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Atomoxetine in the treatment of children and adolescents with ADHD

Näytönastekatsaukset
Maria Laine
19.5.2025

Näytön aste: A

Atomoxetine compared to placebo improves the core symptoms of ADHD (inattention, impulsivity and hyperactivity) in children and adolescents at least in the short-term (less than half a year) treatment.

In a meta-analysis publiced 2014 «Schwartz S, Correll CU. Efficacy and safety of ato...»1, efficacy and safety of atomoxetine (ATX) was compared with placebo in the treatment of ADHD in children and adolescents. Study inclusion criteria were as follows: ATX monotherapy versus placebo; double blinded randomized controlled design; primary ADHD of any type, with oppositional defiant disorder (ODD), anxiety, and depression comorbidities allowed; patient age < 18 years; patient IQ of > 75. The primary outcome measure was baseline to end-point change in parent-rated, 18-item ADHD efficacy scale (ADHD-RS IV P/I), Swanson, Nolan, and Pelham rating scale-revised-IV ADHD (SNAP-RS IV ADHD), ADHD-RS Japanese version, investigator-administered (ADHD-RS J/I Total) or Parent/Investigator ADHD checklist score. Data from the safety outcomes were also extracted.

Altogether 25 RCTs, with 3 928 participants were included in the analysis. The mean follow-up time was 8,6 weeks (range: 4 – 18 weeks). The average ATX dose was 1,17 mg/kg/day. Mean age was 10,3 years, with 68,2 % being <13 years old. Altogether, 51,3 % were anti-ADHD medication naïve, and 44,6 % had comorbid ODD/CD.  

Based on all 25 studies with 3 928 participants, ATX outperformed placebo regarding overall ADHD symptoms (Effect Size = -0,67; CI 95 % -0,56 to -0,71; p<0,0001), hyperactivity / impulsivity (ES = -0,67; CI 95 % -0,53 to -0,81; p<0,0001), and inattention (ES = -0,59; CI 95 % -0,51 to -0,67; p<0,0001). Based on 14 studies with 2 384 participants, 44,4 % versus 21,4 % of patients improved by ≥40 % (NNT=4), the relative risk for not improving being 0,69 (CI 95 % 0,63 – 0,75). Respectively, based on 16 studies with 2 630 participants, 39,9 % versus 65,9 % improved by <25 % (NNT=4), relative risk of not improving being 0,60 (CI 95 % 0,55 – 0,67).

All-cause discontinuation with ATX was similar to that of placebo. However, ATX had higher discontinuation rate due to adverse effects (AEs) (RR = 1,89; CI 95 % = 1,08 – 3,31; p=0,03). At least 1 AE (70,4 % versus 56,1 %; p<0,01) and ≥1 psychiatric AE (21,5 % versus 7,4; p<0,01) were more frequent with ATX, whereas serious AEs, aggression, and suicidal ideation were not different from placebo.

  • Study quality: Moderate
  • Applicability: Good for short term treatment of children and adolescents in Finland  
  • Comment: The quality of evidence from this meta-analysis is downgraded, because no assessment of included studies was reported.

Another meta-analysis publiced 2015 «Stuhec M, Munda B, Svab V ym. Comparative efficacy...»2, having more strict inclusion criteria than «Schwartz S, Correll CU. Efficacy and safety of ato...»1, included 17 high quality studies with 2 459 participants in analysis of efficacy of atomoxetine (ATX) in core symptoms of ADHD in children and adolescents. Double-blind, randomized, parallel studies with placebo, lasting from 2 weeks at least to 3 months at most, and including children and adolescents under the age of 18 were included. Studies with comorbid conditions other than ODD were excluded. Studies where research methodology was not clear and affected the final clinical score, and studies where demographic data about children and adolescents and clinical outcomes was not clearly presented, were also excluded.

The following scales were used to measure outcomes in the included studies: ADHD Rating Scale-IV(ADHD-IV), Conners' Parent Rating Scale (CPRS), Conners' Teacher Rating Scale (CTRS), IOWA inattentive-impulsive-overactive scale (IOWA-IO), Swanson, Nolan, and Pelham, Version IV(SNAP-IV), Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN). All-cause discontinuation was used as a measure of acceptability.

Compared to placebo, treatment with ATX resulted in larger decrease in total ADHD symptom scores (Standard Mean Difference = -0,68; CI 95 % -0,59 to -0,76). Compared to placebo, discontinuation with ATX treatment was not statistically different (OR=0,91; CI 95 % 0,66 – 1,24).  

  • Study quality: Moderate
  • Applicability: Good for short term treatment of children and adolescents in Finland  

A review and network meta-analyses (NMA) published in Lancet Psychiatry August 7 2018 «Cortese S, Adamo N, Del Giovane C, ym. Comparative...»3 compared efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents and adults. The methodical quality of the NMA was good. 81 double-blind randomised controlled trials comparing amphetamines, atomoxetine (ATX), buprobion, clonidine, guanfacine, methylphenidate and modafinil with each other or placebo in the treatment of ADHD in children and adolescents were included. The exact number of studies comparing ATX with placebo in the treatment of ADHD in children and adolescents was not reported. However from the figure (Figure 2) it can be concluded that many of those included RCTs compared either ATX or methylphenidate with placebo. For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks ATX was superior to placebo (SMD –0,56, 95 % CI: -0,66 to -0,44). The result was significant but quality of evidence was low. For available comparison based on teachers' ratings ATX was not significantly more efficacious than placebo (SMD -0,32, 95 % CI: -0,82 to -0,18). The quality of evidence of this result reported to be very low. Authors did not find sufficient data for long-term effects of any of studied drugs.

  • Study quality: Moderate
  • Applicability: Good for short term treatment of children and adolescents in Finland  
  • Comment: Despite the low or very low quality of evidence this more recent NMA confirms previous evidence of efficacy of ATX with similar results.

Kirjallisuutta

  1. Schwartz S, Correll CU. Efficacy and safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: results from a comprehensive meta-analysis and metaregression. J Am Acad Child Adolesc Psychiatry 2014;53:174-87 «PMID: 24472252»PubMed
  2. Stuhec M, Munda B, Svab V ym. Comparative efficacy and acceptability of atomoxetine, lisdexamfetamine, bupropion and methylphenidate in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis with focus on bupropion. J Affect Disord 2015;178:149-59 «PMID: 25813457»PubMed
  3. Cortese S, Adamo N, Del Giovane C, ym. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry 2018;5(9):727-738 «PMID: 30097390»PubMed