Attention-deficit hyperactivity disorder (ADHD) is a behavioural condition characterised by impairing levels of inattention, hyperactivity, or impulsivity – or a combination of these behaviours. The condition is usually diagnosed in childhood with a prevalence of around 5% in school-age children and 2.5% in adults worldwide. The exact cause of ADHD is unknown; however, current evidence suggests that genetics may play a role. Individuals with ADHD may also experience other problems, such as sleep and anxiety disorders.
Current pharmacological treatments for ADHD include psychostimulants and non-psychostimulant medications. Prescriptions for ADHD treatments have been on the rise in recent years, in line with clinical guidelines; however, the efficacy and safety of these medications remain uncertain. Furthermore, clinical guidelines are inconsistent in their treatment recommendations. For example, while some guidelines rank methylphenidate over amphetamines (both psychostimulants), others recommend psychostimulants as a first-line treatment with no distinction made between the two medications. The methods used for sequencing the recommendations for treatment (i.e., first-line, second-line, and third-line treatments) are not always specified.
Previous network meta-analyses, designed to estimate the comparative efficacy and tolerability of two or more interventions, have focused on either children and adolescents or adults only, have typically compared only a few drugs, or have addressed exclusively the safety of treatments. The authors of a recent systematic review aimed to fill this gap with a network meta-analysis of double-blind randomised controlled trials in children, adolescents and adults with ADHD. The aim was specifically “to compare ADHD medications in terms of efficacy on core ADHD symptoms, clinical global functioning, tolerability, acceptability, and other clinically important outcomes.”
Design and Methods of the Study
The review included double-blind randomised controlled trials of at least one week’s duration, that enrolled children, adolescents, or adults with a primary diagnosis of ADHD according to appropriate diagnostic criteria.
Studies were included if they assessed any of the following medications as oral monotherapy, compared with each other or with placebo: amphetamines, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate (including dexmethylphenidate), and modafinil.
The primary outcome for analysis was efficacy, which was measured by change in severity of ADHD core symptoms based on clinician’s ratings. For children and adolescents, the researchers also considered teachers’ ratings as a primary efficacy outcome. The tolerability of medications in children, adolescents, and adults was also considered.
Secondary outcomes included the change in severity of ADHD core symptoms based on parents’ ratings for children and adolescents and self-reports for adults, clinical global functioning measured by the Clinical Global Impression–Improvement, acceptability, and change in weight and blood pressure.
Results of the Study
A total of 133 randomised controlled trials were included in the final network meta-analysis. Overall, all medications, except modafinil in adults, were more efficacious than placebo for the short-term treatment of ADHD core symptoms. However, they were less efficacious and less well tolerated in adults than in children and adolescents. While amphetamines were the most efficacious treatment in children, adolescents, and adults, the effects of medications varied across age groups for several outcomes.
In children, only amphetamines and guanfacine were less well tolerated than placebo, while in adults, methylphenidate, amphetamines, and atomoxetine were worse than placebo. Amphetamines were also found to significantly increase diastolic blood pressure in children and adolescents but not in adults. In children and adolescents, methylphenidate was the only drug with better acceptability than placebo; in adults, amphetamines were the only compound with better acceptability than placebo.
Atomoxetine had the lowest mean effect size in children and adolescents based on clinicians’ ratings, but in adults, its efficacy on ADHD core symptoms was comparable with that of methylphenidate. However, the authors of the current study note that, the large confidence interval in relation to the efficacy and tolerability of bupropion, clonidine, guanfacine, and modafinil suggests that caution should be used when interpreting these data. Furthermore, the absence of significant differences between amphetamine and methylphenidate on the Clinical Global Impression–Improvement measure is another relevant finding which requires replication in head-to-head trials.
Having accounted for all included outcomes, the authors of this systematic review and network meta-analyses conclude that current evidence supports the use of methylphenidate in children and adolescents, and amphetamines in adults, as the first pharmacological choice for ADHD treatment. The authors also note the importance of monitoring secondary outcomes, including weight and blood pressure changes with atomoxetine as much as with stimulants.
The findings of this study concur in part with the guidelines from the National Institute of Health and Care Excellence (NICE), in which methylphenidate is recommended as the first choice in children and adolescents and methylphenidate or lisdexamfetamine as the first choice in adults. However, it is noted that NICE recommendations were informed not only by empirical evidence but also by considerations on costs and licence and flexibility of formulations.
The authors do note some limitations to this study – for example, most studies included for review compared active drugs to placebo while the number of head-to-head comparisons was quite small. Therefore, comparative efficacy between interventions was frequently based on indirect comparisons. Nonetheless, the authors conclude: “our findings represent the best currently available evidence base (not constrained by local costs and licencing) to inform future guidelines internationally and shared decision-making between patients, carers, and clinicians, when a balance has to be made between efficacy and tolerability of ADHD medications.”