Attention-Deficit Hyperactivity Disorder Across the Lifespan
Abstract
Up to 10% of school-age children have attention-deficit hyperactivity disorder (ADHD), which often persists into adulthood. ADHD can be associated with significant comorbidity of disruptive, mood, and anxiety disorders. Although many children with ADHD have good long-term outcomes, a significant subset has substance abuse, antisocial behavior, and mood disorders as adults. Pharmacotherapy with stimulants, atomoxetine, and alpha-agonists is highly effective in the short term; behavior therapy is valuable as an adjunct to medication or to address comorbid conditions. Multiple genes each likely contribute small effects to the risk of ADHD. Neuroimaging studies suggest that individuals with ADHD have insufficient activation of cortical attention networks, reduced activity of ventral striatal reward systems, and dysregulated control of the default mode network. No neuroimaging technique is yet useful clinically. More long-term studies of both medication and psychosocial interventions are needed to improve outcomes.
In 1902, George Still (1) published one of the first clinical descriptions of what today would be recognized as attention-deficit hyperactivity disorder (ADHD). The first treatment of impulsive, hyperactive, and disruptive behavior with stimulant medication was reported in the 1930s (2). Virginia Douglas (3) first suggested that “attention deficits,” rather than hyperactivity, were the core symptoms of the disorder. Since then, the criteria have undergone refinements leading to the current terminology of ADHD in DSM-5 (Box 1).
BOX 1. DSM-5 Criteria for Attention-Deficit Hyperactivity Disordera
A.
1.
Inattention: six (or more) of the following symptoms have persisted for at least 6 months to a degree that is inconsistent with developmental level and that negatively impacts directly on social and academic/occupational activities. Note: The symptoms are not solely a manifestation of oppositional behavior, defiance, hostility, or failure to understand tasks or instructions. For older adolescents and adults (age 17 and older), at least five symptoms are required.
a.
Often fails to give close attention to details or makes careless mistakes in schoolwork, at work, or during other activities (e.g., overlooks or misses details, work is inaccurate).
b.
Often has difficulty sustaining attention in tasks or play activities (e.g., has difficulty remaining focused during lectures, conversations, or lengthy reading).
c.
Often does not seem to listen when spoken to directly (e.g., mind seems elsewhere, even in the absence of any obvious distraction).
d.
Often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (e.g., starts tasks but quickly loses focus and is easily sidetracked).
e.
Often has difficulty organizing tasks and activities (e.g., 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 (e.g., schoolwork or homework; for older adolescents and adults, preparing reports, completing forms, reviewing lengthy papers).
g.
Often loses things necessary for tasks or activities (e.g., 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 (e.g., 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 have persisted for at least 6 months to a degree that is inconsistent with developmental level and that negatively impacts directly on social and academic/occupational activities. Note: The symptoms are not solely a manifestation of oppositional behavior, defiance, hostility, or a failure to understand tasks or instructions. For older adolescents and adults (age 17 and older), at least five symptoms are required.
a.
Often fidgets with or taps hands or feet or squirms in seat.
b.
Often leaves seat in situations when remaining seated is expected (e.g., 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 (note: 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” (e.g., is unable to be or uncomfortable being still for extended time, as in restaurants and 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 (e.g., completes people’s sentences; cannot wait for turn in conversation).
h.
Often has difficulty waiting his or her turn (e.g., while waiting in line).
i.
Often interrupts or intrudes on others (e.g., butts into conversations, games, or activities; may start using other people’s things without asking or receiving permission; for adolescents and adults, may intrude into or take over what others are doing).
B.
Several inattentive or hyperactive-impulsive symptoms were present prior to age 12 years.
C.
Several inattentive or hyperactive-impulsive symptoms are present in two or more settings (e.g., at home, school, or work; with friends or relatives; in other activities).
D.
There is clear evidence that the symptoms interfere with, or reduce the quality of, social, academic, or occupational functioning.
E.
The symptoms do not occur exclusively during the course of schizophrenia or another psychotic disorder and are not better explained by another mental disorder (e.g., mood disorder, anxiety disorder, dissociative disorder, personality disorder, substance intoxication or withdrawal).
______________________
a Reprinted from the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC, American Psychiatric Association, 2013. Copyright 2013, American Psychiatric Association. Used with permission.
ADHD is a neurodevelopmental disorder in which the ability to attend and/or control impulses (including inhibiting motor activity when appropriate) (a) is significantly less than that of a typically developing individual of a given age; (b) causes impairment in the individual’s academic, employment, or social functioning; and (c) is not better accounted for by some other medical or psychiatric condition. Box 1 presents the specific criteria, including the definition of the three presentations of ADHD: inattentive, hyperactive-impulsive, and combined. The only major change in the criteria from DSM-IV is the change in the age of onset, which now requires some symptoms to be present before age 12 years, rather than age 7 years. The individual symptom descriptions have been broadened to also include behaviors typical of an adolescent or adult, rather than just a young child.
Epidemiology
Looking at ADHD among children, a review and meta-analysis suggested a worldwide prevalence rate of 5.3% (4), but recent data suggest that the rate of diagnosis is increasing. The 2011 National Survey of Children’s Health researchers performed telephone interviews of nearly 100,000 parents of children ages 4–17 years (5). Eleven percent of children had received a diagnosis of ADHD at some point in their lives, 8.8% were reported as having a current diagnosis of ADHD, and 6.9% were taking medication for ADHD. Epidemiological studies suggest a prevalence of 4.4% for ADHD among adults (6).
Comorbidity
Both oppositional defiant and conduct disorders, as well as anxiety disorders, affect 25%−33% of children with ADHD; learning and language disorders affect another one-quarter of children with ADHD (7). Many children with ADHD will have two or more comorbid disorders, complicating clinical management. Compared with children with ADHD alone, those with oppositional defiant/conduct disorders show more severe symptoms of impulsivity, higher rates of aggression, a greater prevalence of learning disorders, and a greater propensity to develop both antisocial personality and substance abuse during their adolescent years (8). Compared with those with ADHD alone, individuals with comorbid anxiety (without oppositional defiant/conduct disorders) show lower levels of impulsivity on laboratory measures of attention as well as a greater tendency to respond to psychosocial interventions (9–11).
In the Multimodality Treatment of ADHD study (12), 11% of the sample also met criteria for major depressive disorder. How depression affects the clinical expression of ADHD has not been explored; family studies suggest that ADHD and major depressive disorder might share genetic factors (13). Because treatment of depression rarely leads to remission of ADHD symptoms, it seems unlikely that major depressive disorder masquerades as ADHD to any significant degree. If a child with ADHD meets the full DSM-5 criteria for major depressive disorder, this most likely represents the full syndrome of major depressive disorder and not a state of demoralization as a result of the ADHD symptoms (14). As individuals mature into adulthood, the comorbidity of mood and anxiety disorders remains problematic (6).
Etiology and Risk Factors
Approximately 71%−90% of the variance in ADHD traits is found to be attributable to genetics (15). Heritability estimates include the effects of gene-environment interactions; thus, the high heritability rates in ADHD do not minimize the effect of environment. Genome-wide association studies to date have not yet revealed any gene variant that passes the very high statistical threshold for genomewide significance (16). Maternal smoking during pregnancy and prenatal/perinatal adversity have been established as risk factors for ADHD (17–19). Children with ADHD exposed to smoking during pregnancy have more severe behavioral problems, lower IQ, and poorer neuropsychological test performance than nonexposed children with ADHD, even when controlling for income level, ethnicity, maternal age, and maternal alcohol use (20). Severe head injury can result in ADHD, even when preinjury ADHD diagnosis is controlled for (21, 22).
Pathophysiology
Cognitive Deficits
Recent research has suggested multiple cognitive deficits of children with ADHD (23, 24). Working memory deficits robustly delineate individuals with ADHD from those in a control group, particularly central executive working memory deficits such as updating of working memory, manipulating information in working memory, and mental manipulation of temporal order (25). Differential response to reward and delay aversion have also been proposed as key deficits in ADHD (23, 26). That is, children with ADHD either cannot tolerate a delay to wait for an anticipated reward or are hyporesponsive to the reward, making their behavior difficult to shape by the normal reinforcements and punishments in the environment. Despite these findings, many children with ADHD show no deficits on either neuropsychological or laboratory testing of cognition (27).
Neuroanatomical Findings
A meta-analysis of anatomical MRI studies showed reduced volume of multiple brain regions in persons with ADHD versus controls (28). Over the last several decades, the National Institute of Mental Health intramural program has performed MRI scans of children with ADHD and matched controls in a longitudinal design (29, 30). These studies have shown a global cortical maturational delay in the development of both cortical surface area and cortical thickness relative to control participants. In control groups, surface area rises through childhood, peaks around age 12 years, and then declines as pruning progresses. A study by Shaw et al. (29) showed that individuals with ADHD had less cortical surface area than those in the control group at study entry and were delayed approximately 2 years in reaching peak area, with the effect more pronounced on the right cortex. Cortical thickness followed a similar pattern (peaking in early adolescence and then declining). Individuals with ADHD have a thinner cortex at baseline than controls and prune later; interestingly, decreased pruning (resulting in thickness more similar to controls) is associated with remission of ADHD symptoms in adulthood (30).
Functional Neuroimaging
Functional studies in ADHD have been performed principally using tasks assessing response inhibition (such as the Go/No Go or Stop Signal Task), as well as tasks measuring attention. In a meta-analysis of these data, Hart et al. (31) found that relative to a control group, patients with ADHD showed reduced activation during response inhibition in the right inferior frontal cortex, supplementary motor area, and anterior cingulate cortex (ACC), as well as in striatothalamic areas. For attention tasks, patients with ADHD showed reduced activation relative to the control group for attention in the right dorsolateral prefrontal cortex, posterior basal ganglia, and thalamic and parietal regions. Another meta-analysis by Rubia et al. (32) of 14 functional magnetic resonance imaging (fMRI) data sets involving 212 children showed that acute methylphenidate treatment in ADHD consistently enhanced right inferior frontal cortex/insula activation.
Recent fMRI work has shifted from the study of discrete regions activated by tasks to resting state networks (33). A key area of study is the default mode network consisting of the precuneus/posterior cingulate cortex, the medial prefrontal cortex, and lateral/inferior parietal cortex. This circuit is active in task-irrelevant, “daydreaming” activities and is turned off when the attention circuits are activated. A recent large-scale, resting-state fMRI study compared 481 control participants with 276 adolescents with ADHD (34). Sripada et al. (34) found ADHD to be associated with a lack of anticorrelation between the default mode network and both the ventral attention (bottom-up) and frontoparietal (top-down) networks.
As noted earlier, patients with ADHD have difficulty delaying gratification and often seem unresponsive to reward. For patients in a control group, anticipation of a reward leads to increased dopamine in the ventral striatum; on fMRI, these can be detected as an increase in signal in the ventral striatum. Plichta and Scheres (35) reviewed fMRI studies comparing patients with ADHD with control subjects using reward tasks; they found that individuals with ADHD had hyporesponsiveness of the ventral striatum during anticipation of reward. This would suggest that individuals with ADHD are not as motivated as control participants by ordinary rewards. Family members often note that both children and adults with ADHD are hard to get motivated for day-to-day tasks.
Relative to control groups, adolescents with ADHD have greater amygdala activity when looking at subliminal angry faces and greater amygdala-cortical connectivity (36). Children with ADHD who have high ratings of emotional lability were found to have greater connectivity between the amygdala and ACC than those in a control group or children with ADHD who were not emotionally labile (37). These two studies suggest that patients with ADHD (particularly those with mood dysregulation) have an abnormally increased influence of the limbic system on cortical functions.
Course and Prognosis
Results of the Montreal Children’s Hospital Study, a longitudinal study of hyperactive children into adulthood, revealed that 50% still showed symptoms of inattention, impulsivity, low self-esteem, and social skills deficits (38). Barkley et al. (39) and Fischer et al. (40) followed up with 158 children with ADHD 8–10 years after diagnosis and compared them on a large number of functional measures with a control group of 81 children. Not only did 83% of the children with ADHD still meet criteria for the disorder in their late teen years, but they were more likely than the control group to have car accidents (41), to smoke cigarettes (39), and to have failed a grade or been suspended (40). Biederman et al. (42) compared boys with ADHD with matched controls 16 years after initial diagnosis. Individuals with ADHD had significantly higher rates of mood, antisocial, anxiety, and addictive disorders; moreover, they had more psychosocial impairments than did the boys in the control group. The Multimodality Treatment of ADHD study showed that one-third of a sample of 7- to 9-year-old children still met criteria for ADHD 8 years later and that the patients with ADHD fared poorly on multiple outcome measures, including lower academic progress, more psychiatric hospitalizations, and more police contacts and arrests (43). Type of treatment (medication versus psychosocial) in the first year of the study did not predict outcome, and nearly two-thirds of the sample was not taking medication at the 8-year follow-up. Substance abuse also was more common in patients with ADHD than in controls (44). Despite the fact that ADHD is a chronic condition, the Multimodality Treatment of ADHD study showed that most individuals receive no or sporadic treatment through adolescence, limiting the potential effect on long-term outcomes.
Adults with a childhood history of ADHD have higher-than-expected rates of antisocial behavior (45), injuries and accidents (46), employment and marital difficulties, health problems, teen pregnancies, and children out of wedlock (47). A 33-year prospective follow-up of 135 boys with ADHD and matched control participants was recently completed (48). There were 15 deaths in the ADHD group relative to five deaths in the control group; 10 of the 15 deaths in the ADHD group were due to suicide, homicide, or accident. Risky sexual behavior, traffic tickets, and accidents were more prevalent in the ADHD group, with comorbid conduct disorder predicting poor outcome.
Clinical Evaluation
Interview
Table 1 illustrates the major aspects of the clinical interview across the lifespan. The central theme of the interview process is to identify and quantify the specific symptoms of ADHD, keeping in mind the various developmental expressions of these symptoms. When possible, documentation of early life impairment should be obtained from adults presenting with ADHD. The clinician should screen for all of the major comorbidities (anxiety, depression, and disruptive behaviors) and rule out psychosis or severe mood disorder, which would require primary treatment.
| Topic | Preschool | School Age | Adolescent | Adult |
|---|---|---|---|---|
| Symptom presentation | Hyperactivity and impulsivity predominate, difficulty attending to story time, refusal to nap, climbing on furniture, will not hold hand in store | Combined presentation of ADHD most common; failure to attend to and complete school work leads to referral; shows classic DSM-5 symptoms | Inattentive presentation becomes more common, hyperactivity presents as internal restlessness, impulsivity as poor choices; milder cases may present for first time, but symptoms should have started in childhood | Failure to enter or complete college despite intelligence, job terminations; moving from job to job; disorganization and poor time management |
| Interview with patient | Observation of child, only, take note of developmental milestones particularly language | Interview patient alone to explore mood/anxiety issues, only a minority of children will acknowledge ADHD symptoms; sitting still in interview does not rule out ADHD | Separate interviews of parent and child preferred; ask adolescent about illicit drug/alcohol use, relationship issues; adolescent more aware of symptoms but may minimize impact | Adult is primary source of history; review 18 ADHD symptoms with focus on job and social functioning; adult ADHD rating scales are highly useful to prompt interview; must establish childhood onset of impairment |
| Collateral information | Obtain reports from preschool or daycare | Rating scales from teacher, school conduct folder | More difficult to get rating scales from middle/high school teachers; report cards can be useful substitutes | Spouse or parents can provided useful collateral; negative work evaluations may show evidence of ADHD symptoms |
| Common comorbidities | Language delays, ask about social skills, screen for autism spectrum disorders | Oppositional defiant disorder, anxiety disorders | Oppositional defiant disorder, anxiety, depression, substance use disorders | Anxiety, depression, mania, or early-onset dementia in 40- to 50-year-old group; substance use and diversion |
| Health issues | If developmental delays present, review medical history for any congenital conditions | Medical history negative in most cases, pediatric referral for specific medical conditions only | Obesity, accidental injury, sexually transmitted diseases | Hypertension, thyroid issues, and diabetes become more common; counsel patient to see primary care physician regularly |
| Treatment issues | Stimulant response rate somewhat lower than in other age groups | Stimulant response rate up to 90% | Stimulant response rate up to 90%; beware of diversion of stimulant | Stimulant response rate up to 90%; be aware of drug interactions with other agents |
Psychological Testing
Achievement and IQ testing to rule out learning disabilities is not mandatory before making a diagnosis of ADHD. Such testing may yield the most valid results after the symptoms of inattention have been controlled. If a child’s academic performance does not improve with control of ADHD symptoms or if the developmental history or mental status examination yields evidence of language or motor delays, then IQ and achievement testing should be performed, because the child most likely has a comorbid language/learning disorder.
Medical Evaluation and Laboratory Tests
The patient’s medical history should be obtained, as well as a physical examination within the last year. Patients with a history of cardiovascular disease or significant cardiac symptoms should have consultation with a primary care physician or cardiologist prior to starting stimulant medication. There is no need for cardiac screening (i.e., ECG) of otherwise healthy individuals.
Pharmacotherapy
Stimulants
The pharmacotherapy of ADHD with both stimulants and nonstimulants is well established by hundreds of double-blind placebo-controlled trials dating back to the 1960s (49). Dosing and titration of these agents is shown in Table 2. Response rates to stimulants can be as high as 90% when both methylphenidate and amphetamine are fully titrated (50). Although preschoolers may have a slightly decreased rate of response relative to school-age children (51), adults show a response equally robust to that of school-age children and adolescents (52, 53). Short-term side effects of stimulants include decreased appetite, insomnia, and headaches, whereas mood changes and tics are much rarer and may be idiosyncratic (49). Long-term effects on height, up to about 2 cm, have been found in long-term studies (54). A nationwide survey found a small but significantly increased rate of cardiovascular side effects (broadly defined), but no deaths, among patients with ADHD treated with stimulants, a finding consistent with an earlier large-scale study (55, 56).
| Medication and Dosing | Preschool Age Range (<25 kg) | Later School Age and Younger Adolescents (25–40 kg) | Older Adolescents and Adults (>40 kg) |
|---|---|---|---|
| Stimulants | |||
| Methylphenidate (t.i.d.) | 2.5–10 | 15–20 | 25–30 |
| Methylphenidate OROS (every morning) | 18–36 | 54–72 | 90–108 |
| Dexmethylphenidate (b.i.d.) | 1.25–5 | 7.5–10 | 12.5–15 |
| Controlled-release dexmethylphenidate (every morning) | 5–10 | 15–20 | 30 |
| Amphetamine (b.i.d.) | 1.25–5 | 7.5–10 | 12.5–30 |
| Controlled-release amphetamine | 5–10 | 15–20 | 25–60 |
| Lisdexamfetamine (every morning) | 20–30 | 40–50 | 60–70 |
| Nonstimulants | |||
| Clonidine | 0.05–0.1 h.s. | 0.1 b.i.d. to 0.1 t.i.d. | 0.1 q.i.d. |
| Extended-release clonidine | 0.1 h.s. | 0.1 b.i.d. to 0.1 every morning/0.02 h.s. | 0.2 b.i.d. |
| Guanfacine | 0.5 h.s. to 0.5 b.i.d. | 1 b.i.d. to 1 every morning/2 h.s. | 2 b.i.d. or 1 q.i.d. |
| Extended-release guanfacine | 1 every morning | 2–3 every morning | 4 every morning |
| Atomoxetine | 10–20 every morning/10 every night | 18–25 b.i.d. | 40 b.i.d. |
a
All doses are in milligrams.
Atomoxetine
This nonstimulant agent is a noradrenergic reuptake blocker that has some indirect agonism on dopamine. Numerous studies (57) show that atomoxetine is superior to placebo in the treatment of ADHD for children and adolescents; however, in one major study, atomoxetine was less efficacious than long-acting methylphenidate (58). Some patients may not see its full therapeutic effect until after a month of treatment (59).
Alpha-Agonists
The alpha-2 receptor agonists clonidine and guanfacine have varied effects on noradrenergic function. In recent years, long-acting versions of both agents have been the focus of studies either as monotherapy or as an add-on to stimulant treatment (60). Both alpha-agonists are superior to placebo for treatment of ADHD and oppositional defiant symptoms; adding extended-release versions of clonidine or guanfacine to a stimulant significantly improves ADHD symptoms over the addition of placebo (61, 62).
Psychosocial Interventions
Behavior therapy is the only psychosocial intervention validated in the treatment of ADHD (63). General principles of behavior therapy in the treatment of ADHD are as follows: information about the nature of ADHD, learning to attend more carefully to the child’s misbehavior and to when the child complies, establishing a home token economy, using time out effectively, managing noncompliant behaviors in public settings, using a daily school report card, and anticipating future misconduct. Occasional booster sessions often are recommended.
Conclusions
The clinical presentation, epidemiology, and acute pharmacotherapy of ADHD are now well established. Behavior therapy is an important adjunct treatment, particularly for partial responders or those with comorbid conditions. At least one-third of children with ADHD continue to meet criteria for the disorder as adults, with many more suffering some degree of impairment. Although genetics plays a major role in the disorder, specific genes for ADHD have not been discovered. Neuroimaging is not yet useful as a diagnostic marker or in tracking treatment. Future research is needed to further understand the interaction of genetic and environmental factors involved in both etiology and outcome; such understanding may lead to new pharmacological and psychosocial interventions.
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Published in print: Winter 2016
Published online: 14 January 2016
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The author has received research support from Shire, Purdue, and Ironshore Pharma and served on an advisory board for Ironshore Pharma.
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