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Evidence-Based Reviews

Attention-deficit/hyperactivity disorder: Tips to individualize drug therapy

What help can we offer parents of children with ADHD? Can adults hope to conquer chronic attention deficits that interfere with on-the-job and social function? Here are answers, as a leading team of psychiatrists describes an up-to-date treatment approach

Vol. 1, No. 5 / May 2002

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.


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


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


  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


Management of ADHD includes nonpharmacologic and pharmacologic interventions.1 Support groups (e.g., Children and Adults with Attention Deficit/Hyperactivity Disorder (CHADD), 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.


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



Starting dosage

Maximum dosage

Usual dosing (hr)

Methylphenidate (short-acting)


5 mg bid

2 mg/kg/day

tid (4 hr)

Dexmethylphenidate (short-acting)


2.5 mg bid

1 mg/kg/day

bid (5 hr)

Methylphenidate (extended-release)


18 mg once daily

2 mg/kg/day

Once (12 hr)

 Metadate CD

20 mg once daily


Once (8-9 hr)

 Ritalin LA

10 mg once daily


Once (8-9 hr)

Amphetamine compounds


2.5 to 5 mg once daily

1.5 mg/kg/day

bid (6 hr)

 Adderall XR

10 mg


Once (12 hr)



2.5 to 5 mg once daily

1.5 mg/kg/day

bid/tid (4 hr)

 Dex Spansule

5 mg


bid (6 hr)

Magnesium pemoline


37.5 mg once in the morning

3 mg/kg/day


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 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.

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