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Cited by 29Attention Deficit Hyperactivity DisorderDevelopmental and Educational NeuropsychologySchizophrenia research and treatment

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

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Vertessen, Karen, Luman, Marjolein, Staff, Anouck, Bet, Pierre, de Vries, Ralph, Twisk, Jos, Oosterlaan, Jaap·2022·Journal of the American Academy of Child & Adolescent Psychiatry
DOI 10.1016/j.jaac.2021.08.023
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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.

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  • Four meta-analyses testing predominantly single dose effects of stimulants on cognitive performance in children and adults with ADHD have most consistently found effects on mean reaction time (MRT), attention, inhibition and working memory (WM).

    “Four meta-analyses testing predominantly single dose effects of stimulants on cognitive performance in children and adults with ADHD, have most consistently found effects on mean reaction time (MRT), attention, inhibition and WM (17, 22, 29, 30).”

    From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [30]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • Methylphenidate both in acute and longer-term dosage has been shown to improve inhibitory measures.

    “This was also unexpected as methylphenidate both in acute and longer-term dosage has been shown to improve inhibitory measures (17, 22, 29–31).”

    From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [30]

    The Discussion (page unavailable) reports a small overall beneficial effect of methylphenidate on inhibitory control. Table 1 lists inhibitory-control studies with treatment periods ranging from one day to 14 days, but the paper does not establish a separate longer-term effect; its analysis concerns dose rather than treatment duration. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The study's findings could extend evidence for acute and chronic methylphenidate administration significantly improving timing and attention functions in children with ADHD including the same tasks.

    “These findings could extend evidence for acute and chronic methylphenidate administration significantly improving timing (66, 94) and attention functions in children with ADHD including the same tasks (22, 29–31).”

    From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [30]

    The paper’s Conclusion reports that methylphenidate improved a broad range of neurocognitive functions in children with ADHD, and its study table includes attention-related tasks (Variability in Responding). But the Discussion says the meta-analysis could assess only short-term effects, so it does not establish significant improvement after chronic administration. In the citing sentence, the timing claim is attached to other citations, not this paper. (LLM, conf=0.86)

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  • The lisdexamfetamine effects on RT and CV extend findings that methylphenidate consistently improves RTV and RT in children with ADHD.

    “They extend findings of methylphenidate consistently improving RTV and RT in children with ADHD (22, 29–31), with meta-analytic fMRI evidence showing that this may be underpinned neurofunctionally by MPH-induced deactivation of frontal areas of the DMN which is associated with RTV in people with ADHD (75).”

    From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [30]

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Cited by

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Authors
Vertessen, K., Luman, M., Staff, A., Bet, P., de Vries, R., Twisk, J., & Oosterlaan, J.
Affiliations
  • Vrije Universiteit Amsterdam (NL)
  • Amsterdam University Medical Centers (NL)
Corresponding author
Vertessen, Karen
ORCID
Venue
Journal of the American Academy of Child & Adolescent Psychiatry
Publisher
Elsevier BV
Published
2022-05
Volume
61
Issue
5
Pages
626-646
ISSN
0890-8567 (ISSN-L)
DOI
10.1016/j.jaac.2021.08.023
OpenAlex
W3200541655
Cited by
29
References
17
Citations by year
2026: 5 · 2025: 8 · 2024: 7 · 2023: 4 · 2022: 4 · 2021: 1
FWCI
0.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American Academy of Child & Adolescent Psychiatry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • VU Research Portal (publishedVersion, cc-by)
  • Lirias (submittedVersion, cc-by)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
Innovatiefonds Zorgverzekeraars (3119)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Social Sciences › Psychology › Neuropsychology and Physiological Psychology › Developmental and Educational Neuropsychology
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
methylphenidate, attention deficit hyperactivity disorder, dose-response relationship, neurocognitive function, children and adolescents, executive function, inhibitory control, cognitive flexibility, response variability, ADHD symptoms, stimulant medication
MeSH terms
Adolescent, Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Child, Humans, Methylphenidate, Treatment Outcome

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