Attention-deficit/hyperactivity disorder (ADHD) is widely recognized as one of the most common psychiatric disorders initially diagnosed and treated in childhood; however, it is less widely recognized as a disorder that often persists into adolescence and adulthood. In recent years, there has been increased awareness that adult ADHD is marked by significant impulsivity and impairments of attention and executive function, symptoms that can be linked to, personal, social, and professional dysfunction. Clinicians are increasingly recognizing adult ADHD as a disorder linked to considerable dysfunction and distress, warranting appropriate pharmacologic treatment.

Psychostimulants, such as amphetamines and methylphenidate, are recommended as first-line pharmacotherapeutic agents for the management of ADHD in children, adolescents, and adults. Because most research on psychostimulant use has involved pediatric ADHD patients, little is known about the safety and efficacy of these agents in adult ADHD.

Objectives: Assess the bioavailability of mixed amphetamine salts extended-release (MAS XR) 30-mg capsules and the dose proportionality of pharmacokinetic measures for MAS XR 20,40, and 60 mg.

Methods: Study A, an open-label single-period study, and Study B, a randomized, open-label, three threeway crossover study, were conducted in healthy adults in a clinical research unit. In Study A, 20 subjects received a single MAS XR 30-mg capsule by mouth daily for 7 days. In Study B, 12 subjects received single oral doses of MAS XR 20,40, and 60 mg separated by 7-14-day washout periods.

Findings: Plasma dextroamphetamine (D-amphetamine) and levoamphetamine (L-amphetamine) concentrations were measured using a validated LC-MS/MS method. In Study A, a 3:1 ratio of D-amphetamine to L-amphetamine was observed for AUC0-∞ and Cmax. Tmax was 4.2 and 4.3 hours for D-amphetamine to Lamphetamine, respectively. In Study B, for D- and Lamphetamine, statistically significant differences were observed for AUC0-t, AVC0-∞, and Cmax between all doses; there was a linear relationship between pharmacokinetic variables and dose and Tmax was similar for each isomer (range: 4.5–5.3 hours) with all given MAS XR doses.

Conclusion: The extent of exposure as assessed by mean AUC0-24 and Cmax reflected the 3:1 ratio of D-amphetamine to L-amphetamine in MAS XR 30-mg capsules. The pharmacokinetic profiles of MAS XR 20, 40, and 60 mg are dose proportional for the isomers.

Objective: Assess the long-term safety and effectiveness of mixed amphetamine salts extended release (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD) combined subtype.

Methods: A 24-month, open-label extension of a 4-week, multicenter, double-blind, placebo-controlled, parallel-group, forced–dose-escalation study of MAS XR in adults (≥ 18 years of age) with ADHD. The 223 enrolled subjects started treatment at 20 mgl day for 1 week, with subsequent titration up to 60 mgl day for optimal therapeutic effects. At monthly visits, efficacy was assessed based on the ADHD Rating Scale IV (ADHD-RS-N). Safety assessments included spontaneously reported adverse events, laboratory assessments, and monitoring of vital signs.

Findings: ADHD symptoms significantly improved for all subjects as measured by change from baseline in mean ADHD-RS-IV total scores (-7.2±13.04 unit points; P<.001); this was sustained for up to 24 months. The most common treatment-related adverse events were dry mouth (43% of subjects reporting at least one occurrence), infection (33%), insomnia (32%), anorexia/decreased appetite (32%), headache (30%), and nervousness (26%). Most adverse events were mild to moderate in intensity.

Conclusion: Treatment with MAS XR 20–60 mgl day for adult ADHD was generally well tolerated and was associated with sustained symptomatic improvement for up to 24 months.

Objective: Evaluate safety and efficacy of mixed amphetamine salts extended release (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD).

Methods: 10-week interim analysis of the Quality of life, Effectiveness, Safety, and Tolerability (QU.E.S.T.) trial, an ongoing, 30-week, open-label, multicenter investigation of once-daily MAS XR (10–60 mg/day) in adults (≥18 years of age) with ADHD in community practice settings.

Findings: With up to 10 weeks of open-label MAS XR 10 to 60 mg/day (final visit mean dose: 37.2 mg/day), 725 adults exhibited rapid, sustained improvement in ADHD symptoms. At end point, significant decreases from baseline were seen in ADHD Rating Scale IV total scores (-19.8±11.6; P<.0001), hyperactivity/impulsivity subscak (-8.1±6.1; P<.0001), and inattentive subscale (-11.6±6.7; P<.0001). Most subjects (74.4%) were rated as very much/much improved. Based on the 36- item Short Form Health Survey (version 2), significant improvements in quality of life were seen in the domains of general health, physical and mental health, vitality, and social, emotional and physical role functioning (P<.0001). Few subjects (6.9%) withdrew due to adverse events; the most common MAS XR-related adverse events were decreased appetite and dry mouth (19.2% each), insomnia (17.8%), and headache (16.8%).

Conclusion: In adults with ADHD, MAS XR treatment is generally safe and demonstrates significant improvement in ADHD symptoms and related quality of life.

Objective: To assess long-term cardiovascular effects of mixed amphetamine salts extended release (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD) combined subtype.

Methods: 223 otherwise healthy adults (≥18 years of age) with ADHD combined subtype were exposed to ≤24 months of MAS XR (20–60 mg/day). Resting sitting diastolic blood pressure (DBP) and systolic blood pressur (SBP) and pulse were measured at baseline and weekly, then monthly during long-term treatment. Twelve-lead electrocardiograms were obtained at screening/baseline, weekly, then at 3-and 6-month intervals up to 24 months.

Findings: With MAS XR 20–60 mg/day, mean changes in DBP (1.3±9.2 mm Hg; P=.O42), SBP (2.3±12.5 mmHg; P=.OO6), and pulse (2.1±13.4 bpm; P=.019) were small and not clinically significant. A clinically insignificant increase in QTcB (corrected by Bazett's formula) interval (7.2 msec; P<.001) was observed at 24 months. No subject exhibited QTcB interval >480 msec (QTcF [corrected by Fridericia's formula] >454 msec). Seven subjects discontinued due to a car-diovascular adverse event (hypertension, n=5, palpitation/tachycardia, n=2); none of these events was reported as serious. Few subjects with normal baseline vital signs (using approved parameters at the time of study initiation) exhibited clinically significant abnormalities at end point; several subjects with borderline baseline values exhibited shifts to abnormal values during MAS XR therapy.

Conclusion: Cardiovascular effects of long-term MAS XR (≤60 mg/day) were minimal in otherwise healthy adults with ADHD. Nevertheless, vital signs should be monitored prior to and during treatment with any stimulant.