Attention Deficit Hyperactivity Disorder

Article about attention deficit hyperactivity disorder (ADHD) in detail. This article is written in technical medical language and is US based.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood behavioral disorder diagnosed in outpatient settings in the United States. Polanczyk and colleagues, using a meta-analysis that included hundreds of articles and more than 100,000 patients, estimated its worldwide prevalence to be 5.2 percent.

Although prevalence estimates for ADHD vary by country and region, as well as by age, a pooled estimate of worldwide prevalence is 5.29 percent. This figure showed the most variation geographically between Europe and North America. Angold and colleagues reported similar rates of ADHD as defined by the criteria of the Diagnostic and Statistical Manual of Mental Disorders, revised third edition (DSM-III-R), in 4,500 youth ages 9 to 13 years (5.3 percent in boys, 1.5 percent in girls) from the Smoky Mountain region of the United States, based on a structured diagnostic interview for children and their parents, the Child and Adolescent Psychiatric Assessment (CAPA). Barbaresi et al. estimated a cumulative incidence of 7.5 percent (95 percent confidence interval of 6.55 to 8.4 percent) from an epidemiological study involving 6,000 elementary and secondary school children in Rochester, Minnesota, which was similar to the Centers for Disease Control and Prevention's national phone survey estimate of 7.8 percent from interviewing parents of 100,000 children of ages 4 to 17 years.

Although ADHD begins in childhood, less than 40 percent of such children continue to meet diagnostic criteria in their teenage years. Barkley et al. followed a cohort of boys with ADHD from age 10 to age 20 years and found that parent ratings reported that 46 percent continued to meet full childhood diagnostic criteria for the disorder as they grew into adult life. However, only 3 percent of the ADHD individuals rated themselves as still having ADHD. Ninety percent of the ADHD individuals rated less than 60 on Columbia Global Assement Scale (C-Gas) of global functioning. In the same study, the adults with childhood histories of ADHD were found to have higher rates of accidents, injuries, health problems, pregnancies, and job and marital problems. Kessler and colleagues used the National Comorbidity Survey to estimate that 4.4 percent of individuals aged 19 to 44 years screened met full childhood criteria for ADHD.

Definition

According to the fourth edition of the American Psychiatric Association's (APA) DSM (DSM-IV), ADHD is a behavioral and neurocognitive condition characterized by developmentally inappropriate and impairing levels of gross motor overactivity, inattention, and impulsivity. There are five main diagnostic criteria: (1) an onset before age 7 years; (2) duration greater than 6 months; (3) an 18-item symptom list of which 6 of 9 inattention or 6 of 9 hyperactive/impulsive symptoms have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level; (4) some impairment in two or more settings; and (5) symptoms that do not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychotic disorder and are not better accounted for by another mental disorder, such as depression.

ADHD is diagnosed by history taken from the parent and at least one other adult, such as a teacher or coach. As with many psychiatric disorders, there is no simple objective test, such as a blood test, that can aid in making the diagnosis.

History

ADHD first was described by in 1902 George Still, who wrote about children who were restless, impulsive, and inattentive, with intense affective responses and conduct problems. He believed that a combination of organic and environmental factors resulted in a lack of inhibitory control and inattention, which he thought were the primary deficits in this condition.

After the influenza pandemic and the epidemic of encephalitis lethargica in 1919 to 1920, children who survived the flu frequently developed severe behavior problems similar to those described in Still's monograph. The flu survivors now are thought to have suffered organic brain damage. For that reason, the childhood condition was termed “minimal brain damage syndrome,” even though brain damage could not be proven. Not only did the term postulate an unproven etiological mechanism, it was also stigmatizing.

In 1937, C. Bradley published a report that d,l-amphetamine reduced restlessness and improved concentration in children with behavior problems in a residential treatment center. However, this finding was ignored for 30 years until Keith Conners and Leon Isenberg evaluated the efficacy of dextroamphetamine (d-AMP) in a double-blind, placebo-controlled trial for children with learning disabilities and behavior problems.

In the early 1960s, the condition was renamed “minimal brain dysfunction.” However, this implied a specific anatomical location and possible etiology of the disorder, something that was not proven. Later in the 1960s, the first attempts were made to create a more descriptive and less stigmatizing name. The ninth revision of the International Classification of Diseases and Related Health Problems (ICD-9) and the second edition of the DSM adopted the same descriptive term for the condition—hyperkinetic syndrome of childhood. The term reflected the early prevailing belief that hyperactivity was the core phenomenological feature of ADHD.

In the 1970s, further research suggested that the main disability involved in this condition was the difficulty of maintaining sustained attention and impulsivity, whereas gross motor overactivity was secondary. As a result, the 1980 version of the APA classificatory system, DSM-III, renamed this diagnosis attention-deficit disorder (ADD). Its algorithm included three symptom categories and required that a minimum number of diagnostic criteria be endorsed: Three of five inattention items, three of six impulsive items, and two of five overactivity items. Three subtypes of ADD were allowed: Attention-deficit disorder with hyperactivity, attention-deficit disorder without hyperactivity, and ADD, a residual type that included adults or others who had disabling ADD symptoms but who no longer met full criteria for the disorder. The residual diagnosis was the first that applied to adults with ADD.

The 1987 DSM version, designated DSM III-R, included a single criterion list requiring 8 of the 14 possible symptoms of hyperactivity, impulsivity, and inattention be endorsed to reach the threshold required to make the ADHD diagnosis. Duration criteria were added, such that the behaviors needed to be present since age 7 years and for at least 6 months. The ADHD symptoms had to occur more frequently in patients and to have persisted for at least 6 months. This 1987 version of the DSM had no subgroups, and ADD without hyperactivity was no longer a subtype.

In 1994, the APA published the fourth edition of the DSM, the DSM-IV, and in 2000, a text revision, DSM-IV-TR, which is the current version. The diagnostic categories and algorithms for making the diagnosis were based on multisite field trials that included 600 child and adolescent patients seen in university settings. These patients were evaluated to help better define the validity of the proposed ADHD symptoms through structured diagnostic instruments and unstructured clinical interviews. 

At this stage, diagnosis of the ADHD condition has existed for more than a century. Each DSM revision has refined concepts of etiology, phenomenology, risk profiles, symptom picture, and impairments over the course of development. This chapter provides an overview of current thinking concerning ADHD's epidemiology, etiology, clinical presentation, and response to treatment. This understanding will most probably change in the future as additional etiological evidence and treatment studies come to light.

Comparative Nosology

Clinicians in Europe use a very different diagnostic description of ADHD than that in the DSM-IV-TR: The ICD-10 diagnosis of “hyperkinetic disorder (HD).” The differences include the extent to which medication should be used and the algorithm used to diagnose the disorder. The DSM-IV diagnosis of ADHD and the ICD-10 diagnosis of HD are based on the same 18 symptoms, but the two systems use different decisions rules. ICD-10 requires that the child with HD must have a minimum number of symptoms in three different areas: 6 of 9 inattentive symptoms, 3 of 5 hyperactivity symptoms, and 1 of 4 impulsive symptoms. Furthermore, one cannot apply the diagnosis of HD in comorbid cases when criteria for emotional disorder (anxiety or depression) are met. In addition, children with ADHD who do not meet HD criteria must be managed psychologically before medication can be started. The DSM-IV requires that children with ADHD have 6 of 9 symptoms of inattention for ADHD, Predominately Inattentive Type; 6 of 9 symptoms of hyperactivity/impulsivity for ADHD, Predominately Hyperactive-Impulsive Type; and 6 of 9 symptoms in both areas for ADHD, Combined Type.

How does this affect the diagnosis of ADHD? Investigators applied an algorithm to 579 children with DSM-IV ADHD, Combined Subtype, in the National Institute of Mental Health (NIMH) Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder (MTA trial) to generate an ICD-10 diagnosis of HD and discovered that only 25% of the MTA sample met the diagnostic criteria for HD. However, there is a greater difference between the United States and European countries in the administrative prevalence of the disorders and the frequency with which the diagnoses are made in clinical practice. This suggests that cultural differences in referral practices and clinician preferences play a role in determining international differences in diagnoses of ADHD and HD.

Limitations of the DSM-IV-TR

Although the clinical picture and natural history of ADHD as a disorder are clearly described in the DSM-IV-TR, key terms needed to make the diagnosis are not always operationalized. For example, all 18 items in the symptom criteria are required to be present “often,” but “often” is not defined. It is suggested that there be a “persistent pattern of inattention and/or hyperactivity/impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development,” but the word “persistence” is not defined. Nor is the term “impairment” that is used in the criteria defined. For example, a child who has an intelligence quotient (IQ) of 130 but is barely passing in school may be impaired relative to his or her academic potential but unimpaired relative to general peer norms. There is no gold standard for an objective measure of impairment in children, so clinicians must rely on subjective opinions of the child's parent or teacher.

The DSM-IV-TR criteria were derived from field trials conducted almost two decades ago limited to school-aged children between 6 and 12 years of age, and thus the results may not be developmentally specific or directly applicable to preschool children, adolescents, and adults. For example, motor hyperactivity appears far less frequently in affected adolescents and adults, who continue to have attentional and organizational problems, poor anger management, job instability, and problems with social relationships and self-esteem. The criteria threshold required for the diagnosis, that is, two sets of 6 of 9 symptoms, may not be appropriate for much younger or older individuals with ADHD. Recalling symptoms before age 7 years is difficult for adolescents and adults. Comorbidity, which increases with age, is not addressed by DSM-IV criteria. The APA plans to review the DSM-IV-TR ADHD criteria for the DSM-V, which is scheduled for publication in 2012.

The APA has identified a number of areas for possible revision, including the lack of validity of the current age-of-onset criterion; the need to adjust symptom description for the age of the patient; the lack of predictive validity of the DSM-IV-TR subtypes (Predominately Hyperactive-Impulsive, Predominately Inattentive, and Combined); the need to account for severity and heterogeneity of symptom presentation; and the overlap between mood and behavior disorder symptoms found in patients who have both ADHD and bipolar spectrum disorders. The committee addressing these issues will also review which DSM-IV criteria are most diagnostically informative in adults and which are redundant when making an ADHD diagnosis in adults. The committee will examine the predictive validity of ADHD criteria across genders, ethnic groups, and developmental stages. Furthermore, the committee will assess reports that suggest that the coexistence of ADHD and conduct disorder in the same child may be a strong predictor of long-term impairment.

Etiology

Although the etiology of ADHD yet has to be determined, there is a growing consensus that the condition involves functional and anatomical dysfunction in the brain's frontal cortex and basal ganglia segments of the cortico-basal ganglia-thalamo-cortical circuitry. These areas support the regulation of attentional resources, the programming of complex motor behaviors, and the learning of responses to reinforcement. Theories involving these areas have been examined in series involving neurobiological studies of healthy humans, humans with ADHD, and animal models. Reviews by Castellanos and Swanson have delineated ADHD's complexity, its theoretical diversity, and the many questions yet to be resolved. The symptoms of ADHD are multidimensional, suggesting the interaction of neuroanatomical and neurochemical systems. The current evidence for the neurobiological factors suggests that genetics and neurochemistry play key roles.

Genetics

Family genetic studies, including twin, sibling, adoption, and family studies, have all suggested that genetic factors play an important role in ADHD.

Twin Studies

Twin studies have shown that monozygotic twins are more concordant for ADHD symptoms of hyperactivity, inattention, and impulsivity than are same-sex dizygotic twins. The concordance rate among monozygotic twins ranges from 59 to 92 percent, whereas the concordance rate in dizygotic twins ranges from 29 to 42 percent. Twin studies suggest that 75 percent of the variance in the transmission of ADHD is attributable to genetics.

Sibling and Half-Sibling Studies

An early study compared the incidence of ADHD symptoms in 29 full-sibling and 22 half-sibling pairs for evidence of minimal brain dysfunction. Each pair had been raised together by a common mother. More than half (10) of the 19 full-sib pairs were concordant for ADHD, compared with only 2 of the 22 half-sib pairs, a significant difference, supporting the genetic influence on the transmission of ADHD in families.

Adoption Studies

Biological relatives of children with ADHD are more likely to have ADHD or associated disorders and perform more poorly on standardized measures of attention than adoptive relatives. In a study of international adoptees aged 10 to15 years, Van den Oord and colleagues estimated that genes accounted for 47 percent of the variance of inattention scores on the Child Behavior Checklist. Eighteen percent of biological relatives of adopted-away children with ADHD were found to be at risk for the disorder versus 6 percent of the child's adopted relatives.

Family Studies

Family studies of children with ADHD are based on the assumption that a genetic component in this condition is reflected in higher rates of the disorder in families of probands versus families of controls. First-degree relatives of children with ADHD have a 20 to 25 percent risk for ADHD, compared with 4 to 5 percent for relatives of controls. If a parent has ADHD, 50 percent of his or her offspring are likely to have that condition. Twin, sibling, adoption, and family studies all suggest a strong genetic component in the development of hyperactivity, inattention, and impulsivity, ranging from 0.6 to 0.98. This leaves questions regarding the role and importance of environmental factors and the mode of inheritance unanswered.

Mode of Inheritance

Several hypotheses of ADHD's mode of transmission have been advanced. G. S. Omenn explored the possibility of sex-linked transmission because of the male preponderance in the condition. Other theories include a polygenetic inheritance model, including those of Morrison and Stewart, but limitations in sample size made this hard to prove. S. H. Rhee and colleagues postulated a polygenetic multiple threshold model after analyzing sex differences in an Australian twin and sibling-pair study. However, differences in fit between genetic models were modest, as is true for comparisons of multifactorial and single-gene inheritance. This led to the suggestion that symptoms of ADHD may be caused by several interacting genes of modest effect. This hypothesis is consistent with ADHD's high population prevalence and high concordance in monozygotic twins but modest recurrence risk for first-degree relatives.

However, diagnostic uncertainty impedes progress in developing genetic models of inheritance. Longitudinal studies of prospectively identified individuals with ADHD and their offspring are the best ways to resolve the methodological problems of family and genetic studies.

Molecular Genetic Studies

There has been increasing interest in attempting to identify the specific genes and the abnormalities associated with their variance that may be implicated in patients with ADHD.

Thyroid Receptor B Gene

Early molecular genetic studies showed that mutation of the thyroid receptor B gene, which causes resistance to thyroid hormone, was associated with high rates (61 percent) of hyperactivity and impulsivity (but not inattention) in affected children and adults. However, only 1 of 2,500 patients with ADHD had this thyroid abnormality, which generally was very rare. Thus, this gene could not be a major cause of ADHD.

Dopamine Type D2 Receptor Gene

Another early gene studied was the dopamine type D2 receptor gene (DRD2). The gene was not specific to ADHD (46.2 percent) but was also seen with increasing frequency in autism (54.5 percent), alcoholism (42.3 percent), and posttraumatic stress disorder (PTSD) (45.7 percent) versus normal controls (24.5 percent). In light of the fact that fewer than half of the ADHD patients had this gene, it was not believed to be a primary cause of the disorder. Rather, it was believed to modify the expression of other genes (making symptoms better or worse). More recently, Rowe and colleagues found no significant linkage between subjects with ADHD and this gene. Similarly, Winsberg and Comings, exploring dopamine genes and their relationship to response to methylphenidate in African-American children with ADHD, found no relationship with the DRD2 gene.

Dopamine Transporter Gene

Cook, Waldman, Gill, and Daly showed an association between ADHD and the dopamine transporter gene 1 (DAT1) with 480–base pair allele. Other studies found no association or evidence of linkage disequilibrium between DAT1 and ADHD. However, the dopamine transport gene remains a promising target for ADHD research.

Dopamine 4 Receptor Gene

Both family-based and population studies have shown a positive association between the dopamine 4 receptor seven-repeat allele gene (DRD4) and ADHD. However, as with the DAT1 gene, the findings are not consistent, and a number of studies have shown negative results and the absence of an association between the DRD4 receptor gene and ADHD. Like the dopamine transport gene, the DRD4 receptor gene holds some promise in clarifying the genetic basis of ADHD. However, these genes may exert their influence in ADHD in combination with other genes and in conjunction with other neurotransmitter systems.

Other Genes

Genes that code for dopamine β-hydroxylase (DBH), the dopamine 5 receptor (DRD5), catechol-O-methyltransferase (COMT), androgen receptors, and factors in immune function and regulation have been reported to correlate with ADHD symptoms but only have been examined in single studies that require replication.

Summary of Molecular Genetic Studies

Most molecular studies that have reported associations between specific genes and ADHD have focused on genes that influence the metabolism or action of dopamine. Positive associations with ADHD symptoms have been replicated most often with the DAT1 and DRD4 seven-repeat allele genes. However, these positive associations are not limited to ADHD but occur with other conditions as well and so are not specific to ADHD. Furthermore, for each of these genes, there are studies that do not support the association with ADHD.

Neuroanatomical Aspects

Investigators have postulated the presence of an anterior attention network for promoting multiple aspects of attention, including focusing, executing, sustaining, and shifting functions. The attention networks are widespread through the cortex of the brain and are closely related to the default mode network described by Castellanos and others. Mirsky and Castellanos described neuroanatomical correlations for the superior and temporal cortices with the focusing of attention; external parietal and corpus striatal regions with motor executive function; the hippocampus with the encoding of memory traces; the prefrontal cortex with the act of shifting from one salient stimulus to another; and brainstem areas such as reticular thalamic nuclei with the sustaining of attention.

Hechtman's review of magnetic resonance imaging (MRI), positron emission tomography (PET), single emission computed tomography (SPECT), and functional MRI studies suggested decreased volume and activity in prefrontal areas, anterior cingulate, globus pallidus, caudate, thalamus, hippocampus, and cerebellum in children with ADHD. These findings are supported by morphological studies of Castellanos and colleagues.

Neurotransmitters in ADHD

Certain brain areas have been associated with specific neurotransmitters—for example, the caudate nucleus and corpus striatum with dopamine and the median raphe with serotonin. Even so, neuroanatomical studies of neurotransmitters have proven to be very complex because these neuroanatomical regions of interest receive projections from multiple nuclei and neurotransmitter pathways, confounding theories that posit dysfunction in a single neurotransmitter system as the etiology of ADHD. However, for clarity, each neurotransmitter system is discussed separately in what follows.

Dopamine System

The efficacy of stimulant medications in the treatment of children with ADHD suggests that medication may affect brain systems involving catecholamines. Molecular genetic studies have targeted genes that code for dopamine receptors, the DRD4 genes, and the gene that controls extracellular dopamine concentrations, the dopamine transporter (DAT) gene. Stimulant drugs bind strongly to DAT and compete with dopamine molecules at the DAT site to prevent reuptake of dopamine back into the presynaptic axon for metabolism. PET scans in adults with ADHD have provided imaging data that correlate stimulant-driven increases in dopamine concentration with binding of DAT by methylphenidate.

Noradrenergic System

Children with ADHD display inattention, cognitive deficits, and higher levels of gross motor activity. Dysfunction in brain norepinephrine systems, particularly a lack of inhibition of locus coeruleus neurons, could explain these clinical findings. One review of plasma and urinary epinephrine concentration in children with ADHD compared to non-ADHD children suggested an imbalance in the ratio of epinephrine to norepinephrine, with epinephrine being much lower than normal. Randomized clinical trials have suggested that tricyclic antidepressants (TCAs) and atomoxetine are potent norepinephrine reuptake inhibitors (NRIs), perhaps restoring a more normal ratio of epinephrine and norepinephrine.

Serotonergic System

There is weak evidence for serotonin's role in ADHD. Some medications, such as tricyclic TCAs and monoamine oxidase inhibitors (MAOIs), that have limited efficacy in ADHD also affect serotonin pathways. However, medications that exclusively affect serotonin function—for example, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine—have no efficacy in the treatment of children with ADHD. For that reason, serotonin is thought to play a secondary role in the pathology of ADHD.

Nonspecific Catecholamine Hypothesis

The nonspecific catecholamine hypothesis of ADHD posits that the psychophysiology of ADHD symptomatology emerges from an imbalance among various neurotransmitters, including norepinephrine, epinephrine, and dopamine.

Environmental Factors

High lead exposure and maternal smoking have been associated with higher rates of diagnosis of ADHD. However, it has been difficult for investigators working with children affected by adversity to determine whether their ADHD symptoms reflect a response to negative parenting, a harsh environment, a genetically influenced biological problem, or some interaction among these factors. Only with further multifaceted prospective research, such as the Centers for Disease Control and Prevention/National Institutes of Health National Children's Study in the United States, will there be a clearer, more comprehensive understanding of the possible etiology, natural history, and treatment of ADHD.

Diagnosis and Clinical Features

Most children with ADHD are referred for care because of impairment in academic, family, and/or peer relationship functioning. Symptoms of impulsivity, overactivity, and inattention drive this impairment across the lifespan. Although the symptoms of gross motor overactivity decreases with age, impairment from inattention and impulsivity may continue as the child ages, leading to problems in new domains, such as automobile driving infractions. In addition, the presence of psychiatric comorbidity increases with age, further complicating the clinical picture. Since 1994, the diagnosis of ADHD has been most often made using the DSM-IV criteria, which are outlined in Table 1 below.

Clinical Features

Hyperactivity

Rigorous and reliable activity ratings have been provided in multiple studies using portable actometers. The increases in activity are cross-situational, that is, they are significantly greater for children with ADHD than in control children with no mental disorder. The increase in activity has another characteristic: It does not change with the set demands of the situation. Therefore, children with ADHD are more active in the classroom and less active on the playground compared to age-matched controls. Activity increases occur during sleep as well. The level of gross motor activity usually decreases with age, but fidgetiness and an inner sense of restlessness may continue into young adult life. Attentional Difficulties Attentional difficulties are most often seen in routine settings in which the youth with ADHD must P.3564 sit and carry out tasks that involve repetition under conditions of low levels of reinforcement and external motivation. In these settings, the child with ADHD often fulfills many of the system criteria in DSM-IV associated with inattention, such as showing easy distractibility, inability to sustain attention on task, failure to follow instruction, inability to complete tasks without constant supervision, and forgetfulness in daily routines, not seeming to listen when spoken to, making careless errors on tasks in class, procrastinating, avoiding effortful mental tasks, and losing items necessary for schoolwork.

Table 1  Diagnostic Criteria for Attention-Deficit/Hyperactivity Disorder According to the Text Revision of the Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders
  1. Either (1) or (2):
    1. six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:
      Inattention
      1. often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities
      2. often has difficulty sustaining attention in tasks or play activities
      3. often does not seem to listen when spoken to directly
      4. often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions)
      5. often has difficulty organizing tasks and activities
      6. often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework)
      7. often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools)
      8. is often easily distracted by extraneous stimuli
      9. is often forgetful in daily activities
    2. six (or more) of the following symptoms of hyperactivity impulsivity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:
      Hyperactivity
      1. often fidgets with hands or feet or squirms in seat
      2. often leaves seat in classroom or in other situations in which remaining seated is expected
      3. often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness)
      4. often has difficulty playing or engaging in leisure activities quietly
      5. is often “on the go” or often acts as if “driven by a motor”
      6. often talks excessively
        Impulsivity
      7. often blurts out answers before questions have been completed
      8. often has difficulty awaiting turn
      9. often interrupts or intrudes on others (e.g., butts into conversations or games)
  2. Some hyperactive impulsive or inattentive symptoms that caused impairment were present before age 7 years.
  3. Some impairment from the symptoms is present in two or more settings (e.g., at school [or work] and at home).
  4. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning.
  5. The symptoms do not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychotic disorder and are not better accounted for by another mental disorder (e.g., mood disorder, anxiety disorder, dissociative disorder, or a personality disorder).
Code based on type:
Attention-Deficit/Hyperactivity Disorder, Combined Type: If both Criteria A1 and A2 are met for the past 6 months.
Attention-Deficit/Hyperactivity Disorder, Predominantly Inattentive Type: If Criterion A1 is met but Criterion A2 is not met for the past 6 months.
Attention-Deficit/Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type: If Criterion A2 is met but Criterion A1 is not met for the past 6 months.
Coding note: For individuals (especially adolescents and adults) who currently have symptoms that no longer meet full criteria, “In Partial Remission” should be specified.
Reprinted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; 2000.
Impulsivity

Impulsivity might be seen when the child engages in dangerous activities, yells out in class, or interrupts or intrudes on others during games or conversations. Impulsive behavior might also result in trouble with parents, teachers, or other children, including verbal or physical fights. Children with ADHD might demonstrate overly quick and error-prone performance on standardized tasks, such as the Embedded Figures Test (EFT) or the Matching Familiar Figures Test (MFFT). This tendency also shows up in overly quick responses on school tests, negatively affecting performance because the child cannot take the time to reason out the question systematically but seems forced by internal pressures to respond quickly without thinking.

Associated Factors

Children with ADHD might have areas of impairment that are not listed under the DSM-IV symptom criteria covered exactly by the 18 symptom exemplars of hyperactivity, impulsivity, or inattention. Behavioral Children with ADHD often lack persistence. They become bored with interactive games with peers, and leave such games early before they are finished. They find it difficult to delay gratification. They show variable performance on tasks, which may negatively affect self-esteem.

Cognitive

Children and adolescents with ADHD often show difficulty with time management and do not develop an internal sense of pace in planning tasks. This poor sense of time leads to problems in estimating the actual difficulty of waiting in line, planning how much time a task requires, or even knowing when to come home when out playing with other children.

Deficit of Behavioral Inhibition and Executive Functioning

Lack of behavioral inhibition has been postulated to lead to impairments in motivation, arousal, ability to delay gratification, working memory, and self-regulation of affect. Dysfunction in these areas is said to impair executive functioning, interfering with goal-directed behavior. However, executive functioning problems occur in other psychiatric disorders of childhood, such as depression, and are not specific to ADHD. Neuropsychological tests often used by clinicians tap into but do not totally explain a child's or adolescent's executive functioning. Recent data show that academic functioning is more strongly affected by an impulsive need to get through tests quickly, a deficit closely linked to poor behavioral inhibition rather than poor executive functioning.

Poor inhibitory control has been postulated to lead to impairments in motivation, arousal, delay of gratification, working memory, and self-regulation of affect. This has been assessed in the laboratory using Stop Signal Tasks and the Go-No Go test. Other deficits include greater intraindividual variability of reaction time, cerebellar associated deficits in motor timing, inability to delay response to reward, and possible alternations in synchronization in the cingulate-precuneus default mode network. 

Dysfunction in these areas is said to impair executive functioning, interfering with goal-directed behavior. However, executive functioning problems occur in other psychiatric disorders of childhood, such as depression, and are not specific to ADHD. On any given measure of executive function, less than half of children with ADHD have been found to be impaired. Although findings of executive function deficits can appear in the results of testing children with ADHD, the lack of such deficits does not rule out the disorder. Some neuropsychologists use the Behavior Rating Inventory of Executive Function (BRIEF) as part of their evaluation battery, but this measure has not been used in a prospective manner to assess the effect of stimulant medications.

Emotional

ADHD is often associated with dysregulation of affect, resulting in temper outbursts, mood lability, and reactivity. Moods can change dramatically with no obvious connection with what's going on in the environment. The reaction of others and the consequences of an action are often poorly understood by the individual with ADHD, who has moved on to something else and does not understand what the fuss is about.

Social

Individuals with ADHD may have problems accurately interpreting nonverbal social cues and thus react inappropriately. This is associated with reports from peers, who report these individuals to be intrusive, bossy, and insensitive to the needs of others. There is trouble cooperating with other children and following rules in games. Children with ADHD often have strong reactions, overreacting to situations that can be predictably triggered by others, leading to teasing and ridicule. Their tendency to respond to frustration in social situations can lead to verbal or physical aggression, a strong stimulus for peer rejection, which has been shown to be a reliable long-term negative predictor of development, particularly in adolescence.

Pathology and Laboratory Examination

Children with ADHD should be given a medical evaluation, with a thorough history and physical examination, to rule out physical disorders that can mimic the symptoms of ADHD. The medical examination also identifies other physical problems that increase the risk of serious adverse events should a stimulant medication treatment be initiated to treat the ADHD symptoms. The medical history should cover the prenatal, perinatal, toddler, and preschool phases of development. Inquiries about pregnancy complications, such as maternal illness (eclampsia, diabetes), maternal smoking, alcohol, or illicit drug use, need to be made. The perinatal period should identify the presence of labor problems, delivery complications, prematurity, jaundice, and low birth weight. Feeding and sleeping routines during the perinatal and postnatal periods need to be described. Developmental milestones, illnesses, injuries, and symptomatology need to be reviewed. Medical problems that might aid in the differential diagnosis, such as petit mal epilepsy, hearing and vision difficulty, thyroid dysfunction, and hypoglycemia, all need to be ruled out. Exploration of cardiac status needs to be carried out, as well as monitoring of height and weight at baseline for possible future medication treatment.

Differential Diagnosis

One must make a differential diagnosis when judging whether a patient meets criteria for ADHD. In addition, the distinction between differential diagnosis and comorbidity is not well defined in the DSM-IV-TR. If the impairing condition is best accounted for by another disorder, that other disorder rules out ADHD. However, with symptoms present from both disorders, both conditions may coexist and be comorbid. The DSM-IV only excludes two conditions from the list or allowed comobidities, namely-pervasive developmental disorder and bipolar disorder in youth.

With children younger than the age of 6 years, it might be hard to distinguish symptoms of ADHD from age-appropriate overactivity in active but otherwise normal children. For children with mental retardation, inattention may be a natural accompaniment of the intellectual limitations, so the diagnosis of ADHD should only be applied if that symptom is excessive for the mental age of the child. Children from chaotic, disorganized, or inadequate home environments may also show symptoms of overactivity or inattention. The symptoms of children with oppositional defiant behavior must be distinguished from the reluctance and resistance that children with ADHD exhibit when they avoid effortful mental tasks. One should not diagnose if the symptoms are better accounted for by another disorder, such as mood disorder, dissociative disorder, personality disorder, or substance-related disorder. In these other disorders, the symptoms of inattention come on much later than the age of 7 years, and the previous behavior in the first two grades of elementary school is not reported to be disruptive. Symptoms of impulsivity, gross motor hyperactivity, or inattention may appear during the use of medications, such as the akathisia that accompanies second-generation antipsychotics or from bronchodilators. Such children should not receive a diagnosis of ADHD, but one of Other Substance-Related Disorder Not Specified.

Some large multisite clinical trials, such as the MTA study, did not exclude children with comorbidities. They reported that more than two thirds of the children referred had at least one other Axis I psychiatric disorder qualifying as a comorbid condition. Other studies found that the number and severity of the comorbid conditions increase with age. Because of bias in data gathering, much higher rates of comorbidity occur in referred samples than in those gathered using epidemiological techniques. Thus rates of co-occurring disorders vary with the patient's age, sex, and source of identification.

ADHD and oppositional defiant disorder is the most frequently reported comorbidity found in the NIMH MTA study, occurring in 50 percent of the 579 children ages 7 to 9 years who were enrolled. Other comorbid conditions occurred less frequently in those ADHD patients, including anxiety disorder (34 percent), conduct disorder (14.3 percent), and depression (4 percent). The rates of conduct and mood disorder were lower than reported in other clinically referred samples and may have been a result of the younger age of the MTA children (e.g., 7 to 9 years versus the 6 to 12-year range in other ADHD studies). The MTA subjects may not have yet developed the conduct disorder or depression seen in older children with ADHD.

Some outpatient research clinics for children with ADHD have reported 15 percent rates of comorbid bipolar disorder. Bipolar disorder has been reported to begin at or around age 10 years, much earlier than the peak age of admission to hospital, that is, age 20 years. On the other hand, the NIMH MTA study found no child that met its exclusion criterion of having both ADHD and bipolar disorder. Some critics have cautioned that ADHD and bipolar disorder have overlapping symptom pictures, and that some studies have not required euphoria or episodicity in the children diagnosed with bipolar disorder. Studies that used adult bipolar disorder inclusion and exclusion criteria were said to be adhering to the “narrow phenotype,” whereas those studies that used persistent impairment and irritability as inclusion criteria for bipolarity were said to be using the “broad phenotype.” Prospective studies of the “narrow phenotype” and “broad phenotype” have shown that children diagnosed with the “narrow phenotype” are more likely to develop full-blown bipolar disorder in adulthood than those with the “broad phenotype.” However, the controversy of diagnosing child bipolar disorder in young children continues.  

Course and Prognosis

Parents often notice very high levels of gross motor activity when the child with ADHD is a toddler, just when the child has learned to walk independent of the parent's help. However, the energy, oppositionality, and curiosity of toddlers can be confused with the excessive, almost random motion of older children with ADHD, so that one must be cautious when applying the ADHD diagnosis to a preschooler. Usually, the ADHD diagnosis is first applied in primary school, during grades 1 to 6, when adjustment to the sedentary learning style is compromised. The motor and attentional symptoms and impairment create a consistent picture through early adolescence, when often the external overactivity lessens but the internal restlessness does not. Whereas the school-age child is mostly at risk for academic failure and peer rejection, the adolescent with ADHD who is untreated has other risks in excess of peers with no mental disorder, including a threefold increase in substance use and abuse, trouble with the law, and an increased rate of automobile accidents when the teenager begins to drive. Approximately 60 percent of those who develop childhood ADHD continue to be impaired well into adult life, with prevalence estimates suggesting that 4 percent of adults may suffer from ADHD. These individuals may show instability in job status and relationships, even if the numbers of ADHD symptoms do not meet the threshold required for the childhood diagnosis.

Treatment

Stimulants

Amphetamines and methylphenidates are two groups of stimulant medication that have received U.S. Food and Drug Administration (FDA) approval for the treatment of youth with ADHD. They are marketed in both immediate release (IR) and long-acting preparations and can be purchased as either generic or branded versions. Since 2000, multiple stimulants have been marketed with FDA approval for ADHD treatment, including long-duration mixed salts of amphetamine, dexmethylphenidate, osmotic-release methylphenidate, the prodrug lisdexamfetamine, and beaded methylphenidate. All of these products include either amphetamine or methylphenidate as the active ingredient. These chemicals structurally resemble the catecholamine neurotransmitters dopamine (DA) and norepinephrine (NE). All can be described as psychostimulants, which refers to their ability to increase central nervous system activity in brain regions (Table 2 below).

Psychostimulants share the ability to reduce gross motor overactivity, increase sustained attention on tasks, and reduce impulsive responding on laboratory measures. These characteristics have been shown in more than 200 short-duration, double-blind, placebo-controlled clinical trials involving patients with ADHD across a wide age range, including preschoolers, school-age children, adolescents, and adults. Typically, more than 70 percent of school-age children with ADHD respond to psychostimulants; some respond preferentially to methylphenidate, whereas others respond preferentially to the amphetamines. Thirteen percent respond to placebo. Greater effects occur in behavioral domains than in cognitive areas.

Pharmacology and Pharmacokinetics

Methylphenidate (MPH) and amphetamine are members of the catecholamine psychostimulant medication family and increase the concentration of dopamine in the synapse by binding to the dopamine transport protein. Berridge et al. showed that in vivo microdialysis of low-dose MPH in rodents substantially increased norepinephrine and dopamine reflux within the prefrontal cortex (PFC) while enhancing PFC-dependent cognitive functioning.

Immediate-release stimulants are rapidly absorbed, reaching maximal concentration in plasma (Cmax) within 90 to 120 minutes, which parallels the increasing concentration of extracellular synaptic dopamine. Due to first-pass effects in the gastrointestinal tract, the circulating plasma concentrations of dextro-methylphenidate (d-MPH) are much higher—and thus more potent for reducing ADHD symptoms—than are the molecule's levo isomer (l-MPH). With regard to just the dextro isomers, dextroamphetamine (d-AMP) is 1.5 times more potent, milligram for milligram, than is d-MPH. Another popular product—mixed salts of amphetamine (MAS)—is marketed as Adderall, and combines four different salts of amphetamine, including both d-AMP and l-AMP. One small study showed that there are no efficacy differences between d-AMP and MAS.

Table 2  Stimulant Drugs, Doses, and Pharmacodynamics
Medication Forms Pediatric Dose, Start/Typical Peak Effect (hrs) Duration of Action (hrs)
Dexmethylphenidate
Short-acting 2.5-, 5-, 10-mg tabs 2.5 mg AM/10 mg b.i.d. 1–4 5–6
Long-acting 5-, 10-, 15-, 20-mg caps 5 mg AM/10 mg AM 1–4 12
Dextroamphetamine
Short-acting 5-, 10-mg tabs 5 mg b.i.d./10 mg b.i.d. 1–3 4–6
Long-acting 5-, 10-, 15-mg caps 5 mg AM/15 mg AM 1–4 6–8
  20-, 30-, 40-, 50-, 60-, 70-mg caps 30 mg AM/70 mg AM 2–3 up to 12
Methylphenidate
Short-acting 5-, 10-, 20-mg tabs 5 mg b.i.d./10 mg t.i.d. 1–3 3–5
  2.5-, 5-, 10-mg chewable tablets 5 mg b.i.d./10 mg t.i.d. 1–2 3–5
  5 mg/5 mL, 10 mg/5 mLb oral solution 5 mg b.i.d./10 mg t.i.d. 1–3 3–5
Immediate-acting 20-mg tabsc 20 mg AM/40 mg AM 3 3–8
  10-, 20-mg tabsc 10 mg b.i.d./30 mg AM 3 3–8
Long-acting 10-, 20-, 30-, 40-, 50-, 60-mg tabs 10 mg AM/30 mg AM 5 8–12
  10-, 20-, 30-, 40-mg caps 10 mg AM/30 mg AM 5 8–12
  18-, 27-, 36-, 54-mg tabsc 18 mg AM/36 mg AM 8 10–12
  10-, 15-, 20-, 30-mg transdermal patchd 10-mg patch on 9 hrs, off 15 hrs
30-mg patch on 9 hrs, off 15 hrs
7–9 10–12
Mixed salts of amphetamine
Short-acting 5-, 7.5-, 10-, 12.5-, 15-, 20-, 30-mg tabs 5 mg b.i.d./10 mg b.i.d. 1–3 4–6
Long-acting 5-, 10-, 15-, 20-, 25-, 30-mg caps 5 mg AM/30 mg AM 1–4 8–10
b.i.d., twice daily; t.i.d., thrice daily.
aShould not be taken with antacids or other drugs that decrease gastric acidity.
bAvailable in bottles containing 500 mL.
cMust be swallowed whole, not crushed or chewed.
dThe four patch sizes deliver 10-, 15-, 20-, and 30- mg over 9 hours, respectively, supplied in sealed trays containing 10 to 30 patches in individual pouches.

More than a decade has passed since a number of new long-duration stimulant preparations were approved by the FDA for use in school-age children, adolescents, and adults. One osmotically released MPH (OROS-MPH, or Concerta) formulation uses racemic methylphenidate that releases the stimulant in an ascending dose curve over an 8-hour period. Pharmacokinetic (PK) studies carried out using repeated pharmacological and behavioral measures in a laboratory classroom (the Irvine Laboratory School Protocol) show that OROS-MPH, compared to another version of long-duration d-MPH (beaded d-MPH, or Focalin XR) shows significant ability to reduce ADHD symptoms as long as 12 hours after oral dosing. Similar comparisons have been carried out with OROS-MPH and another long-duration, beaded racemic methylphenidate product, Metadate CD, and OROS-MPH, showing the same greater ability of the beaded product to reduce ADHD symptoms in the first few hours but showing less effectiveness than OROS-MPH at 12 hours.

Although absorption of MPH products is generally not affected by foods, some long-duration preparations of d-AMP show decreased concentrations with high-fat foods. Whereas MPH is metabolized in the gut wall and plasma by esterases, the metabolism of d-AMP and MAS takes place in the liver. Urinary excretion of AMP metabolites is increased by foods of acidic content (vitamin C and orange juice), thus lowering plasma concentration. Conversely, foods that shift urinary pH higher reduce excretion and thus increase the plasma concentration of d-AMP or MAS.

Efficacy

Efficacy studies of stimulants consistently show high numbers of children who are responders: The MTA study found that 77 percent responded to MPH, and an additional 10 percent of MPH nonresponders responded to d-AMP. Effect size was 0.8 to 1.0 standard deviation (SD) on behavioral measures and 0.5 SD for cognitive measures for those children randomized to active drug. Placebo response rates in controlled studies have tended to be low, generally less than 20% of those randomized to that condition.

Cognitive Effects

Stimulants have been shown to improve vigilance and reaction time and reduce variability, short-term memory, and learning of verbal and nonverbal material in children with ADHD. The MTA Titration Trial showed a linear dose–response curve for behavioral measures between 0.5 and 1.0 mg/kg per day. Although earlier studies showed no long-term academic benefit from stimulant treatment, recent controlled trials revealed improvements in school-based productivity and accuracy in children with ADHD consistently treated with stimulants.

Behavioral Effects

Psychostimulant medications have been shown to reduce gross motor overactivity, out-of-seat behavior, calling-out behavior in the classroom, disruptiveness, impulsive behavior, and noncompliance while improving peer nominations of the child with ADHD, self-perception, and mother–child interaction.

Treatment of ADHD Comorbidities

Tic Disorder

Stimulants, either alone or in combination with clonidine, reduce symptoms of ADHD in individuals with both ADHD and Tourette's syndrome. Even so, tic frequency and severity increase in one third of those patients. There have been rare reports that the appearance of or increase in frequency of tics may not stop when the psychostimulant is discontinued. Thus, careful titration and monitoring of stimulant medication are recommended in children with these comorbidities.

Seizure Disorder

Children with seizure disorders may also suffer from ADHD. Although there are concerns about psychostimulants, particularly MPH, lowering the seizure threshold, experiencing a first seizure when starting a psychostimulant is extremely rare. Studies of EEG epileptiform activity, seizure rates, or interactions between antiepileptic drugs (AEDs) and psychostimulants have not shown any additional seizure risk. On the contrary, studies have shown that children with ADHD and a seizure disorder that is adequately controlled on an AED show reduced ADHD symptoms and no change in seizure frequency.

Aggression and Conduct Disorder

Children with ADHD and comorbid conduct disorder have been shown to improve on standard doses of methylphenidate in a randomized, controlled trial. Stimulants also reduced negative social interactions and covert antisocial behavior (stealing and vandalism but not cheating). The short- and long-term consequences of these reductions are important because continued conduct disorder and antisocial behavior predispose to later drug and alcohol abuse and generally more negative outcomes.

Anxiety Disorder

Some studies have suggested that children with ADHD and comorbid anxiety disorder are less responsive and experience more side effects to stimulant medication than children with ADHD alone. More recently, the MTA study's randomized, controlled trial found that children comorbid for ADHD and parent-reported anxiety disorder were as responsive as children with ADHD alone. The MTA's careful, slow titration may have resulted in fewer side effects and better response in this cohort, with analyses showing that comorbid anxiety disorder does not moderate the response to psychostimulant treatment.

Mood Disorder

It has also been suggested that children with ADHD and comorbid depression benefit less from stimulant medication than children who have ADHD alone. Again, the MTA study failed to show that the presence of either comorbid depression or bipolar disorder in the children with ADHD moderated the response to psychostimulants or the level of adverse events reported. Small numbers of open case studies have failed to show any liability for children with comorbid ADHD and bipolar disorder, but more research is needed. Generally, it is suggested that patients comorbid for ADHD and bipolar disorder be stabilized on mood stabilizers before stimulants are introduced.

Developmental Disorders

ADHD-like symptoms of inattention and hyperactivity are seen in children with mental retardation and autism spectrum disorders (ASDs). Stimulants have been shown to be beneficial in both groups, particularly in those children with IQs greater than 50. One recent randomized, controlled trial found that MPH was more effective than placebo in reducing symptoms of ADHD in children with autism. However, these populations may also be more susceptible to the adverse events of psychostimulants, such P.3568 as stereotypy, fearfulness, agitation, and delusions. For those children with combined ASD, ADHD, and severe irritability, the psychostimulants may need to be combined with low-dose second-generation antipsychotic medications, such as risperidone.

Adverse Effects

Short-Term Adverse Effects

Several reviews by Russell Barkley, Rachel Klein, and L. Greenhill focused on side effects of stimulant medication. Most of the short-term side effects of stimulants can often be dealt with by changing the time or dose of medication, or both.

Common side effects include decreased appetite, weight loss, delayed onset of sleep, headaches, stomachaches, and increases in blood pressure and pulse. Preschool children can experience increased irritability and crying.

Infrequent side effects include motor tics, the unmasking of Tourette's syndrome, and late withdrawal effects, sometimes called rebound. Rebound overactivity, impulsivity, and inattention have been defined as being more severe than reported at baseline off medication. They may occur in the late afternoon or early evening. They have been reported by parents to occur in up to one third of children and vary from day to day. Of interest, attempts to demonstrate their presence in full-day, laboratory classrooms have been unsuccessful, so these effects may be subject to interaction with changes in the child with ADHD's environmental setting. Long-acting psychostimulant preparations and added small doses of immediate-release medication before onset of the rebound usually result in adequate management.

Stimulants rarely produce visual and tactile hallucinations, depressed mood, symptoms of obsessive-compulsive disorder, choreiform movements, and self-directed behavior, such as lip licking, nail biting, and rubbing of sores. These are all indications to discontinue the medication until the adverse event disappears.

Recently, the American Heart Association has recommended that children have electrocardiograms before they are started on stimulant medication to rule out possible undetected structural and/or conduction problems. The American Academy of Child and Adolescent Psychiatry and the American Pediatric Society have both agreed that given the delay in treatment in which these investigations might result and the relative infrequency of positive findings, investigation can occur after treatment has started.

Pemoline (Cylert) is no longer used as a treatment for ADHD because of reports of liver failure resulting in death or the need for transplants.

Long-Term Adverse Events

Effects on Growth

Two large-scale NIMH-supported randomized, clinical trials have shown that methylphenidate can reduce the rate of height and weight gains in developing children with ADHD. This suppression effect, which may be dose related in some children, has been more pronounced in those children treated with d-AMP and occurs predominately in the first year of treatment. Overall effects on adult height and weight have not been reported. These effects on growth are thought to be secondary to appetite suppression and reduction of caloric intake. Small, single-site studies are discordant concerning whether psychostimulants suppress human growth hormone (HGH). The two main practice parameters for the treatment of children with ADHD recommend that clinicians regularly monitor height and weight of children with ADHD treated chronically with psychostimulant medication. In addition, clinicians are encouraged to institute drug holidays during summer vacations to increase the probability of growth rebound.

Substance Abuse

One controlled, large-scale prospective study showed no evidence that ADHD per se or that stimulant treatment of children with ADHD increases the risk of later substance abuse. In fact, two open retrospective studies suggested that patients treated with stimulants in childhood are less likely to subsequently have substance abuse.

Summary of Stimulant Medication

Long-duration stimulant treatment—with OROS-MPH, MAS, or beaded d-MPH—of children with ADHD is both effective and safe. Once-daily administration in the morning by parents provides reduction of ADHD behaviors during the 8-hour school day. Many adverse events can be handled by adjustment of dose and/or the time of administration of the medication. Long-term adverse events such as growth rate suppression concern parents but can be managed by instituting drug holidays to permit growth rebound. Stimulant medication of children with ADHD has not been shown to increase their risk for involvement with drugs of abuse during later development. However, as many as 20 percent of children with ADHD experience adverse events or stimulant nonresponse. Other medications need to be considered for this subgroup of children.

Nonstimulant Medication in the Treatment of Children with ADHD

Whereas psychostimulants constitute the first-line treatment for children with ADHD, other medications need to be used for nonresponders or those who experience moderate to severe adverse events. Although the nonstimulant atomoxetine has been approved by the FDA for the treatment of children and adolescents, off-label medications for ADHD treatment—for example, TCAs, bupropion, clonidine, and guanfacine—have been used, although they are less efficacious than the approved medications. Although off-label treatments might have worrisome adverse events—such as seizures with doses of bupropion greater than 400 mg per day—these medications have a longer duration of action and do not produce psychostimulant effects such as behavioral rebound or delay of sleep onset.

Atomoxetine HCl

Atomoxetine is a norepinephrine reuptake inhibitor (NRI). Its putative mechanism of action is thought to involve selective inhibition of the presynaptic norepinephrine transporter. Atomoxetine (ATX) is well absorbed after oral administration and is minimally affected by food. High-fat meals may decrease the rate of absorption. Maximum plasma concentrations are reached approximately 1 to 2 hours after ingestion. Ninety-eight percent of circulating ATX is bound to plasma protein, mainly albumin. ATX is dosed by weight, with randomized clinical trials (RCT) showing no benefit from exceeding total daily doses of 1.4 mg/kg.

ATX has been shown to reduce ADHD behaviors in children, adolescents, and adults. Common adverse events involve abdominal discomfort, nausea, decrease in appetite, slowdown in the rate of weight increases, sedation, daytime sleepiness, dizziness, vertigo, irritability, and mood swings. Sexual side effects have also been reported. Increased suicidality and liver toxicity, although rare, have been noted. Daytime sleepiness and gastrointestinal tract problems may be diminished by titration to full dose over 1 week in twice-daily dosing. Minor increases in blood pressure and pulse have been reported. Thus, weight, height, blood pressure, and pulse should be regularly monitored.

ATX is metabolized by the cytochrome P450 (CYP) 2D6 hepatic enzyme system, resulting in a half-life of approximately 5 hours. Even so, the effects of once-daily or twice-daily dosing may last for the full 24-hour period, so pharmacodynamic factors play a large role in its duration of action. A fraction of the population (approximately 7 percent of whites and 2 percent of African Americans) are poor metabolizers of CYP 2D6–metabolized drugs. Such individuals may experience elevated plasma concentrations—up to fivefold—and plasma half-life might extend to 24 hours. Alternatively, very slow initial titration may be required to prevent excessive dosing of these patients. Patients taking other medications metabolized by CYP 2D6, such as fluoxetine (Prozac), paroxetine (Paxil), and quinidine (Cardioquin), might show signs of competitive inhibition, namely increased plasma levels of both ATX and the competing drug.

One large RCT conducted in Europe compared the efficacy of ATX and MPH. Results of this one trial suggested that MPH provides a greater effect size for ADHD behaviors and is effective in more children with ADHD than is ATX.

Tricyclic Antidepressants

Spencer reviewed 29 studies of children and adults treated with TCAs—imipramine, desipramine, and nortriptyline but not clomipramine—and found significant reductions in ADHD symptoms in 22 of the studies. Patients unresponsive to one TCA may respond to another. This response differs from that reported for depression, for which adolescents do not respond to TCAs any better than to placebo.

Generally, lower doses of TCAs are used in treatment of ADHD versus depression—generally 3 mg/kg per day for ADHD versus 5 mg/kg per day for depression. Plasma level guides for depression are much too high for use in children with ADHD.

Adverse Events of TCAs

Cardiovascular (CV) adverse events are the most serious adverse events of these medications and are thought to explain why these medications are rarely used in children with ADHD. Several cases of sudden death have been reported in children taking TCAs. CV adverse events include the slowing of cardiac conduction, increasing the electrocardiographic reading of the PR and QRS intervals. For that reason, many clinicians monitor the PR interval and do not enroll patients in the treatment if that interval exceeds 0.2 second. Such slowing increases the risk of cardiac arrhythmias and heart block. Although TCAs have not proven to be the cause of these deaths, electrocardiograms at baseline and after each dose adjustment need to be taken in routine monitoring of the PR interval.

Other side effects might be commonly experienced. These include cholinergic side effects, such as constipation, dry mouth, or blurred vision. To minimize side effects, TCAs are given to children and adolescents in divided doses. One begins with 10 mg per day and increases up to 25 mg twice a day for adolescents. The dose can be increased by similar amounts every 2 weeks to a maximum daily dose of 3 mg/kg. When discontinued, TCAs should be tapered over several weeks.

The fact that TCAs are less effective than stimulants for ADHD and have a much more serious side effect profile (with fatigue, sedating, and CV side effects) have made them much less popular with patients and clinicians.

Contraindications

TCAs should not be used in patients with a history of cardiac conduction problems or in conjunction with MAOIs. TCAs might lower the seizure threshold, so they should be used with great caution in patients with seizure disorder.

α-Adrenergic Agents

Clinicians use α-adrenergic agents in the treatment of ADHD, often in combination with stimulants, even though the use is not FDA approved. The medications are approved for the management of hypertension in adults. They include immediate-release clonidine (Catapres) and guanfacine (Tenex). Recently, Shire pharmaceuticals received an approval letter for a long-duration formulation of guanfacine, so the medication may become available for the treatment of ADHD. Several meta-analyses of these medications have suggested a weak to moderate effect size, clearly less efficacious than the psychostimulants. However, a small multisite, double-blind, RCT showed that children and adolescents comorbid for ADHD and Tourette's syndrome benefited from clonidine alone or in combination with MPH, in both case significantly better than placebo. A large multisite trial showed that a preparation of long-duration guanfacine was significantly more effective in treating ADHD than was placebo.

Clonidine is very sedating and has been used to treat sleep difficulties of children with ADHD, as well as to offset the delay in sleep onset caused by stimulant medications. It is initiated at low doses, 0.05 mg at bedtime. If daytime sedation becomes a problem, clonidine needs to be discontinued. At very low doses the effect on blood pressure and pulse is minimal, so that total daily doses greater than 0.3 mg are not recommended. Clonidine needs to be discontinued very slowly to prevent rebound adrenergic overdrive, with hypertension, agitation, fever, headache, tachycardia, chest pain, sleep disturbance, nausea, and vomiting. This can create a problem if a family goes on holiday and the parents forget the child's medication. Potential cardiac effects and a handful of deaths from the combination of clonidine and stimulants have raised concerns and have resulted in the recommendation that clonidine not be used in the presence of preexisting cardiac or vascular disease.

Guanfacine is slightly less sedating than clonidine and so may be tried if sedation with clonidine is a significant problem. It is used in higher total daily doses than clonidine, between 1 and 3 mg.

Bupropion

Bupropion is a non-TCA antidepressant that has shown efficacy in ADHD but is less effective than TCAs or stimulants. It is available in extended-release preparations (Wellbutrin SR, Wellbutrin XL) that permit once-daily dosing. It might be more effective in adolescents than in children and is not recommended for children. Starting dose for young adolescents is 75 mg twice a day to a maximum of 200 to 300 mg per day. The doses can be increased once weekly until improvement is noted. Side effects of bupropion include fatigue, dry mouth, insomnia, headaches, nausea, vomiting constipation, tremor, and skin rash. Seizures will reliably occur if the adolescent's dose exceeds 400 mg per day. This medication is FDA approved for the treatment of depression and smoking cessation but not ADHD in individuals older than 18 years of age.

Other Alternative Medications

Anticonvulsants, including carbamazepine (Tegretol), lithium (Eskalith), SSRIs, and second-generation antipsychotic medications such as aripiprazole (Abilify), have not been shown to be effective for primary symptoms of ADHD. Modafinil (Provigil) was shown to be effective in one double-blind, placebo-controlled RCT but failed to achieve FDA approval because of a severe Stevens-Johnson skin rash that might have occurred in one patient. In summary, then, these medications might be useful in treating some comorbid conditions that children with ADHD often have.

Summary of Medication Treatments

In general, most children with ADHD respond to stimulant medication, which remains the first-line treatment choice for the condition. However, if stimulants are ineffective, practice parameters first suggest turning to ATX. This serotonin-norepinephrine reuptake inhibitor has been shown to be effective in ADHD and provides an approved alternative to stimulants. Detection of slow CYP 2D6 hepatic enzyme “poor metabolizers” and/or careful, slow initial titration should be conducted with this medication. Alternatively, one can combine a stimulant medication that shows only partial response with an off-label medication. If the child shows severe adverse events on stimulants, off-label medications can be tried. One must keep in mind that bupropion is less effective than either the TCAs or stimulants and carries a risk of seizures at high doses. Clonidine and guanfacine are sedating and have significant CV side effects. For all these drugs, careful monitoring and slow, cautious discontinuation are essential. Most clinicians do not use TCAs for the treatment of ADHD because of the risk of sudden death.

Psychosocial Treatment of Children with ADHD

Psychosocial treatment of children with ADHD refers to nonmedication treatment. This type of treatment includes different modalities, such as psychoeducation, academic organization skill teaching and remediation, parent training, behavior modification, cognitive–behavioral therapy (CBT), social skills training, and individual therapy. Of these modalities, parent training, intensive behavior modification, and social skills training have shown efficacy for children with ADHD in controlled trials.

Among nonpharmacological treatments, direct contingency management uses systematic manipulation of punishments and rewards, often in specialized settings. Although it can produce impressive effects on behavior and performance in the classroom, its effects tend not to generalize or be maintained outside of the settings in which they are applied. In addition, published outcomes are achieved through single-case designs. In the field, behavior therapy often is carried out in consultation with teachers and parents regarding in-school and home management. Published trials often depend on parent and teacher ratings of improvement but do not include independent evaluators. Although controlled studies of systematic combinations of direct contingency management plus intensive behavior therapy have yielded significant improvement, effect sizes of clinical change are smaller than those found with stimulant medication.

Intensive behavioral interventions are based on a number of principles. These begin with psychoeducation about the course, risk factors, and long-term outcomes of ADHD. Second, the parents are encouraged to attend more carefully to their child's behavior, particularly when the child complies. Third, the parents are trained to use time out effectively. Fourth, the parents are instructed in establishing a contingency management or token economy system at home. Then the parents learn how to manage noncompliant behaviors in public settings. Finally, advances in prosocial behavior in school are supported by use of a daily report card.

It is crucial to evaluate the parents and family for dysfunction related to the child's ADHD. Parental ADHD may interfere with behavioral modification programs, indicating that treatment of the affected parent may be necessary before the child's intervention can be successful. Other dysfunctions might be present in the family as well, such as marital problems, substance abuse, or parental depression.

Behavior modification has been successfully applied to the classroom, with a meta-analysis of 70 studies showing an effect size of 0.6 standard deviation compared to an attention control condition. In contrast, cognitive–behavioral therapy has not been shown to be effective. Practice parameters published for child and adolescent psychiatrists strongly suggest that behavior therapy be added to psychopharmacological treatment if the child is shown to be a partial responder to stimulant medications or exhibits a comorbid psychiatric disorder whose impairment does not respond to the medication.

Multimodal Treatment (MTA Study)

In the last decade, two multisite, RCTs have tried to address the multiple deficits in emotional, social, and academic functioning of children with ADHD via a multimodal treatment approach. The first of these studies was a two-center, NIMH-supported parallel-design RCT involving 103 children with ADHD (age 7 to 9 years) who responded to short-term MPH and were randomized for 2 years to receive one of three treatments: MPH alone, which was well titrated and carefully monitored; MPH plus psychosocial treatment, which included parent training and counseling, social skills training, psychotherapy, and academic skills training and remediation; and MPH plus attentional control treatments, which controlled for the professional attention in the multimodal group but did not provide the specific interventions.

Each of the psychosocial treatments was provided weekly in the first year, with monthly boosters in the second year in the context of a clinic-based after-school program two afternoons a week. Children were assessed through parent, teacher, and psychiatrist ratings and direct school observations in academic and gym classes.

Results showed that all three groups improved significantly in academic, social, and emotional domains. The improvement was seen at 6 months and maintained over the 2 years, even when treatments became less intense in the second year. However, there were no significant differences among the three groups. The authors concluded that for motivated, well-functioning families in which children are not severely comorbid, well-titrated immediate-release MPH (whose optimal dose was determined on an individual basis) given three times a day, 7 days a week resulted in significant improvement in all domains, which was maintained for 2 years.

The second study, the NIMH-supported MTA six-site study, recruited a sample of 579 children with moderate to severe ADHD, combined subtype, ages 7 to 10 years old. After an intensive, detailed, multidomain assessment, children were randomly assigned to one of four parallel treatments for 14 months:

  1. stimulant medication management, involving primarily MPH and d-AMP, which included a 1-month, double-blind, titration trial involving daily switches of doses with five repeats of each of dose, followed by monthly monitoring; (2)
  2. an intensive behavioral, no-medication treatment involving regular teacher consultation, a daily teacher-rated report card rewarded at home by the parents, parent training in groups plus individual parent counseling, a comprehensive 8-week summer treatment program, and an aide in the classroom half-days, 5 days a week for 12 weeks; (3)
  3. a combined treatment group involving both monomodal treatments; and (4)
  4. assessment followed by standard care in the community, which was a variant of treatment as usual.

Outcomes were assessed in 19 different domains that included parents at home, teachers in school, and peer relationships, as well as emotional and academic functioning. At the end of the 14 months, all groups showed improvement. The medication management and combined treatment groups showed significantly greater reduction in ADHD symptoms and impairment than did the intensive behavioral and community care groups. Combined treatment, but not medication management, was superior to community care and intensive behavioral treatment for oppositional and aggressive symptoms, internalizing symptoms, teacher-rated social skills, parent–child relationships, and reading achievement. In addition, protocol-driven medication strategies in the medication management and combined treatment arms were superior to stimulant medication management delivered in the community.

For composite measures assessed during the 14-month active trial, combined treatment was best, followed by medication management, then by behavioral, and finally by the community care group. The presence of comorbid anxiety or single-parent status moderated outcome, showing greater benefit from intensive behavior management over groups that had ADHD alone.

Psychosocial treatment appears to be an important adjunct to medication treatment for children with ADHD. Efficacy for parent training, behavior therapy, and social skills training had been documented separately in other studies, as well as in the MTA study. Family therapy may be beneficial in decreasing family conflict and improving the emotional climate at home.

Individual therapy may help in areas of self-esteem and secondary problems of depression and anxiety. However, the latter interventions have not been rigorously studied. Generally, benefits noted with the ADHD treatments, whether medication management or psychosocial intervention alone, decreased in the MTA study once the full treatment program was discontinued. The significant differences found between the medication and nonmedication arms at the end of the active 14-month study gradually disappeared as the MTA cohort was followed in their community but no treatment was provided by the MTA treatment team. Combining psychosocial treatments with MTA-style medication management while providing behavioral modification booster sessions to maintain treatment gains might prevent relapse and ensure better long-term outcome, but this remains to be tested.

Specific Case of Childhood ADHD

Identifying Information

Ben was an 8.5-year-old, second-generation, African-American adopted boy who lived with his parents and an 11-year-old brother. He attended his local public school, was in third grade in a regular education classroom, and received special services including speech, physical, and occupational therapy. His biological mother had abused “crack,” and no information was available about his biological father. His adopting father was a bus driver, his adopting mother worked half-time in a bakery, and they lived in a working-class neighborhood of a moderate-sized city.

Chief Complaint

Ben's parents had heard a public service radio announcement for a study of children “who may be having trouble paying attention.” This ad caught their eye because his teacher had stated that Ben might have ADHD and recommended that the parents should get him evaluated.

History of Present Illness

Ben's adopting parents were drained from the nightly battles over homework and discouraged by his lack of focus and “spaciness.” He seemed unconcerned about his academic success. Even though his adopting parents cajoled, begged, and threatened punishments, he continued to be indifferent. Now in third grade, he demonstrated variability in school performance, achieving grades that range from B to F. His performance in reading was poor.

Since kindergarten, teachers had complained that Ben did “not seem to listen,” had “poor concentration,” and was constantly “out of seat, wandering about.” These teachers also commented on his undirected and unfocused activity in the classroom, plus a style characterized as “daydreamy.” During second grade, when expectations for homework increased substantially, Ben's adopting parents engaged in nightly battles with him about completing school work; they continued to be exasperated by his poor attention, focus, and motivation.

Ben had never had close friends. Other children did not openly dislike him but rather seemed to avoid him because he could not stick with a game or activity for very long. He had become alienated as a result of annoying his peers because he was always “in their space.” He tended to tune out when others were talking. In group activities, the leaders constantly had to prompt him to make eye contact and stay on task, which bothered the other children in the group.

Past Psychiatric History

As noted, Ben had had difficulty with daydreaming and wandering about since kindergarten. His inattention and impulsivity put him in danger and caused injury. He had run into traffic on several occasions, even after being hit by a truck with resulting injuries. Three months before his referral he had run into a wall, suffering a scalp laceration that required 10 stitches. He had developmental coordination disorder, expressive and receptive language disorder, and subthreshold signs of conduct disorder, including touching girls inappropriately and playing with “his own sex parts in public.”

Medical History

Ben had suffered several upper respiratory infections at age 2 years, some of which had been quite protracted, requiring several rounds of antibiotics.

Developmental History

Although his drug screen at birth was negative, Ben's biological mother was said to have used crack and methadone during her pregnancy. Some motor delays were reported, with crawling by 1 year and walking by age 2 years. By age 3½ years, when he was evaluated for preschool, his expressive language had improved, but he still was behind his peers in fluency. He demonstrated difficulties with following multipart directions, even though his hearing tested in the normal range. His preschool teachers reported awkwardness of gait; this issue showed improvement over time.

Mental Status Exam

Ben presented as a cute, well-developed boy who easily separated from his mother for the interview and was related but tended to avoid eye contact when he was asked about his school or homework situations. No gross neurological signs were present. Speech was normal rate and fluent, with no articulation errors. His sensory, perceptual, and cognitive functions were intact. Yet there were occasional delays in his verbal response to the clinician's questions, as if there was some delay in processing as one might see in a child with receptive language problems. Although eager to please, Ben was distractible, fidgety, and restless during the interview. He wanted to run out of the room on several occasions. No evidence was manifested of tics or other abnormal movements. There was no evidence of a thought disorder, and his comments were coherent and logical. Affect was euthymic. He appeared mostly happy, but was appropriately reactive when asked about his frustration with academics.

The initial evaluation included the obtaining of parent and teacher rating scales, a developmental history from the parents, a structured interview with them, and an examination of Ben, which included a brief office neurological exam, as well as cognitive and attention testing.

Rating Scales

Ben's parents and his third-grade teachers, completed the SNAP Rating Scale. Results were consistent across raters: Clinician assessment revealed seven symptoms of inattention, often leading to difficulty with concentrating on tasks, organizing, and following through on instructions from others, avoiding tasks requiring sustained mental effort, being easily distracted by external stimuli, being forgetful in daily activities, often losing things, seeming not to listen when spoken to by others, and failing to pay attention to details, resulting in making careless errors. His mother also endorsed all nine symptoms of hyperactivity/impulsivity, leading to being fidgety, having difficulty remaining seated in the classroom, climbing on things excessively, talking excessively, having difficulty doing things quietly or waiting for turn in games or group activities, blurting out answers before the question was finished, and interrupting or intruding on others. These symptoms were moderately to severely impairing across multiple settings, including home, peer relations, personal safety, and during athletics. The Child Behavior Checklist and Teacher Report Form each revealed T scores greater than 65 for the narrow-band Attention Problems scale.

During a classroom observation, the clinician noted that Ben was a loner in the class who initially engaged in the assignments or group projects directed by the teacher. However, Ben became disengaged when the teacher was giving directions, often staring out the window or talking to peers. During a videotaped parent–child interaction in the clinic, Ben became sullen and resistant when asked to read a paragraph, and when the parents began to cajole and beg him to perform, their exasperation with his opposition to reading became intense. 

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