This meta-analysis must be seen in the broader context of previous research on Health-Related Quality of Life (HR-QoL) in children and adolescents with ADHD [45
]. Several studies have investigated HR-QoL in these patients. These studies have shown robust negative effects on HR-QoL as reported both by parents and in patient self-reports. However, children with ADHD tend to rate their own HR-QoL less negatively than their parents and do not always see themselves as functioning less well than healthy controls [6
]. More severe symptoms and greater impairment predict poorer HR-QoL. Evidence is increasing that HR-QoL improves with effective treatment, both with psychostimulants and with atomoxetine, but most treatment studies have had relatively short follow-up periods [6
In comparing children and adolescents with ADHD, this meta-analysis investigated three different aspects: the evaluation of HR-QoL at baseline, the association between HR-QoL and ADHD core symptoms, and the treatment effect of atomoxetine on HR-QoL. The first two aspects were based on all 5 studies, whilst the treatment effect could only be evaluated in the 3 placebo-controlled trials.
In the population of the five studies, gender distribution was similar across age groups. As the studies were not designed to include the same proportion of boys across different age-groups, this finding is surprising. Usually one would assume that there would be a larger proportion of boys in a sample of children compared to a sample of adolescents. This could be due to the composition of samples in clinical trials as opposed to epidemiological samples.
Analyzing the ADHD-RS in the present post-hoc analysis, children had significantly higher hyperactive/impulsive sub-scores and total scores compared with adolescents at baseline. This finding is in line with previous literature regarding the differences in symptom patterns across age groups. Specifically, hyperactive/impulsive symptoms show a definite decline over time, while inattentive symptoms may become even more pronounced during adolescence [3
]. In our sample, adolescents showed numerically higher inattentive sub-scores, although the difference in scores did not reach statistical significance and are unlikely to be clinically relevant. However, as the hyperactivity/impulsivity issues decrease, the relative importance of the inattention problems may increase. These findings need to put into perspective. Goodman et al 2010 [46
] showed that ADHD-RS total score of 38.7 corresponded to moderately ill patients and 45.5 corresponded to markedly ill patients as measured by the CGI-S. Unfortunately, such data is lacking for the sub-scores of the ADHD-RS.
Baseline impairments in HR-QoL as measured by the CHIP-CE were seen on several dimensions (e.g., Satisfaction with Self, Threats to Achievement, and Academic Performance) in both age groups. Previous studies consistently reported on remarkable impairments in HR-QoL among children and adolescents with ADHD, especially in the emotional, behavioral, and achievement aspects [6
]. Similarly, in our meta-analysis clinically relevant impairments were found in the Risk Avoidance and Achievement domains (and in their sub-domains), in the Emotional Comfort and in the Satisfaction with Self sub-domains as well as Family involvement and Social Problem Solving. Adolescents were generally more impaired, compared with children, in the Satisfaction with Self sub-domain, the Family Involvement sub-domain and in the Achievement domain, while children were more impaired on the Emotional Comfort sub-domain. It may be that inter-family relationships, cooperation with family members, self-satisfaction, and academic performance are more sensitive areas of life in an adolescent compared to a child (especially in the lower age-range, 6-7 years), and that ADHD symptoms might have a more pronounced effect on these domains among adolescents relative to children.
The baseline correlations between the CHIP-CE and ADHD-RS scores indicated a consistent, small-to-moderate negative correlation between the core symptoms of ADHD and HR-QoL in both age groups without substantial age differences. This finding provides additional insight into the broad effect of ADHD symptoms. However, it should be noted that these correlations do not fully explain the background of the impaired HR-QoL in children and adolescents with ADHD. Besides the core symptoms (as measured by the ADHD-RS), other factors might play a role in the observed HR-QoL impairments. For example, comorbidities such as oppositional defiant disorder (ODD), conduct disorder (CD), anxiety, and depression were found to increase impairment and decrease HR-QoL in children and adolescents with ADHD as measured by the CHIP-CE in a cross-sectional analysis of observational data [47
]. This may explain the low to moderate correlation between ADHD core symptoms and HR-QoL in this meta-analysis. However, in order to analyze differential effects between children and adolescents in terms of factors influencing the impairment of HR-QoL, an even larger sample size would be required.
Based on our analysis, atomoxetine was effective in improving certain HR-QoL dimensions in both age groups. This finding is in line with several previous studies [15
]. Our results indicate that adolescents might benefit more from atomoxetine treatment than children with regard to improvement in the Risk Avoidance domain and Threats to Achievement sub-domain. It must be taken into account that the sample size of adolescents in these studies was rather low, which may have prevented some of the observed therapeutic effects from reaching statistical significance (e.g. in the Achievement domain).
In both age groups, correlations between the ADHD core symptoms and the HR-QoL were small to moderate at endpoint and with regard to the change from baseline. There was no substantial age effect on the correlations, except for a clear trend in the Risk Avoidance domain and sub-domains. Specifically, the correlations between the ADHD-RS scores (both sub-scores and total score) and the Risk Avoidance domain and sub-domains were smaller in adolescents with regard to change from baseline. This reduction in the strength of the correlation between changes in core symptoms and HR-QoL may indicate a slight detachment from the primary therapeutic effect of atomoxetine on core symptoms, especially when taking into account that atomoxetine showed the highest effect sizes in improving HR-QoL in the Risk Avoidance domain and sub-domains. Our findings regarding the low and moderate correlations between core symptoms and HR-QoL (and the small correlations found in several instances regarding change from baseline after treatment), warrant further investigation to determine more precisely which additional factors contribute to the overall impairment in ADHD beyond core symptoms, and which particular factors have an adverse impact on the HR-QoL of the individuals and their family.
The results of this meta-analysis need to be interpreted in light of a number of limitations. First, the samples of the five clinical trials showed heterogeneity in terms of cultural diversity, history of stimulant medication, and comorbidity. For example, the patients were from five different countries, where both public opinion on ADHD and approaches to treatment by physicians vary considerably. Such differences in terms of cultural diversity could have had an impact on the evaluation both of core symptoms as measured with the ADHD-RS, and health-related quality of life as measured with the CHIP-CE. Moreover, the pooled sample size of the adolescent treatment group from the three placebo-controlled trials was rather small, and thus, effect size estimations have to be interpreted with caution.
Second, drug history of the patients was mostly unknown (with the exception of Studies 2 and 4, where one of the inclusion criteria was that the patients had to be treatment-naïve): this could have introduced some variability in the evaluation of treatment efficacy. It has been already suggested in the literature that medication-naïve patients show better improvement [19
]. However, in Study 4, authors reported a lack of interaction between the treatment group (atomoxetine or standard care) and whether patients had been previously treated with medication for their ADHD, indicating that the treatment effect was similar for both groups of patients (treatment-naïve or not) in terms of improving CHIP-CE total score [23
]. Unfortunately, power to detect such interactions is generally low and further research is needed to obtain more information on treatment effect modifiers to ultimately tailor the medication to the individual patient.
Third, 8-12 weeks of follow-up might have been too brief for the evaluation of the improvement of HR-QoL. Though the findings of Perwien et al. [19
] indicate that the treatment effect of atomoxetine with regard to the improvement in HR-QoL can be detected after 7 to 8 weeks of treatment with atomoxetine, long-term studies are warranted in this regard: primary symptoms might change significantly within 3 months, but the consequences, at least in part, might need a longer period for improvement and/or stabilization. This needs to be taken into account when evaluating the clinical impact of the differences. The developers of the CHIP-CE have proposed that a threshold of 0.6 standard deviations is clinically meaningful [49
Fourth, in all studies, parents were the source of information on both core symptoms of ADHD and HR-QoL. This might have influenced the results in the sense that the parents and patients might have provided different responses, especially when evaluating adolescents. The views of the young people themselves, however, need to be sought in addition to parent reports, as the patient perspective reflects the subjective well-being of these children and adolescents and takes into account their autonomy as individuals [45
An additional limitation that introduces a difficulty in interpreting our results is that HR-QoL is a construct that, to date has not yet been well-defined. Hence, measuring this construct is still a challenge, as are all measurements of subjectively perceived psychological constructs [6
]. Although the CHIP-CE was validated and standardized on a large community sample of children and adolescents, it cannot be assured that CHIP-CE really reflects and captures all the relevant aspects of HR-QoL with regard to the evaluation of the broad impact of ADHD on the individual's life.
This meta-analysis also had several strengths. Most importantly, the sample size was large. Secondly, three of the five studies were placebo-controlled. Thirdly, the analysis was based on individual patient data rather than publication-based meta-analysis. Fourthly, the inclusion and exclusion criteria of the five studies included in the meta-analysis [47
] were very similar, resulting in a fairly homogeneous sample in terms of patient characteristics. Finally, the meta-analysis included patient reported HR-QoL outcomes as a secondary endpoint. Thus, the analysis can be considered an important contribution to the body of data on the relationship between outcomes in terms of ADHD core symptoms and HR-QoL outcomes based on closely monitored clinical trials rather than cross-sectional (or observational) studies.