Attention-deficit/hyperactivity disorder, or ADHD, affects 4% to 5% of youths worldwide and is the most common neurobehavioral disorder treated in children.¹ Recent research and clinical experience are changing our understanding of ADHD in two important ways:

First, we now recognize that ADHD is often chronic. Its symptoms and/or associated impairment persist into adolescence in approximately three-quarters of cases and into adulthood in approximately one-half of childhood cases.^2-3 Throughout the lifespan, ADHD is associated with significant psychopathology, school and occupational failure, and peer and emotional difficulties.⁴

Second, the presence of impaired cognition has largely replaced the view that ADHD was characterized primarily by overactivity and impulsivity.⁵ This insight is leading to innovations in pharmacotherapy that offer youths and adults improved control of ADHD symptoms, with less-frequent dosing and lower risk of side effects.

Neurobiology

Although the precise neurobiology of ADHD remains unknown, frontal network abnormality or frontal-striatal dysfunction appears critical.⁶ Catecholamine dysregulation affecting both the dopaminergic and noradrenergic systems appears to be important in the underlying pathophysiology.⁶ For example, a small replicated study using SPECT imaging found adults with ADHD had twice the dopamine transporter binding potential of age-matched controls.⁷ Recent data also suggest the cholinergic system is involved in mediating symptoms of ADHD, particularly attentional regulation. Data from adoption, twin, and family-genetic studies suggest a genetic contribution in ADHD, with molecular studies focusing on the dopamine D2, D4, and the dopamine transporter as candidate genes.⁸

Diagnosis

Symptoms of ADHD are related to the patient’s age at presentation. In youth, ADHD is characterized by inattention, distractibility, impulsivity, and hyperactivity excessive for the child’s developmental level.^1,5 Other symptoms include low frustration tolerance, frequent shifting of activities, difficulty organizing tasks, and daydreaming. While these symptoms are typically pervasive, they may not occur in all settings.

Older adolescents and adults tend to present with prominent attentional difficulties (distractibility, shifting activities frequently, forgetfulness, disorganization) that affect work, schooling, and relationships.⁹ These older patients frequently also manifest residual impulsivity (intrusiveness, impatience) and hyperactivity (fidgetiness, restlessness).⁶ Adults with ADHD have a history of childhood onset of the disorder, with persistence through adolescence and beyond. Diagnosis of adult ADHD requires evidence of impairment in academic, work, and interpersonal domains.

Table 1

DSM-IV CRITERIA FOR DIAGNOSING ADHD

1. Either (1) or (2)
2. Some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7.
3. Some impairment from the symptoms is present in two or more settings (e.g., at school/work or at home).
4. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning.
5. The symptoms do not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychiatric disorder and are not better accounted for by a mood, anxiety, dissociative, personality, or other mental disorder.

Code based on type:

314.01 ADHD, Combined Type—if both criteria A1 and A2 have been met for the past 6 months.

314.00 ADHD, Predominantly Inattentive Type—if criterion A1 has been met but criterion A2 has not been met for the past 6 months.

314.01 ADHD, Predominantly Hyperactive-Impulsive Type—if criterion A2 has been met but criterion A1 has not been met for the past 6 months.

(Specify “In partial remission” in patients whose symptoms no longer meet full criteria).

Adapted from: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision. Washington: American Psychiatric Association, 2000.

DSM-IV recognizes three subtypes of ADHD based on presenting symptoms:

• predominantly inattentive (20% to 30% of cases);
• predominantly hyperactive-impulsive (<15%);
• combined inattentive and hyperactive-impulsive (50% to 75%).

ADHD is diagnosed by clinical history, applying DSM-IV criteria ( Table 1). Rating scales, checklists, and neuropsychological batteries—although not diagnostic—may help provide evidence for the disorder and accompanying comorbid conditions (e.g., Conners Rating Scales, Brown Rating Scales).⁵

Complicating the clinical picture of ADHD is the common co-occurrence of other psychiatric disorders. Almost three-quarters of individuals with ADHD have psychiatric comorbidity, including:

• oppositional disorders (40% to 60% of ADHD cases);
• conduct disorders (10% to 20%);
• anxiety disorders (30% to 40%);
• mood disorders (20% to 30%).¹⁰

For example, although few people with ADHD develop bipolar illness, an excess of ADHD is reported in depressed (20% to 30%) and bipolar youth (50% to 90%).¹¹ ADHD and its associated comorbid conditions also place sufferers at risk for higher rates and younger onset of cigarette smoking and substance abuse.¹² Most studies, however, indicate that pharmacotherapy reduces the risk for later drug and alcohol use disorders.¹³

Treatment

Management of ADHD includes nonpharmacologic and pharmacologic interventions.¹ Support groups (e.g., Children and Adults with Attention Deficit/Hyperactivity Disorder (CHADD), www.chadd.org) are invaluable and inexpensive sources of information about ADHD.

For children in school, a specialized educational plan with frequent re-evaluations of the child’s progress is recommended. Encourage parents to work closely with the child’s teacher, guidance counselor, or school psychologist. Children with ADHD tend to perform better in school when given structure, a predictable routine, checked homework, learning aids, and resource room time.⁵ Specific remediation plans are recommended for comorbid learning disorders, found in approximately one-third of individuals with ADHD.

Adults with ADHD may need to modify their school or work settings to function well. College students should be encouraged to use their school’s study center, and may require accommodations for taking examinations.

Focused cognitive behavioral therapies have shown benefit in children, adolescents, and adults with ADHD.¹⁴ Training children and their parents in behavioral modification can help control the child’s disruptive behaviors, inflexibility, anxiety, or outbursts. Other useful adjuncts to treatment include remediation to improve interpersonal skills and coaching to address organization and study skills.

Pharmacotherapy

Medications are fundamental in treating ADHD¹ (Table 2). In fact, a 14-month, multisite study demonstrated that medication management of ADHD was the most important variable in outcome when patients received combined pharmacologic and nonpharmacologic therapies.¹⁵ Stimulants, antihypertensives, and antidepressants are used to treat ADHD symptoms. Children, adolescents, and adults with ADHD respond similarly to pharmacotherapy.¹⁶

Psychostimulants: First-line agents

Psychostimulants are first-line agents for ADHD, based in part on extensive data showing efficacy (>250 controlled trials) and safety.^17,18 Stimulants are sympathomimetic drugs that increase intrasynaptic catecholamines (mainly dopamine) by inhibiting the presynaptic reuptake mechanism (amphetamine, methylphenidate, and pemoline) and releasing presynaptic catecholamines (amphetamine).¹⁹ Methylphenidate, dextroamphetamine, amphetamine compounds, and magnesium pemoline are among the most commonly used compounds in this class.

New approaches Prescribing stimulants for ADHD has changed in two fundamental ways. Frist, in the past we covered a child’s ADHD symptoms only during school hours, but we now include time after school and weekends and holidays. Second, we also are using longer-acting stimulant preparations, which recently became available. Extended-release preparations are usually preferred for lack of in-school dosing requirements, improved compliance, reduced stigma and wear-off, and lower risk of abuse or diversion—i.e., the medication being given or sold by an individual with ADHD to someone who is using it recreationally.

Short-acting compounds such as methylphenidate, D-methylphenidate, and D-amphetamine begin working within 30 to 60 minutes. Their clinical effect usually peaks 1 and 2 hours after administration and lasts 2 to 5 hours. The amphetamine compounds (e.g., Adderall) and older sustained-release methylphenidate begin working within 60 minutes, with a clinical effect that usually peaks between 1 and 3 hours and is maintained for 5 to 8 hours).

Table 2

RECOMMENDED DOSING OF PSYCHOSTIMULANTS FOR ADHD

Newer extended-release methylphenidate products (e.g., Ritalin LA and Metadate CD), with 8 to 9 hours’ duration of action, were developed to approximate twice-daily short-acting methylphenidate. The Concerta brand of methylphenidate, with 10 to 12 hours’ duration of action, approximates short-acting methylphenidate given three times daily. The extended-release Adderall XR brand of amphetamine compound, with a 10- to 12-hour duration of action, is similar to twice-daily Adderall.

Methylphenidate is the most studied, but among the available stimulants the literature suggests more similarities than differences in patient response.^17,18 Because of the agents’ marginally different mechanisms of action, however, some patients who do not respond satisfactorily to one stimulant or manifest adverse effects may respond more favorably to another agent of this type.

Start stimulants at the lowest available dose and increase every 3 to 4 days until a response is noted or adverse effects emerge. Dose-response data indicate more robust response at higher dosages of stimulants; therefore, efficacy—rather than onset of side effects—should guide titration to an optimal dose.

Predictable short-term adverse effects include reduced appetite, insomnia, edginess, and GI upset.²⁰ To manage these effects, consider when they occur:

• Within 2 hours after administration may signal the need to reduce the dose or change to another preparation.
• Within 4 to 6 hours after administration (e.g., moodiness) suggests the need for a longer-acting preparation or low dosing prior to the anticipated wear-off.

For insomnia, strategies include using a shorter-acting stimulant preparation, reducing the stimulant load in the afternoon, or providing adjunct treatment for the insomnia (i.e., clonidine, imipramine, mirtazapine).¹⁷ Edginess and headaches—more common in adolescents and adults—can be reduced with low-dose beta blockers. For diminished appetite in youths, caloric intake can be enhanced with a hearty breakfast, late-afternoon and evening snacks, and caloric supplements. Appetite enhancers such as cyproheptadine given nightly may be considered. Pemoline may rarely cause hepatitis and requires liver function monitoring.

Chronic use of stimulants is controversial.^17,18 Although stimulants may produce anorexia and weight loss, their effect on a youth’s ultimate height is less certain. Initial reports of a persistent stimulant-associated growth decrease have not been substantiated. Other studies suggest that growth deficits may represent maturational delays related to ADHD rather than to stimulant treatment.²¹

Stimulants may precipitate or exacerbate tic symptoms in children with ADHD. Recent work suggests that stimulants can be used safely in youth with tic disorders,²² although up to one-third may experience worsening of tic symptoms.

Despite case reports of stimulant misuse, there is little data to support stimulant abuse among treated children with ADHD.¹³ However, the diversion of stimulants to youth without ADHD is a concern.

Antidepressants

Antidepressants are generally considered second-line drugs for ADHD.^1,16 Bupropion, an antidepressant with indirect dopamine and noradrenergic effects, has been shown effective in ADHDin controlled trials of both children and adults.^23,24

Bupropion is often prescribed first for complex patients with ADHD and substance abuse or an unstable mood disorder because of its ability to reduce cigarette smoking and improve mood, lack of monitoring requirements, and few adverse effects. Dosing is typically initiated at 100 mg of the sustained-release preparation and increased weekly to a maximum of 300 mg in younger children and 400 mg in older children or adults (i.e., 200 mg bid). Adverse effects include insomnia, activation, irritability, and (rarely) seizures.

The tricyclic antidepressants (TCAs) used in ADHD—imipramine, desipramine and nortriptyline—block the reuptake of neurotransmitters including norepinephrine. TCAs are effective in controlling abnormal behaviors and improving cognitive impairments associated with ADHD, but less so than the stimulants. TCAs are particularly useful when:

• stimulants fail to control ADHD symptoms;
• oppositional behavior, anxiety, tics, or depressive symptoms coexist within ADHD or occur during its treatment.

Desipramine appears to be the most effective TCA for ADHD, followed by nortriptyline and imipramine.^25,26 TCAs are dosed starting with 25 mg/d and slowly increased to a maximum of 5 mg/kg/day (2 mg/kg/day for nortriptyline). Although immediate relief can be seen, a delay of up to 6 weeks for maximal effect is common. Typical adverse effects include dry mouth, constipation, sedation, and weight gain.

Four deaths have been reported in children with ADHD treated with desipramine; however, independent evaluation of these cases failed to support a causal link. As minor increases in heart rate and ECG intervals are predictable with TCAs, ECG monitoring at baseline and at therapeutic dosages is recommended.

Although serotonin reuptake inhibitors are not generally useful for ADHD, venlafaxine appears to have mild efficacy, perhaps because of its dose-dependent noradrenergic reuptake inhibition.²⁷

Monoamine oxidase inhibitors (MAOIs) have been shown effective in juvenile ADHD. Response to treatment is rapid, and standard antidepressant dosing is often necessary.¹⁶ A major limitation to the use of MAOIs is the potential for hypertensive crisis associated with dietetic transgressions and drug interactions.

Other treatment options

Antihypertensives The antihypertensive agents clonidine²⁸ and guanfacine²⁹ are used to treat the hyperactive-impulsive symptoms of ADHD in youth. Clonidine is relatively shortacting, with usual daily dosage ranges from 0.05 to 0.4 mg.²⁸ Guanfacine is longer acting and less potent, with usual daily dosage ranges from 0.5 to 4 mg.²⁹

Antihypertensives have been used to treat ADHD and associated tics, aggression, and sleep disturbances, particularly in younger children.¹⁶ Although sedation is more common with clonidine than guanfacine, both agents may cause depression and rebound hypertension. Cardiovascular monitoring (vital signs, ECG) remains optional.

New agents Novel compounds, along with new preparations and delivery systems of existing stimulant medications, are being investigated for managing ADHD. New agents are being tested in adults with ADHD because adults and youth respond similarly to ADHD medications, and there are ethical concerns about drug testing in children.

Atomoxetine, a noradrenergic reuptake inhibitor under development, has been shown in open and controlled studies of adults and youth³⁰ to be effective in treating ADHD. Atomoxetine appears well tolerated, with no blood monitoring requirements.

Cholinergics and genes Selective use of cholinergic agents (e.g., donepezil) may also be helpful for the cognitive dysfunction in ADHD,²⁴ either as monotherapy or in combination with other agents for ADHD. Multiple centers are investigating the possible link between response to pharmacologic therapy and ADHD genotype.

Combination therapy

Combinations of pharmacologic agents can be used to treat comorbid ADHD, to augment response to a single agent, for pharmacokinetic synergism, and to manage adverse effects that emerge during treatment. Examples include:

• a tricyclic antidepressant and a stimulant to heighten response to treatment;
• an antidepressant plus a stimulant for ADHD and comorbid depression;
• adjunctive use of clonidine for sleep or to manage aggressive behavior;
• use of mood stabilizers with ADHD medications for comorbid bipolar disorder.¹⁶

Pharmacologic intervention for prominent concomitant mood disorders (depression and bipolarity) and anxiety should be sequenced prior to ADHD treatment.

Summary of treatment recommendations

Based on efficacy and safety, stimulants are first-line agents for routine management of ADHD, followed by antidepressants and antihypertensives. Patients who do not respond to the initial stimulant or who manifest adverse effects should be considered for a trial with an alternate stimulant. If two stimulant trials are unsuccessful, bupropion and the tricyclic antidepressants are reasonable second-line agents.

Antihypertensives alone or in combination with other ADHD medication may help youths with tics,³¹ prominent hyperactivity, impulsivity, or aggressiveness. MAOIs may be considered for refractory patients, and cholinergic agents (e.g., donepezil) may be used for excessive cognitive difficulties such as organization, planning, and time management.

Related resources

• Barkley RA. Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. New York: The Guilford Press, 1998.
• Wilens T. Straight Talk About Psychiatric Medications for Kids. New York: The Guilford Press, 1998.
• Children and Adults with Attention-Deficit/Hyperactivity Disorder (CHADD), www.chadd.org

Drug brand names

• Atomoxetine • (under development)
• Bupropion • Wellbutrin
• Clonidine • Catapress
• Dextro-amphetamine • Dexedrine
• Dexmethylphenidate • Focalin
• Donepezil • Aricept
• Guanfacine • Tenex
• Methylphenidate • Ritalin, Concerta, Metadate
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

Dr. Biederman reports that he receives research/grant support from, and is on the speaker’s bureau and advisory boards of Eli Lilly & Co. and Shire Laboratories. He also reports that he receives research/grant support from Wyeth-Ayerst Pharmaceuticals, Pfizer Inc., Cephalon Pharmaceutical, Janssen Pharmaceutica, and Noven Pharmaceutical; is on the speaker's bureau of GlaxoSmithKline, Pfizer Inc., Wyeth-Ayerst Pharmaceuticals, Alza/McNeil Pharmaceutical and Cephalon Pharmaceutical; and is on the advisory board of Cell Tech, Noven Pharmaceutical, and Alza/McNeil Pharmaceuticals.

Drs. Wilens and Spencer report that they receive research/grant support from, are on the speakers bureau of, and/or serve as consultants to Abbott Laboratories, McNeil Pharmaceuticals, Celltech Medieva, GlaxoSmithKline, Eli Lilly & Co., Novartis Pharmaceuticals Corp., Pfizer Inc., Shire Pharmaceuticals Group, and Wyeth-Ayerst Pharmaceuticals.

Attention-deficit/hyperactivity disorder, or ADHD, affects 4% to 5% of youths worldwide and is the most common neurobehavioral disorder treated in children.¹ Recent research and clinical experience are changing our understanding of ADHD in two important ways:

First, we now recognize that ADHD is often chronic. Its symptoms and/or associated impairment persist into adolescence in approximately three-quarters of cases and into adulthood in approximately one-half of childhood cases.^2-3 Throughout the lifespan, ADHD is associated with significant psychopathology, school and occupational failure, and peer and emotional difficulties.⁴

Second, the presence of impaired cognition has largely replaced the view that ADHD was characterized primarily by overactivity and impulsivity.⁵ This insight is leading to innovations in pharmacotherapy that offer youths and adults improved control of ADHD symptoms, with less-frequent dosing and lower risk of side effects.

Neurobiology

Although the precise neurobiology of ADHD remains unknown, frontal network abnormality or frontal-striatal dysfunction appears critical.⁶ Catecholamine dysregulation affecting both the dopaminergic and noradrenergic systems appears to be important in the underlying pathophysiology.⁶ For example, a small replicated study using SPECT imaging found adults with ADHD had twice the dopamine transporter binding potential of age-matched controls.⁷ Recent data also suggest the cholinergic system is involved in mediating symptoms of ADHD, particularly attentional regulation. Data from adoption, twin, and family-genetic studies suggest a genetic contribution in ADHD, with molecular studies focusing on the dopamine D2, D4, and the dopamine transporter as candidate genes.⁸

Diagnosis

Symptoms of ADHD are related to the patient’s age at presentation. In youth, ADHD is characterized by inattention, distractibility, impulsivity, and hyperactivity excessive for the child’s developmental level.^1,5 Other symptoms include low frustration tolerance, frequent shifting of activities, difficulty organizing tasks, and daydreaming. While these symptoms are typically pervasive, they may not occur in all settings.

Older adolescents and adults tend to present with prominent attentional difficulties (distractibility, shifting activities frequently, forgetfulness, disorganization) that affect work, schooling, and relationships.⁹ These older patients frequently also manifest residual impulsivity (intrusiveness, impatience) and hyperactivity (fidgetiness, restlessness).⁶ Adults with ADHD have a history of childhood onset of the disorder, with persistence through adolescence and beyond. Diagnosis of adult ADHD requires evidence of impairment in academic, work, and interpersonal domains.

Table 1

DSM-IV CRITERIA FOR DIAGNOSING ADHD

1. Either (1) or (2)
2. Some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7.
3. Some impairment from the symptoms is present in two or more settings (e.g., at school/work or at home).
4. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning.
5. The symptoms do not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychiatric disorder and are not better accounted for by a mood, anxiety, dissociative, personality, or other mental disorder.

Code based on type:

314.01 ADHD, Combined Type—if both criteria A1 and A2 have been met for the past 6 months.

314.00 ADHD, Predominantly Inattentive Type—if criterion A1 has been met but criterion A2 has not been met for the past 6 months.

314.01 ADHD, Predominantly Hyperactive-Impulsive Type—if criterion A2 has been met but criterion A1 has not been met for the past 6 months.

(Specify “In partial remission” in patients whose symptoms no longer meet full criteria).

Adapted from: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision. Washington: American Psychiatric Association, 2000.

DSM-IV recognizes three subtypes of ADHD based on presenting symptoms:

• predominantly inattentive (20% to 30% of cases);
• predominantly hyperactive-impulsive (<15%);
• combined inattentive and hyperactive-impulsive (50% to 75%).

ADHD is diagnosed by clinical history, applying DSM-IV criteria ( Table 1). Rating scales, checklists, and neuropsychological batteries—although not diagnostic—may help provide evidence for the disorder and accompanying comorbid conditions (e.g., Conners Rating Scales, Brown Rating Scales).⁵

Complicating the clinical picture of ADHD is the common co-occurrence of other psychiatric disorders. Almost three-quarters of individuals with ADHD have psychiatric comorbidity, including:

• oppositional disorders (40% to 60% of ADHD cases);
• conduct disorders (10% to 20%);
• anxiety disorders (30% to 40%);
• mood disorders (20% to 30%).¹⁰

For example, although few people with ADHD develop bipolar illness, an excess of ADHD is reported in depressed (20% to 30%) and bipolar youth (50% to 90%).¹¹ ADHD and its associated comorbid conditions also place sufferers at risk for higher rates and younger onset of cigarette smoking and substance abuse.¹² Most studies, however, indicate that pharmacotherapy reduces the risk for later drug and alcohol use disorders.¹³

Treatment

Management of ADHD includes nonpharmacologic and pharmacologic interventions.¹ Support groups (e.g., Children and Adults with Attention Deficit/Hyperactivity Disorder (CHADD), www.chadd.org) are invaluable and inexpensive sources of information about ADHD.

For children in school, a specialized educational plan with frequent re-evaluations of the child’s progress is recommended. Encourage parents to work closely with the child’s teacher, guidance counselor, or school psychologist. Children with ADHD tend to perform better in school when given structure, a predictable routine, checked homework, learning aids, and resource room time.⁵ Specific remediation plans are recommended for comorbid learning disorders, found in approximately one-third of individuals with ADHD.

Adults with ADHD may need to modify their school or work settings to function well. College students should be encouraged to use their school’s study center, and may require accommodations for taking examinations.

Focused cognitive behavioral therapies have shown benefit in children, adolescents, and adults with ADHD.¹⁴ Training children and their parents in behavioral modification can help control the child’s disruptive behaviors, inflexibility, anxiety, or outbursts. Other useful adjuncts to treatment include remediation to improve interpersonal skills and coaching to address organization and study skills.

Pharmacotherapy

Medications are fundamental in treating ADHD¹ (Table 2). In fact, a 14-month, multisite study demonstrated that medication management of ADHD was the most important variable in outcome when patients received combined pharmacologic and nonpharmacologic therapies.¹⁵ Stimulants, antihypertensives, and antidepressants are used to treat ADHD symptoms. Children, adolescents, and adults with ADHD respond similarly to pharmacotherapy.¹⁶

Psychostimulants: First-line agents

Psychostimulants are first-line agents for ADHD, based in part on extensive data showing efficacy (>250 controlled trials) and safety.^17,18 Stimulants are sympathomimetic drugs that increase intrasynaptic catecholamines (mainly dopamine) by inhibiting the presynaptic reuptake mechanism (amphetamine, methylphenidate, and pemoline) and releasing presynaptic catecholamines (amphetamine).¹⁹ Methylphenidate, dextroamphetamine, amphetamine compounds, and magnesium pemoline are among the most commonly used compounds in this class.

New approaches Prescribing stimulants for ADHD has changed in two fundamental ways. Frist, in the past we covered a child’s ADHD symptoms only during school hours, but we now include time after school and weekends and holidays. Second, we also are using longer-acting stimulant preparations, which recently became available. Extended-release preparations are usually preferred for lack of in-school dosing requirements, improved compliance, reduced stigma and wear-off, and lower risk of abuse or diversion—i.e., the medication being given or sold by an individual with ADHD to someone who is using it recreationally.

Short-acting compounds such as methylphenidate, D-methylphenidate, and D-amphetamine begin working within 30 to 60 minutes. Their clinical effect usually peaks 1 and 2 hours after administration and lasts 2 to 5 hours. The amphetamine compounds (e.g., Adderall) and older sustained-release methylphenidate begin working within 60 minutes, with a clinical effect that usually peaks between 1 and 3 hours and is maintained for 5 to 8 hours).

Table 2

RECOMMENDED DOSING OF PSYCHOSTIMULANTS FOR ADHD

Newer extended-release methylphenidate products (e.g., Ritalin LA and Metadate CD), with 8 to 9 hours’ duration of action, were developed to approximate twice-daily short-acting methylphenidate. The Concerta brand of methylphenidate, with 10 to 12 hours’ duration of action, approximates short-acting methylphenidate given three times daily. The extended-release Adderall XR brand of amphetamine compound, with a 10- to 12-hour duration of action, is similar to twice-daily Adderall.

Methylphenidate is the most studied, but among the available stimulants the literature suggests more similarities than differences in patient response.^17,18 Because of the agents’ marginally different mechanisms of action, however, some patients who do not respond satisfactorily to one stimulant or manifest adverse effects may respond more favorably to another agent of this type.

Start stimulants at the lowest available dose and increase every 3 to 4 days until a response is noted or adverse effects emerge. Dose-response data indicate more robust response at higher dosages of stimulants; therefore, efficacy—rather than onset of side effects—should guide titration to an optimal dose.

Predictable short-term adverse effects include reduced appetite, insomnia, edginess, and GI upset.²⁰ To manage these effects, consider when they occur:

• Within 2 hours after administration may signal the need to reduce the dose or change to another preparation.
• Within 4 to 6 hours after administration (e.g., moodiness) suggests the need for a longer-acting preparation or low dosing prior to the anticipated wear-off.

For insomnia, strategies include using a shorter-acting stimulant preparation, reducing the stimulant load in the afternoon, or providing adjunct treatment for the insomnia (i.e., clonidine, imipramine, mirtazapine).¹⁷ Edginess and headaches—more common in adolescents and adults—can be reduced with low-dose beta blockers. For diminished appetite in youths, caloric intake can be enhanced with a hearty breakfast, late-afternoon and evening snacks, and caloric supplements. Appetite enhancers such as cyproheptadine given nightly may be considered. Pemoline may rarely cause hepatitis and requires liver function monitoring.

Chronic use of stimulants is controversial.^17,18 Although stimulants may produce anorexia and weight loss, their effect on a youth’s ultimate height is less certain. Initial reports of a persistent stimulant-associated growth decrease have not been substantiated. Other studies suggest that growth deficits may represent maturational delays related to ADHD rather than to stimulant treatment.²¹

Stimulants may precipitate or exacerbate tic symptoms in children with ADHD. Recent work suggests that stimulants can be used safely in youth with tic disorders,²² although up to one-third may experience worsening of tic symptoms.

Despite case reports of stimulant misuse, there is little data to support stimulant abuse among treated children with ADHD.¹³ However, the diversion of stimulants to youth without ADHD is a concern.

Antidepressants

Antidepressants are generally considered second-line drugs for ADHD.^1,16 Bupropion, an antidepressant with indirect dopamine and noradrenergic effects, has been shown effective in ADHDin controlled trials of both children and adults.^23,24

Bupropion is often prescribed first for complex patients with ADHD and substance abuse or an unstable mood disorder because of its ability to reduce cigarette smoking and improve mood, lack of monitoring requirements, and few adverse effects. Dosing is typically initiated at 100 mg of the sustained-release preparation and increased weekly to a maximum of 300 mg in younger children and 400 mg in older children or adults (i.e., 200 mg bid). Adverse effects include insomnia, activation, irritability, and (rarely) seizures.

The tricyclic antidepressants (TCAs) used in ADHD—imipramine, desipramine and nortriptyline—block the reuptake of neurotransmitters including norepinephrine. TCAs are effective in controlling abnormal behaviors and improving cognitive impairments associated with ADHD, but less so than the stimulants. TCAs are particularly useful when:

• stimulants fail to control ADHD symptoms;
• oppositional behavior, anxiety, tics, or depressive symptoms coexist within ADHD or occur during its treatment.

Desipramine appears to be the most effective TCA for ADHD, followed by nortriptyline and imipramine.^25,26 TCAs are dosed starting with 25 mg/d and slowly increased to a maximum of 5 mg/kg/day (2 mg/kg/day for nortriptyline). Although immediate relief can be seen, a delay of up to 6 weeks for maximal effect is common. Typical adverse effects include dry mouth, constipation, sedation, and weight gain.

Four deaths have been reported in children with ADHD treated with desipramine; however, independent evaluation of these cases failed to support a causal link. As minor increases in heart rate and ECG intervals are predictable with TCAs, ECG monitoring at baseline and at therapeutic dosages is recommended.

Although serotonin reuptake inhibitors are not generally useful for ADHD, venlafaxine appears to have mild efficacy, perhaps because of its dose-dependent noradrenergic reuptake inhibition.²⁷

Monoamine oxidase inhibitors (MAOIs) have been shown effective in juvenile ADHD. Response to treatment is rapid, and standard antidepressant dosing is often necessary.¹⁶ A major limitation to the use of MAOIs is the potential for hypertensive crisis associated with dietetic transgressions and drug interactions.

Other treatment options

Antihypertensives The antihypertensive agents clonidine²⁸ and guanfacine²⁹ are used to treat the hyperactive-impulsive symptoms of ADHD in youth. Clonidine is relatively shortacting, with usual daily dosage ranges from 0.05 to 0.4 mg.²⁸ Guanfacine is longer acting and less potent, with usual daily dosage ranges from 0.5 to 4 mg.²⁹

Antihypertensives have been used to treat ADHD and associated tics, aggression, and sleep disturbances, particularly in younger children.¹⁶ Although sedation is more common with clonidine than guanfacine, both agents may cause depression and rebound hypertension. Cardiovascular monitoring (vital signs, ECG) remains optional.

New agents Novel compounds, along with new preparations and delivery systems of existing stimulant medications, are being investigated for managing ADHD. New agents are being tested in adults with ADHD because adults and youth respond similarly to ADHD medications, and there are ethical concerns about drug testing in children.

Atomoxetine, a noradrenergic reuptake inhibitor under development, has been shown in open and controlled studies of adults and youth³⁰ to be effective in treating ADHD. Atomoxetine appears well tolerated, with no blood monitoring requirements.

Cholinergics and genes Selective use of cholinergic agents (e.g., donepezil) may also be helpful for the cognitive dysfunction in ADHD,²⁴ either as monotherapy or in combination with other agents for ADHD. Multiple centers are investigating the possible link between response to pharmacologic therapy and ADHD genotype.

Combination therapy

Combinations of pharmacologic agents can be used to treat comorbid ADHD, to augment response to a single agent, for pharmacokinetic synergism, and to manage adverse effects that emerge during treatment. Examples include:

• a tricyclic antidepressant and a stimulant to heighten response to treatment;
• an antidepressant plus a stimulant for ADHD and comorbid depression;
• adjunctive use of clonidine for sleep or to manage aggressive behavior;
• use of mood stabilizers with ADHD medications for comorbid bipolar disorder.¹⁶

Pharmacologic intervention for prominent concomitant mood disorders (depression and bipolarity) and anxiety should be sequenced prior to ADHD treatment.

Summary of treatment recommendations

Based on efficacy and safety, stimulants are first-line agents for routine management of ADHD, followed by antidepressants and antihypertensives. Patients who do not respond to the initial stimulant or who manifest adverse effects should be considered for a trial with an alternate stimulant. If two stimulant trials are unsuccessful, bupropion and the tricyclic antidepressants are reasonable second-line agents.

Antihypertensives alone or in combination with other ADHD medication may help youths with tics,³¹ prominent hyperactivity, impulsivity, or aggressiveness. MAOIs may be considered for refractory patients, and cholinergic agents (e.g., donepezil) may be used for excessive cognitive difficulties such as organization, planning, and time management.

Related resources

• Barkley RA. Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. New York: The Guilford Press, 1998.
• Wilens T. Straight Talk About Psychiatric Medications for Kids. New York: The Guilford Press, 1998.
• Children and Adults with Attention-Deficit/Hyperactivity Disorder (CHADD), www.chadd.org

Drug brand names

• Atomoxetine • (under development)
• Bupropion • Wellbutrin
• Clonidine • Catapress
• Dextro-amphetamine • Dexedrine
• Dexmethylphenidate • Focalin
• Donepezil • Aricept
• Guanfacine • Tenex
• Methylphenidate • Ritalin, Concerta, Metadate
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

Dr. Biederman reports that he receives research/grant support from, and is on the speaker’s bureau and advisory boards of Eli Lilly & Co. and Shire Laboratories. He also reports that he receives research/grant support from Wyeth-Ayerst Pharmaceuticals, Pfizer Inc., Cephalon Pharmaceutical, Janssen Pharmaceutica, and Noven Pharmaceutical; is on the speaker's bureau of GlaxoSmithKline, Pfizer Inc., Wyeth-Ayerst Pharmaceuticals, Alza/McNeil Pharmaceutical and Cephalon Pharmaceutical; and is on the advisory board of Cell Tech, Noven Pharmaceutical, and Alza/McNeil Pharmaceuticals.

Drs. Wilens and Spencer report that they receive research/grant support from, are on the speakers bureau of, and/or serve as consultants to Abbott Laboratories, McNeil Pharmaceuticals, Celltech Medieva, GlaxoSmithKline, Eli Lilly & Co., Novartis Pharmaceuticals Corp., Pfizer Inc., Shire Pharmaceuticals Group, and Wyeth-Ayerst Pharmaceuticals.

Attention-deficit/hyperactivity disorder, or ADHD, affects 4% to 5% of youths worldwide and is the most common neurobehavioral disorder treated in children.¹ Recent research and clinical experience are changing our understanding of ADHD in two important ways:

First, we now recognize that ADHD is often chronic. Its symptoms and/or associated impairment persist into adolescence in approximately three-quarters of cases and into adulthood in approximately one-half of childhood cases.^2-3 Throughout the lifespan, ADHD is associated with significant psychopathology, school and occupational failure, and peer and emotional difficulties.⁴

Second, the presence of impaired cognition has largely replaced the view that ADHD was characterized primarily by overactivity and impulsivity.⁵ This insight is leading to innovations in pharmacotherapy that offer youths and adults improved control of ADHD symptoms, with less-frequent dosing and lower risk of side effects.

Neurobiology

Although the precise neurobiology of ADHD remains unknown, frontal network abnormality or frontal-striatal dysfunction appears critical.⁶ Catecholamine dysregulation affecting both the dopaminergic and noradrenergic systems appears to be important in the underlying pathophysiology.⁶ For example, a small replicated study using SPECT imaging found adults with ADHD had twice the dopamine transporter binding potential of age-matched controls.⁷ Recent data also suggest the cholinergic system is involved in mediating symptoms of ADHD, particularly attentional regulation. Data from adoption, twin, and family-genetic studies suggest a genetic contribution in ADHD, with molecular studies focusing on the dopamine D2, D4, and the dopamine transporter as candidate genes.⁸

Diagnosis

Symptoms of ADHD are related to the patient’s age at presentation. In youth, ADHD is characterized by inattention, distractibility, impulsivity, and hyperactivity excessive for the child’s developmental level.^1,5 Other symptoms include low frustration tolerance, frequent shifting of activities, difficulty organizing tasks, and daydreaming. While these symptoms are typically pervasive, they may not occur in all settings.

Older adolescents and adults tend to present with prominent attentional difficulties (distractibility, shifting activities frequently, forgetfulness, disorganization) that affect work, schooling, and relationships.⁹ These older patients frequently also manifest residual impulsivity (intrusiveness, impatience) and hyperactivity (fidgetiness, restlessness).⁶ Adults with ADHD have a history of childhood onset of the disorder, with persistence through adolescence and beyond. Diagnosis of adult ADHD requires evidence of impairment in academic, work, and interpersonal domains.

Table 1

DSM-IV CRITERIA FOR DIAGNOSING ADHD

1. Either (1) or (2)
2. Some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7.
3. Some impairment from the symptoms is present in two or more settings (e.g., at school/work or at home).
4. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning.
5. The symptoms do not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychiatric disorder and are not better accounted for by a mood, anxiety, dissociative, personality, or other mental disorder.

Code based on type:

314.01 ADHD, Combined Type—if both criteria A1 and A2 have been met for the past 6 months.

314.00 ADHD, Predominantly Inattentive Type—if criterion A1 has been met but criterion A2 has not been met for the past 6 months.

314.01 ADHD, Predominantly Hyperactive-Impulsive Type—if criterion A2 has been met but criterion A1 has not been met for the past 6 months.

(Specify “In partial remission” in patients whose symptoms no longer meet full criteria).

Adapted from: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision. Washington: American Psychiatric Association, 2000.

DSM-IV recognizes three subtypes of ADHD based on presenting symptoms:

• predominantly inattentive (20% to 30% of cases);
• predominantly hyperactive-impulsive (<15%);
• combined inattentive and hyperactive-impulsive (50% to 75%).

ADHD is diagnosed by clinical history, applying DSM-IV criteria ( Table 1). Rating scales, checklists, and neuropsychological batteries—although not diagnostic—may help provide evidence for the disorder and accompanying comorbid conditions (e.g., Conners Rating Scales, Brown Rating Scales).⁵

Complicating the clinical picture of ADHD is the common co-occurrence of other psychiatric disorders. Almost three-quarters of individuals with ADHD have psychiatric comorbidity, including:

• oppositional disorders (40% to 60% of ADHD cases);
• conduct disorders (10% to 20%);
• anxiety disorders (30% to 40%);
• mood disorders (20% to 30%).¹⁰

For example, although few people with ADHD develop bipolar illness, an excess of ADHD is reported in depressed (20% to 30%) and bipolar youth (50% to 90%).¹¹ ADHD and its associated comorbid conditions also place sufferers at risk for higher rates and younger onset of cigarette smoking and substance abuse.¹² Most studies, however, indicate that pharmacotherapy reduces the risk for later drug and alcohol use disorders.¹³

Treatment

Management of ADHD includes nonpharmacologic and pharmacologic interventions.¹ Support groups (e.g., Children and Adults with Attention Deficit/Hyperactivity Disorder (CHADD), www.chadd.org) are invaluable and inexpensive sources of information about ADHD.

For children in school, a specialized educational plan with frequent re-evaluations of the child’s progress is recommended. Encourage parents to work closely with the child’s teacher, guidance counselor, or school psychologist. Children with ADHD tend to perform better in school when given structure, a predictable routine, checked homework, learning aids, and resource room time.⁵ Specific remediation plans are recommended for comorbid learning disorders, found in approximately one-third of individuals with ADHD.

Adults with ADHD may need to modify their school or work settings to function well. College students should be encouraged to use their school’s study center, and may require accommodations for taking examinations.

Focused cognitive behavioral therapies have shown benefit in children, adolescents, and adults with ADHD.¹⁴ Training children and their parents in behavioral modification can help control the child’s disruptive behaviors, inflexibility, anxiety, or outbursts. Other useful adjuncts to treatment include remediation to improve interpersonal skills and coaching to address organization and study skills.

Pharmacotherapy

Medications are fundamental in treating ADHD¹ (Table 2). In fact, a 14-month, multisite study demonstrated that medication management of ADHD was the most important variable in outcome when patients received combined pharmacologic and nonpharmacologic therapies.¹⁵ Stimulants, antihypertensives, and antidepressants are used to treat ADHD symptoms. Children, adolescents, and adults with ADHD respond similarly to pharmacotherapy.¹⁶

Psychostimulants: First-line agents

Psychostimulants are first-line agents for ADHD, based in part on extensive data showing efficacy (>250 controlled trials) and safety.^17,18 Stimulants are sympathomimetic drugs that increase intrasynaptic catecholamines (mainly dopamine) by inhibiting the presynaptic reuptake mechanism (amphetamine, methylphenidate, and pemoline) and releasing presynaptic catecholamines (amphetamine).¹⁹ Methylphenidate, dextroamphetamine, amphetamine compounds, and magnesium pemoline are among the most commonly used compounds in this class.

New approaches Prescribing stimulants for ADHD has changed in two fundamental ways. Frist, in the past we covered a child’s ADHD symptoms only during school hours, but we now include time after school and weekends and holidays. Second, we also are using longer-acting stimulant preparations, which recently became available. Extended-release preparations are usually preferred for lack of in-school dosing requirements, improved compliance, reduced stigma and wear-off, and lower risk of abuse or diversion—i.e., the medication being given or sold by an individual with ADHD to someone who is using it recreationally.

Short-acting compounds such as methylphenidate, D-methylphenidate, and D-amphetamine begin working within 30 to 60 minutes. Their clinical effect usually peaks 1 and 2 hours after administration and lasts 2 to 5 hours. The amphetamine compounds (e.g., Adderall) and older sustained-release methylphenidate begin working within 60 minutes, with a clinical effect that usually peaks between 1 and 3 hours and is maintained for 5 to 8 hours).

Table 2

RECOMMENDED DOSING OF PSYCHOSTIMULANTS FOR ADHD

Newer extended-release methylphenidate products (e.g., Ritalin LA and Metadate CD), with 8 to 9 hours’ duration of action, were developed to approximate twice-daily short-acting methylphenidate. The Concerta brand of methylphenidate, with 10 to 12 hours’ duration of action, approximates short-acting methylphenidate given three times daily. The extended-release Adderall XR brand of amphetamine compound, with a 10- to 12-hour duration of action, is similar to twice-daily Adderall.

Methylphenidate is the most studied, but among the available stimulants the literature suggests more similarities than differences in patient response.^17,18 Because of the agents’ marginally different mechanisms of action, however, some patients who do not respond satisfactorily to one stimulant or manifest adverse effects may respond more favorably to another agent of this type.

Start stimulants at the lowest available dose and increase every 3 to 4 days until a response is noted or adverse effects emerge. Dose-response data indicate more robust response at higher dosages of stimulants; therefore, efficacy—rather than onset of side effects—should guide titration to an optimal dose.

Predictable short-term adverse effects include reduced appetite, insomnia, edginess, and GI upset.²⁰ To manage these effects, consider when they occur:

• Within 2 hours after administration may signal the need to reduce the dose or change to another preparation.
• Within 4 to 6 hours after administration (e.g., moodiness) suggests the need for a longer-acting preparation or low dosing prior to the anticipated wear-off.

For insomnia, strategies include using a shorter-acting stimulant preparation, reducing the stimulant load in the afternoon, or providing adjunct treatment for the insomnia (i.e., clonidine, imipramine, mirtazapine).¹⁷ Edginess and headaches—more common in adolescents and adults—can be reduced with low-dose beta blockers. For diminished appetite in youths, caloric intake can be enhanced with a hearty breakfast, late-afternoon and evening snacks, and caloric supplements. Appetite enhancers such as cyproheptadine given nightly may be considered. Pemoline may rarely cause hepatitis and requires liver function monitoring.

Chronic use of stimulants is controversial.^17,18 Although stimulants may produce anorexia and weight loss, their effect on a youth’s ultimate height is less certain. Initial reports of a persistent stimulant-associated growth decrease have not been substantiated. Other studies suggest that growth deficits may represent maturational delays related to ADHD rather than to stimulant treatment.²¹

Stimulants may precipitate or exacerbate tic symptoms in children with ADHD. Recent work suggests that stimulants can be used safely in youth with tic disorders,²² although up to one-third may experience worsening of tic symptoms.

Despite case reports of stimulant misuse, there is little data to support stimulant abuse among treated children with ADHD.¹³ However, the diversion of stimulants to youth without ADHD is a concern.

Antidepressants

Antidepressants are generally considered second-line drugs for ADHD.^1,16 Bupropion, an antidepressant with indirect dopamine and noradrenergic effects, has been shown effective in ADHDin controlled trials of both children and adults.^23,24

Bupropion is often prescribed first for complex patients with ADHD and substance abuse or an unstable mood disorder because of its ability to reduce cigarette smoking and improve mood, lack of monitoring requirements, and few adverse effects. Dosing is typically initiated at 100 mg of the sustained-release preparation and increased weekly to a maximum of 300 mg in younger children and 400 mg in older children or adults (i.e., 200 mg bid). Adverse effects include insomnia, activation, irritability, and (rarely) seizures.

The tricyclic antidepressants (TCAs) used in ADHD—imipramine, desipramine and nortriptyline—block the reuptake of neurotransmitters including norepinephrine. TCAs are effective in controlling abnormal behaviors and improving cognitive impairments associated with ADHD, but less so than the stimulants. TCAs are particularly useful when:

• stimulants fail to control ADHD symptoms;
• oppositional behavior, anxiety, tics, or depressive symptoms coexist within ADHD or occur during its treatment.

Desipramine appears to be the most effective TCA for ADHD, followed by nortriptyline and imipramine.^25,26 TCAs are dosed starting with 25 mg/d and slowly increased to a maximum of 5 mg/kg/day (2 mg/kg/day for nortriptyline). Although immediate relief can be seen, a delay of up to 6 weeks for maximal effect is common. Typical adverse effects include dry mouth, constipation, sedation, and weight gain.

Four deaths have been reported in children with ADHD treated with desipramine; however, independent evaluation of these cases failed to support a causal link. As minor increases in heart rate and ECG intervals are predictable with TCAs, ECG monitoring at baseline and at therapeutic dosages is recommended.

Although serotonin reuptake inhibitors are not generally useful for ADHD, venlafaxine appears to have mild efficacy, perhaps because of its dose-dependent noradrenergic reuptake inhibition.²⁷

Monoamine oxidase inhibitors (MAOIs) have been shown effective in juvenile ADHD. Response to treatment is rapid, and standard antidepressant dosing is often necessary.¹⁶ A major limitation to the use of MAOIs is the potential for hypertensive crisis associated with dietetic transgressions and drug interactions.

Other treatment options

Antihypertensives The antihypertensive agents clonidine²⁸ and guanfacine²⁹ are used to treat the hyperactive-impulsive symptoms of ADHD in youth. Clonidine is relatively shortacting, with usual daily dosage ranges from 0.05 to 0.4 mg.²⁸ Guanfacine is longer acting and less potent, with usual daily dosage ranges from 0.5 to 4 mg.²⁹

Antihypertensives have been used to treat ADHD and associated tics, aggression, and sleep disturbances, particularly in younger children.¹⁶ Although sedation is more common with clonidine than guanfacine, both agents may cause depression and rebound hypertension. Cardiovascular monitoring (vital signs, ECG) remains optional.

New agents Novel compounds, along with new preparations and delivery systems of existing stimulant medications, are being investigated for managing ADHD. New agents are being tested in adults with ADHD because adults and youth respond similarly to ADHD medications, and there are ethical concerns about drug testing in children.

Atomoxetine, a noradrenergic reuptake inhibitor under development, has been shown in open and controlled studies of adults and youth³⁰ to be effective in treating ADHD. Atomoxetine appears well tolerated, with no blood monitoring requirements.

Cholinergics and genes Selective use of cholinergic agents (e.g., donepezil) may also be helpful for the cognitive dysfunction in ADHD,²⁴ either as monotherapy or in combination with other agents for ADHD. Multiple centers are investigating the possible link between response to pharmacologic therapy and ADHD genotype.

Combination therapy

Combinations of pharmacologic agents can be used to treat comorbid ADHD, to augment response to a single agent, for pharmacokinetic synergism, and to manage adverse effects that emerge during treatment. Examples include:

• a tricyclic antidepressant and a stimulant to heighten response to treatment;
• an antidepressant plus a stimulant for ADHD and comorbid depression;
• adjunctive use of clonidine for sleep or to manage aggressive behavior;
• use of mood stabilizers with ADHD medications for comorbid bipolar disorder.¹⁶

Pharmacologic intervention for prominent concomitant mood disorders (depression and bipolarity) and anxiety should be sequenced prior to ADHD treatment.

Summary of treatment recommendations

Based on efficacy and safety, stimulants are first-line agents for routine management of ADHD, followed by antidepressants and antihypertensives. Patients who do not respond to the initial stimulant or who manifest adverse effects should be considered for a trial with an alternate stimulant. If two stimulant trials are unsuccessful, bupropion and the tricyclic antidepressants are reasonable second-line agents.

Antihypertensives alone or in combination with other ADHD medication may help youths with tics,³¹ prominent hyperactivity, impulsivity, or aggressiveness. MAOIs may be considered for refractory patients, and cholinergic agents (e.g., donepezil) may be used for excessive cognitive difficulties such as organization, planning, and time management.

Related resources

• Barkley RA. Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. New York: The Guilford Press, 1998.
• Wilens T. Straight Talk About Psychiatric Medications for Kids. New York: The Guilford Press, 1998.
• Children and Adults with Attention-Deficit/Hyperactivity Disorder (CHADD), www.chadd.org

Drug brand names

• Atomoxetine • (under development)
• Bupropion • Wellbutrin
• Clonidine • Catapress
• Dextro-amphetamine • Dexedrine
• Dexmethylphenidate • Focalin
• Donepezil • Aricept
• Guanfacine • Tenex
• Methylphenidate • Ritalin, Concerta, Metadate
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

Dr. Biederman reports that he receives research/grant support from, and is on the speaker’s bureau and advisory boards of Eli Lilly & Co. and Shire Laboratories. He also reports that he receives research/grant support from Wyeth-Ayerst Pharmaceuticals, Pfizer Inc., Cephalon Pharmaceutical, Janssen Pharmaceutica, and Noven Pharmaceutical; is on the speaker's bureau of GlaxoSmithKline, Pfizer Inc., Wyeth-Ayerst Pharmaceuticals, Alza/McNeil Pharmaceutical and Cephalon Pharmaceutical; and is on the advisory board of Cell Tech, Noven Pharmaceutical, and Alza/McNeil Pharmaceuticals.

Drs. Wilens and Spencer report that they receive research/grant support from, are on the speakers bureau of, and/or serve as consultants to Abbott Laboratories, McNeil Pharmaceuticals, Celltech Medieva, GlaxoSmithKline, Eli Lilly & Co., Novartis Pharmaceuticals Corp., Pfizer Inc., Shire Pharmaceuticals Group, and Wyeth-Ayerst Pharmaceuticals.

Program Chairmen and Editors:
Gary S. Hoffman, MD, and John H. Stone, MD, MPH

Contents

I. PATHOGENESIS

A. Immune Predisposition and Infectious Etiology of Systemic Vasculitis
Moderators: Coen Stegeman and Herbert Virgin

Keynote Presentation
Host and viral genes that control herpesvirus vasculitis
Herbert W. Virgin IV

Plenary Session Abstracts (1-3)
1-090. Induction of pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) by intravenous administration of anti-myeloperoxidase (anti-MPO) antibodies to recombinase activating gene-2 deficient (RAG-2 -/-) mice
J.C. Jennette, H. Xiao, P. Heeringa, Z. Liu, P. Hu, M. Zhao, Y. Aratani, R.J. Falk

2-091. Induction of necrotizing and crescentic glomerulonephritis (NCGN) and small-vessel vasculitis (SVV) by adoptive transfer of anti-myeloperoxidase (anti-MPO) lymphocytes into recombinase activating gene-2 deficient (RAG-2 -/-) mice
H. Xiao, P. Heeringa, Z. Liu, P. Hu, M. Zhao, Y. Aratani, R.J. Falk, J.C. Jennette

3-049. Contribution of activated neurotrophils and MPO-ANCA to the development of crescentic glomerulonephritis in SCG/KJ mice
A. Ishida-Okawara, T. Ito-Ihara, T. Ono, E. Muso, K. Saiga, K. Nemoto, K. Suzuki

Keynote Presentations
Known causes of vasculitis in man
Stanley J. Naides

HCV and cryoglobulinemic vasculitis
Clodoveo Ferri, A.L. Zignego, D. Giuggioli, M. Sebastiani, M. Cazzato, A. Antonelli, L. La Civita, P. Fadda, G. Longombardo, and S. Pileri

Infections in primary vasculitides
Jan W. Cohen Tervaert

Plenary session Abstracts (4-5)
4-093. Staphylococcal toxic-shock-syndrome-toxin-1 (TSST-1) is a risk factor for disease relapse in Wegener's granulomatosis
E.R. Popa, B. van der Meer, J. Arends, W.M. Manson, N.A. Bos, C.G.M. Kallenberg, J.W. Cohen Tervaert, C.A. Stegeman

5-104.Chlamydia pneumoniae and giant-cell arteritis: Failure to detect Chlamydia pneumoniae in temporal artery biopsies by polymerase chain reaction
M.J. Regan, B.J. Wood, Y.-H. Hsieh, M.L. Theodore, T.C. Quinn, D.B. Hellmann, W.R. Green, C.A. Gaydos, J.H. Stone

B. Patterns of Injury: Implications for Pathogenesis
Moderators: Loïc Guillevin and Cornelia Weyand

Keynote Presentations
Pathogenic mechanisms in giant cell arteritis
Cornelia M. Weyand and Jörg J. Goronzy

Implications for pathogenesis of patterns of injury in small- and medium-sized-vessel vasculitis
J. Charles Jennette

Plenary Session Abstracts (6-7)

6-037. Superantigenic activation of T lymphocytes and endothelial cells: A mechanism for superantigen-induced vasculitis
P.A. Brogan, V. Shah, N. Klein, M.J. Dillon

7-108. Analysis of autoantibody repertoires in small and medium sized vessel vasculitis: Evidence for disease-specific perturbations in classic polyarteritis nodosa (PAN), micropolyangiitis (MPA), Churg-Strauss syndrome (CSS) and Wegener's granulomatosis (WG)
Y. Chanseaud, L. Guillevin, M. Kambouchner, M.C. Boissier, L. Mouthon

Keynote Presentation
Granuloma formation, implications for the pathogenesis of vasculitis
Michael C. Sneller

Plenary Session Abstracts (8-9)
8-052. Chemokine receptor expression on CD4+ and CD8+ memory T-cells and in granulomas in Wegener's granulomatosis
P. Lamprecht, A. Erdmann, A. Mueller, E. Csernok, H. Bruehl, W.L. Gross, M. Mack

9-016. Genetic resistance to Wegener's granulomatosis—a role for CCR5 in patients without antineutrophil cytoplasmic antibodies
Y. Zhou, D. Huang, C. Farver, G. Hoffman

Keynote Presentation
Endothelial cell biology, perivascular inflammation, and vasculitis
Maria C. Cid

Plenary Session Abstract (10)
10-023. Novel effects of inflammatory cell proteases on vascular endothelia
G.A. Preston, W.F. Pendergraft, J.J. Yang, J.C. Jennette, R.J. Falk

C. Possible Role of ANCA and AECA in Select Forms of Systemic Vasculitis
Moderators: Wolfgang Gross and Caroline Savage

Keynote Presentation
Understanding the pathogenesis of ANCA: Where are we today?
Gloria A. Preston, Jia Jin Yang, Hong Xiao, and Ronald J. Falk

Plenary Session Abstracts (11-12)
11-027. TNF-alpha accelerated apoptosis abrogates ANCA-mediated neutrophil respiratory burst by a caspase-dependent mechanism
R. Kettritz, J. Scheumann, Y. Xu, F.C. Luft, H. Haller

12-071. Membrane expression of neurotrophil proteinase 3 (PR3) is associated with relapse in PR3-ANCA related vasculitis
A.A. Rarok, C.A. Stegeman, P.C. Limburg, C.G.M. Kallenberg

Keynote Presentation
ANCA subsets: Influence on disease phenotype
Ulrich Specks

Plenary Session Abstract (13)
13-096. Sequential epitope mapping of the myeloperoxidase antigen
D.M. Wynn, J.A. James

Keynote Presentation
Genetics of ANCA-associated vasculitis
Cees G.M. Kallenberg, Agnieszka Rarok, and Coen A. Stegeman

Plenary Session Abstracts (14-15)
14-028. Membrane expression of proteinase 3 is genetically controlled
A. Schreiber, A. Bushjahn, F.C. Luft, R. Kettritz

15-015. Genetic polymorphisms in TNF, IL-1, IL-6 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in Wegener's granulomatosis (WG)
Y. Zhou, D. Huang, G.S. Hoffman

Keynote Presentation
Classification of anti-endothelial cell antibodies into antibodies against microvascular and macrovascular endothelial cells: The pathogenic and diagnostic implications
Yehuda Shoenfeld

Plenary Session Abstract (16)
16-029. HMG-COA reductase inhibitors decrease ANCA-mediated activation of human neutrophils
M. Choi, S. Rolle M. Rane, H. Haller, F.C. Luft, R. Kettritz

II. EPIDEMIOLOGY OF VASCULITIS
Moderators: Miguel Gonzalez-Gay and Gene Hunder

Keynote Presentations
Kawasaki disease: Etiology, pathogenesis, and treatment
Karyl S. Barron

Epidemiology of giant-cell arteritis
Gene G. Hunder

Plenary Session Abstract (17)
17-102. Ethnic disparity in the incidence of temporal arteritis: A 32-year experience at an urban medical center
M.J. Regan, W.R. Green, J.H. Stone

Keynote Presentations
Epidemiology of Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome
Richard A. Watts, David G.I. Scott, and Suzanne E. Lane

Epidemiology of Henoch-Schönlein purpura
Frank Saulsbury

Plenary Session Abstract (18)
18-010. Henoch-Schönlein purpura and cutaneous leukocytoclastic angiitis exhibit different HLA-DRB1 associations
M.M. Amoli, W. Thomson, A.H. Hajeer, M.C. Calviño, C. Garcia-Porrua, W.E.R. Ollier, M.A. Gonzalez-Gay

III. DIAGNOSTIC MODALITIES, SURROGATE MARKERS OF DISEASE ACTIVITY, AND TOOLS FOR OUTCOME MEASUREMENTS
Moderators: Carol Langford and Raashid Luqmani

Keynote Presentations
Cytokines in giant-cell arteritis
Jörg J. Goronzy and Cornelia M. Weyand

Utility of imaging studies in assessment of vascular inflammation
Daniël Blockmans

Measuring disease activity and outcomes in clinical studies
Raashid Luqmani

Plenary Session Abstracts (19-21)
19-022. Increases of PR3 and MPO gene transcription in circulating leukocyte of ANCA-associated disease correlate with disease activity
J.J. Yang, G.A. Preston, D.A. Alcorta, B.D. Phillips, R.P. Thomas, S.L. Hogan, J.C. Jennette, R.J. Falk

20-119. Cardiac involvement in Wegener's granulomatosis: Echocardiographic features and clinical outcomes
G.H.M. Oliveira, J.B. Seward, U. Specks

21-041. Endothelial microparticles: Just blood "dust," or a "must" for the diagnosis and monitoring of disease activity in childhood vasculitides?
P.A. Brogan, V. Shah, C. Brachet, N. Klein, M.J. Dillon

Keynote Presentation
Diagnostic strategies in vasculitis affecting the central nervous system
Leonard H. Calabrese

Plenary Session Abstracts (22-23)
Moderator: Leonard Calabrese

22-082. Circulating endothelial cells and vasculitis
A. Woywodt, F. Streiber, K. de Groot, H. Haller, M. Haubitz

23-051. Diffuse endothelial dysfunction is a common feature of SNV
P.A. Bacon, D.M. Carruthers, A.D. Diler, K. Raza, J. Townend

IV. TREATMENT AND OUTCOMES
Moderators: Charles Pusey and Fokko van der Woude

Keynote Presentation
Conventional treatment and outcome of Wegener's granulomatosis and microscopic polyangiitis
David R.W. Jayne

Plenary Session Abstract (24)
24-012. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in "non-renal" ANCA-associated vasculitis
K. de Groot, N. Rasmussen, J.W. Cohen Tervaert, D.R.W. Jayne for EUVAS (European Vasculitis Study Group)

Keynote Presentations
Treatment of giant-cell arteritis: Where we have been and why we must move on
Gary S. Hoffman

Henoch-Schönlein purpura (treatment and outcome)
Michael J. Dillon

Targeted therapies in systemic vasculitis
John H. Stone

Plenary Session Abstract (25)
25-070. Campath 1-H (anti-CD52) for refractory vasculitis: Retrospective Cambridge experience 1989-1999
D.R.W. Jayne

V. TREATING THE PERMANENT SEQUELAE OF VASCULITIS
Moderators: Robert Kimberly and John Stone

Keynote Presentations
Inflammation in acute coronary syndromes
Mark Robbins and Eric J. Topol

Kidney transplantation and ANCA-associated vasculitis
Fokko J. van der Woude

Surgical treatment of Takayasu's disease
Joseph M. Giordano

New approaches to the management of subglottic stenosis in Wegener's granulomatosis
Isaac Eliachar, James Chan, and Lee Akst

Sinonasal complications of vasculitic diseases
Robert S. Lebovics

POSTER PRESENTATIONS (26-120)

Pathogenesis—Immune Predisposition and Infectious Etiology of Systemic Vasculitis

Pathogenesis—Patterns of Injury: Implications for Pathogenesis

Pathogenesis—Possible Role of ANCA and AECA in Selected Forms of Systemic Vasculitis

Epidemiology of Vasculitis

Diagnostic Modalities, Surrogate Markers of Disease Activity, and Tools for Outcome Measurements

Treatment and Outcomes

Treating the Permanent Sequelae of Vasculitis

Program Chairmen and Editors:
Gary S. Hoffman, MD, and John H. Stone, MD, MPH

Contents

I. PATHOGENESIS

A. Immune Predisposition and Infectious Etiology of Systemic Vasculitis
Moderators: Coen Stegeman and Herbert Virgin

Keynote Presentation
Host and viral genes that control herpesvirus vasculitis
Herbert W. Virgin IV

Plenary Session Abstracts (1-3)
1-090. Induction of pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) by intravenous administration of anti-myeloperoxidase (anti-MPO) antibodies to recombinase activating gene-2 deficient (RAG-2 -/-) mice
J.C. Jennette, H. Xiao, P. Heeringa, Z. Liu, P. Hu, M. Zhao, Y. Aratani, R.J. Falk

2-091. Induction of necrotizing and crescentic glomerulonephritis (NCGN) and small-vessel vasculitis (SVV) by adoptive transfer of anti-myeloperoxidase (anti-MPO) lymphocytes into recombinase activating gene-2 deficient (RAG-2 -/-) mice
H. Xiao, P. Heeringa, Z. Liu, P. Hu, M. Zhao, Y. Aratani, R.J. Falk, J.C. Jennette

3-049. Contribution of activated neurotrophils and MPO-ANCA to the development of crescentic glomerulonephritis in SCG/KJ mice
A. Ishida-Okawara, T. Ito-Ihara, T. Ono, E. Muso, K. Saiga, K. Nemoto, K. Suzuki

Keynote Presentations
Known causes of vasculitis in man
Stanley J. Naides

HCV and cryoglobulinemic vasculitis
Clodoveo Ferri, A.L. Zignego, D. Giuggioli, M. Sebastiani, M. Cazzato, A. Antonelli, L. La Civita, P. Fadda, G. Longombardo, and S. Pileri

Infections in primary vasculitides
Jan W. Cohen Tervaert

Plenary session Abstracts (4-5)
4-093. Staphylococcal toxic-shock-syndrome-toxin-1 (TSST-1) is a risk factor for disease relapse in Wegener's granulomatosis
E.R. Popa, B. van der Meer, J. Arends, W.M. Manson, N.A. Bos, C.G.M. Kallenberg, J.W. Cohen Tervaert, C.A. Stegeman

5-104.Chlamydia pneumoniae and giant-cell arteritis: Failure to detect Chlamydia pneumoniae in temporal artery biopsies by polymerase chain reaction
M.J. Regan, B.J. Wood, Y.-H. Hsieh, M.L. Theodore, T.C. Quinn, D.B. Hellmann, W.R. Green, C.A. Gaydos, J.H. Stone

B. Patterns of Injury: Implications for Pathogenesis
Moderators: Loïc Guillevin and Cornelia Weyand

Keynote Presentations
Pathogenic mechanisms in giant cell arteritis
Cornelia M. Weyand and Jörg J. Goronzy

Implications for pathogenesis of patterns of injury in small- and medium-sized-vessel vasculitis
J. Charles Jennette

Plenary Session Abstracts (6-7)

6-037. Superantigenic activation of T lymphocytes and endothelial cells: A mechanism for superantigen-induced vasculitis
P.A. Brogan, V. Shah, N. Klein, M.J. Dillon

7-108. Analysis of autoantibody repertoires in small and medium sized vessel vasculitis: Evidence for disease-specific perturbations in classic polyarteritis nodosa (PAN), micropolyangiitis (MPA), Churg-Strauss syndrome (CSS) and Wegener's granulomatosis (WG)
Y. Chanseaud, L. Guillevin, M. Kambouchner, M.C. Boissier, L. Mouthon

Keynote Presentation
Granuloma formation, implications for the pathogenesis of vasculitis
Michael C. Sneller

Plenary Session Abstracts (8-9)
8-052. Chemokine receptor expression on CD4+ and CD8+ memory T-cells and in granulomas in Wegener's granulomatosis
P. Lamprecht, A. Erdmann, A. Mueller, E. Csernok, H. Bruehl, W.L. Gross, M. Mack

9-016. Genetic resistance to Wegener's granulomatosis—a role for CCR5 in patients without antineutrophil cytoplasmic antibodies
Y. Zhou, D. Huang, C. Farver, G. Hoffman

Keynote Presentation
Endothelial cell biology, perivascular inflammation, and vasculitis
Maria C. Cid

Plenary Session Abstract (10)
10-023. Novel effects of inflammatory cell proteases on vascular endothelia
G.A. Preston, W.F. Pendergraft, J.J. Yang, J.C. Jennette, R.J. Falk

C. Possible Role of ANCA and AECA in Select Forms of Systemic Vasculitis
Moderators: Wolfgang Gross and Caroline Savage

Keynote Presentation
Understanding the pathogenesis of ANCA: Where are we today?
Gloria A. Preston, Jia Jin Yang, Hong Xiao, and Ronald J. Falk

Plenary Session Abstracts (11-12)
11-027. TNF-alpha accelerated apoptosis abrogates ANCA-mediated neutrophil respiratory burst by a caspase-dependent mechanism
R. Kettritz, J. Scheumann, Y. Xu, F.C. Luft, H. Haller

12-071. Membrane expression of neurotrophil proteinase 3 (PR3) is associated with relapse in PR3-ANCA related vasculitis
A.A. Rarok, C.A. Stegeman, P.C. Limburg, C.G.M. Kallenberg

Keynote Presentation
ANCA subsets: Influence on disease phenotype
Ulrich Specks

Plenary Session Abstract (13)
13-096. Sequential epitope mapping of the myeloperoxidase antigen
D.M. Wynn, J.A. James

Keynote Presentation
Genetics of ANCA-associated vasculitis
Cees G.M. Kallenberg, Agnieszka Rarok, and Coen A. Stegeman

Plenary Session Abstracts (14-15)
14-028. Membrane expression of proteinase 3 is genetically controlled
A. Schreiber, A. Bushjahn, F.C. Luft, R. Kettritz

15-015. Genetic polymorphisms in TNF, IL-1, IL-6 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in Wegener's granulomatosis (WG)
Y. Zhou, D. Huang, G.S. Hoffman

Keynote Presentation
Classification of anti-endothelial cell antibodies into antibodies against microvascular and macrovascular endothelial cells: The pathogenic and diagnostic implications
Yehuda Shoenfeld

Plenary Session Abstract (16)
16-029. HMG-COA reductase inhibitors decrease ANCA-mediated activation of human neutrophils
M. Choi, S. Rolle M. Rane, H. Haller, F.C. Luft, R. Kettritz

II. EPIDEMIOLOGY OF VASCULITIS
Moderators: Miguel Gonzalez-Gay and Gene Hunder

Keynote Presentations
Kawasaki disease: Etiology, pathogenesis, and treatment
Karyl S. Barron

Epidemiology of giant-cell arteritis
Gene G. Hunder

Plenary Session Abstract (17)
17-102. Ethnic disparity in the incidence of temporal arteritis: A 32-year experience at an urban medical center
M.J. Regan, W.R. Green, J.H. Stone

Keynote Presentations
Epidemiology of Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome
Richard A. Watts, David G.I. Scott, and Suzanne E. Lane

Epidemiology of Henoch-Schönlein purpura
Frank Saulsbury

Plenary Session Abstract (18)
18-010. Henoch-Schönlein purpura and cutaneous leukocytoclastic angiitis exhibit different HLA-DRB1 associations
M.M. Amoli, W. Thomson, A.H. Hajeer, M.C. Calviño, C. Garcia-Porrua, W.E.R. Ollier, M.A. Gonzalez-Gay

III. DIAGNOSTIC MODALITIES, SURROGATE MARKERS OF DISEASE ACTIVITY, AND TOOLS FOR OUTCOME MEASUREMENTS
Moderators: Carol Langford and Raashid Luqmani

Keynote Presentations
Cytokines in giant-cell arteritis
Jörg J. Goronzy and Cornelia M. Weyand

Utility of imaging studies in assessment of vascular inflammation
Daniël Blockmans

Measuring disease activity and outcomes in clinical studies
Raashid Luqmani

Plenary Session Abstracts (19-21)
19-022. Increases of PR3 and MPO gene transcription in circulating leukocyte of ANCA-associated disease correlate with disease activity
J.J. Yang, G.A. Preston, D.A. Alcorta, B.D. Phillips, R.P. Thomas, S.L. Hogan, J.C. Jennette, R.J. Falk

20-119. Cardiac involvement in Wegener's granulomatosis: Echocardiographic features and clinical outcomes
G.H.M. Oliveira, J.B. Seward, U. Specks

21-041. Endothelial microparticles: Just blood "dust," or a "must" for the diagnosis and monitoring of disease activity in childhood vasculitides?
P.A. Brogan, V. Shah, C. Brachet, N. Klein, M.J. Dillon

Keynote Presentation
Diagnostic strategies in vasculitis affecting the central nervous system
Leonard H. Calabrese

Plenary Session Abstracts (22-23)
Moderator: Leonard Calabrese

22-082. Circulating endothelial cells and vasculitis
A. Woywodt, F. Streiber, K. de Groot, H. Haller, M. Haubitz

23-051. Diffuse endothelial dysfunction is a common feature of SNV
P.A. Bacon, D.M. Carruthers, A.D. Diler, K. Raza, J. Townend

IV. TREATMENT AND OUTCOMES
Moderators: Charles Pusey and Fokko van der Woude

Keynote Presentation
Conventional treatment and outcome of Wegener's granulomatosis and microscopic polyangiitis
David R.W. Jayne

Plenary Session Abstract (24)
24-012. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in "non-renal" ANCA-associated vasculitis
K. de Groot, N. Rasmussen, J.W. Cohen Tervaert, D.R.W. Jayne for EUVAS (European Vasculitis Study Group)

Keynote Presentations
Treatment of giant-cell arteritis: Where we have been and why we must move on
Gary S. Hoffman

Henoch-Schönlein purpura (treatment and outcome)
Michael J. Dillon

Targeted therapies in systemic vasculitis
John H. Stone

Plenary Session Abstract (25)
25-070. Campath 1-H (anti-CD52) for refractory vasculitis: Retrospective Cambridge experience 1989-1999
D.R.W. Jayne

V. TREATING THE PERMANENT SEQUELAE OF VASCULITIS
Moderators: Robert Kimberly and John Stone

Keynote Presentations
Inflammation in acute coronary syndromes
Mark Robbins and Eric J. Topol

Kidney transplantation and ANCA-associated vasculitis
Fokko J. van der Woude

Surgical treatment of Takayasu's disease
Joseph M. Giordano

New approaches to the management of subglottic stenosis in Wegener's granulomatosis
Isaac Eliachar, James Chan, and Lee Akst

Sinonasal complications of vasculitic diseases
Robert S. Lebovics

POSTER PRESENTATIONS (26-120)

Pathogenesis—Immune Predisposition and Infectious Etiology of Systemic Vasculitis

Pathogenesis—Patterns of Injury: Implications for Pathogenesis

Pathogenesis—Possible Role of ANCA and AECA in Selected Forms of Systemic Vasculitis

Epidemiology of Vasculitis

Diagnostic Modalities, Surrogate Markers of Disease Activity, and Tools for Outcome Measurements

Treatment and Outcomes

Treating the Permanent Sequelae of Vasculitis

Program Chairmen and Editors:
Gary S. Hoffman, MD, and John H. Stone, MD, MPH

Contents

I. PATHOGENESIS

A. Immune Predisposition and Infectious Etiology of Systemic Vasculitis
Moderators: Coen Stegeman and Herbert Virgin

Keynote Presentation
Host and viral genes that control herpesvirus vasculitis
Herbert W. Virgin IV

Plenary Session Abstracts (1-3)
1-090. Induction of pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) by intravenous administration of anti-myeloperoxidase (anti-MPO) antibodies to recombinase activating gene-2 deficient (RAG-2 -/-) mice
J.C. Jennette, H. Xiao, P. Heeringa, Z. Liu, P. Hu, M. Zhao, Y. Aratani, R.J. Falk

2-091. Induction of necrotizing and crescentic glomerulonephritis (NCGN) and small-vessel vasculitis (SVV) by adoptive transfer of anti-myeloperoxidase (anti-MPO) lymphocytes into recombinase activating gene-2 deficient (RAG-2 -/-) mice
H. Xiao, P. Heeringa, Z. Liu, P. Hu, M. Zhao, Y. Aratani, R.J. Falk, J.C. Jennette

3-049. Contribution of activated neurotrophils and MPO-ANCA to the development of crescentic glomerulonephritis in SCG/KJ mice
A. Ishida-Okawara, T. Ito-Ihara, T. Ono, E. Muso, K. Saiga, K. Nemoto, K. Suzuki

Keynote Presentations
Known causes of vasculitis in man
Stanley J. Naides

HCV and cryoglobulinemic vasculitis
Clodoveo Ferri, A.L. Zignego, D. Giuggioli, M. Sebastiani, M. Cazzato, A. Antonelli, L. La Civita, P. Fadda, G. Longombardo, and S. Pileri

Infections in primary vasculitides
Jan W. Cohen Tervaert

Plenary session Abstracts (4-5)
4-093. Staphylococcal toxic-shock-syndrome-toxin-1 (TSST-1) is a risk factor for disease relapse in Wegener's granulomatosis
E.R. Popa, B. van der Meer, J. Arends, W.M. Manson, N.A. Bos, C.G.M. Kallenberg, J.W. Cohen Tervaert, C.A. Stegeman

5-104.Chlamydia pneumoniae and giant-cell arteritis: Failure to detect Chlamydia pneumoniae in temporal artery biopsies by polymerase chain reaction
M.J. Regan, B.J. Wood, Y.-H. Hsieh, M.L. Theodore, T.C. Quinn, D.B. Hellmann, W.R. Green, C.A. Gaydos, J.H. Stone

B. Patterns of Injury: Implications for Pathogenesis
Moderators: Loïc Guillevin and Cornelia Weyand

Keynote Presentations
Pathogenic mechanisms in giant cell arteritis
Cornelia M. Weyand and Jörg J. Goronzy

Implications for pathogenesis of patterns of injury in small- and medium-sized-vessel vasculitis
J. Charles Jennette

Plenary Session Abstracts (6-7)

6-037. Superantigenic activation of T lymphocytes and endothelial cells: A mechanism for superantigen-induced vasculitis
P.A. Brogan, V. Shah, N. Klein, M.J. Dillon

7-108. Analysis of autoantibody repertoires in small and medium sized vessel vasculitis: Evidence for disease-specific perturbations in classic polyarteritis nodosa (PAN), micropolyangiitis (MPA), Churg-Strauss syndrome (CSS) and Wegener's granulomatosis (WG)
Y. Chanseaud, L. Guillevin, M. Kambouchner, M.C. Boissier, L. Mouthon

Keynote Presentation
Granuloma formation, implications for the pathogenesis of vasculitis
Michael C. Sneller

Plenary Session Abstracts (8-9)
8-052. Chemokine receptor expression on CD4+ and CD8+ memory T-cells and in granulomas in Wegener's granulomatosis
P. Lamprecht, A. Erdmann, A. Mueller, E. Csernok, H. Bruehl, W.L. Gross, M. Mack

9-016. Genetic resistance to Wegener's granulomatosis—a role for CCR5 in patients without antineutrophil cytoplasmic antibodies
Y. Zhou, D. Huang, C. Farver, G. Hoffman

Keynote Presentation
Endothelial cell biology, perivascular inflammation, and vasculitis
Maria C. Cid

Plenary Session Abstract (10)
10-023. Novel effects of inflammatory cell proteases on vascular endothelia
G.A. Preston, W.F. Pendergraft, J.J. Yang, J.C. Jennette, R.J. Falk

C. Possible Role of ANCA and AECA in Select Forms of Systemic Vasculitis
Moderators: Wolfgang Gross and Caroline Savage

Keynote Presentation
Understanding the pathogenesis of ANCA: Where are we today?
Gloria A. Preston, Jia Jin Yang, Hong Xiao, and Ronald J. Falk

Plenary Session Abstracts (11-12)
11-027. TNF-alpha accelerated apoptosis abrogates ANCA-mediated neutrophil respiratory burst by a caspase-dependent mechanism
R. Kettritz, J. Scheumann, Y. Xu, F.C. Luft, H. Haller

12-071. Membrane expression of neurotrophil proteinase 3 (PR3) is associated with relapse in PR3-ANCA related vasculitis
A.A. Rarok, C.A. Stegeman, P.C. Limburg, C.G.M. Kallenberg

Keynote Presentation
ANCA subsets: Influence on disease phenotype
Ulrich Specks

Plenary Session Abstract (13)
13-096. Sequential epitope mapping of the myeloperoxidase antigen
D.M. Wynn, J.A. James

Keynote Presentation
Genetics of ANCA-associated vasculitis
Cees G.M. Kallenberg, Agnieszka Rarok, and Coen A. Stegeman

Plenary Session Abstracts (14-15)
14-028. Membrane expression of proteinase 3 is genetically controlled
A. Schreiber, A. Bushjahn, F.C. Luft, R. Kettritz

15-015. Genetic polymorphisms in TNF, IL-1, IL-6 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in Wegener's granulomatosis (WG)
Y. Zhou, D. Huang, G.S. Hoffman

Keynote Presentation
Classification of anti-endothelial cell antibodies into antibodies against microvascular and macrovascular endothelial cells: The pathogenic and diagnostic implications
Yehuda Shoenfeld

Plenary Session Abstract (16)
16-029. HMG-COA reductase inhibitors decrease ANCA-mediated activation of human neutrophils
M. Choi, S. Rolle M. Rane, H. Haller, F.C. Luft, R. Kettritz

II. EPIDEMIOLOGY OF VASCULITIS
Moderators: Miguel Gonzalez-Gay and Gene Hunder

Keynote Presentations
Kawasaki disease: Etiology, pathogenesis, and treatment
Karyl S. Barron

Epidemiology of giant-cell arteritis
Gene G. Hunder

Plenary Session Abstract (17)
17-102. Ethnic disparity in the incidence of temporal arteritis: A 32-year experience at an urban medical center
M.J. Regan, W.R. Green, J.H. Stone

Keynote Presentations
Epidemiology of Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome
Richard A. Watts, David G.I. Scott, and Suzanne E. Lane

Epidemiology of Henoch-Schönlein purpura
Frank Saulsbury

Plenary Session Abstract (18)
18-010. Henoch-Schönlein purpura and cutaneous leukocytoclastic angiitis exhibit different HLA-DRB1 associations
M.M. Amoli, W. Thomson, A.H. Hajeer, M.C. Calviño, C. Garcia-Porrua, W.E.R. Ollier, M.A. Gonzalez-Gay

III. DIAGNOSTIC MODALITIES, SURROGATE MARKERS OF DISEASE ACTIVITY, AND TOOLS FOR OUTCOME MEASUREMENTS
Moderators: Carol Langford and Raashid Luqmani

Keynote Presentations
Cytokines in giant-cell arteritis
Jörg J. Goronzy and Cornelia M. Weyand

Utility of imaging studies in assessment of vascular inflammation
Daniël Blockmans

Measuring disease activity and outcomes in clinical studies
Raashid Luqmani

Plenary Session Abstracts (19-21)
19-022. Increases of PR3 and MPO gene transcription in circulating leukocyte of ANCA-associated disease correlate with disease activity
J.J. Yang, G.A. Preston, D.A. Alcorta, B.D. Phillips, R.P. Thomas, S.L. Hogan, J.C. Jennette, R.J. Falk

20-119. Cardiac involvement in Wegener's granulomatosis: Echocardiographic features and clinical outcomes
G.H.M. Oliveira, J.B. Seward, U. Specks

21-041. Endothelial microparticles: Just blood "dust," or a "must" for the diagnosis and monitoring of disease activity in childhood vasculitides?
P.A. Brogan, V. Shah, C. Brachet, N. Klein, M.J. Dillon

Keynote Presentation
Diagnostic strategies in vasculitis affecting the central nervous system
Leonard H. Calabrese

Plenary Session Abstracts (22-23)
Moderator: Leonard Calabrese

22-082. Circulating endothelial cells and vasculitis
A. Woywodt, F. Streiber, K. de Groot, H. Haller, M. Haubitz

23-051. Diffuse endothelial dysfunction is a common feature of SNV
P.A. Bacon, D.M. Carruthers, A.D. Diler, K. Raza, J. Townend

IV. TREATMENT AND OUTCOMES
Moderators: Charles Pusey and Fokko van der Woude

Keynote Presentation
Conventional treatment and outcome of Wegener's granulomatosis and microscopic polyangiitis
David R.W. Jayne

Plenary Session Abstract (24)
24-012. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in "non-renal" ANCA-associated vasculitis
K. de Groot, N. Rasmussen, J.W. Cohen Tervaert, D.R.W. Jayne for EUVAS (European Vasculitis Study Group)

Keynote Presentations
Treatment of giant-cell arteritis: Where we have been and why we must move on
Gary S. Hoffman

Henoch-Schönlein purpura (treatment and outcome)
Michael J. Dillon

Targeted therapies in systemic vasculitis
John H. Stone

Plenary Session Abstract (25)
25-070. Campath 1-H (anti-CD52) for refractory vasculitis: Retrospective Cambridge experience 1989-1999
D.R.W. Jayne

V. TREATING THE PERMANENT SEQUELAE OF VASCULITIS
Moderators: Robert Kimberly and John Stone

Keynote Presentations
Inflammation in acute coronary syndromes
Mark Robbins and Eric J. Topol

Kidney transplantation and ANCA-associated vasculitis
Fokko J. van der Woude

Surgical treatment of Takayasu's disease
Joseph M. Giordano

New approaches to the management of subglottic stenosis in Wegener's granulomatosis
Isaac Eliachar, James Chan, and Lee Akst

Sinonasal complications of vasculitic diseases
Robert S. Lebovics

POSTER PRESENTATIONS (26-120)

Pathogenesis—Immune Predisposition and Infectious Etiology of Systemic Vasculitis

Pathogenesis—Patterns of Injury: Implications for Pathogenesis

Pathogenesis—Possible Role of ANCA and AECA in Selected Forms of Systemic Vasculitis

Epidemiology of Vasculitis

Diagnostic Modalities, Surrogate Markers of Disease Activity, and Tools for Outcome Measurements

Treatment and Outcomes

Treating the Permanent Sequelae of Vasculitis

Supplement Editor:
Marc C. Hochberg, MD, MPH

Contents

Preface and Foreword
Marc C. Hochberg, MD, MPH

Development and clinical application of COX-2–selective inhibitors for the treatment of osteoarthritis and rheumatoid arthritis
Clifton G. Bingham III, MD

Cyclooxygenase-2–selective inhibitors: Translating pharmacology into clinical utility
Bruce N. Cronstein, MD

COX-2–selective inhibitors in the treatment of arthritis
Thomas J. Schnitzer, MD, PhD, and Marc C. Hochberg, MD, MPH

Gastrointestinal safety and tolerability of non-selective nonsteroidal anti-inflammatory agents and cyclooxygenase-2–selective inhibitors
David A. Peura, MD

Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors
James M. Scheiman, MD

Current perspective on the cardiovascular effects of coxibs
Marvin A. Konstam, MD, and Matthew R. Weir, MD

Renal effects of nonselective NSAIDs and coxibs
Matthew R. Weir, MD

Developing an economic rationale for the use of selective COX-2 inhibitors for patients at risk for NSAID gastropathy
A. Mark Fendrick, MD

Cyclooxygenase-2–selective inhibitors in the management of acute and perioperative pain
Warren A. Katz, MD

Emerging options with coxib therapy
Mark J. Lema, MD, PhD

Supplement Editor:
Marc C. Hochberg, MD, MPH

Contents

Preface and Foreword
Marc C. Hochberg, MD, MPH

Development and clinical application of COX-2–selective inhibitors for the treatment of osteoarthritis and rheumatoid arthritis
Clifton G. Bingham III, MD

Cyclooxygenase-2–selective inhibitors: Translating pharmacology into clinical utility
Bruce N. Cronstein, MD

COX-2–selective inhibitors in the treatment of arthritis
Thomas J. Schnitzer, MD, PhD, and Marc C. Hochberg, MD, MPH

Gastrointestinal safety and tolerability of non-selective nonsteroidal anti-inflammatory agents and cyclooxygenase-2–selective inhibitors
David A. Peura, MD

Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors
James M. Scheiman, MD

Current perspective on the cardiovascular effects of coxibs
Marvin A. Konstam, MD, and Matthew R. Weir, MD

Renal effects of nonselective NSAIDs and coxibs
Matthew R. Weir, MD

Developing an economic rationale for the use of selective COX-2 inhibitors for patients at risk for NSAID gastropathy
A. Mark Fendrick, MD

Cyclooxygenase-2–selective inhibitors in the management of acute and perioperative pain
Warren A. Katz, MD

Emerging options with coxib therapy
Mark J. Lema, MD, PhD

Supplement Editor:
Marc C. Hochberg, MD, MPH

Contents

Preface and Foreword
Marc C. Hochberg, MD, MPH

Development and clinical application of COX-2–selective inhibitors for the treatment of osteoarthritis and rheumatoid arthritis
Clifton G. Bingham III, MD

Cyclooxygenase-2–selective inhibitors: Translating pharmacology into clinical utility
Bruce N. Cronstein, MD

COX-2–selective inhibitors in the treatment of arthritis
Thomas J. Schnitzer, MD, PhD, and Marc C. Hochberg, MD, MPH

Gastrointestinal safety and tolerability of non-selective nonsteroidal anti-inflammatory agents and cyclooxygenase-2–selective inhibitors
David A. Peura, MD

Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors
James M. Scheiman, MD

Current perspective on the cardiovascular effects of coxibs
Marvin A. Konstam, MD, and Matthew R. Weir, MD

Renal effects of nonselective NSAIDs and coxibs
Matthew R. Weir, MD

Developing an economic rationale for the use of selective COX-2 inhibitors for patients at risk for NSAID gastropathy
A. Mark Fendrick, MD

Cyclooxygenase-2–selective inhibitors in the management of acute and perioperative pain
Warren A. Katz, MD

Emerging options with coxib therapy
Mark J. Lema, MD, PhD

ABSTRACT

BACKGROUND: About 10% of people in the United States develop at least 1 symptomatic kidney stone during their lives. The recurrence rate after 10 years is at least 50%. Many physicians recommend a low-calcium diet in patients with calcium oxalate stones to prevent recurrence. Recent studies suggest that a low-calcium diet may not be effective and that intake of animal protein and salt may influence renal calcium excretion. This study compares the traditional low-calcium diet with a diet that is low in animal protein and salt.

POPULATION STUDIED: This study enrolled 120 men with idiopathic hypercalciuria (urinary calcium excretion of more than 300 mg per day on an unrestricted diet) who had been referred to a nephrology clinic in Parma, Italy, and who had had at least 2 episodes of symptomatic renal stones. Reasons for exclusion included previous visits to any “stone disease center” and conditions associated with calcium stones, such as hyperparathyroidism or inflammatory bowel disease.

STUDY DESIGN AND VALIDITY: The investigators randomly assigned subjects, using concealed allocation, to 1 of 2 diets in this randomized controlled study. The low-calcium diet limited calcium intake to about 400 mg per day. The other diet, which included about 1200 mg per day of calcium, limited sodium chloride to about 3000 mg and animal protein to 93 g (15% of total calories). Both groups were advised to limit intake of high-oxalate foods and encouraged to drink 2 liters of water per day in cold weather and 3 liters in warm weather. Subjects were allowed moderate consumption of beer, wine, coffee, and sodas. (Detailed dietary instructions are available to New England Journal of Medicine subscribers in the supplement to the publication at www.nejm.org.) The study followed the patients for 5 years or until they developed clinical or radiologic evidence of a renal stone. Annual x-ray and ultrasound studies identified asymptomatic stone recurrences.

OUTCOMES MEASURED: The primary outcome was the time to development of the first recurrence of a renal stone, whether or not it was clinically evident. Other outcomes included changes in calcium and oxalate excretion and calcium oxalate saturation in the urine.

RESULTS: After 5 years, the low-protein, low-sodium diet led to fewer recurrences (20% compared with 38% in the low-calcium group, relative risk 0.49, number needed to treat with diet for 5 years = 5.5). The risk of recurrence in the low-calcium group was similar to the 35% to 40% expected in the absence of any intervention. The disease-oriented changes in urine characteristics were predictable: urinary calcium decreased in both groups, but oxalate secretion increased in the low-calcium group, causing greater calcium oxalate saturation.

ABSTRACT

BACKGROUND: About 10% of people in the United States develop at least 1 symptomatic kidney stone during their lives. The recurrence rate after 10 years is at least 50%. Many physicians recommend a low-calcium diet in patients with calcium oxalate stones to prevent recurrence. Recent studies suggest that a low-calcium diet may not be effective and that intake of animal protein and salt may influence renal calcium excretion. This study compares the traditional low-calcium diet with a diet that is low in animal protein and salt.

POPULATION STUDIED: This study enrolled 120 men with idiopathic hypercalciuria (urinary calcium excretion of more than 300 mg per day on an unrestricted diet) who had been referred to a nephrology clinic in Parma, Italy, and who had had at least 2 episodes of symptomatic renal stones. Reasons for exclusion included previous visits to any “stone disease center” and conditions associated with calcium stones, such as hyperparathyroidism or inflammatory bowel disease.

STUDY DESIGN AND VALIDITY: The investigators randomly assigned subjects, using concealed allocation, to 1 of 2 diets in this randomized controlled study. The low-calcium diet limited calcium intake to about 400 mg per day. The other diet, which included about 1200 mg per day of calcium, limited sodium chloride to about 3000 mg and animal protein to 93 g (15% of total calories). Both groups were advised to limit intake of high-oxalate foods and encouraged to drink 2 liters of water per day in cold weather and 3 liters in warm weather. Subjects were allowed moderate consumption of beer, wine, coffee, and sodas. (Detailed dietary instructions are available to New England Journal of Medicine subscribers in the supplement to the publication at www.nejm.org.) The study followed the patients for 5 years or until they developed clinical or radiologic evidence of a renal stone. Annual x-ray and ultrasound studies identified asymptomatic stone recurrences.

OUTCOMES MEASURED: The primary outcome was the time to development of the first recurrence of a renal stone, whether or not it was clinically evident. Other outcomes included changes in calcium and oxalate excretion and calcium oxalate saturation in the urine.

RESULTS: After 5 years, the low-protein, low-sodium diet led to fewer recurrences (20% compared with 38% in the low-calcium group, relative risk 0.49, number needed to treat with diet for 5 years = 5.5). The risk of recurrence in the low-calcium group was similar to the 35% to 40% expected in the absence of any intervention. The disease-oriented changes in urine characteristics were predictable: urinary calcium decreased in both groups, but oxalate secretion increased in the low-calcium group, causing greater calcium oxalate saturation.

ABSTRACT

BACKGROUND: About 10% of people in the United States develop at least 1 symptomatic kidney stone during their lives. The recurrence rate after 10 years is at least 50%. Many physicians recommend a low-calcium diet in patients with calcium oxalate stones to prevent recurrence. Recent studies suggest that a low-calcium diet may not be effective and that intake of animal protein and salt may influence renal calcium excretion. This study compares the traditional low-calcium diet with a diet that is low in animal protein and salt.

POPULATION STUDIED: This study enrolled 120 men with idiopathic hypercalciuria (urinary calcium excretion of more than 300 mg per day on an unrestricted diet) who had been referred to a nephrology clinic in Parma, Italy, and who had had at least 2 episodes of symptomatic renal stones. Reasons for exclusion included previous visits to any “stone disease center” and conditions associated with calcium stones, such as hyperparathyroidism or inflammatory bowel disease.

STUDY DESIGN AND VALIDITY: The investigators randomly assigned subjects, using concealed allocation, to 1 of 2 diets in this randomized controlled study. The low-calcium diet limited calcium intake to about 400 mg per day. The other diet, which included about 1200 mg per day of calcium, limited sodium chloride to about 3000 mg and animal protein to 93 g (15% of total calories). Both groups were advised to limit intake of high-oxalate foods and encouraged to drink 2 liters of water per day in cold weather and 3 liters in warm weather. Subjects were allowed moderate consumption of beer, wine, coffee, and sodas. (Detailed dietary instructions are available to New England Journal of Medicine subscribers in the supplement to the publication at www.nejm.org.) The study followed the patients for 5 years or until they developed clinical or radiologic evidence of a renal stone. Annual x-ray and ultrasound studies identified asymptomatic stone recurrences.

OUTCOMES MEASURED: The primary outcome was the time to development of the first recurrence of a renal stone, whether or not it was clinically evident. Other outcomes included changes in calcium and oxalate excretion and calcium oxalate saturation in the urine.

RESULTS: After 5 years, the low-protein, low-sodium diet led to fewer recurrences (20% compared with 38% in the low-calcium group, relative risk 0.49, number needed to treat with diet for 5 years = 5.5). The risk of recurrence in the low-calcium group was similar to the 35% to 40% expected in the absence of any intervention. The disease-oriented changes in urine characteristics were predictable: urinary calcium decreased in both groups, but oxalate secretion increased in the low-calcium group, causing greater calcium oxalate saturation.

Making a quick diagnosis in a hyperactive, inattentive child is often difficult. The National Institutes of Health concluded in a consensus statement that no independent diagnostic test for attention-deficit/hyperactivity disorder (ADHD) exists.¹ Furthermore, the American Academy of Child & Adolescent Psychiatry (AACAP) issued a treatment guideline classifying ADHD as a clinical diagnosis.

With the time constraints imposed by managed care organizations, questioning and history gathering must be precisely aimed to elicit specific information. Over the years, I have identified the following 5 red flags that help distinguish ADHD from mood problems,² anxiety, psychosis, obsessions, and other psychiatric disorders.

1. Moodiness is not part of ADHD. The DSM-IV criteria for ADHD do not include elevated mood. “Mood swings,” persistent clowning, or angry affect should prompt further questioning about similar features in relatives. Frequently we hear that “his father was never diagnosed with anything, but he was the class clown.”
2. ADHD is not an intermittent condition. By asking if the child has “good days and bad days,” we can obtain valuable information. ADHD has a biological basis and is present every day, like Parkinson’s disease or diabetes. Obviously, some days can be more challenging than others, but if a parent says, “Some days she is a perfect child,” the possibility of ADHD is small.
3. Symptoms are not present in kindergarten. The child with ADHD begins to show signs of this condition very early in life; parents are frequently informed of problems by preschool and kindergarten teachers. The usual complaints are inability to stay with a task and disrupting the class. Start of these symptoms as late as first or second grade is a red flag to question the ADHD diagnosis.
4. More than one diagnosis probably means “none of the above.” When a child has been diagnosed with conduct disorder (CD) and/or oppositional-defiant disorder (ODD) along with ADHD, chances are that we are missing the real diagnosis. I have seen cases of social anxiety disorder that had been diagnosed as ADHD/ODD because the child was inattentive secondary to nervousness. Incidentally, DSM-IV does not allow the diagnosis of ODD in the presence of CD.
5. Worsening of symptoms is not an expected outcome of stimulant medications for ADHD. Lack of response to psychostimulants or only mild improvement may occur in ADHD. Frequently, however, we see children with histories of getting worse after starting medication for presumed ADHD.

Making a quick diagnosis in a hyperactive, inattentive child is often difficult. The National Institutes of Health concluded in a consensus statement that no independent diagnostic test for attention-deficit/hyperactivity disorder (ADHD) exists.¹ Furthermore, the American Academy of Child & Adolescent Psychiatry (AACAP) issued a treatment guideline classifying ADHD as a clinical diagnosis.

With the time constraints imposed by managed care organizations, questioning and history gathering must be precisely aimed to elicit specific information. Over the years, I have identified the following 5 red flags that help distinguish ADHD from mood problems,² anxiety, psychosis, obsessions, and other psychiatric disorders.

1. Moodiness is not part of ADHD. The DSM-IV criteria for ADHD do not include elevated mood. “Mood swings,” persistent clowning, or angry affect should prompt further questioning about similar features in relatives. Frequently we hear that “his father was never diagnosed with anything, but he was the class clown.”
2. ADHD is not an intermittent condition. By asking if the child has “good days and bad days,” we can obtain valuable information. ADHD has a biological basis and is present every day, like Parkinson’s disease or diabetes. Obviously, some days can be more challenging than others, but if a parent says, “Some days she is a perfect child,” the possibility of ADHD is small.
3. Symptoms are not present in kindergarten. The child with ADHD begins to show signs of this condition very early in life; parents are frequently informed of problems by preschool and kindergarten teachers. The usual complaints are inability to stay with a task and disrupting the class. Start of these symptoms as late as first or second grade is a red flag to question the ADHD diagnosis.
4. More than one diagnosis probably means “none of the above.” When a child has been diagnosed with conduct disorder (CD) and/or oppositional-defiant disorder (ODD) along with ADHD, chances are that we are missing the real diagnosis. I have seen cases of social anxiety disorder that had been diagnosed as ADHD/ODD because the child was inattentive secondary to nervousness. Incidentally, DSM-IV does not allow the diagnosis of ODD in the presence of CD.
5. Worsening of symptoms is not an expected outcome of stimulant medications for ADHD. Lack of response to psychostimulants or only mild improvement may occur in ADHD. Frequently, however, we see children with histories of getting worse after starting medication for presumed ADHD.

Making a quick diagnosis in a hyperactive, inattentive child is often difficult. The National Institutes of Health concluded in a consensus statement that no independent diagnostic test for attention-deficit/hyperactivity disorder (ADHD) exists.¹ Furthermore, the American Academy of Child & Adolescent Psychiatry (AACAP) issued a treatment guideline classifying ADHD as a clinical diagnosis.

With the time constraints imposed by managed care organizations, questioning and history gathering must be precisely aimed to elicit specific information. Over the years, I have identified the following 5 red flags that help distinguish ADHD from mood problems,² anxiety, psychosis, obsessions, and other psychiatric disorders.

1. Moodiness is not part of ADHD. The DSM-IV criteria for ADHD do not include elevated mood. “Mood swings,” persistent clowning, or angry affect should prompt further questioning about similar features in relatives. Frequently we hear that “his father was never diagnosed with anything, but he was the class clown.”
2. ADHD is not an intermittent condition. By asking if the child has “good days and bad days,” we can obtain valuable information. ADHD has a biological basis and is present every day, like Parkinson’s disease or diabetes. Obviously, some days can be more challenging than others, but if a parent says, “Some days she is a perfect child,” the possibility of ADHD is small.
3. Symptoms are not present in kindergarten. The child with ADHD begins to show signs of this condition very early in life; parents are frequently informed of problems by preschool and kindergarten teachers. The usual complaints are inability to stay with a task and disrupting the class. Start of these symptoms as late as first or second grade is a red flag to question the ADHD diagnosis.
4. More than one diagnosis probably means “none of the above.” When a child has been diagnosed with conduct disorder (CD) and/or oppositional-defiant disorder (ODD) along with ADHD, chances are that we are missing the real diagnosis. I have seen cases of social anxiety disorder that had been diagnosed as ADHD/ODD because the child was inattentive secondary to nervousness. Incidentally, DSM-IV does not allow the diagnosis of ODD in the presence of CD.
5. Worsening of symptoms is not an expected outcome of stimulant medications for ADHD. Lack of response to psychostimulants or only mild improvement may occur in ADHD. Frequently, however, we see children with histories of getting worse after starting medication for presumed ADHD.