Attention deficit hyperactivity disorder: More than a child's disease

Key Points

Abstract

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral condition characterized by inattention, increased motor activity, and impulsiveness. It is often thought of as a childhood disease, yet evidence has shown it can continue into adolescence and adulthood, affecting 4.4% of the adult population. ADHD in adults is more difficult to diagnose because diagnostic criteria are extrapolated from pediatric assessment tools, and the disease often manifests differently in the adult population. Stimulant therapy, in conjunction with education and psychosocial intervention, is the mainstay of treatment; however, nonstimulant alternatives provide options if these medications cannot be tolerated or are contraindicated. (Formulary. 2010;45:318-327.)

CLINICAL PRESENTATION AND DIAGNOSTIC CRITERIA

According to the 2004 Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR), ADHD is a neurobehavioral disorder characterized by inattention, increased motor activity, and impulsiveness.⁴ These characteristics manifest more frequently and with greater severity than is typical for a person at a corresponding developmental level.⁴

The core symptoms of ADHD are hyperactivity, impulsivity, and inattention.¹

Hyperactivity, a common symptom in children with ADHD, is not as evident in adults. Adults, however, may experience restlessness and fidgeting, difficulty relaxing, and an ever-present feeling of being nervous or edgy.^2,5

Impulsivity in adults may be exhibited as blurting out rude or inappropriate comments or interrupting others during conversation.^3,5 In addition, adults with characteristics of impulsivity often choose highly active jobs, avoid situations with little to no physical activity, work long hours or multiple jobs, become easily bored or impatient, have low tolerance levels for frustration, are hot tempered, make impulsive decisions, and display irresponsible behavior.^2,3,5 Symptoms of inattention in adults are often exhibited as forgetting important appointments, deadlines, and social obligations; procrastination; indecisiveness; poor time management; avoiding tasks requiring extended attention; difficulty initiating tasks, completing tasks, and multitasking; and shifting attention from one task to another. ^2,3,5 This lack of concentration and attention often manifests in adolescence and early adulthood when levels of responsibility increase.⁵

Adults with ADHD can experience symptoms that interfere with work such as not being able to prioritize important tasks.⁵ These tasks may never be completed because much attention and time is given to unimportant tasks instead.⁵ Inattentiveness and impulsivity can have a substantial impact on an adult's social and professional life. Impact on a patient's personal life can include failed relationships, multiple marriages, and legal troubles.³ Adults with ADHD may have a poor employment history or driving record and are more likely to experience sexually transmitted diseases, be smokers, and have problems with substance abuse.^2,3

COMORBID CONDITIONS

ADHD is associated with several comorbid conditions, especially those of a psychiatric origin. Kessler and colleagues identified several DSM-IV disorder comorbidities in adults aged 18 to 44 years in the United States with ADHD via the National Comorbidity Survey Replication study (n=3,199). Mood, anxiety, substance use, and impulse control disorders were more prevalent in patients with ADHD than in those without the condition. Mood disorders, most commonly major depressive disorder and bipolar disorder, were present in 38.3% of patients with ADHD compared with 11.1% of patients without ADHD. Anxiety occurred in 47.1% of patients surveyed with ADHD compared with only 19.5% of patients without ADHD. Of the anxiety disorders, social and specific phobias occurred most often. The incidence of substance use (drugs, alcohol, or both) was 3 times higher in patients with ADHD (15.2% versus 5.6%).¹

Comorbidities have an impact on both diagnosis and treatment of ADHD, especially since there are similarities in symptoms between ADHD and psychiatric comorbidities. Patients often require several pharmacologic agents to treat both ADHD and accompanying comorbid conditions.

PHARMACOLOGIC TREATMENTS

Treatment of ADHD in adults should include pharmacotherapy, cognitive behavioral therapy, or a combination of both.⁶ Although stimulants are routinely considered first-line agents for the treatment of ADHD, there are certain instances in which nonstimulants may be preferred.²

Stimulants. Stimulants are the most widely used agents and are considered the first-line pharmacologic treatment for ADHD.^2,3 In 1937, Bradley first documented their use in children for the treatment of behavioral disorders.⁶ Since then, there have been more than 200 clinical trials evaluating the use of immediate-release (IR) and sustained-release (SR) stimulant formulations for the preschool, school-aged, adolescent, and adult ADHD populations.⁶ Although clinical trials in the adult population are limited, data supporting use in this population are nonetheless strong.⁶ These agents exert their effect by promoting the release of and/or blocking the reuptake of dopamine and norepinephrine, which leads to accumulation of these neurotransmitters in the presynaptic cleft.⁷

Stimulant medications used in ADHD include methylphenidate (MPH), dexmethylphenidate, amphetamines (dextroamphetamine and lisdexamfetamine dimesylate), and mixed amphetamine salts (MAS). Pemoline, a weak stimulant, was withdrawn from the market because of increased risk of hepatotoxicity.² MPH and amphetamines have not shown significant differences in side effect profiles and response rates across age groups.²

Methylphenidate. Methylphenidate (MPH) is available in IR, extended-release (ER), SR, and transdermal forms.^6-8 All formulations are readily absorbed, metabolized hepatically via de-esterification, excreted 90% as metabolites and unchanged drug in the urine, and do not require dosage adjustments in patients with renal or hepatic impairment.^7,8 In adults, the onset of action is immediate, and the terminal half-lives of IR and SR tablets are 2.8 to 3.5 hours and 3.4 hours, respectively.^7,8

There have been few controlled trials assessing efficacy of MPH in the adult ADHD population, and their results have been ambiguous.⁹ A meta-analysis published in 2004 examined 6 randomized, double-blind, placebo-controlled trials to determine the efficacy of MPH for treating ADHD in adults. All patients were selected using DSM-III, DSM-III-R, or DSM-IV criteria. The meta-analysis included 253 adult patients with ADHD (140 were treated with MPH, and 113 received placebo). Mean daily doses were 44 mg (0.63 mg/kg) for low-dose groups and 69 mg (1.05 mg/kg) for high-dose groups. The authors concluded that MPH is efficacious for the treatment of adult ADHD and that larger effect sizes were correlated with physician rating of outcomes and the use of higher doses.¹⁰ An ongoing phase 3 trial is evaluating the efficacy and safety of the MPH transdermal patch in adults with ADHD.¹¹

The safety and efficacy of MPH ER in the adult ADHD population was studied by Adler et al in 226 subjects during a randomized, 7-week, double-blind, placebo-controlled, dose-escalation, parallel-group study.¹² With regard to efficacy, the authors concluded that compared with placebo, osmotic-controlled release oral delivery system (OROS) MPH demonstrated a statistically significant lower least-squares mean change from baseline on the Adults ADHD Investigator Symptom Report Scale (P=.012) and the Clinical Global Impressions-Improvement score (P=.008) at the final visit. OROS MPH adverse events led to a discontinuation of the study in 14.5% of (16) patients in the OROS MPH group and 5.2% (6) in the placebo group. Most commonly reported adverse events included decreased appetite (25.5%), headache (25.5%), dry mouth (20.0%), anxiety (16.4%), nausea (12.7%), and increased blood pressure (10.0%).¹²

Dexmethylphenidate. Dexmethylpenidate is a more pharmacologically active enantiomer of racemic MPH, available in IR, ER, and extended-release (XR) formulations.^7,8 The IR product is readily absorbed; the ER product produces a bimodal concentration time profile with 2 distinct peaks approximately 4 hours apart.⁷ Both formulations are metabolized hepatically via de-esterification and are excreted in the urine; however, there is no experience with their use in patients with renal or hepatic impairment.^7,8,13 Half-life elimination of the IR formulations in adults is 2 to 4.5 hours.^7,8 When switching a patient from an MPH product to a dexmethylphenidate product, the initial dosing should be half of the total daily dose of MPH.^7,8

The efficacy of dexmethylphenidate for treatment of adult ADHD with childhood onset was studied in a 5-week, randomized, double-blind, placebo-controlled, multicenter trial.¹⁴ Patients aged 18 to 60 years were eligible for inclusion if they had a DSM-IV ADHD-Rating Scale (ADHD-RS) score of >24 at screening and at baseline. Inclusion criteria also included functional impairment. Dexmethylphenidate was initiated at 10 mg/d, then was increased to the assigned dosages of 20 mg (n=58), 30 mg (n=55), or 40 mg (n=55) in 10-mg increments.¹⁴ The final dosage was continued for at least 2 weeks.¹⁴ Compared with baseline, ADHD-RS scores were reduced by 37% in the 20-mg group, 36% in the 30-mg group, and 46% in the 40-mg group, and these reductions were significantly greater than the 21% reduction seen in the placebo group (P<.05).¹⁴

Patients who completed the double-blind trial were eligible for enrollment in a 6-month open-label extension trial.¹⁵ A total of 170 patients enrolled, including 131 who were initially treated with dexmethylphenidate XR and 38 who had received placebo in the double-blind randomized trial; 103 patients completed the extension study. During the extension, all patients were treated with dexmethylphenidate 10 mg/d for the first week and then increased to flexible dosages of 20 to 40 mg/d. The mean dexmethylphenidate XR dose was 0.32 mg/kg/d, and the mean treatment duration was 4.5 months. The efficacy analysis of the extension phase (n=102) suggested further reductions in ADHD-RS scores; however, P values were not reported. The most common treatment-related adverse events were headache (27.6%), insomnia (20.0%), decreased appetite (17.6%), and feeling jittery (13.5%).¹⁵

In a randomized, double-blind, placebo-controlled, parallel-group trial, the safety and efficacy of lisdexamfetamine 30-, 50-, and 70-mg daily were evaluated in 420 adults aged 18 to 55 years with moderate-to-severe ADHD by DSM IV-TR criteria. At 4 weeks, improvements in ADHD scores were significantly greater for the 30-, 50- and 70-mg lisdexamfetamine groups compared with placebo (-16.2, -17.4, -18.6 versus -8.2; P<.0001); however, changes in ADHD scores were not significantly different between the doses. The most commonly reported adverse events for the 30-, 50- and 70-mg doses were decreased appetite (29%, 28%, 23%), dry mouth (21%, 25%, 31%), insomnia (19%, 17%, 21%), nausea (8%, 6%, 7%), diarrhea (7%, 10%, 3%), anxiety (4%, 6%, 7%), anorexia (3%, 7%, 5%), and feeling jittery (2%, 3%, 7%).¹⁸ Wigal and colleagues recently published a study evaluating the efficacy and safety of lisdexamfetamine in adults with ADHD in a simulated workplace environment design. The authors noticed patients taking lisdexamfetamine experienced sustained improvement in measure performance scores from 2 to 14 hours.¹⁹

Mixed amphetamine salts. MAS are also available in IR and XR formulations that contain d-amphetamine and l-amphetamine in a 3:1 ratio. Peak plasma concentrations are reached in approximately 3 hours.⁷ Metabolism of MAS occurs hepatically via CYP450 monooxygenase and glucuronidation, and excretion occurs through the urine. The elimination half-life for d-amphetamine and l-amphetamine in adults is 10 hours and 13 hours, respectively.⁷

Safety and efficacy of MAS XR was demonstrated by a prospective, double-blind, parallel-group, multisite study in adults with ADHD (n=259). Participants were randomized to placebo or MAS XR at a dose of 20 mg, 40 mg, or 60 mg, given for 4 weeks. At end point, ADHD symptom reduction was statistically and clinically significant for all MAS XR groups when compared with placebo (-6.6 [95% CI, -11.0 to -2.3], -7.2 [95% CI, -11.5 to -2.8], -7.8 [95% CI, -12.2 to -3.4] for the 3 doses respectively; P<.001). No serious adverse events were reported, and the most common ones were dry mouth (27.4%), anorexia/decreased appetite (25.5%), insomnia (23.9%), and headache (23.6%).²⁰

Stimulant dose titration. Titration of stimulant medication to effective doses should be accompanied by the monitoring of ADHD symptoms and side effects. The dose should be increased every 3 to 5 days, stopping when there is no further reduction in ADHD symptoms and side effects are still controllable.^6,7 Since stimulant dosing is individualized, tailoring the choice of formulation makes sense as well. Adults may elect to take multiple daily doses of the IR formulation, a single morning dose of an ER formulation, or a combination of an ER formulation in the morning with either another ER or IR formulation in the afternoon.³

Safety profile. Adverse effects associated with the use of stimulants include but are not limited to decreased appetite, headache, nervousness, insomnia, or dysphoria. These effects can be seen at high or low stimulant doses and may be lessened with dose titration. In addition, over time, some negative effects diminish.²¹ Suppression of appetite is mostly noted in the child and adolescent populations. Appetite suppression is reported as mild, and significant weight loss is not commonly reported in adults. A mild increase in blood pressure (3 to 5 mmHg) may occur, which is especially concerning when cardiovascular compromise is present.³

Stimulant medications also carry a black-box warning due to their abuse potential along with warnings and precautions regarding serious cardiovascular effects.^7,8 All stimulants are schedule II controlled substances.³ When snorted or used intravenously, stimulants can cause intense euphoric effects, with large doses leading to psychosis, seizures, and cardiovascular events. Although abuse is more commonly reported with amphetamines than with MPH, addiction and abuse can occur with both. Prescribers should be aware of abuse potential and warn patients of the dangers associated with abuse.³

Nonstimulants. Because of warnings and precautions associated with stimulants, nonstimulant medications are the agents of choice in patients with psychiatric comorbidities, a history of substance abuse, or those with high blood pressure or heart disease.² Nonstimulant alternatives for treating ADHD include atomoxetine, tricyclic antidepressants, clonidine, bupropion, and modafinil.^7,8

Atomoxetine. Atomoxetine exerts its pharmacologic effects in ADHD by selectively inhibiting presynaptic norepinephrine reuptake, leading to increased amounts of synaptic norepinephrine.⁸ Oral atomoxetine is rapidly absorbed and can be taken with or without food. It is mostly metabolized via the CYP2D6 pathway but is not an inhibitor or inducer of this pathway. The mean half-life of atomoxetine ranges from 5 to 5.2 hours and up to 21.6 to 24 hours in poor metabolizers.⁸

Data from 2 large 10-week trials (combined n=536) were used to support FDA approval of atomoxetine for ADHD treatment in adults. These 2 identically designed, multicenter, randomized, double-blind, placebo-controlled trials evaluated mean reductions in total ADHD symptom scores. Atomoxetine was more effective in decreasing symptom scores compared with placebo in both studies (study I: 28.3% vs 18.1%, P<.01; study II: 30.1% vs 19.6%, P<.01). The most commonly reported adverse events in patients taking atomoxetine were dry mouth (21.2%), insomnia (20.8%), nausea (12.3%), decreased appetite (11.5%), and constipation (10.8%).²²

Bupropion. Bupropion-an aminoketone norepinephrine and dopamine reuptake inhibitor indicated for depression-sometimes is used off-label as a treatment option for adults with ADHD.⁷ Bupropion is extensively metabolized, primarily by the CYP2B6 isoenzyme system and is an inhibitor of the CYP2D6 isoenzyme system.^7,8 Caution should be used when administering bupropion with CYP2B6 substrates, inducers, or inhibitors (eg, cyclophosphamide, orphenadrine, and thiotepa).^7,8 When bupropion is used with CYP2D6 substrates (eg, certain antiarrhythmics, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, and beta-blockers), dosages should be modified as necessary.^7,8 Bupropion can lower seizure threshold, which is further lowered when it is used with antidepressants, antipsychotics, systemic steroids, or theophylline.⁷ Bupropion is available in IR, SR, and XL formulations. The SR formulation is dosed twice daily and the XL is dosed once daily.^7,8

Efficacy of bupropion has been demonstrated in several studies. A small randomized controlled trial (n=59) evaluated the short-term (6 weeks) efficacy of bupropion SR (mean daily dose, approximately 300 mg) in adults with ADHD. Bupropion SR decreased ADHD symptoms scores more than placebo; however, results were not statistically significant.²³ In contrast, another randomized controlled trial (n=162; mean daily dose, 393) evaluated once-daily bupropion XL in adults with ADHD compared with placebo.²⁴ A majority of the patients in this study were male, and most had combined-type ADHD. Response was defined as a reduction of at least 30% in ADHD-RS score. The response rate was significantly higher with bupropion XL than placebo (53% versus 31%; P=.004). Bupropion XL also decreased ADHD-RS total scores (-12.7 versus -6.9; P<.001), ADHD-RS inattentive symptoms (-7 vs -4.2; P=.003), and ADHD-RS hyperactive symptoms (-5.6 vs -2.6; P<.001) more effectively than placebo. No serious adverse events were reported in the study; however, the most common adverse events were headache (17%), dry mouth (12%), and insomnia (12%).²⁴

Desipramine. Desipramine, a secondary amine tricyclic antidepressant, is another nonstimulant medication that has been evaluated for treatment of ADHD.^8,25 Although the mechanism of desipramine is not completely understood, it is thought that normal levels of neurotransmitters are restored by blocking their reuptake.⁷ Evidence suggests desipramine may have greater norepinephrine blocking activity than tertiary amines such as imipramine and amitriptyline.²⁵ Tricyclic antidepressants also have histaminergic and cholingeric properties; however, it is theorized that the effect of tricyclic antidepressants on ADHD is due primarily to its action on norepinephrine reuptake.²⁵ Desipramine is well absorbed from the gastrointestinal tract and metabolized in the liver via the CYP2D6 isoenzyme system.⁸

A small randomized controlled trial (n=41) investigated desipramine in adult patients with ADHD. In this 6-week study, 68% of the patients receiving desipramine responded versus none of the patients receiving placebo. Patients in the desipramine group demonstrated a reduction in ADHD symptoms as well as decreases in hyperactivity, impulsivity, and inattentiveness categories. However, this study is limited by its small sample size.²⁶

Modafinil. Modafinil, a wake-promoting agent used for the treatment of narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder, has been studied in patients with ADHD. Unfortunately, studies in adults have included a small number of patients (approximately 40 combined) and were of short duration.^27,28 More information is needed before modafinil can be considered a first-line treatment option for ADHD in adult patients.

Alpha₂-adrenergic agonists. Alpha₂-adrenergic agonists, specifically clonidine and guanfacine, play a role in synaptic norepinephrine activity and are also considered ADHD treatment options.²⁵ However, as with modafinil, not enough evidence is available in adult populations to recommend these agents as first-line treatment without further studies.

NONPHARMACOLOGIC THERAPIES

In addition to medication, management of ADHD should include patient education and psychosocial interventions.³ Education regarding epidemiology, etiology, and pathogenesis of the disease, as well as medication counseling, should be provided to the patient and family to dispel common myths and misinformation.^3,6 Psychosocial interventions in the adult ADHD patient may include individual and/or group counseling and marital therapy, if needed.³ Counseling sessions should address the effect of ADHD on the patient, family relationships, substance abuse, education, and employment.⁶ Instruction in organizational skills to improve performance in the academic and work settings may also be beneficial.³

SPECIAL PATIENT POPULATIONS

When treating adult patients with ADHD, special consideration should be given to patients with a history of substance abuse disorder (SUD) and women who are pregnant or lactating.^29,30

Patients with SUD. Diagnosis of ADHD is complicated in patients with SUD because of the effect addictions have on cognition, behavior, sleep, and mood.²⁹ Patients with SUD should first be treated for their addiction, postponing treatment of ADHD until the patient has become drug and/or alcohol free.²⁹ Treatment for ADHD should begin with either bupropion or atomoxetine, which have less risk of abuse and diversion compared with stimulant medications. If an ADHD patient with SUD does not respond to nonstimulant therapy, ER formulations of stimulant medications should be prescribed, because they are harder to misuse than are IR formulations.²⁹ Patients with SUD should be monitored closely. Compliance assessment, random drug screens, and therapy with addiction counselors are all methods to help avoid abuse of ADHD medications.³

Pregnant and Lactating Women. It is especially important to be familiar with the risks and benefits associated with ADHD treatment in pregnant and lactating women.² The safety of ADHD medications in pregnancy and lactation has not been well established. Although limited data do not suggest a significant risk from use of ADHD medications during pregnancy, not enough information is available to recommend them. However, fetal exposure to ADHD medications is often unavoidable because patients with ADHD have 38% more unplanned pregnancies, and even in planned pregnancies, it is often necessary for the mother to continue taking her ADHD medication in order to maintain functioning.²

All currently available ADHD medications are considered pregnancy category C, which means that risk cannot be ruled out because human studies are lacking and animal studies either have demonstrated fetal harm or are lacking. The only exception is bupropion, which is considered category C by the manufacturer but category B in Drugs in Pregnancy and Lactation.^7,30

A large cohort study (n=50,282) examined the effects of various medication exposures during the first trimester of pregnancy. The trial included 367 women taking dextroamphetamine and 215 women taking unspecified amphetamines. The estimated standardized risk of malformations was 1.08 (95% CI, 0.65–1.68) using corrected data, suggesting no increase in risk of congenital abnormalities.³¹ Little evidence exists regarding teratogenic effects of MPH. The large cohort study mentioned above included 11 mother-child pairs with first-trimester MPH exposure, among whom there were no significant increases in abnormalities.

Unfortunately, there have been no human studies evaluating atomoxetine in pregnancy; however, 3 pregnancies during clinical trials in adults have been reported with 2 resulting in healthy births and 1 lost to follow-up.³⁰

Similarly, data are lacking to guide clinical recommendations as to use of ADHD medications during lactation. Effects of dexmethylphenidate during lactation has not been studied in humans; however, because of its low molecular weight, excretion into breast milk is expected.³⁰ Dexmethylphenidate has a short plasma half-life, which should limit the amount of exposure a nursing infant receives.³⁰ If dexmethylphenidate is used, the infant should be monitored for adverse effects including abdominal pain, fever, anorexia, and nausea. MPH is excreted into breast milk, which is expected due to its low molecular weight. In a study of a 6.4-month-old breast-fed infant receiving milk from a mother taking 80 mg MPH 5 days each week, the absolute dose the infant received was low and the mother did not report any adverse effects. Breast feeding toxicity is rare in infants over the age of 6 months; therefore, if MPH is used, the greatest potential for toxicity most likely will occur during the first month of life. Although there are no reports of atomoxetine use in lactating mothers, atomoxetine and/or its metabolites were excreted into the breast milk of lactating rats. This is expected because of atomoxetine's low molecular weight and long elimination half-life. According to the American Academy of Pediatrics, amphetamine use is contraindicated in women who are breastfeeding because levo- and dextroamphetamine are concentrated in breast milk.³⁰

CONCLUSION

ADHD can affect an adult patient's work and personal life. Stimulant therapy remains the first-line treatment for ADHD in adults, and atomoxetine shows promising outcomes as well. When stimulants and atomoxetine cannot be tolerated, a trial of bupropion, desipramine, clonidine, or modafinil may be warranted, even though evidence of their efficacy in adult populations is limited. Education and cognitive-behavioral therapy should accompany pharmacologic treatment to help patients control their disease.

Mohundro and Dr Wicker are both assistant professors at the University of Louisiana at Monroe College of Pharmacy-Baton Rouge Campus, Baton Rouge, LA.

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