39 ATTENTION-DEFICIT HYPERACTIVITY DISORDER

Kevin W. Cleveland and John Erramouspe

LEARNING OBJECTIVES
UPON COMPLETION OF THE CHAPTER, THE READER WILL BE ABLE TO:
1. Explain the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision criteria necessary for the diagnosis of attention-decit hyperactivity disorder.
2. Recommend a therapeutic plan, including initial doses, dosage forms, and monitoring

parameters, for a patient with attention-decit hyperactivity disorder.

3. Differentiate between the available pharmacotherapy used for attention-decit hyperactivity

disorder with respect to pharmacology and pharmaceutical formulation.

4. Recommend second-line and/or adjunctive agents that can be effective alternatives in the

treatment of attention-decit hyperactivity disorder when stimulant therapy is less than adequate.
5. Address potential cost-benet issues associated with pharmacotherapy of attention-decit

hyperactivity disorder.
6. Recommend strategies for minimizing adverse effects of attention-decit hyperactivity

disorder medications.

KEY CONCEPTS To meet present attention-decit hyperactivity disorder diag

nostic criteria, patients need to display either hyperactivity, impulsivity, and/or inattentiveness before the age of 7 years. The exact cause of attention-decit hyperactivity disorder is unknown, but dysfunction in neurotransmitters norepinephrine and dopamine has been implicated as a key component. Attention-decit hyperactivity disorder is rarely encountered without comorbid conditions. Treatment goals for attention-decit hyperactivity disorder are to improve behavior, increase attention/response inhibition (ability to stay on task), and minimize side effects associated with pharmacotherapy. Pharmacotherapy is superior to behavioral therapy in the treatment of attention-decit hyperactivity disorder. Behavior modication provided by parents and teachers in conjunction with pharmacotherapy improves treatment outcomes more than behavior therapy alone. Stimulants are rst-line agents for the treatment of attentiondecit hyperactivity disorder. If the initial trial of a stimulant

therapy fails, then a second trial of an alternative stimulant should be tried. On failure of a second trial of stimulant pharmacotherapy, it is rational to attempt a third trial with another stimulant formulation or select a nonstimulant agent such as bupropion, imipramine, or atomoxetine.

Attention-decit hyperactivity disorder (ADHD) is the most common mental disorder that occurs in the pediatric population.13 This disorder must begin in childhood before the age of 7 years and can continue into adulthood. ADHD is characterized by a core group of symptoms: hyperactivity, impulsivity, and inattention. Further, ADHD can be classied into three basic forms: inattentive, hyperactive/impulsive, and combined. It can have a severe impact on a patients ability to function in both academic and social environments, leading to a signicant burden on family and school personnel. The exact cause of ADHD is unknown, but twin studies strongly suggest a genetic etiology.35 Early diagnosis and appropriate treatment are essential to compensate for areas of decit and to allow the patient to cope in both family and social environments.

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Patient Encounter, Part 1

A single mother and her rambunctious 6-year-old boy, AD, come to your clinic. The mother is concerned because her neighbor, who watches AD after school for no charge, has complained about the problems he is causing among her own children (41/2- and 6-year-old boys). AD refuses to wait for his own turn in games and frequently hits the younger boy. The neighbor has said that unless AD becomes more manageable, she will not watch him after school. This is very distressing to ADs mother, who barely provides for her son and herself by working at the local convenience store for minimum wage. She cannot afford a professional babysitter for AD. She does not qualify for medical assistance. Further, she explains that his performance at school is getting worse, and he is becoming unmanageable in the classroom. Which of the patients symptoms are suggestive of ADHD? What other information do you need to assess for ADHD? What help/suggestions could you offer to ADs mother?

and concentrating on ideas.4,6 Further, children with ADHD often alternate between inattentiveness to monotonous tasks and overexcitement. Multiple brain studies have failed to elucidate any pathophysiologic basis for ADHD, although they have associated ADHD with atypical brain development in early childhood. Cerebral volume, the prefrontal cortex, the basal ganglia, and the caudate tend to be signicantly smaller in children with ADHD than in children without the disorder.4 Dysfunction in the roles of the neurotransmitters dopamine and norepinephrine is thought to be key in the pathology of ADHD. Norepinephrine is responsible for maintaining alertness and attention, whereas dopamine is responsible for regulating learning, motivation, goal setting, and memory. Both these neurotransmitters predominate in the frontal subcortical system, an area of the brain responsible for maintaining attention and memory. Also, the propensity for a genetic link with this disorder is high. There is a 50% chance that a child who has a parent with ADHD will develop ADHD. Further, studies of twins have demonstrated a concordance rate of 92% for ADHD. An association has been made between the development of ADHD and predisposing factors such as fetal alcohol syndrome, lead poisoning, maternal smoking, and hypoxia.4

CLINICAL PRESENTATION AND DIAGNOSIS EPIDEMIOLOGY AND ETIOLOGY

This disorder usually begins by 3 years of age but must occur prior to 7 years of age to meet diagnostic criteria. In the United States, ADHD is the most common neurobehavioral disorder that affects children.13,6 ADHD has been estimated to occur in between 4.3% and 12% of school-aged children.6,7 ADHD tends to occur at a greater incidence in males than in females by approximately 3:1 in school-aged children.7 However, during adolescence, the incidence of ADHD is equal between males and females. As adults, females have a greater incidence of ADHD symptoms than males. Although ADHD generally is considered a childhood disorder, symptoms can persist into adolescence and adulthood. The prevalence of adulthood ADHD is estimated to be 4%, with 60% of adults having manifested symptoms of ADHD from childhood.8,9 Further, problems associated with ADHD (e.g., social, marital, academic, career, anxiety, depression, smoking, and substance-abuse problems) increase with the transition of patients into adulthood.
PATHOPHYSIOLOGY

Clinical Presentation
General Patients with ADHD can present with inattention and/or hyperactivity-impulsivity. ADHD is rarely encountered without comorbid conditions. Symptoms Inattentionhas difculty paying attention to details in school, work, and social activities, difculty completing tasks that require a lot of mental effort; is easily distracted, forgetful. Hyperactivity/impulsivityhas difculty sitting still, dgets, has trouble playing quietly and waiting turns, frequently interrupts. Combinedexhibit both inattention and hyperactivity/ impulsivity. Diagnostic Criteria Must exhibit symptoms before 7 years of age that persist for greater than 6 months. Symptoms must be present in two or more settings and adversely affect functioning in social situations, school, or work. Must meet the diagnostic criteria in DSM-IV-TR (Table 391). Symptoms cannot be better explained by another mental disorder (e.g., autism).

The exact pathologic cause of ADHD has not been identied. ADHD is generally thought of as a disorder of self-regulation or response inhibition. Patients who meet the criteria for ADHD have difculty maintaining self-control, resisting distractions,

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TABLE 391. DSM-IV Diagnostic Criteria for ADHD

I. Either A or B: A. Inattention. Must have at least six or more of the following symptoms of inattention for at least 6 months: 1. Does not pay close attention to details in schoolwork, work, or other activities. 2. Has trouble maintaining attention for tasks or activities. 3. Has trouble actively listening when directly spoken to. 4. Has difculty following instructions and fails to nish important daily tasks, i.e., homework, chores, responsibilities at work. 5. Demonstrates difculty in organizing tasks/activities. 6. Tends to avoid or put off activities that requires concentration. 7. Tends to misplace items needed to complete tasks or activities. 8. Is easily distracted from current tasks or activities. 9. Forgetful. B. Hyperactivity/impulsivity. Must have at least six or more of the following symptoms of hyperactivity/impulsivity for at least 6 months: Hyperactivity 1. Fidgets and is restless in a sitting position. 2. Cannot sit still for extended periods. 3. Runs around when it is not appropriate. 4. Cannot play quietly. 5. Often on the move. 6 Talks excessively. Impulsivity 7. Answers questions prematurely. 8. Difculty waiting ones turn. 9. Interruptive or intrudes on others. II. Above symptoms were present before 7 years of age. III. Above symptoms are present in two or more settings. IV. Impairment is clearly evident in social, school, or work functioning. V. Symptoms cannot be attributed to another mental disorder (e.g., anxiety, depression, autism, or a personality disorder). Based on the above criteria, ADHD can be divided into three types: 1. ADHD combined type: Both 1A and 1B. 2. ADHD inattentive type: 1A criteria are met. 3. ADHD hyperactive-impulsive type: 1B criteria are met.
Reprinted, with permission, from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (Copyright 2000). American Psychiatric Association.11

obtained from various settings, including the family and school. Information is gathered from parent interviews, school reports, and an interview with and observation of the patient. This information should include the age of onset, frequency, severity, and duration of symptoms.10 The most useful diagnostic criteria for ADHD is the Diagnostic and Statisical Manual of Mental Health Disorders, 4th edition, Text Revision (DSM-IV-TR) (see Table 391). The DSM-IV-TR denes three subtypes of ADHD: (1) predominately inattentive, (2) predominantly hyperactive/impulsive, and (3) combined, in which both inattentive and hyperactive symptoms are evident.11 Other diagnostic tests, such as brain imaging, electroencephalograms, and continuous performance examinations, should be regarded as investigational and not used clinically for diagnosis. While some brain studies have demonstrated differences in brain morphology between ADHD patients and control individuals, these differences are not diagnostic.4 Although ADHD is considered a childhood disorder, signs and symptoms persist into adolescence and adulthood in approximately 40% to 80% and 60% of cases, repectively.1,9 Adult ADHD is difcult to assess, and diagnosis is always suspect in patients failing to display clear symptoms prior to the age of 7 years.4 Adults with ADHD have higher rates of psychopathology, substance abuse, social dysfunction, and occupational underachievement.

Patient Encounter, Part 2, Medical History, Physical Examination, and ADHD Evaluation
ADs baseline physical examination was unremarkable. Family history is positive for cardiovascular disease, and there is no documented history of ADHD in the family. Patient weight: 20 kg Allergies: None known Patient height: 45 in BP: 96/55 mm Hg Pulse: 80 beats/min ADs mother does not qualify for medical assistance, and she can hardly afford the monthly expenses. What stimulant and/or nonstimulant regimen(s) is(are) available that might control ADs symptoms? Which medications will facilitate adherence, minimize potential side effects, and offer an acceptable cost for ADs mother? What other information do you need before starting certain pharmacotherapy options? What are important counseling points to discuss with ADs mother?

ADHD is rarely encountered without comorbid conditions and often is underdiagnosed. Between 40% and 75% of patients with ADHD will have one or more comorbidities (e.g., learning disabilities, oppositional deant, conduct, anxiety, or depressive disorders).10 It is important to identify other coexisting conditions in patients with ADHD to assist in initial and ongoing selection of treatment. When a patient presents with inattention, hyperactivity, academic underachievement, and/or behavior problems, he or she should be evaluated for ADHD. Initial evaluation of the patient primarily should be for the purpose of information gathering. Evidence of the patients behavior should be

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TREATMENT Desired Outcomes

of a reward/consequence system.13 Success of behavioral modications depends on the cooperation and involvement of the patients parents and teachers.

The primary therapeutic objectives in ADHD are to improve behavior and increase attention; secondary goals of treatment are to
Improve relationships with family, teachers, and peers Decrease disruptive behavior in academic and social settings Improve academic performance Increase independence in activities Minimize undesirable adverse effects of therapy

Pharmacologic Therapy
The proposed mechanism of ADHD pharmacotherapy is to modulate neurotransmitters in order to improve academic and social functioning. Pharmacologic therapy can be divided into two categories: stimulants and nonstimulants. Stimulant medications include methylphenidate, dexmethylphenidate, amphetamine salts, and dextroamphetamine, whereas nonstimulant medications include atomoxetine, tricyclic antidepressants (e.g., imipramine), clonidine, guanfacine, and bupropion.

Nonpharmacologic (Behavioral) Therapy

Behavioral therapy can be used to treat patients with ADHD; however, it is generally not recommended as rst-line monotherapy.8 Several studies have demonstrated that treatment with medication alone is superior to behavioral intervention alone in improving attention.12 However, behavioral therapy in combination with stimulant therapy was better at improving oppositional and aggressive behaviors.12 Behavioral modication involves training parents, teachers, and caregivers to change the physical and social environment and establishment

Psychostimulants (e.g., methylphenidate and dextroamphetamine with or without amphetamine) are the most effective agents in treating ADHD. Once the diagnosis of ADHD has been made, a stimulant medication should be used rst line in treating ADHD (Fig. 391). Stimulants are safe and effective, with a response rate of 70% to 90% in patients with ADHD.3,13,14 Generally, a trial of at least 3 months on a stimulant is appropriate, and this includes dose titration to response

Stimulants

FIGURE 391. ADHD diagnosis and treatment algorithm. (Data from references 8, 13, and 16.)

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while balancing side effects.8,13 If treatment with the rst stimulant formulation fails, it is recommended to switch to a different stimulant formulation.13 For example, if the patient was started on methylphenidate but could not tolerate the side effects, switching to dextroamphetamine with or without amphetamine is rational. The majority of patients who fail one stimulant will respond to an alternative stimulant.13 If the patient fails two appropriate trials of different stimulant medications, a third stimulant formulation or second-line nonstimulant such as bupropion, imipramine, or atomoxetine can be considered. The diagnosis of ADHD should be revalidated as well. Stimulants theoretically exert their effect by blocking the reuptake of dopamine and norepinephrine, thus improving academic performance and decreasing motor activity in ADHD patients. Stimulants have been shown to decrease dgeting and nger tapping, increase on-task classroom behavior and positive interactions at home and in social environments, and ameliorate conduct and anxiety disorders.14 Stimulants should be initiated at recommended starting doses and titrated up with a consistent dosing schedule to the appropriate response while minimizing side effects (Table 392). Generally, stimulants should not be used in patients who have glaucoma, severe hypertension or cardiovascular disease, hyperthyroidism, severe anxiety, or previous illicit or stimulant drug abuse. Further, stimulants can be used, albeit cautiously, in patient with seizure disorders, Tourettes syndrome, and motor tics.14 Initial response to short-acting stimulant formulations (e.g., methylphenidate and dextroamphetamine) is seen within 30 minutes and can last for 4 to 6 hours.13,14 This short duration of effect frequently requires that short-acting stimulant formulations be dosed at least twice daily, thus increasing the chance of missed doses and noncompliance. Further, patients using any stimulant formulation but especially shortacting formulations can experience a rebound effect of ADHD symptoms as the stimulant wears off.14 To minimize rebound problems associated with shortacting formulations and still maintain early stimulant release, once-daily products (Adderall XR, Concerta, Metadate CD, and Ritalin LA) have been developed. Stimulant drug formulations can be divided into short-, intermediate-, and extended-acting preparations (see Table 392). Most intermediate-acting agents release the medication in a slow, continuous fashion without any early release (except Dexedrine Spansules). All extended-acting formulations have early release of medication and deliver a delayed release of stimulant in either a pulsed or continuous manner. Most of the extended-acting stimulants are capsules containing coated beads that can be opened and sprinkled on semisolid food. The exception, Concerta tablets, uses an oral osmotic controlled-release delivery system (the empty tablet shell can be detected in the stool). Adverse effects of stimulants can be generalized to the whole class (Table 393). Most of these side effects can be

managed by changing dosing routine, i.e., giving with food, dividing daily dose, or giving the dose earlier in the day. Serious side effects such as hallucinations and abnormal movements require discontinuation of medication.13,14 Growth suppression or delay is a major concern for parents of children taking stimulants. However, the evidence of this side effect is not clear. At present, growth delay appears to be transient and to resolve by midadolescence, but more data are needed to rmly resolve this issue.10 Another concern is the risk of substance abuse with stimulant use. A diagnosis of ADHD alone increases the risk of substance abuse in adolescents and adults. However, stimulant use has not been shown to further increase this risk but actually may decrease this risk, provided ADHD is treated adequately.15 The choice of ADHD medication should be made based on the patients condition, the prescribers familiarity with the medications, the ease of administration, and cost. Stimulants should be used rst line in most ADHD patients, although there is no clear advantage of using one stimulant over another in managing symptoms of ADHD.16
Nonstimulants Atomoxetine

Atomoxetine is the most recent addition to the ADHD armamentarium in both children and adults. In clinical studies, atomoxetine has demonstrated superior efcacy over placebo and equivalent efcacy when compared with a suboptimal immediate-release methylphenidate dose.1720 However, it is not clear whether atomoxetine is superior to typical methylphenidate doses or other stimulant formulations. Atomoxetine may be used as a second- or third-line medication for ADHD. Atomoxetine selectively inhibits the reuptake of adrenergic neurotransmitters, principally norepinepherine.1720 Atomoxetine is metabolized through the cytochrome P-450 CYP2D6 pathway. Approximately 5% to 10% of the population are CYP2D6 poor metabolizers, and atomoxetines half-life is increased signicantly in this population.21 The recommended dosing for atomoxetine depends on the weight of the patient and is given daily in either a single or two divided doses21 (see Table 392). In poor metabolizers, atomoxetine should be dosed once daily at 25% to 50% of the dose typically used in normal metabolizers.21 The maximum therapeutic effect of atomoxetine may take up to 4 weeks to be seen, which is signicantly longer than what is required with stimulants. Common side effects of atomoxetine are similar to those of stimulants: dyspepsia, nausea, vomiting, somnolence, and decreased appetite. Some studies have reported an increase in blood pressure and heart rate.1820 There is evidence that atomoxetine can slow growth rate and cause weight loss; thus height and weight should be monitored routinely in pediatric patients1820 (see Table 393). Further, atomoxetine labeling includes strong warnings about severe hepatotoxicity and increased association with suicidal thinking.

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TABLE 392. Selected Medications in Treating ADHDa

Drug, Generic (Brand) Stimulants Short-acting Methylphenidateb (Methylin, Ritalin) Dexmethylphenidateb (Focalin) Dextroamphetamineb (Dexedrine) Intermediate-acting Methylphenidateb (Ritalin SR, Metadate ER, Methylin ER) Dextroamphetamine/ amphetaminea (Adderall) Dextroamphetamineb (Dexedrine Spansule) Extended-acting Methylphenidateb (Concerta) (Metadate CD) (Ritalin LA) Dextroamphetamine/ amphetamineb (Adderall XR) Dexmethylphenidate (Focalin XR) Nonstimulants Atomoxetineb (Strattera) Initial Dose Titration Schedule Typical Dosing Range (Maximum Dose)

5 mg two times daily 2.5 mg two times daily 2.55 mg every morning

510 mg/d in weekly intervals 2.55 mg/d in weekly intervals 2.55 mg/d in weekly intervals 10 mg/d in weekly intervals 2.55 mg in weekly intervals 5 mg/d in weekly intervals

520 mg two to three times daily (60 mg/d) 510 mg twice daily (20 mg/d) 520 mg twice daily (40 mg/d)

10 mg once daily 2.55 mg once to twice daily

5 mg every morning

2040 mg daily in the morning (60 mg/d) 1030 mg every morning or 520 mg twice daily (40 mg/d) 530 mg daily or 515 mg twice daily (40 mg/d)

18 mg every morning 20 mg every morning 20 mg every morning 510 mg every morning (children) 20 mg once daily (adults) 5 mg every morning (children) 10 mg every morning (adults) 70 kg: 0.5 mg/kg per day divided once to twice daily >70 kg: 40 mg once daily 1.5 mg/kg per day in one or two divided doses

918 mg/d in weekly intervals 1020 mg/d in weekly intervals 1020 mg/d in weekly intervals 510 mg/d in weekly intervals 510 mg/d in weekly intervals 1040 mg/d after 3 days 4080 mg/d after 3 days (may to total of 100 mg/d after 23 weeks) 1 mg/kg per day every 3 to 4 days

1854 mg every morning (72 mg/d) 2040 mg daily in the morning (60 mg/d) 2040 mg daily in the morning (60 mg/d) 1030 mg every morning or 515 mg twice daily (30 mg/d, children) (60 mg/d, adult) 1020 mg daily in the morning (20 mg/d) 4060 mg/d (1.4 mg/kg or 100 mg/d, whichever is less) 4080 mg/d divided once to twice daily (100 mg/d) 1.53 mg/kg per day in one or two divided doses (5 mg/kg per day, child) 100300 mg/d in one or two divided doses (300 mg/d, adult) 0.1 mg once to four times daily (0.4 mg/d) 1.53 mg/d divided into two or three times daily (4 mg/d) 6 mg/kg per day or 400 mg/d whichever is smaller (children); 150450 mg/d (400 mg/d SR; 450 mg/d XL - adults)

Imipramine (Tofranil)

Clonidine (Catapres) Guanfacine (Tenex) Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL)
a

0.05 mg once daily 0.5 mg at bedtime 3 mg/kg per day for 7 days (children); 150 mg once daily of SR or XL (adults)

0.05 mg/d every 3 to 7 days 0.5 mg every 3 to 14 days 3 mg/kg per day in weekly intervals (children); 150300 mg/d in weekly intervals (adults)

Pediatric dosing except where adult dosing specied. FDA approved for treatment of ADHD.

Atomoxetine is similar to extended-acting stimulants in that it can be given once daily in many patients. Atomoxetine appears to lack any abuse potential and is not a controlled substance.22 One big disadvantage of atomoxetine is cost compared with other ADHD medications (Table 394). Owing to the high cost and lack of long-term efcacy and comparison studies with stimulants, atomoxetine should be

advocated only if the patient has failed or is intolerant to the standard stimulant therapy (see Fig. 391).
Bupropion

Bupropion is a monocyclic antidepressant that inhibits the reuptake of norepinephrine and dopamine. Bupropion is effective for relieving symptoms of ADHD in children but is

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TABLE 393. ADHD Medication Side-Effect Proles, Management, and Monitoring

Drug Stimulants Methylphenidate, dextroamphetamine, mixed-salts amphetamine Side Effects GI upset, nausea, decreased appetite, potential growth delay Management Administer after meals Encourage high-calorie meals Divide dose Give snacks in the evening Change to shorter-acting stimulant Use drug holiday or different medication if severe growth delay Give dose earlier in the day Give clonidine or guanfacine at bedtime Discontinue all doses given afternoon Change to a shorter-acting stimulant Change to longer-acting stimulant Overlap stimulant dosing dose or change to longer-acting stimulant Verify diagnosis/comorbidity Evaluate time of occurrence Early onset: dose or change to longeracting stimulant Late onset: Switch to longer-acting stimulant Evaluate for comorbidity dose or change to longer-acting stimulant Discountinue or change to a different stimulant Give clonidine or guanfacine dose or change to another medication Monitoring Height, weight, blood pressure, pulse Eating and sleeping patterns Evaluate every 2 to 4 weeks until stable dose is achieved; then evaluate every 3 months

Sleep disturbance

Rebound symptoms Moodiness

Irritability

blood pressure and pulse Tics Nonstimulants Atomoxetine

Tricyclic antidepressants (imipramine)

blood pressure and pulse, nausea, vomiting, fatigue, and insomnia Hepatotoxicity, suicidal thoughts Sedation Cardiac conduction delay, dizziness, pulse Anticholinergic effects (constipation, dry mouth, difculty urinating, blurry vision) Sedation, arrthymias, constipation, dizziness ( blood pressure) GI upset, restlessness, sleep disturbances, rash, tics, risk of seizures

Same as above but with baseline and routine liver function tests for hepatotoxicity

Discountinue or change to a another medication Administer later in the day dose or change medication dose or change medication

Blood pressure, pulse, sleeping pattern Evaluate every 3 days until stable dose is achieved; then evaluate every 3 months

Clonidine and guanfacine

Sedation: administer later in the day dose or change medication dose or change medication Tics, rash, and seizures: discontinue medication

Same as above but with electrocardiogram (ECG)

Bupropion

Height, weight, blood pressure, pulse every month Eating and sleeping patterns

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TABLE 394. 30-Day Costa of Selected ADHD Medication Regimens

Generic Short-Acting Stimulants Methylphenidate Generic Methylin Dexmethylphenidate Focalin Dextroamphetamine Generic Intermediate-Acting Stimulants Methylphenidate Methylin ER Dextroamphetaminec Dexedrine Spansule Dextroamphetamine/amphetamine Generic Extended-Acting Stimulants Methylphenidate Concertac Metadate CDb Ritalin LAb Dextroamphetamine/amphetamine Adderall XRb Dexmethylphenidate Focalin XRb Nonstimulants Atomoxetine Strattera Regimen (Brand) Costa

5-, 10-, or 20-mg tab bid 5 mg/5 mL soln bid 2.5- or 5-mg tab bid 10-mg tab bid 5- or 10-mg tab bid

$ $$$ $$ $$$ $

10- or 20-mg ER tab daily 5-, 10-, or 15-mg cap daily 5-, 7.5-, 10-, 12.5-, 15-, 20-, or 30-mg tab daily or bid

$ $ $

18-, 27-, 36-, or 54-mg tab daily 10-, 20-, or 30-mg cap daily 10-, 20-, 30-, or 40-mg cap daily 5-, 10-, 15-, 20-, 25-, or 30-mg cap daily 5-, 10-, or 20-mg cap daily 10-, 18-, 25-, 40-, 60-, 80d-, or 100d-mg cap daily 10-, 18-, 25-, or 40-mg cap bid 10-, 25-, or 50-mg tab bid 0.1-, 0.2-, or 0.3-mg tab bid 1-mg tab bid 2-mg tab bid 75- or 100-mg tab bid 100- or 150-mg SR tab bid 200-mg SR tab bid 150-mg XL tab daily 300-mg XL tab daily

$$$$ $$$ $$$ $$$$ $$$$

$$$ $$$$ $ $ $ $$ $$ $$$ $$$$ $$$ $$$$

Imipramine Generic Clonidine Generic Guanfacine Generic Bupropion Generic Wellbutrin SR Wellbutrin XL
a

Cost based on brand regimen specied without a dispensing fee or discount for a 1-month supply. Bimodal release (early then late; mimics bid dosing of shorter-acting stimulant counterpart). c Ascending release (early then gradual/continuous). d New dosage strength; cost not yet available. $, less than $40; $$, $40 to $79; $$$, $80 to $120; $$$$, greater than $120. tab, tablet; cap, capsule; chew tab, chewable tablet; soln, solution bid, twice daily; tid, thrice daily; SR, sustain release; ER, extended release; XL, extended release; LA, longacting; CD, extended release (biphasic immediate release with extended release).
b

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not as effective as stimulants.23,24 Similar results have been shown in adults.23 Specic dosing recommendations are outlined in Table 392. Bupropion is well tolerated with minimal side effects (e.g., insomnia, headache, and nausea). Side effects typically disappear with continuation of therapy and are minimized with slow titration of dose. Bupropion can worsen tics and movement disorders. Bupropion is a rational choice in an ADHD patient with comorbid depression.23 However, seizures have been associated with bupropion doses greater than 6 mg/kg per day.25 Seizures related to high doses can be minimized by reducing the dose or switching to a longer-acting formulation. Owing to the propensity of seizures with bupropion, its use is contraindicated in patients with seizure and eating disorders.
Tricyclic Antidepressants

The tricyclic antidepressants (TCAs), such as imipramine, can alleviate symptoms of ADHD. Like bupropion, TCAs likely will improve symptoms associated with comorbid anxiety and depression. The mechanism of action of TCAs is in blocking norepinephrine transporters, thus increasing norepinephrine concentrations in the synapse; the increase in norepinephrine is believed to alleviate the symptoms of ADHD. TCAs have been demonstrated to be an effective nonstimulant option for ADHD but less effective than stimulants. However, their use in ADHD has declined owing to case reports of sudden death and anticholinergic side effects6,13 (see Table 393). Further, TCAs may lower seizure threshold and increase the risk of cardiotoxicity, e.g., arrythmias. Patients starting on TCAs should have a baseline and routine electrocardiograms.
Clonidine and Guanfacine

of ADHD can be attributed to the direct cost of pharmacotherapy, ofce visits, diagnostic measurements, therapy monitoring, and indirect costs (e.g., lost work time and productivity). It is estimated that children with ADHD are up to nine times more likely than other children to have prescriptions lled and incur ofce visits. When selecting a treatment for an ADHD patient, the cost burden to the patients family should be considered. Immediaterelease stimulants may be more cost-effective in many patients compared with longer-acting stimulant formulations (see Table 394), but in certain circumstances, longer-acting stimulant formulations may provide a cost benet owing to increased adherence to the medication and prolonged control of symptoms of ADHD. Some nonstimulant ADHD medications (e.g., TCAs, 2-adrenergic agonists, and bupropion) appear to be less costly than many stimulant formulations; however, these agents have not been proven to have superior efcacy over stimulants in treating ADHD. Decisions on selection of specic ADHD medications should not be based solely on cost, but efcacy and safety, along with adherence to the prescribed regimen, should be considered foremost.

OUTCOME EVALUATION
It is important to carefully document core ADHD symptoms at baseline to provide a reference point from which to evaluate effectiveness of treatment. Improvement in individualized patient outcomes are desired, such as (1) family and social relationships, (2) disruptive behavior, (3) completing required tasks, (4) self-motivation, (5) appearance, and (6) self-esteem. It is very important to elicit evaluations of the patients behavior from family, school, and social environments in order to assess the preceding. Using standardized rating scales (e.g., Conners Rating ScalesRevised, Brown Attention-Decit Disorder Scale, and IOWA Conners Scale) in both children and adults with ADHD helps to minimize variability in evaluation.29 After initiation of therapy, evaluations should be done every 2 to 4 weeks to determine efcacy of treatment, height, weight, pulse, and blood pressure. Physical examination or liver function tests may be used to monitor for adverse effects. Typically, therapeutic benets will be seen within days of initiating stimulants and within a month or two with atomoxetine and bupropion. Once a maintenance dosing has been achieved, schedule follow-up visits every 3 months. At these visits, assess height and weight, and screen for possible adverse drug effects. If a patient has failed to respond to multiple agents, reevaluate for other possible causes of behavior dysfunction. Counsel patients and their families that treatment is generally long term. Typically, appropriately treated patients learn to better control their ADHD symptoms as adults.

Clonidine and guanfacine are central 2-adrenergic agonists that inhibit the release of norepinephrine presynaptically. Both these agents are less effective than stimulants in treating symptoms of ADHD but typically are used as adjuncts to stimulants to control disruptive or aggressive behavior and alleviate insomnia.26 Guanfacine will last 3 to 4 hours longer than clonidine and requires less frequent dosing. Common side effects with clonidine and guanfacine are low blood pressure and sedation. Sedation is transient and should subside after 2 to 3 weeks of therapy.26 Rarely, severe side effects such as bradycardia, rebound hypertension, irregular heart beats, and sudden death have been reported.

Pharmacoeconomic and Treatment Adherence Considerations

Proper ADHD treatment is a substantial nancial burden.27,28 Annual health care costs of patients with ADHD are more than double those of patients without ADHD ($1343 versus $503, respectively).27 Further, the total cost of ADHD in the United States in 2000 was $31.6 billion.28 The nancial burden

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SECTION 6 / PSYCHIATRIC DISORDERS

Patient Care and Monitoring

1. Assess the patients symptoms and parent/teacher evaluations to determine whether they meet the DSM-IV-TR diagnostic criteria for ADHD. Evaluate whether the symptoms can be explained by another disorder? 2. Interview the patient and/or caregivers to obtain a complete medical history, which should include family medical history, current and past prescription and nonprescription medications, and dietary intake. Determine whether the patient is taking medication/supplements that could interfere with the therapy? 3. Educate the patients parents and/or caregivers that behavioral therapy is not as effective as stimulant therapy. Educate parents regarding the issues of growth delay and substance abuse risks with stimulants. 4. Perform a baseline physical examination before starting stimulant therapy. Include blood pressure, pulse, and height and weight measurements. In patients taking stimulants, perform a general physical examination yearly, and monitor blood pressure quarterly in adults. 5. Start patients on a low initial dose of a stimulant and titrate up to the desired response in order to minimize side effects and costs. 6. If the patient is not responding to therapy after an adequate trial, assess compliance with the prescribed regimen. If the patient is not compliant, counsel the patient and caregivers and explore reasons for noncompliance. In some cases, switching to another stimulant formulation may improve compliance. 7. Important counseling points to convey to the patient and/or caregiver: What is ADHD? What are the complications of untreated ADHD? When to take medications and what to expect with therapy. What side effects to expect and what to do if these occur. Controversy over substance abuse and growth delay with stimulant therapy. What medications, prescription and nonprescription, to avoid.

ABBREVIATIONS
ADHD: attention-decit hyperactivity disorder DSM-IV-TR: Diagnostic and Statisical Manual of Mental Disorders, 4th edition, Text Revision

Reference lists and self-assessment questions and answers are available at <insert web address here>.

KEY REFERENCES AND READINGS

American Academy of Pediatrics. Subcommittee on AttentionDecit/Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: Treatment of the school-aged child with attention-decit/hyperactivity disorder. Pediatrics 2001;108(4):10331044. American Academy of Pediatrics: Subcommittee on AttentionDecit/Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: Treatment of the school-aged child with attention-decit/hyperactivity disorder. Pediatrics 2001;108:10331044. Herrerias CT, Perrin JM, Stein MT. The child with ADHD: Using the AAP clinical practice guideline. Am Fam Phys 2001;63(9): 18031810. Rappley MD. Attention decit-hyperactivity disorder. New Engl J Med 2005;352:165173. Voeller KKS. Attention-decit hyperactivity disorder (ADHD). J Chil Neurol 2004;19:798814. Wolraich ML, Wibbelsman CJ, Brown TE, et al. Attentiondecit/hyperactivity disorder among adolescents: A review of the diagnosis, treatment, and clinical implications. Pediatrics 2005;115(6):17341746.