ADHD Update

Introduction*

The appropriate identification and treatment of attention deficit/hyperactivity disorder (ADHD) is a growing public health concern.^[1] The disorder has been increasingly accepted as a disorder in children.^[2,3] However, it is only in recent years that adult ADHD has truly been recognized as an entity unto its own and that adequate treatment for adults has become available. It is clearly stated in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), that attention deficit disorder is a disorder that can continue into adulthood. As ADHD is a longitudinal, neuropsychiatric disorder, the criteria require the onset of some ADHD symptoms in childhood, with onset prior to the age of 7 years. Approximately half of the children who are diagnosed with ADHD will have symptoms that persist into adulthood.^[4]

The appropriate recognition and treatment of adults with ADHD is a particularly pressing problem for busy primary care physicians, given: (1) the high prevalence of and resulting impairments from the disorder, (2) that ADHD patients are high utilizers of medical services, (3) the lower identification rates of the disorder in adults as compared with children, and (4) the ready availability of relatively safe and effective treatments.

A major recent advance in the treatment of adults has been the advent of longer-acting stimulant preparations; their longer duration of effect better suits the extended day of adults with ADHD as compared with shorter-acting agents. It should be noted that currently available medications for adults are being prescribed off-label; they were specifically developed for children, and their use has been extended to adults (which is actually the reverse of the medication development process for most agents). This off-label characterization, in addition to the schedule II nature of stimulants, may in part account for the some of the lack of comfort primary care physicians express in treating adults with ADHD (Thomas Spencer, personal communication, September 2002). Future development of novel agents is likely to offer wider treatment options to physicians and patients alike.

We will review in this manuscript the history, epidemiology, diagnostic considerations, related impairments, and treatment considerations for adults with ADHD, with a special focus on issues pertinent to primary care clinicians.

History

Adult ADHD was not diagnosed until the mid-1970s due to a general lack of awareness. However, states of pathologic restlessness have been diagnosed in children and adults for more than a century. In the mid 1920s, an encephalitis pandemic (encephalitis lethargica, von Economo's disease) occurred. Children and adolescents who survived the infection commonly suffered a postencephalitic behavioral syndrome that was characterized by overactivity, lack of coordination, learning disability, impulsivity, and aggression.^[5,6]

The children's behavior was labeled as minimal brain dysfunction-like behavior. Adults who were afflicted had Parkinson-like symptoms, including severe tremors, pathologic restlessness, and akathisia. Patients also had specific lesions in areas of the brain rich in dopamine, providing the first indication that states of pathologic restlessness were secondary to true neuropathologic deficits and not merely driven by purely psychological causes. Subsequently, we have identified dopamine as one the neurochemicals specifically involved in the pathophysiology of ADHD. The similarities of the clinical presentations of children after encephalitis and what we currently see as ADHD contributed to the understanding that structural damage could lead to symptoms like restlessness, inattention, distractibility, and behavioral disturbances.

ADHD is generally thought to be a genetically transmitted neurobiologic disorder of the dopaminergic and noradrenergic pathways. It appears to have a high genetic rate, with roughly 50% concordance in first-degree relatives. ADHD affects approximately 6% to 9% of children. Of those children, somewhere between one third and two thirds continue to manifest ADHD symptoms into adulthood, meaning that 2% to 6% (the most common estimate is 4%) of the adult population has ADHD.^[4] However, much of the data for these estimates were collected at a time when the ADHD classification schema did not differentiate between the hyperactive and inattentive subtypes, as it does now. As hyperactivity symptoms tend to wane in adults with ADHD and become a sense of internal restlessness, it is likely that these estimates somewhat underestimate the true prevalence of the disorder in adults.

Comorbidity is widely prevalent in adult ADHD, affecting by some estimates up to 3 in 4 individuals with the disorder. The mood disorders (major depression, bipolar disorder, and dysthymia) have a comorbidity ranging from 19% to 37%. For anxiety disorders, comorbidity is 25% to 50%. The range for alcohol abuse is 32% to 53% and for other types of substance abuse, including THC and cocaine abuse, is 8% to 32%. Self-medication with nicotine and excessive doses of caffeine are often overlooked. The public health concerns for primary care physicians are readily apparent, as there are increased rates of nicotine abuse seen in adults with ADHD The rate of occurrence with personality disorders is 10% to 20% and with antisocial behavior is 18% to 28%.^[7-11] There is a 20% comorbidity for learning disabilities, particularly auditory processing problems like dyslexia and auditory processing deficits.^[7] These high rates of psychiatric comorbidity have several implications for primary care physicians. ADHD response rates are likely to be decreased if significant comorbid conditions are not considered in treatment planning. Furthermore, it is important not only to look for other psychiatric conditions in patients with ADHD, but also to examine for ADHD in patients whose primary presenting problems are psychiatric in nature. For example, for patients presenting with mood disorders, it is critical to initially treat the mood disorder; however, if concomitant ADHD is missed, the likelihood of successful long-term treatment is diminished.

Diagnosing the Adult With ADHD

Despite the medical evidence for persistence of the disorder, until recently, adult ADHD was seldom diagnosed. Historically, awareness of adult ADHD has been limited, but growing medical evidence in this area and changed DSM diagnostic criteria for childhood ADHD have spawned more widespread recognition of this syndrome. Studies dating back to the mid-1970s report the persistence into adulthood of ADHD symptoms such as inattention, impulsivity, and overactivity. In 1980, DSM-III designated an Attention Deficit Disorder classification, describing it as residual for adults, but that edition offered only a vague description of adult symptoms.^[12] In the revised third edition of the DSM (DSM-III-R),^[13] the authors stated that approximately one third of children with ADHD showed continuing signs in adulthood, but they still did not code adult ADHD as a separate category. Only in the fourth edition of DSM (DSM-IV) is there acknowledgement that the ADHD diagnosis persists into adulthood.^[14] This edition states that "symptoms attenuate during late adolescence and adulthood, although a minority experience the full complement of symptoms of ADHD into mid-adulthood."^[15] It is important to note that while adult presentation of ADHD can occur, adult-onset ADHD is not a valid diagnosis and most likely represents another condition. According to the DSM-IV definition, ADHD begins in childhood. The diagnostic criteria state that evidence of the condition must be demonstrated by age 7 years (Table 1).

Table 1. Evolving Diagnostic Criteria for ADHD^[5]

Diagnosis and Clinical Features

The overall diagnostic criteria for an ADHD diagnosis include onset by age 7 years, impairment from symptoms in at least 2 settings, and significant impairment in social, academic, or occupational functioning. There are 3 subtypes of ADHD that have been defined by the DSM: a predominantly inattentive type, a predominantly hyperactive type, and a combined type in which elements of both inattention and hyperactivity are present. Diagnostic criteria suggest that those diagnosed with the inattentive type have 6 or more inattentive symptoms present for more than 6 months and that those with the hyperactive type have 6 or more symptoms of hyperactivity present for at least 6 months. To be diagnosed with the combined subtype, a person must have 6 or more inattentive symptoms and 6 or more hyperactive symptoms.

For those with the inattentive subtype, symptoms may include difficulty sustaining attention in tasks or play and a lack of close attention to details in schoolwork or on the job. Other inattentive symptoms include difficulty organizing tasks or activities; avoiding, disliking, or being hesitant to engage in tasks of sustained mental effort; not following through on instructions at school or work; and not listening when directly spoken to. Other symptoms include often losing things, becoming easily distracted, and often being forgetful in daily activities.

Hallmark hyperactive subtype symptoms include fidgeting or squirming and leaving one's seat in the classroom or in other situations where the expectation is to remain seated. Other symptoms include talking excessively, feeling "on the go" or "motor driven," running about or climbing excessively, having difficulty playing quietly, blurting out answers before questions are completed, interrupting others, and having difficulty waiting one's turn.

Childhood Vs Adult ADHD

As children mature into adulthood, the DSM-IV diagnostic threshold (at least 6 symptoms of hyperactivity/impulsivity and/or inattention) often manifest differently. The formal restlessness and hyperactivity that occurs in children is instead manifested as internal restlessness for adults with ADHD. Whereas a child may be feeling "on the go" or running about and climbing too much, adults may tend to overwork or choose occupations where getting up and down is an essential component of the job. Examples include positions like sales representative or stockbroker.

Impulsivity symptoms can lead to more serious consequences in adulthood. Adults with ADHD often have a low frustration tolerance, which can lead to issues like high job and relationship turnover, explosive or irritable episodes, and reckless driving. Poor time management and difficulty completing and changing tasks are common manifestations of inattention. If possible, adults often attempt to compensate for limited organizational skills by enlisting the assistance of support staff.^[16]

Though ADHD symptoms generally may abate somewhat in adulthood, life also tends to become more complex. Adults with ADHD have to get themselves up and organized for the day, and then they often also have to get their children (who may also have ADHD) prepared for the day. After a full workday, parents come home to children who need dinner, help with homework, and their parents' time and attention. Adults with ADHD experience limitations in executive functioning that make completing such multifaceted tasks taxing and difficult.

Validity of Adult ADHD Diagnosis

As described by Faraone and colleagues,^[17] consistent evidence across a number of domains is necessary to validate the adult ADHD diagnosis. One domain is reporting, which can demonstrate that the person has had the clinical features that correlate with childhood ADHD. This reporting can include self-report and the observations of significant others who knew the person as far back as early childhood, such as a parent or older sibling. Both children and adults show a family history of ADHD and a genetic concordance rate, which provides further evidence.

Neuroimaging analysis shows somewhat similar brain abnormalities in children and adults, although there are not enough comparable data to make a definitive statement.^[17] All of the brain imaging work with children and adolescents has used structural imaging, whereas the studies on adults have employed functional imaging. In juveniles, the areas of the brain in which abnormalities were observed were the prefrontal cortex, the striatum, the cerebellum, and the corpus callosum.^[18] In adults, it was the frontal brain regions.

In studies of molecular genetics, the evidence appears robust for both children and adults that the D4 dopamine receptor gene is involved in the etiology of ADHD. This gene is known to mediate a blunted response to the neurotransmitter dopamine, one of the presumed active neurotransmitters in ADHD.^[19]

Medication response is also another way to validate the diagnosis in adults. Two lines of evidence support the validity.^[17] Medications used in children are usually effective in adults with ADHD. Furthermore, agents that treat ADHD, such as stimulant medications and reuptake inhibitors, generally have effects on the two neurochemicals posited to be involved in ADHD, namely norepinephrine and dopamine.

The course and outcome of impairments are similar in both groups, with both syndromatic and symptomatic persistence. Based upon the limited clinical data available, both groups appear to respond to treatment similarly. Moreover, numerous clinical correlates have been identified in children and adults, including antisocial, depressive, and anxiety disorders. Adults also show the clinically significant impairments that will be discussed below, including histories of school failure, occupational problems, and traffic accidents.

Related Impairments

One area in which adults with ADHD suffer is educational outcome. According to evidence gleaned from self-reports and high school transcripts, adults with ADHD experience significantly more grade retention (Milwaukee Young Adult Study [MKE]: 42% of people with ADHD vs 13% of the control group).^[7] More students with ADHD are suspended (MKE: 60% ADHD vs 19% control) and more are expelled (MKE: 14% vs 6%). The drop-out rate is also higher (MKE: 32% vs 0%). On average, students with ADHD also had lower class rankings (MKE: 69% vs 50%) and lower GPAs (MKE: 1.7 vs 2.6). In addition, fewer enter college (MKE: 22% vs 77%). For those who do go to college, those with ADHD have a lower college graduation rate (5% vs 35%).^[7]

Once in the work world, problems continue. Employees with ADHD are more likely to be fired (MKE: 55% of adults with ADHD vs 23% of the control group). They change jobs more often (MKE: 2.7 jobs for people with ADHD vs 1.3 jobs in the control group over the 2-8 years since leaving high school). They also display more ADHD/oppositional defiant disorder symptoms on the job and garner lower work performance ratings (MKE: as rated by current supervisors). The employment problems mentioned above lead 35% of those with ADHD to become self-employed by the time they are in their 30s.^[7]

Self-reports reveal that those with ADHD also have higher sexual-reproductive risks. They begin sexual activity earlier than their peers (15 years vs 16 years), have many more lifetime sexual partners (18.6 vs 6.5), and tend to stay with each partner for less time than other adults do. They are less likely to employ contraception and have a far greater risk of teen pregnancy (38% vs 4%). Fifty-four percent of adults with ADHD do not have custody of their offspring. Adults with ADHD are also at a higher risk of contracting sexually transmitted diseases (16% vs 4%).^[7]

Motor vehicle driving risks are one additional area where there are striking differences between those with ADHD and the general population. According to assessments based on self-report, driving records, lab testing, driving simulators, and behind-the-wheel tests, adults with ADHD are at significantly higher risk for motor vehicle accidents. Driving risk assessments revealed that adults with ADHD displayed poorer steering, more false braking, and slower reaction times to significant events than did other adults. When placed on driving simulators, ADHD patients tended to accelerate into critical incidents rather than breaking away from them.^[20] Adults with ADHD were reported as using fewer safe driving habits, being more likely to drive before licensing, and having more accidents (and more faults) than other drivers (2 to 3 for ADHD adults vs 0 to 2 in the control group). There is a far higher percentage of ADHD adults with 2 or more crashes than in the control group (40% vs 6%). The same is true for 3 or more crashes (26% vs 9%). They also had more citations for speeding (4 to 5 vs 1 to 2), worse accidents ($4200 to $5000 in damage vs $1600 to $2200), and a greater percentage of crashes with injuries (60% vs 17%). Drivers with ADHD had more suspensions/revocations (mean 2.2 vs 0.7) and license suspensions (22% to 24% vs 4% to 5%).^[7] Clearly, the presence of ADHD symptomatology correlates with significant differences in one's life course and quality of life.

Pharmacologic Treatments

The medications shown to be effective for adults are similar to those that have been examined in children. However, no medications are specifically approved for the treatment of adult ADHD, and the vast majority of the research has been on children and adolescents. To date, the medical literature contains reports of just 9 controlled trials of off-label use of stimulants in 272 adults.^[4,21-27] The existing evidence has shown that stimulants are effective, but the response rates of adults have been somewhat less consistent than the response rates in trials with children. This may in part be due to the lower doses and less strict diagnostic criteria employed in earlier trials, as compared with those in later studies. For example, when stricter criteria and appropriate adult doses are studied, such as in the mixed amphetamine salt trial by Spencer and colleagues,^[27] 70% of patients showed improvement of ADHD symptoms with the active compound, compared with 7% of those taking placebo.

In the last several years, several longer-acting stimulant preparations have been marketed; these include agents in the methylphenidate (Concerta, Ritalin-LA, and Metadate CD) and mixed amphetamine salt (Adderall XR) classes. These medications offer significant advantages of longer duration and less variability of effect than shorter acting versions of stimulants. The risk of noncompliance and possible "rebound" effects (where ADHD symptoms dramatically return after wearing off a dose) is reduced with these agents. Their durations of effect are generally in the range of 8 to 12 hours, which fits the profile of a full day for an adult with ADHD. However, a preliminary survey did find that almost 4 in 10 patients treated with a long-acting methylphenidate preparation did require supplementation with shorter acting stimulants either in the morning (to "ramp up" the onset of action) or in the afternoon (to extend the duration of effect).^[28]

Stimulants remain the standard-bearers of ADHD treatment, but nonstimulants also offer the possibility of effective treatment. Studies of off-label use of nonstimulants for adult ADHD have assessed the efficacy of essentially 3 classes of drugs: those that affect norepinephrine and serotonin (tricyclic antidepressants and venlafaxine), those that affect norepinephrine and dopamine (bupropion), and those that affect norepinephrine alone (atomoxetine). Monoamine oxidase inhibitors, nicotinic agonists, and antihypertensives have also all been studied in relatively small numbers. The tricyclic antidepressants have generally not been used in adults because of concerns about the side effects associated with their use. SSRIs appear to have little effect on core ADHD symptoms, although they seem to be beneficial for those with comorbid depressive disorders.^[4]

Clinical investigation of the efficacy of a new drug called atomoxetine, which is a norepinephrine reuptake inhibitor currently undergoing US Food and Drug Administration (FDA) review, has suggested its efficacy in the adult population. An initial double-blind, placebo-controlled, crossover study of adults with ADHD (n = 21) demonstrated a mean reduction in the ADHD rating scale of approximately 8.5 points (vs 0.3 points for placebo, n = 21) over a 3-week period with a dose of 80 mg/day (Spencer et al 1998).^[29] Two additional large-scale, randomized, controlled trials of atomoxetine in adult ADHD have also been undertaken. At a daily dose of 60 mg/day titrated to a maximum dose of 120 mg/day, the atomoxetine effects were apparent by week 4 and persisted and grew over 8 weeks of treatment. Significant effects were demonstrated in both trials.^[30,31] If approved by the FDA for use in adults who have ADHD, atomoxetine will represent the first ADHD drug specifically available for this indication. It has been considered for once-daily dosing since it has a relatively long duration of effect. Also, because atomoxetine is not a stimulant, there is the possibility of a lower risk of inducing tics and psychosis, although this has not been clinically demonstrated to date (Table 2).

Table 2. Adult ADHD Trials

ADHD, attention deficit/hyperactivity disorder; RDC, Research Diagnostic Criteria of Spitzer et al^[49]; DSM, Diagnostic and Statistical Manual of Mental Disorders; D-B, double-blind; P-C, placebo-controlled; MPH, methylphenidate; TCAs, tricyclic antidepressants; WURS, Wender Utah Rating Scale^[50]

Conclusion

Since adult ADHD has been underdiagnosed and undertreated for an extended period of time, it is important for physicians to understand the adult ADHD diagnosis and learn to recognize its symptoms. Adult ADHD is a highly prevalent and impairing condition. Appropriate recognition of the condition is critical since effective and well tolerated treatments, particularly longer-acting, newer-generation versions of stimulants, are now available. New drugs, like the norepinephrine reuptake inhibitor atomoxetine, are currently being developed, which may fit the lifestyle of the adult with ADHD. Appropriate identification of adult ADHD is likely to lead to a substantial reduction in the burden of the illness, not only to the individual, but also to his/her family and the healthcare system in general.

*This update mentions off-label uses for some medications. These may describe clinical uses for medications that have not been approved by the US Food and Drug Administration.

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