Meta-analysis: Dose-Dependent Effects of Methylphenidate on Neurocognitive Functioning in Children With Attention-Deficit/Hyperactivity Disorder
Karen Vertessen, Marjolein Luman, Anouck I. Staff, Pierre M. Bet, Ralph de Vries, Jos W. R. Twisk, Jaap Oosterlaan
Abstract
OBJECTIVE: Neurocognitive deficits are at the heart of explanatory models of attention-deficit/hyperactivity disorder (ADHD), and lead to significant impairments in daily life. Determining the dosing effects of methylphenidate (MPH) on a broad range of neurocognitive functions and investigating possible impairing effects of high doses is therefore important. METHOD: Placebo-controlled trials were included that investigated MPH dosing effects on neurocognitive functions in children and adolescents (aged 5-18 years) diagnosed with ADHD. Effect sizes (standardized mean differences [SMDs]) were calculated for different neurocognitive functions (baseline speed, variability in responding, nonexecutive memory and executive memory, inhibitory control, and cognitive flexibility) and, if available, for ADHD symptoms. Meta-regression analysis were used to investigate linear effects of dose (mg/kg/dose), and separate meta-analyses compared SMDs for 3 MPH dose ranges: low (0.10-0.30 mg/kg/dose), medium (0.31-0.60 mg/kg/dose), and high (0.61-1.00 mg/kg/dose). RESULTS: A total of 31 studies fulfilled inclusion criteria, comprising 804 children with ADHD. Methylphenidate had beneficial effects on all neurocognitive functions (d = 0.20-0.73). Significant linear dosing effects were found for ADHD symptoms and lower-order neurocognitive functions (baseline speed, variability in responding, nonexecutive memory), with greater enhancement of functioning with increasing dose. No dosing effects were found for higher-order neurocognitive functions (executive memory, inhibitory control, and cognitive flexibility). No detrimental effects of MPH were found on any of the investigated functions. CONCLUSION: Methylphenidate was superior to placebo in improving ADHD symptoms and a broad range of neurocognitive functions; however, effects sizes regarding the effects of dose vary substantially between functions. Our data highlight the importance of considering both neurocognitive and symptomatic aspects of ADHD in clinical practice.