Definition of Response in Randomized Controlled Trials of Medications for Attention-Deficit/Hyperactivity Disorder Across the Lifespan: A Systematic Review.

Abstract

Objectives: Randomized controlled trials (RCTs) are the gold standard for evaluating medication efficacy. The absence of a universal definition of treatment response, based on the degree of symptom improvement measured by standardized rating scales in the field of attention-deficit/hyperactivity disorder (ADHD), makes it difficult to compare treatment outcomes across RCTs. Here, we aimed to assess to what extent and how "treatment response" is defined across RCTs of ADHD medications. Methods: We identified eligible RCTs via the MED-ADHD database (https://med-adhd.org/), which compiles RCTs evaluating the efficacy and safety of pharmacological treatments for children, adolescents, and adults with ADHD, based on a comprehensive search in multiple electronic databases, including PubMed, BIOSIS Previews, CINAHL, the Cochrane Central Registry of Controlled Trials, and EMBASE, up to 17 January 2025, alongside additional unpublished information gathered from manufacturers/study authors. Results: Out of 167 RCTs in MED-ADHD, 88 defined treatment response based on reductions in ADHD core symptom severity using rating scale scores. The most frequently used threshold was a ≥30% reduction in attention-deficit/hyperactivity disorder (ADHD-RS) scores, with other RCTs using ≥25%, ≥40%, or ≥50%. In addition, RCTs applied similar cutoff values to alternative scales, including Conner's Adult ADHD Rating Scale, SNAP-IV, Adult ADHD Investigator Rating Scale, and Wender-Reimherr Adult Attention Deficit Disorder Scale. However, 79 studies did not specify any response threshold. Conclusion: Our review underscores and quantitatively defines the inconsistency in the definition of treatment response across ADHD medication trials, highlighting the urgent need for the field to reach a consensus on the use of a standardized definition of "treatment response" for each rating scale, based on the percentage reduction in ADHD core symptom severity.