Once-Daily Atomoxetine for Treating Pediatric Attention-Deficit/Hyperactivity Disorder: Comparison of Morning and Evening Dosing

Abstract

In this 3-arm, randomized, double-blind trial, once-daily morning-dosed atomoxetine, evening-dosed atomoxetine, and placebo were compared for treating pediatric attention-deficit/hyperactivity disorder (ADHD). Patients received morning atomoxetine/evening placebo (n = 102), morning placebo/evening atomoxetine (n = 93), or morning placebo/evening placebo (n = 93) for about 6 weeks. Core symptom efficacy was measured at weeks 0, 1, 3, and 6. Parent assessments of the child's home behaviors in the evening and early morning were collected daily during the first 2 weeks of treatment. Morning-dosed and evening-dosed atomoxetine significantly decreased core ADHD symptoms relative to placebo and produced symptom improvements that were measured up to 24 hours later. Morning dosing was superior to evening dosing on some efficacy measures. Evening dosing showed greater tolerability with significantly more patients receiving morning atomoxetine reporting at least 1 adverse event than those receiving evening atomoxetine.

Systematic review of atomoxetine data in childhood and adolescent attention-deficit hyperactivity disorder 2009–2011: Focus on clinical efficacy and safety

“…In the 6-week study there appeared to be a linear reduction with no suggestion of plateau at 6 weeks (Martényi et al, 2010). In a further placebo RCT 6-week study (not in treatment-naïve patients) comparing morning and evening dosing, measuring change in the ADHD-RS total score, both cohorts showed continuing improvements until week 6 with no evident plateau, with an effect size in the morning dosing group of 0.7; evening dosing was not significantly different to placebo on this measure (Block et al, 2009). A Japanese placebo RCT using three doses also suggested no plateau at 8 weeks with two out of three doses; however, only the 1.8 mg/kg cohort separated from placebo (Takahashi et al, 2009).…”

“…In none of the recent studies was a plateau reported for ATX clinical effects at or before 6 weeks (Block et al, 2009;Martényi et al, 2010;Montoya et al, 2009;Newcorn et al, 2009;Svanborg et al, 2009), with data somewhat supportive that time to optimal response may be at least 12 weeks. A critical finding in the treatment-naïve studies (Martényi et al, 2010;Montoya et al, 2009;Svanborg et al, 2009) was that effect size of ATX was greatest at study completion (6, 10, and 12 weeks, respectively), and in the Montoya study showed no sign of plateau even at 12 weeks (Montoya et al, 2009).…”

“…In a couple of studies looking at dosing regimens, ATX had greater effect size when given as a single morning dose compared with evening dosing, with an effect size benefit of 0.4, but evening dosing reduced adverse events, in particular, in relation to weight loss and appetite suppression (Block et al, 2009). An open-label study evaluating the role of behavioural intervention also reported in a post hoc analysis that the primary outcome measure (number of classroom rule violations) was significantly reduced with once-daily compared with twice-daily dosing (Waxmonsky et al, 2011).…”

“…In a 6-week RCT of treatment-naïve patients, the ATX cohort was significantly improved at 4 weeks (p=0.042) (at 2 weeks p=0.054) (Martényi et al, 2010) and treatment-naïve studies of longer durations (10 and 12 weeks) reported onset of response at Week 3 (p<0.001) and Week 4 (p=0.003), respectively (Montoya et al, 2009;Svanborg et al, 2009). In non-treatment-naïve trials a 6-week study comparing morning and evening dosing with placebo reported significant improvement in ADHD-RS at 1 week in both dosing arms (Block et al, 2009), and an 8-week study reported improvement at week 2 but only in the 1.8 mg/kg cohort (Takahashi et al, 2009 In a post hoc analysis of two open-label studies (n=421) over 24 weeks using the Weekly Rating of Evening and Morning Behaviour (WREMB-R) and Global Impression of Perceived Difficulties (GIPD) scales, significant improvement was measured predominantly over the initial 2 weeks with maintenance over 24 weeks . The IDEA study pooled data from six ATX RCTs (n=618) (Newcorn et al, 2009).…”

ADHD Treatments, Sleep, and Sleep Problems: Complex Associations

“…Although there are reports of insomnia as an adverse event with atomoxetine [57], multiple trials in ADHD have noted somnolence to be much more common [58], especially during the early stages of a trial or if the titration is too rapid [59]. However, somnolence can be minimized with evening administration, although daytime efficacy may be decreased [59].…”