Attention-deficit/hyperactivity disorder: an update. (Review Article).

ABSTRACT: Attention-deficit/hyperactivity disorder, a syndrome involving inattention, impulsivity, and hyperactivity, was originally thought to occur only in children. It is now a recognized condition throughout life in some individuals. For a valid diagnosis, the onset of symptoms should occur before age 7. Dysfunction of catecholamine neurotransmission is implied by the clinical improvement induced by stimulants. Positron emission tomography studies reveal reduced glucose metabolism in the basal gangila and sometimes in the frontal cortex. Excessive cortical slowing is documented on the electroencephalogram. Twin studies show a familial, genetic influence. Data from multiple sources are necessary for a diagnosis, and rating scales are particularly useful for the adult syndrome. Older individuals typically manifest disorganization and impulsivity more than hyperactivity. Stimulant drugs are the principal forms of treatment for all ages, but bupropion is favored for patients with substance abuse history.

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MEDICAL PROFESSIONALS are confronted with adults who report a cluster of behavioral and cognitive symptoms once thought to occur only in children. This disorder, now recognized throughout life in some persons, is called attention-deficit/hyperactivity disorder (ADHD) or attention-deficit disorder (ADD). Although there is significant information about childhood ADHD, less is known about this disorder later in life. For the purpose of this paper, the term ADHD applies to children and adolescents; adult ADD refers to people over age 20 with deficits in attention.

EPIDEMIOLOGY

The prevalence rate of ADHD is approximately 3% to 5% of the general population. (1) Up to one half of children brought to psychiatric clinics are diagnosed with ADHD (2); 15% to 20% of them have symptoms throughout their lives. (3) Attention-deficit/hyperactivity disorder is 4 to 6 times more prevalent in boys, and they are more prone to display behavioral disturbances. (4) Girls tend to experience inattentiveness, which may result in poor academic performance, but they exhibit fewer problems with other people.

Although the onset of ADHD generally occurs before age 7, symptoms of increased motor activity and inconsistent sleeping or eating can appear as early as 10 to 18 months of age. (5) Approximately 50% of children with ADHD also meet criteria for socially disruptive conduct or oppositional defiant disorders. (6) Children with conduct disorder may later have antisocial personality disorder. Approximately 75% of adults with attention deficits have other psychiatric conditions, (7) and there is considerable psychosocial impairment from adult ADD itself, with poor overall functioning.

ETIOLOGY

Although the precise mechanism of ADHD is unknown, various causes have been proposed. (8) Children with a diagnosis of ADHD display cognitive impairments of memory, planning ability, and capacity to shift from one task to another. (9) Those treated with psychostimulants show improvement in executive function but not in spatial recognition memory (9); this response to psychostimulants implies catecholamine dysfunction. Inappropriate behavior may reflect dysfunction of serotoninergic, dopaminergic, and noradrenergic systems. Reduction in dopamine pathways might imply inadequate reward systems, as well as deficiencies in selective attention and information processing. Since stimulant drugs strongly influence dopaminergic activity, dopamine is a prime suspect for a regulation abnormality in ADHD. Norepinephrine-mediated circuits may be intensified, causing inattention, hyperactivity, impulsiveness, and aggression.

Research with brain imaging in ADHD is providing objective diagnostic information. Magnetic resonance imaging in affected children reveals a smaller caudate volume on the right side. (10,11) Positron emission tomography studies show a decrease in glucose metabolism in the basal ganglia, areas that regulate body movements and possibly behavior. (12,13) Some subjects display low activity in the frontal cortex, which might explain difficulties with planning, judgment, and time perception.

Quantitative electroencephalography (EEG) also reveals changes in people with attention deficits. Excessive cortical slowing, indicated by higher theta-beta power ratios, are specific EEG changes documented in ADHD/ADD. (14) Tracings during academic challenge display an increase in slow-wave activity in prefrontal midline areas, with a decrease in posterior beta activity, supporting underarousal.

GENETIC INFLUENCE

Heredity plays a distinct role. Monozygotic twins have a higher concordance rate for ADHD than dizygotic twins. (15) Children of a parent with ADHD have a 50% likelihood of having ADHD. Among affected children, 8% of biologic parents and only 2% of adoptive parents also had ADHD. (16) The biologic families of ADHD children have high rates of alcoholism, mood disorders, and antisocial personality. (16)

DIAGNOSIS

Making an accurate diagnosis is difficult in children and even harder in adults, since no specific test is diagnostic of ADHD/ADD. When other disorders coexist, a further level of complexity is added. Symptoms overlap with other psychiatric disorders, confounding precise diagnosis. A thorough history and evaluation of the clinical presentation are critical. Reports from parents, teachers, and others involved help substantiate patient information.

Inattention, hyperactivity, and impulsiveness relative to same-age peers are the essential three features of ADHD. The identification of ADHD relies heavily on teacher observations while the child is performing academically. Disruptive behavior and inability to stay on task can be compared with that of peers. (5) It can be helpful to ask parents questions such as, "Can your child sit still and eat supper with the family?"

Assessment of attention can be done indirectly by monitoring task completion. A child continually distracted from homework by irrelevant environmental stimuli usually has an attention deficit. Manifestations include careless errors, omitting details, difficult social interactions, and low self-esteem-all problems of poor impulse control. The Diagnostic and Statistical Manual IV requires evidence of symptom onset before age 7 for diagnosis of adult ADD. (1) Symptoms must have occurred in more than one setting and must have been associated with impairment or distress.

Diagnosing adult ADD is especially difficult in those not considered to have ever previously exhibited ADHD. Not only is there a problem obtaining correct information from multiple sources, as is the practice of diagnosing the childhood syndrome, but also recollection of what one was like in the past is prone to distortion.

Psychologic testing has been helpful in establishing the diagnosis of ADHD/ADD, though it is not itself sufficient. The Wender Utah Rating Scale is designed specifically for diagnosing adult ADD; its 61-item questionnaire helps people recall memories of childhood ADHD symptoms. (17) A score of 46 or higher accurately identified 86% of adult patients with attention deficit; normal subjects and depressed persons have lower scores. This scale helps fulfill the requirement that onset be traceable to childhood before confirming the diagnosis.

COMORBIDITY

Boys with a diagnosis of both ADHD and conduct disorder are more likely to exhibit antisocial behavior than those with ADHD alone. (18) Antisocial behavior carries a high prevalence of progression to stealing, property destruction, and deception. Children who received treatment for ADHD tended to have lower rates of such problems than did unmedicated control subjects. Methylphenidate reduced antisocial behaviors. (19)

Affective and anxiety disorders coexist in approximately 11% of children with ADHD. (20) Comorbid neurologic illnesses can also occur. Neurologic evaluation is indicated when there are concerns.

CLINICAL FEATURES

The symptoms of ADHD vary with age and development. (5) Infants with ADHD are sensitive to environmental stimuli such as temperature, noise, and light. They are active, sleep little, and cry a lot, though the opposite also may be seen. (3) School-aged children with ADHD often have trouble waiting their turn. They may blurt Out answers and interrupt others. These children can be explosive, irritable, and easily provoked. Mood and performance are variable and unpredictable. They do not follow through with directions, fail to complete homework and chores, and do not pay attention to details. Impulsiveness and immediate gratification demands are characteristic. Symptoms that get the attention of others include hyperactivity, emotional lability, inability to complete tasks, and learning disabilities. About 75% of these children are aggressive and defiant. (3)

Because hyperactivity lessens with age, adolescents with ADHD have more appropriate activity levels. (5) They tend rather to have problems with organization and establishing priorities. Some teenagers display shoplifting, truancy, careless driving, and substance abuse.

Adult ADD is characterized by disorganization, impulsivity, and poor work skills. Such persons are disorderly and impatient. Managing ordinary household affairs, consistency in rearing children, setting priorities, keeping appointments, and maintaining their possessions are all problematic. Adults with ADD tend to be easily bored. Typically, they will misplace personal items. They may invest money foolishly, have brief or poor relationships and tempestuous love affairs, and make frequent job changes, often without reaching their goals. (16) These people experience high levels of academic failure and interact inappropriately in social situations. (21) Although not unique to adult ADD, wives often report that husbands do not listen to them.

DIFFERENTIAL DIAGNOSIS

Careful evaluation with a detailed history is important because a number of other disorders have similar presentations. Persons with hypomania can be hyperactive, irritable, impulsive, and unable to focus or to complete tasks, but symptoms usually last for weeks and are confined to discrete episodes. Mood and anxiety disorders can also be manifested by symptoms similar to those of adult ADD but not on a continual basis. Children with vision problems may have poor reading comprehension, difficulty with spelling, and failure to complete work in a timely manner; a vision examination will separate them from those with ADHD. (22)

Dyslexia, affective disorders, and poor impulse control are other conditions that have overlapping symptoms. When children with ADHD and adequate reading ability are compared with dyslexic children, the dyslexic ones do better on measures of attention and perform poorly on reading, while the reverse is true for those with ADHD. (23) Conduct disorder can coexist with ADHD. Among children with conduct disorder, 50% will have antisocial personality disorder as an adult.' Those with both ADHD and conduct disorder are more likely to engage in substance abuse. Children who are socially dysfunctional have more problems with behavior and personal relationships. (3)

COURSE AND PROGNOSIS

Since 10% to 60% of childhood onset cases of ADHD persist into adulthood, ADD in adults may be common, yet not consistently recognized. (2) It is estimated that between 2 and 5 million adults are affected by deficits in attention. (20)

The course of ADHD/ADD is unpredictable. Symptoms are inconsistent between children and adults, though decreased attention span and problems with impulse control commonly persist. (3) Difficulties occur in all areas of life: family and social relationships, education, and career or employment. Learning problems frequently continue. In cases of remission, it occurs generally between the ages of 12 and 20 years. (3) Some persons may experience a partial remission but are still vulnerable to antisocial personality disorder, chemical dependence, and mood disorders.

TREATMENT

Commonly Used Medications

Pharmacotherapy is one of the primary treatments. Children with behavioral disturbances show rapid and impressive improvements in both conduct and academic performance when treated with amphetamines. (24) Psychostimulants have been established as the drugs of choice in the management of ADHD for all age groups. (25) In 1999, psychostimulant expenditures for ADHD approached $670 million. (26)

The mechanism of psychostimulant action is thought to result from a release of norepinephrine from subcellular particles in sympathetic nerve endings and chromaffin cells. (27) These drugs directly stimulate [alpha]- and [beta]-adrenergic receptor sites in the cerebral cortex and reticular activating system. These medications are relatively short acting but are now available in sustained release forms. Clinical coverage is better with sustained release formulations, but there is variability with the absorption and onset of action. (28)

For the elementary school child, an initial dose of dextroamphetamine or amphetamine/dextroamphetamine is 2.5 mg, given after breakfast. A 5-mg starting dose is used for adults and adolescents. Weekly dose adjustments, typically in increments of 5 mg, are based on adverse effects, completion of assignments, and reports of behavioral changes, obtained from the child, teachers, and parents. The maximum daily dose is 40 mg. (28) It is often helpful to provide two prescriptions, one for the morning "home" dose and one for the noon "school" administration. Increased attentiveness is reflected in tasks being performed more completely and with improved grades. Parent and teacher contact is essential, with feedback to the treating physician.

When prescribing for children, methylphenidate is started at 5 mg in the morning and at noon. Increments of 5 to 10 mg can be added to obtain the lowest effective dose (<60 mg per day). A regimen of two to three doses per day is required because of the short duration of action. Conservative recommendations for beginning methylphenidate in adults would be 10 mg per day. (29) A more aggressive titration of this drug in adults follows: 0.5 mg/kg/day during the first week, 0.75 mg,/kg/day in the second week, and 1 mg/kg/day thereafter, as tolerated. A marked therapeutic response to this regimen has been reported. (30)

Side effects from stimulants are usually transient and commonly include anorexia, abdominal discomfort, insomnia, headaches, and irritability. Difficulties with sleep are usually temporary and minimized by avoiding dosing late in the day. Pulse and blood pressure may increase slightly and should be monitored. Growth retardation is a controversial long-term adverse effect; if present, it is often reported not to be a major problem. (25,28) Stimulants are eliminated more rapidly in children than in adults because of relatively greater hepatic capacity; more glomerular clearance, and less body fat. In children, when stimulant levels decline, hyperactivity often returns.

Worsening of tics is observed; however, tics usually subside over time with dose reduction or when treatment is stopped. (28) Development of a chronic tic disorder caused by stimulant medication is rare. (31) Risperidone is reported to be more beneficial in the management of tics than haloperidol and has usefulness in reducing aggression in children. (32) The initial daily risperidone dose is 0.5 mg in children and 1 mg for adults, with a maximum of 4 to 6 mg daily.

Other Agents

Additional medications are available for the treatment of ADHD. These drugs, however, have been associated with adverse effects, limited study data, reduced effectiveness, or potentially dangerous drug-drug interactions.

Pemoline is a psychostimulant that acts through dopamine mechanisms. A starting dose for school-aged children is 37.5 mg in the morning, with weekly dose increases of 18.5 mg as necessary, to a maximum of 112.5 mg per day. (33) Toxic hepatitis is a potential complication of pemoline. In 11 cases, death or liver transplantation has been related to pemoline. (28) Frequent monitoring of hepatic function is necessary. Abnormal involuntary movements have also been reported. (34) Pemoline is now less commonly prescribed.

Modafinil is a new stimulant that does not act through a dopaminergic mechanism. (35) This drug may be selective for the hypothalamus and the tuberomamillary nucleus. A controlled study comparing modafinil and amphetamine in adults with ADD reported similar efficacy from both drugs. (35)

Antidepressant drugs have not been consistently beneficial. The tricyclic compounds often exhibit the development of tolerance after an initial response. (36) The improvement induced by desipramine or impramine in ADHD is less than that of stimulants. (28) Serious problems have occurred with antidepressants in children. Six sudden deaths have been reported from tricyclics in healthy children up to age 14. (37,38) The serotonin reuptake inhibitors have documented symptom reduction only when depression coexists with ADHD. (36) These antidepressants are safe, yet not widely prescribed for ADHD. An open label investigation of venlafaxine has shown ADHD symptom reduction. (39)

Bupropion is another antidepressant medication commonly considered to be a "secondline" treatment for attention deficit. In adults with problems of substance abuse who also have ADD, bupropion may be a good choice, since it is rarely abused. There is proof of therapeutic benefit with bupropion in adult ADD, but the degree of efficacy was less than that of stimulants. (40) The most frequent dose was 200 mg of sustained release bupropion, given twice per day (morning and afternoon) to minimize insomnia.

Clonidine, an [[alpha].sub.2]-adrenergic agonist, inhibits the release of norepinephrine, but is not as effective as psychostimulants for ADHD, and bothersome side effects limit its usefulness. (41) Four deaths have been recorded when methylphenidate was combined with clonidine. (42,43) A specific causal relationship between these drugs and the fatalities has not been established, however. (28) Guanfacine, another [[alpha].sub.2]adrenergic agonist, has also been used. When compared with clonidine, it has a lower frequency of sedation and less effect on blood pressure, with reduced risk of rebound hypertension. The starting dose is 0.5 mg in the morning. Every 3 days, the dose can be increased by 0.5 mg, with a usual maintenance regimen at 2 to 4 mg or 0.1 mg/kg. Divided doses of two to three per day are recommended, with the greatest quantity at bedtime.

Some physicians prescribe mood stabilizers such as valproic acid, carbamazepine, or lithium to persons with ADHD/ADD. These agents are not widely used in children. Atypical antipsychotic drugs also have occasional application.

Combination therapy, such as the administration of a stimulant with an antidepressant, neuroleptic, or an [alpha]-adrenergic drug, may be prescribed in cases not responding to traditional treatments. It is recommended that combination therapy be used with caution, especially in children.

Additional Interventions

Nonpharmaceutical therapies are recommended in addition to medications. Individual psychotherapy, behavior modification, parenting classes, parent support groups, school involvement, and education about ADHD/ADD can enhance results. Establishing a partnership between the school, parents, and therapist should improve learning and social skills. When parents and teachers provide a structured, predictable environment, the child experiences less anxiety and seems to function better.

A form of EEG biofeedback termed neurofeedback is used for treatment of hyperactivity, learning difficulties, and attention problems. (4) Selected children, adolescents, and adults have had significant long-term improvement with neurofeedback. Some were able to decrease or even discontinue stimulant medications. (4) Specific guidelines have been developed to determine appropriate candidates; for those who meet the criteria and have the time and money, neurofeedback offers an additional option. Unfortunately, only certain individuals will benefit, and it requires about 40 to 50 rather costly sessions.

Behavioral techniques have been used with adults and children. Because ADHD/ADD causes difficulties with time management, problem resolution, prioritization, and socialization, it has been suggested that these issues should be addressed. With effective use of behavioral interventions and consequences of failure, parents should understand the concept of limit setting and be able to convey this idea to their children.

Individual therapy for adults with ADD also focuses on skills of problem resolution, time management, prioritization of tasks, and socialization. They benefit from structure, consistent rules, and directions that are easily understood, brief, and reiterated. (44) Cognitive therapy teaches people to take time to think before talking or acting and to decrease impulsivity. This in turn may heighten confidence and self-esteem.

Family therapy helps children, parents, and siblings. Parents are taught how to approach their child with a united position. Consistency in setting limits helps reduce confusion for the child. The parents must be able to recognize impending loss of control and to manage those situations. Parental attention must be shared with all of the children in the family, rather than just the one with ADHD.

Treatment of the patient with ADHD/ADD remains challenging. The stimulant medications are the mainstay of treatment. Although the nonpharmaceutical treatment methods seem to make sense intuitively, their efficacy is questioned. (44) Development of new diagnostic techniques and safer medications provide hope for more effective management.

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RELATED ARTICLE: KEY POINTS

* The Diagnostic and Statistical Manual IV requires evidence of symptom onset before age 7 for a diagnosis of attention deficit disorder (ADD).

* Adults with ADD who also abuse substances may benefit from bupropion, which is rarely abused.

* For children, establishing a partnership between the patient, the parents, the school, and the therapist may help improve learning and social skills.

* The symptoms of attention deficit hyperactivity disorder (ADHD) vary with age and development. Hyperactivity usually lessens with age.

* Pharmacotherapy remains the primary treatment for ADHD.

From the Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Ky.

Reprint requests to Raymond Pary, MD, VA Medical Center, 800 Zorn Aye, Louisville, KY 40206.