Meta-analysis: Dose-Dependent Effects of Methylphenidate on Neurocognitive Functioning in Children With Attention-Deficit/Hyperactivity Disorder

Karen Vertessen, Marjolein Luman, Anouck Staff, Pierre Bet, Ralph de Vries, Jos Twisk, Jaap Oosterlaan

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
JournalJournal of the American Academy of Child and Adolescent Psychiatry
Early online date2021
Publication statusE-pub ahead of print - 2021

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