Attention-deficit/hyperactivity disorder (ADHD) may be the only mental disorder that was discovered in children and later acknowledged in adults. Although controlled studies of adults with ADHD are few, we know that ADHD is common in adults, it can be diagnosed reliably, and 75% of those treated respond to treatment.¹

The hallmark symptom of ADHD in children—hyperactivity—is usually attenuated in adults. In fact, some adults prefer the term ADD to ADHD because they are not hyperactive. This may be especially true of women, as their attention problems during childhood often were not recognized as ADHD (Box 1).

Box 1

Characteristics of adult ADHD

Adults with ADHD visit a psychiatrist for a variety of reasons. Often they are parents of children diagnosed with ADHD, and the possibility that they are similarly affected has arisen during their children’s evaluation and treatment. Sometimes they have recognized themselves in consumer articles about ADHD, or others have seen them in this light.

Adults with ADHD continue to experience their childhood difficulties in sustaining attention, listening, following instructions, and organizing tasks; inattention to details; lack of sustained mental effort; losing things; distractibility, and forgetfulness. Typical complaints include underachievement and poor adjustment at work or home. Comorbid ADHD may also be identified in patients who present with depression, anxiety, substance misuse, and mood swings.

The cognitive impairment of ADHD continues into adulthood, even in adults without hyperactive symptoms. It may be that adults are not hyperactive because the basal ganglia, which control motor activity in the brain, have over the years accommodated the problem through behavior modification or neurodevelopmental changes in late adolescence.²

Children with ADHD have abnormal cerebrospinal fluid (CSF) and blood levels of the dopaminergic metabolite homovanillic acid (HVA), but adults with ADHD may not. The primary origin for CSF HVA is the nigrostriatum, which suggests that subcortical dopaminergic nuclei are more often affected in children than adults.² This may mean that compensatory changes occur as persons with ADHD mature, or perhaps the forms of ADHD that persist into adulthood have a different pathology or pathophysiology.

Comorbidities with ADHD

Rarely does one see pure ADHD; comorbidity is the rule. ADHD can be diagnosed quickly if you know what to look for. But a facile diagnosis may overlook a comorbidity that must be treated first—especially if you plan to use stimulants. Many patients with ADHD also have bipolar disorder, and a smaller proportion of patients with bipolar disorder have undetected ADHD. Placing a patient with undetected bipolar disorder on a stimulant could precipitate mania.

Table 1

COMMON COMORBIDITIES WITH ADHD

From the initial assessment, your treatment plan must address comorbid conditions (Table 1). This means taking a good history that includes corroborating information from relatives and data from the past, if possible. The case will then be much easier to manage, and quality of care greatly enhanced.

Stimulants: Usual first-choice therapy

In most cases, adult ADHD responds well to stimulant medications, although most available evidence is limited to studies in children. Several nonstimulant medications are also available, and the FDA is considering a new-drug application for a medication indicated for adult ADHD. Stimulants produce significant improvement in 30% of patients and mixed results in another 40%. Comorbidities may account for the 10 to 30% of patients who do not respond to stimulant therapy.

Methylphenidate, taken multiple times daily, is the most common treatment for ADHD. Dextroamphetamine and mixed salts of amphetamine also are used (Table 2).³ Patients usually respond to either methylphenidate or an amphetamine, and typically 25% of those who do not respond to one will respond to the other. When the clinical efficacy of amphetamines diminishes over time, many psychiatrists rotate medications. Replacing one amphetamine with another often eliminates the need to slowly increase the dosage and allows the clinician to maintain a relatively stable regimen.

When administering stimulants to adults, consider the individual’s total dosage requirement and daily schedule. Will he or she fare better with multiple daily dosing or a sustained-release form? How long is his or her average day? Does the patient have to be alert for 12 hours—or longer?

Some patients cannot sleep unless they take their last stimulant dose at bedtime. Others will have insomnia if a last dose is taken too late in the afternoon, especially with a sustained-release formulation.

When starting a patient on stimulants, begin with a 12-hour day and titrate the dosage—usually up, sometimes down—depending on response and side effects. Educating patients about their medications enables them to participate in decision-making.

Common side effects of stimulants include insomnia, decreased appetite, upset stomach, headache, anxiety, agitation, and increased pulse rate and blood pressure. The increase in blood pressure is usually less than 10%, but patients with poorly controlled hypertension should not be treated with stimulants until their blood pressure is well controlled. Until more is known about long-term effects, periodic assessment of blood pressure may be warranted.

Table 2

STIMULANT THERAPY FOR ADULTS WITH ADHD

Box 2

Adults with ADHD have been treated with mixed amphetamine salts with positive results. In a 7-week controlled, crossover study, 27 adults with ADHD received an average of 54 mg/d administered in two doses. Symptoms improved significantly—a 42% decrease on the ADHD Rating Scale. The medication was well-tolerated, and 70% of those receiving mixed amphetamine salts improved, compared with 7% of those who received a placebo.⁴

Duration of action of mixed salts of amphetamine has been measured at 3.5 hours with a 5-mg dose and 6.4 hours with a 20-mg dose.⁵ With methylphenidate, a dose of 12.5 mg worked for 4 hours. The maximum recommended dosage of mixed salts of amphetamine is 40 mg/d in divided doses.

Stimulant medications are well-tolerated. Addiction and the need for increased dosages can occur over long-term use (months to years). Reducing the dosage or switching from methylphenidate to an amphetamine variant can usually prevent these problems.

The FDA recently approved a single-enantiomer form of methylphenidate. It contains only the active “d” enantiomer, whereas the racemic mixture contains both the “d” and “l” enantiomers. Because the “l” enantiomer is inert, the resulting medication is more potent and may be prescribed at half the dosage of the racemic mixture.

Pemoline, a once-daily stimulant, is considered a second-line treatment because of reports of hepatic failure in some patients. Its use requires written informed consent and liver function tests at baseline and every 2 weeks. In a controlled trial, pemoline at high dosages (120 to 160 mg/d) was found moderately effective in adults with ADHD.⁶

Newer options: Longer-acting stimulants

Newer forms of slow-release methylphenidate and mixed amphetamine salts with sophisticated delivery systems are available.

Metadate CD is delivered in capsules containing beads with polymer coatings that dissolve and release their contents at different times. The capsules contain a 30:70 ratio of immediate- and extended-release beads.

Metadate CD has not been tested for adults in controlled clinical trials. In children ages 6 to 15, a single morning dose has been shown to be clinically effective in the morning and afternoon. A supplemental immediate-release capsule can be given in the morning if a patient’s medication levels need to be increased quickly. Dosage supplementation may also be required later in the day.

Concerta is delivered in 18-mg and 36-mg tablets. The immediate-release coating on the tablets delivers medication within the first hour. The drug inside then dissolves in the GI tract and is released at a controlled rate by osmotic pressure. The indigestible tablet is passed in the stool.

Concerta was investigated in children ages 6 to 12 and provides 10 to 12 hours of sustained medication. From child studies, we know that when a patient takes a 36-mg tablet at 6 AM, blood levels decline in late afternoon. An 18-mg dose at noon covers the 4 to 6 hours needed for evening chores.

Adderall XR is an extended-release, once-daily form of mixed amphetamine salts. No controlled trials of this formulation are available in adults with ADHD. Its efficacy was established after two clinical trials of children aged 6 to 12 who met DSM-IV criteria for ADHD.

Individualized and flexible dosing improves symptom control and compliance when treating adults with ADHD. For some patients, once-daily dosing is more convenient than multiple doses, while others prefer the immediate-release form because they like its midday “pause” and bid dosing. The immediate-release tablet allows the flexibility of bid or tid dosing, depending on the day’s requirements.

Antidepressants: Another choice

Antidepressants are usually considered second-line treatment for ADHD because of concerns about efficacy and side effects. The few available studies show antidepressants work as well as stimulants but more slowly. It is good practice, therefore, to advise patients that—unlike feeling the effect of a stimulant in 60 minutes—they will not feel an effect from an antidepressant for days or weeks, and that achieving an optimal effect may take 4 to 6 weeks.

Antidepressants have several advantages over stimulants. They are not classified as narcotics, work without the on-off effects of stimulants, and can treat comorbid depression and anxiety. For adult ADHD, the most effective agents work on the catecholamine systems—norepinephrine and/or dopamine. This includes the tricyclic antidepressants, MAO inhibitors, bupropion, and venlafaxine. The serotonin reuptake inhibitors have not shown promise in ADHD, nor have mirtazapine or nefazodone demonstrated much effect.

Desipramine, a tricyclic antidepressant, is a strong inhibitor of norepinephrine reuptake. In a double-blind, controlled study in 41 adults with ADHD, 68% of patients receiving desipramine, 200 mg/d, responded positively, compared with no patients who took a placebo.⁷

When venlafaxine was given in standard dosages to 10 adults with ADHD in an open, 8-week clinical trial, an effect was seen by week two. Of the nine patients who completed the study, seven were considered responders. Symptoms were reduced significantly with venlafaxine treatment, and most side effects were mild.⁸

In an open study, bupropion treatment resulted in moderate to marked response in 74% of 19 patients. Ten of those patients who responded chose to continue bupropion rather than their previous medication.⁹ In a 6-week controlled study of 40 patients, bupropion use was associated with a 42% reduction in ADHD symptoms in the 38 patients who completed the study. Patients who received a placebo showed only a 24% reduction in symptoms. According to the CGI, 52% of patients who received bupropion reported being “much improved” or “very improved” compared with 11% of those receiving a placebo.¹⁰

Other treatment options that have shown mixed results include modafinil, alpha-2a agonists, acetylcholinesterase inhibitors, and the histaminergic agents.

Managing adverse effects

Substance abuse Stimulant abuse has been a concern, but it has not become the problem many feared. In fact, some studies have found that methylphenidate may help stanch the craving for cocaine in adults with ADHD.^11,12 Treating ADHD with pharmacotherapy also has been shown to reduce the risk for substance abuse in adolescence by 85%.¹³

With careful screening, you can usually identify drug-seeking behavior in adult patients. For patients with substance abuse problems, you can prescribe the nonstimulants.

Tics that can occur with stimulant medications usually can be suppressed by reducing the dosage, being vigilant, and waiting it out. Tics may ameliorate over weeks to months.

Cardiac and cognitive effects Long-term use of stimulant medications at high dosages has been associated with cardiac and cognitive toxicity, as noted in the 1998 NIH consensus statement on diagnosis and treatment of ADHD. It is important to provide patients with this information as part of their informed-consent briefing. (See “Related resources,” to view the consensus statement.)

Nonpharmacologic management

Nonpharmacologic treatments such as EEG biofeedback; psychoeducational approaches; and individual, family, and group psychotherapy are widely used to treat adults with ADHD. Clinicians and patients often perceive these interventions as beneficial, although none have been tested in randomized, placebo-controlled studies.

Patients often function better when their home and work environments are thoughtfully organized, with a designated work/study space and regularly scheduled times for meals, sleep, and exercise. An ADHD coach may facilitate such structure and discipline (Box 2).

New agents in the pipeline

Efforts are being made to increase awareness of adult ADHD and to improve its treatment. For example, the National Institute of Mental Health is funding research on adult ADHD and displays on its Web site a PET scan of an adult brain with ADHD (see “Related resources”).¹⁴ Several medications also are being developed to treat ADHD.

Atomoxetine, a nonstimulant medication awaiting FDA approval for adult ADHD, is a selective norepinephrine reuptake inhibitor. In a double-blind, placebo-controlled, crossover study of adults with well-characterized ADHD, 11 of 21 patients improved with use of atomoxetine, compared with 2 of 21 who improved with use of a placebo. The average dosage of 76 mg/d was well-tolerated.¹⁵ The 52% response rate is similar to the 54% average improvement rate reported for methylphenidate in previous studies of adult ADHD.

In clinical trials, atomoxetine was given bid. Insomnia was not a side effect, so bid dosing does not interfere with sleep. Approximately 10 to 15% of patients experienced weight loss as a side effect.

Other treatment options under development include:

• a transdermal system for delivery of methylphenidate¹⁶
• a novel nicotinic analogue
• glutamate AMPA receptor modulation
• omega-3 fatty acids.

Related resources

• Hallowell EM, Ratey JJ. Driven to distraction: Recognizing and coping with attention deficit disorder from childhood through adulthood. New York: Simon and Schuster; Reprint edition 1995.
• Solanto MV, Arnstein AFT, Castellanos FX, eds. Stimulant drugs and ADHD: Basic and clinical neuroscience. New York: Oxford University Press; 2001.
• Weiss M, Trokenberg-Hechtman L, Weiss G. ADHD in adulthood: A guide to current theory, diagnosis, and treatment. Baltimore: Johns Hopkins University Press; 1999.
• National Institute of Mental Health. http://www.nimh.nih.gov

Drug brand names

• Atomoxetine • (investigational)
• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Methamphetamine • Desoxyn
• Methylphenidate • Focalin, Ritalin
• Methylphenidate SR • Concerta, Metadate CD, Metadate ER, Methylin ER, Ritalin SR
• Mixed salts of amphetamine • Adderall, Adderall XR
• Modafinil • Provigil
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

The author reports that he serves as a consultant to Eli Lilly and Company and is on the speaker’s bureaus of Wyeth Pharmaceuticals and AstraZeneca.

Attention-deficit/hyperactivity disorder (ADHD) may be the only mental disorder that was discovered in children and later acknowledged in adults. Although controlled studies of adults with ADHD are few, we know that ADHD is common in adults, it can be diagnosed reliably, and 75% of those treated respond to treatment.¹

The hallmark symptom of ADHD in children—hyperactivity—is usually attenuated in adults. In fact, some adults prefer the term ADD to ADHD because they are not hyperactive. This may be especially true of women, as their attention problems during childhood often were not recognized as ADHD (Box 1).

Box 1

Characteristics of adult ADHD

Adults with ADHD visit a psychiatrist for a variety of reasons. Often they are parents of children diagnosed with ADHD, and the possibility that they are similarly affected has arisen during their children’s evaluation and treatment. Sometimes they have recognized themselves in consumer articles about ADHD, or others have seen them in this light.

Adults with ADHD continue to experience their childhood difficulties in sustaining attention, listening, following instructions, and organizing tasks; inattention to details; lack of sustained mental effort; losing things; distractibility, and forgetfulness. Typical complaints include underachievement and poor adjustment at work or home. Comorbid ADHD may also be identified in patients who present with depression, anxiety, substance misuse, and mood swings.

The cognitive impairment of ADHD continues into adulthood, even in adults without hyperactive symptoms. It may be that adults are not hyperactive because the basal ganglia, which control motor activity in the brain, have over the years accommodated the problem through behavior modification or neurodevelopmental changes in late adolescence.²

Children with ADHD have abnormal cerebrospinal fluid (CSF) and blood levels of the dopaminergic metabolite homovanillic acid (HVA), but adults with ADHD may not. The primary origin for CSF HVA is the nigrostriatum, which suggests that subcortical dopaminergic nuclei are more often affected in children than adults.² This may mean that compensatory changes occur as persons with ADHD mature, or perhaps the forms of ADHD that persist into adulthood have a different pathology or pathophysiology.

Comorbidities with ADHD

Rarely does one see pure ADHD; comorbidity is the rule. ADHD can be diagnosed quickly if you know what to look for. But a facile diagnosis may overlook a comorbidity that must be treated first—especially if you plan to use stimulants. Many patients with ADHD also have bipolar disorder, and a smaller proportion of patients with bipolar disorder have undetected ADHD. Placing a patient with undetected bipolar disorder on a stimulant could precipitate mania.

Table 1

COMMON COMORBIDITIES WITH ADHD

From the initial assessment, your treatment plan must address comorbid conditions (Table 1). This means taking a good history that includes corroborating information from relatives and data from the past, if possible. The case will then be much easier to manage, and quality of care greatly enhanced.

Stimulants: Usual first-choice therapy

In most cases, adult ADHD responds well to stimulant medications, although most available evidence is limited to studies in children. Several nonstimulant medications are also available, and the FDA is considering a new-drug application for a medication indicated for adult ADHD. Stimulants produce significant improvement in 30% of patients and mixed results in another 40%. Comorbidities may account for the 10 to 30% of patients who do not respond to stimulant therapy.

Methylphenidate, taken multiple times daily, is the most common treatment for ADHD. Dextroamphetamine and mixed salts of amphetamine also are used (Table 2).³ Patients usually respond to either methylphenidate or an amphetamine, and typically 25% of those who do not respond to one will respond to the other. When the clinical efficacy of amphetamines diminishes over time, many psychiatrists rotate medications. Replacing one amphetamine with another often eliminates the need to slowly increase the dosage and allows the clinician to maintain a relatively stable regimen.

When administering stimulants to adults, consider the individual’s total dosage requirement and daily schedule. Will he or she fare better with multiple daily dosing or a sustained-release form? How long is his or her average day? Does the patient have to be alert for 12 hours—or longer?

Some patients cannot sleep unless they take their last stimulant dose at bedtime. Others will have insomnia if a last dose is taken too late in the afternoon, especially with a sustained-release formulation.

When starting a patient on stimulants, begin with a 12-hour day and titrate the dosage—usually up, sometimes down—depending on response and side effects. Educating patients about their medications enables them to participate in decision-making.

Common side effects of stimulants include insomnia, decreased appetite, upset stomach, headache, anxiety, agitation, and increased pulse rate and blood pressure. The increase in blood pressure is usually less than 10%, but patients with poorly controlled hypertension should not be treated with stimulants until their blood pressure is well controlled. Until more is known about long-term effects, periodic assessment of blood pressure may be warranted.

Table 2

STIMULANT THERAPY FOR ADULTS WITH ADHD

Box 2

Adults with ADHD have been treated with mixed amphetamine salts with positive results. In a 7-week controlled, crossover study, 27 adults with ADHD received an average of 54 mg/d administered in two doses. Symptoms improved significantly—a 42% decrease on the ADHD Rating Scale. The medication was well-tolerated, and 70% of those receiving mixed amphetamine salts improved, compared with 7% of those who received a placebo.⁴

Duration of action of mixed salts of amphetamine has been measured at 3.5 hours with a 5-mg dose and 6.4 hours with a 20-mg dose.⁵ With methylphenidate, a dose of 12.5 mg worked for 4 hours. The maximum recommended dosage of mixed salts of amphetamine is 40 mg/d in divided doses.

Stimulant medications are well-tolerated. Addiction and the need for increased dosages can occur over long-term use (months to years). Reducing the dosage or switching from methylphenidate to an amphetamine variant can usually prevent these problems.

The FDA recently approved a single-enantiomer form of methylphenidate. It contains only the active “d” enantiomer, whereas the racemic mixture contains both the “d” and “l” enantiomers. Because the “l” enantiomer is inert, the resulting medication is more potent and may be prescribed at half the dosage of the racemic mixture.

Pemoline, a once-daily stimulant, is considered a second-line treatment because of reports of hepatic failure in some patients. Its use requires written informed consent and liver function tests at baseline and every 2 weeks. In a controlled trial, pemoline at high dosages (120 to 160 mg/d) was found moderately effective in adults with ADHD.⁶

Newer options: Longer-acting stimulants

Newer forms of slow-release methylphenidate and mixed amphetamine salts with sophisticated delivery systems are available.

Metadate CD is delivered in capsules containing beads with polymer coatings that dissolve and release their contents at different times. The capsules contain a 30:70 ratio of immediate- and extended-release beads.

Metadate CD has not been tested for adults in controlled clinical trials. In children ages 6 to 15, a single morning dose has been shown to be clinically effective in the morning and afternoon. A supplemental immediate-release capsule can be given in the morning if a patient’s medication levels need to be increased quickly. Dosage supplementation may also be required later in the day.

Concerta is delivered in 18-mg and 36-mg tablets. The immediate-release coating on the tablets delivers medication within the first hour. The drug inside then dissolves in the GI tract and is released at a controlled rate by osmotic pressure. The indigestible tablet is passed in the stool.

Concerta was investigated in children ages 6 to 12 and provides 10 to 12 hours of sustained medication. From child studies, we know that when a patient takes a 36-mg tablet at 6 AM, blood levels decline in late afternoon. An 18-mg dose at noon covers the 4 to 6 hours needed for evening chores.

Adderall XR is an extended-release, once-daily form of mixed amphetamine salts. No controlled trials of this formulation are available in adults with ADHD. Its efficacy was established after two clinical trials of children aged 6 to 12 who met DSM-IV criteria for ADHD.

Individualized and flexible dosing improves symptom control and compliance when treating adults with ADHD. For some patients, once-daily dosing is more convenient than multiple doses, while others prefer the immediate-release form because they like its midday “pause” and bid dosing. The immediate-release tablet allows the flexibility of bid or tid dosing, depending on the day’s requirements.

Antidepressants: Another choice

Antidepressants are usually considered second-line treatment for ADHD because of concerns about efficacy and side effects. The few available studies show antidepressants work as well as stimulants but more slowly. It is good practice, therefore, to advise patients that—unlike feeling the effect of a stimulant in 60 minutes—they will not feel an effect from an antidepressant for days or weeks, and that achieving an optimal effect may take 4 to 6 weeks.

Antidepressants have several advantages over stimulants. They are not classified as narcotics, work without the on-off effects of stimulants, and can treat comorbid depression and anxiety. For adult ADHD, the most effective agents work on the catecholamine systems—norepinephrine and/or dopamine. This includes the tricyclic antidepressants, MAO inhibitors, bupropion, and venlafaxine. The serotonin reuptake inhibitors have not shown promise in ADHD, nor have mirtazapine or nefazodone demonstrated much effect.

Desipramine, a tricyclic antidepressant, is a strong inhibitor of norepinephrine reuptake. In a double-blind, controlled study in 41 adults with ADHD, 68% of patients receiving desipramine, 200 mg/d, responded positively, compared with no patients who took a placebo.⁷

When venlafaxine was given in standard dosages to 10 adults with ADHD in an open, 8-week clinical trial, an effect was seen by week two. Of the nine patients who completed the study, seven were considered responders. Symptoms were reduced significantly with venlafaxine treatment, and most side effects were mild.⁸

In an open study, bupropion treatment resulted in moderate to marked response in 74% of 19 patients. Ten of those patients who responded chose to continue bupropion rather than their previous medication.⁹ In a 6-week controlled study of 40 patients, bupropion use was associated with a 42% reduction in ADHD symptoms in the 38 patients who completed the study. Patients who received a placebo showed only a 24% reduction in symptoms. According to the CGI, 52% of patients who received bupropion reported being “much improved” or “very improved” compared with 11% of those receiving a placebo.¹⁰

Other treatment options that have shown mixed results include modafinil, alpha-2a agonists, acetylcholinesterase inhibitors, and the histaminergic agents.

Managing adverse effects

Substance abuse Stimulant abuse has been a concern, but it has not become the problem many feared. In fact, some studies have found that methylphenidate may help stanch the craving for cocaine in adults with ADHD.^11,12 Treating ADHD with pharmacotherapy also has been shown to reduce the risk for substance abuse in adolescence by 85%.¹³

With careful screening, you can usually identify drug-seeking behavior in adult patients. For patients with substance abuse problems, you can prescribe the nonstimulants.

Tics that can occur with stimulant medications usually can be suppressed by reducing the dosage, being vigilant, and waiting it out. Tics may ameliorate over weeks to months.

Cardiac and cognitive effects Long-term use of stimulant medications at high dosages has been associated with cardiac and cognitive toxicity, as noted in the 1998 NIH consensus statement on diagnosis and treatment of ADHD. It is important to provide patients with this information as part of their informed-consent briefing. (See “Related resources,” to view the consensus statement.)

Nonpharmacologic management

Nonpharmacologic treatments such as EEG biofeedback; psychoeducational approaches; and individual, family, and group psychotherapy are widely used to treat adults with ADHD. Clinicians and patients often perceive these interventions as beneficial, although none have been tested in randomized, placebo-controlled studies.

Patients often function better when their home and work environments are thoughtfully organized, with a designated work/study space and regularly scheduled times for meals, sleep, and exercise. An ADHD coach may facilitate such structure and discipline (Box 2).

New agents in the pipeline

Efforts are being made to increase awareness of adult ADHD and to improve its treatment. For example, the National Institute of Mental Health is funding research on adult ADHD and displays on its Web site a PET scan of an adult brain with ADHD (see “Related resources”).¹⁴ Several medications also are being developed to treat ADHD.

Atomoxetine, a nonstimulant medication awaiting FDA approval for adult ADHD, is a selective norepinephrine reuptake inhibitor. In a double-blind, placebo-controlled, crossover study of adults with well-characterized ADHD, 11 of 21 patients improved with use of atomoxetine, compared with 2 of 21 who improved with use of a placebo. The average dosage of 76 mg/d was well-tolerated.¹⁵ The 52% response rate is similar to the 54% average improvement rate reported for methylphenidate in previous studies of adult ADHD.

In clinical trials, atomoxetine was given bid. Insomnia was not a side effect, so bid dosing does not interfere with sleep. Approximately 10 to 15% of patients experienced weight loss as a side effect.

Other treatment options under development include:

• a transdermal system for delivery of methylphenidate¹⁶
• a novel nicotinic analogue
• glutamate AMPA receptor modulation
• omega-3 fatty acids.

Related resources

• Hallowell EM, Ratey JJ. Driven to distraction: Recognizing and coping with attention deficit disorder from childhood through adulthood. New York: Simon and Schuster; Reprint edition 1995.
• Solanto MV, Arnstein AFT, Castellanos FX, eds. Stimulant drugs and ADHD: Basic and clinical neuroscience. New York: Oxford University Press; 2001.
• Weiss M, Trokenberg-Hechtman L, Weiss G. ADHD in adulthood: A guide to current theory, diagnosis, and treatment. Baltimore: Johns Hopkins University Press; 1999.
• National Institute of Mental Health. http://www.nimh.nih.gov

Drug brand names

• Atomoxetine • (investigational)
• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Methamphetamine • Desoxyn
• Methylphenidate • Focalin, Ritalin
• Methylphenidate SR • Concerta, Metadate CD, Metadate ER, Methylin ER, Ritalin SR
• Mixed salts of amphetamine • Adderall, Adderall XR
• Modafinil • Provigil
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

The author reports that he serves as a consultant to Eli Lilly and Company and is on the speaker’s bureaus of Wyeth Pharmaceuticals and AstraZeneca.

Attention-deficit/hyperactivity disorder (ADHD) may be the only mental disorder that was discovered in children and later acknowledged in adults. Although controlled studies of adults with ADHD are few, we know that ADHD is common in adults, it can be diagnosed reliably, and 75% of those treated respond to treatment.¹

The hallmark symptom of ADHD in children—hyperactivity—is usually attenuated in adults. In fact, some adults prefer the term ADD to ADHD because they are not hyperactive. This may be especially true of women, as their attention problems during childhood often were not recognized as ADHD (Box 1).

Box 1

Characteristics of adult ADHD

Adults with ADHD visit a psychiatrist for a variety of reasons. Often they are parents of children diagnosed with ADHD, and the possibility that they are similarly affected has arisen during their children’s evaluation and treatment. Sometimes they have recognized themselves in consumer articles about ADHD, or others have seen them in this light.

Adults with ADHD continue to experience their childhood difficulties in sustaining attention, listening, following instructions, and organizing tasks; inattention to details; lack of sustained mental effort; losing things; distractibility, and forgetfulness. Typical complaints include underachievement and poor adjustment at work or home. Comorbid ADHD may also be identified in patients who present with depression, anxiety, substance misuse, and mood swings.

The cognitive impairment of ADHD continues into adulthood, even in adults without hyperactive symptoms. It may be that adults are not hyperactive because the basal ganglia, which control motor activity in the brain, have over the years accommodated the problem through behavior modification or neurodevelopmental changes in late adolescence.²

Children with ADHD have abnormal cerebrospinal fluid (CSF) and blood levels of the dopaminergic metabolite homovanillic acid (HVA), but adults with ADHD may not. The primary origin for CSF HVA is the nigrostriatum, which suggests that subcortical dopaminergic nuclei are more often affected in children than adults.² This may mean that compensatory changes occur as persons with ADHD mature, or perhaps the forms of ADHD that persist into adulthood have a different pathology or pathophysiology.

Comorbidities with ADHD

Rarely does one see pure ADHD; comorbidity is the rule. ADHD can be diagnosed quickly if you know what to look for. But a facile diagnosis may overlook a comorbidity that must be treated first—especially if you plan to use stimulants. Many patients with ADHD also have bipolar disorder, and a smaller proportion of patients with bipolar disorder have undetected ADHD. Placing a patient with undetected bipolar disorder on a stimulant could precipitate mania.

Table 1

COMMON COMORBIDITIES WITH ADHD

From the initial assessment, your treatment plan must address comorbid conditions (Table 1). This means taking a good history that includes corroborating information from relatives and data from the past, if possible. The case will then be much easier to manage, and quality of care greatly enhanced.

Stimulants: Usual first-choice therapy

In most cases, adult ADHD responds well to stimulant medications, although most available evidence is limited to studies in children. Several nonstimulant medications are also available, and the FDA is considering a new-drug application for a medication indicated for adult ADHD. Stimulants produce significant improvement in 30% of patients and mixed results in another 40%. Comorbidities may account for the 10 to 30% of patients who do not respond to stimulant therapy.

Methylphenidate, taken multiple times daily, is the most common treatment for ADHD. Dextroamphetamine and mixed salts of amphetamine also are used (Table 2).³ Patients usually respond to either methylphenidate or an amphetamine, and typically 25% of those who do not respond to one will respond to the other. When the clinical efficacy of amphetamines diminishes over time, many psychiatrists rotate medications. Replacing one amphetamine with another often eliminates the need to slowly increase the dosage and allows the clinician to maintain a relatively stable regimen.

When administering stimulants to adults, consider the individual’s total dosage requirement and daily schedule. Will he or she fare better with multiple daily dosing or a sustained-release form? How long is his or her average day? Does the patient have to be alert for 12 hours—or longer?

Some patients cannot sleep unless they take their last stimulant dose at bedtime. Others will have insomnia if a last dose is taken too late in the afternoon, especially with a sustained-release formulation.

When starting a patient on stimulants, begin with a 12-hour day and titrate the dosage—usually up, sometimes down—depending on response and side effects. Educating patients about their medications enables them to participate in decision-making.

Common side effects of stimulants include insomnia, decreased appetite, upset stomach, headache, anxiety, agitation, and increased pulse rate and blood pressure. The increase in blood pressure is usually less than 10%, but patients with poorly controlled hypertension should not be treated with stimulants until their blood pressure is well controlled. Until more is known about long-term effects, periodic assessment of blood pressure may be warranted.

Table 2

STIMULANT THERAPY FOR ADULTS WITH ADHD

Box 2

Adults with ADHD have been treated with mixed amphetamine salts with positive results. In a 7-week controlled, crossover study, 27 adults with ADHD received an average of 54 mg/d administered in two doses. Symptoms improved significantly—a 42% decrease on the ADHD Rating Scale. The medication was well-tolerated, and 70% of those receiving mixed amphetamine salts improved, compared with 7% of those who received a placebo.⁴

Duration of action of mixed salts of amphetamine has been measured at 3.5 hours with a 5-mg dose and 6.4 hours with a 20-mg dose.⁵ With methylphenidate, a dose of 12.5 mg worked for 4 hours. The maximum recommended dosage of mixed salts of amphetamine is 40 mg/d in divided doses.

Stimulant medications are well-tolerated. Addiction and the need for increased dosages can occur over long-term use (months to years). Reducing the dosage or switching from methylphenidate to an amphetamine variant can usually prevent these problems.

The FDA recently approved a single-enantiomer form of methylphenidate. It contains only the active “d” enantiomer, whereas the racemic mixture contains both the “d” and “l” enantiomers. Because the “l” enantiomer is inert, the resulting medication is more potent and may be prescribed at half the dosage of the racemic mixture.

Pemoline, a once-daily stimulant, is considered a second-line treatment because of reports of hepatic failure in some patients. Its use requires written informed consent and liver function tests at baseline and every 2 weeks. In a controlled trial, pemoline at high dosages (120 to 160 mg/d) was found moderately effective in adults with ADHD.⁶

Newer options: Longer-acting stimulants

Newer forms of slow-release methylphenidate and mixed amphetamine salts with sophisticated delivery systems are available.

Metadate CD is delivered in capsules containing beads with polymer coatings that dissolve and release their contents at different times. The capsules contain a 30:70 ratio of immediate- and extended-release beads.

Metadate CD has not been tested for adults in controlled clinical trials. In children ages 6 to 15, a single morning dose has been shown to be clinically effective in the morning and afternoon. A supplemental immediate-release capsule can be given in the morning if a patient’s medication levels need to be increased quickly. Dosage supplementation may also be required later in the day.

Concerta is delivered in 18-mg and 36-mg tablets. The immediate-release coating on the tablets delivers medication within the first hour. The drug inside then dissolves in the GI tract and is released at a controlled rate by osmotic pressure. The indigestible tablet is passed in the stool.

Concerta was investigated in children ages 6 to 12 and provides 10 to 12 hours of sustained medication. From child studies, we know that when a patient takes a 36-mg tablet at 6 AM, blood levels decline in late afternoon. An 18-mg dose at noon covers the 4 to 6 hours needed for evening chores.

Adderall XR is an extended-release, once-daily form of mixed amphetamine salts. No controlled trials of this formulation are available in adults with ADHD. Its efficacy was established after two clinical trials of children aged 6 to 12 who met DSM-IV criteria for ADHD.

Individualized and flexible dosing improves symptom control and compliance when treating adults with ADHD. For some patients, once-daily dosing is more convenient than multiple doses, while others prefer the immediate-release form because they like its midday “pause” and bid dosing. The immediate-release tablet allows the flexibility of bid or tid dosing, depending on the day’s requirements.

Antidepressants: Another choice

Antidepressants are usually considered second-line treatment for ADHD because of concerns about efficacy and side effects. The few available studies show antidepressants work as well as stimulants but more slowly. It is good practice, therefore, to advise patients that—unlike feeling the effect of a stimulant in 60 minutes—they will not feel an effect from an antidepressant for days or weeks, and that achieving an optimal effect may take 4 to 6 weeks.

Antidepressants have several advantages over stimulants. They are not classified as narcotics, work without the on-off effects of stimulants, and can treat comorbid depression and anxiety. For adult ADHD, the most effective agents work on the catecholamine systems—norepinephrine and/or dopamine. This includes the tricyclic antidepressants, MAO inhibitors, bupropion, and venlafaxine. The serotonin reuptake inhibitors have not shown promise in ADHD, nor have mirtazapine or nefazodone demonstrated much effect.

Desipramine, a tricyclic antidepressant, is a strong inhibitor of norepinephrine reuptake. In a double-blind, controlled study in 41 adults with ADHD, 68% of patients receiving desipramine, 200 mg/d, responded positively, compared with no patients who took a placebo.⁷

When venlafaxine was given in standard dosages to 10 adults with ADHD in an open, 8-week clinical trial, an effect was seen by week two. Of the nine patients who completed the study, seven were considered responders. Symptoms were reduced significantly with venlafaxine treatment, and most side effects were mild.⁸

In an open study, bupropion treatment resulted in moderate to marked response in 74% of 19 patients. Ten of those patients who responded chose to continue bupropion rather than their previous medication.⁹ In a 6-week controlled study of 40 patients, bupropion use was associated with a 42% reduction in ADHD symptoms in the 38 patients who completed the study. Patients who received a placebo showed only a 24% reduction in symptoms. According to the CGI, 52% of patients who received bupropion reported being “much improved” or “very improved” compared with 11% of those receiving a placebo.¹⁰

Other treatment options that have shown mixed results include modafinil, alpha-2a agonists, acetylcholinesterase inhibitors, and the histaminergic agents.

Managing adverse effects

Substance abuse Stimulant abuse has been a concern, but it has not become the problem many feared. In fact, some studies have found that methylphenidate may help stanch the craving for cocaine in adults with ADHD.^11,12 Treating ADHD with pharmacotherapy also has been shown to reduce the risk for substance abuse in adolescence by 85%.¹³

With careful screening, you can usually identify drug-seeking behavior in adult patients. For patients with substance abuse problems, you can prescribe the nonstimulants.

Tics that can occur with stimulant medications usually can be suppressed by reducing the dosage, being vigilant, and waiting it out. Tics may ameliorate over weeks to months.

Cardiac and cognitive effects Long-term use of stimulant medications at high dosages has been associated with cardiac and cognitive toxicity, as noted in the 1998 NIH consensus statement on diagnosis and treatment of ADHD. It is important to provide patients with this information as part of their informed-consent briefing. (See “Related resources,” to view the consensus statement.)

Nonpharmacologic management

Nonpharmacologic treatments such as EEG biofeedback; psychoeducational approaches; and individual, family, and group psychotherapy are widely used to treat adults with ADHD. Clinicians and patients often perceive these interventions as beneficial, although none have been tested in randomized, placebo-controlled studies.

Patients often function better when their home and work environments are thoughtfully organized, with a designated work/study space and regularly scheduled times for meals, sleep, and exercise. An ADHD coach may facilitate such structure and discipline (Box 2).

New agents in the pipeline

Efforts are being made to increase awareness of adult ADHD and to improve its treatment. For example, the National Institute of Mental Health is funding research on adult ADHD and displays on its Web site a PET scan of an adult brain with ADHD (see “Related resources”).¹⁴ Several medications also are being developed to treat ADHD.

Atomoxetine, a nonstimulant medication awaiting FDA approval for adult ADHD, is a selective norepinephrine reuptake inhibitor. In a double-blind, placebo-controlled, crossover study of adults with well-characterized ADHD, 11 of 21 patients improved with use of atomoxetine, compared with 2 of 21 who improved with use of a placebo. The average dosage of 76 mg/d was well-tolerated.¹⁵ The 52% response rate is similar to the 54% average improvement rate reported for methylphenidate in previous studies of adult ADHD.

In clinical trials, atomoxetine was given bid. Insomnia was not a side effect, so bid dosing does not interfere with sleep. Approximately 10 to 15% of patients experienced weight loss as a side effect.

Other treatment options under development include:

• a transdermal system for delivery of methylphenidate¹⁶
• a novel nicotinic analogue
• glutamate AMPA receptor modulation
• omega-3 fatty acids.

Related resources

• Hallowell EM, Ratey JJ. Driven to distraction: Recognizing and coping with attention deficit disorder from childhood through adulthood. New York: Simon and Schuster; Reprint edition 1995.
• Solanto MV, Arnstein AFT, Castellanos FX, eds. Stimulant drugs and ADHD: Basic and clinical neuroscience. New York: Oxford University Press; 2001.
• Weiss M, Trokenberg-Hechtman L, Weiss G. ADHD in adulthood: A guide to current theory, diagnosis, and treatment. Baltimore: Johns Hopkins University Press; 1999.
• National Institute of Mental Health. http://www.nimh.nih.gov

Drug brand names

• Atomoxetine • (investigational)
• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Methamphetamine • Desoxyn
• Methylphenidate • Focalin, Ritalin
• Methylphenidate SR • Concerta, Metadate CD, Metadate ER, Methylin ER, Ritalin SR
• Mixed salts of amphetamine • Adderall, Adderall XR
• Modafinil • Provigil
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

The author reports that he serves as a consultant to Eli Lilly and Company and is on the speaker’s bureaus of Wyeth Pharmaceuticals and AstraZeneca.

ABSTRACT

BACKGROUND: Several case-control and cohort studies since the early 1990s have shown conflicting results on a possible association between vasectomy and prostate cancer risk. A recent systematic review failed to show a causal association and suggested several possible mechanisms for inconclusive results. This study addressed some of these limitations.
POPULATION STUDIED: The study included 923 men in New Zealand between the ages of 40 and 74 years with newly diagnosed prostate cancer (cases). All men were on the general electoral roll and had a history of marriage. The control group was randomly selected from the general electoral roll (n = 1224), and frequency matching to cases was performed in 5-year age groups. The mean age for cases and controls was 66.3 and 65.1 years, respectively. All cases and controls had telephone numbers for data collection purposes. Because nearly all study subjects were of European descent (97%), the results may not apply to other ethnic groups.
STUDY DESIGN AND VALIDITY: This national, population-based, case-control study was performed on all newly diagnosed cases of prostate cancer during a specified time (April 1, 1996, to December 31, 1998). Controls were randomly selected from the general electoral roll in which about 95% of adults are listed. Of potential cases and controls, only 12% and 20%, respectively, could not be contacted due to death, doctor or subject refusal, severe illness, inability to trace, or language difficulties.
OUTCOMES MEASURED: The primary outcome measured was the relative risk (RR) of prostate cancer for men who had vasectomies compared with that for men who had not undergone the procedure.
RESULTS: No association between prostate cancer and vasectomy was found (RR = 0.92; 95% confidence interval [CI], 0.75–1.14). Even after 25 years since vasectomy, no association was found (RR = 0.92; 95% CI, 0.68–1.23). Adjustments were made for social class, geographic region, religious affiliation, and family history of prostate cancer without any effect on the risk.

ABSTRACT

BACKGROUND: Several case-control and cohort studies since the early 1990s have shown conflicting results on a possible association between vasectomy and prostate cancer risk. A recent systematic review failed to show a causal association and suggested several possible mechanisms for inconclusive results. This study addressed some of these limitations.
POPULATION STUDIED: The study included 923 men in New Zealand between the ages of 40 and 74 years with newly diagnosed prostate cancer (cases). All men were on the general electoral roll and had a history of marriage. The control group was randomly selected from the general electoral roll (n = 1224), and frequency matching to cases was performed in 5-year age groups. The mean age for cases and controls was 66.3 and 65.1 years, respectively. All cases and controls had telephone numbers for data collection purposes. Because nearly all study subjects were of European descent (97%), the results may not apply to other ethnic groups.
STUDY DESIGN AND VALIDITY: This national, population-based, case-control study was performed on all newly diagnosed cases of prostate cancer during a specified time (April 1, 1996, to December 31, 1998). Controls were randomly selected from the general electoral roll in which about 95% of adults are listed. Of potential cases and controls, only 12% and 20%, respectively, could not be contacted due to death, doctor or subject refusal, severe illness, inability to trace, or language difficulties.
OUTCOMES MEASURED: The primary outcome measured was the relative risk (RR) of prostate cancer for men who had vasectomies compared with that for men who had not undergone the procedure.
RESULTS: No association between prostate cancer and vasectomy was found (RR = 0.92; 95% confidence interval [CI], 0.75–1.14). Even after 25 years since vasectomy, no association was found (RR = 0.92; 95% CI, 0.68–1.23). Adjustments were made for social class, geographic region, religious affiliation, and family history of prostate cancer without any effect on the risk.

ABSTRACT

BACKGROUND: Several case-control and cohort studies since the early 1990s have shown conflicting results on a possible association between vasectomy and prostate cancer risk. A recent systematic review failed to show a causal association and suggested several possible mechanisms for inconclusive results. This study addressed some of these limitations.
POPULATION STUDIED: The study included 923 men in New Zealand between the ages of 40 and 74 years with newly diagnosed prostate cancer (cases). All men were on the general electoral roll and had a history of marriage. The control group was randomly selected from the general electoral roll (n = 1224), and frequency matching to cases was performed in 5-year age groups. The mean age for cases and controls was 66.3 and 65.1 years, respectively. All cases and controls had telephone numbers for data collection purposes. Because nearly all study subjects were of European descent (97%), the results may not apply to other ethnic groups.
STUDY DESIGN AND VALIDITY: This national, population-based, case-control study was performed on all newly diagnosed cases of prostate cancer during a specified time (April 1, 1996, to December 31, 1998). Controls were randomly selected from the general electoral roll in which about 95% of adults are listed. Of potential cases and controls, only 12% and 20%, respectively, could not be contacted due to death, doctor or subject refusal, severe illness, inability to trace, or language difficulties.
OUTCOMES MEASURED: The primary outcome measured was the relative risk (RR) of prostate cancer for men who had vasectomies compared with that for men who had not undergone the procedure.
RESULTS: No association between prostate cancer and vasectomy was found (RR = 0.92; 95% confidence interval [CI], 0.75–1.14). Even after 25 years since vasectomy, no association was found (RR = 0.92; 95% CI, 0.68–1.23). Adjustments were made for social class, geographic region, religious affiliation, and family history of prostate cancer without any effect on the risk.

ABSTRACT

BACKGROUND: Asthma management guidelines recommend patients with persistent asthma use asthma controller therapy in addition to as-needed short-acting beta-agonist therapy to improve symptom control, maintain pulmonary function, and decrease exacerbations. This study compared 2 asthma controllers, inhaled fluticasone and oral montelukast, with respect to clinical efficacy, patient preference, asthma-specific quality of life, and safety.
POPULATION STUDIED: The patients in this study were men and women aged 15 years and older with asthma recruited from multiple centers across the United States. Nonsmoking patients were included with a forced expiratory volume in 1 second (FEV 1 ) of 50% to 80% of predicted that reversed by at least 15% with bronchodilator use. Patients were then eligible for randomization if, after an 8- to 14-day run-in period, their FEV 1 remained within 15% of initial values, they used albuterol at least 6 of the last 7 days, and they had asthma symptom scores of 2 (on a 0 to 5 scale) for at least 4 of the last 7 days.
STUDY DESIGN AND VALIDITY: This study was a double-blinded, randomized trial sponsored by the makers of fluticasone. Patients meeting initial inclusion criteria underwent an 8- to 14-day run-in period in which only short-acting beta-agonist use was allowed. Patients were then randomized to 1 of 2 treatment groups if they met the secondary inclusion criteria. Personal communication with the lead author confirmed that allocation assignment was concealed. Patients received either fluticasone 88 μg twice daily via metered dose inhaler (MDI) and montelukast placebo, or montelukast 10 mg daily with a placebo MDI. Patients kept daily records and had clinical evaluations at regular intervals for 24 weeks. Seventy-six percent of the patients completed the study.
OUTCOMES MEASURED: The primary outcome was percent change in FEV 1 . Other outcomes included peak flow rate, symptom-free days, daily albuterol use, asthma symptom scores, asthma quality-of-life scores, and patient-rated satisfaction with treatment. Safety was also assessed by reports of clinical adverse events and number of asthma exacerbations.
RESULTS: Using an intent-to-treat analysis, the fluticasone group had a significantly greater sustained change in FEV 1 (22% vs 14%; P < .001). Significant differences were noted after just 2 weeks of treatment. Significant differences favoring fluticasone were also found in all secondary outcomes including the patient-oriented outcomes of change in asthma symptom scores (–0.91 vs –0.57; P < .001), asthma quality-of-life scores (1.3 vs 1.0; P = .004), and patient-rated satisfaction with treatment (83% of fluticasone patients satisfied vs 66% of montelukast patients satisfied; P < .001). No differences were noted in overall incidence of adverse events between treatment groups, but significantly more fluticasone-treated patients reported hoarseness (9 vs 0; P = .002) and oral pharyngeal candidiasis (8 vs 0; P = .008). The incidence of asthma exacerbations was similar (19 fluticasone-treated patients vs 21 montelukast-treated patients).

ABSTRACT

BACKGROUND: Asthma management guidelines recommend patients with persistent asthma use asthma controller therapy in addition to as-needed short-acting beta-agonist therapy to improve symptom control, maintain pulmonary function, and decrease exacerbations. This study compared 2 asthma controllers, inhaled fluticasone and oral montelukast, with respect to clinical efficacy, patient preference, asthma-specific quality of life, and safety.
POPULATION STUDIED: The patients in this study were men and women aged 15 years and older with asthma recruited from multiple centers across the United States. Nonsmoking patients were included with a forced expiratory volume in 1 second (FEV 1 ) of 50% to 80% of predicted that reversed by at least 15% with bronchodilator use. Patients were then eligible for randomization if, after an 8- to 14-day run-in period, their FEV 1 remained within 15% of initial values, they used albuterol at least 6 of the last 7 days, and they had asthma symptom scores of 2 (on a 0 to 5 scale) for at least 4 of the last 7 days.
STUDY DESIGN AND VALIDITY: This study was a double-blinded, randomized trial sponsored by the makers of fluticasone. Patients meeting initial inclusion criteria underwent an 8- to 14-day run-in period in which only short-acting beta-agonist use was allowed. Patients were then randomized to 1 of 2 treatment groups if they met the secondary inclusion criteria. Personal communication with the lead author confirmed that allocation assignment was concealed. Patients received either fluticasone 88 μg twice daily via metered dose inhaler (MDI) and montelukast placebo, or montelukast 10 mg daily with a placebo MDI. Patients kept daily records and had clinical evaluations at regular intervals for 24 weeks. Seventy-six percent of the patients completed the study.
OUTCOMES MEASURED: The primary outcome was percent change in FEV 1 . Other outcomes included peak flow rate, symptom-free days, daily albuterol use, asthma symptom scores, asthma quality-of-life scores, and patient-rated satisfaction with treatment. Safety was also assessed by reports of clinical adverse events and number of asthma exacerbations.
RESULTS: Using an intent-to-treat analysis, the fluticasone group had a significantly greater sustained change in FEV 1 (22% vs 14%; P < .001). Significant differences were noted after just 2 weeks of treatment. Significant differences favoring fluticasone were also found in all secondary outcomes including the patient-oriented outcomes of change in asthma symptom scores (–0.91 vs –0.57; P < .001), asthma quality-of-life scores (1.3 vs 1.0; P = .004), and patient-rated satisfaction with treatment (83% of fluticasone patients satisfied vs 66% of montelukast patients satisfied; P < .001). No differences were noted in overall incidence of adverse events between treatment groups, but significantly more fluticasone-treated patients reported hoarseness (9 vs 0; P = .002) and oral pharyngeal candidiasis (8 vs 0; P = .008). The incidence of asthma exacerbations was similar (19 fluticasone-treated patients vs 21 montelukast-treated patients).

ABSTRACT

BACKGROUND: Asthma management guidelines recommend patients with persistent asthma use asthma controller therapy in addition to as-needed short-acting beta-agonist therapy to improve symptom control, maintain pulmonary function, and decrease exacerbations. This study compared 2 asthma controllers, inhaled fluticasone and oral montelukast, with respect to clinical efficacy, patient preference, asthma-specific quality of life, and safety.
POPULATION STUDIED: The patients in this study were men and women aged 15 years and older with asthma recruited from multiple centers across the United States. Nonsmoking patients were included with a forced expiratory volume in 1 second (FEV 1 ) of 50% to 80% of predicted that reversed by at least 15% with bronchodilator use. Patients were then eligible for randomization if, after an 8- to 14-day run-in period, their FEV 1 remained within 15% of initial values, they used albuterol at least 6 of the last 7 days, and they had asthma symptom scores of 2 (on a 0 to 5 scale) for at least 4 of the last 7 days.
STUDY DESIGN AND VALIDITY: This study was a double-blinded, randomized trial sponsored by the makers of fluticasone. Patients meeting initial inclusion criteria underwent an 8- to 14-day run-in period in which only short-acting beta-agonist use was allowed. Patients were then randomized to 1 of 2 treatment groups if they met the secondary inclusion criteria. Personal communication with the lead author confirmed that allocation assignment was concealed. Patients received either fluticasone 88 μg twice daily via metered dose inhaler (MDI) and montelukast placebo, or montelukast 10 mg daily with a placebo MDI. Patients kept daily records and had clinical evaluations at regular intervals for 24 weeks. Seventy-six percent of the patients completed the study.
OUTCOMES MEASURED: The primary outcome was percent change in FEV 1 . Other outcomes included peak flow rate, symptom-free days, daily albuterol use, asthma symptom scores, asthma quality-of-life scores, and patient-rated satisfaction with treatment. Safety was also assessed by reports of clinical adverse events and number of asthma exacerbations.
RESULTS: Using an intent-to-treat analysis, the fluticasone group had a significantly greater sustained change in FEV 1 (22% vs 14%; P < .001). Significant differences were noted after just 2 weeks of treatment. Significant differences favoring fluticasone were also found in all secondary outcomes including the patient-oriented outcomes of change in asthma symptom scores (–0.91 vs –0.57; P < .001), asthma quality-of-life scores (1.3 vs 1.0; P = .004), and patient-rated satisfaction with treatment (83% of fluticasone patients satisfied vs 66% of montelukast patients satisfied; P < .001). No differences were noted in overall incidence of adverse events between treatment groups, but significantly more fluticasone-treated patients reported hoarseness (9 vs 0; P = .002) and oral pharyngeal candidiasis (8 vs 0; P = .008). The incidence of asthma exacerbations was similar (19 fluticasone-treated patients vs 21 montelukast-treated patients).

Evidence summary

Several systematic reviews help clarify theophylline’s role in asthma management. When compared with placebo in the management of acute exacerbations, theophylline confers no added benefit to beta-agonist therapy (with or without steroids) in improving pulmonary function or reducing hospitalization rates. Side effects occurred more often in the theophylline group: palpitations/arrhythmias (OR = 2.9; 95% CI: 1.5 to 5.7) and vomiting (OR = 4.2; 95% CI: 2.4 to 7.4).¹ For moderately severe asthma in patients already receiving inhaled corticosteroids (ICS), theophylline as maintenance therapy equaled long-acting beta-2-agonists in increasing FEV 1 and PEFR, but was less effective in controlling night time symptoms. Use of long-acting beta-agonists resulted in fewer side effects (RR = 0.38; 95%CI: 0.25-0.57).² When added to low-dose ICS for maintenance, theophylline was as effective as high-dose ICS alone in improving FEV 1 , decreasing day and night symptoms, and reducing the need for rescue medications and the incidence of attacks. This suggests theophylline has utility as a steroid sparing agent.³

Intravenous aminophylline does appear to be clinically beneficial for children with severe exacerbations, defined as an FEV 1 of 35%-40% of predicted value. Critically ill children receiving aminophylline in addition to usual care exhibited an improved FEV 1 at 24 hours (mean difference = 8.4%; 95% CI: 0.82 to 15.92) and reduced symptom scores at 6 hours.⁴ The largest RCT of aminophylline in children demonstrated a reduced intubation rate (NNT = 14 CI: 7.8-77).⁵ Children receiving aminophylline experienced more vomiting (RR = 3.69; 95%CI: 2.15-6.33). Treatment with aminophylline did not reduce length of hospital stay or the number of rescue nebulizers needed (Table).⁴

TABLE
Theophylline use in asthma

Recommendations from others

Three evidence-supported guidelines concur that theophylline has a limited role as maintenance therapy for moderate-to-severe persistent asthma when symptom control with ICS alone is not adequate. Much stronger evidence supports the use of long-acting beta-2-agonists or leukotriene modifiers in this setting.^6-8 The guidelines do not recommend using theophylline to treat acute asthma exacerbations; nor do they address using theophylline in children.

Read a Clinical Commentary by M. Lee Chambliss, MD, MSPH, at www.fpin.org.

Evidence summary

Several systematic reviews help clarify theophylline’s role in asthma management. When compared with placebo in the management of acute exacerbations, theophylline confers no added benefit to beta-agonist therapy (with or without steroids) in improving pulmonary function or reducing hospitalization rates. Side effects occurred more often in the theophylline group: palpitations/arrhythmias (OR = 2.9; 95% CI: 1.5 to 5.7) and vomiting (OR = 4.2; 95% CI: 2.4 to 7.4).¹ For moderately severe asthma in patients already receiving inhaled corticosteroids (ICS), theophylline as maintenance therapy equaled long-acting beta-2-agonists in increasing FEV 1 and PEFR, but was less effective in controlling night time symptoms. Use of long-acting beta-agonists resulted in fewer side effects (RR = 0.38; 95%CI: 0.25-0.57).² When added to low-dose ICS for maintenance, theophylline was as effective as high-dose ICS alone in improving FEV 1 , decreasing day and night symptoms, and reducing the need for rescue medications and the incidence of attacks. This suggests theophylline has utility as a steroid sparing agent.³

Intravenous aminophylline does appear to be clinically beneficial for children with severe exacerbations, defined as an FEV 1 of 35%-40% of predicted value. Critically ill children receiving aminophylline in addition to usual care exhibited an improved FEV 1 at 24 hours (mean difference = 8.4%; 95% CI: 0.82 to 15.92) and reduced symptom scores at 6 hours.⁴ The largest RCT of aminophylline in children demonstrated a reduced intubation rate (NNT = 14 CI: 7.8-77).⁵ Children receiving aminophylline experienced more vomiting (RR = 3.69; 95%CI: 2.15-6.33). Treatment with aminophylline did not reduce length of hospital stay or the number of rescue nebulizers needed (Table).⁴

TABLE
Theophylline use in asthma

Recommendations from others

Three evidence-supported guidelines concur that theophylline has a limited role as maintenance therapy for moderate-to-severe persistent asthma when symptom control with ICS alone is not adequate. Much stronger evidence supports the use of long-acting beta-2-agonists or leukotriene modifiers in this setting.^6-8 The guidelines do not recommend using theophylline to treat acute asthma exacerbations; nor do they address using theophylline in children.

Read a Clinical Commentary by M. Lee Chambliss, MD, MSPH, at www.fpin.org.

Evidence summary

Several systematic reviews help clarify theophylline’s role in asthma management. When compared with placebo in the management of acute exacerbations, theophylline confers no added benefit to beta-agonist therapy (with or without steroids) in improving pulmonary function or reducing hospitalization rates. Side effects occurred more often in the theophylline group: palpitations/arrhythmias (OR = 2.9; 95% CI: 1.5 to 5.7) and vomiting (OR = 4.2; 95% CI: 2.4 to 7.4).¹ For moderately severe asthma in patients already receiving inhaled corticosteroids (ICS), theophylline as maintenance therapy equaled long-acting beta-2-agonists in increasing FEV 1 and PEFR, but was less effective in controlling night time symptoms. Use of long-acting beta-agonists resulted in fewer side effects (RR = 0.38; 95%CI: 0.25-0.57).² When added to low-dose ICS for maintenance, theophylline was as effective as high-dose ICS alone in improving FEV 1 , decreasing day and night symptoms, and reducing the need for rescue medications and the incidence of attacks. This suggests theophylline has utility as a steroid sparing agent.³

Intravenous aminophylline does appear to be clinically beneficial for children with severe exacerbations, defined as an FEV 1 of 35%-40% of predicted value. Critically ill children receiving aminophylline in addition to usual care exhibited an improved FEV 1 at 24 hours (mean difference = 8.4%; 95% CI: 0.82 to 15.92) and reduced symptom scores at 6 hours.⁴ The largest RCT of aminophylline in children demonstrated a reduced intubation rate (NNT = 14 CI: 7.8-77).⁵ Children receiving aminophylline experienced more vomiting (RR = 3.69; 95%CI: 2.15-6.33). Treatment with aminophylline did not reduce length of hospital stay or the number of rescue nebulizers needed (Table).⁴

TABLE
Theophylline use in asthma

Recommendations from others

Three evidence-supported guidelines concur that theophylline has a limited role as maintenance therapy for moderate-to-severe persistent asthma when symptom control with ICS alone is not adequate. Much stronger evidence supports the use of long-acting beta-2-agonists or leukotriene modifiers in this setting.^6-8 The guidelines do not recommend using theophylline to treat acute asthma exacerbations; nor do they address using theophylline in children.

Read a Clinical Commentary by M. Lee Chambliss, MD, MSPH, at www.fpin.org.