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Objective: To review currently available formulations and emphasize unmet needs in the pharmacologic management of attention-deficit/hyperactivity disorder (ADHD)., Data Sources: Publications and clinical trials were identified through PubMed and ClinicalTrials.gov, respectively. A Web-based search identified prescribing information for approved agents for treating ADHD, along with relevant guidelines and diagnostic criteria., Study Selection: The following search terms were used: (1) ADHD or attention-deficit/hyperactivity disorder or ADD or attention deficit hyperactivity disorder and/or (2) amphetamine or methylphenidate or atomoxetine or guanfacine or clonidine. Additional searches were performed using product brand names, and clinical trial was applied as a filter. Relevant studies were only included if published in English-language peer-reviewed journals and if involved agents were currently available (or pursuing approval) in the United States. Reviews of literature prior to 2005 and from 2005 to 2008 have been published previously; therefore, the present search focused on studies published from January 2009 through May 2016. In addition, reference lists of review articles and relevant studies were also examined to help identify additional studies., Data Extraction: A total of 578 publications were identified from the PubMed search, from which 426 publications were initially excluded based on review of the title and abstract. Reasons for exclusion included a focus on comorbid disorders, specific subpopulations, endpoints unrelated to improving ADHD symptomatology (eg, executive function, cognition, substance use), or quality of life measures. A more thorough assessment of the remaining citations, including publications and prescribing information, produced the final 219., Results: Pharmacotherapy with stimulant and nonstimulant options is the most common approach for treating ADHD in adults and children. Stimulants are mostly formulated as either tablets or capsules; however, the newer generation includes transdermal patches, oral suspensions (liquids), chewable tablets, and orally disintegrating tablets. Nonstimulants are available in oral capsule (atomoxetine) and tablet (guanfacine and clonidine) formulations., Conclusions: Despite the broad range of treatment options currently available, nonadherence remains a significant problem in ADHD. While evidence is currently lacking, the availability of new formulations may improve adherence., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Objective: Little is known regarding the temporal trends in prescriptions, nonmedical use, and emergency department (ED) visits involving prescription stimulants in the United States. Our aim was to examine these 3 national trends involving dextroamphetamine-amphetamine and methylphenidate in adults and adolescents., Method: Three national surveys conducted between 2006-2011 were used: National Disease and Therapeutic Index, a survey of office-based practices; National Survey on Drug Use and Health, a population survey of substance use; and Drug Abuse Warning Network, a survey of ED visits. Ordinary least squares regression was used to examine temporal changes over time and the associations between the 3 trends., Results: In adolescents, treatment visits involving dextroamphetamine-amphetamine and methylphenidate decreased over time; nonmedical dextroamphetamine-amphetamine use remained stable, while nonmedical methylphenidate use declined by 54.4% in 6 years. ED visits involving either medication remained stable. In adults, treatment visits involving dextroamphetamine-amphetamine remained unchanged, while nonmedical use went up by 67.1% and ED visits went up by 155.9%. These 3 trends involving methylphenidate remained unchanged. Across age groups, the major source for nonmedical use of both medications was a friend or relative; two-thirds of these friends and relatives had obtained the medication from a physician., Conclusions: Trends in prescriptions for stimulants do not correspond to trends in reports of nonmedical use and ED visits. Increased nonmedical stimulant use may not be simply attributed to increased prescribing trends. Future studies should focus on deeper understanding of the proportion of, risk factors for, and motivations for drug diversions., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Objective: The authors investigated trends and patterns in stimulant treatment of adults visiting office-based medical practices in the United States., Method: A time series analysis of data from the 1994 to 2009 National Ambulatory Medical Care Surveys (no. of visits = 372,702) was performed, focusing on adult (aged ≥ 18 years) visits in which stimulant medications (amphetamine salts, methylphenidate, or pemoline) were prescribed. The authors computed trends in the percentage of visits in which a stimulant was prescribed stratified by background and clinical patient characteristics. Results are reported as odds ratios (ORs) over the 1994 to 2009 period. The authors also compare visits to psychiatrists and nonpsychiatrist physicians that yielded a stimulant prescription to an adult., Results: The percentage of visits in which stimulants were prescribed increased from 0.11% (1994-1997) to 0.70% (2006-2009) (OR = 13.72, 95% confidence interval [CI], 9.40-20.03). Among adults aged 18 to 29 years, the corresponding increase in stimulant visits was from 0.17% to 1.83% (OR = 30.14, 95% CI, 15.84-57.36). Stimulant prescriptions increased significantly more rapidly among visits without a clinical ADHD diagnosis (OR = 11.86, 95% CI, 7.49-18.80) than among visits with such a diagnosis (OR = 5.45, 95% CI, 2.96-10.04) (interaction P = .04) and among visits to nonpsychiatrist physicians (OR = 21.54, 95% CI, 12.84-36.12) than psychiatrists (OR = 10.64, 95% CI, 6.72-16.86) (interaction P = .03). By 2006-2009, nonpsychiatrist physicians provided most (57.7%) of the stimulant prescriptions linked to adult office-based visits. As compared with psychiatrists, nonpsychiatrist physicians diagnosed ADHD in a significantly smaller proportion of their adult visits in which stimulants were prescribed (62.5% vs 34.4%, P < .0001)., Conclusions: Between 1994 and 2009, there was a substantial increase in stimulant prescriptions during adult outpatient visits, especially during visits of younger adults. The increase in stimulant treatment occurred significantly more rapidly in the practices of nonpsychiatrist physicians than in those of psychiatrists., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Background: Sleep disturbances may cause distress among individuals with attention-deficit/hyperactivity disorder (ADHD), but few studies have examined the impact of stimulant pharmacotherapy for ADHD on sleep in adults., Method: These post hoc analyses included sleep data collected with the Pittsburgh Sleep Quality Index (PSQI), a self-rated questionnaire, from 831 adults with DSM-IV-TR-defined ADHD in 2 large, randomized, double-blind, placebo-controlled, forced-dose titration studies of lisdexamfetamine (N = 420; conducted from May 25, 2006, to November 16, 2006) and triple-bead mixed amphetamine salts (MAS) (N = 411; conducted from April 25, 2005, to November 4, 2005). Change from baseline to endpoint in PSQI clinically meaningful change categories (ie, "decrease," "no change," or "increase") was analyzed by treatment group in each study using the χ² test. The Cochran-Mantel-Haenszel method was used (1) to determine whether there was a statistically significant difference in Clinical Global Impressions-Improvement (CGI-I) score of 1 or 2 (improved) versus > 2 (not improved) relative to a decrease or an increase in PSQI and (2) to analyze shifts from good sleep at baseline (PSQI ≤ 5) to poor sleep at endpoint (PSQI > 5)., Results: Impaired sleep (PSQI score > 5) relative to baseline was demonstrated in 8.3% and 9.7% of the treatment and placebo groups, respectively (P = .18), in the MAS study and 7.7% and 8.2%, respectively (P = .03), in the lisdexamfetamine study. Clinically meaningful change in baseline to endpoint PSQI was not statistically significantly different between treatment and placebo groups in either study. A significant difference in CGI-I 1 and 2 relative to an increase or decrease in PSQI was found in both the triple-bead MAS (P < .0001) and the lisdexamfetamine (P = .0008) trials. More subjects with improved CGI-I rating of 1 or 2 had improvement in PSQI than had worsening., Conclusions: Approximately one-third of subjects receiving treatment or placebo had clinically meaningful sleep improvement, emphasizing that change in sleep quality during treatment may not necessarily be related to stimulant therapy. When managing complaints of sleep difficulties in ADHD subjects, clinicians should undertake a broad assessment and consider underlying conditions that may contribute to sleep disruption., Trial Registration: clinicaltrials.gov Identifiers: NCT00334880 and NCT00152022., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Objective: The Quality of Life, Effectiveness, Safety, and Tolerability (QU.E.S.T.) study was designed to evaluate effectiveness of long-acting amphetamines in adults with attention-deficit/hyperactivity disorder (ADHD) in community practice settings. This article reports moderators and mediators of symptoms and quality of life outcomes., Method: This was an open-label study of 725 adults with DSM-IV-diagnosed ADHD, treated with mixed amphetamine salts extended release and followed for up to 8 months. Multiple regressions were used to determine if patient moderators impact response in ADHD symptoms and how ADHD symptoms and medication satisfaction mediate quality of life. The study was conducted from December 2003 to December 2004., Results: Amphetamine treatment of ADHD resulted in a robust and enduring symptom response. Patient characteristics such as age, female gender, severity of illness, and treatment-naive status moderate improved symptom outcome. Symptom change and satisfaction with medication independently mediate change in mental but not physical quality of life outcomes. There is no time lag between changes in symptoms and improved quality of life. Attention is a stronger mediator of ADHD-specific quality of life outcomes than disruptive behavior., Conclusions: If symptoms and quality of life improve simultaneously, improvement in quality of life can be understood as more than just a downstream, secondary effect of symptom remission. Satisfaction with medication is a direct measure of the complex interplay of symptom change, tolerability, and patient perception of treatment that predicts self-report of quality of life benefits. Although the disruptive symptoms of ADHD are more obvious, adults self-report that attention has greater impact., (Copyright 2010 Physicians Postgraduate Press, Inc.)

The U.S. Food and Drug Administration has approved 3 medications, atomoxetine and the extended-release formulations of amphetamine salts and dexmethylphenidate, for the treatment of adult attention-deficit hyperactivity disorder (ADHD). Different formulations of the same drugs, as well as other agents and cognitive-behavioral therapy, have been tested to determine efficacy in ADHD alone and in ADHD with comorbid substance use disorders, mood disorders, and anxiety disorders. A deficit in research exists in regard to these comorbidities in adults with ADHD., (Copyright 2009 Physicians Postgraduate Press, Inc.)

Introduction: The efficacy and safety of triple-bead mixed amphetamine salts (MAS), an oral, once-daily, enhanced extended-release amphetamine formulation designed for a duration of action up to 16 hours, were evaluated in adults with attention-deficit/hyperactivity disorder (ADHD)., Method: In this phase 3, 7-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, dose-optimization study of 272 adults with ADHD (DSM-IV-TR criteria), subjects (aged 18 to 55 years) were randomly assigned to triple-bead MAS (starting dose 12.5 mg) or placebo. The primary outcome measure was change in ADHD Rating Scale-IV (ADHD-RS-IV). Secondary outcome measures included Clinical Global Impressions (CGI) scale, Time-Sensitive ADHD Symptom Scale (TASS) (measuring extended duration), Brown Attention-Deficit Disorder Scale (BADDS) (measuring executive function), Adult ADHD Impact Module (AIM-A) (measuring quality of life [QOL]), and ADHD-RS-IV hyperactivity-impulsivity and inattentiveness subscales. Adverse events (AEs), vital signs, electrocardiograms (ECGs), and laboratory data were collected. The trial was conducted from January 2005 to June 2005., Results: Triple-bead MAS resulted in significantly greater improvement versus placebo in mean ADHD-RS-IV total score change (p < .0001), CGI-Improvement (p < .0001), TASS total score at 13-16 hours postdose (p = .002), BADDS total score (p < .0001), all AIM-A domains (p < or = .01), and ADHD-RS-IV subscales (p < .01), demonstrating extended duration of efficacy and improvements in executive function and QOL. The most common treatment-emergent AEs included insomnia, dry mouth, decreased appetite and weight, and headache. Most treatment-emergent AEs were mild or moderate in severity., Conclusions: Triple-bead MAS was significantly more effective than placebo in treating adult ADHD. The extended duration of action up to 16 hours and significant improvements in executive function and QOL address unique treatment needs of adults with ADHD. Treatment-emergent AEs with triple-bead MAS were consistent with amphetamine treatment., (Copyright 2008 Physicians Postgraduate Press, Inc.)

Narcolepsy, which affects 1 in 2000 people in the general population, is characterized by excessive daytime sleepiness (EDS), cataplexy, and other dissociated manifestations of rapid eye movement sleep (hypnagogic hallucinations and sleep paralysis). The disease is currently treated with amphetamine-like central nervous system stimulants (for EDS) and antidepressants (for cataplexy). Some compounds from other classes, such as modafinil (a non-amphetamine wake-promoting compound for EDS) and sodium oxybate (a short-acting sedative for EDS and cataplexy, administered at night), are also employed. The major pathophysiology of human narcolepsy has recently been revealed by the extension of discoveries of narcolepsy genes in animal models: hypocretin/orexin ligand deficiency has been shown in about 90% of human narcolepsy-cataplexy. This finding led directly to the development of new diagnostic tests (i.e., cerebrospinal fluid hypocretin measures). Hypocretin replacement is also likely to be a new therapeutic option for hypocretin-deficient narcolepsy, but is still not available in humans. In this review, the pharmacologic and pathophysiologic aspects of narcolepsy are discussed.

Objective: To evaluate the short-term tolerability of an extended-release preparation of the stimulant medication mixed amphetamine salts (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD) whose hypertension has been successfully treated with antihypertensive medications., Method: An 8-week, 2-phase, open-label study design was implemented. All adults had ADHD (DSM-IV diagnosis) and essential hypertension and were required to be normotensive (blood pressure < 135/85 mm Hg, treated) for at least 4 weeks at entry into the study. MAS XR was given for a 6-week period, titrated once each week to a target maximum dose of 60 mg/day given once daily in the morning (phase 1), and then discontinued for 2 weeks at the end of the study (phase 2). At baseline, subjects underwent a comprehensive clinical assessment, medical history, vital signs assessment, and electrocardiogram (ECG). Rating scales were used throughout the study to assess response to treatment, and blood pressure was measured manually at each study visit. The primary outcome was the effect of MAS XR on blood pressure and the development of hypertension., Results: Thirteen subjects receiving antihypertensive therapy were entered and placed on MAS XR treatment and completed the trial. There were no serious adverse events. No sustained elevated blood pressure (> 140/90 mm Hg at 2 consecutive visits) was observed in the subjects treated with MAS XR. Similar rates of single episodes of hypertension were observed in phases 1 and 2. Similarly, there was no group mean increase in systolic or diastolic blood pressure or pulse during treatment with MAS XR. No clinically significant changes in the ECG were observed. During the 6-week medication phase, significant improvement was found on rating scales assessing ADHD symptoms and severity that reversed with discontinuation of MAS XR., Conclusion: The results of this open study suggest that adults with ADHD and controlled hypertension can be safely treated with MAS XR.

Attention-deficit/hyperactivity disorder (ADHD) is common, chronic, and associated with significant functional impairment. It is highly treatable. It is therefore not only a major public health problem but also one that provides a unique opportunity in medicine to make a significant difference. This article will discuss the methodology needed to demonstrate empirically the impact of treatment on actual burden of illness in practice. Where efficacy studies demonstrate whether a treatment can work, effectiveness studies tell us whether they actually do work. Clinical trials exclude incompetent, non-compliant, and seriously comorbid patients, so that the information obtained from these trials tells us the most about the patients we see the least. Small differences in effect size in pivotal trials of efficacy have become a key variable for rating treatments as first line or second line, without consideration of effectiveness variables such as comorbidity, difficulty with appetite or sleep, patient preference, capacity for compliance, timing of functional impairment, and substance use. These effectiveness variables are less well studied, but critical to clinical decision making. In reality, fewer than 10% of our patients comply with and persist with treatment. To learn more about why patients are discontinuing treatment, we need to explore measures of effectiveness empirically. Effectiveness studies are also important to provide regulatory bodies with the data they need to balance the risk of treatment with the risk of failing to treat. Practical clinical trials and naturalistic follow-up studies will allow us to evaluate the true clinical impact of short-term efficacy trials.

Objective: To evaluate the effects of medications used in the treatment of adults with attention-deficit/hyperactivity disorder (ADHD) on blood pressure and pulse., Method: Subjects were those with DSM-III-R-/DSM-IV-diagnosed ADHD enrolled in placebo-controlled studies of 5 different medications for ADHD. Cardiovascular data from these studies of both stimulants (methylphenidate, amphetamine compounds, pemoline) and nonstimulants (bupropion, desipramine) were reanalyzed for baseline-to-endpoint active-treatment or placebo effects on blood pressure and heart rate., Results: There were 125 subjects with a mean +/- SD age of 39 +/- 9 years. In general, active drug treatment for ADHD compared to baseline was associated with several statistically significant changes in systolic blood pressure (bupropion: +5.9 mm Hg, p < .05 by paired t test; amphetamine: +5.4 mm Hg, p < .05), diastolic blood pressure (desipramine: +7.1 mm Hg, p < .05), and heart rate (bupropion: +6.9 mm Hg, p < .05; amphetamine: +7.3 mm Hg, p < .05; methylphenidate: +4.5 mm Hg, p < .05). New-onset cases of systolic or diastolic hypertension (blood pressure > or = 140/90) were recorded in 8% (7/89) of placebo-treated subjects and 10% (9/89) of subjects receiving active medication, regardless of the class (stimulant, nonstimulant)., Conclusion: Both stimulant and nonstimulant catecholaminergic medications used in adults with ADHD are associated with minor, but statistically significant, changes in heart rate and blood pressure that were often observed in those receiving placebo. Given the minor pressor and chronotropic effect of these medications, adults with ADHD should have their blood pressure and heart rate checked at baseline and periodically during treatment.

Excessive daytime sleepiness and abnormal sleep-wake patterns are becoming increasingly pervasive in modern society. The major causes of excessive daytime sleepiness include pathologic abnormalities of the central nervous system, such as narcolepsy and idiopathic hypersomnia; deficiencies in quality or quantity of sleep, such as those caused by sleep apnea and poor sleep hygiene; disturbances to the body's natural circadian rhythm, such as those caused by shift work or jet lag; and drugs, which can increase sleepiness either therapeutically or as a side effect. Determining the cause of daytime sleepiness is the first step in treating it. Setting appropriate and realistic treatment goals with the patient and initiating treatment are the next steps. Although the medications available to improve daytime wakefulness (e.g., amphetamines, methylphenidate, pemoline, and modafinil) are effective, they are not a substitute for sleep. Finally, timely follow-up is necessary to monitor treatment adherence, response, and side effects.

Although first identified in children in the 19th century, attention-deficit/hyperactivity disorder (ADHD) in adults was not described in the literature until 1976. The symptoms of adult ADHD resemble the symptoms of childhood ADHD, but symptom intensity, especially hyperactivity, may decrease over time. However, due to the challenges and responsibilities of adulthood, a normal day is extremely complicated for the ADHD adult. Molecular genetics and neuroimaging studies confirm that ADHD is a heterogeneous, neurobiological disorder, mainly of dopaminergic and noradrenergic pathways. Trials of pharmacologic treatments in adults with ADHD have produced mixed results due to considerable variability in diagnostic criteria, dosing, and response. This article reviews the history, neurobiology, and pharmacologic management of adult ADHD.

Background: Effective treatments for attention-deficit/hyperactivity disorder (ADHD) in adults are still being defined. Pediatric studies have suggested that a mixed amphetamine salt product (Adderall) is safe and effective in the treatment of childhood forms of ADHD. Presently, there are no reports in the scientific literature concerning the safety and efficacy of Adderall in adults with ADHD, which is the focus of this study., Method: Twenty-four outpatients (mean age = 33.3 years) with DSM-IV ADHD were administered Adderall in an open-label fashion, starting at 5 mg p.o. b.i.d., with titration according to clinical response, across a 16-week period. Relatives or spouses of each patient completed serial checklists (including the Copeland Symptom Checklist and the Brown Attention-Deficit Disorder Scales). Prospectively collected data were analyzed retrospectively., Results: Thirteen patients (54%) responded in a positive manner to Adderall, based on Clinical Global Impressions-Improvement scale scores. The mean end dose for responders was 10.77 mg/day (0.14 mg/kg/day). An intent-to-treat analysis revealed a decrease in the mean Copeland score from 99.05 to 63.3 (p < .001), while the mean Brown score dropped from 76.75 to 50.85 (p < .0001). Nine patients (38%) were poor responders or nonresponders to Adderall. Acute anxiety symptoms occurred in 4 of 7 patients with a comorbid anxiety diagnosis., Conclusion: Adderall may be an effective agent for the treatment of adult forms of ADHD, with positive responses occurring at relatively low doses, at least for some individuals. However, Adderall may precipitate anxiety in vulnerable individuals. Further study is required.

Medications can provide significant salutary effects for children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Due to their well-established safety and efficacy, psychostimulants are generally considered first-line pharmacotherapy for most young patients with ADHD. Since psychostimulant treatment often requires frequent dosing and may be associated with unacceptable side effects and risks, other classes of medication have been studied as possible treatment alternatives. The most extensively researched nonstimulant medications are the tricyclic antidepressants. In addition, alpha2 agonists have also been shown to reduce symptoms of ADHD. However, concerns regarding potential cardiotoxicity have tempered the enthusiasm for both of these classes of medication. Newer antidepressants such as bupropion and venlafaxine may hold promise as treatments for ADHD.