Amphetamine-based treatments such as lisdexamfetamine dimesylate (LDX) and methylphenidate (MPH)-based agents are first-line treatments for adolescents with attention-deficit/hyperactivity disorder (ADHD), and each has been proven superior to placebo in numerous trials [Woolraich M et al. Pediatrics. 2011; Atkinson M, Hollis C. Arch Dis Child Educ Pract Ed. 2010]. A meta-analysis of clinical trials reported that amphetamine-based agents have greater effects than MPH-based agents [Faraone SV, Buitelaar J. Eur Child Adolesc Psychiatry. 2010]. Another meta-analysis indicated that amphetamine-based treatments were associated with higher probability of response when compared with various MPH-based agents [Roskell NS et al. Curr Med Res Opin. 2014]. Although such systematic assessments of existing data provide useful information about differential efficacy, they are indirect by nature.

Jeffrey Newcorn, MD, Icahn School of Medicine at Mount Sinai, New York, New York, USA, and colleagues conducted 2 studies directly comparing LDX with osmotic controlled-release MPH (OROS-MPH) in adolescents with ADHD. The primary end point was efficacy, as measured with the ADHD Rating Scale IV. Study 1 [NCT015529115] was an 8-week flexible-dose study, and study 2 [NCT01552902] was a 6-week forced-dose titration study. In study 1, patients were randomized 2:2:1 to once-daily LDX 30 to 70 mg, OROS-MPH 18 to 72 mg, or placebo. In study 2, the randomization was 2:2:1 to once-daily LDX 70 mg, OROS-MPH 72 mg, or placebo.

The least squares mean ± standard error of the mean was greater with LDX than with OROS-MPH in the flexible-dose study, but the difference was not significant (Table 1). The benefit of LDX over OROS-MPH was significant in the forced-dose study.

The key secondary end point was Clinical Global Impressions–Improvement scale score. Similar to what was seen with the ADHD scores from the 2 agents in each study, the scale score was greater with LDX than with OROS-MPH in the flexible-dose study (Table 1), but the difference was not significant. In the forced-dose study, the score was significantly greater with LDX than with OROS-MPH.

LDX was approved by the US FDA in 2007 for use in patients ≥6 years old with ADHD. The safety and tolerability profile of LDX has been consistent across clinical trials, with small increases in heart rate and/or blood pressure observed. The most frequently observed treatment-emergent adverse events (TEAEs) associated with LDX treatment include decreased appetite, decreased weight, and insomnia [Coghill D et al. Eur Neuropsychopharmacol. 2013; Findling RL et al. J Am Acad Child Adolesc Psychiatry. 2011].

Dr Newcorn and colleagues evaluated the safety and tolerability of LDX and OROS-MPH as secondary end points. Safety assessments included recording adverse events and vital signs. In the flexible-dose study, TEAEs were reported in 83.2% of patients receiving LDX, compared with 82.1% receiving OROS-MPH. In the forced-dose study, 66.5% of patients receiving LDX reported TEAEs, compared with 58.9% of patients receiving OROS-MPH. In the placebo groups, 63.7% and 44.5% of patients reported TEAEs in the flexible- and forced-dose studies, respectively. Consistent with known effects of LDX and OROS-MPH, TEAEs that occurred in ≥10% of patients included decreased appetite and headache with LDX and OROS-MPH in both studies, decreased weight with LDX in both studies and with OROS-MPH in the forced-dose study, and irritability with LDX in the flexible-dose study.

Dr Newcorn and colleagues concluded that LDX was not statistically superior to OROS-MPH in a flexible-dose design but was statistically superior in a forced-dose design, while the safety and tolerability profiles of both agents were consistent with those observed in previous studies.