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Efficacy and Safety of Atomoxetine in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: Results From a Comprehensive Meta-Analysis and Metaregression

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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.

Section snippets

Materials and Methods

We conducted an electronic search, using MEDLINE/PubMed, www.clinicaltrialsresults.com, www.clinicaltrials.gov, and www.lillytrials.com for all published and unpublished, acute DBRCTs and for meta-analyses of ATX published until August 2012. Studies had to be published in English. Search terms included: (ADHD OR Attention-Deficit Hyperactivity OR Deficit/Hyperactivity OR Attention Deficit-Hyperactivity OR Attention Deficit Hyperactivity) AND (Atomoxetine OR ATX OR Strattera) AND (random*). Hand

Search

The search identified 374 potentially eligible sources, consisting of 245 references in PubMed, 68 trials in clinicaltrials.gov, and 61 trials in clinicaltrialresults.com or lillytrials.com. At the title/abstract level, 253 sources could be excluded. Of the remaining 121 references another 70 sources were excluded after full text review. The remaining 51 data sources were included in this review (29 from PubMed, 17 from clinicaltrials.gov, and 5 from clinicaltrialresults.com or lillytrials.com

Discussion

This largest and most comprehensive meta-analysis including 3,928 pediatric patients found ATX to be superior to placebo for ADHD on a number of relevant outcomes. Efficacy advantages compared to placebo included the following: significantly greater decreases in total, inattentive, and hyperactive parent-rated and total teacher-rated ADHD symptom scores with medium ESs of −0.59 to −0.67; greater response rates with a NNT of 4 using study-defined response criteria as well as ≥25% and ≥40%

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  • Cited by (0)

    This article is discussed in and editorial by Dr. Michael H. Bloch on page 135.

    Clinical guidance is available at the end of this article.

    Dr. Correll served as the statistical expert for this research.

    Disclosure: Dr. Correll has received grant or research support from the National Institute of Mental Health (NIMH), Bristol-Myers Squibb/Otsuka, the Feinstein Institute for Medical Research, Janssen/Johnson and Johnson, and the National Alliance for Research in Schizophrenia and Depression. He has served as a consultant to Actelion, Alexza Pharmaceuticals, the American Academy of Child and Adolescent Psychiatry, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Co., Genentech, the Gerson Lehrman Group, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, NIMH, Janssen/Johnson and Johnson, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva, and Vanda. He has served on the speakers' bureau of Merck (nonpromotional lectures only). He owns stock in Alexza Pharmaceuticals. He has participated in continuing medical education (CME) article preparation for Medscape. He is a member of the Data Safety Monitoring Boards for Cephalon, Janssen/Johnson and Johnson, Lundbeck, Pfizer, Takeda, and Teva. Dr. Schwartz reports no biomedical financial interests or potential conflicts of interest.

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