This meta-analysis synthesized data from all trials comparing atomoxetine and methylphenidate in treatment of ADHD in children and adolescents. Placebo controlled trials have established that both methylphenidate and atomoxetine are effective in treatment of ADHD in children and adolescents [15
]. This meta-analysis shows that in children and adolescents with ADHD, although the effect size favours methylphenidate the difference was not statistically significant. Subgroup analysis shows a significant standardized mean difference favouring OROS methylphenidate over atomoxetine. However immediate release methylphenidate was not superior to atomoxetine. There was no difference in acceptability as measured by all cause drop-out rate for methylphenidate and atomoxetine.
Two previous meta-analysis comparing atomoxetine and methylphenidate have included a smaller number of studies. Meta- analysis by Gibson et al. included five head to head trials comparing psychostimulants and atomoxetine [33
]. The most recent meta-analysis excluded the largest studies by Kemner et al. as the study duration was only three weeks [34
]. Our findings support those by Gibson et al. that OROS methylphenidate showed superior efficacy but there was no significant difference between atomoxetine and immediate release methylphenidate [33
There is some evidence from randomized open label trials that OROS methylphenidate was superior to the immediate release form in treatment of ADHD [26
]. However other studies have found no significant difference in efficacy between immediate release MPH three times a day and once daily OROS MPH [36
Several methodological factors may have influenced the outcome of individual trials. The relatively lower efficacy of IR MPH may be explained by the dosing schedules. Only two studies administered an evening dose of IR MPH [16
]. Symptom severity was assessed using the parent version of ADHDRS-IV and parents are likely to evaluate behaviours occurring outside school hours. The effect of IR MPH may wear off later in the day and this could account for the lower efficacy when IR MPH was administered only once or twice daily. Our meta-analysis found that the standardized mean difference in ADHD scores between atomoxetine and methylphenidate using parent ratings were relatively small and the difference may have been much larger if studies had used teacher ratings, because teacher ratings evaluate behavior during school hours. However only one study included in this meta-analysis used teacher ratings [30
]. A meta-analysis by Cheng et al. showed that the effect size of atomoxetine using parent ratings was 0.34, about half of the effect size in teacher rating of 0.62 [39
]. The meta-analysis reported a much smaller effect size for atomoxetine than that reported for MPH in studies using teacher ratings. Therefore the advantage of methylphenidate over atomoxetine appears larger in school than at home.
In contrast long acting OROS-methylphenidate which provides coverage in the late afternoon and evening may have an advantage over the immediate release form. The immediate release MPH equivalent does of OROS MPH used in the trials was 0.84 mg/kg-0.97 mg/kg. Therefore dose alone cannot account for the superiority of OROS methylphenidate.
Four trials used high doses of atomoxetine (> 1.4 mg/kg) administered twice daily [18
]. The outcome in three of these trials favoured atomoxetine suggesting that higher doses of atomoxetine administered twice daily may be more effective.
Some design features would have been disadvantageous to atomoxetine. The trial with the largest number of participants was of short duration of three weeks [19
]. This time period may not be adequate as optimal efficacy of atomoxetine requires 4-6 weeks of treatment [40
]. Two trials excluded participants with previous poor response to methylphenidate, a design feature which would have favoured methylphenidate [27
]. Although ADHD has high rates of comorbidity, subjects with tics, family history of Tourette syndrome and anxiety were excluded in most studies because methylphenidate use is contraindicated in these conditions. This may have exclude participants who are poor methylphenidate responders. Atomoxetine may not be as effective in patients with comorbid oppositional defiant disorder (ODD) [41
]. Of all the trial participants 36% were diagnosed as having comorbid ODD.
Atomoxetine may be recommended for those with comorbid conditions where methylphenidate is contraindicated. Methylphenidate is contraindicated in individuals with structural cardiac abnormalities, arrhythmias, psychosis and suicidal ideation. However reports of suicidal ideation with atomoxetine and hepatic disorders have prompted warnings about the use of atomoxetine in these conditions [42
]. In cardiovascular disease too, atomoxetine must be used with caution. There are concerns about the use of stimulants in children with comorbid seizure disorder and tics. There is evidence that in individuals with well controlled epilepsy, stimulants can be used safely and atomoxetine may also be associated with increased risk of seizures [43
]. A recent review suggests that stimulants may not worsen tics in most with tic disorders [44
The findings of this meta-analysis have to be interpreted cautiously because of several limitations. Interpretation of our findings is hampered by the substantial heterogeneity across studies. Sensitivity analysis showed the source of heterogeneity is the open label studies. Open label studies introduce bias as patient and investigator expectations can influence outcome. Because the number of studies within each subgroup is small there may not be adequate power to detect a difference between the two treatments. We did not include unpublished data from conference abstracts, dissertations and unpublished pharmaceutical company data, therefore publication bias is a distinct possibility. Tests for funnel plot asymmetry were not done as the Cochrane handbook for systematic reviews recommends that tests for funnel plot asymmetry should be used only when there are at least 10 studies included in the meta-analysis [45
]. Since many of the trials excluded subpopulations with comorbid conditions the results of the meta-analysis cannot be generalized to these subpopulations. Seven studies were funded by Eli Lilly and Company manufacturers of atomoxetine and one study was sponsored by McNeil Consumer and Specialty Pharmaceuticals [19
]. In addition several design features would have influenced the outcome of trials including non- inclusion of teacher rating scales which would have been a disadvantage for methylphenidate.
The findings of the meta-analysis have implications for clinical practice. The results from the meta-analysis show that in general atomoxetine and methylphenidate have comparable efficacy and equal acceptability in treatment of ADHD in children and adolescents. It also suggests that OROS methylphenidate is more effective and may be considered as first line treatment in treatment of ADHD in children and adolescents. Atomoxetine may be used in those with poor response to methylphenidate or where stimulant abuse is a cause for concern. Use of higher doses of atomoxetine administered twice daily may result in better outcome.