Journal Pre-proof

Meta-analysis: Dose-dependent Effects of Methylphenidate on Neurocognitive

Functioning in Children With Attention-Deficit/Hyperactivity Disorder

Karen Vertessen, MD, Marjolein Luman, PhD, Anouck Staff, MSc, Pierre Bet, PhD,
Ralph de Vries, MSc, Jos Twisk, PhD, Jaap Oosterlaan, PhD
PII: S0890-8567(21)01709-3
DOI: https://doi.org/10.1016/j.jaac.2021.08.023
Reference: JAAC 3679

To appear in: Journal of the American Academy of Child & Adolescent

Psychiatry

Received Date: 12 August 2020

Revised Date: 9 August 2021
Accepted Date: 20 August 2021

Please cite this article as: Vertessen K, Luman M, Staff A, Bet P, de Vries R, Twisk J, Oosterlaan J,
Meta-analysis: Dose-dependent Effects of Methylphenidate on Neurocognitive Functioning in Children
With Attention-Deficit/Hyperactivity Disorder, Journal of the American Academy of Child & Adolescent
Psychiatry (2021), doi: https://doi.org/10.1016/j.jaac.2021.08.023.

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© 2021 Published by Elsevier Inc. on behalf of the American Academy of Child and Adolescent
Psychiatry.
Meta-analysis: Dose-dependent Effects of Methylphenidate on Neurocognitive Functioning in
Children With Attention-Deficit/Hyperactivity Disorder
RH = Effect of Methylphenidate on Cognition

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

Accepted September 7, 2021

Editorial
Supplemental Material

Mss. Vertessen and Staff, Dr. Luman, Mr. de Vries, and Prof. Oosterlaan are with VU
Amsterdam, the Netherlands. Ms. Vertessen is also with the University Psychiatric Centre,
Katholieke Universiteit Leuven, Belgium. Dr. Bet and Profs. Twisk and Oosterlaan are with

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Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands.

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This manuscript is part of the project ‘Reduce and optimize methylphenidate use in children
and adolescents with ADHD’, project number 3119 funded by Innovatiefonds
Zorgverzekeraars. -p
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Prof. Twisk served as the statistical expert for this research.
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Author Contributions
Conceptualization: Vertessen, Luman, Bet, Oosterlaan
Data curation: Staff, de Vries, Oosterlaan
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Formal analysis: Vertessen, Twisk

Funding acquisition: Oosterlaan
Investigation: Vertessen, Staff
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Methodology: Vertessen, Oosterlaan

Project administration: Vertessen
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Supervision: Luman, Twisk, Oosterlaan

Visualization: Vertessen
Writing – original draft: Vertessen
Writing – review and editing: Luman, Staff, Bet, de Vries, Twisk, Oosterlaan

ORCID
Karen Vertessen, MD: https://orcid.org/0000-0001-8601-6406
Marjolein Luman, PhD: https://orcid.org/0000-0002-1539-2831
Anouck Staff, MSc: https://orcid.org/0000-0002-2333-7189
Pierre Bet, PhD:
Ralph de Vries, MSc: https://orcid.org/0000-0002-2075-7495
Jos Twisk, PhD:
Jaap Oosterlaan, PhD: https://orcid.org/0000-0002-0218-5630

Disclosure: Dr. Vertessen has been involved in a clinical trial sponsored by Takeda. Drs.
Luman and Bet, Profs. Twisk and Oosterlaan, Ms. Staff, and Mr. de Vries have reported no
biomedical financial interests or potential conflicts of interest.
Correspondence to Karen Vertessen, MD, VU Amsterdam, Van der Boechorststraat 7, 1081
BT Amsterdam, The Netherlands; e-mail: k.vertessen@vu.nl

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Abstract

Objective: Neurocognitive deficits are at the heart of explanatory models of ADHD and lead

to significant impairments in daily life. Determine dosing effects of methylphenidate (MPH)

on a broad range of neurocognitive functions and investigate 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 (5–18 years) diagnosed with ADHD. Effect sizes (SMD)

were calculated for different neurocognitive functions (baseline speed, variability in

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responding, non-executive memory and executive memory, inhibitory control and cognitive

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flexibility) and, if available, for ADHD symptoms. Meta-regression analysis were used to
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investigate linear effects of dose (mg/kg/dose) and separate meta-analyses compared SMDs
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for three MPH dose ranges: low (0.10-0.30 mg/kg/dose), medium (0.31-0.60 mg/kg/dose) and
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high dose (0.61-1.00 mg/kg/dose).

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Results: Thirty-one studies fulfilled inclusion criteria comprising 804 children with ADHD.

MPH had beneficial effects on all neurocognitive functions (d=0.20-0.73). Significant linear
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dosing effects were found for ADHD symptoms and lower-order neurocognitive functions
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(baseline speed, variability in responding, non-executive 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 for MPH were found on any of the investigated functions.

Conclusion: MPH is 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 highlights the importance of considering both

neurocognitive and symptomatic aspects of ADHD in clinical practice.

Key words: attention-deficit disorder with hyperactivity, drug therapy

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Introduction

Attention-Deficit/Hyperactivity Disorder (ADHD) is the most prevalent childhood-onset

psychiatric disorder1. Methylphenidate (MPH) is a preferred pharmacological agent for

treating the core symptoms of the disorder, including inattention, hyperactivity and

impulsivity, and producing large-sized beneficial effects (d = 0.83)2, 3.

Neurocognitive dysfunction is at the heart of many explanatory models of ADHD4-10,

with extensive studies showing impaired functioning across a broad range of neurocognitive

functions among children with ADHD. These neurocognitive functions can be classified into

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higher and lower-order neurocognitive functions, which range from executive functioning, an

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umbrella term for higher-order neurocognitive functions that require a high level of effort
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(e.g., executive memory, inhibitory control, cognitive flexibility)11, to non-executive, lower-
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order functions that are less consciously controlled (e.g., reward processing12, mean response
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time, response time variability13, temporal information processing14 and memory13). Within
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most explanatory models of ADHD, neurocognitive difficulties are considered to be

heterogenous and are assumed to originate from multiple neurobiologically independent

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pathways12, 15. This idea is confirmed by the finding that some children may have difficulty
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with one or more specific neurocognitive functions, that very few children exhibit difficulties

with all functions15, and that some children show no neurocognitive impairment at all11, 16.

Furthermore, there is an emergent body of evidence on the role played by neurocognitive

functioning in functional impairments of children with ADHD17. These impairments include,

academic deficiencies18, 19, as well as increased risk of experiencing major physical injury and

hospitalization20.

MPH treatment has been found to have beneficial, but heterogenous effects on

neurocognitive functioning21-25. One important explanation for this heterogeneity is the use of

different doses across studies. Some studies comparing different doses of MPH reported that

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higher doses produced better effects on certain neurocognitive functions26, 27, while

simultaneously showing no effects on other neurocognitive functions26, 27. However, concerns

have been raised about the potential detrimental effects of high MPH doses. Some studies

have shown that medium doses have better outcomes than high doses for specific

neurocognitive functions (e.g., inhibitory control, cognitive flexibility), suggesting that using

higher doses to improve ADHD symptoms might actually impair neurocognitive performance

in comparison to lower doses28-30.

The relation between improvements in ADHD symptoms and neurocognitive

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outcomes has been studied by Coghill et al.24 showing that the beneficial effects of MPH on

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neurocognitive functions, and in particularly on lower-order neurocognitive functions, were
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paralleled by beneficial effects on ADHD symptoms in the same participants31, 32. However,
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the relationship between neurocognitive functioning and symptomatology in ADHD is
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complex and literature suggesting a causal relationship between the two is inconsistent33.
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Although some have argued that ADHD symptoms and neurocognitive functioning

may be part of a shared underlying mechanism, with some neurocognitive functions playing a
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more central role in ADHD than others (e.g., lower-order cognitive functioning, see also the
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model by Halperin and Schulz17), an alternative explanation may be that neurocognitive and

symptomatic changes in response to MPH may independently contribute to an improvement

in functional impairments. In other words, it remains unclear whether neurocognitive

difficulties cause ADHD symptoms or merely reflect the pleiotropic outcomes of risk

factors10, 15, 25.

Gaining a better understanding of the effects of MPH on neurocognitive functioning is

warranted in light of the central role of neurocognitive functioning within explanatory models

of ADHD, the contradictory evidence regarding the dosing effects of MPH across the broad

range of neurocognitive functions affected, as well as the ongoing concern about the

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detrimental effects of high doses in particular. Currently, there is only one meta-analysis on

the impact of MPH on neurocognitive functioning in ADHD21. That meta-analysis included

36 studies and showed that MPH had beneficial effects across all neurocognitive functions

investigated. However, dose effects were not studied.

The current study expands upon this work in several respects. First, we were able to

add seven years of recent literature on this topic, along with including the effects of MPH on

cognitive flexibility in our analysis. Second, we investigated the dose-response relationship of

MPH. Finally, we investigated whether high MPH doses may lead to a deterioration in

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neurocognitive outcomes compared to lower doses.

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Method
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This meta-analysis was conducted in accordance with the Preferred Reporting Items for
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Systematic Reviews and Meta-Analyses (PRISMA)-statement34.

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Search strategy
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To identify all relevant publications, systematic searches were conducted in the bibliographic
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databases PubMed, Embase, PsycINFO and the Cochrane Library, from inception until 12

December 2019. The following terms and their equivalents were combined as index terms or

free-text words: methylphenidate, attention deficit hyperactivity disorder and dose. In the

initial search, no specific neurocognitive functions or tests were used in order to include the

broadest possible range of neurocognitive functions. Next, all duplicate articles were

excluded. See Figure 1 for the flow diagram. The full search strategy can be found in Table

S1-4, available online.

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Study selection

This meta-analysis included all studies that (1) evaluated the effects of MPH on one or more

neurocognitive functions; (2) included a sample of children aged 5-18 years who had a

primary diagnosis of ADHD (DSM III-R and later versions or ICD-10 criteria); (3) used a

double-blind within-subject placebo-controlled crossover design; (4) reported sufficient data

from which to derive dosing in mg/kg; and (5) were published in an English-language peer-

reviewed journal. Single case studies were excluded.

Titles and abstracts were independently screened by two authors (K.V. and A.S.) using

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the Covidence systematic review tool35. Thereafter, the full-text articles were screened for

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their eligibility. In the case of disagreement, a consensus was subsequently reached after
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discussion with a third author (M.L. or J.O.). We only analysed the available data reported in
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the manuscripts. In the event that articles described overlapping cohorts, we included all the
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papers that reported on separate neurocognitive functions. If articles reported on similar

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neurocognitive functions among overlapping cohorts, then, ultimately, the one with the largest

sample size was included.

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Measures

The primary measurement potential was determined for all neurocognitive measures for

which MPH effects were reported. This was done using hallmark publications on the

taxonomy of neurocognitive functions13, 14, 36, 37. The results are shown in Table S5-11,

available online. In the event of any doubt, a consensus was subsequently reached after

discussion between the authors K.V., M.L. and J.O. A neurocognitive function was included

in the current meta-analysis if three or more studies reported data for that function. If they

were reported in the available studies, the dose effects were meta-analysed for ADHD

symptom counts.

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Statistical Analysis

The statistical analyses were conducted using Comprehensive Meta-Analysis software,

version 3.038. For each study, one SMD was calculated for each neurocognitive function,

taking into account all the outcome measures that were reported in the study38. The

standardized mean difference (SMD) was then used as the effect size, with 0.2, 0.5 and 0.8

used as the thresholds for small, medium and large effects, respectively39.

For each individual study, the effect sizes (SMD) were calculated for each neurocognitive

function and for each dose of MPH in comparison to a placebo. We adopted a two-step

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approach to determine the effects of the dose. First, we performed meta-regression analyses to

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quantify the linear relationship between the dose (mg/kg) and each of the neurocognitive
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functions considered. Second, three dose ranges were created, namely low (0.10-0.30
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mg/kg/dose), medium (0.31-0.60 mg/kg/dose) and high dose (0.61-1.00 mg/kg/dose), and the
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effects of each of these three dose ranges were compared to a placebo. For long acting MPH,
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the dose was converted into mg/kg/dose of immediate release MPH, based on the

pharmacokinetic profile40. This categorical approach allowed for the possibility of detecting
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non-linear dose-response curves, as well as providing clear cut-offs to translate this research
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into clinical practice. The distinction drawn between low, medium and high dose was based

on commonly used doses in clinical practice41, 42 and the categorization used in the included

studies43-45, which, ultimately, resulted in an arbitrary division into three equally wide

categories. Comparisons between the effects of the three dose ranges were interpreted as

being significantly different from another if the point estimate of the aggregated effect size for

a certain dose range did not fall within the 95% confidence interval (CI) of the other dose

ranges.

In the analyses, the results for the different doses tested in a given study were treated

as parallel study results46. Although the results of this approach approximate those from a

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paired analysis, the resulting 95% CIs are likely to be too wide rather than too narrow, thus

mitigating against Type I errors47. Given the heterogeneity of the studies included in the meta-

analysis, both in terms of the study designs and the neurocognitive measures used, random

effects models were used46. The I2 statistic was calculated for each dose range as an estimate

of between-trial heterogeneity in SMD48. We used the Cochrane guidelines49 to interpret the I2

statistic with values up to 40% representing variance unlikely to be important, values 30-60%

representing moderate heterogeneity, values 50-90% representing substantial heterogeneity,

and values 75-100% representing considerable heterogeneity.

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Publication Bias
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Two methods were used to assess the likelihood that publication bias might have influenced
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the results: (a) The degree of funnel plot asymmetry was determined50 (two sided, α = .05),
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and (b) Rosenthal’s failsafe N was calculated to determine the number of studies needed to
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nullify the meta-analytic effect51.

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Study Quality
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The Cochrane Risk of Bias 2.0 tool (cross-over trials) was used to assess the study quality. All

the included studies were independently rated by two of the authors (K.V. and A.S.). In the

event of disagreement, a consensus was subsequently reached after discussion with a third

author (M.L. or J.O.)

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Results

A total of 31 unique studies contributed data to the meta-analysis and meta-regression

including 804 children. Table 1 provides an overview of the studies included. These

encompassed the following six neurocognitive functions: baseline speed (e.g., Stop-Signal

Task, mean RT), variability in responding (e.g., Continuous Performance Task, RT SD), non-

executive memory (e.g., Digit Span Forward, correct responses), executive memory (e.g.,

Digit Span Backward, correct responses), inhibitory control (e.g., Go/No-Go task, errors of

commission), cognitive flexibility (e.g., Trail Making Task Form B, execution time).

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Dose effects of MPH on neurocognitive functioning and symptom counts
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The dose effects are presented in detail for each task in Table 2 and Figure 2. Table 2
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provides an overview of the meta-analytic findings, the heterogeneity statistics, and the
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publication bias analysis. Figure 2 shows the results of the meta-regression analysis with the
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dose in mg/kg/dose as a predictor.

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Publication bias
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Egger’s test for publication bias indicated no asymmetry between any of the neurocognitive

functions, with the exception of the overall results for non-executive memory and the low

dose range results for executive memory. It is thus unlikely that publication bias meaningfully

influenced the results of the meta-analysis, with the exception of the results for non-executive

and executive memory.

Study Quality

All the included studies were scored as having a low risk of bias (Table S12, available

online).

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Baseline Speed

Twenty-five studies contributed data on baseline speed, which concerns the time it takes a

person to respond to a stimulus78. With respect to this measure, the beneficial effects of

treatment with MPH would become evident in shorter reaction times. Across all the dose

ranges, MPH produced a small positive effect (SMD=0.29). In the meta-regression analysis,

there was no significant linear relationship found between dose and baseline speed (=0.07;

95%CI: -0.49 to 0.65; p=.80), thus indicating that the beneficial effects of MPH were not

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dependent on the size of the dose. The meta-analyses comparing each of the three dose ranges

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to a placebo showed a small aggregated effect size for low and medium doses and a medium-
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sized effect for high doses. High doses resulted in significantly larger effects than low and
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medium doses. Consequently, despite the non-significant findings of the meta-regression,
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high doses did result in larger reductions in baseline speed compared to small and medium
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doses. There was no evidence of heterogeneity in any of the findings. (Figures S1-4, available

online)
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Variability in Responding

Fifteen group studies contributed data on variability in responding, which refers to

inconsistencies in individuals’ response speed13, 79. Here, the beneficial effects of MPH

treatment would become evident in reduced variability. Across all the dose ranges, there was

a medium-sized reduction in variability with MPH (SMD=0.73). The meta-regression

analysis showed a significant linear relationship between dose and variability in responding

(=0.88; 95%CI: 0.19 to 1.57; p=.01), thus indicating that higher doses of MPH resulted in

larger beneficial effects. The meta-analyses comparing each of the three dose ranges to a

placebo showed a medium effect size for low and medium doses and a large effect for high

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doses. Specifically, high doses resulted in a larger reduction in the variability in responding

compared to medium doses, while medium doses induced a larger reduction than low doses.

There was no evidence of heterogeneity in any of the findings. (Figures S5-8, available

online)

Non-Executive Memory

Ten group studies contributed data on non-executive memory, which pertains to a person’s

memory span80, that is, the ability to retain information in short-term memory. In this

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instance, the beneficial effects of MPH would become evident in increased memory span or

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recall accuracy. Across all the doses, MPH produced a small-sized beneficial effect
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(SMD=0.33). The meta-regression analysis showed a significant linear relationship between
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dose and non-executive memory (=0.78; 95%CI: -0.05 to 1.50; p=.04), thus indicating that
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higher doses of MPH resulted in larger beneficial effects. The meta-analyses comparing each
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of the three dose ranges to a placebo, showed a small aggregated effect size for a low dose, a

medium-sized effect for a medium dose, and a large effect size for a high dose. A high dose
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resulted in a greater memory span or recall accuracy compared to small and medium doses.
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There was substantial heterogeneity (65.74%) among those studies examining the size of the

effect for high doses. Due to the relative lack of available studies, no subgroup analyses could

be performed to investigate the factors that may have contributed towards this heterogeneity.

(Figures S9-12, available online)

Executive Memory

Eight group studies contributed data on executive memory (i.e., working memory), a core

executive function which involves the ability to hold information in one’s mind and mentally

work with it36, 81, 82. The beneficial effects of MPH would become evident in increased

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memory span or recall accuracy. Across all the doses, MPH produced a small beneficial effect

(SMD=0.20). We found no significant linear relationship between dose and executive

memory (=0.45; 95%CI: -0.78 to 1.68; p=.47), which indicates that the beneficial effects of

MPH are not dependent on the size of the dose. However, the results of this meta-regression

analysis must be interpreted with caution, for the simple fact that a meta-regression analysis is

generally not performed with less than ten studies. Meta-analyses comparing each of the three

dose ranges to a placebo could only be performed in the case of the low and medium doses,

due to the lack of studies (k=1) examining the effects of high doses, and showed a non-

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significant aggregated effect size for low and medium doses. There was a substantial degree

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of heterogeneity (62.59%) among the effect sizes for studies examining medium dose ranges.
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A sensitivity analysis that excluded the study by Mehta67, which had larger effect sizes
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compared to the other included studies, did not change the results (Supplement 1, available
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online). (Figures S13-15, available online)

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Inhibitory Control
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Thirty-one group studies contributed data on inhibitory control, which pertains to a person’s

ability to suppress irrelevant thoughts, responses or attentional shifts36. In this case, the

beneficial effects of MPH would become evident in decreased commission errors/false

alarms, and/or shorter stop-signal reaction times. Across all the doses, MPH produced a small

beneficial effect (SMD=0.32). The meta-regression analysis showed no significant linear

relationship between dose and inhibitory control (=0.22; 95%CI: -0,31 to 0.75; p=.0.42),

thus indicating that the beneficial effects of MPH were not dependent on the size of the dose.

The meta-analyses comparing each of the three dose ranges to a placebo showed medium-

sized aggregated effect sizes for low, medium, and high doses. There were no differences

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found between the dosages, and there was no evidence for heterogeneity in the findings.

(Figures S16-19, available online)

Cognitive Flexibility

Ten group studies contributed data on cognitive flexibility, a core executive function that

includes being able to change perspectives36. The beneficial effects of MPH would become

evident in either quicker task completion or fewer errors. Across all the doses, MPH produced

a medium-sized beneficial effect (SMD= 0.62). The meta-regression analysis showed no

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significant linear relationship between dose and cognitive flexibility (=0.70; 95%CI: -0.42 to

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1.81; p=.22), thus indicating that the beneficial effects of MPH were not dependent on the
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size of the dose. The meta-analyses for dose ranges compared to a placebo could only be
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performed for low and medium doses, due to the relative lack of studies (k=2) examining the
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effects of high doses, and showed a medium-sized effect size for low and medium doses. In
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line with the meta-regression results, a medium-sized dose did not result in improved

cognitive flexibility compared to a low dose. The study by Tannock and colleagues45 had
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larger effect sizes than the other included studies, which resulted in substantial heterogeneity
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(70.61-82.47%). Although removing that study from the analysis resulted in significantly

smaller effect sizes, both across the doses and for each of the dose ranges, it did not change

the results of the meta-regression analysis (Supplement 2, and Figures S20-22, available

online)

ADHD Symptoms
Sixteen group studies assessing the impact of MPH on neurocognitive functioning also

contributed data on ADHD symptoms. The beneficial effects of MPH would become evident

in lower scores on total aggregated parent and teacher symptom rating scales. Across all the

doses, MPH produced a large beneficial effect (SMD=0.95). The meta-regression analyses

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showed a significant linear relationship between dose and improvement in ADHD symptoms

(=1.10; 95%CI:0.40 to 1.81; p =.00), thus indicating that the beneficial effects of MPH were

dependent on the size of the dose. Meta-analyses for the dose ranges compared to a placebo

could only be performed for low and medium doses, and showed a medium effect size for low

doses and a large effect size for medium doses. The point estimate of the aggregated effect

size for medium doses did not fall within the CI interval of the small dose range, thus

indicating that, in line with the meta-regression, medium doses of MPH resulted in a greater

reduction in ADHD symptoms. There was a moderate degree of heterogeneity (52.24%)

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identified for the low dose range. (Figures S23-25, available online)

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Discussion
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Our results demonstrated the overall beneficial effects of MPH on all the neurocognitive
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functions considered in our analysis. More specifically, small effect sizes were found for
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executive memory, baseline speed, non-executive memory and inhibitory control, while

medium effect sizes were found for variability in responding and cognitive flexibility. Large
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effect sizes were found for ADHD symptoms. With respect to lower-order neurocognitive
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functions and ADHD symptoms, dose-dependent effects were found: regarding variability in

responding and non-executive memory, the meta-regression analysis showed a significant

linear and positive relationship between MPH dose and task performance, which was

confirmed by the subsequent comparisons between the different dose ranges. For baseline

speed, although the meta-regression analyses showed no linear effect for dose, performance

was found to improve with high doses compared to medium and/or low doses, thus indicating

that the dose effect might be non-linear. With regard to the higher-order neurocognitive

functions, namely inhibitory control, executive memory and cognitive flexibility, neither the

meta-regression analysis nor the dose range comparisons revealed the effects of dosing. There

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was no evidence that MPH at any dose resulted in impaired neurocognitive functioning. It is

important to highlight here the relative lack of studies examining the effects of high MPH

doses on executive memory and cognitive flexibility.

This meta-analysis showed substantial heterogeneity vis-à-vis the effects of MPH on

the neurocognitive functions studied, both in terms of the magnitude of the effect sizes and

the dose-response relationships. There are two potential explanations for this heterogeneity.

The first possibility is that MPH exerts its beneficial effects on neurocognitive functioning

through one key aspect of neurocognitive functioning, namely variability in responding,

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which has been strongly linked to ADHD13. This measure pertains to inconsistencies in

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individuals’ response speeds13, 79, and has been used as a measure of temporal low frequency
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lapses in attention83. In accordance with previous studies, our meta-analysis found clear dose-
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dependent beneficial effects of MPH for variability in responding with substantial effect sizes,
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which were remarkably close to those observed for ADHD symptoms in both the present
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study and previous studies3. The observed decrease in lapses of attention resulting from

treatment with MPH, might thus in turn lead to improvements in other cognitive functions,
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and hence in fact underlie the observed dose-depended improvements for baseline speed and
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non-executive memory. However, we were not able to perform additional analysis

investigating the mediating role of response variability due to the paucity of studies including

both response variability and one of the other investigated outcomes, which would be an

important step to be performed in future studies. Second, the heterogeneous effects of MPH

might be understood through recourse to Halperin and Schulz’s17 model, which considers

lower-order neurocognitive functions as the core neurocognitive deficits of ADHD, while

higher-order neurocognitive functions are deemed to be more transient and the consequence

of a developmental delay in individuals with ADHD. Following this model, similar MPH

effects would be expected on ADHD symptoms and lower-order functions, which is line with

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our findings of a significant positive linear effect of MPH dose for both domains. For higher-

order functions, a significant positive effect of MPH was found, however with no additional

benefits of increasing doses. The finding that MPH effects on ADHD symptoms parallel those

for lower-order, but not higher-order cognitive functioning may suggest that that lower-order

cognitive functions are more central to ADHD.

The current findings should be viewed with some limitations in mind. First, given the

paucity of studies on executive memory, our meta-regression analysis of these studies has

limited reliability. Moreover, there were insufficient studies available to calculate the meta-

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analytic effect sizes for high doses of MPH on executive memory and cognitive flexibility.

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Second, the available literature only allowed for a meta-analysis of results related to a limited
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number of neurocognitive functions, once again due to a lack of data. For example, there was
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a lack of studies investigating the effects of MPH dose on reward sensitivity (k < 3). Third,
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we could only assess the short-term effects of MPH on neurocognitive functioning, insofar as
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there were only a few studies examining the long-term outcomes65, 71. However, the few

studies that are available suggest that the long-term effects of MPH on neurocognitive
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performance do not differ from the short-term effects84. Fourth, the children that participated
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in the included studies were selected based on the presence of ADHD symptoms, and, as

such, may have differed in terms of their baseline levels of cognitive functioning. Due to

power issues and variability in the types of measures used, we were unable to investigate the

moderating role of potential differences in the baseline levels of cognitive functioning on the

effect of MPH on cognitive functioning. Fifth, regarding the categorical approach, dose was

transformed into three categories, which obviously has led to a loss of information. However,

classifying doses into predefined ranges facilitates the translation of our study findings into

implications for clinical practice.

15
 Despite these limitations, our findings nevertheless provide innovative knowledge,

which highlights important differences in the dose-dependent effects of MPH on

neurocognitive functioning. Currently, MPH titration is primarily based on its effects on

ADHD symptoms, with larger effects expected with increasing doses85, as confirmed by the

present study. However, such a linear relationship between dose and effect was not present for

all neurocognitive functions. Given the crucial role of neurocognitive deficits in ADHD18, 19,

our findings highlight the importance of considering both the neurocognitive and

symptomatic aspects of ADHD when evaluating ADHD treatment in clinical practice. Future

of
research on alternative avenues for titration might include neurocognitive functioning as an

ro
important target of treatment, particularly if a child with ADHD shows specific
-p
neurocognitive weaknesses. Given the linear effects of dose observed in the current study and
re
the paucity of research into the effects of high doses of MPH on neurocognitive functioning,
lP

future studies should consider studying the effects of different doses of MPH on
na

neurocognitive functioning, including high doses.

ur
Jo

16
Table 1: Overview of Included Studies
Reference -Number of Outcome Instruments: Outcome MPH dose, Days on Additional
participants domain: Cognitive Task measure mg/kg/dose (dose each inclusion and
-Age in Cognitive and ADHD range) dose exclusion
years (yr), function rating scale criteria
M (SD) and ADHD Immediate
-DSM/ICD symptoms Release (IR) /
used Sustained
-% males Release (SR)
-IQ formula
Bedard, -59 children Baseline -Response -Mean RT 0.28 (low); 1 day Inclusion
200352 -8.7yr (1.4) Speed execution task 0.45 (medium); criteria:
-DSM-V (go trials) 0.61 (high) -stimulant
-85% male medication
-IQ>80 Variability -Response -RT SD IR: 3x/day recommended
in execution task by clinical
Responding (go trials) diagnostic team

of
Inhibitory -Stop-signal -SSRT Exclusion
control task criteria:

ro
-neurological
-% early invalid
dysfunction
responses
-p
-% inhibition
-poor physical
health
re
-uncorrected
given the selected
sensory
auditory signal
lP

impairments
-history of
psychosis
na

Bedard, Sample 1: Non- -Digit span -Number correct 0.28 (low); 1 day Inclusion
200843 -130 children Executive forward responses 0.45 (medium); criteria:
-9.0yr (1.5) Memory 0.61 (high) -stimulant
ur

-DSM-IV medication
-85% male -Finger -Number correct IR: 3x/day recommended
Jo

-IQ >80 windows responses by clinical

forward diagnostic team
Executive -Digit span -Number correct
Sample 2: Memory backwards responses Exclusion
-59 children criteria:
-9.2yr (1.6) -Finger -Number correct -neurological
-DSM-IV windows responses dysfunction
-83% male backwards -poor physical
-IQ >80 health
-uncorrected
sensory
impairments
-history of
psychosis

ADHD -IOWA- -Total score

symptoms Conners’ rating
scale
(examiner)

17
Berman, -17 children Non- -Visual memory -Total errors 0.3 (low); 8 days Exclusion
199944 -10.7yr (0.8) Executive search 0.6 (medium); criteria:
-DSM-III-R Memory 0.9 (high) -serious visual,
-100% male auditory or
IR: 2x/day speech deficits
-neurological
damage
-stressful
events that
could explain
symptoms

Carlson, -13 children Baseline -Divided -Mean RT hand 0.3 (low) 2 days Inclusion
199153 -8.4yr (0.8) Speed attention task criteria:
-DSM-IIIR -Mean RT foot -participated in
-100% male IR ADHD summer

of
treatment
program

ro
Coghill, -75 children Baseline -Go/no-go task -Mean RT go 0.3 (low); 28 days Inclusion
200724 -7-15yr
-DSM-IV
Speed -p
trials 0.6 (medium) criteria:
-combined
re
-100% male IR: 2x/day subtype ADHD
-IQ>80 -5 Choice -Mean RT
lP

reaction time Exclusion

task criteria:
-neurological
na

Non- -Spatial span -Maximal span impairment

Executive reached -chronic
Memory physical illness
ur

-Delayed -% correct -sensory or

matching to responses motor
Jo

sample: impairment
simultaneous -exposure to
stimulant
-Delayed -% correct medication
matching to responses -abuse of any
sample: 0,4 and illegal drugs
12 sec
combined

-Paired -Stage reached

associates
-Total errors
learning
-Total number of
trials

Executive -Spatial -Total between

Memory working search errors
memory task

18
 Inhibitory -Go/no-go task -Errors of
control commission

Cognitive -Intra-/Extra -Stage Reached

Flexibility dimensional Set
Shifting

-ADHD Conners’ global -Total score

symptoms index rating
scales (Teacher
and Parent)
Cubillo, -20 children Executive -N-back task -% correct 0.3 (low) 1 day Inclusion
201454 -10-17yr Memory responses criteria:
-DSM-IV IR -medication-
-100% male naïve
-IQ>70 -ADHD

of
combined
subtype

ro
Exclusion
-p criteria:
-history of
re
substance abuse
or neurological
lP

deficits
-presence of
psychiatric
na

disorders (except
for ADHD and
CD/ODD)
ur

-learning
disability and
Jo

reading, speech
or language
disorder

Cubillo, -19 children Inhibitory -Stop-signal -SSRT 0.3 (low) 1 day Inclusion
201455 -13.1yr (1.6) control task criteria:
-DSM-IV IR -medication-
-100% male naïve
-IQ>70
Exclusion
criteria: -
history of
substance abuse
or neurological
deficits
-presence of
psychiatric
disorders (except
ADHD and
CD/ODD)

19
 -learning
disability
-reading. speech
or language
disorder

Douglas, -17 children Cognitive -Wisconsin card -Perseverative 0.3 (low); Two Exclusion
199556 -9.4yr (0.1) Flexibility sorting test errors 0.6 (medium); testing criteria:
-DSM-IIIR -Sorting 0.9 (high) weeks. -visual/ auditory/
-94% male categories random speech deficits
-IQ>85 IR order of -organic damage
-Trial making -Total time the 4 -suggesting that
form B dosages. symptoms could
-Total errors be attributed to
emotional
problems or a

of
-Contingency -Rule use-errors
stressful home
naming test
environment

ro
-Rule reversal-
errors

-Verbal fluency
test (instances
-p
-% correct
re
test)
lP

-Alternate uses -% correct

test
na

Epstein, -9 children Baseline -Go/no-go task -Mean RT: go 0.3 (low) One day Inclusion
200757 -range 7-9yr Speed trials criteria:
ur

-DSM-IV IR -ADHD
-78% male Variability -Go/no-go task: -RT SD combined type
Jo

-IQ>80 in go trial
Responding Exclusion
criteria:
Inhibitory -Go/no-go task -Errors of -neurological
Control commission disease
-bipolar
disorder.
psychosis. or
pervasive
developmental
disorder
-history of head
trauma

Gadow, -71 children Inhibitory -Continuous -Errors of 0.1 (low); 14 days Inclusion
200758 -8.9yr (1.9) Control performance commission 0.3 (low); criteria:
-DSM-IIIR task 0.5 (medium) -ADHD + either
or DSM-IV chronic motor
-80% male IR: 2x/day tic disorder or
-IQ>70 Tourette
syndrome.

20
 ADHD -IOWA -Total score
Symptoms Conners Exclusion
(teacher) criteria:
-too severely ill
or psychotic
-had a seizure
disorder. major
organic brain
dysfunction.
major medical
illness. medical
-contraindication
to medication
-pervasive
developmental
disorder

of
-tics so severe
that either the

ro
parent or child
requested
-p immediate
intervention or
re
were extremely
mild
lP

Gruber, -37 children -Baseline -Continuous -Mean RT 0.5 (medium) 7 days Exclusion
200759 -9.2yr (1.2) Speed performance criteria:
na

-DSM-IV task IR: 2x/day -diagnosed with

-84% male psychosis/
-IQ>80 -Variability -Continuous -RT SE Tourette
ur

in performance syndrome/pervas
Responding task ive
Jo

developmental
-Inhibitory -Continuous -Errors of disorder
Control performance commission -taking any
task medication other
than MPH
-previous
intolerance or
allergic reactions
to any
psychostimulant

Hawk, -17 children Inhibitory -Tone -% false alarms 0.3 (low) Inclusion
200360 -11.4yr (0.9) Control discrimination criteria:
-DSM-IV task (ignored IR -a stable dose of
-100% male tones) methylphenidate
for at least 1

21
 -Tone -% false alarms month
discrimination immediately
task (attended preceding entry
tones)

Jonkman, -18 children Baseline -Eriksen flanker -Mean RT 0.42 (medium)a On Inclusion
199761 -10.6yr (2.0) Speed task: target (between 0.24- testing criteria:
-DSM-IIIR alone trials 0.62) day -normal or
-98% male corrected-to-
Inhibitory -Auditory -False alarms IR normal vision
Control selective attended standards -no color
attention task (commission blindness
errors) -normal hearing

of
-Visual -False alarms
selective attended standards

ro
attention task (commission
errors)

Jonkman.
199962
-28 children
-9.5yr (2.2)
Baseline
Speed
-Eriksen flanker
task: target
-p
-Mean RT 0.53 (medium)
(between 0.36-
On
testing
Inclusion
criteria:
re
-DSM-IIIR alone trials 0.79) day -normal or
-93% male corrected-to-
lP

IR normal vision
na

Konrad, -60 children Baseline -Stop-signal -Mean RT go 0.25 (low); Within Inclusion
200422 -10.8yr (1.6) Speed task trials the 6-day criteria:
-DSM-IV IR protocol. -medication
ur

-43 % male the order naïve

-IQ>80 -Baseline speed -Mean RT of drug
Jo

task condition Exclusion

s was criteria:
Variability -Baseline speed -RT SD randomiz -potentially
in task ed. confounding
Responding diagnoses
-any kind of
-Cognitive -Visual set- -Median RT additional
Flexibility shifting task: medication
incompatible -Median SD
trials
-Errors
incompatible
trials

Inhibitory -Stop-signal -SSRT

control task

Konrad, -44 children Inhibitory -Stop-signal -SSRT 0.25 (low); Each Inclusion
200563 -10.3yr (1.9) Control task 0.5 (medium) dose on criteria:
-DSM-IV two

22
 -84% male IR: 2x/day occasion -ADHD
-IQ>80 s during combined
a 6-day subtype
period
ADHD -German -Total score Exclusion
symptoms teachers report criteria:
on ADHD -pervasive
symptoms developmental
disorders or
receptive
language
disorders, visual
impairments or
any kind of
additional
medication

of
Kowalczyk -14 children Baseline -Sustained -Mean RT 0.15 (low)a On Inclusion

ro
, 201964 -13.3yr (1.6) Speed attention task: testing criteria:
-DSM-IV long delays SR day -medication
-100% male
-IQ>70
-p naive
-combined type
re
-Sustained -Mean RT ADHD
attention task:
lP

short delays Exclusion

criteria:
Variability -Sustained -SD intrasubject -MRI-related
na

in attention task short delays contraindication

Responding s.
-history of
ur

-SD intrasubject substance abuse

long delays or neurological
Jo

deficits
Inhibitory -Sustained -Number of -presence of
Control attention task premature errors psychiatric
short delays disorders (except
for CD/ODD
-Number of learning
premature errors disability,
long delays reading, speech
or language
disorder)

Lijffijt, -15 children Baseline -Stop task -Mean RT go 0.5 (medium); On Inclusion
200665 -10.7yr (1.3) Speed trials 1.0 (high) testing criteria:
-DSM-IV day -good sight and
-87% male -Change task -Mean RT go hearing
trials
-IQ > 80 IR -familiar with
Variability -Stop task -RT SD go trials the intake of
in MPH for at least
Responding -Change task -RT SD go trials 1 year

23
 Inhibitory -Stop-signal -SSRT
Control task

-Change task -SSRT

Lufi, -19 children Cognitive -Trail making -Total time 0.4 (medium) 21 days Inclusion
200766 -9.5yr (1.6) Flexibility task form B IR criteria:
-DSM-IV -Total errors -attended regular
-63% male school
ADHD -Conners’ ASQ: -Total score -medication
symptoms combined short naïve
version of the -no
Teacher Rating psychological
Scales and the treatment before
Conners’ Parent or while in the

of
Rating Scales study

ro
Mehta, -14 children Executive -Spatial -Total between 0.5 (medium) On Exclusion
200467 -10.9yr (1.2) Memory working search errors IR testing criteria:
-DSM-IV
-100% male
memory task -p day -comorbid
disorders
re
Cognitive -Attentional set- -Stage passed -inattentive
Flexibility shifting task subtype of
lP

AD/HD.
Nigg, -23 children Inhibitory -Continuous -RT 0.3 (low); 7 days Inclusion
199668 -8.6yr (1.7) control performance 0.6 (medium) criteria:
na

-DSM-III-R task -previous

-100% male IR: 2x/day treatment with
-IQ >75 Baseline -Continuous -Errors of stimulants
ur

Speed performance commission

task Exclusion
Jo

criteria:
-evidence of a
neurological
disorder

Novak, -16 children Baseline -Reaction time -Median RT 0.3 (low) On

199569 -11.2yr (1.4) Speed task IR testing
-DSM-III-R day
-94% male
-IQ 80

24
O'Driscoll, Group Inhibitory -Antisaccade -Errors of 0.5 (medium) On Inclusion
200570 ADHD-I Control task commission testing criteria:
-12 children IR day -visual acuity
-12.7yr (0.6) (corrected) of at
--DSM-IV least 20/40.
-100% male
-IQ  85 Exclusion
criteria:
-comorbid
Group disorders with
ADHD-C the exception of
-10 children ODD
-12.4yr (0.6)
-DSM-IV
-100% male
-IQ  85

of
ro
O'Toole, -23 children Non- -Easy nonverbal -Number of 0.3 (low); On Inclusion
199771 -9.2yr Executive learning task: correct responses 0.8 (high) testing criteria:
-DSM-III-R
-78% male
Memory immediate
recall
-p day -responded to be
positive
re
stimulant
-Easy nonverbal -Number of -taking stimulant
lP

learning task: correct responses medication for at

delayed recall least 6 months
na

-Hard learning -Number of Exclusion

task: immediate correct responses criteria:
recall -comorbid Axis
ur

I disorders with
-Hard learning -Number of the exception of
Jo

task: delayed correct responses ODD and CD

recall

Overtoom, -16 children Inhibitory -Stop-signal -SSRT 0.43 (medium)a On Exclusion

200372 -10.4yr (1.4) Control task testing criteria:
-DSM-III-R IR day -tic disorder or
-100% male pervasive
developmental
disorder
-contraindication
for medication.
-family history
of severe heart
problems

Pollak, -27 children Inhibitory -Continuous -Errors of 0.3 (low) On Exclusion

201073 -13.7yr (1.6) Control performance commission testing criteria:
-DSM-IV task (Virtual day -serious
-59% male Reality and systemic or
non-Virtual neurological
Reality ) condition

25
 -severe visual
impairment
-pervasive
developmental
disorder or
psychotic
disorders

Rubia, -12 children Inhibitory -Simon task -Error rate 0.3 (low) On Inclusion
201174 -13.0yr (1.0) Control incongruent trials testing criteria:
-DSM-IV IR day -medication
-100% male naïve

Exclusion
criteria:
-other

of
psychiatric
disorder (except

ro
for ODD/CD,
learning
-p disability and
specific reading
re
disorder)
-neurological
lP

abnormalities
-drug or
substance abuse
na

Solanto, Combined Inhibitory -Continuous -Errors of 0.15 (low); 7 days Exclusion

200975 subtype: Control performance commission 0.3 (low); criteria:
ur

-15 children task 0.6 (medium) -receiving

-8.53yr (1.3) psychotropic
Jo

-40% male IR: 3x/dayb medication

-IQ >80 -mood disorder/
ADHD -ADHD-rating -Total score
Tourette’s
symptoms scale-IV
disorder/
(Examiner)
Inattentive psychotic
subtype: disorder/pervasi
-10 children ve
-9.2yr (1.6) developmental
-50% male disorder
-IQ >80 -sensory
impairment or
chronic medical
or neurological
condition that
required
systemic
medication.
-colorblindness.

26
Sunohara, -20 children Baseline -Continuous -Mean RT 0.3 (low); Exclusion
199976 -10.5yr (1.9) Speed performance 0.56 (medium) criteria:
-DSM-III-R task (between 0.28– -coexisting
-80% male 0.70) anxiety
-IQ > 80 Variability -Continuous -RT SD -coexisting
in performance conduct disorder
Responding task

Inhibitory -Continuous -Errors of

Control performance commission
task

Tannock, -28 children Baseline -Reaction time -Mean RT 0.3 (low); On Exclusion
199545 -8.9yr (1.2) Speed task (primary 0.6 (medium); testing criteria:
-DSM-III-R task) 0.9 (high) day -anxiety disorder
-89% male -major

of
-IQ > 80 Variability -Reaction time -RT SD IR neurological.
in task (primary physical or

ro
Responding task) sensory
impairment
Inhibitory
Control
-Stop-signal
task
-p
-SSRT
re
Cognitive -Change task -Mean RT
lP

Flexibility
-Mean SD
na

Zeiner, -36 children Executive -Paced auditory -Number correct 0.25 (low) 21 days Inclusion
199977 -8.7yr (1.2) Memory serial addition responses criteria:
-DSM-IIIR task: repeat last IR: 2x/day -no pervasive
ur

and DSM-IV but one version developmental

-100% male disorder,
Jo

-IQ > 70 -Paced auditory -Number correct psychosis or

serial addition responses mood disorder
task: addition -no medical or
version neurological
disease
Inhibitory -Continuous -Errors of
-never used
Control performance commission
stimulants or
task
any other
psychotropic
ADHD -Parental -Total score
drug
Symptoms account of
childhood
symptoms
Conners

-Teacher rating -Total score

scale
(hyperactivity
scale)

27
Note: CD = conduct disorder; ODD = oppositional defiant disorder; RT = reaction time; SSRT = stop-signal reaction time
a
When long acting MPH was used, dose was converted to mg/kg/dose of immediate release MPH,
b
A third daily dose, which was half of the morning and noon dose.

Table 2: Meta-analytic Results for Effects of Low, Medium and High Doses of Methylphenidate (MPH) for 6
Functions of Neurocognitive Functioning and Attention-Deficit/Hyperactivity Disorder (ADHD) Symptoms

All doses Low dose range Medium dose High dose Dose range
0.10-0.30 mg/kg range range comparison
0.31-0.60 mg/kg 0.61-1.00 mg/kg

of
k I2 (%) k I2 (%) k I2 (%) k I2 (%)
SMD Fs N SMD Fs N SMD Fs N SMD Fs N

ro
(95% CI) p(EF) (95% p(EF) (95% p(EF) (95% p(EF)
CI) CI) CI)

Baseline 25 0 13 0
-p 9 0 3 0 L=M<H
re
speed 0.29*** 187 0.29*** 39 0.26*** 15 0.44*** 4
(0.19 to 0.48 (0.14 to 0.40 (0.10 to 0.75 (0.16 to 0.78
0.39) 0.43) 0.42) 0.72)
lP

Variability 15 0 6 0 6 0 3 0 L<M<H
in 0.73*** 405 0.54*** 34 0.77*** 67 1.02*** 30
responding (0.60 to 0.68 (0.34 to 0.90 (0.56 to 0.36 (0.73 to 0.67
na

0.85) 0.75) 0.97) 1.32)

Non- 10 23.13 4 0 3 27.59 3 65.74 L=M<H
0.33*** 67 3 5 10
ur

executive 0.23* 0.31* 0.61*

memory (0.18 to <0.001 (0.03 to 0,053 (0.05 to 0.27 (0.09 to 0.11
0.48) 0.43) 0.58) 1.14)
Jo

Executive 8 0 4 0 3 62.59 NA L=M

memory 0.20* 7 0.12 0 0.46 3
(-0.03 to 0.18 (-0.11 to 0.11 (-0.13 to 0.56
0.38) 0.35) 1.04)
Inhibitory 31 0 15 0 13 0 3 0 L=M=H
control 0.32*** 353 0.30*** 59 0.32*** 56 0.43*** 5
(0.23 to 0.88 (0.18 to 0.47 (0.18 to 0.64 (0.12 to 0.68
0.41) 0.43) 0.45) 0.69)
Cognitive 12 81.78 4 70.61 6 82.47 NA L=M
flexibility 0.67*** 187 0.49* 14 0.61* 32
(0.33 0.91 (0.07 to 0.50 (0.11 to 0.13
to1.01) 0.91) 1.12)
ADHD 16 56.24 7 52.24 7 25.82 NA L<M
symptoms 0.95*** 1186 0.69*** 1186 1.06*** 139
(0.78 to 0.97 (0.55 to 0.97 (0.90 to 0.68
1.14) 0.82) 1.22)

Note: Fs N= Fail safe N; H = high dose range, I2= heterogeneity index; L = low dose range; M = medium dose range; NA = not
available. p(EF): p for heterogeneity.
a
p<.05; bp<0.01; cp<0.001

28
Figures

Figure 1: Flow diagram

Figure 2: Results of the Meta-regression Analysis With the Dose in mg/kg/Dose as a Predictor

of
ro
-p
re
lP
na
ur
Jo

29
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