Efficacy and safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: results from a comprehensive meta-analysis and metaregression

Abstract

Objective: To comprehensively evaluate the efficacy and safety of atomoxetine (ATX) in pediatric attention-deficit/hyperactivity disorder (ADHD).

Method: Meta-analysis of all double-blind randomized controlled trials (DBRCTs) evaluating the efficacy and tolerability of ATX for ADHD. Pooled, random-effects analyses were conducted, calculating standardized mean difference (SMD), yielding effect sizes (ES), relative risk (RR), and number-needed-to-treat/harm (NNT/NNH).Moderator/mediator analyses were also conducted, including metaregression.

Results: Across 25 DBRCTs (56 treatment arms, N = 3,928), ATX outperformed placebo regarding overall ADHD symptoms (ES = -0.64, 95% confidence interval [CI] = -0.56 to -0.71, p < 0.0001), hyperactivity/impulsivity (ES = -0.67, CI = -0.53 to -0.81, p < 0.0001), and inattention (ES = -0.59, CI = -0.51 to -0.67, p < 0.0001). Altogether, 44.4% versus 21.4% of patients improved by ≥40% (NNT = 4), whereas 39.9% versus 65.9% improved by <25% (NNT = 4). Oppositional defiant disorder symptoms (ES = -0.33) and quality-of-life-related outcomes (ES = -0.48 to -0.25) improved somewhat less. A higher percentage of treatment-naïve patients moderated the efficacy of ATX for overall ADHD symptoms (p = 0.017). All-cause discontinuation with ATX was similar to that for placebo (p = 1.00), with lower discontinuation because of inefficacy (relative risk [RR] = 0.51, CI = 0.36-0.74, p < 0.0001, NNT = 34), but higher discontinuation because of adverse effects (AEs) (RR = 1.89, CI = 1.08-3.31, p = 0.03, NNH = 50) with ATX. At least 1 adverse effect (AE) (70.4% versus 56.1%, p < 0.01, NNH = 6) and ≥1 psychiatric AE (21.5% versus 7.4%, NNH = 7, p < 0.01) were more frequent with ATX, whereas serious AEs (1.5% versus 1.0%), aggression (7.5% versus 6.0%), and suicidal ideation (1.3% versus 0.9%) were not different from placebo.

Conclusions: Short-term ATX treatment is safe and superior to placebo for overall ADHD symptoms and key secondary outcomes, with a medium ES. However, a relevant patient subgroup (40%) continues to have significant symptomatology, requiring additional clinical attention.

Keywords: atomoxetine; attention-deficit/hyperactivity disorder (ADHD); children; efficacy; safety.