ADHD

Appetite suppression and insomnia—both common, dose-related side effects of psychostimulants—can jeopardize treatment adherence for patients with attention-deficit/hyperactivity disorder (ADHD). The following strategies can minimize these effects.

First, wait and see

For most patients, the optimal psychostimulant dosage produces few or no side effects. Those that occur are usually minor, transient, and disappear as patients develop tolerance within days of starting medication.

The two most commonly used stimulants—methylphenidate and amphetamine—cause similar side effects.¹ No evidence suggests either is more effective or less tolerable than the other.

Fine-tune psychostimulants to the lowest dosage that produces maximum benefit and minimum side effects. If side effects persist beyond 7 to 10 days, the dosage is probably too high or the patient is taking another stimulating medication. Before you attribute insomnia or appetite suppression to psychostimulants, ask the patient if he or she is using a decongestant, caffeine, diet pills, systemic corticosteroids, systemic albuterol, or theophylline.

Countering appetite suppression

Approximately one-third of adult and pediatric ADHD patients report appetite suppression at therapeutic psychostimulant dosages, but in most patients this effect is transient or clinically insignificant. If a child taking psychostimulants is not eating or gaining weight appropriately:

• suggest that parents plan mealtimes before the patient’s next dose or give high-calorie snacks throughout the day. (This strategy, although recommended by the American Academy of Pediatrics, can be cumbersome and has limited long-term efficacy.)
• switch from amphetamine to methylphenidate or vice versa.
• add the antihistamine cyproheptadine, 4 mg, with morning and evening meals
• add mirtazapine, one-half of a 15-mg tablet at bedtime to stimulate appetite and initiate sleep.

If none of these interventions work, recommend drug holidays from ADHD medications as a last resort when impairment is lowest, such as during weekends, holidays, or summers.

Curbing insomnia

About 20% of prepubertal children and 75% to 80% of adults have difficulty falling asleep while taking ADHD medications.² For many patients it is not the medications but the mental and physical restlessness of ADHD that disturbs sleep. Take a careful baseline sleep history before starting psychostimulants to help you determine later if they are causing insomnia.

Avoid benzodiazepines, which may promote tolerance and dependence. I discourage using any hypnotic to treat insomnia that occurs as a side effect. Also avoid antihistamines (Benedryl, trazodone) that may leave the patient sedated the next day.

Try a trial nap. After fine-tuning the psychostimulant to the lowest optimal dosage, ask the patient to test his ability to sleep while on that dose by taking an afternoon nap. Most patients discover they can sleep well, proving to both patient and doctor that ADHD medications usually help sleep initiation or are sleep-neutral. A successful nap can ease a patient’s fear that her medication will keep her awake.

Even the longest extended-release psychostimulant formulations do not last the 14 to 16 hours of a typical waking day. This no-risk trial nap reassures patients that they can take supplemental doses as prescribed to assist them through even the longest workdays, without fear of sleep disruption.

Time-release formulations smooth the abrupt kinetics and rebound activation seen with immediate-release psychostimulants. But for patients taking immediate-release formulations, reducing the day’s last dose or taking the last dose earlier can often prevent medication-associated insomnia.

If insomnia persists, try:

• melatonin, 0.5 to 1.0 mg, at bedtime, 1 hour before bedtime, at sunset, or 6 hours before anticipated bedtime. I try to mimic the natural release of melatonin triggered by sunset, but no definitive data prove the most effective dosing time.
• alpha agonists such as clonidine, 0.1 to 0.2 mg at bedtime, or guanfacine, 1 to 2 mg at bedtime. These agents have proven efficacy for treating hyperactivity and sleep disturbances without causing tolerance but may be associated with nightmares in some children.³
• mirtazapine, one-half of a 15-mg tablet at bedtime.

Appetite suppression and insomnia—both common, dose-related side effects of psychostimulants—can jeopardize treatment adherence for patients with attention-deficit/hyperactivity disorder (ADHD). The following strategies can minimize these effects.

First, wait and see

For most patients, the optimal psychostimulant dosage produces few or no side effects. Those that occur are usually minor, transient, and disappear as patients develop tolerance within days of starting medication.

The two most commonly used stimulants—methylphenidate and amphetamine—cause similar side effects.¹ No evidence suggests either is more effective or less tolerable than the other.

Fine-tune psychostimulants to the lowest dosage that produces maximum benefit and minimum side effects. If side effects persist beyond 7 to 10 days, the dosage is probably too high or the patient is taking another stimulating medication. Before you attribute insomnia or appetite suppression to psychostimulants, ask the patient if he or she is using a decongestant, caffeine, diet pills, systemic corticosteroids, systemic albuterol, or theophylline.

Countering appetite suppression

Approximately one-third of adult and pediatric ADHD patients report appetite suppression at therapeutic psychostimulant dosages, but in most patients this effect is transient or clinically insignificant. If a child taking psychostimulants is not eating or gaining weight appropriately:

• suggest that parents plan mealtimes before the patient’s next dose or give high-calorie snacks throughout the day. (This strategy, although recommended by the American Academy of Pediatrics, can be cumbersome and has limited long-term efficacy.)
• switch from amphetamine to methylphenidate or vice versa.
• add the antihistamine cyproheptadine, 4 mg, with morning and evening meals
• add mirtazapine, one-half of a 15-mg tablet at bedtime to stimulate appetite and initiate sleep.

If none of these interventions work, recommend drug holidays from ADHD medications as a last resort when impairment is lowest, such as during weekends, holidays, or summers.

Curbing insomnia

About 20% of prepubertal children and 75% to 80% of adults have difficulty falling asleep while taking ADHD medications.² For many patients it is not the medications but the mental and physical restlessness of ADHD that disturbs sleep. Take a careful baseline sleep history before starting psychostimulants to help you determine later if they are causing insomnia.

Avoid benzodiazepines, which may promote tolerance and dependence. I discourage using any hypnotic to treat insomnia that occurs as a side effect. Also avoid antihistamines (Benedryl, trazodone) that may leave the patient sedated the next day.

Try a trial nap. After fine-tuning the psychostimulant to the lowest optimal dosage, ask the patient to test his ability to sleep while on that dose by taking an afternoon nap. Most patients discover they can sleep well, proving to both patient and doctor that ADHD medications usually help sleep initiation or are sleep-neutral. A successful nap can ease a patient’s fear that her medication will keep her awake.

Even the longest extended-release psychostimulant formulations do not last the 14 to 16 hours of a typical waking day. This no-risk trial nap reassures patients that they can take supplemental doses as prescribed to assist them through even the longest workdays, without fear of sleep disruption.

Time-release formulations smooth the abrupt kinetics and rebound activation seen with immediate-release psychostimulants. But for patients taking immediate-release formulations, reducing the day’s last dose or taking the last dose earlier can often prevent medication-associated insomnia.

If insomnia persists, try:

• melatonin, 0.5 to 1.0 mg, at bedtime, 1 hour before bedtime, at sunset, or 6 hours before anticipated bedtime. I try to mimic the natural release of melatonin triggered by sunset, but no definitive data prove the most effective dosing time.
• alpha agonists such as clonidine, 0.1 to 0.2 mg at bedtime, or guanfacine, 1 to 2 mg at bedtime. These agents have proven efficacy for treating hyperactivity and sleep disturbances without causing tolerance but may be associated with nightmares in some children.³
• mirtazapine, one-half of a 15-mg tablet at bedtime.

Appetite suppression and insomnia—both common, dose-related side effects of psychostimulants—can jeopardize treatment adherence for patients with attention-deficit/hyperactivity disorder (ADHD). The following strategies can minimize these effects.

First, wait and see

For most patients, the optimal psychostimulant dosage produces few or no side effects. Those that occur are usually minor, transient, and disappear as patients develop tolerance within days of starting medication.

The two most commonly used stimulants—methylphenidate and amphetamine—cause similar side effects.¹ No evidence suggests either is more effective or less tolerable than the other.

Fine-tune psychostimulants to the lowest dosage that produces maximum benefit and minimum side effects. If side effects persist beyond 7 to 10 days, the dosage is probably too high or the patient is taking another stimulating medication. Before you attribute insomnia or appetite suppression to psychostimulants, ask the patient if he or she is using a decongestant, caffeine, diet pills, systemic corticosteroids, systemic albuterol, or theophylline.

Countering appetite suppression

Approximately one-third of adult and pediatric ADHD patients report appetite suppression at therapeutic psychostimulant dosages, but in most patients this effect is transient or clinically insignificant. If a child taking psychostimulants is not eating or gaining weight appropriately:

• suggest that parents plan mealtimes before the patient’s next dose or give high-calorie snacks throughout the day. (This strategy, although recommended by the American Academy of Pediatrics, can be cumbersome and has limited long-term efficacy.)
• switch from amphetamine to methylphenidate or vice versa.
• add the antihistamine cyproheptadine, 4 mg, with morning and evening meals
• add mirtazapine, one-half of a 15-mg tablet at bedtime to stimulate appetite and initiate sleep.

If none of these interventions work, recommend drug holidays from ADHD medications as a last resort when impairment is lowest, such as during weekends, holidays, or summers.

Curbing insomnia

About 20% of prepubertal children and 75% to 80% of adults have difficulty falling asleep while taking ADHD medications.² For many patients it is not the medications but the mental and physical restlessness of ADHD that disturbs sleep. Take a careful baseline sleep history before starting psychostimulants to help you determine later if they are causing insomnia.

Avoid benzodiazepines, which may promote tolerance and dependence. I discourage using any hypnotic to treat insomnia that occurs as a side effect. Also avoid antihistamines (Benedryl, trazodone) that may leave the patient sedated the next day.

Try a trial nap. After fine-tuning the psychostimulant to the lowest optimal dosage, ask the patient to test his ability to sleep while on that dose by taking an afternoon nap. Most patients discover they can sleep well, proving to both patient and doctor that ADHD medications usually help sleep initiation or are sleep-neutral. A successful nap can ease a patient’s fear that her medication will keep her awake.

Even the longest extended-release psychostimulant formulations do not last the 14 to 16 hours of a typical waking day. This no-risk trial nap reassures patients that they can take supplemental doses as prescribed to assist them through even the longest workdays, without fear of sleep disruption.

Time-release formulations smooth the abrupt kinetics and rebound activation seen with immediate-release psychostimulants. But for patients taking immediate-release formulations, reducing the day’s last dose or taking the last dose earlier can often prevent medication-associated insomnia.

If insomnia persists, try:

• melatonin, 0.5 to 1.0 mg, at bedtime, 1 hour before bedtime, at sunset, or 6 hours before anticipated bedtime. I try to mimic the natural release of melatonin triggered by sunset, but no definitive data prove the most effective dosing time.
• alpha agonists such as clonidine, 0.1 to 0.2 mg at bedtime, or guanfacine, 1 to 2 mg at bedtime. These agents have proven efficacy for treating hyperactivity and sleep disturbances without causing tolerance but may be associated with nightmares in some children.³
• mirtazapine, one-half of a 15-mg tablet at bedtime.

“What’s the best treatment for comorbid ADHD/bipolar mania?” by Drs. Nick C. Patel and Floyd R. Sallee (Current Psychiatry, April 2005) was well-written and offers excellent treatment guidelines. However, the idea that patients can have comorbid bipolar disorder and attention-deficit/hyperactivity disorder (ADHD) is a fallacy.

I challenge any colleague, from the leading expert to the most recent graduate, to present a bona fide case of “comorbid” ADHD/bipolar disorder. I can prove that only one diagnosis is correct because:

• Bipolar disorder is more heritable than other psychiatric illnesses. Many patients labeled as having “comorbid” bipolar disorder and ADHD have parents with bipolar disorder or schizophrenia or are in foster care and their biological parents’ histories are unknown.
• I’ve seen hundreds of patients enter full-blown psychosis after another clinician put them on amphetamines or antidepressants while being treated for ADHD.
• Bipolar disorder can explain any so-called ADHD symptom.
• ADHD does not include moodiness or predatory aggression.

Over 10 years, I have diagnosed three or four patients as having comorbid bipolar disorder and ADHD. After a few years and inpatient treatments, these patients proved the second diagnosis wrong. We can decrease costs and avoid patients’ suffering by refining diagnostic criteria.

Manuel Mota-Castillo, MD, medical director
The Grove Academy, Sanford, FL
and Lake Mary Psychiatric Services
Lake Mary, FL

Drs. Patel and Sallee respond

Dr. Mota-Castillo’s argument is most often stated from the opposite point of view that bipolar symptoms, particularly in patients age <10, are almost indistinguishable from those of ADHD. Our article did not—and cannot—address this controversy.

Because the evidence has been inconclusive, it is unclear if comorbid bipolar disorder and ADHD result from overlapping DSM-IV-TR diagnostic criteria, or whether two concurrent disorders exist. Suffice it to say that ADHD and bipolar disorder have many phenotypes and are both highly—but distinctly—heritable.

Overlapping symptoms may confound clinical diagnosis and result in “false positives” but may not account for most bipolar youths with comorbid ADHD. In one study,¹ 56% of subjects with both disorders maintained a bipolar disorder diagnosis when overlapping ADHD symptoms were subtracted.

Combination pharmacotherapy is needed because mood stabilizers do not treat attention and neurocognitive problems associated with ADHD. Therefore, a psychostimulant trial may help euthymic bipolar children and adolescents. In a recent placebo-controlled study by Scheffer et al,² ADHD symptoms—as measured with the Clinical Global Impression of Improvement scale and based upon Conners’ Teachers and Parent Ratings—significantly improved among divalproex sodium responders receiving mixed amphetamine salts.

Dr. Mota-Castillo, however, brings up two important questions:

• Are childhood symptoms that result in ADHD diagnosis a prodromal manifestation of bipolar disorder in some patients? Data from the first 1,000 STEP-BD participants suggest that ADHD may be part of the developmental phenotype of bipolar disorder comorbidity. Participants with mood symptom onset before age 13 had higher rates of comorbid ADHD than did those whose mood symptoms surfaced later on.³
• Do psychostimulants hasten mood disorder onset in a child diagnosed with ADHD who has a high familial risk of a mood disorder? How these agents influence the course of bipolar disorder is unclear. DelBello et al⁴ reported that psychostimulant exposure may be a stressor in youths at risk for bipolar disorder, may progressively worsen affective symptoms over time, and may lead to earlier mood symptom onset.

Both questions need further exploration as the implications for clinical practice may be tremendous.

Results from numerous independent studies consistently suggest that patients can be diagnosed with comorbid bipolar disorder and ADHD. More research is needed, however, to solve this diagnostic conundrum.

Nick C. Patel, PharmD, PhD
Assistant professor
Departments of pharmacy practice and psychiatry
Floyd R. Sallee, MD, PhD
Professor, department of psychiatry
University of Cincinnati

“What’s the best treatment for comorbid ADHD/bipolar mania?” by Drs. Nick C. Patel and Floyd R. Sallee (Current Psychiatry, April 2005) was well-written and offers excellent treatment guidelines. However, the idea that patients can have comorbid bipolar disorder and attention-deficit/hyperactivity disorder (ADHD) is a fallacy.

I challenge any colleague, from the leading expert to the most recent graduate, to present a bona fide case of “comorbid” ADHD/bipolar disorder. I can prove that only one diagnosis is correct because:

• Bipolar disorder is more heritable than other psychiatric illnesses. Many patients labeled as having “comorbid” bipolar disorder and ADHD have parents with bipolar disorder or schizophrenia or are in foster care and their biological parents’ histories are unknown.
• I’ve seen hundreds of patients enter full-blown psychosis after another clinician put them on amphetamines or antidepressants while being treated for ADHD.
• Bipolar disorder can explain any so-called ADHD symptom.
• ADHD does not include moodiness or predatory aggression.

Over 10 years, I have diagnosed three or four patients as having comorbid bipolar disorder and ADHD. After a few years and inpatient treatments, these patients proved the second diagnosis wrong. We can decrease costs and avoid patients’ suffering by refining diagnostic criteria.

Manuel Mota-Castillo, MD, medical director
The Grove Academy, Sanford, FL
and Lake Mary Psychiatric Services
Lake Mary, FL

Drs. Patel and Sallee respond

Dr. Mota-Castillo’s argument is most often stated from the opposite point of view that bipolar symptoms, particularly in patients age <10, are almost indistinguishable from those of ADHD. Our article did not—and cannot—address this controversy.

Because the evidence has been inconclusive, it is unclear if comorbid bipolar disorder and ADHD result from overlapping DSM-IV-TR diagnostic criteria, or whether two concurrent disorders exist. Suffice it to say that ADHD and bipolar disorder have many phenotypes and are both highly—but distinctly—heritable.

Overlapping symptoms may confound clinical diagnosis and result in “false positives” but may not account for most bipolar youths with comorbid ADHD. In one study,¹ 56% of subjects with both disorders maintained a bipolar disorder diagnosis when overlapping ADHD symptoms were subtracted.

Combination pharmacotherapy is needed because mood stabilizers do not treat attention and neurocognitive problems associated with ADHD. Therefore, a psychostimulant trial may help euthymic bipolar children and adolescents. In a recent placebo-controlled study by Scheffer et al,² ADHD symptoms—as measured with the Clinical Global Impression of Improvement scale and based upon Conners’ Teachers and Parent Ratings—significantly improved among divalproex sodium responders receiving mixed amphetamine salts.

Dr. Mota-Castillo, however, brings up two important questions:

• Are childhood symptoms that result in ADHD diagnosis a prodromal manifestation of bipolar disorder in some patients? Data from the first 1,000 STEP-BD participants suggest that ADHD may be part of the developmental phenotype of bipolar disorder comorbidity. Participants with mood symptom onset before age 13 had higher rates of comorbid ADHD than did those whose mood symptoms surfaced later on.³
• Do psychostimulants hasten mood disorder onset in a child diagnosed with ADHD who has a high familial risk of a mood disorder? How these agents influence the course of bipolar disorder is unclear. DelBello et al⁴ reported that psychostimulant exposure may be a stressor in youths at risk for bipolar disorder, may progressively worsen affective symptoms over time, and may lead to earlier mood symptom onset.

Both questions need further exploration as the implications for clinical practice may be tremendous.

Results from numerous independent studies consistently suggest that patients can be diagnosed with comorbid bipolar disorder and ADHD. More research is needed, however, to solve this diagnostic conundrum.

Nick C. Patel, PharmD, PhD
Assistant professor
Departments of pharmacy practice and psychiatry
Floyd R. Sallee, MD, PhD
Professor, department of psychiatry
University of Cincinnati

“What’s the best treatment for comorbid ADHD/bipolar mania?” by Drs. Nick C. Patel and Floyd R. Sallee (Current Psychiatry, April 2005) was well-written and offers excellent treatment guidelines. However, the idea that patients can have comorbid bipolar disorder and attention-deficit/hyperactivity disorder (ADHD) is a fallacy.

I challenge any colleague, from the leading expert to the most recent graduate, to present a bona fide case of “comorbid” ADHD/bipolar disorder. I can prove that only one diagnosis is correct because:

• Bipolar disorder is more heritable than other psychiatric illnesses. Many patients labeled as having “comorbid” bipolar disorder and ADHD have parents with bipolar disorder or schizophrenia or are in foster care and their biological parents’ histories are unknown.
• I’ve seen hundreds of patients enter full-blown psychosis after another clinician put them on amphetamines or antidepressants while being treated for ADHD.
• Bipolar disorder can explain any so-called ADHD symptom.
• ADHD does not include moodiness or predatory aggression.

Over 10 years, I have diagnosed three or four patients as having comorbid bipolar disorder and ADHD. After a few years and inpatient treatments, these patients proved the second diagnosis wrong. We can decrease costs and avoid patients’ suffering by refining diagnostic criteria.

Manuel Mota-Castillo, MD, medical director
The Grove Academy, Sanford, FL
and Lake Mary Psychiatric Services
Lake Mary, FL

Drs. Patel and Sallee respond

Dr. Mota-Castillo’s argument is most often stated from the opposite point of view that bipolar symptoms, particularly in patients age <10, are almost indistinguishable from those of ADHD. Our article did not—and cannot—address this controversy.

Because the evidence has been inconclusive, it is unclear if comorbid bipolar disorder and ADHD result from overlapping DSM-IV-TR diagnostic criteria, or whether two concurrent disorders exist. Suffice it to say that ADHD and bipolar disorder have many phenotypes and are both highly—but distinctly—heritable.

Overlapping symptoms may confound clinical diagnosis and result in “false positives” but may not account for most bipolar youths with comorbid ADHD. In one study,¹ 56% of subjects with both disorders maintained a bipolar disorder diagnosis when overlapping ADHD symptoms were subtracted.

Combination pharmacotherapy is needed because mood stabilizers do not treat attention and neurocognitive problems associated with ADHD. Therefore, a psychostimulant trial may help euthymic bipolar children and adolescents. In a recent placebo-controlled study by Scheffer et al,² ADHD symptoms—as measured with the Clinical Global Impression of Improvement scale and based upon Conners’ Teachers and Parent Ratings—significantly improved among divalproex sodium responders receiving mixed amphetamine salts.

Dr. Mota-Castillo, however, brings up two important questions:

• Are childhood symptoms that result in ADHD diagnosis a prodromal manifestation of bipolar disorder in some patients? Data from the first 1,000 STEP-BD participants suggest that ADHD may be part of the developmental phenotype of bipolar disorder comorbidity. Participants with mood symptom onset before age 13 had higher rates of comorbid ADHD than did those whose mood symptoms surfaced later on.³
• Do psychostimulants hasten mood disorder onset in a child diagnosed with ADHD who has a high familial risk of a mood disorder? How these agents influence the course of bipolar disorder is unclear. DelBello et al⁴ reported that psychostimulant exposure may be a stressor in youths at risk for bipolar disorder, may progressively worsen affective symptoms over time, and may lead to earlier mood symptom onset.

Both questions need further exploration as the implications for clinical practice may be tremendous.

Results from numerous independent studies consistently suggest that patients can be diagnosed with comorbid bipolar disorder and ADHD. More research is needed, however, to solve this diagnostic conundrum.

Nick C. Patel, PharmD, PhD
Assistant professor
Departments of pharmacy practice and psychiatry
Floyd R. Sallee, MD, PhD
Professor, department of psychiatry
University of Cincinnati

Knowing what to look for can help you differentiate between pediatric bipolar disorder and attention-deficit/hyperactivity disorder (ADHD):

• Bipolar disorder is a problem with mood. Children with bipolar mania are elated and/or irritable and experience mood states that appear uncontrollable.
• ADHD is a problem with cognitive functioning, including attention, distractibility, and energy level.

Mood and cognitive symptoms may overlap,^1,2 but recognizing manic features is the key to distinguishing between these disorders—even when they co-occur.

We offer tips from our experience and a recent clinical trial to help you sort out the core symptoms that point to bipolar mania.

BIPOLAR CORE SYMPTOMS

Pediatric bipolar disorder is relatively rare, but children with it can experience substantial impairment and developmental delay. Intervening early with effective treatment³ can improve their quality of life, function, and prognosis.

Diagnostic criteria for type I bipolar disorder require at least one manic episode and are the same for all ages. Many clinicians and researchers have advocated adapting DSM-IV criteria for children, but we believe separate adult and pediatric criteria would confuse discussions about the same phenomena. We do agree that symptoms should be evaluated in a developmentally appropriate context, as mania can present differently across the ages (Table 1).

Mania in children and young adolescents tends to present with rapid cycling and a primarily irritable mood.⁴ Older adolescents and adults may present with more-distinct mood changes, with a primarily euphoric mood. Euphoric mania is less common in adults than previously thought. Forty percent to 60% of adults with bipolar disorder experience a chronic course, rather than more-discrete mood episodes.

A manic episode is an abnormally and persistently elevated (euphoria) or irritable mood that lasts at least 1 week. To satisfy DSM-IV-TR diagnostic criteria for a manic episode:

• patients with euphoria require three additional symptoms
• those who are irritable (and not euphoric) require another four symptoms.⁵

These symptoms must significantly impair several areas of functioning and not be caused by other mental or physical illness, including substance use or abuse. When depressive symptoms occur in the same week as mania, the mixed mania modifier is used.

Table 1

Diagnostic features of bipolar mania in adolescents vs adults

Disruptive and aggressive behavior are common and are what usually prompts parents to bring children to psychiatrists. These behaviors are not diagnostic of mania, however, and aggression has many other causes.

The threshold between a variant of normal and pathologic disruptive behavior can be difficult to establish and varies from culture to culture. Some families, for example, would allow a child to tell the parents what to do, whereas other families consider this a serious boundary violation.

Prolonged rages have been used as a proxy for mood swings. Although we agree that rages lasting >15 minutes and out-of-proportion to the circumstances may signal bipolar disorder, they are not diagnostic.

Other symptoms. Psychotic symptoms (hallucinations, delusions, disorganization) can occur in youths with bipolar disorder. Evaluation often reveals impaired social and cognitive development. Keep in mind that a child’s developmental level can affect symptom expression.

ADHD CORE SYMPTOMS

Children with ADHD often present with hyperactive, uncontrollable behaviors and academic failure. To meet DSM-IV-TR diagnostic criteria, they must show symptoms before age 7. Primary symptoms may be inattention, hyperactivity and impulsivity, or both.

ADHD is a disorder of attention and the cognitive skills related to attention, rather than a mood disorder. Children with ADHD show substantially impaired function in at least two settings (such as at home and in school), and—unlike bipolar disorder—their symptoms are persistent rather than episodic.

DIFFERENTIATING BY SYMPTOMS

When differentiating between ADHD and bipolar disorder in children, remain focused on both diagnoses’ core symptoms.

Euphoria, or elation, is a key distinguishing factor in bipolar disorder.⁶ Although all children are at times giddy or silly in appropriate environments—such as during slumber parties—consider a threshold of appropriateness when making a bipolar diagnosis. Families perceive the giddiness, inappropriate laughter, and elevated mood of children with mania as disturbing and inappropriate, not funny or endearing. They are often annoyed and concerned.

Children with primary ADHD do not show inappropriately elevated mood. In fact, their failures often make these children dysphoric.

Irritability is common in children with psychiatric illnesses. Manic youngsters can be very irritable most of the time. Families describe “walking on eggshells” because of these children’s touchiness. Unpredictable triggers set off explosive, prolonged tantrums that may be associated with aggression, and their mood swings are almost constant.

Children with ADHD can be irritable, but their irritability is less severe and intense than that seen in bipolar disorder. Stimulant medication “wear-off” can cause irritability in ADHD, so consider this possibility if symptoms occur mostly in the evening.

Grandiosity can be confusing to evaluate in children but is often a core symptom in bipolar disorder. All children sometimes say self-inflating things, but those with pathologic grandiosity cross the threshold into the dysfunctional belief that they are better, stronger, smarter, or more talented than others.

For example, a 7-year-old patient insisted he was the world’s best chess player and could beat anyone, including Russian chess masters. When the therapist asked him about chess, he did not know the names of the pieces or how they moved. Yet despite facing these contradictory facts, he continued to insist that he was the best.

Children with grandiosity may act inappropriately on their beliefs, such as by telling adults what to do or engaging in risky, daredevil acts with no concern for their safety or the law.

Children with ADHD are not usually grandiose. Instead, they often become demoralized and develop poor self-esteem from negative feedback about their behavior.

Decreased need for sleep is the hallmark symptom of mania that is absent in other psychiatric disorders. A true decreased need for sleep is only indicated in someone sleeping less than his or her usual cumulative hours each day, without fatigue or recuperative sleep.

Children with bipolar disorder may need 1 or more hours less sleep or deny needing sleep at all. Use age-appropriate amounts of sleep as a standard. A school age child usually averages 9 to 11 hours of sleep per night. If the patient is getting only 6 hours and is not tired, this would be a decreased need for sleep. A 24-hour sleep history can easily assess decreased need for sleep (Box).

Determine daytime fatigue by self-report or observation by parents or teachers. Then ascertain if there are periods of days with less fatigue. Many bipolar youth have a nearly continuous decreased need for sleep.

Children with ADHD often have difficulty settling at night, which delays their falling asleep. The sleep history will likely show that—once asleep—they sleep well for an appropriate amount of time or are fatigued during the day.

Box

Pressured speech, or the need to talk excessively, is a relatively straightforward symptom. Children experiencing mania often speak so quickly and excessively that others cannot understand or interrupt them. Flight of ideas and racing thoughts are reflected in their speech.

By contrast, rapid speech by children with ADHD is related to hyperactivity. They speak too fast and often become distracted from the topic.

Racing thoughts. Children with bipolar disorder may report that their thoughts come so quickly they cannot get them out fast enough. The idea that their thoughts “need a stop-sign” suggests racing thoughts, a core bipolar symptom. Their speech can be unintelligible, with rapid changes in thought patterns, flight of ideas, and sentence fragments. Children with ADHD are energetic and quick but do not report racing thoughts.

LESS-HELPFUL SYMPTOMS

Distractibility—a core symptom of both inattentive ADHD and manic episodes—does not help differentiate the two diagnoses. The high comorbidity of ADHD with bipolar disorder increases the likelihood that the child will be easily distracted.

Multi-tasking. Increased goal-directed activity is often associated with the high energy of children with mania. They have more energy than most people, are always on the go, and engage in multiple projects or activities that may be markedly creative or unrealistic. This increased energy—combined with other hallmark manic symptoms—can lead to high-risk behaviors.

Hyperactivity in ADHD can appear similar to agitation in bipolar disorder. In both disorders, children may engage in many tasks—not finishing any of them—or appear to move quickly from one task to another.

High-risk behaviors. Parents often report their children with bipolar disorder have tried to jump from moving vehicles, “fly” off of roofs, and jump their bicycles or skateboards over impossible distances. These children behave as if the laws of nature do not apply to them. Children with ADHD behave impulsively but are not always “daredevils.” Their activities appear more impulsive and feature high activity in inappropriate situations, rather than distinctly high-risk activities.

RESPONSE TO THERAPY

Our group⁷ showed that pediatric manic and ADHD symptoms respond differently to mood-stabilizer treatment (Table 2).

We first used open-label divalproex sodium to treat manic symptoms in 40 children ages 6 to 17 with bipolar I or II disorder and concurrent ADHD. Serum valproic acid levels averaged 82 μg/mL. Manic symptoms improved in 80% of patients, whereas ADHD symptoms improved in <10%. Most children’s symptoms still met severity criteria for ADHD.

In a subsequent double-blind, crossover trial, we compared the effects of mixed amphetamine salts (MAS) or placebo on ADHD symptoms in 30 children whose manic symptoms stabilized on divalproex. MAS showed a significant, independent effect on ADHD symptoms One patient’s manic symptoms recurred during stimulant therapy and subsided with MAS discontinuation.

In this trial, mania symptoms responded to divalproex, whereas ADHD symptoms did not. MAS treatment showed a specific effect on ADHD symptoms of inattention, impulsivity, and hyperactivity. The shared symptoms of mania and ADHD (impulsivity and hyperactivity) decreased with divalproex to some extent.

Table 2

Pediatric mania and ADHD
respond differently to mood-stabilizer therapy

WHEN MANIA/ADHD CO-OCCUR

ADHD and bipolar disorder symptoms overlap to a great extent, and the disorders can co-occur:

• Up to 20% of children diagnosed with ADHD also meet bipolar criteria.
• Two-thirds of children with bipolar disorder may also meet criteria for ADHD, with reports ranging from 29% to 98%.^1,2

When trying to differentiate ADHD and bipolar disorder in children, consider the core symptoms of each diagnosis (Table 3).

Table 3

Core symptoms: Pediatric bipolar disorder vs ADHD

Related resources

• Geller B, DelBello MP (eds). Bipolar disorder in childhood and early adolescence. New York: Guilford Press, 2003.
• Papolos DF, Papolos J. Bipolar child: The definitive and reassuring guide to childhood’s most misunderstood disorder. New York: Broadway Books, 2002.
• Fristad MA, Goldberg Arnold JS. Raising a moody child: How to cope with depression and bipolar disorder. New York: Guilford Press, 2003.
• Child and Adolescent Bipolar Foundation. Available at www.cabf.org. Accessed March 4, 2005.

Drug brand names

• Divalproex sodium • Depakote
• Mixed amphetamine salts • Adderall

Disclosures

Dr. Scheffer receives research support from and is a speaker for Abbott Laboratories.

Dr. Apps reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Knowing what to look for can help you differentiate between pediatric bipolar disorder and attention-deficit/hyperactivity disorder (ADHD):

• Bipolar disorder is a problem with mood. Children with bipolar mania are elated and/or irritable and experience mood states that appear uncontrollable.
• ADHD is a problem with cognitive functioning, including attention, distractibility, and energy level.

Mood and cognitive symptoms may overlap,^1,2 but recognizing manic features is the key to distinguishing between these disorders—even when they co-occur.

We offer tips from our experience and a recent clinical trial to help you sort out the core symptoms that point to bipolar mania.

BIPOLAR CORE SYMPTOMS

Pediatric bipolar disorder is relatively rare, but children with it can experience substantial impairment and developmental delay. Intervening early with effective treatment³ can improve their quality of life, function, and prognosis.

Diagnostic criteria for type I bipolar disorder require at least one manic episode and are the same for all ages. Many clinicians and researchers have advocated adapting DSM-IV criteria for children, but we believe separate adult and pediatric criteria would confuse discussions about the same phenomena. We do agree that symptoms should be evaluated in a developmentally appropriate context, as mania can present differently across the ages (Table 1).

Mania in children and young adolescents tends to present with rapid cycling and a primarily irritable mood.⁴ Older adolescents and adults may present with more-distinct mood changes, with a primarily euphoric mood. Euphoric mania is less common in adults than previously thought. Forty percent to 60% of adults with bipolar disorder experience a chronic course, rather than more-discrete mood episodes.

A manic episode is an abnormally and persistently elevated (euphoria) or irritable mood that lasts at least 1 week. To satisfy DSM-IV-TR diagnostic criteria for a manic episode:

• patients with euphoria require three additional symptoms
• those who are irritable (and not euphoric) require another four symptoms.⁵

These symptoms must significantly impair several areas of functioning and not be caused by other mental or physical illness, including substance use or abuse. When depressive symptoms occur in the same week as mania, the mixed mania modifier is used.

Table 1

Diagnostic features of bipolar mania in adolescents vs adults

Disruptive and aggressive behavior are common and are what usually prompts parents to bring children to psychiatrists. These behaviors are not diagnostic of mania, however, and aggression has many other causes.

The threshold between a variant of normal and pathologic disruptive behavior can be difficult to establish and varies from culture to culture. Some families, for example, would allow a child to tell the parents what to do, whereas other families consider this a serious boundary violation.

Prolonged rages have been used as a proxy for mood swings. Although we agree that rages lasting >15 minutes and out-of-proportion to the circumstances may signal bipolar disorder, they are not diagnostic.

Other symptoms. Psychotic symptoms (hallucinations, delusions, disorganization) can occur in youths with bipolar disorder. Evaluation often reveals impaired social and cognitive development. Keep in mind that a child’s developmental level can affect symptom expression.

ADHD CORE SYMPTOMS

Children with ADHD often present with hyperactive, uncontrollable behaviors and academic failure. To meet DSM-IV-TR diagnostic criteria, they must show symptoms before age 7. Primary symptoms may be inattention, hyperactivity and impulsivity, or both.

ADHD is a disorder of attention and the cognitive skills related to attention, rather than a mood disorder. Children with ADHD show substantially impaired function in at least two settings (such as at home and in school), and—unlike bipolar disorder—their symptoms are persistent rather than episodic.

DIFFERENTIATING BY SYMPTOMS

When differentiating between ADHD and bipolar disorder in children, remain focused on both diagnoses’ core symptoms.

Euphoria, or elation, is a key distinguishing factor in bipolar disorder.⁶ Although all children are at times giddy or silly in appropriate environments—such as during slumber parties—consider a threshold of appropriateness when making a bipolar diagnosis. Families perceive the giddiness, inappropriate laughter, and elevated mood of children with mania as disturbing and inappropriate, not funny or endearing. They are often annoyed and concerned.

Children with primary ADHD do not show inappropriately elevated mood. In fact, their failures often make these children dysphoric.

Irritability is common in children with psychiatric illnesses. Manic youngsters can be very irritable most of the time. Families describe “walking on eggshells” because of these children’s touchiness. Unpredictable triggers set off explosive, prolonged tantrums that may be associated with aggression, and their mood swings are almost constant.

Children with ADHD can be irritable, but their irritability is less severe and intense than that seen in bipolar disorder. Stimulant medication “wear-off” can cause irritability in ADHD, so consider this possibility if symptoms occur mostly in the evening.

Grandiosity can be confusing to evaluate in children but is often a core symptom in bipolar disorder. All children sometimes say self-inflating things, but those with pathologic grandiosity cross the threshold into the dysfunctional belief that they are better, stronger, smarter, or more talented than others.

For example, a 7-year-old patient insisted he was the world’s best chess player and could beat anyone, including Russian chess masters. When the therapist asked him about chess, he did not know the names of the pieces or how they moved. Yet despite facing these contradictory facts, he continued to insist that he was the best.

Children with grandiosity may act inappropriately on their beliefs, such as by telling adults what to do or engaging in risky, daredevil acts with no concern for their safety or the law.

Children with ADHD are not usually grandiose. Instead, they often become demoralized and develop poor self-esteem from negative feedback about their behavior.

Decreased need for sleep is the hallmark symptom of mania that is absent in other psychiatric disorders. A true decreased need for sleep is only indicated in someone sleeping less than his or her usual cumulative hours each day, without fatigue or recuperative sleep.

Children with bipolar disorder may need 1 or more hours less sleep or deny needing sleep at all. Use age-appropriate amounts of sleep as a standard. A school age child usually averages 9 to 11 hours of sleep per night. If the patient is getting only 6 hours and is not tired, this would be a decreased need for sleep. A 24-hour sleep history can easily assess decreased need for sleep (Box).

Determine daytime fatigue by self-report or observation by parents or teachers. Then ascertain if there are periods of days with less fatigue. Many bipolar youth have a nearly continuous decreased need for sleep.

Children with ADHD often have difficulty settling at night, which delays their falling asleep. The sleep history will likely show that—once asleep—they sleep well for an appropriate amount of time or are fatigued during the day.

Box

Pressured speech, or the need to talk excessively, is a relatively straightforward symptom. Children experiencing mania often speak so quickly and excessively that others cannot understand or interrupt them. Flight of ideas and racing thoughts are reflected in their speech.

By contrast, rapid speech by children with ADHD is related to hyperactivity. They speak too fast and often become distracted from the topic.

Racing thoughts. Children with bipolar disorder may report that their thoughts come so quickly they cannot get them out fast enough. The idea that their thoughts “need a stop-sign” suggests racing thoughts, a core bipolar symptom. Their speech can be unintelligible, with rapid changes in thought patterns, flight of ideas, and sentence fragments. Children with ADHD are energetic and quick but do not report racing thoughts.

LESS-HELPFUL SYMPTOMS

Distractibility—a core symptom of both inattentive ADHD and manic episodes—does not help differentiate the two diagnoses. The high comorbidity of ADHD with bipolar disorder increases the likelihood that the child will be easily distracted.

Multi-tasking. Increased goal-directed activity is often associated with the high energy of children with mania. They have more energy than most people, are always on the go, and engage in multiple projects or activities that may be markedly creative or unrealistic. This increased energy—combined with other hallmark manic symptoms—can lead to high-risk behaviors.

Hyperactivity in ADHD can appear similar to agitation in bipolar disorder. In both disorders, children may engage in many tasks—not finishing any of them—or appear to move quickly from one task to another.

High-risk behaviors. Parents often report their children with bipolar disorder have tried to jump from moving vehicles, “fly” off of roofs, and jump their bicycles or skateboards over impossible distances. These children behave as if the laws of nature do not apply to them. Children with ADHD behave impulsively but are not always “daredevils.” Their activities appear more impulsive and feature high activity in inappropriate situations, rather than distinctly high-risk activities.

RESPONSE TO THERAPY

Our group⁷ showed that pediatric manic and ADHD symptoms respond differently to mood-stabilizer treatment (Table 2).

We first used open-label divalproex sodium to treat manic symptoms in 40 children ages 6 to 17 with bipolar I or II disorder and concurrent ADHD. Serum valproic acid levels averaged 82 μg/mL. Manic symptoms improved in 80% of patients, whereas ADHD symptoms improved in <10%. Most children’s symptoms still met severity criteria for ADHD.

In a subsequent double-blind, crossover trial, we compared the effects of mixed amphetamine salts (MAS) or placebo on ADHD symptoms in 30 children whose manic symptoms stabilized on divalproex. MAS showed a significant, independent effect on ADHD symptoms One patient’s manic symptoms recurred during stimulant therapy and subsided with MAS discontinuation.

In this trial, mania symptoms responded to divalproex, whereas ADHD symptoms did not. MAS treatment showed a specific effect on ADHD symptoms of inattention, impulsivity, and hyperactivity. The shared symptoms of mania and ADHD (impulsivity and hyperactivity) decreased with divalproex to some extent.

Table 2

Pediatric mania and ADHD
respond differently to mood-stabilizer therapy

WHEN MANIA/ADHD CO-OCCUR

ADHD and bipolar disorder symptoms overlap to a great extent, and the disorders can co-occur:

• Up to 20% of children diagnosed with ADHD also meet bipolar criteria.
• Two-thirds of children with bipolar disorder may also meet criteria for ADHD, with reports ranging from 29% to 98%.^1,2

When trying to differentiate ADHD and bipolar disorder in children, consider the core symptoms of each diagnosis (Table 3).

Table 3

Core symptoms: Pediatric bipolar disorder vs ADHD

Related resources

• Geller B, DelBello MP (eds). Bipolar disorder in childhood and early adolescence. New York: Guilford Press, 2003.
• Papolos DF, Papolos J. Bipolar child: The definitive and reassuring guide to childhood’s most misunderstood disorder. New York: Broadway Books, 2002.
• Fristad MA, Goldberg Arnold JS. Raising a moody child: How to cope with depression and bipolar disorder. New York: Guilford Press, 2003.
• Child and Adolescent Bipolar Foundation. Available at www.cabf.org. Accessed March 4, 2005.

Drug brand names

• Divalproex sodium • Depakote
• Mixed amphetamine salts • Adderall

Disclosures

Dr. Scheffer receives research support from and is a speaker for Abbott Laboratories.

Dr. Apps reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Knowing what to look for can help you differentiate between pediatric bipolar disorder and attention-deficit/hyperactivity disorder (ADHD):

• Bipolar disorder is a problem with mood. Children with bipolar mania are elated and/or irritable and experience mood states that appear uncontrollable.
• ADHD is a problem with cognitive functioning, including attention, distractibility, and energy level.

Mood and cognitive symptoms may overlap,^1,2 but recognizing manic features is the key to distinguishing between these disorders—even when they co-occur.

We offer tips from our experience and a recent clinical trial to help you sort out the core symptoms that point to bipolar mania.

BIPOLAR CORE SYMPTOMS

Pediatric bipolar disorder is relatively rare, but children with it can experience substantial impairment and developmental delay. Intervening early with effective treatment³ can improve their quality of life, function, and prognosis.

Diagnostic criteria for type I bipolar disorder require at least one manic episode and are the same for all ages. Many clinicians and researchers have advocated adapting DSM-IV criteria for children, but we believe separate adult and pediatric criteria would confuse discussions about the same phenomena. We do agree that symptoms should be evaluated in a developmentally appropriate context, as mania can present differently across the ages (Table 1).

Mania in children and young adolescents tends to present with rapid cycling and a primarily irritable mood.⁴ Older adolescents and adults may present with more-distinct mood changes, with a primarily euphoric mood. Euphoric mania is less common in adults than previously thought. Forty percent to 60% of adults with bipolar disorder experience a chronic course, rather than more-discrete mood episodes.

A manic episode is an abnormally and persistently elevated (euphoria) or irritable mood that lasts at least 1 week. To satisfy DSM-IV-TR diagnostic criteria for a manic episode:

• patients with euphoria require three additional symptoms
• those who are irritable (and not euphoric) require another four symptoms.⁵

These symptoms must significantly impair several areas of functioning and not be caused by other mental or physical illness, including substance use or abuse. When depressive symptoms occur in the same week as mania, the mixed mania modifier is used.

Table 1

Diagnostic features of bipolar mania in adolescents vs adults

Disruptive and aggressive behavior are common and are what usually prompts parents to bring children to psychiatrists. These behaviors are not diagnostic of mania, however, and aggression has many other causes.

The threshold between a variant of normal and pathologic disruptive behavior can be difficult to establish and varies from culture to culture. Some families, for example, would allow a child to tell the parents what to do, whereas other families consider this a serious boundary violation.

Prolonged rages have been used as a proxy for mood swings. Although we agree that rages lasting >15 minutes and out-of-proportion to the circumstances may signal bipolar disorder, they are not diagnostic.

Other symptoms. Psychotic symptoms (hallucinations, delusions, disorganization) can occur in youths with bipolar disorder. Evaluation often reveals impaired social and cognitive development. Keep in mind that a child’s developmental level can affect symptom expression.

ADHD CORE SYMPTOMS

Children with ADHD often present with hyperactive, uncontrollable behaviors and academic failure. To meet DSM-IV-TR diagnostic criteria, they must show symptoms before age 7. Primary symptoms may be inattention, hyperactivity and impulsivity, or both.

ADHD is a disorder of attention and the cognitive skills related to attention, rather than a mood disorder. Children with ADHD show substantially impaired function in at least two settings (such as at home and in school), and—unlike bipolar disorder—their symptoms are persistent rather than episodic.

DIFFERENTIATING BY SYMPTOMS

When differentiating between ADHD and bipolar disorder in children, remain focused on both diagnoses’ core symptoms.

Euphoria, or elation, is a key distinguishing factor in bipolar disorder.⁶ Although all children are at times giddy or silly in appropriate environments—such as during slumber parties—consider a threshold of appropriateness when making a bipolar diagnosis. Families perceive the giddiness, inappropriate laughter, and elevated mood of children with mania as disturbing and inappropriate, not funny or endearing. They are often annoyed and concerned.

Children with primary ADHD do not show inappropriately elevated mood. In fact, their failures often make these children dysphoric.

Irritability is common in children with psychiatric illnesses. Manic youngsters can be very irritable most of the time. Families describe “walking on eggshells” because of these children’s touchiness. Unpredictable triggers set off explosive, prolonged tantrums that may be associated with aggression, and their mood swings are almost constant.

Children with ADHD can be irritable, but their irritability is less severe and intense than that seen in bipolar disorder. Stimulant medication “wear-off” can cause irritability in ADHD, so consider this possibility if symptoms occur mostly in the evening.

Grandiosity can be confusing to evaluate in children but is often a core symptom in bipolar disorder. All children sometimes say self-inflating things, but those with pathologic grandiosity cross the threshold into the dysfunctional belief that they are better, stronger, smarter, or more talented than others.

For example, a 7-year-old patient insisted he was the world’s best chess player and could beat anyone, including Russian chess masters. When the therapist asked him about chess, he did not know the names of the pieces or how they moved. Yet despite facing these contradictory facts, he continued to insist that he was the best.

Children with grandiosity may act inappropriately on their beliefs, such as by telling adults what to do or engaging in risky, daredevil acts with no concern for their safety or the law.

Children with ADHD are not usually grandiose. Instead, they often become demoralized and develop poor self-esteem from negative feedback about their behavior.

Decreased need for sleep is the hallmark symptom of mania that is absent in other psychiatric disorders. A true decreased need for sleep is only indicated in someone sleeping less than his or her usual cumulative hours each day, without fatigue or recuperative sleep.

Children with bipolar disorder may need 1 or more hours less sleep or deny needing sleep at all. Use age-appropriate amounts of sleep as a standard. A school age child usually averages 9 to 11 hours of sleep per night. If the patient is getting only 6 hours and is not tired, this would be a decreased need for sleep. A 24-hour sleep history can easily assess decreased need for sleep (Box).

Determine daytime fatigue by self-report or observation by parents or teachers. Then ascertain if there are periods of days with less fatigue. Many bipolar youth have a nearly continuous decreased need for sleep.

Children with ADHD often have difficulty settling at night, which delays their falling asleep. The sleep history will likely show that—once asleep—they sleep well for an appropriate amount of time or are fatigued during the day.

Box

Pressured speech, or the need to talk excessively, is a relatively straightforward symptom. Children experiencing mania often speak so quickly and excessively that others cannot understand or interrupt them. Flight of ideas and racing thoughts are reflected in their speech.

By contrast, rapid speech by children with ADHD is related to hyperactivity. They speak too fast and often become distracted from the topic.

Racing thoughts. Children with bipolar disorder may report that their thoughts come so quickly they cannot get them out fast enough. The idea that their thoughts “need a stop-sign” suggests racing thoughts, a core bipolar symptom. Their speech can be unintelligible, with rapid changes in thought patterns, flight of ideas, and sentence fragments. Children with ADHD are energetic and quick but do not report racing thoughts.

LESS-HELPFUL SYMPTOMS

Distractibility—a core symptom of both inattentive ADHD and manic episodes—does not help differentiate the two diagnoses. The high comorbidity of ADHD with bipolar disorder increases the likelihood that the child will be easily distracted.

Multi-tasking. Increased goal-directed activity is often associated with the high energy of children with mania. They have more energy than most people, are always on the go, and engage in multiple projects or activities that may be markedly creative or unrealistic. This increased energy—combined with other hallmark manic symptoms—can lead to high-risk behaviors.

Hyperactivity in ADHD can appear similar to agitation in bipolar disorder. In both disorders, children may engage in many tasks—not finishing any of them—or appear to move quickly from one task to another.

High-risk behaviors. Parents often report their children with bipolar disorder have tried to jump from moving vehicles, “fly” off of roofs, and jump their bicycles or skateboards over impossible distances. These children behave as if the laws of nature do not apply to them. Children with ADHD behave impulsively but are not always “daredevils.” Their activities appear more impulsive and feature high activity in inappropriate situations, rather than distinctly high-risk activities.

RESPONSE TO THERAPY

Our group⁷ showed that pediatric manic and ADHD symptoms respond differently to mood-stabilizer treatment (Table 2).

We first used open-label divalproex sodium to treat manic symptoms in 40 children ages 6 to 17 with bipolar I or II disorder and concurrent ADHD. Serum valproic acid levels averaged 82 μg/mL. Manic symptoms improved in 80% of patients, whereas ADHD symptoms improved in <10%. Most children’s symptoms still met severity criteria for ADHD.

In a subsequent double-blind, crossover trial, we compared the effects of mixed amphetamine salts (MAS) or placebo on ADHD symptoms in 30 children whose manic symptoms stabilized on divalproex. MAS showed a significant, independent effect on ADHD symptoms One patient’s manic symptoms recurred during stimulant therapy and subsided with MAS discontinuation.

In this trial, mania symptoms responded to divalproex, whereas ADHD symptoms did not. MAS treatment showed a specific effect on ADHD symptoms of inattention, impulsivity, and hyperactivity. The shared symptoms of mania and ADHD (impulsivity and hyperactivity) decreased with divalproex to some extent.

Table 2

Pediatric mania and ADHD
respond differently to mood-stabilizer therapy

WHEN MANIA/ADHD CO-OCCUR

ADHD and bipolar disorder symptoms overlap to a great extent, and the disorders can co-occur:

• Up to 20% of children diagnosed with ADHD also meet bipolar criteria.
• Two-thirds of children with bipolar disorder may also meet criteria for ADHD, with reports ranging from 29% to 98%.^1,2

When trying to differentiate ADHD and bipolar disorder in children, consider the core symptoms of each diagnosis (Table 3).

Table 3

Core symptoms: Pediatric bipolar disorder vs ADHD

Related resources

• Geller B, DelBello MP (eds). Bipolar disorder in childhood and early adolescence. New York: Guilford Press, 2003.
• Papolos DF, Papolos J. Bipolar child: The definitive and reassuring guide to childhood’s most misunderstood disorder. New York: Broadway Books, 2002.
• Fristad MA, Goldberg Arnold JS. Raising a moody child: How to cope with depression and bipolar disorder. New York: Guilford Press, 2003.
• Child and Adolescent Bipolar Foundation. Available at www.cabf.org. Accessed March 4, 2005.

Drug brand names

• Divalproex sodium • Depakote
• Mixed amphetamine salts • Adderall

Disclosures

Dr. Scheffer receives research support from and is a speaker for Abbott Laboratories.

Dr. Apps reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Psychostimulants benefit many patients with attention-deficit/hyperactivity disorder (ADHD)¹ and thus might seem a logical choice to manage hyperactivity and inattention in youths with a pervasive developmental disorder (PDD). Some PDD patients do respond to psychostimulant therapy, but others worsen—and side effects are common.

Youths with PDDs often exhibit maladaptive behaviors—aggression, self-injury, irritability, hyperactivity, inattention—with repetitive activity patterns and fundamentally impaired social interaction and communication.² To help you treat youths with PDD, we draw on the evidence, clinical experience, and our research to suggest psychostimulants’ role in a multimodal approach.

Targeting hyperactivity and inattentions

Step 1. Our approach begins with behavioral therapy (Figure), which includes identifying situations that trigger maladaptive behavior and environments that yield optimum behavior. The therapist assesses the child’s baseline attention and works with him or her to gradually increase it, using reinforcement and visual token boards.

Algorithm Suggested approach to hyperactivity and/or inattention in patients with PDDs

Step 2. Many patients will not respond to behavior therapy alone and will require added drug therapy. Based on evidence, we suggest starting with an alpha-2 adrenergic agonist. Guanfacine may be considered the drug of choice because of clonidine’s higher risk of adverse effects, such as hypotension and sedation. Obtain a baseline ECG with either agent, as clonidine has been associated with rare cardiovascular events.

Clonidine. Two small studies showed that clonidine may be of some benefit to patients with PDDs:

• Results were mixed in a 6-week, double-blind, placebo-controlled, crossover study of clonidine (4 to 10 μg/kg/d) in 8 autistic children ages 5 to 13.³ Teacher and parent rating instruments reflected significantly improved hyperactivity, irritability, and oppositional behavior. Clinician ratings, however, showed no significant difference between clonidine and placebo. Adverse effects with clonidine included hypotension, sedation, and decreased activity.
• In a 4-week, double-blind, placebo-con-trolled, crossover study of transdermal clonidine (0.16 to 0.48 mg/kg/d; mean: 3.6 μg/kg/d), clinician ratings showed significantly decreased hyperactivity, impulsivity, and anxiety in 9 autistic males ages 5 to 33. Sedation and fatigue were common adverse effects.

Guanfacine. In a recent retrospective review,⁵ we examined outcomes of 80 PDD patients ages 3 to 18 who received guanfacine (0.25 to 9 mg/d; mean: 2.6). Hyperactivity, inattention, and tics decreased in 19 patients (24%) treated for a mean 10 months.

Step 3. If clonidine or guanfacine fails to reduce hyperactivity and inattention, discontinue it and consider a psychostimulant trial.

Because psychostimulants’ efficacy in PDDs remains inconclusive, we suggest beginning with a low dosage and carefully monitoring the patient for worsening target symptoms and activation, such as emerging aggression or irritability.

Step 4. If hyperactivity and inattention remain prominent and treatment-refractory, we suggest that you discontinue the stimulant and consider an atypical antipsychotic trial. With the atypicals, monitor patients closely for adverse effects, including weight gain, extrapyramidal symptoms, and tardive dyskinesia. Fasting serum glucose and lipid profiles and liver function tests are recommended at least every 6 months and more often in individuals at risk for diabetes or hepatic disease.

Two studies provide evidence of atypicals’ efficacy in PDDs:

• In a 6-week open-label comparison,⁶ olanzapine significantly reduced hyperactivity and anger or uncooperativeness in 12 children with autistic disorder, but haloperidol did not. Average weight gain was 9 lbs in patients receiving olanzapine vs 3.2 lbs in those receiving haloperidol.
• An 8-week, double-blind study⁷ compared risperidone (0.5 to 3.5 mg/d; mean: 1.8) with placebo in 101 children and adolescents with autistic disorder. Response rates were 69% in the risperidone group and 12% in the control group. Risperidone reduced hyperactivity, aggression, agitation, and repetitive behavior. Adverse drug effects included weight gain (2.7 kg vs. 0.8 kg with placebo), increased appetite, and sedation.

Psychostimulant use in PDDs

Evidence is conflicting on psychostimulant use in patients with PDDs (Table). Early reviews suggested that stimulants were ineffective in PDDs and associated with adverse effects.^8,9 Some preliminary studies supported that view, but recent reports have been mixed.

Dextroamphetamine. Campbell et al¹⁰ published a placebo-controlled study comparing triiodothyronine and dextroamphetamine (mean dosage, 4.8 mg/d; range 1.25 to 10 mg/d) in 16 children ages 3 to 6 (mean, 4.3 years) with diagnoses of autism, schizophrenia, and organic brain syndrome. All diagnostic groups worsened clinically with dextroamphetamine, and adverse effects—hyperactivity, worsened stereotypy, irritability, and decreased appetite—were common.

A subsequent case report¹¹ found dex-troamphetamine effective when 2 patients ages 9 and 12 with PDD were treated with 10 and 5 mg/d, respectively. Hyperactivity, inattention, and impulsivity improved in both patients, and core PDD features did not worsen.

Levoamphetamine. In an 8-week, double-blind, crossover comparison with levodopa,¹² levoamphetamine, 3.5 to 42 mg/d (mean, 13.4), worsened symptoms in 12 children ages 3 to 12 who had schizophrenia with autistic features. stereotypy emerged or increased in 9 of the 11 patients (82%) available for follow-up, and levoamphetamine was poorly tolerated.

Methylphenidate. In an early report, methylphenidate decreased hyperactivity and impulsivity in 9 of 15 children (60%) ages 2 to 13 with infantile autism.¹³ Dosages of 5 to 10 mg/d or 0.3 to 1 mg/kg/d were given for 2 to 60 weeks (mean, 26). Adverse effects included irritability, insomnia, and anorexia.

Table

Selected reports of stimulant use in pervasive developmental disorders

A subsequent open-label study and a case report also indicated that methylphenidate improved hyperactivity in patients with autistic disorder:

• In the 2-week, open-label study,¹⁴ 9 patients ages 4 to 16 received methylphenidate, 10 to 50 mg/d. Two patients also received haloperidol, 4 and 5 mg/d. Hyperactivity improved significantly, as measured by the Conners Teacher Questionnaire.
• In the case report,¹⁵ one child, age 6, was. treated with methylphenidate, 10 mg bid, for 31 days. The drug significantly alleviated hyperactivity and improved concentration. Adverse effects included dysphoria and outbursts of anger.

Box

Controlled trials. These early reports were followed by two double-blind, placebo-controlled, crossover studies of methylphenidate in children with autistic disorder.

• In the first trial,¹⁶ methylphenidate, 10 or 20 mg/d, improved irritability and hyperactivity in 10 children ages 7 to 11 but was only modestly more beneficial than placebo. Side-effect incidence—including decreased appetite, irritability, and insomnia—was similar during active and placebo treatments. Two patients required adjunctive haloperidol for prevailing behavioral problems.
• In the second trial,¹⁷ 8 of 13 children (62%) ages 5 to 11 responded to methylphenidate, 0.3 and 0.6 mg/kg per dose. Hyperactivity and inattention improved significantly, as measured by a minimum 50% decrease in Conners Hyperactivity Index score. Ratings of stereotypy and inappropriate speech also decreased, but no changes were seen in the Child Autism Rating Scale. Adverse effects, which were more common with the 0.6 mg/kg dose, included social withdrawal and irritability.

Retrospective trial. Our group recently completed a retrospective study of 195 youth (mean age, 7.3 years; range, 2 to 19 years) with PDDs treated with a stimulant medication.¹⁸ As a whole, stimulants appeared ineffective.

Analysis of response by PDD subtype found that individuals with Asperger’s disorder—in contrast to those with autistic disorder or PDD not otherwise specified—were significantly more likely to respond to a stimulant medication. Gender, intelligence quotient (IQ), type of stimulant, and dosage did not significantly affect response. Adverse effects—including agitation, dysphoria, and irritability—occurred in 57.5% of the trials.

Atomoxetine. This nonstimulant medication has been approved for treating ADHD. However, research is needed to understand its use in patients with PDDs (Box)¹⁹

Summary. These mixed findings—combined with anecdotal reports from physicians describing the onset or exacerbation of hyperactivity, irritability, and aggression—indicate that much more evidence is needed regarding psychostimulant use in patients with PDDs.

To help meet this need, the National Institutes of Mental Health’s Research Units on Pediatric Psychopharmacology (RUPP) autism network recently completed a large, double-blind, placebo-controlled study to investigate methylphenidate’s efficacy and tolerability in PDDs. It is anticipated that the results will help us discern whether factors such as PDD subtype, patient age, dosage, or degree of mental retardation are associated with response.

Related resources

• Autism Society of America. www.autism-society.org
• McDougle CJ. Current and emerging therapeutics of autistic disorder and related pervasive developmental disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: The fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, Charney DS, Leckman JF (eds). Pediatric psychopharmacology: Principles and practice.New York: Oxford University Press, 2002.

Drug brand names

• Atomoxetine • Strattera
• Clomipramine • Anafranil
• Clonidine • Catapres
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Guanfacine • Tenex
• Haloperidol • Haldol
• Levoamphetamine • Adderall
• Levodopa • Dopar, Laradopa
• Methylphenidate • Ritalin
• Olanzapine • Zyprexa
• Pemoline • Cylert
• Risperidone • Risperdal

Disclosure

Dr. Stigler reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Posey receives research support from Janssen Pharmaceutica and Eli Lilly and Co. and is a speaker for Janssen Pharmaceutica.

Dr. McDougle receives research support from Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., and Bristol-Myers Squibb Co. He is a consultant to or speaker for Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., RepliGen Corp., and Bristol-Myers Squibb Co.

Acknowledgments

This work was supported in part by a Daniel X. Freedman Psychiatric Research Fellowship Award (Dr. Posey), a National Alliance for Research in Schizophrenia and Depression (NARSAD) Young Investigator Award (Dr. Posey), a Research Units on Pediatric Psychopharmacology Grant (U10MH66766-02) from the National Institute of Mental Health (NIMH) to Indiana University (Dr. McDougle, Dr. Stigler, and Dr. Posey), a Research Career Development Award (K23-MH068627-01) from the NIMH (Dr. Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development (HUD) grant (B-01-SP-IN-0200) (Dr. McDougle).

Psychostimulants benefit many patients with attention-deficit/hyperactivity disorder (ADHD)¹ and thus might seem a logical choice to manage hyperactivity and inattention in youths with a pervasive developmental disorder (PDD). Some PDD patients do respond to psychostimulant therapy, but others worsen—and side effects are common.

Youths with PDDs often exhibit maladaptive behaviors—aggression, self-injury, irritability, hyperactivity, inattention—with repetitive activity patterns and fundamentally impaired social interaction and communication.² To help you treat youths with PDD, we draw on the evidence, clinical experience, and our research to suggest psychostimulants’ role in a multimodal approach.

Targeting hyperactivity and inattentions

Step 1. Our approach begins with behavioral therapy (Figure), which includes identifying situations that trigger maladaptive behavior and environments that yield optimum behavior. The therapist assesses the child’s baseline attention and works with him or her to gradually increase it, using reinforcement and visual token boards.

Algorithm Suggested approach to hyperactivity and/or inattention in patients with PDDs

Step 2. Many patients will not respond to behavior therapy alone and will require added drug therapy. Based on evidence, we suggest starting with an alpha-2 adrenergic agonist. Guanfacine may be considered the drug of choice because of clonidine’s higher risk of adverse effects, such as hypotension and sedation. Obtain a baseline ECG with either agent, as clonidine has been associated with rare cardiovascular events.

Clonidine. Two small studies showed that clonidine may be of some benefit to patients with PDDs:

• Results were mixed in a 6-week, double-blind, placebo-controlled, crossover study of clonidine (4 to 10 μg/kg/d) in 8 autistic children ages 5 to 13.³ Teacher and parent rating instruments reflected significantly improved hyperactivity, irritability, and oppositional behavior. Clinician ratings, however, showed no significant difference between clonidine and placebo. Adverse effects with clonidine included hypotension, sedation, and decreased activity.
• In a 4-week, double-blind, placebo-con-trolled, crossover study of transdermal clonidine (0.16 to 0.48 mg/kg/d; mean: 3.6 μg/kg/d), clinician ratings showed significantly decreased hyperactivity, impulsivity, and anxiety in 9 autistic males ages 5 to 33. Sedation and fatigue were common adverse effects.

Guanfacine. In a recent retrospective review,⁵ we examined outcomes of 80 PDD patients ages 3 to 18 who received guanfacine (0.25 to 9 mg/d; mean: 2.6). Hyperactivity, inattention, and tics decreased in 19 patients (24%) treated for a mean 10 months.

Step 3. If clonidine or guanfacine fails to reduce hyperactivity and inattention, discontinue it and consider a psychostimulant trial.

Because psychostimulants’ efficacy in PDDs remains inconclusive, we suggest beginning with a low dosage and carefully monitoring the patient for worsening target symptoms and activation, such as emerging aggression or irritability.

Step 4. If hyperactivity and inattention remain prominent and treatment-refractory, we suggest that you discontinue the stimulant and consider an atypical antipsychotic trial. With the atypicals, monitor patients closely for adverse effects, including weight gain, extrapyramidal symptoms, and tardive dyskinesia. Fasting serum glucose and lipid profiles and liver function tests are recommended at least every 6 months and more often in individuals at risk for diabetes or hepatic disease.

Two studies provide evidence of atypicals’ efficacy in PDDs:

• In a 6-week open-label comparison,⁶ olanzapine significantly reduced hyperactivity and anger or uncooperativeness in 12 children with autistic disorder, but haloperidol did not. Average weight gain was 9 lbs in patients receiving olanzapine vs 3.2 lbs in those receiving haloperidol.
• An 8-week, double-blind study⁷ compared risperidone (0.5 to 3.5 mg/d; mean: 1.8) with placebo in 101 children and adolescents with autistic disorder. Response rates were 69% in the risperidone group and 12% in the control group. Risperidone reduced hyperactivity, aggression, agitation, and repetitive behavior. Adverse drug effects included weight gain (2.7 kg vs. 0.8 kg with placebo), increased appetite, and sedation.

Psychostimulant use in PDDs

Evidence is conflicting on psychostimulant use in patients with PDDs (Table). Early reviews suggested that stimulants were ineffective in PDDs and associated with adverse effects.^8,9 Some preliminary studies supported that view, but recent reports have been mixed.

Dextroamphetamine. Campbell et al¹⁰ published a placebo-controlled study comparing triiodothyronine and dextroamphetamine (mean dosage, 4.8 mg/d; range 1.25 to 10 mg/d) in 16 children ages 3 to 6 (mean, 4.3 years) with diagnoses of autism, schizophrenia, and organic brain syndrome. All diagnostic groups worsened clinically with dextroamphetamine, and adverse effects—hyperactivity, worsened stereotypy, irritability, and decreased appetite—were common.

A subsequent case report¹¹ found dex-troamphetamine effective when 2 patients ages 9 and 12 with PDD were treated with 10 and 5 mg/d, respectively. Hyperactivity, inattention, and impulsivity improved in both patients, and core PDD features did not worsen.

Levoamphetamine. In an 8-week, double-blind, crossover comparison with levodopa,¹² levoamphetamine, 3.5 to 42 mg/d (mean, 13.4), worsened symptoms in 12 children ages 3 to 12 who had schizophrenia with autistic features. stereotypy emerged or increased in 9 of the 11 patients (82%) available for follow-up, and levoamphetamine was poorly tolerated.

Methylphenidate. In an early report, methylphenidate decreased hyperactivity and impulsivity in 9 of 15 children (60%) ages 2 to 13 with infantile autism.¹³ Dosages of 5 to 10 mg/d or 0.3 to 1 mg/kg/d were given for 2 to 60 weeks (mean, 26). Adverse effects included irritability, insomnia, and anorexia.

Table

Selected reports of stimulant use in pervasive developmental disorders

A subsequent open-label study and a case report also indicated that methylphenidate improved hyperactivity in patients with autistic disorder:

• In the 2-week, open-label study,¹⁴ 9 patients ages 4 to 16 received methylphenidate, 10 to 50 mg/d. Two patients also received haloperidol, 4 and 5 mg/d. Hyperactivity improved significantly, as measured by the Conners Teacher Questionnaire.
• In the case report,¹⁵ one child, age 6, was. treated with methylphenidate, 10 mg bid, for 31 days. The drug significantly alleviated hyperactivity and improved concentration. Adverse effects included dysphoria and outbursts of anger.

Box

Controlled trials. These early reports were followed by two double-blind, placebo-controlled, crossover studies of methylphenidate in children with autistic disorder.

• In the first trial,¹⁶ methylphenidate, 10 or 20 mg/d, improved irritability and hyperactivity in 10 children ages 7 to 11 but was only modestly more beneficial than placebo. Side-effect incidence—including decreased appetite, irritability, and insomnia—was similar during active and placebo treatments. Two patients required adjunctive haloperidol for prevailing behavioral problems.
• In the second trial,¹⁷ 8 of 13 children (62%) ages 5 to 11 responded to methylphenidate, 0.3 and 0.6 mg/kg per dose. Hyperactivity and inattention improved significantly, as measured by a minimum 50% decrease in Conners Hyperactivity Index score. Ratings of stereotypy and inappropriate speech also decreased, but no changes were seen in the Child Autism Rating Scale. Adverse effects, which were more common with the 0.6 mg/kg dose, included social withdrawal and irritability.

Retrospective trial. Our group recently completed a retrospective study of 195 youth (mean age, 7.3 years; range, 2 to 19 years) with PDDs treated with a stimulant medication.¹⁸ As a whole, stimulants appeared ineffective.

Analysis of response by PDD subtype found that individuals with Asperger’s disorder—in contrast to those with autistic disorder or PDD not otherwise specified—were significantly more likely to respond to a stimulant medication. Gender, intelligence quotient (IQ), type of stimulant, and dosage did not significantly affect response. Adverse effects—including agitation, dysphoria, and irritability—occurred in 57.5% of the trials.

Atomoxetine. This nonstimulant medication has been approved for treating ADHD. However, research is needed to understand its use in patients with PDDs (Box)¹⁹

Summary. These mixed findings—combined with anecdotal reports from physicians describing the onset or exacerbation of hyperactivity, irritability, and aggression—indicate that much more evidence is needed regarding psychostimulant use in patients with PDDs.

To help meet this need, the National Institutes of Mental Health’s Research Units on Pediatric Psychopharmacology (RUPP) autism network recently completed a large, double-blind, placebo-controlled study to investigate methylphenidate’s efficacy and tolerability in PDDs. It is anticipated that the results will help us discern whether factors such as PDD subtype, patient age, dosage, or degree of mental retardation are associated with response.

Related resources

• Autism Society of America. www.autism-society.org
• McDougle CJ. Current and emerging therapeutics of autistic disorder and related pervasive developmental disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: The fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, Charney DS, Leckman JF (eds). Pediatric psychopharmacology: Principles and practice.New York: Oxford University Press, 2002.

Drug brand names

• Atomoxetine • Strattera
• Clomipramine • Anafranil
• Clonidine • Catapres
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Guanfacine • Tenex
• Haloperidol • Haldol
• Levoamphetamine • Adderall
• Levodopa • Dopar, Laradopa
• Methylphenidate • Ritalin
• Olanzapine • Zyprexa
• Pemoline • Cylert
• Risperidone • Risperdal

Disclosure

Dr. Stigler reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Posey receives research support from Janssen Pharmaceutica and Eli Lilly and Co. and is a speaker for Janssen Pharmaceutica.

Dr. McDougle receives research support from Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., and Bristol-Myers Squibb Co. He is a consultant to or speaker for Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., RepliGen Corp., and Bristol-Myers Squibb Co.

Acknowledgments

This work was supported in part by a Daniel X. Freedman Psychiatric Research Fellowship Award (Dr. Posey), a National Alliance for Research in Schizophrenia and Depression (NARSAD) Young Investigator Award (Dr. Posey), a Research Units on Pediatric Psychopharmacology Grant (U10MH66766-02) from the National Institute of Mental Health (NIMH) to Indiana University (Dr. McDougle, Dr. Stigler, and Dr. Posey), a Research Career Development Award (K23-MH068627-01) from the NIMH (Dr. Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development (HUD) grant (B-01-SP-IN-0200) (Dr. McDougle).

Psychostimulants benefit many patients with attention-deficit/hyperactivity disorder (ADHD)¹ and thus might seem a logical choice to manage hyperactivity and inattention in youths with a pervasive developmental disorder (PDD). Some PDD patients do respond to psychostimulant therapy, but others worsen—and side effects are common.

Youths with PDDs often exhibit maladaptive behaviors—aggression, self-injury, irritability, hyperactivity, inattention—with repetitive activity patterns and fundamentally impaired social interaction and communication.² To help you treat youths with PDD, we draw on the evidence, clinical experience, and our research to suggest psychostimulants’ role in a multimodal approach.

Targeting hyperactivity and inattentions

Step 1. Our approach begins with behavioral therapy (Figure), which includes identifying situations that trigger maladaptive behavior and environments that yield optimum behavior. The therapist assesses the child’s baseline attention and works with him or her to gradually increase it, using reinforcement and visual token boards.

Algorithm Suggested approach to hyperactivity and/or inattention in patients with PDDs

Step 2. Many patients will not respond to behavior therapy alone and will require added drug therapy. Based on evidence, we suggest starting with an alpha-2 adrenergic agonist. Guanfacine may be considered the drug of choice because of clonidine’s higher risk of adverse effects, such as hypotension and sedation. Obtain a baseline ECG with either agent, as clonidine has been associated with rare cardiovascular events.

Clonidine. Two small studies showed that clonidine may be of some benefit to patients with PDDs:

• Results were mixed in a 6-week, double-blind, placebo-controlled, crossover study of clonidine (4 to 10 μg/kg/d) in 8 autistic children ages 5 to 13.³ Teacher and parent rating instruments reflected significantly improved hyperactivity, irritability, and oppositional behavior. Clinician ratings, however, showed no significant difference between clonidine and placebo. Adverse effects with clonidine included hypotension, sedation, and decreased activity.
• In a 4-week, double-blind, placebo-con-trolled, crossover study of transdermal clonidine (0.16 to 0.48 mg/kg/d; mean: 3.6 μg/kg/d), clinician ratings showed significantly decreased hyperactivity, impulsivity, and anxiety in 9 autistic males ages 5 to 33. Sedation and fatigue were common adverse effects.

Guanfacine. In a recent retrospective review,⁵ we examined outcomes of 80 PDD patients ages 3 to 18 who received guanfacine (0.25 to 9 mg/d; mean: 2.6). Hyperactivity, inattention, and tics decreased in 19 patients (24%) treated for a mean 10 months.

Step 3. If clonidine or guanfacine fails to reduce hyperactivity and inattention, discontinue it and consider a psychostimulant trial.

Because psychostimulants’ efficacy in PDDs remains inconclusive, we suggest beginning with a low dosage and carefully monitoring the patient for worsening target symptoms and activation, such as emerging aggression or irritability.

Step 4. If hyperactivity and inattention remain prominent and treatment-refractory, we suggest that you discontinue the stimulant and consider an atypical antipsychotic trial. With the atypicals, monitor patients closely for adverse effects, including weight gain, extrapyramidal symptoms, and tardive dyskinesia. Fasting serum glucose and lipid profiles and liver function tests are recommended at least every 6 months and more often in individuals at risk for diabetes or hepatic disease.

Two studies provide evidence of atypicals’ efficacy in PDDs:

• In a 6-week open-label comparison,⁶ olanzapine significantly reduced hyperactivity and anger or uncooperativeness in 12 children with autistic disorder, but haloperidol did not. Average weight gain was 9 lbs in patients receiving olanzapine vs 3.2 lbs in those receiving haloperidol.
• An 8-week, double-blind study⁷ compared risperidone (0.5 to 3.5 mg/d; mean: 1.8) with placebo in 101 children and adolescents with autistic disorder. Response rates were 69% in the risperidone group and 12% in the control group. Risperidone reduced hyperactivity, aggression, agitation, and repetitive behavior. Adverse drug effects included weight gain (2.7 kg vs. 0.8 kg with placebo), increased appetite, and sedation.

Psychostimulant use in PDDs

Evidence is conflicting on psychostimulant use in patients with PDDs (Table). Early reviews suggested that stimulants were ineffective in PDDs and associated with adverse effects.^8,9 Some preliminary studies supported that view, but recent reports have been mixed.

Dextroamphetamine. Campbell et al¹⁰ published a placebo-controlled study comparing triiodothyronine and dextroamphetamine (mean dosage, 4.8 mg/d; range 1.25 to 10 mg/d) in 16 children ages 3 to 6 (mean, 4.3 years) with diagnoses of autism, schizophrenia, and organic brain syndrome. All diagnostic groups worsened clinically with dextroamphetamine, and adverse effects—hyperactivity, worsened stereotypy, irritability, and decreased appetite—were common.

A subsequent case report¹¹ found dex-troamphetamine effective when 2 patients ages 9 and 12 with PDD were treated with 10 and 5 mg/d, respectively. Hyperactivity, inattention, and impulsivity improved in both patients, and core PDD features did not worsen.

Levoamphetamine. In an 8-week, double-blind, crossover comparison with levodopa,¹² levoamphetamine, 3.5 to 42 mg/d (mean, 13.4), worsened symptoms in 12 children ages 3 to 12 who had schizophrenia with autistic features. stereotypy emerged or increased in 9 of the 11 patients (82%) available for follow-up, and levoamphetamine was poorly tolerated.

Methylphenidate. In an early report, methylphenidate decreased hyperactivity and impulsivity in 9 of 15 children (60%) ages 2 to 13 with infantile autism.¹³ Dosages of 5 to 10 mg/d or 0.3 to 1 mg/kg/d were given for 2 to 60 weeks (mean, 26). Adverse effects included irritability, insomnia, and anorexia.

Table

Selected reports of stimulant use in pervasive developmental disorders

A subsequent open-label study and a case report also indicated that methylphenidate improved hyperactivity in patients with autistic disorder:

• In the 2-week, open-label study,¹⁴ 9 patients ages 4 to 16 received methylphenidate, 10 to 50 mg/d. Two patients also received haloperidol, 4 and 5 mg/d. Hyperactivity improved significantly, as measured by the Conners Teacher Questionnaire.
• In the case report,¹⁵ one child, age 6, was. treated with methylphenidate, 10 mg bid, for 31 days. The drug significantly alleviated hyperactivity and improved concentration. Adverse effects included dysphoria and outbursts of anger.

Box

Controlled trials. These early reports were followed by two double-blind, placebo-controlled, crossover studies of methylphenidate in children with autistic disorder.

• In the first trial,¹⁶ methylphenidate, 10 or 20 mg/d, improved irritability and hyperactivity in 10 children ages 7 to 11 but was only modestly more beneficial than placebo. Side-effect incidence—including decreased appetite, irritability, and insomnia—was similar during active and placebo treatments. Two patients required adjunctive haloperidol for prevailing behavioral problems.
• In the second trial,¹⁷ 8 of 13 children (62%) ages 5 to 11 responded to methylphenidate, 0.3 and 0.6 mg/kg per dose. Hyperactivity and inattention improved significantly, as measured by a minimum 50% decrease in Conners Hyperactivity Index score. Ratings of stereotypy and inappropriate speech also decreased, but no changes were seen in the Child Autism Rating Scale. Adverse effects, which were more common with the 0.6 mg/kg dose, included social withdrawal and irritability.

Retrospective trial. Our group recently completed a retrospective study of 195 youth (mean age, 7.3 years; range, 2 to 19 years) with PDDs treated with a stimulant medication.¹⁸ As a whole, stimulants appeared ineffective.

Analysis of response by PDD subtype found that individuals with Asperger’s disorder—in contrast to those with autistic disorder or PDD not otherwise specified—were significantly more likely to respond to a stimulant medication. Gender, intelligence quotient (IQ), type of stimulant, and dosage did not significantly affect response. Adverse effects—including agitation, dysphoria, and irritability—occurred in 57.5% of the trials.

Atomoxetine. This nonstimulant medication has been approved for treating ADHD. However, research is needed to understand its use in patients with PDDs (Box)¹⁹

Summary. These mixed findings—combined with anecdotal reports from physicians describing the onset or exacerbation of hyperactivity, irritability, and aggression—indicate that much more evidence is needed regarding psychostimulant use in patients with PDDs.

To help meet this need, the National Institutes of Mental Health’s Research Units on Pediatric Psychopharmacology (RUPP) autism network recently completed a large, double-blind, placebo-controlled study to investigate methylphenidate’s efficacy and tolerability in PDDs. It is anticipated that the results will help us discern whether factors such as PDD subtype, patient age, dosage, or degree of mental retardation are associated with response.

Related resources

• Autism Society of America. www.autism-society.org
• McDougle CJ. Current and emerging therapeutics of autistic disorder and related pervasive developmental disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: The fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, Charney DS, Leckman JF (eds). Pediatric psychopharmacology: Principles and practice.New York: Oxford University Press, 2002.

Drug brand names

• Atomoxetine • Strattera
• Clomipramine • Anafranil
• Clonidine • Catapres
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Guanfacine • Tenex
• Haloperidol • Haldol
• Levoamphetamine • Adderall
• Levodopa • Dopar, Laradopa
• Methylphenidate • Ritalin
• Olanzapine • Zyprexa
• Pemoline • Cylert
• Risperidone • Risperdal

Disclosure

Dr. Stigler reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Posey receives research support from Janssen Pharmaceutica and Eli Lilly and Co. and is a speaker for Janssen Pharmaceutica.

Dr. McDougle receives research support from Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., and Bristol-Myers Squibb Co. He is a consultant to or speaker for Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., RepliGen Corp., and Bristol-Myers Squibb Co.

Acknowledgments

This work was supported in part by a Daniel X. Freedman Psychiatric Research Fellowship Award (Dr. Posey), a National Alliance for Research in Schizophrenia and Depression (NARSAD) Young Investigator Award (Dr. Posey), a Research Units on Pediatric Psychopharmacology Grant (U10MH66766-02) from the National Institute of Mental Health (NIMH) to Indiana University (Dr. McDougle, Dr. Stigler, and Dr. Posey), a Research Career Development Award (K23-MH068627-01) from the NIMH (Dr. Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development (HUD) grant (B-01-SP-IN-0200) (Dr. McDougle).

As a psychiatrist specializing in college health, I see 40 to 50 young adults yearly with undiagnosed attention-deficit/hyperactivity disorder (ADHD). I have found that understanding five fundamentals of ADHD is key to recognizing this disorder in adults.

1. There is no “adult onset” ADHD. Although ADHD may manifest itself differently in adults than in children, studies indicate that the disorder is a continuation of childhood ADHD rather than a discrete adult disorder. Clinicians thus need to establish that adult patients exhibited symptomatic and functional impairment before age 7 (as per DSM-IV), although some experts suggest preadolescence as a cutoff.¹
2. Most people do not “outgrow” ADHD. We once assumed that most patients with ADHD became asymptomatic as they matured from adolescence into adulthood. Research reveals that hyperactivity and impulsivity decline over time but inattention and executive dysfunction usually persist into adulthood.² These residual deficits cause continued vocational, academic, and interpersonal difficulties.
3. ADHD can mimic other psychiatric disorders. The hyperkinesis, impulsivity, and inattention that are the essence of ADHD are also commonly observed in adults with anxiety disorders, mood disorders, substance abuse problems, and learning disorders. Patients who present with atypical affective or anxiety symptoms or learning problems, or who do not respond to conventional treatments, should be screened for ADHD.
4. The genetic apple does not fall far from the tree in ADHD. Many adults with ADHD are identified in middle age after their children are diagnosed. Adoption data and multiple twin studies have placed the heritability of ADHD at approximately 75%,³ putting first-degree relatives at fairly high predisposition.
5. Stimulant medications do not promote substance abuse in ADHD patients. Stimulant medication is more likely to reduce the risk of substance abuse in ADHD than enhance it.⁴ For patients at high-risk for substance abuse disorders, however, atomoxetine and bupropion offer nonstimulant alternatives. Also, the newer, longer-acting dextroamphetamine/amphetamine and methylphenidate preparations are more difficult to abuse because of their slow-release mechanisms.

As a psychiatrist specializing in college health, I see 40 to 50 young adults yearly with undiagnosed attention-deficit/hyperactivity disorder (ADHD). I have found that understanding five fundamentals of ADHD is key to recognizing this disorder in adults.

1. There is no “adult onset” ADHD. Although ADHD may manifest itself differently in adults than in children, studies indicate that the disorder is a continuation of childhood ADHD rather than a discrete adult disorder. Clinicians thus need to establish that adult patients exhibited symptomatic and functional impairment before age 7 (as per DSM-IV), although some experts suggest preadolescence as a cutoff.¹
2. Most people do not “outgrow” ADHD. We once assumed that most patients with ADHD became asymptomatic as they matured from adolescence into adulthood. Research reveals that hyperactivity and impulsivity decline over time but inattention and executive dysfunction usually persist into adulthood.² These residual deficits cause continued vocational, academic, and interpersonal difficulties.
3. ADHD can mimic other psychiatric disorders. The hyperkinesis, impulsivity, and inattention that are the essence of ADHD are also commonly observed in adults with anxiety disorders, mood disorders, substance abuse problems, and learning disorders. Patients who present with atypical affective or anxiety symptoms or learning problems, or who do not respond to conventional treatments, should be screened for ADHD.
4. The genetic apple does not fall far from the tree in ADHD. Many adults with ADHD are identified in middle age after their children are diagnosed. Adoption data and multiple twin studies have placed the heritability of ADHD at approximately 75%,³ putting first-degree relatives at fairly high predisposition.
5. Stimulant medications do not promote substance abuse in ADHD patients. Stimulant medication is more likely to reduce the risk of substance abuse in ADHD than enhance it.⁴ For patients at high-risk for substance abuse disorders, however, atomoxetine and bupropion offer nonstimulant alternatives. Also, the newer, longer-acting dextroamphetamine/amphetamine and methylphenidate preparations are more difficult to abuse because of their slow-release mechanisms.

As a psychiatrist specializing in college health, I see 40 to 50 young adults yearly with undiagnosed attention-deficit/hyperactivity disorder (ADHD). I have found that understanding five fundamentals of ADHD is key to recognizing this disorder in adults.

1. There is no “adult onset” ADHD. Although ADHD may manifest itself differently in adults than in children, studies indicate that the disorder is a continuation of childhood ADHD rather than a discrete adult disorder. Clinicians thus need to establish that adult patients exhibited symptomatic and functional impairment before age 7 (as per DSM-IV), although some experts suggest preadolescence as a cutoff.¹
2. Most people do not “outgrow” ADHD. We once assumed that most patients with ADHD became asymptomatic as they matured from adolescence into adulthood. Research reveals that hyperactivity and impulsivity decline over time but inattention and executive dysfunction usually persist into adulthood.² These residual deficits cause continued vocational, academic, and interpersonal difficulties.
3. ADHD can mimic other psychiatric disorders. The hyperkinesis, impulsivity, and inattention that are the essence of ADHD are also commonly observed in adults with anxiety disorders, mood disorders, substance abuse problems, and learning disorders. Patients who present with atypical affective or anxiety symptoms or learning problems, or who do not respond to conventional treatments, should be screened for ADHD.
4. The genetic apple does not fall far from the tree in ADHD. Many adults with ADHD are identified in middle age after their children are diagnosed. Adoption data and multiple twin studies have placed the heritability of ADHD at approximately 75%,³ putting first-degree relatives at fairly high predisposition.
5. Stimulant medications do not promote substance abuse in ADHD patients. Stimulant medication is more likely to reduce the risk of substance abuse in ADHD than enhance it.⁴ For patients at high-risk for substance abuse disorders, however, atomoxetine and bupropion offer nonstimulant alternatives. Also, the newer, longer-acting dextroamphetamine/amphetamine and methylphenidate preparations are more difficult to abuse because of their slow-release mechanisms.

Methylphenidate and other amphetamine-based agents are mainstays in treating attention-deficit/hyperactivity disorder (ADHD). Although these stimulants are considered safe, their potentially addictive properties have concerned clinicians, adult patients, and parents of children and adolescents with ADHD.

Table

Atomoxetine: fast facts

Atomoxetine—a nonaddictive, nonstimulant medication—has demonstrated efficacy in placebo-controlled trials.

HOW IT WORKS

Atomoxetine enhances synaptic concentrations of norepinephrine via the presynaptic transporter. The agent has a strong affinity with norepinephrine transporters, modest affinity with serotonin transporters, and no affinity with dopamine transporters.¹

When applied directly to the prefrontal cortex, however, atomoxetine has been shown to increase both extracellular norepinephrine and dopamine. Sustained levels of norepinephrine and dopamine in the prefrontal cortex may explain why atomoxetine works well beyond its 5.3-hour biologic half-life.¹

In contrast, methylphenidate has shown high affinity with dopamine transporters. It produces intense, brief prefrontal increases in norepinephrine and dopamine and sustained dopamine increases in the nucleus accumbens and striatum.² This might explain methylphenidate’s rewarding properties and its association with stereotypic motor activity and tics. By comparison, atomoxetine has a lower abuse potential and does not affect basal ganglia motor output.³

Atomoxetine’s pharmacokinetics have been evaluated in more than 400 children and adolescents. Its half-life, clearance (0.35 L/hr/kg), and volume of distribution are similar across age groups, and the dose-plasma concentration relationship is linear, suggesting that dosing can be reliably adjusted according to weight. Atomoxetine is rapidly absorbed, food does not appreciably affect absorption, and peak plasma concentrations are achieved within 1 to 2 hours. The drug is distributed mostly in total body water and is highly protein bound.

Atomoxetine is metabolized primarily through the cytochrome P (CYP)-450 2D6 pathway. The major metabolite is 4-hydroxyatomoxetine, which is equipotent to atomoxetine as a norepinephrine transporter inhibitor.

WHAT RESEARCHERS SAY

In an 8-week study, 297 patients ages 8 to 18 received a divided fixed dosage of atomoxetine (0.5, 1.2 or 1.8 mg/kg/d) or placebo. The 1.2 and 1.8 mg/kg/d dosages were more effective than placebo and were equally effective against hyperactivity/impulsivity and inattention symptoms. The 0.5 mg/kg/d dosage was not much more effective than placebo.⁴

In a 6-week, placebo-controlled study, 85 subjects ages 6 to 16 who received a single dose of atomoxetine each morning (mean dosage 1.3 mg/kg/d) achieved favorable outcomes based on investigator, parent, and teacher ratings and on an ADHD Rating Scale (ADHD-RS) primary outcome measure. The treatment effect size (0.71) was similar to that found in the twice-daily dosing studies, suggesting that single-daily dosing is effective.⁵

Box

Two controlled, comparison studies involving 291 subjects ages 7 to 13 with ADHD found that atomoxetine (mean final dosage 1.6 mg/kg/d) compares favorably to methylphenidate with similar effect sizes across ADHD symptom domains (unpublished data). Limited published data indicate that randomized, open-label atomoxetine and methylphenidate are similarly effective across ADHD symptom domains in children.⁶

Atomoxetine also was shown to improve ADHD symptoms in two placebo-controlled trials involving a total of 536 adults (mean daily divided dose 95 mg).⁷ Inattention, hyperactivity, and impulsivity—as measured with the Conners Adult ADHD Rating Scale—were reduced among both treatment groups.

DOSING AND ADMINISTRATION

No age- or gender-related differences in response to atomoxetine have been reported, although dosing varies with age and weight (Box).

The agent should be used cautiously in patients with cardiovascular or cerebrovascular disease, as side effects include slight elevation of pulse and blood pressure. Atomoxetine also may exacerbate urinary retention or hesitation in some adults. The drug may impair sexual function; at least 7% of men in placebo-controlled trials experienced erectile disturbance, and 3% experienced impotence.⁷

In children and adolescents, gastrointestinal discomfort, asthenia, fatigue, mild appetite decreases, and slight weight loss were reported adverse effects.⁵ Nausea and vomiting were the most troublesome acute side effects in children, with most episodes lasting 1 to 2 days.⁵

CLINICAL IMPLICATIONS

Atomoxetine may help patients with ADHD who respond inadequately or do not respond to stimulants. Its lack of abuse potential suggests it may be useful in adults with comorbid substance use disorders. Atomoxetine also does not appear to exacerbate insomnia—a potential benefit for ADHD patients with poor sleep quality.

Given its pharmacologic profile, the agent will reduce the impact of comorbidities (such as anxiety and depression) common to adults with ADHD. Research is needed to determine its role in treating more complicated pathologies, such as ADHD with comorbid bipolar disorder.

Whereas some stimulants require multiple daily dosing, atomoxetine is administered once daily. This could save clinicians time by reducing the need for refills, out-of-visit prescribing, and monthly patient visits (our pediatric practice writes 20 to 40 stimulant refills per day)and enhance convenience for patients.

Related resources

• Spencer T, Biederman J, Wilens T, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998;155:693-5.

Drug Brand Names

• Methylphenidate • Concerta, Ritalin

Disclosure

The author receives research/grant support from and is a consultant to and speaker for Eli Lilly and Co. He also receives research/grant support from Shire Pharmaceuticals and Johnson & Johnson, and is a consultant to Abbott Laboratories, Merck and Co., Pfizer Inc., and Organon.

Methylphenidate and other amphetamine-based agents are mainstays in treating attention-deficit/hyperactivity disorder (ADHD). Although these stimulants are considered safe, their potentially addictive properties have concerned clinicians, adult patients, and parents of children and adolescents with ADHD.

Table

Atomoxetine: fast facts

Atomoxetine—a nonaddictive, nonstimulant medication—has demonstrated efficacy in placebo-controlled trials.

HOW IT WORKS

Atomoxetine enhances synaptic concentrations of norepinephrine via the presynaptic transporter. The agent has a strong affinity with norepinephrine transporters, modest affinity with serotonin transporters, and no affinity with dopamine transporters.¹

When applied directly to the prefrontal cortex, however, atomoxetine has been shown to increase both extracellular norepinephrine and dopamine. Sustained levels of norepinephrine and dopamine in the prefrontal cortex may explain why atomoxetine works well beyond its 5.3-hour biologic half-life.¹

In contrast, methylphenidate has shown high affinity with dopamine transporters. It produces intense, brief prefrontal increases in norepinephrine and dopamine and sustained dopamine increases in the nucleus accumbens and striatum.² This might explain methylphenidate’s rewarding properties and its association with stereotypic motor activity and tics. By comparison, atomoxetine has a lower abuse potential and does not affect basal ganglia motor output.³

Atomoxetine’s pharmacokinetics have been evaluated in more than 400 children and adolescents. Its half-life, clearance (0.35 L/hr/kg), and volume of distribution are similar across age groups, and the dose-plasma concentration relationship is linear, suggesting that dosing can be reliably adjusted according to weight. Atomoxetine is rapidly absorbed, food does not appreciably affect absorption, and peak plasma concentrations are achieved within 1 to 2 hours. The drug is distributed mostly in total body water and is highly protein bound.

Atomoxetine is metabolized primarily through the cytochrome P (CYP)-450 2D6 pathway. The major metabolite is 4-hydroxyatomoxetine, which is equipotent to atomoxetine as a norepinephrine transporter inhibitor.

WHAT RESEARCHERS SAY

In an 8-week study, 297 patients ages 8 to 18 received a divided fixed dosage of atomoxetine (0.5, 1.2 or 1.8 mg/kg/d) or placebo. The 1.2 and 1.8 mg/kg/d dosages were more effective than placebo and were equally effective against hyperactivity/impulsivity and inattention symptoms. The 0.5 mg/kg/d dosage was not much more effective than placebo.⁴

In a 6-week, placebo-controlled study, 85 subjects ages 6 to 16 who received a single dose of atomoxetine each morning (mean dosage 1.3 mg/kg/d) achieved favorable outcomes based on investigator, parent, and teacher ratings and on an ADHD Rating Scale (ADHD-RS) primary outcome measure. The treatment effect size (0.71) was similar to that found in the twice-daily dosing studies, suggesting that single-daily dosing is effective.⁵

Box

Two controlled, comparison studies involving 291 subjects ages 7 to 13 with ADHD found that atomoxetine (mean final dosage 1.6 mg/kg/d) compares favorably to methylphenidate with similar effect sizes across ADHD symptom domains (unpublished data). Limited published data indicate that randomized, open-label atomoxetine and methylphenidate are similarly effective across ADHD symptom domains in children.⁶

Atomoxetine also was shown to improve ADHD symptoms in two placebo-controlled trials involving a total of 536 adults (mean daily divided dose 95 mg).⁷ Inattention, hyperactivity, and impulsivity—as measured with the Conners Adult ADHD Rating Scale—were reduced among both treatment groups.

DOSING AND ADMINISTRATION

No age- or gender-related differences in response to atomoxetine have been reported, although dosing varies with age and weight (Box).

The agent should be used cautiously in patients with cardiovascular or cerebrovascular disease, as side effects include slight elevation of pulse and blood pressure. Atomoxetine also may exacerbate urinary retention or hesitation in some adults. The drug may impair sexual function; at least 7% of men in placebo-controlled trials experienced erectile disturbance, and 3% experienced impotence.⁷

In children and adolescents, gastrointestinal discomfort, asthenia, fatigue, mild appetite decreases, and slight weight loss were reported adverse effects.⁵ Nausea and vomiting were the most troublesome acute side effects in children, with most episodes lasting 1 to 2 days.⁵

CLINICAL IMPLICATIONS

Atomoxetine may help patients with ADHD who respond inadequately or do not respond to stimulants. Its lack of abuse potential suggests it may be useful in adults with comorbid substance use disorders. Atomoxetine also does not appear to exacerbate insomnia—a potential benefit for ADHD patients with poor sleep quality.

Given its pharmacologic profile, the agent will reduce the impact of comorbidities (such as anxiety and depression) common to adults with ADHD. Research is needed to determine its role in treating more complicated pathologies, such as ADHD with comorbid bipolar disorder.

Whereas some stimulants require multiple daily dosing, atomoxetine is administered once daily. This could save clinicians time by reducing the need for refills, out-of-visit prescribing, and monthly patient visits (our pediatric practice writes 20 to 40 stimulant refills per day)and enhance convenience for patients.

Related resources

• Spencer T, Biederman J, Wilens T, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998;155:693-5.

Drug Brand Names

• Methylphenidate • Concerta, Ritalin

Disclosure

The author receives research/grant support from and is a consultant to and speaker for Eli Lilly and Co. He also receives research/grant support from Shire Pharmaceuticals and Johnson & Johnson, and is a consultant to Abbott Laboratories, Merck and Co., Pfizer Inc., and Organon.

Methylphenidate and other amphetamine-based agents are mainstays in treating attention-deficit/hyperactivity disorder (ADHD). Although these stimulants are considered safe, their potentially addictive properties have concerned clinicians, adult patients, and parents of children and adolescents with ADHD.

Table

Atomoxetine: fast facts

Atomoxetine—a nonaddictive, nonstimulant medication—has demonstrated efficacy in placebo-controlled trials.

HOW IT WORKS

Atomoxetine enhances synaptic concentrations of norepinephrine via the presynaptic transporter. The agent has a strong affinity with norepinephrine transporters, modest affinity with serotonin transporters, and no affinity with dopamine transporters.¹

When applied directly to the prefrontal cortex, however, atomoxetine has been shown to increase both extracellular norepinephrine and dopamine. Sustained levels of norepinephrine and dopamine in the prefrontal cortex may explain why atomoxetine works well beyond its 5.3-hour biologic half-life.¹

In contrast, methylphenidate has shown high affinity with dopamine transporters. It produces intense, brief prefrontal increases in norepinephrine and dopamine and sustained dopamine increases in the nucleus accumbens and striatum.² This might explain methylphenidate’s rewarding properties and its association with stereotypic motor activity and tics. By comparison, atomoxetine has a lower abuse potential and does not affect basal ganglia motor output.³

Atomoxetine’s pharmacokinetics have been evaluated in more than 400 children and adolescents. Its half-life, clearance (0.35 L/hr/kg), and volume of distribution are similar across age groups, and the dose-plasma concentration relationship is linear, suggesting that dosing can be reliably adjusted according to weight. Atomoxetine is rapidly absorbed, food does not appreciably affect absorption, and peak plasma concentrations are achieved within 1 to 2 hours. The drug is distributed mostly in total body water and is highly protein bound.

Atomoxetine is metabolized primarily through the cytochrome P (CYP)-450 2D6 pathway. The major metabolite is 4-hydroxyatomoxetine, which is equipotent to atomoxetine as a norepinephrine transporter inhibitor.

WHAT RESEARCHERS SAY

In an 8-week study, 297 patients ages 8 to 18 received a divided fixed dosage of atomoxetine (0.5, 1.2 or 1.8 mg/kg/d) or placebo. The 1.2 and 1.8 mg/kg/d dosages were more effective than placebo and were equally effective against hyperactivity/impulsivity and inattention symptoms. The 0.5 mg/kg/d dosage was not much more effective than placebo.⁴

In a 6-week, placebo-controlled study, 85 subjects ages 6 to 16 who received a single dose of atomoxetine each morning (mean dosage 1.3 mg/kg/d) achieved favorable outcomes based on investigator, parent, and teacher ratings and on an ADHD Rating Scale (ADHD-RS) primary outcome measure. The treatment effect size (0.71) was similar to that found in the twice-daily dosing studies, suggesting that single-daily dosing is effective.⁵

Box

Two controlled, comparison studies involving 291 subjects ages 7 to 13 with ADHD found that atomoxetine (mean final dosage 1.6 mg/kg/d) compares favorably to methylphenidate with similar effect sizes across ADHD symptom domains (unpublished data). Limited published data indicate that randomized, open-label atomoxetine and methylphenidate are similarly effective across ADHD symptom domains in children.⁶

Atomoxetine also was shown to improve ADHD symptoms in two placebo-controlled trials involving a total of 536 adults (mean daily divided dose 95 mg).⁷ Inattention, hyperactivity, and impulsivity—as measured with the Conners Adult ADHD Rating Scale—were reduced among both treatment groups.

DOSING AND ADMINISTRATION

No age- or gender-related differences in response to atomoxetine have been reported, although dosing varies with age and weight (Box).

The agent should be used cautiously in patients with cardiovascular or cerebrovascular disease, as side effects include slight elevation of pulse and blood pressure. Atomoxetine also may exacerbate urinary retention or hesitation in some adults. The drug may impair sexual function; at least 7% of men in placebo-controlled trials experienced erectile disturbance, and 3% experienced impotence.⁷

In children and adolescents, gastrointestinal discomfort, asthenia, fatigue, mild appetite decreases, and slight weight loss were reported adverse effects.⁵ Nausea and vomiting were the most troublesome acute side effects in children, with most episodes lasting 1 to 2 days.⁵

CLINICAL IMPLICATIONS

Atomoxetine may help patients with ADHD who respond inadequately or do not respond to stimulants. Its lack of abuse potential suggests it may be useful in adults with comorbid substance use disorders. Atomoxetine also does not appear to exacerbate insomnia—a potential benefit for ADHD patients with poor sleep quality.

Given its pharmacologic profile, the agent will reduce the impact of comorbidities (such as anxiety and depression) common to adults with ADHD. Research is needed to determine its role in treating more complicated pathologies, such as ADHD with comorbid bipolar disorder.

Whereas some stimulants require multiple daily dosing, atomoxetine is administered once daily. This could save clinicians time by reducing the need for refills, out-of-visit prescribing, and monthly patient visits (our pediatric practice writes 20 to 40 stimulant refills per day)and enhance convenience for patients.

Related resources

• Spencer T, Biederman J, Wilens T, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998;155:693-5.

Drug Brand Names

• Methylphenidate • Concerta, Ritalin

Disclosure

The author receives research/grant support from and is a consultant to and speaker for Eli Lilly and Co. He also receives research/grant support from Shire Pharmaceuticals and Johnson & Johnson, and is a consultant to Abbott Laboratories, Merck and Co., Pfizer Inc., and Organon.

Should you prescribe a stimulant to treat attention and hyperactivity problems in teenagers and adults with a history of substance abuse? Evidence suggests that using a stimulant to treat attention-deficit/hyperactivity disorder (ADHD) may place such patients at risk for stimulant abuse or for relapse into abuse of other substances. But a stimulant may be the only option for patients whose ADHD symptoms do not respond to alternate medications, such as antidepressants.

Growing numbers of adults are being treated for ADHD. Because substance abuse problems are common in adults with ADHD (Box 1 ),^1-3 prescribing an antidepressant instead of a stimulant in some cases may be prudent. Consider the following factors when choosing ADHD therapy for patients with a history of substance abuse.

Prevalence of stimulant use and abuse

In the United States, more than 95% of medications prescribed for children and adults with ADHD are stimulants—usually methylphenidate.⁴ Stimulant use has increased as more children and adults are diagnosed with ADHD. Methylphenidate prescriptions increased five-fold from 1990 to 1995.⁵ Visits to psychiatrists and physicians that included stimulant prescriptions grew from 570,000 to 2.86 million from 1985 to 1994, with most of that increase occurring during visits to primary care and other physicians.⁶

When used as prescribed, methylphenidate is safe and effective for treating most children and adults with ADHD. Methylphenidate’s pharmacologic properties, however, are similar to those of amphetamines and cocaine (Box 2, Figure 1),^7,8 which is why methylphenidate is a schedule-II controlled substance.

Published data. Fifteen reports of methylphenidate abuse were published in the medical literature between 1960 and 1999,⁷ but little is known about the prevalence of stimulant abuse among patients with ADHD. Banov and colleagues recently published what may be the only data available, when they reported that 3 of 37 (8%) patients abused the stimulants they were prescribed for ADHD.⁹ The three patients who abused stimulants had histories of drug and alcohol abuse at study entry. In all three cases, stimulant abuse did not develop immediately but became apparent within 6 months after the study began.

In a study of 651 students ages 11 to 18 in Wisconsin and Minnesota, more than one-third of those taking stimulants reported being asked to sell or trade their medications. More than one-half of those not taking ADHD medications said they knew someone who sold or gave away his or her medication.¹⁰

Stimulant theft, recreational use. Methylphenidate has been identified as the third most abused prescribed substance in the United States.¹¹ It was the 10th most frequently stolen controlled drug from pharmacies between 1990 and 1995, and 700,000 dosage units were reported stolen in 1996 and 1997.¹²

Box 1

The popular media have reported recreational use of methylphenidate—with street names such as “R-Ball” and “Vitamin R”—among teens and college students.¹³ Illegal stimulants are perceived to be easily accessible on college campuses, but no data have been reported.

The use of stimulant medication for ADHD patients with substance abuse problems remains controversial. For such patients, this author reserves stimulant medication for those:

• whose ADHD symptoms have not responded adequately to alternate treatments
• who have been reliable with prescription medications
• and whose functional level is seriously impaired by their ADHD.

Antidepressants vs. stimulants

Although few well-designed controlled studies have been published, four antidepressants appear to be reasonably equivalent in effectiveness for adults with ADHD and do not carry potential for stimulant abuse.¹⁴

Desipraime, bupropion, venlafaxine, and the experimental drug atomoxetine (Table 1) all increase norepinephrine at the synapse by inhibiting presynaptic reuptake. Though dopamine has traditionally been considered the neurotransmitter of choice for ADHD treatment, norepinephrine may be equally potent.

Impulse control center. Several lines of research have recently established a connection between the prefrontal cortex, norepinephrine, and ADHD.¹⁵ This evidence suggests that the prefrontal cortex plays a major role in inhibiting impulses and responses to distractions:

Box 2

HOW STIMULANTS—THERAPEUTIC OR ILLICIT—AFFECT THE BRAIN

Figure 1

PET scans of the brain using carbon 11 (¹¹C)-labeled cocaine and methylphenidate HCl show similar distributions in the striatium when the drugs are administered intravenously.

Source: Reproduced with permission from Volkow ND, Ding YS, Fowler JS, et al. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry 1995;52:456-63.

Stimulants are classified as schedule-II drugs because they produce powerful reinforcing effects by increasing synaptic dopamine.⁷ Positron-emission tomography (PET) scans using carbon labeling have shown similar distributions of methylphenidate and cocaine in the brain (Figure 1).⁸ When administered intravenously, both drugs occupy the same receptors in the striatum and produce a “high” that parallels rapid neuronal uptake. Methylphenidate and cocaine similarly increase stimulation of the postsynaptic neuron by blocking the dopamine reuptake pump (dopamine transporter).

How a substance gets to the brain’s euphoric receptors greatly affects its addictive properties. Delivery systems with rapid onset—smoking, “snorting,” or IV injection—have much greater ability to produce a “high” than do oral or transdermal routes. The greater the “high,” the greater the potential for abuse.

Because methylphenidate is prescribed for oral use, the potential for abuse is minimal. However, we need to be extremely cautious when giving methylphenidate or similar stimulant medications to patients who have shown they are unable to control their abuse of other substances.

Stimulants can also re-ignite a dormant substance abuse problem. Though little has been written about this in the medical literature, Elizabeth Wurtzel, author of the controversial Prozac Nation, chronicles the resumption of her cocaine abuse in More, Now, Again: A Memoir of Addiction. She contends that after her doctor added methylphenidate to augment treatment of partially remitting depression, she began abusing it and eventually was using 40 tablets per day before slipping back into cocaine dependence.

• Patients with prefrontal cortex deficits can have problems with inattention and poor impulse control.
• Patients with ADHD have frontal lobe impairments, as neuropsychological testing and imaging studies have shown.
• Norepinephrine neurons, with cell bodies in the locus coeruleus, have projections that terminate in the prefrontal cortex.
• Agents with norepinephrine activity, but without mood-altering properties (e.g., clonidine), have been shown to improve ADHD symptoms.

Table 1

ADHD IN ADULTS: ANTIDEPRESSANT DOSAGES AND SIDE EFFECTS

Additional evidence suggests that the prefrontal cortex has projections back to the locus coeruleus, which may explain the relationship between the two areas. It may be that the brain’s higher-functioning areas, such as the prefrontal cortex, provide intelligent screening of impulses from the brain’s older areas, such as the locus coeruleus. Therefore, increased prefrontal cortex activity may modulate some impulses that ADHD patients cannot control otherwise.

No ‘high’ with antidepressants. Patients with ADHD who have experienced the powerful effects of street drugs such as cocaine, methamphetamine, or even alcohol may report that antidepressants do not provide the effect they desire. It is difficult to know if these patients are reporting a lack of benefit or simply the absence of a euphoric “high” they are used to experiencing with substances of abuse. The newer antidepressants do not activate the brain’s euphoric receptors to an appreciable degree.

Patients who take stimulants as prescribed also do not report a “high” but can detect the medication’s presence and absence. Most do not crave this feeling, but substance abusers tend to like it. A patient recently told me he didn’t think stimulants improved his ADHD, but said, “I just liked the way they made me feel.”

Desipramine

The tricyclic antidepressant desipramine is a potent norepinephrine reuptake inhibitor that is effective in treating ADHD in children and adults. In a double-blind, placebo-controlled study of adults with ADHD, subjects receiving desipramine showed robust improvement in symptom scores on the ADHD Rating Scale,¹⁶ compared with those receiving the placebo (Figure 2).¹⁷

During the 6-week trial, 41 adults with ADHD received desipramine, 200 mg/d, or a placebo. Those receiving desipramine showed significant improvement in 12 of 14 ADHD symptoms and less hyperactivity, impulsivity, and inattentiveness, whereas those receiving the placebo showed no improvement. According to the study criteria, 68% of those who received desipramine and none who received the placebo were considered positive responders.

Though no head-to-head studies have compared desipramine with methylphenidate, the same researchers conducted a similar placebo-controlled study with methylphenidate. The 6-week symptom score on the ADHD Rating Scale was 12.5 for methylphenidate, compared with a score of 12 for desipramine.¹⁸

Recommendation. Desipramine may be the most effective of the antidepressant treatments for patients with ADHD. Because of its side effects, however, it is not this author’s first choice and is usually reserved for patients whose symptoms fail to respond to other antidepressants. Desipramine can cause sedation, dry mouth, and constipation, which are related to blockade of adrenergic, histamine, and muscarinic cholinergic receptors. It also can be lethal in overdose.

Some substance abusers lose confidence in a medication that they cannot feel working. The side effects of desipramine, which can be intolerable for some patients, can reassure others with a history of substance abuse that they are being medicated.

Bupropion

Bupropion is a unique antidepressant that inhibits the presynaptic reuptake of dopamine and norepinephrine. Open-label studies demonstrate good responses to bupropion by adults with ADHD. One placebo-controlled, double-blind study found improved ADHD symptoms in 76% of patients receiving bupropion SR, compared with 37% of those receiving a placebo; the difference was statistically significant.¹⁹

Figure 2 IMPROVED ADHD SYMPTOMS WITH DESIPRAMINE

Adults with ADHD who received desipramine, 200 mg/d, in a double-blind trial showed significantly less hyperactivity, impulsivity, and inattentiveness after 6 weeks of therapy than a control group that received a placebo.

Source: Adapted with permission from Wilens TE, Biederman J, Prince J, et al. Six-week, double-blind, placebo-controlled study of desipramine for adult attention-deficit/hyperactivity disorder. Am J Psychiatry 1996;153:1147-53.Another study of adults with ADHD compared bupropion SR to methylphenidate and a placebo.²⁰ Using a primary outcome of the Clinical Global Impression (CGI) scale, response rates were 64% for bupropion SR, 50% for methylphenidate, and 27% for the placebo. The difference in response rates between the two agents was not statistically significant (p = 0.14).

Recommendation. The risk of seizures with bupropion is about 1 in 1,000. Therefore, bupropion should not be given to patients with a seizure disorder or to those with conditions that alter the seizure threshold (e.g., eating disorders, recent head trauma, or benzodiazepine withdrawal).²¹

This author uses bupropion as first-line treatment for appropriate patients with ADHD and a substance abuse history. Bupropion’s mild benefit with smoking cessation may provide some crossover effect for other substances of abuse. The low incidence of sexual side effects is another benefit. Drawbacks include twice-daily dosing and lack of a robust effect on attention and concentration.

Venlafaxine

Venlafaxine is a potent inhibitor of serotonin reuptake, a moderate inhibitor of norepinephrine, and a mild inhibitor of dopamine. Venlafaxine has displayed response rates similar to those of desipramine and bupropion in open-label studies in adults with ADHD,¹⁴ but no placebo-controlled studies exist.

As noted above, these antidepressants are believed to improve ADHD symptoms by making norepinephrine more available at the synapse. Hypothetically, then, one would need to administer venlafaxine at dosages that adequately inhibit the norepinephrine reuptake receptor. Venlafaxine XR, 150 mg/d, provides significant norepinephrine activity, according to several lines of evidence.

Recently, Upadhyaya et al reported the use of venlafaxine in one of the few treatment studies of patients with ADHD and comorbid alcohol/cocaine abuse. In an open-label trial, 10 subjects received venlafaxine, up to 300 mg/d, along with psychotherapy and attendance at Alcoholics Anonymous meetings. The nine who completed 4 weeks of treatment showed significantly improved ADHD symptoms and decreased alcohol craving.²²

Recommendation. Venlafaxine is this author’s second choice for patients with ADHD and substance abuse problems. Sexual side effects that some patients experience with venlafaxine can limit its use. Some clinicians are concerned about increases in blood pressure associated with venlafaxine, although significant changes do not seem to occur at dosages below 300 mg/d.²³

Atomoxetine

Atomoxetine is an investigational antidepressant in phase-III trials as a treatment for ADHD. Evidence shows atomoxetine to be a potent inhibitor of the presynaptic norepinephrine transporter, with minimal affinity for other neurotransmitter receptors. Initial studies suggest that atomoxetine is effective for adults and children with ADHD:

• In a small, double-blind, placebo-controlled, crossover trial, 11 of 20 adults showed improvement in ADHD symptoms within 3 weeks of starting atomoxetine.²⁴
• In 297 children and adolescents, atomoxetine at dosages averaging approximately 1.2 mg/kg/d was more effective than a placebo in reducing ADHD symptoms and improving social and family functioning. Treatment was well tolerated and without significant side effects.²⁵
• In a randomized open-label trial, 228 children received atomoxetine or methylphenidate. Both treatments significantly reduced inattention and hyperactive/impulsive symptoms.²⁶

Related resources

• Arnsten AF. Genetics of childhood disorders (XVIII). ADHD, Part 2: Norepinephrine has a critical modulatory influence on prefrontal cortical function. J Am Acad Child Adolesc Psychiatry. 2000;39:1201-3.
• Ward MF, Wender PH, Reimherr FW. The Wender Utah Rating Scale: An aid in the retrospective diagnosis of childhood attention-deficit/hyperactivity disorder. Am J Psychiatry. 1993;150:885-90.
• Research Report: Prescription Drugs—abuse and addiction. National Institute on Drug Abuse, Substance Abuse and Mental Health Services Administration.

Drug brand names

• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Methylphenidate • Ritalin, Concerta
• Venlafaxine • Effexor

Disclosure

Dr. Higgins reports that he is on the speakers’ bureaus for Wyeth-Ayerst Pharmaceuticals and Eli Lilly and Co.

Should you prescribe a stimulant to treat attention and hyperactivity problems in teenagers and adults with a history of substance abuse? Evidence suggests that using a stimulant to treat attention-deficit/hyperactivity disorder (ADHD) may place such patients at risk for stimulant abuse or for relapse into abuse of other substances. But a stimulant may be the only option for patients whose ADHD symptoms do not respond to alternate medications, such as antidepressants.

Growing numbers of adults are being treated for ADHD. Because substance abuse problems are common in adults with ADHD (Box 1 ),^1-3 prescribing an antidepressant instead of a stimulant in some cases may be prudent. Consider the following factors when choosing ADHD therapy for patients with a history of substance abuse.

Prevalence of stimulant use and abuse

In the United States, more than 95% of medications prescribed for children and adults with ADHD are stimulants—usually methylphenidate.⁴ Stimulant use has increased as more children and adults are diagnosed with ADHD. Methylphenidate prescriptions increased five-fold from 1990 to 1995.⁵ Visits to psychiatrists and physicians that included stimulant prescriptions grew from 570,000 to 2.86 million from 1985 to 1994, with most of that increase occurring during visits to primary care and other physicians.⁶

When used as prescribed, methylphenidate is safe and effective for treating most children and adults with ADHD. Methylphenidate’s pharmacologic properties, however, are similar to those of amphetamines and cocaine (Box 2, Figure 1),^7,8 which is why methylphenidate is a schedule-II controlled substance.

Published data. Fifteen reports of methylphenidate abuse were published in the medical literature between 1960 and 1999,⁷ but little is known about the prevalence of stimulant abuse among patients with ADHD. Banov and colleagues recently published what may be the only data available, when they reported that 3 of 37 (8%) patients abused the stimulants they were prescribed for ADHD.⁹ The three patients who abused stimulants had histories of drug and alcohol abuse at study entry. In all three cases, stimulant abuse did not develop immediately but became apparent within 6 months after the study began.

In a study of 651 students ages 11 to 18 in Wisconsin and Minnesota, more than one-third of those taking stimulants reported being asked to sell or trade their medications. More than one-half of those not taking ADHD medications said they knew someone who sold or gave away his or her medication.¹⁰

Stimulant theft, recreational use. Methylphenidate has been identified as the third most abused prescribed substance in the United States.¹¹ It was the 10th most frequently stolen controlled drug from pharmacies between 1990 and 1995, and 700,000 dosage units were reported stolen in 1996 and 1997.¹²

Box 1

The popular media have reported recreational use of methylphenidate—with street names such as “R-Ball” and “Vitamin R”—among teens and college students.¹³ Illegal stimulants are perceived to be easily accessible on college campuses, but no data have been reported.

The use of stimulant medication for ADHD patients with substance abuse problems remains controversial. For such patients, this author reserves stimulant medication for those:

• whose ADHD symptoms have not responded adequately to alternate treatments
• who have been reliable with prescription medications
• and whose functional level is seriously impaired by their ADHD.

Antidepressants vs. stimulants

Although few well-designed controlled studies have been published, four antidepressants appear to be reasonably equivalent in effectiveness for adults with ADHD and do not carry potential for stimulant abuse.¹⁴

Desipraime, bupropion, venlafaxine, and the experimental drug atomoxetine (Table 1) all increase norepinephrine at the synapse by inhibiting presynaptic reuptake. Though dopamine has traditionally been considered the neurotransmitter of choice for ADHD treatment, norepinephrine may be equally potent.

Impulse control center. Several lines of research have recently established a connection between the prefrontal cortex, norepinephrine, and ADHD.¹⁵ This evidence suggests that the prefrontal cortex plays a major role in inhibiting impulses and responses to distractions:

Box 2

HOW STIMULANTS—THERAPEUTIC OR ILLICIT—AFFECT THE BRAIN

Figure 1

PET scans of the brain using carbon 11 (¹¹C)-labeled cocaine and methylphenidate HCl show similar distributions in the striatium when the drugs are administered intravenously.

Source: Reproduced with permission from Volkow ND, Ding YS, Fowler JS, et al. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry 1995;52:456-63.

Stimulants are classified as schedule-II drugs because they produce powerful reinforcing effects by increasing synaptic dopamine.⁷ Positron-emission tomography (PET) scans using carbon labeling have shown similar distributions of methylphenidate and cocaine in the brain (Figure 1).⁸ When administered intravenously, both drugs occupy the same receptors in the striatum and produce a “high” that parallels rapid neuronal uptake. Methylphenidate and cocaine similarly increase stimulation of the postsynaptic neuron by blocking the dopamine reuptake pump (dopamine transporter).

How a substance gets to the brain’s euphoric receptors greatly affects its addictive properties. Delivery systems with rapid onset—smoking, “snorting,” or IV injection—have much greater ability to produce a “high” than do oral or transdermal routes. The greater the “high,” the greater the potential for abuse.

Because methylphenidate is prescribed for oral use, the potential for abuse is minimal. However, we need to be extremely cautious when giving methylphenidate or similar stimulant medications to patients who have shown they are unable to control their abuse of other substances.

Stimulants can also re-ignite a dormant substance abuse problem. Though little has been written about this in the medical literature, Elizabeth Wurtzel, author of the controversial Prozac Nation, chronicles the resumption of her cocaine abuse in More, Now, Again: A Memoir of Addiction. She contends that after her doctor added methylphenidate to augment treatment of partially remitting depression, she began abusing it and eventually was using 40 tablets per day before slipping back into cocaine dependence.

• Patients with prefrontal cortex deficits can have problems with inattention and poor impulse control.
• Patients with ADHD have frontal lobe impairments, as neuropsychological testing and imaging studies have shown.
• Norepinephrine neurons, with cell bodies in the locus coeruleus, have projections that terminate in the prefrontal cortex.
• Agents with norepinephrine activity, but without mood-altering properties (e.g., clonidine), have been shown to improve ADHD symptoms.

Table 1

ADHD IN ADULTS: ANTIDEPRESSANT DOSAGES AND SIDE EFFECTS

Additional evidence suggests that the prefrontal cortex has projections back to the locus coeruleus, which may explain the relationship between the two areas. It may be that the brain’s higher-functioning areas, such as the prefrontal cortex, provide intelligent screening of impulses from the brain’s older areas, such as the locus coeruleus. Therefore, increased prefrontal cortex activity may modulate some impulses that ADHD patients cannot control otherwise.

No ‘high’ with antidepressants. Patients with ADHD who have experienced the powerful effects of street drugs such as cocaine, methamphetamine, or even alcohol may report that antidepressants do not provide the effect they desire. It is difficult to know if these patients are reporting a lack of benefit or simply the absence of a euphoric “high” they are used to experiencing with substances of abuse. The newer antidepressants do not activate the brain’s euphoric receptors to an appreciable degree.

Patients who take stimulants as prescribed also do not report a “high” but can detect the medication’s presence and absence. Most do not crave this feeling, but substance abusers tend to like it. A patient recently told me he didn’t think stimulants improved his ADHD, but said, “I just liked the way they made me feel.”

Desipramine

The tricyclic antidepressant desipramine is a potent norepinephrine reuptake inhibitor that is effective in treating ADHD in children and adults. In a double-blind, placebo-controlled study of adults with ADHD, subjects receiving desipramine showed robust improvement in symptom scores on the ADHD Rating Scale,¹⁶ compared with those receiving the placebo (Figure 2).¹⁷

During the 6-week trial, 41 adults with ADHD received desipramine, 200 mg/d, or a placebo. Those receiving desipramine showed significant improvement in 12 of 14 ADHD symptoms and less hyperactivity, impulsivity, and inattentiveness, whereas those receiving the placebo showed no improvement. According to the study criteria, 68% of those who received desipramine and none who received the placebo were considered positive responders.

Though no head-to-head studies have compared desipramine with methylphenidate, the same researchers conducted a similar placebo-controlled study with methylphenidate. The 6-week symptom score on the ADHD Rating Scale was 12.5 for methylphenidate, compared with a score of 12 for desipramine.¹⁸

Recommendation. Desipramine may be the most effective of the antidepressant treatments for patients with ADHD. Because of its side effects, however, it is not this author’s first choice and is usually reserved for patients whose symptoms fail to respond to other antidepressants. Desipramine can cause sedation, dry mouth, and constipation, which are related to blockade of adrenergic, histamine, and muscarinic cholinergic receptors. It also can be lethal in overdose.

Some substance abusers lose confidence in a medication that they cannot feel working. The side effects of desipramine, which can be intolerable for some patients, can reassure others with a history of substance abuse that they are being medicated.

Bupropion

Bupropion is a unique antidepressant that inhibits the presynaptic reuptake of dopamine and norepinephrine. Open-label studies demonstrate good responses to bupropion by adults with ADHD. One placebo-controlled, double-blind study found improved ADHD symptoms in 76% of patients receiving bupropion SR, compared with 37% of those receiving a placebo; the difference was statistically significant.¹⁹

Figure 2 IMPROVED ADHD SYMPTOMS WITH DESIPRAMINE

Adults with ADHD who received desipramine, 200 mg/d, in a double-blind trial showed significantly less hyperactivity, impulsivity, and inattentiveness after 6 weeks of therapy than a control group that received a placebo.

Source: Adapted with permission from Wilens TE, Biederman J, Prince J, et al. Six-week, double-blind, placebo-controlled study of desipramine for adult attention-deficit/hyperactivity disorder. Am J Psychiatry 1996;153:1147-53.Another study of adults with ADHD compared bupropion SR to methylphenidate and a placebo.²⁰ Using a primary outcome of the Clinical Global Impression (CGI) scale, response rates were 64% for bupropion SR, 50% for methylphenidate, and 27% for the placebo. The difference in response rates between the two agents was not statistically significant (p = 0.14).

Recommendation. The risk of seizures with bupropion is about 1 in 1,000. Therefore, bupropion should not be given to patients with a seizure disorder or to those with conditions that alter the seizure threshold (e.g., eating disorders, recent head trauma, or benzodiazepine withdrawal).²¹

This author uses bupropion as first-line treatment for appropriate patients with ADHD and a substance abuse history. Bupropion’s mild benefit with smoking cessation may provide some crossover effect for other substances of abuse. The low incidence of sexual side effects is another benefit. Drawbacks include twice-daily dosing and lack of a robust effect on attention and concentration.

Venlafaxine

Venlafaxine is a potent inhibitor of serotonin reuptake, a moderate inhibitor of norepinephrine, and a mild inhibitor of dopamine. Venlafaxine has displayed response rates similar to those of desipramine and bupropion in open-label studies in adults with ADHD,¹⁴ but no placebo-controlled studies exist.

As noted above, these antidepressants are believed to improve ADHD symptoms by making norepinephrine more available at the synapse. Hypothetically, then, one would need to administer venlafaxine at dosages that adequately inhibit the norepinephrine reuptake receptor. Venlafaxine XR, 150 mg/d, provides significant norepinephrine activity, according to several lines of evidence.

Recently, Upadhyaya et al reported the use of venlafaxine in one of the few treatment studies of patients with ADHD and comorbid alcohol/cocaine abuse. In an open-label trial, 10 subjects received venlafaxine, up to 300 mg/d, along with psychotherapy and attendance at Alcoholics Anonymous meetings. The nine who completed 4 weeks of treatment showed significantly improved ADHD symptoms and decreased alcohol craving.²²

Recommendation. Venlafaxine is this author’s second choice for patients with ADHD and substance abuse problems. Sexual side effects that some patients experience with venlafaxine can limit its use. Some clinicians are concerned about increases in blood pressure associated with venlafaxine, although significant changes do not seem to occur at dosages below 300 mg/d.²³

Atomoxetine

Atomoxetine is an investigational antidepressant in phase-III trials as a treatment for ADHD. Evidence shows atomoxetine to be a potent inhibitor of the presynaptic norepinephrine transporter, with minimal affinity for other neurotransmitter receptors. Initial studies suggest that atomoxetine is effective for adults and children with ADHD:

• In a small, double-blind, placebo-controlled, crossover trial, 11 of 20 adults showed improvement in ADHD symptoms within 3 weeks of starting atomoxetine.²⁴
• In 297 children and adolescents, atomoxetine at dosages averaging approximately 1.2 mg/kg/d was more effective than a placebo in reducing ADHD symptoms and improving social and family functioning. Treatment was well tolerated and without significant side effects.²⁵
• In a randomized open-label trial, 228 children received atomoxetine or methylphenidate. Both treatments significantly reduced inattention and hyperactive/impulsive symptoms.²⁶

Related resources

• Arnsten AF. Genetics of childhood disorders (XVIII). ADHD, Part 2: Norepinephrine has a critical modulatory influence on prefrontal cortical function. J Am Acad Child Adolesc Psychiatry. 2000;39:1201-3.
• Ward MF, Wender PH, Reimherr FW. The Wender Utah Rating Scale: An aid in the retrospective diagnosis of childhood attention-deficit/hyperactivity disorder. Am J Psychiatry. 1993;150:885-90.
• Research Report: Prescription Drugs—abuse and addiction. National Institute on Drug Abuse, Substance Abuse and Mental Health Services Administration.

Drug brand names

• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Methylphenidate • Ritalin, Concerta
• Venlafaxine • Effexor

Disclosure

Dr. Higgins reports that he is on the speakers’ bureaus for Wyeth-Ayerst Pharmaceuticals and Eli Lilly and Co.

Should you prescribe a stimulant to treat attention and hyperactivity problems in teenagers and adults with a history of substance abuse? Evidence suggests that using a stimulant to treat attention-deficit/hyperactivity disorder (ADHD) may place such patients at risk for stimulant abuse or for relapse into abuse of other substances. But a stimulant may be the only option for patients whose ADHD symptoms do not respond to alternate medications, such as antidepressants.

Growing numbers of adults are being treated for ADHD. Because substance abuse problems are common in adults with ADHD (Box 1 ),^1-3 prescribing an antidepressant instead of a stimulant in some cases may be prudent. Consider the following factors when choosing ADHD therapy for patients with a history of substance abuse.

Prevalence of stimulant use and abuse

In the United States, more than 95% of medications prescribed for children and adults with ADHD are stimulants—usually methylphenidate.⁴ Stimulant use has increased as more children and adults are diagnosed with ADHD. Methylphenidate prescriptions increased five-fold from 1990 to 1995.⁵ Visits to psychiatrists and physicians that included stimulant prescriptions grew from 570,000 to 2.86 million from 1985 to 1994, with most of that increase occurring during visits to primary care and other physicians.⁶

When used as prescribed, methylphenidate is safe and effective for treating most children and adults with ADHD. Methylphenidate’s pharmacologic properties, however, are similar to those of amphetamines and cocaine (Box 2, Figure 1),^7,8 which is why methylphenidate is a schedule-II controlled substance.

Published data. Fifteen reports of methylphenidate abuse were published in the medical literature between 1960 and 1999,⁷ but little is known about the prevalence of stimulant abuse among patients with ADHD. Banov and colleagues recently published what may be the only data available, when they reported that 3 of 37 (8%) patients abused the stimulants they were prescribed for ADHD.⁹ The three patients who abused stimulants had histories of drug and alcohol abuse at study entry. In all three cases, stimulant abuse did not develop immediately but became apparent within 6 months after the study began.

In a study of 651 students ages 11 to 18 in Wisconsin and Minnesota, more than one-third of those taking stimulants reported being asked to sell or trade their medications. More than one-half of those not taking ADHD medications said they knew someone who sold or gave away his or her medication.¹⁰

Stimulant theft, recreational use. Methylphenidate has been identified as the third most abused prescribed substance in the United States.¹¹ It was the 10th most frequently stolen controlled drug from pharmacies between 1990 and 1995, and 700,000 dosage units were reported stolen in 1996 and 1997.¹²

Box 1

The popular media have reported recreational use of methylphenidate—with street names such as “R-Ball” and “Vitamin R”—among teens and college students.¹³ Illegal stimulants are perceived to be easily accessible on college campuses, but no data have been reported.

The use of stimulant medication for ADHD patients with substance abuse problems remains controversial. For such patients, this author reserves stimulant medication for those:

• whose ADHD symptoms have not responded adequately to alternate treatments
• who have been reliable with prescription medications
• and whose functional level is seriously impaired by their ADHD.

Antidepressants vs. stimulants

Although few well-designed controlled studies have been published, four antidepressants appear to be reasonably equivalent in effectiveness for adults with ADHD and do not carry potential for stimulant abuse.¹⁴

Desipraime, bupropion, venlafaxine, and the experimental drug atomoxetine (Table 1) all increase norepinephrine at the synapse by inhibiting presynaptic reuptake. Though dopamine has traditionally been considered the neurotransmitter of choice for ADHD treatment, norepinephrine may be equally potent.

Impulse control center. Several lines of research have recently established a connection between the prefrontal cortex, norepinephrine, and ADHD.¹⁵ This evidence suggests that the prefrontal cortex plays a major role in inhibiting impulses and responses to distractions:

Box 2

HOW STIMULANTS—THERAPEUTIC OR ILLICIT—AFFECT THE BRAIN

Figure 1

PET scans of the brain using carbon 11 (¹¹C)-labeled cocaine and methylphenidate HCl show similar distributions in the striatium when the drugs are administered intravenously.

Source: Reproduced with permission from Volkow ND, Ding YS, Fowler JS, et al. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry 1995;52:456-63.

Stimulants are classified as schedule-II drugs because they produce powerful reinforcing effects by increasing synaptic dopamine.⁷ Positron-emission tomography (PET) scans using carbon labeling have shown similar distributions of methylphenidate and cocaine in the brain (Figure 1).⁸ When administered intravenously, both drugs occupy the same receptors in the striatum and produce a “high” that parallels rapid neuronal uptake. Methylphenidate and cocaine similarly increase stimulation of the postsynaptic neuron by blocking the dopamine reuptake pump (dopamine transporter).

How a substance gets to the brain’s euphoric receptors greatly affects its addictive properties. Delivery systems with rapid onset—smoking, “snorting,” or IV injection—have much greater ability to produce a “high” than do oral or transdermal routes. The greater the “high,” the greater the potential for abuse.

Because methylphenidate is prescribed for oral use, the potential for abuse is minimal. However, we need to be extremely cautious when giving methylphenidate or similar stimulant medications to patients who have shown they are unable to control their abuse of other substances.

Stimulants can also re-ignite a dormant substance abuse problem. Though little has been written about this in the medical literature, Elizabeth Wurtzel, author of the controversial Prozac Nation, chronicles the resumption of her cocaine abuse in More, Now, Again: A Memoir of Addiction. She contends that after her doctor added methylphenidate to augment treatment of partially remitting depression, she began abusing it and eventually was using 40 tablets per day before slipping back into cocaine dependence.

• Patients with prefrontal cortex deficits can have problems with inattention and poor impulse control.
• Patients with ADHD have frontal lobe impairments, as neuropsychological testing and imaging studies have shown.
• Norepinephrine neurons, with cell bodies in the locus coeruleus, have projections that terminate in the prefrontal cortex.
• Agents with norepinephrine activity, but without mood-altering properties (e.g., clonidine), have been shown to improve ADHD symptoms.

Table 1

ADHD IN ADULTS: ANTIDEPRESSANT DOSAGES AND SIDE EFFECTS

Additional evidence suggests that the prefrontal cortex has projections back to the locus coeruleus, which may explain the relationship between the two areas. It may be that the brain’s higher-functioning areas, such as the prefrontal cortex, provide intelligent screening of impulses from the brain’s older areas, such as the locus coeruleus. Therefore, increased prefrontal cortex activity may modulate some impulses that ADHD patients cannot control otherwise.

No ‘high’ with antidepressants. Patients with ADHD who have experienced the powerful effects of street drugs such as cocaine, methamphetamine, or even alcohol may report that antidepressants do not provide the effect they desire. It is difficult to know if these patients are reporting a lack of benefit or simply the absence of a euphoric “high” they are used to experiencing with substances of abuse. The newer antidepressants do not activate the brain’s euphoric receptors to an appreciable degree.

Patients who take stimulants as prescribed also do not report a “high” but can detect the medication’s presence and absence. Most do not crave this feeling, but substance abusers tend to like it. A patient recently told me he didn’t think stimulants improved his ADHD, but said, “I just liked the way they made me feel.”

Desipramine

The tricyclic antidepressant desipramine is a potent norepinephrine reuptake inhibitor that is effective in treating ADHD in children and adults. In a double-blind, placebo-controlled study of adults with ADHD, subjects receiving desipramine showed robust improvement in symptom scores on the ADHD Rating Scale,¹⁶ compared with those receiving the placebo (Figure 2).¹⁷

During the 6-week trial, 41 adults with ADHD received desipramine, 200 mg/d, or a placebo. Those receiving desipramine showed significant improvement in 12 of 14 ADHD symptoms and less hyperactivity, impulsivity, and inattentiveness, whereas those receiving the placebo showed no improvement. According to the study criteria, 68% of those who received desipramine and none who received the placebo were considered positive responders.

Though no head-to-head studies have compared desipramine with methylphenidate, the same researchers conducted a similar placebo-controlled study with methylphenidate. The 6-week symptom score on the ADHD Rating Scale was 12.5 for methylphenidate, compared with a score of 12 for desipramine.¹⁸

Recommendation. Desipramine may be the most effective of the antidepressant treatments for patients with ADHD. Because of its side effects, however, it is not this author’s first choice and is usually reserved for patients whose symptoms fail to respond to other antidepressants. Desipramine can cause sedation, dry mouth, and constipation, which are related to blockade of adrenergic, histamine, and muscarinic cholinergic receptors. It also can be lethal in overdose.

Some substance abusers lose confidence in a medication that they cannot feel working. The side effects of desipramine, which can be intolerable for some patients, can reassure others with a history of substance abuse that they are being medicated.

Bupropion

Bupropion is a unique antidepressant that inhibits the presynaptic reuptake of dopamine and norepinephrine. Open-label studies demonstrate good responses to bupropion by adults with ADHD. One placebo-controlled, double-blind study found improved ADHD symptoms in 76% of patients receiving bupropion SR, compared with 37% of those receiving a placebo; the difference was statistically significant.¹⁹

Figure 2 IMPROVED ADHD SYMPTOMS WITH DESIPRAMINE

Adults with ADHD who received desipramine, 200 mg/d, in a double-blind trial showed significantly less hyperactivity, impulsivity, and inattentiveness after 6 weeks of therapy than a control group that received a placebo.

Source: Adapted with permission from Wilens TE, Biederman J, Prince J, et al. Six-week, double-blind, placebo-controlled study of desipramine for adult attention-deficit/hyperactivity disorder. Am J Psychiatry 1996;153:1147-53.Another study of adults with ADHD compared bupropion SR to methylphenidate and a placebo.²⁰ Using a primary outcome of the Clinical Global Impression (CGI) scale, response rates were 64% for bupropion SR, 50% for methylphenidate, and 27% for the placebo. The difference in response rates between the two agents was not statistically significant (p = 0.14).

Recommendation. The risk of seizures with bupropion is about 1 in 1,000. Therefore, bupropion should not be given to patients with a seizure disorder or to those with conditions that alter the seizure threshold (e.g., eating disorders, recent head trauma, or benzodiazepine withdrawal).²¹

This author uses bupropion as first-line treatment for appropriate patients with ADHD and a substance abuse history. Bupropion’s mild benefit with smoking cessation may provide some crossover effect for other substances of abuse. The low incidence of sexual side effects is another benefit. Drawbacks include twice-daily dosing and lack of a robust effect on attention and concentration.

Venlafaxine

Venlafaxine is a potent inhibitor of serotonin reuptake, a moderate inhibitor of norepinephrine, and a mild inhibitor of dopamine. Venlafaxine has displayed response rates similar to those of desipramine and bupropion in open-label studies in adults with ADHD,¹⁴ but no placebo-controlled studies exist.

As noted above, these antidepressants are believed to improve ADHD symptoms by making norepinephrine more available at the synapse. Hypothetically, then, one would need to administer venlafaxine at dosages that adequately inhibit the norepinephrine reuptake receptor. Venlafaxine XR, 150 mg/d, provides significant norepinephrine activity, according to several lines of evidence.

Recently, Upadhyaya et al reported the use of venlafaxine in one of the few treatment studies of patients with ADHD and comorbid alcohol/cocaine abuse. In an open-label trial, 10 subjects received venlafaxine, up to 300 mg/d, along with psychotherapy and attendance at Alcoholics Anonymous meetings. The nine who completed 4 weeks of treatment showed significantly improved ADHD symptoms and decreased alcohol craving.²²

Recommendation. Venlafaxine is this author’s second choice for patients with ADHD and substance abuse problems. Sexual side effects that some patients experience with venlafaxine can limit its use. Some clinicians are concerned about increases in blood pressure associated with venlafaxine, although significant changes do not seem to occur at dosages below 300 mg/d.²³

Atomoxetine

Atomoxetine is an investigational antidepressant in phase-III trials as a treatment for ADHD. Evidence shows atomoxetine to be a potent inhibitor of the presynaptic norepinephrine transporter, with minimal affinity for other neurotransmitter receptors. Initial studies suggest that atomoxetine is effective for adults and children with ADHD:

• In a small, double-blind, placebo-controlled, crossover trial, 11 of 20 adults showed improvement in ADHD symptoms within 3 weeks of starting atomoxetine.²⁴
• In 297 children and adolescents, atomoxetine at dosages averaging approximately 1.2 mg/kg/d was more effective than a placebo in reducing ADHD symptoms and improving social and family functioning. Treatment was well tolerated and without significant side effects.²⁵
• In a randomized open-label trial, 228 children received atomoxetine or methylphenidate. Both treatments significantly reduced inattention and hyperactive/impulsive symptoms.²⁶

Related resources

• Arnsten AF. Genetics of childhood disorders (XVIII). ADHD, Part 2: Norepinephrine has a critical modulatory influence on prefrontal cortical function. J Am Acad Child Adolesc Psychiatry. 2000;39:1201-3.
• Ward MF, Wender PH, Reimherr FW. The Wender Utah Rating Scale: An aid in the retrospective diagnosis of childhood attention-deficit/hyperactivity disorder. Am J Psychiatry. 1993;150:885-90.
• Research Report: Prescription Drugs—abuse and addiction. National Institute on Drug Abuse, Substance Abuse and Mental Health Services Administration.

Drug brand names

• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Methylphenidate • Ritalin, Concerta
• Venlafaxine • Effexor

Disclosure

Dr. Higgins reports that he is on the speakers’ bureaus for Wyeth-Ayerst Pharmaceuticals and Eli Lilly and Co.

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.

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.