DOI: 10.25934/pr00009360
title: Moderators of treatment response to stimulants in preschoolers with attention-deficit/hyperactivity disorder: an individual patient data meta-analysis

description: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity that lead to interference in functioning and/or development in at least two different scenarios (e.g., at home and at school) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). As usual with neurodevelopmental disorders, ADHD onsets early in life, with currently available estimates indicating that approximately 2% of preschool children meet diagnostic criteria for ADHD. ADHD in preschoolers is a relatively stable diagnosis into the school years. Besides, preschool ADHD is associated with increased morbidity (ie. other illnesses) and mortality for children between 3-5 years. Therefore, effective interventions for preschool ADHD are warranted.

Current recommendations from clinical practice guidelines (CPGs) such as those from the American Academy of Pediatrics or the UK National Institute for Health & Care Excellence indicate that parent training should be adopted as a first-line treatment in the management of ADHD in preschoolers. However, assessors (e.g. parents) who are aware of the behavioral intervention (ie., they are not blinded) tend to indicate better improvement in severity scores (ie. more efficacy) than assessores who are not aware of the behavioral intervention (ie., they are blinded). Besides, most children with preschool ADHD who undergo a trial of parent training may still require additional treatment with stimulants due to lack of improvement with the behavioral intervention. 

The two main drug treatments for ADHD are stimulants and antipsychotics. Stimulants (e.g., methylphenidate, amphetamines) enhance dopamine signaling in the brain. Antipsychotics have the opposite effect to stimulants, blocking dopamine signaling in the brain. Dopamine is a chemical messenger involved in the brain's reward center and in many body functions, including mood, attention etc. Although antipsychotics are efficacious for the treatment of several psychiatric disorders, they have significant side effects and should be used cautiously, particularly in children and adolescents.

We have recently conducted a systematic review (ie. a review of all available literature through systematic processes) and a meta-analysis (ie. the use of statistical methods to summarize the results of eligible research studies) of aggregated data from randomized clinical trials (RCTs) of stimulants (methylphenidate, amphetamines) versus placebo for preschoolers with ADHD and demonstrated that stimulants are more efficacious than placebo. This previous study reinforces the importance of stimulants in the treatment of preschoolers and calls into question the practices adopted in routine clinical practice as often other medications (e.g., antipsychotics, for example risperidone or aripiprazole) are administered prior to stimulants for very young children with ADHD. However, we were not capable of investigating the baseline (ie. immediately prior to starting an intervention) characteristics that were associated with a larger effect of stimulants as compared to placebo because that would require individual participant data instead of group-level information.

Identifying who may benefit most from stimulants is a highly clinically relevant question in the field of preschool ADHD. We recently conducted a landmark RCT comparing methylphenidate against parent training which showed that in terms of improvement in ADHD symptoms, methylphenidate outperformed placebo while behavioral parent training did not. Nevertheless, head-to-head comparisons between methylphenidate and parent training did not show significant differences across treatment groups. Therefore, in a scenario where treatments may be equally efficacious, if we know who are the individuals that benefit the most from stimulants we may be able to prioritize certain treatments and improve our practices in the management of preschoolers with ADHD. For instance, if we find that the severity of symptoms at baseline moderates the association between treatment with stimulants and improvement in preschoolers, then CPGs should amend their recommendations and indicate that preschool children with severe ADHD should receive stimulants as a first-line treatment instead of behavioral parent training.

Because individual RCTs are typically designed to have statistical power (ie. sensitivity to detect an effect) for the primary outcome involving the randomized treatment groups, analyses to evaluate differences in subsets of individuals based on only one RCT are typically underpowered and their results may not be generalizable, which limits applicability and impact of the findings. Individual participant data (IPD) meta-analysis collating data from all RCTs that are available provides an opportunity to address these limitations. 

In this study, we aim to fill this gap and conduct an IPD meta-analysis of RCTs of stimulants against placebo for preschool ADHD. The resulting findings will hopefully be of great clinical relevance and will help stratify current treatment recommendations for preschool ADHD.