating scales were positive because teacher reports confirm the positive findings in a large percentage of cases (28).

On the other hand, teacher expectations may have an impact on teachers’ rating of children. A Finnish population-based study found an association between younger relative age in the school year and receiving medication for ADHD (300). The association between children’s birth month and ADHD medication was more pronounced at younger ages, supporting the conclusion that relative immaturity, which would be expected to be more disparate at younger ages, was prompting the use of ADHD medication. This study supports the contention that ADHD represents the extreme of a continuum of neurodevelopment, with the attendant risk of immaturity being misinterpreted as pathology.

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 (211; 295), motor disorders (115; 159), and language disorders. Regulatory problems in infancy are associated with later ADHD if the child has the DRDr-7r allele (26).

A study questioned whether adult-onset ADHD was a distinct entity. In a longitudinal study of a cohort from Dunedin, Moffitt and colleagues found that only 5% of children with ADHD manifested the full DSM-5 syndrome in adulthood, and that of the adults who met ADHD criteria, save for the age of onset by 12 years, almost 90% were de novo cases (197). Both the childhood and adult-onset groups showed psychosocial impairment, but adults showed general intellectual ability that was comparable to those without ADHD and negligible neuropsychological impairments. Reimherr and colleagues identified a subset of adults with ADHD who had high levels of emotional symptoms and suggested two types of adult ADHD—1 with inattentive presentation and the other with emotional dysregulation presentation (239). The latter presentation was associated with higher rates of impairment.

A review of ADHD in adults referred to four factors, which are associated with the persistence of ADHD from childhood to adulthood: severity of childhood ADHD, treatment for ADHD in childhood, comorbid conduct disorder in childhood, and comorbid major depressive disorder in childhood. Sleep problems are more common in adults with ADHD than children. As is the case of children, adults with ADHD experience frequent comorbid mental health conditions and impairments in social, occupational, and educational domains. Stimulant medications are effective in the management of ADHD symptoms in adults, “although long-term findings are less consistent.” The authors discuss newer treatments such as transcranial direct current stimulation (TDCS) and combination medication and behavioral therapy, which have not, as yet, been adequately studied (214).

Frequently, children with ADHD have associated symptoms or comorbidities that are not a component of ADHD (145). These symptoms include fine neuromotor abnormalities (241), gross neuromotor abnormalities, clumsiness, tics, learning problems, speech and language delays, sleep disorders (320), enuresis, encopresis, functional constipation (191), asthma (31), 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 (268). They may be more troubling than the hyperactivity or inattention and may be the motivation for seeking assistance. In fact, there are conditions that may result in symptoms suggestive of ADHD, such as sleep disorders, which, when treated, result in resolution of the ADHD symptoms. Children with primary learning disorders may present as inattentive or hyperactive, but their primary problem is the learning disorder and not ADHD (or at least not exclusively ADHD).

The Society for Developmental and Behavioral Pediatrics developed algorithms to provide specific guidance on the assessment of complex ADHD, psychosocial and pharmacological treatment, preschool-aged children, and treatment of ADHD accompanied by coexisting conditions (15). Complex ADHD was defined as ADHD diagnosed in children who were less than 4 years old or older than 12 at the time of initial presentation of symptoms or the presence or suspicion of coexisting disorders and complicating factors, eg, autism, tics, substance use disorder, anxiety, depression, and disruptive behavior disorders. Action statements in the guideline included initiating a comprehensive assessment and developing an interprofessional, multimodal treatment plan; verification of any previous diagnoses and assessment for coexisting conditions, which included data from multiple settings and sources (home, school, community); taking a comprehensive medical history and physical examination and psychological assessment, based on the degree of functional impairment; initiation of evidence-based behavioral and educational interventions; and combining these approaches with pharmacological treatments when indicated. Ongoing monitoring of patients throughout the lifespan as warranted by functional impairment was also recommended.

A review of six guidelines for the assessment of co‐occurring and differential conditions during an ADHD assessment of school-aged children from the United Kingdom, Canada, Singapore, Malaysia, and the United States found that all the guidelines recommended “assessing for co‐occurring conditions with varying degrees of information on how to do so” (232). The authors noted that “the absence of consensus regarding the process of co‐occurring and differential diagnosis is a significant gap in the literature and highlights the need for further research to guide recommendations for clinicians having to reach diagnostic decisions in complex cases.” Recommendations were made for research “to determine what elements of an assessment are important for ensuring accurate differential and co‐occurring diagnosis when assessing a child for ADHD.”

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 (127). 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.

Prognosis and complications

The prognosis of ADHD depends on a number of factors, including the age at diagnosis, comorbidities, IQ, and external characteristics, such as the length of follow-up, the referral or population cohort, and the discipline providing follow-up (eg, pediatrics or psychiatry) (179). 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 children with hyperactivity who did not have preschool hyperactivity had resolution of their syndrome between 7 and 11 years of age (188). 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 (308). 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.

Another 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%) (180). A subsequent study confirmed these findings but did not find higher rates of anxiety or affective disorders (181). 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 (250). 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 (22). The hyperactive group did less well than the controls on all measures: 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 in 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 three domains. Sixty percent had intermediate outcomes. The authors concluded that persistence of ADHD is not associated with a uniform functional outcome (274).

In a 16-year follow-up of 140 boys with, and 120 without, DSM-III-R ADHD, the ADHD subjects were significantly more impaired in pyschosocial, educational, and neuropsychological functioning. They noted a high level of persisting neuropsychological deficits, even in those whose core ADHD symptoms declined (34).

A European cohort of children (N = 347, mean age 11.4 years) with ADHD were followed over 6 years; the majority of the participants (86.5%) had persistence of ADHD diagnosis. Symptom severity at baseline and family history were associated with poorer outcome (296). Another longitudinal study examining ADHD severity over 10 years from childhood into adulthood found that a group who had severe persistent ADHD had the highest rate of comorbid major depressive disorder and oppositional defiant disorder (286). Caye and colleagues performed a systematic review and meta-analysis of literature for risk markers predicting the persistence of ADHD into adulthood (48). In their review, a severe presentation of ADHD, treatment for ADHD, comorbid conduct disorder, and comorbid major depressive disorder presented in childhood were significantly associated with persistence of symptoms into adulthood.

Studies of patients who first manifest attention deficit in adulthood report they are impulsive, inattentive, and restless. They have similar comorbidities to children with the disorder and often have clinically significant impairments. Studies of biological features show correspondences between child and adult cases of ADHD.

The relation between symptoms and impairments was explored and found not to be consistent across time (327). Multivariate analysis was used to determine which of the ADHD symptom dimensions was most associated with impairment in academic, social, or behavioral domains in early childhood, middle childhood, or adolescence. For social functioning, hyperactivity/impulsivity is more predictive for early childhood, but inattention is more predictive in adolescence. For behavioral functioning in the classroom, hyperactivity/impulsivity decreases across the 3-time epochs and inattention increases. Academic function was most related to inattention.

Biological basis

Etiology and pathogenesis

ADHD is a syndrome that is not defined by etiology. ADHD might be considered a "final common pathway" with multiple causes, including genetic or acquired brain disorders (infectious, traumatic, or toxic). The prevalence of ADHD is associated with prenatal risk factors, such as maternal smoking, maternal pre-pregnancy obesity (297), maternal genitourinary infection, preeclampsia (178), and prenatal emotional distress (190; 326). Linnet and colleagues reviewed 24 studies of maternal smoking and found a greater risk of ADHD-related disorders (171). Rutter and Solantaus, quoting three types of natural experiments—assisted conception design, comparison of different pregnancies, and the Children of Twins design—challenged this association (246).

ADHD is increased in children who were of low birthweight (170). A large population study from Norway found an association between early preterm birth and increased ADHD symptoms in preschoolers, and interestingly, this association was stronger in females (13). Slower prenatal growth has been associated with higher ADHD symptom scores, even after correcting for maternal smoking (125). A Finnish population study showed the risk of ADHD is increased by poor fetal growth and by each declining week of gestation. This increase in risk remained elevated even in late-preterm and early term infants (284). Maternal hypothyroxinemia in early pregnancy has been associated with higher scores for ADHD symptoms in children at 8 years of age in a population cohort in the Netherlands, after adjustments for child and maternal factors (196).

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 (89). Support was voiced for increased nighttime activity, reduced rapid eye movements, and significant daytime somnolence in unmedicated children with ADHD when compared to controls. A systematic literature search of interventional studies that examined the effect of obstructive sleep apnea on change in ADHD symptoms concluded that (1) attentional deficits have been reported in up to 95% of patients with obstructive sleep apnea and (2) obstructive sleep apnea is common in ADHD, with an incidence of 20 to 30% (321). Alternatively, primary sleep disorders may manifest and be mistaken for ADHD. A sleep history should be taken when evaluating children presenting with a complaint of ADHD symptoms. In one study, children with symptoms of impaired attention and hyperactivity subsequently diagnosed with restless leg syndrome had resolution of the so-called ADHD symptoms on treatment of the sleep disturbance (302).

Environmental factors associated with ADHD have been reviewed (98; 290) and include lead, manganese, organophosphates, polychlorinated biphenyls, and phthalates. Low child zinc and omega-3 levels were also associated with ADHD. Artificial food colorings were found to have a deleterious effect on children's behavior, but this was not felt to be specific to ADHD (11). Randomized controlled trials have shown that sodium benzoate intake, a common preservative used in soft drinks and fruit juices, contributed to ADHD-like symptoms in young children (187). A review of randomized clinical trials published since 2000 on the efficacy of zinc and iron supplementation among ADHD children and adolescents indicated that low zinc and iron levels were related to higher baseline levels of ADHD severity and poorer treatment outcomes (110). The authors concluded that “iron supplementation could contribute as a potential intervention to optimize responses to psychostimulants in children with low iron stores at baseline.”

Although a statistically significant relationship was found between amount of television watching in kindergarten and ADHD in first grade, the effect size was small and not thought to represent a meaningful relationship (277). A study that used multivariate analysis did not find television and videogame use to be significant predictors of childhood attention problems (94). A longitudinal study of a large cohort of adolescents (N=2587) found statistically significant association between higher frequency of digital media use at baseline and subsequent symptoms of ADHD (234). In this study, media use included modern digital platforms (eg, social networking, streaming, texting) in addition to traditional television watching and videogame use.

Children repeatedly exposed to procedures requiring general anesthesia before 2 years of age were found to be at increased risk (hazard ratio 1.95) for the later development of ADHD, even after adjusting for comorbidities (276).

A role for neuroinflammation in the etiology of ADHD has been proposed in a study that found significantly higher levels of interleukin-6 (IL-6) in the serum of children with ADHD compared to a control group. Other studies that found elevated levels of cytokines in children with ADHD were cited in this study. The IL-6 levels did not correlate with the severity of the Conners scale scores for ADHD, suggesting that elevated cytokines may be one of multiple factors causing ADHD. The authors note that studies have found linkage of genes involved in cytokine regulation, such as DOCK2 genes, to ADHD.

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.

Genetics. 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.

ADHD has a high level of heritability (approximately 0.75) (274). Studies of twins, siblings, half-siblings, adoptees, and families all point to a strong genetic component in this condition (92; 160). Approximately 25% of first-degree relatives of attention deficit probands are thought to have attention deficits (29). Second-degree relatives are also at a significantly higher risk for ADHD than controls (91).

A prospective study of twins from England and Wales showed that interindividual differences in the changes of ADHD symptoms of hyperactivity/impulsivity between ages 8 and 16 years were under strong additive genetic influences independent of factors that account for variation in the baseline level of symptoms (223). The authors hypothesized that different sets of genes may be associated with the developmental course of ADHD symptoms, accounting for persistence versus decline of ADHD symptoms in different individuals.

A review of the genetics of ADHD noted that eight DNA variants were statistically and significantly associated with ADHD across multiple studies (93). “These variants implicated six genes: the serotonin transporter gene (5HTT), the dopamine transporter gene (DAT1), the D4 dopamine receptor gene (DRD4), the D5 dopamine receptor gene (DRD5), the serotonin 1B receptor gene (HTR1B), and a gene coding for a synaptic vesicle regulating protein known as SNAP25.” The implicated genes included genes associated with speech and language disorders and dopamine regulation. The authors concluded the following: “No common DNA variants are necessary and sufficient causes of ADHD. Genome-wide association studies show that a genetic susceptibility to ADHD comprised of many common DNA variants accounts for about one-third of the twin study estimates of ADHD’s heritability.” Further, “the heritability that cannot be explained by main effects of rare or common variants is likely due to gene−gene interactions, gene−environment interactions or gene−environment correlations.” As with others reviewing the genetics of ADHD, the authors propose that “accumulating evidence from family, twin, and molecular genetic studies suggests that the disorder we know as ADHD is the extreme of a dimensional trait in the population.”

A review of genetic findings in ADHD noted that research using genome-wide association study designs found that ADHD has “significant positive genetic correlations with a wide range of neuropsychiatric disorders, including schizophrenia, bipolar disorder, [Tourette] syndrome, anxiety disorder, and major depressive disorder” (289). The genetic overlap with these disorders led the author to propose that “rather than be considered a behavioral disorder, ADHD should be considered a neurodevelopmental disorder akin to autism spectrum disorder and intellectual disability, and, as in those cases, should be considered to represent the extreme of a continuum.”

A meta-analysis of genome-wide association studies investigating shared genetic variation in attention deficit hyperactivity disorder and major depressive disorder found 14 linkage disequilibrium–independent single nucleotide polymorphisms overlapping ADHD and major depressive disorder (231). Nine of these single nucleotide polymorphisms did not meet reporting thresholds in individual genome-wide association studies for either ADHD or major depressive disorder and were only found when the areas of overlap of the two conditions were investigated.

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 (80; 79). 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 nine controls, Durston and colleagues evaluated the effects of DAT1 genotype in the striatum and cerebellum using an fMRI go/no go task (81) and found that DAT1 genotype influenced MR for individuals at familial risk for ADHD (affected and unaffected siblings), but not controls, in the striatum; however, 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.

One study concluded that the DAT1 gene may have a modulating effect rather than a direct influence on cognitive functioning (148). The review reported that high reaction time variability was associated with absence of the 7-R allele of the DRD4 gene and that speed of processing, set shifting, and cognitive impulsiveness were altered in 7-R carriers. Dadds and colleagues found that higher methylation level of the DRD4 gene was associated with more severe ADHD symptoms. Specifically, increased methylation of the DRD4 gene was associated with higher levels of cognitive/attention problems and not with hyperactivity/impulsivity (65). An opinion piece by Cecil and Nigg discusses the possible role of epigenetic factors in ADHD and focuses on DNA methylation, currently the most widely studied epigenetic marker in mental disorders, including ADHD (49).

A study of children with ADHD in a familial cohort, which limited the phenotype to a primary ADHD diagnosis (without comorbid ASD or ID), found that 52% of the cases were explained by rare de novo or inherited variants (10). The study also found that four of the genes with variants in multiple families were involved in methylation pathways, supporting the hypothesis that atypical methylation is associated with ADHD. The authors concluded: “Our results challenge the prior consensus that ADHD is strictly a polygenic disorder and suggest that single gene variants account for a significant portion of the genomic architecture underlying ADHD.”

One study of children with ADHD and dyslexia found that the genes OPRM1, CHRNA4, and SNCA had the highest priority in the development of comorbidity of dyslexia and ADHD (131). The most relevant genes are involved in biological processes related to signal transduction, positive regulation of transcription from RNA polymerase II promoters, chemical synaptic transmission, response to drugs, ion transmembrane transport, nervous system development, cell adhesion, and neuron migration.

Neuroimaging. 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 have yielded inconsistent findings. No studies of brain structure or function have reached a level of diagnostic certainty (25; 315). 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 (82). Another study showed that reduction in caudate and putamen volume was seen in both subjects with ADHD and their unaffected siblings compared to that of typically developing control individuals (112).

Reviews of structural neuroimaging studies 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 (103; 78; 157; 176; 63). A meta-analysis 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 (294). The volume of the posterior inferior cerebellar vermis was significantly smaller in children with ADHD and predicted a significant amount of the variance in parent-reported hyperactivity, inattention, and restlessness/hyperactivity (35). A study of preschool children showed significant reduction of volume in both caudate nuclei and that left caudate volume predicted hyperactivity/impulsivity (174).

In a longitudinal study of the brain structure of children with ADHD, 152 children and 139 controls had serial MRI scans (47). 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.

Another longitudinal study provided neuroanatomic evidence that supported the theory of delayed cortical maturation in ADHD (262). In 223 children with ADHD and 223 controls, the development of the cortical thickness was estimated over a 2- to 3-years’ period, and the authors 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. 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 (264). A subsequent study of children with and without diagnosed ADHD found an inverse relationship between the levels of hyperactivity/impulsivity and rate of cortical thinning (263). Thinner cortex at baseline and slower cortical thinning with aging were related to higher scores on the Attention Problems subscale of the Child Behavior Checklist (76).

Shaw and colleagues extended their finding of delayed cortical thickness and found delays in the maturing cortical surface area, particularly in the right prefrontal cortex (265). The median age by which 50% of cortical vertices attained peak area was 1.9 years later in children with ADHD (14.6 years vs. 12.7 years). They concluded that their findings supported mechanisms controlling the maturation of multiple cortical dimensions. Neuroanatomical abnormalities on structural imaging that were shared between ADHD probands and their unaffected first degree relatives were also associated with impairments in sustained attention in both groups (224).

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 (258). Others have reported that the anatomic changes seen in children with ADHD are attenuated with stimulant treatment (275).

Using diffusion tensor imaging, Silk and coworkers confirmed anomalous white matter development in cortical regions that have been previously found to be dysfunctional or hypoactive in fMRI studies (267). They found greater fractional anisotropy in white matter regions underlying inferior parietal, occipitoparietal, 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 (267). 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. Another study using voxel-wise analysis found increased fractional anisotropy in the right superior frontal gyrus and posterior thalamic radiation and left dorsal posterior cingulate gyrus, lingual gyrus, and parahippocampal gyrus (222). Region of interest analysis revealed increased fractional anisotropy in the left sagittal striatum and related it to ADHD symptom severity. Subsequent studies have shown associations between integrity of the frontostriatal tracts and measures of ADHD symptoms and executive functions in children with ADHD (260). ADHD combined type was associated with abnormalities in the fronto-subcortical circuit, fronto-limbic pathway, and temporo-occipital areas whereas ADHD inattentive type was related to abnormalities in the temporo-occipital areas (167).

Functional studies have yielded varying results and must be viewed as preliminary. 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 (323). Xenon-133 inhalation and emission tomography showed decreased regional blood flow in striatal areas (172); however, global or absolute measures of metabolism using PET scans and fludeoxyglucose F18 did not statistically differentiate normal adolescents from those with ADHD (322). 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 (88). In addition, PET scans did not show metabolic effects of chronic stimulant treatment even though behavioral data demonstrated effectiveness (186). The dissociation between behavioral and functional imaging data has also been reported in fMRI studies (153).

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% (95). 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 (204).

The range of task-related fMRI studies is wide. Inhibition and attention, reward-related processing, vigilant attention and reaction time variability, timing, emotional regulation, and arousal are some of the constructs that have been studied (23). The Default Mode Network encompassing the precuneus/posterior cingulate cortex, medial prefrontal cortex, and dorsal anterior cingulate cortex has drawn interest in resting-state studies, but the results are mixed.

The most consistent functional MRI 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) (215). 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 (116). SPECT has demonstrated a significant negative correlation between the density of dopamine transporter gene (DAT) in the striatum and cerebral blood flow in the cingulate gyrus, frontal lobe, temporal lobe, and cerebellum, suggesting that higher DAT density in the striatum is associated with a decrease in regional cerebral blood flow in the cortical and subcortical attention network (67). A systematic review of nine task-based fMRI studies showed that the middle and inferior frontal gyri were most often affected by a single dose of methylphenidate during inhibitory control tasks, but that the basal ganglia and cerebellum were also affected (64). Another review suggested that methylphenidate may normalize brain activation patterns as well as functional connectivity during cognitive control, attention, and rest (257).

Functional connectivity. 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 (43). Although the evidence is compelling that frontostriatal dysfunction underlies ADHD, neuroimaging findings point to distributed neural substrates rather than a single one (53; 155) and suggest that abnormalities in brain circuitry in ADHD goes beyond the fronto-striatal model.

It has been argued that ADHD is characterized not only by deficits in the structure and function of isolated frontal, parietal, and cerebellar brain regions but also in the functional interregional connectivity between these regions that form neural networks. In a review, Cubillo and Rubia reported that similar areas of dysfunction (inferior prefrontal cortex, cingulate, striatal parietal and cerebellar regions) were noted in children and adults and concluded that there was a disturbance in fronto-striato-parieto-cerebellar neural networks during executive functions (63). Diffusion tensor imaging, whole-brain tractography, and an imaging connectomics approach were used to characterize white matter connectivity in 71 children and adolescents with ADHD and defined a significant network comprising 25 distinct fiber bundles that linked 23 different brain regions spanning frontal, striatal, and cerebellar regions that showed altered white matter structure in ADHD (130).

A study of a drug-naive sample of right-handed young adults with ADHD using resting state fMRI found that two main symptom dimensions of ADHD are related to altered intrinsic connectivity in orbitofrontal-temporal-occipital and fronto-amygdala-occipital networks and led the authors to conclude that ADHD extended beyond frontostriatal alterations (57). A meta-analysis of 55 studies found dysfunction in higher-level cognitive functions and sensorimotor processing, including the visual system and the default network. Decreased activation was seen in systems involved in executive function (frontoparietal network) and attention (ventral attention network), and increased activation was noted in the default, visual, and somatomotor networks (59). Another meta-analysis that focused on imaging studies of inhibition and attention concluded that there are two distinct domain-dissociated right hemispheric frontobasal ganglia networks including the inferior frontal cortex, supplementary motor area, and anterior cingulate cortex for inhibition and dorsolateral prefrontal cortex, parietal, and cerebellar areas for attention (120).

Neuroimaging has been used to investigate the effects of stimulant medication. Using positron emission tomography, Del Campo and colleagues found decreased dopamine activity in the left caudate nucleus, but treatment with methylphenidate increased dopamine activity in all nigrostriatal regions and normalized the activity in the left caudate (70). Wang and colleagues reported that chronic use of methylphenidate upregulates the dopamine transporter availability and may decrease treatment efficacy and exacerbate symptoms when not taking medication (303). Functional connectivity analysis showed that methylphenidate altered intrinsic connectivity between brain areas involved in sustained attention and induced significant changes in the cortical-cortical and cortico-subcortical connectivity of many other cognitive and sensory-motor resting state networks (203).

A meta-analysis failed to support the use of theta/beta ratios as a reliable diagnostic measure in children with ADHD (12). Increased theta/beta ratios on EEG may have prognostic value in children who deviate on this measure. Another study showed that children with ADHD showed increased theta/beta ratio over the control group; this finding was not seen in adults with ADHD (182).

A complex range of event-related potential deficits have been associated with ADHD. Barry and colleagues noted that differences between subjects with ADHD and controls have been reported in the preparatory responses, auditory modality, and visual attention systems (24). 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. In a follow-up review, the authors note robust differences from controls in early orienting, inhibitory control, and error-processing components (140).

Comparing event-related potentials of children with ADHD to typical 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 (141). Methylphenidate ameliorates some, but not all, deficits and improves processing where no differences with normal children are present (142). Ozdag and colleagues found indirect evidence that ADHD is associated with deficits in signal detection (inattention) and discrimination and information processing (213). Methylphenidate normalized event related potential indices except FN2A and PN2A. The authors 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 ADHD 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 ADHD do not suffer from a shortage in attentional capacity, but from a problem with capacity allocation (143). These findings were extended in an investigation of the effect of intelligence on event-related potentials (40), which evaluated P3 amplitudes in 45 subjects who were divided into three groups, Learning Disability (IQ 70-84), ADHD, and ADHD + LD, and compared to 42 control children. The authors concluded that the behavioral inhibition effect was essentially moderated by the primary intelligence rather than the attention deficit.

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 (161).

The major components of neural systems relevant to ADHD have been reviewed (42). 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; the dysfunction seen in ADHD is likely to occur at multiple levels, and drugs that work at a variety of receptor sites are the most effective therapeutic agents for ADHD (193; 228; 107; 102). A review that draws on the findings of genome-wide studies implicates genes associated with synaptic adhesion molecules, glutamate receptors, and mediators of intracellular signaling pathways and concludes that further investigation of the role of the glutamate system in the pathogenesis of ADHD is warranted (169). A subsequent study using magnetic resonance spectroscopy evaluated 89 participants (37). The authors found that GABA+ levels were altered in a subcortical voxel and change with development. Increased glutamine levels were noted in children but normalized in adults, and glutamate was not different between groups but demonstrated a strong effect across age.

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 relevant thoughts and guiding appropriate behaviors (46). Dorsal frontostriatal circuits have been linked to cognitive control, orbitofrontal-striatal loops to reward processing, and frontocerebellar circuits to timing (83).

Epidemiology

The parent-reported prevalence of ADHD approximates 11% (299). 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% (16). A survey of a nationally representative sample of 8- to 15-year-old children found that 8.7% of the children met DSM IV criteria for ADHD but that fewer than half were diagnosed with ADHD or received regular medication treatment (100). The pooled estimate resulting from a meta-analysis of 175 studies was 7.2% (292). The 2007 National Survey of Children’s Health found significantly increased frequencies of learning disability (46%), speech problems (12%), anxiety (18%), depression (14%), and conduct disorder (27%) in children with ADHD (166).

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 (74). A study of childhood injury before the age of 2 found that children with head injury and burn injury were both twice as likely to be diagnosed with ADHD than a population-based comparison group (149). The authors concluded that “the head injury itself does not seem to be causal in the development of ADHD. Rather, some other factor seems to be associated generally with early injury and the development of ADHD.” The authors proposed that “medically attended injury before age 2 may be an early marker for behavioural traits that lead to diagnosis of ADHD.” ADHD medications have shown a protective effect from unintentional injuries, at least in the short term, according to the systematic review with meta-analysis (245).

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 (168). Compared to those without ADHD, people with ADHD 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 (114).

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 intellectual disability, developmental language disorders, hearing impairment, adjustment disorders, 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. Some children who will develop Tourette syndrome will present with ADHD. The presence of 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 (189). They noted that children with ADHD but without 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. Wassenberg and colleagues noted that children with ADHD performed more slowly on tests of language comprehension (306). 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 (238).

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 (147). A subgroup of ADHD has been defined that demonstrates poor social perception skills and deficits in complex visual perception and fluid reasoning (251).

Attention deficits and impulsivity both interfere with social interactions. The concept of empathy has an affective component, affective empathy (AE), ie, sharing emotions and responding to emotional displays of others, and a cognitive component, cognitive empathy (CE), ie, the ability to understand the perspective of another person. Studies have demonstrated a positive correlation between empathic skills and executive functions in healthy subjects and patients with ADHD. In a review of this topic, the authors report that “some evidence supports the notion that the timely and affective treatment of ADHD symptoms may have beneficial effects not only on core symptoms of ADHD, but also on the social difficulties of youths with ADHD” (90).

Children and adolescents with ADHD are at higher risk for having depression than those without ADHD, and outcomes are poor when both conditions are present. Identification of depression in children with ADHD may be complicated because of an overlap of symptoms. Children with ADHD may underreport their symptoms of depression. When children with ADHD and their parents were interviewed, it was found that children with ADHD reported lower levels of depressive symptoms than their parents, which is the opposite pattern of general population (97).

The overlap of ADHD and the autism spectrum disorders has been recognized in DSM-5. 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 (242). Children with high-functioning autism frequently met criteria for ADHD and did not differ from children with ADHD in communication and restricted/repetitive domains on the Autism Spectrum Screening Questionnaire (317; 121).

Sleep difficulties were found to be more prevalent in children with comorbid ADHD and specific learning disorders compared to children with only ADHD or specific learning disorders; children with ADHD and children with specific learning disorders did not differ from each other (247). The authors concluded that “evaluating sleep disturbances is important when assessing and managing children with ADHD, [specific learning disorders], and, particularly, with the two comorbid conditions, to better understand their difficulties and develop tailored interventions.” The authors speculate that whereas neurodevelopmental disorders might be considered a risk factor for sleep alterations, “sleep alterations might lead to emotional, behavioral, and cognitive symptoms that mimic or aggravate neurodevelopmental disorders. As a consequence, it is possible to hypothesize that similar biochemical disturbances underlie both neurodevelopmental disorders and sleep alterations; for example, a dysfunction in arousal mechanisms might be related to the etiology of both ADHD symptoms and sleep difficulties.”

An assessment of the relative risk of the development of schizophrenia in patients with ADHD, based on psychiatric comorbid disorders included depression, anxiety disorder, intellectual disability, nonorganic sleep disorder, tic disorder, bipolar disorder, autism spectrum disorder (ASD), conduct disorder, obsessive-compulsive disorder, and substance use disorder as psychiatric comorbid disorders (137). ADHD patients who had at least one diagnosis record of these psychiatric disorders within 1 year before the date of diagnosis of ADHD were compared to those without psychiatric disorders. Patients with ADHD with psychiatric comorbidities had a higher risk of being diagnosed with schizophrenia than those without comorbidities. There was a stepwise increase in schizophrenia risk with an increasing number of comorbidities. Autism spectrum disorder, intellectual disability, tic disorders, depression, and bipolar disorder had a relatively higher association with the increased schizophrenia risk than anxiety disorder, nonorganic sleep disorder, conduct disorder, obsessive-compulsive disorder, and substance use disorder. The use of typical antipsychotics, atypical antipsychotics, anxiolytics, anticholinergics, SSRIs/SNRIs, and antiepileptics was associated with an increased subsequent schizophrenia risk (137).

The authors concluded, “These findings highlighted the significance of carefully monitoring psychiatric comorbidities in patients with ADHD to effectively mitigate the burden of schizophrenia” (137).

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 (06; 39; 210; 226).

The use of a stepped diagnostic approach, which includes steps of care before making a definite diagnosis, has been proposed as a means to reduce overdiagnosis without risking undertreatment (291). The steps are as follows:

• Gather baseline data from more than one source.
• Assess for alternative explanations of behavioral problems.
• Watchful waiting: assess, monitor, and follow up before initiating treatment.
• If problems persist, initiate a minimal intervention. If insufficient, provide counseling for coping skills for dealing with hyperactivity and concentration problems. If insufficient, more intensive therapy. Refer for specialty care.

Rating scales are helpful adjuncts to the diagnostic and management process, but they are not adequate for diagnosis when used alone (270). A 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 cutoff point, a child had a 77% chance of having clinical ADHD; a child had a 44% chance of having clinical ADHD if the cutoff point was not reached (52). One study investigated the validity of the Conner’s Teacher and Parent Rating Scales and found a sensitivity of 83.5% and a specificity of 37.5%, causing the authors to conclude that the Conner’s Teacher and Parent Rating Scales were not sufficient to diagnose ADHD (217). Scales are limited by time frame of assessment, general versus specific behavioral targets, psychometric properties, time to administer, cost, and flooding (173). Parent evaluations and teacher evaluations are commonly discordant (195). 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 (58). Parents are good at assessing preschool hyperactivity when their child was not hyperactive (89% accuracy) but were not better than chance (50% accuracy) when the child was hyperactive (133). The Conner's Adult ADHD Rating Scale and the Wender Utah Rating Scale (short form) were found to have the most robust psychometric properties and content validity for adults (287). Focusing on the ADHD symptoms (inattention, impulsivity, hyperactivity) alone is not sufficient; assessment should include inquiry about daily life function impairments and adaptive behavior deficits (eg, peer relations, parenting style, academic functioning) (220).

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. (See Presentation and Course for guidelines on complex ADHD.) Symptoms of sensory modulation dysfunction (eg, tactile defensiveness, repetitive touching, auditory filtering, taste and smell sensitivity) typically associated with the autistic spectrum are commonly noted in children with ADHD (177). Voice problems are also common in children with ADHD (119). They have increased rates of hoarseness, breathiness, and straining in their voices, and they were louder than controls.

The motor examination is of particular interest in children with ADHD. Positive correlations have been established between overflow movements and measures of response inhibition (199). 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 co-localizing motor signs, it is highly likely that ADHD is not the diagnosis” (71). 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 (288). In children with ADHD, gross and fine motor performance may be due to different behavioral processes (293).

Schoemaker and coworkers evaluated the nature of the motor deficit relative to handwriting in children with ADHD. Motor planning (a sequence of abstract spatiotemporal 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 (256).

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 (218). Those with ADHD and developmental coordination disorder showed particular difficulty with force control (225). Children with ADHD performed less well on a task that required them to move a cursor on a horizontal digitizing tablet between two 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 (85). Deficits in bimanual coordination also have been documented (152). 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 (04).

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.

Academic difficulty often accompanies ADHD. The cumulative incidence of reading disability in children with ADHD approximates 48% (318). 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 (185). Dysgraphia is common in children with ADHD and adversely affects academic performance (235). In a population-based birth cohort study, the cumulative incidence of written language disorder by the age of 19 was 65% in boys and 57% in girls (319). In another population study of children 7- to 9-years-old from Norway, more than half (58.5%) of children with ADHD had language impairments (126).

Normal performance on neuropsychological tests does not rule out the diagnosis of ADHD, although impairments on multiple neuropsychological tests are predictive of the disorder (75). 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 (156). 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. Neuropsychological deficits were not predicted by ADHD subtype (54).

Continuous performance tests do not have a high correlation with behavioral questionnaires in the diagnosis of ADHD (77). A review of six commercially available continuous performance tests found mixed findings with regard to their ability to assess and manage medication and contrasting evidence on their ability to support clinical decision making (117). Continuous performance tests have a high rate of false positives; 30% of control children test positive (252). Actigraphy must be interpreted in the context of situational and temporal factors (68).

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 (32). 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 (259). A meta-analysis 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 (0.46 to 0.69) 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 (314).

Executive function measures are related to IQ; for children with average IQ, executive function measures distinguished those with ADHD from those without (175). At high average and superior level IQ, there were no significant group differences on measures of executive function between children with ADHD and controls. 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 autism. Language abilities, rather than executive functions, best predicted teacher ratings of inattention (144). 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 (183).

Children with ADHD have difficulty with time perception. They show poorer ability on time reproduction tasks (192) as well as significant impairment in time discrimination thresholds (269). Children with ADHD evidence a generic motor timing deficit, and the impaired time perception does not seem to be related to motivational factors (298). 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 (72). Poor visual habituation also has been documented in children with ADHD (134).

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. It is for this reason that the number of symptoms in the DSM-5 to make the diagnosis in adolescents over the age of 17 and in adults was reduced from six to five (08). 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 (128). 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 (255). Finally, the requirement to document the onset of symptoms before 12 years of age necessitates the practical archeology of reviewing old report cards, school notes, and other behavior data (309). Unfortunately, when most adults come to attention, such school files are often unavailable.

Management

Protocols have been developed for the treatment of the disorder (07; 129; 111), and algorithms that guide use of medications for the disorder have been published (227; 305). They do not, however, provide clear guidelines for instituting and ceasing the use of stimulants. Consequently, concern remains that stimulants may be overprescribed (136; 248).

Stimulants remain the mainstay of therapy for ADHD (312; 38). Motor activity, aggressiveness, and impulsivity decrease, whereas classroom behavior and relationships with peers and family members improve. 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 ADHD (150) and affect event-related potentials (285). Stimulants are associated with improvement in academic performance in elementary school (253) and may protect against later psychiatric disorders in adolescence and young adulthood (33). 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 (03). Children with ADHD and developmental coordination disorder showed improvement in manual dexterity and quality of handwriting (96). The strokes on a graphomotor task became less fluent but more accurate.

Two primary types of stimulants are used to treat ADHD: amphetamine and methylphenidate. There are many different delivery systems for these agents. Short acting, intermediate acting, and long-acting formulations are available. A transdermal system of methylphenidate and an amphetamine pro-drug (a preparation that is only effective when taken orally) are available. Newer delivery systems have been developed for children who cannot swallow pills or capsules. 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 also need to be addressed to optimize outcomes.

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 (200; 201; 219). Peer ratings failed to find support for the superiority of any of the interventions (132). 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 (202). By 36 months, the earlier advantage of the medication treatment was no 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 (135).

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) (198). 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 (240). Children in families with more education showed superior reduction of ADHD symptoms with combined therapy. Oppositional-aggressive symptoms were most improved with combined therapy in lower socioeconomic status households, whereas 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 three groups: medication alone, medication and intensive behavioral intervention (behavioral therapy, academic assistance, and parent training), and medication and “attention control” (play groups). All three 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 (01; 02; 123).

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 one stimulant without major adverse events if drug titration is done carefully (106). Methylphenidate works in preschool children in a fashion that is similar to their school-aged counterparts (206). Body mass failed to predict optimal dose or gains achieved at optimal dose and did not predict drug response (236). DAT and DRD 4 polymorphisms may be related to stimulant response (99). Children who lack the DAT 10-repeat allele show greater symptom improvement with increasing stimulant dose when compared to DAT 10-repeat carriers. Children lacking the DRD 4-repeat allele show less improvement across methylphenidate doses than 4-repeat carriers.

Regrettably, the benefits of treatment have not been well established. A study assessing the treatment of children with ADHD recruited from demographically, geographically, and socioeconomically diverse school systems (data from the Adolescent Brain Cognitive Development [ABCD] Study), found that among children meeting the criteria of both parent-reported and teacher-reported ADHD only 12.3% were currently receiving ADHD medications, only 33.7% had ever received outpatient mental health care, and only 39.4% had received either service. Children receiving ADHD medications included a significantly higher percentage of boys, white children, children of parents without a high school education, and children with the combined subtype of ADHD. Children receiving outpatient mental health care included a significantly higher percentage of children whose parents had a high school education or some college than a bachelor’s degree or higher, children with family incomes of less than $49,999 than $75,000 or more, and children with the combined subtype of ADHD (212).

The adverse effects of pharmacotherapies for ADHD have been reviewed, 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” (109). Irritability, anorexia, insomnia, and behavioral rebound are the most common short-term side effects.

Concerns have been raised about the possible adverse cardiovascular effects of ADHD medication treatments. A meta-analysis that pooled the results of 19 studies looked for effects of medication on any type of cardiovascular event, including hypertension, ischemic heart disease, cerebrovascular disease, heart failure, venous thromboembolism, tachyarrhythmias, and cardiac arrest (325). The review found that “ADHD medication use was not statistically significantly associated with the risk of any [cerebrovascular disease] among children and adolescents, young and middle-aged adults, older adults or overall.” There was no difference in the cardiovascular risk between stimulant and nonstimulant ADHD medication use. The authors cited studies finding that “ADHD itself is a risk factor for [cerebrovascular disease] independent from comorbid psychiatric and somatic conditions.” The study found a statistically nonsignificant increase in the risk of cardiovascular events associated with ADHD medications in patients with preexisting cardiovascular disease compared with no prior cardiovascular disease. The authors also noted that “the pooled [relative risk] did not exclude a modest risk increase, especially for the risk of cardiac arrest or tachyarrhythmias.” These findings led the authors to conclude that “clinicians should discuss with their patients and families the possible cardiovascular risk of ADHD medication in light of the latest evidence, and they should rigorously follow clinical guidelines that suggest monitoring of blood pressure and heart rate at baseline and each medication review.”

A subsequent study, also by Zhang and colleagues, noted most of the studies reviewed in their prior metaanalysis had an average follow-up time of no more than 2 years (324). This subsequent study assessed the association between the cumulative use of ADHD medication for up to 14 years and the risk of cerebrovascular disease, using nationwide health registers in Sweden. They noted the following data:

“Across the 14-year follow-up, each 1-year increase of ADHD medication use was associated with a 4% increased risk of CVD with a larger increase in risk in the first 3 years of cumulative use (AOR, 1.08 [95%CI, 1.04-1.11]) and stable risk over the remaining follow-up.”

However, the dosage analysis showed that the risk of cerebrovascular disease was only statistically significant among individuals with a mean dose of at least 1.5 times the average daily dose (eg, the average daily dose of methylphenidate was 30 mg). The possibility of residual confounding factors prevents proof of causality (eg, more severe ADHD symptoms being associated with more comorbidities); nevertheless, the authors recommended regular monitoring of cardiovascular signs and symptoms throughout the course of treatment (324).

A randomized controlled trial of interventions for growth suppression in children treated with stimulants randomly assigned children who exhibited a sustained deficit in standardized BMI to one of three weight recovery treatments: increased growth monitoring, drug holidays, and caloric supplementation. Despite a significant increase in the rate of weight gain in all three groups, none of the groups showed an increase in height velocity (307).

Priapism has been the subject of a safety announcement by the FDA and has been seen with methylphenidate, amphetamine, and atomoxetine (84).

ADHD medications did not increase the incidence of epilepsy, and there was a low seizure risk for patients with infrequent seizures.

The treatment of children with ADHD and tics has been the subject of a Cochrane Review (233). ADHD symptoms were effectively treated by methylphenidate, clonidine, desipramine, dextroamphetamine, guanfacine, and atomoxetine. Tic symptoms improved in children treated with guanfacine, desipramine, methylphenidate, clonidine, and the combination of methylphenidate and clonidine. It was concluded that stimulants were safe and effective treatments for ADHD and do not worsen tics. Alpha agonists and atomoxetine are appropriate alternatives for patients whose tics are exacerbated by stimulants.

Concerns 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 (09).

A Cochrane systematic review with meta-analyses and trial sequential analyses of 185 randomized clinical trials has been conducted to assess the effects of methylphenidate on ADHD in children and adolescents (279). The study suggests methylphenidate may improve teacher reported symptoms of ADHD, teacher reported general behavior, and parent reported qualify of life. Additionally, methylphenidate is associated with increased risk of nonserious adverse events, but no evidence to show that it increases the risk of serious adverse events. Banaschewski and colleagues raised concerns about the review in the domains of study inclusion, approaches to quality assessment, and interpretation of data relating to serious adverse events and estimation of the effect size of the primary outcome and determined that the conclusion of the Cochrane review is that the status of the evidence regarding methylphenidate is misplaced (14). In a rebuttal, Storebo and associates conceded that there were people who benefit from methylphenidate but maintained that the overall quality of the studies could be questioned (281). An editorial concluded that the Cochrane review demonstrated the complexities of quantifying the benefits of methylphenidate for ADHD (261).

A systematic review of articles published between January 1, 1999 and January 31, 2016 on ADHD treatment in adolescents identified 16 randomized clinical trials and one meta-analysis (50). Evidence for pharmacological treatment of ADHD in adolescents was stronger for the stimulant class (extended methylphenidate and amphetamine formulations) and atomoxetine. This review only identified one randomized controlled trial of alpha-2 adrenergic agonist, extended-release guanfacine, and therapy in adolescents, which showed efficacy in treating ADHD symptoms. Psychosocial treatments (behavioral, cognitive behavioral, and skills training) were associated with inconsistent effects on ADHD symptoms but robust improvements in academic and organizational skills.

A literature review of studies examining the effects of medication on ADHD-associated functional outcomes “documented major benefits of ADHD medication, particularly stimulant, treatment in mitigating the risks for mood disorders, suicidality, criminality, [sudden unexplained deaths], accidents and injuries, [traumatic brain injury], automobile crashes, and academic impairments” (36). The studies reviewed found that the protective effects of medication for ADHD on functional outcomes “were particularly marked when treatment was adhered to,” emphasizing “the critical need to develop innovative methods to improve adherence to medications in ADHD.”

Nonstimulant medications have been shown to be useful for adults with ADHD. Atomoxetine, a selective norepinephrine reuptake inhibitor (158), has been shown to reduce ADHD symptoms and improve social and family functioning symptoms at a dose of 1.2 mg/kg daily (194). Atomoxetine does less well than osmotic release oral system methylphenidate (209) or mixed amphetamine salts extended release (310) in direct comparisons, but about as well as immediate release methylphenidate (304). Atomoxetine has the advantage of not being a controlled substance and can be prescribed with refills.

A meta-analysis of 133 double-blind randomized controlled trials compared the efficacy of different pharmacotherapies for ADHD across age spans (55). Accounting for both efficacy and tolerability, the study supported methylphenidate as the preferred first-choice medication for the short-term treatment of ADHD in children, adolescents, and adults.

Despite extensive work on pharmacodynamics and pharmacogenomics, no genetic variant or pharmacogenomic test has been found to have any utility in predicting the optimal pharmacotherapy for an individual patient (86).

A study of viloxazine (extended release), a selective norepinephrine reuptake inhibitor (SNRI), found early and sustained improvement in inattention and hyperactivity/impulsivity symptoms based on investigator-rated scales; parent and teacher ratings were not included in the analysis (207). The 50% responder rate at week 6 was 37.8% for placebo, 53.2% for 100 mg/day, 50.3% for 200 mg/day, 56.2% for 400 mg/day, and 53.1% for 600 mg/day. The response rate for medication was significantly higher than placebo (although the placebo response was considerable); there was no dose-response effect.

Among the second line medications are tricyclic antidepressants, bupropion, MAO inhibitors, and clonidine and guanfacine. Carbamazepine 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 (216). Clonidine has been recommended to treat sleep disorders associated with ADHD (311). Cardiac arrhythmias have been reported in otherwise healthy children who were taking clonidine (45). Extended-release clonidine has been useful in reducing ADHD symptomatology in children and adolescents with partial response to stimulants (154) but efficacy has not been demonstrated when used as monotherapy (41). Guanfacine extended release has been shown to decrease ADHD symptoms and may be of particular use in children with ADHD and aggression (249). 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 (313).

Preschool children require modification of therapeutic approaches (146). Behavioral interventions are recommended as first-line therapy for preschoolers who present with ADHD (51). This is due in part to the higher rate and intensity of side effects, including insomnia, anorexia, weight loss, anxiety, and emotional outbursts. However, pharmacotherapy is indicated in preschool children whose ADHD severely impacts function (eg, expelled from preschool), interferes with other therapies, creates severe parental stress, who present a danger to themselves or others, whose ADHD is not managed by behavioral interventions, or who have a strong family history of ADHD. Methylphenidate is not FDA approved for children under 6 years old, but some amphetamine preparations are approved for children over the age of 3 years.

Sonuga-Barke and colleagues performed six meta-analyses of randomized controlled studies that used blinded assessment studies to assess the following: elimination diets, artificial food color exclusions, free fatty-acid supplementation, cognitive training, neurofeedback, and behavioral interventions (272). They found a small but significant effect for free fatty-acid supplementation and artificial food coloring exclusion.

Another systematic review to assess effectiveness of nonpharmacologic treatments, including neurofeedback, cognitive training, cognitive behavioral therapy, child or parent training, dietary omega fatty acid supplementation, and herbal or dietary approaches for ADHD concluded that limited evidence exists to support these treatment options (108).

A large, randomized, double-blind, placebo-controlled clinical trial that used a standard neurofeedback protocol (theta/beta ratio [TBR] protocol, whereby 13 to 21 Hz is rewarded and 4 to 8 Hz is inhibited) demonstrated that the neurofeedback group successfully reduced the TBR on EEG more so than the control group (208). Both the neurofeedback and the control groups showed significant improvement in parent- and teacher-reported ADHD symptoms, with no significant difference between them. Thus, the primary outcome of improvement in ADHD symptoms did not correlate with TBR reduction, suggesting that nonspecific effects of the total treatment package (eg, supportive coaching, practice focusing on a screen, reinforcement for sitting still, placebo response) accounted for the improvement in symptoms. However, the study also found that at 13 months after training, 16% of those who received active neurofeedback reduced or stopped medication versus 7% of controls, and 18% of the neurofeedback group increased medication versus 39% of controls (p < .012). The authors commented that “[t]his study neither proves nor disproves efficacy of the total neurofeedback package. The control improvement appears to be comparable to the longer, more intensive [multimodal treatment of ADHD] behavioral treatment. To what this improvement is attributable requires further research, but the 13-month durability suggests more than placebo response.” The authors noted, “the practice of exerting mental effort to focus on a boring activity with supportive coaching and monetary rewards could have further contributed to the improvement.” (On a personal note, this author believes that the time, effort, and expense devoted to neurofeedback would be better devoted to learning to play a musical instrument; these findings reinforce that belief.)

Moderately intense aerobic exercise improved neurocognitive function and inhibitory control in a group of children with ADHD (229).

A review of 18 nonpharmacologic studies divided the interventions into four categories: neurofeedback, cognitive-behavioral therapy, cognitive training, and physical exercises (163). Outcomes consisted of five measures of cognitive domains: mental flexibility; inhibition; attention; working memory; higher executive function (cognitive functions of planning and reasoning). The review found that all the interventions demonstrated significant results; physical exercise demonstrated the largest effect size, cognitive training interventions had the smallest effect size, and cognitive behavioral therapy and neurofeedback showed a moderate effect size. Regarding outcomes, “the functions with the highest effect sizes were those considered higher cognitive functions, or executive functions, as opposed to basic attention and working memory functions which are less complex and could be categorized as lower cognitive functions.” The authors noted that there was only a slightly higher effect of nonpharmaceutical treatments when combined with medication. However, studies that included only nonmedicated children still produced a moderate to large effect size.

A single site, 4-arm, randomized, controlled, open-label trial of neurocognitive training interventions in children and adolescents with ADHD found no benefits of slow cortical potential or live Z-score training over usual treatment. “In conclusion, we found no support for broad effects of neurofeedback on multiple cognitive functions associated in ADHD.” Working memory training showed improvements in some working memory tasks in comparison to usual treatment and neurofeedback. The specific nature of the improvement suggested “that the effects may not generalize across the full range of working memory functions.”

The addition of a cognitive behavior therapy program to stimulant therapy was studied in a randomized controlled fashion in a group of adults with ADHD and showed moderate to large effect size that continued to improve at follow-up 3 months later and improvement of comorbidities (87).

Organizational skills interventions are associated with significant improvement in the organization of materials, homework management, time management, and planning (165). A review of 11 studies of 747 participants failed to demonstrate benefits of social skills training for 5- to 18-year-old children with ADHD (280).

Individual participant data meta-analysis was used to identify the effect of behavioral intervention and moderators of outcomes for symptoms of ADHD, oppositional defiant disorder, and conduct disorder as well as global impairment in children and adolescents with ADHD (113). Candidate moderators included clinical characteristics of the child (ie, severity of symptoms, comorbidity, and medication use) and demographic variables. Results showed that behavioral interventions achieved small- to medium-sized reductions in ADHD symptoms, behavioral problems, and global impairment according to the reports of raters closest to the delivery of the intervention. For all outcome measures except inattention and global impairment, higher baseline conduct disorder symptoms were associated with larger treatment effects. The results showed that positive intervention effects in children with elevated conduct disorder symptoms were driven by larger symptom deterioration in the control conditions, suggesting that children with more severe conduct disorder symptoms are more likely to suffer an increase in symptoms of ADHD and behavioral problems over time, particularly when not treated. The data suggest a protective rather than an ameliorative effect of behavioral interventions for those with more severe conduct disorder or ADHD symptoms. There was evidence of deterioration in children from single-parent families with regard to oppositional defiant disorder symptoms in the control condition. Inasmuch as for these children, treatment seems to prevent them from further deterioration in terms of ADHD symptoms, behavioral problems, or impairment; prompt diagnosis and intervention are important.

A meta-analysis of 11 studies to evaluate the effectiveness of parent-administered behavioral interventions for ADHD concluded that parenting interventions are effective, and the authors advocated for the availability of parenting interventions in community settings (56). A review of parental behavioral training indicated that “the overarching aim of these programs is teaching parents to prevent and manage their child’s behavior” but noted that the content of the training programs had substantial differences, with some consisting of psychoeducation and others emphasizing disciplinary communication, observation and monitoring, or positive reinforcement (69). The review investigated the effect of behavioral techniques on five different parental domains: positive parenting, negative parenting, parenting sense of competence, quality of the parent–child relationship, and parental mental health. Significant small- to medium-sized main effects favoring parent training over control conditions were found for all outcome categories. Higher dosages of behavioral techniques teaching parents to anticipate potential misbehavior of the child (eg, thinking ahead, preparing a plan before entering a problematic situation) were associated with positive effects on parenting sense of competence and parental mental health. The authors noted that stimulus control techniques, such as applying more structure and clear rules, may also be beneficial for parents themselves, as a significant proportion of the parents of children with ADHD have impairing ADHD symptoms. Higher dosages of behavioral techniques teaching parents to provide children with positive consequences after desired behavior and responding in a consistent way were associated with decreased negative parenting (ie, corporal punishment, harsh discipline, inconsistent parenting, and poor monitoring). The authors concluded that “changing negative parenting is pivotal to ultimately improving the child’s behavior.”

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 (271).

A Cochrane review of homeopathy for ADHD or hyperkinetic disorder concluded that there was little evidence for the efficacy of homeopathy in ADHD (60). 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 (266). A meta-analysis encompassing 16 studies failed to show an effect of sugar on children's behavior or cognition (316). 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 (244). A systematic review of essential fatty acids and ADHD did not support the use of essential fatty acid supplements as a primary or supplementary treatment for children with ADHD (237); this was confirmed in a Cochrane review (104). A restricted elimination diet was associated with improvement of ADHD and oppositional behaviors, and 18 of 32 children relapsed when challenged (221). A systematic review of 11 randomized control studies of food supplements noted that some studies showed positive results but that more studies were required before conclusions could be drawn (278).

An approach to refractory cases concluded that a minimum of two psychostimulant trials should be instituted before a child’s symptoms of ADHD are considered treatment refractory (301). Diagnostic accuracy, comorbid disorders, psychosocial features, medication compliance, symptoms across settings, and behavioral treatment should be addressed before initiating alternative medication trials.

Outcomes

A review of the long-term treatment of children and adolescents with ADHD 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 (122). 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 patients with ADHD who were treated with stimulants and patients with ADHD who were not treated 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. The study concluded that there is a need to continue psychosocial treatments in order to maintain long-term gains.

There are “major benefits of ADHD medication, particularly stimulant, treatment in mitigating the risks for mood disorders, suicidality, criminality, [sudden unexplained deaths], accidents and injuries, [traumatic brain injury], automobile crashes, and academic impairments” (36).

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 (138; 20). 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 three times daily (62). This has been replicated in a real-life driving test (61).

ADHD was associated with significantly higher mortality rates in a Danish population study of 1.92 million people over a 32-year period. This difference persisted after excluding oppositional defiant disorder, conduct disorder, and substance use disorder. The mortality rate ratio was highest in those over 18 years of age. The most common cause of death was accidents (66).

A longitudinal study demonstrated that childhood ADHD–combined type was associated with reduced expected life expectancy by young adulthood, including healthy remaining years of life and a longer period of unhealthy estimated years of remaining life (21). This reduction in expected life expectancy is worse when ADHD persists into adulthood. “The reduced [expected life expectancy] linked to ADHD was found to be a function of the first order variables of less education, less annual income, greater consumption of alcohol and tobacco, diminished sleep, and poorer overall health status relative to the control group.” Expected life expectancy was also shown to be a function of the second order traits of deficient behavioral inhibition in daily life and, much less so, of low verbal IQ, greater interpersonal hostility, and deficient nonverbal fluency. The authors concluded that recommendations regarding health- and lifestyle-related–self-improvement programs should be included in the treatment of ADHD across development in an effort to address the modifiable factors linked to reduced expected life expectancy.

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 of the child. 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 (30). 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 (273). Mothers with ADHD were found to be poorer at monitoring child behavior and less consistent disciplinarians compared to mothers without ADHD (205). Some evidence 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.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

David E Mandelbaum MD PhD

Dr. Mandelbaum has no relevant financial relationships to disclose.
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Editor

Ann Tilton MD

Dr. Tilton has received honorariums from Allergan and Ipsen as an educator, advisor, and consultant.
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Former Authors

Mihee J Bay MD
Michael V Johnston MD†

Patient Profile

Age range of presentation: 1 month to 65+ years
Sex preponderance: male>female, >1:1
Heredity: heredity may be a factor

strong heritability
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Attention deficit hyperactivity disorder, predominantly inattentive type: 314.00

Attention deficit hyperactivity disorder, predominantly hyperactive impulsive type: 314.01

Attention deficit hyperactivity disorder, combined type: 314.01

Attention deficit hyperactivity disorder not otherwise specified: 314.9
ICD-10: Attention deficit disorder without hyperactivity: F98.8

Disturbance of activity and attention: F90.0

Hyperkinetic disorder, unspecified: F90.9

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Attention deficit hyperactivity disorder

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
- Dyscalculia
- Dysgraphia
- Dyslexia
- Epilepsy
- Learning disorders
- Minimal brain dysfunction
- Mood disorders
- Oppositional defiant disorders
- Pervasive developmental disorders
- Receptive expressive language disorders
- Tic disorders

Differential Diagnosis

learning disabilities
intellectual disability
developmental language disorders
autism spectrum disorders
hearing impairment
- mental disorders
- mood disorder
- anxiety disorder
- dissociative disorder
- personality disorder
- pervasive developmental disorder
- Tourette syndrome
- schizophrenia
- psychotic disorder

Also Relevant

Atomoxetine
Autism spectrum disorder
Developmental delay in children: evaluation and management
Executive dysfunction
Fluoxetine
- Intellectual disability
- Methylphenidate
- Modafinil
- Sleep enuresis
- Stimulant-dependent sleep disorder
- Tourette syndrome

Attention deficit hyperactivity disorder (ADHD) …

Attention deficit hyperactivity disorder

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
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Attention deficit hyperactivity disorder

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Zika virus: neurologic complications

Anti-LGI1 encephalitis

Fatal familial insomnia

CNS germinoma

Vein of Galen malformations

Hyperventilation syndrome

Neurologic disorders associated with behavioral symptoms

Cortical blindness

This is an article preview.
Start a Free Account
to access the full version.