Introduction

Methylphenidate is widely prescribed for children with attention-deficit/hyperactivity disorder (ADHD), often for many years (Beau-Lejdstrom, Douglas, Evans, & Smeeth, 2016), despite doubts about its effectiveness after prolonged use. Observational studies have shown that benefits of methylphenidate on ADHD symptom severity may be maintained to a period of two years (Abikoff et al., 2004; Hechtman & Greenfield, 2003; Molina et al., 2009; Swanson et al., 2008, 2017). A recent randomized controlled discontinuation trial study from our group confirmed that on average, methylphenidate was still superior to placebo after treatment for two or more years, albeit with effect sizes that were smaller than those seen in short-term trials. However, at an individual level 60% of children did not deteriorate after withdrawing to placebo, suggesting that in most children, methylphenidate might no longer be beneficial after two or more years (Matthijssen et al., 2019). Thus, there are indications that the magnitude of the effects of methylphenidate on ADHD symptom severity may, at least in a portion of individuals, diminish after prolonged methylphenidate use. Less is known about the effects of methylphenidate on executive functioning after prolonged use, even though ADHD has often been associated with several executive functioning impairments, such as response inhibition (i.e. the ability to withhold a prepotent response), working memory (i.e. the capacity to temporarily maintain and process information) or attentional flexibility (i.e. the ability to switch between task demands; Pievsky & McGrath, 2018). While it has been currently recognized that ADHD symptomatology and cognitive impairments do not always correlate, likely with clear neuropsychological impairments only in a small number of patients, the importance of monitoring cognitive functioning in parallel to ADHD symptoms has been increasingly stressed (Coghill, Hayward, Rhodes, Grimmer, & Matthews, 2014).

Acute (short-term) effects of methylphenidate on executive functioning in children and adolescents with ADHD are well-established; meta-analyses and reviews conclude that most studies found improvements in working memory, response inhibition and reaction time (Coghill, Seth, et al., 2014; Pietrzak, Mollica, Maruff, & Snyder, 2006), and improvements have also been found in attentional flexibility (Bolfer et al., 2017). Functional magnetic resonance imaging studies have shown that acute administration of methylphenidate normalizes brain dysfunction in treatment-naïve children with ADHD in the typically affected frontal regions, possibly explaining the effects of methylphenidate on executive functioning (Rubia, Halari, Cubillo, et al., 2011; Rubia, Halari, Mohammad, Taylor, & Brammer, 2011).

Opposed to the studies that focussed on the immediate effects of methylphenidate associated with short-term use, the acute effects of methylphenidate on executive functioning after prolonged use have, to our knowledge, not yet been studied in humans. So far, a number of studies have investigated whether there would be lasting improvement on executive functioning associated with a history of methylphenidate use; however, little evidence for improvement of long-term methylphenidate use on executive functions was found when comparing pre- and posttreatment functioning off methylphenidate (Huang, Wang, & Chen, 2012; Schweren et al., 2018). Obviously, these observational studies are limited by not assessing the acute effects of methylphenidate in a controlled situation. Thus, to date it remains unknown if ongoing methylphenidate use has an effect on executive functioning after prolonged use in children and adolescents.

In the present study, as part of a double-blind, placebo-controlled methylphenidate discontinuation trial in 94 children and adolescents aged 8–18 years treated in regular clinical practice (Matthijssen et al., 2019), we aimed to investigate the acute effects of methylphenidate after long-term use (>2 years) on a test battery of neuropsychological tasks, measuring executive functioning (i.e. response inhibition, working memory and attentional flexibility), and psychomotor speed (Cepeda, Blackwell, & Munakata, 2013; Kibby, Vadnais, & Jagger-Rickels, 2019), in comparison with children and adolescents who withdrew to placebo over a seven-week period. Specifically, we wanted to know whether children and adolescents who gradually withdraw to placebo would deteriorate in their performance on the cognitive measures compared to those who continued to use methylphenidate. Additionally, to find out whether there would be a relation between changes in global clinical improvement and neuropsychological task measures, we investigated whether children who deteriorated clinically, based on ratings on the Clinical Global Impression Scale of Improvement (CGI-I; Guy, 1976), after withdrawal from methylphenidate performed worse on the task measures compared to children who did not deteriorate.

Method Participants

A total of 94 children aged 8–18 years participated in this study, taking part in the baseline and seven-week follow-up assessment of a randomized placebo-controlled discontinuation study on the continued benefits of methylphenidate in ADHD after two or more years in clinical practice (Matthijssen et al., 2019). Inclusion criteria for all participants included an IQ over 70 and the use of methylphenidate as prescribed in clinical practice in any dose or form for two years or longer. Participants who originally used immediate-release methylphenidate could be included if they had switched to methylphenidate extended release of either 36 or 54 mg per day during the last four weeks before the trial. All participants were allowed to use any kind of co-medication or receive any kind of psychosocial interventions if already ongoing before the trial and if remained stable during the trial. Parents/legal representatives and children ≥12 years provided written informed consent; younger children gave oral assent. The study was approved by the regional ethics board (Medical Ethics Review Board University Medical Center Groningen). This study was registered in the Netherlands Trial Register (www. Trialregister.nl) with identifier 5252, and the reporting of this study is compliant with CONSORT guidelines.

Procedures and measures

Participants were randomly assigned in a 1:1 ratio to either continued use of methylphenidate (n = 47), or to the discontinuation group (n = 47), in which methylphenidate was gradually reduced to placebo over a three-week period followed by four weeks of complete placebo. The reduction schedule was identical for all children in the discontinuation group, independent of the dose at the beginning of the study, 36 mg or 54 mg: week one: 36 mg, week two: 27 mg, week three: 18 mg and weeks four through seven: placebo. The study medication consisted of an over-encapsulation (capsules manufactured by Capsugel) of methylphenidate Osmotic Release Oral System (Concerta®; 18, 27, 36, and 54 mg). For a more detailed description of the study design, we refer to Matthijssen et al., (2019). We used the clinician-rated CGI-I after seven weeks to rate improvement or worsening in global clinical functioning compared to baseline (i.e. before the start of the seven-week discontinuation trial) on a seven-point Likert scale. The outcomes were dichotomized, creating two groups: ‘deteriorated’ (6 = much worse and 7 = very much worse; combining the scores for clinically relevant worsening according to the scoring suggestions for clinical use by Busner & Targum, [2007]) and ‘not deteriorated’ (all else). To keep blinding optimal, side effects were reported by the parents via an online questionnaire which was not available to the clinician. CGI-I ratings were based on all available information from parents including the ADHD Rating Scale, and Swanson, Nolan and Pelham Questionnaire Oppositional Defiant Disorder subscale.

Neuropsychological assessment

Prior to the start of the discontinuation trial and at the end (after seven weeks), the child completed a set of computerized neuropsychological tasks (+/- 45 minutes) from the well-validated Amsterdam Neuropsychological Tasks (ANT; De Sonneville, 1999; de Sonneville, Geeraets, & Woestenburg, 1993; Hanisch, Konrad, Günther, & Herpertz-Dahlmann, 2004), assessing a range of executive functions (i.e. working memory by the Memory Search Letters task (Figure S1); response inhibition and attentional flexibility by the Attentional Set Shifting-Visual task (Figure S2), and simple psychomotor speed from the Baseline Speed task mainly as a control variable (Figure S3; Cepeda et al., 2013). We used parallel tests to prevent possible practice effects. Assessments were all conducted within 12 hr after taking methylphenidate (Concerta) or placebo and we aimed to assess the participants at the same timepoint of day at the baseline and follow-up assessment to control for possible pharmacokinetic variability within the 12-hour window. A higher mean reaction time (slower response) and more errors corresponded to a poorer performance in working memory, response inhibition and attentional flexibility. Psychomotor speed was the mean reaction time in milliseconds averaged across both hands. For a detailed description of all neuropsychological tasks, we refer to the Supporting Information (Appendix S1).

Statistical analyses

Statistical analyses were performed with R version 3.6.0 (R Core Team, 2004). All variables were checked for normal distribution and log transformed where appropriate (i.e. working memory error rate and attentional flexibility reaction time). The mean values reported are without log transformation. Outlier values (z-scores ≥ |3.0|) were removed from further analyses (up to 3.6%).

Differences between the discontinuation and continuation group regarding age, age of onset of methylphenidate use, duration of methylphenidate use and ADHD severity at the baseline visit were analysed with a Mann–Whitney test. Between-group differences in sex were analysed with a Pearson’s chi-square test.

We used mixed-effects models from the ‘lme4’ package for R to assess the changes after 7 weeks in executive functioning (e.g. working memory, response inhibition and attentional flexibility) and psychomotor speed between children with ongoing long-term methylphenidate use (continuation group) compared to those who gradually stopped with long-term methylphenidate use (discontinuation group). Mixed models can properly account for correlation between repeated measurements and can handle missing data (14.1% of individual data points in our study; Gueorguieva & Krystal, 2004); therefore, no participants had to be excluded for the analyses. According to a stepwise model comparison procedure, we started with the simplest model for each outcome measure: a model with group (continuation group versus discontinuation group) and time (baseline versus follow-up after seven weeks) as fixed effects, and age, sex and IQ as confounders, as these are related to executive functioning (Mous et al., 2017). Additionally, we added variables that correlated significantly with the dependent variable to the model, starting with the variable with the strongest correlation to the outcome measure (see Table S1 for the correlations between variables), to adjust for the effect of these correlated variables on the dependent variable. After each addition, the best model was chosen via model comparison on the basis of the Akaike Information Criterium (AIC; Akaike, 1973); that is, models with lower AIC were preferred over models with higher AIC (Cavanaugh & Neath, 2019), until we ended up with an optimal model for each separate outcome measure. Parameter estimates were determined with the restricted maximum likelihood (REML) approach. No assumptions were violated, and the residuals were normally distributed. The Bonferroni correction (Bonferroni, 1936) was used to control for multiple testing, resulting in an alpha level of .00714 (.05 divided by seven cognitive measures). Cohen’s f2 was used to calculate local effect sizes, with f2 ≥ .02, f2 ≥ .15 and f2 ≥ .35, representing small, medium and large effect sizes, respectively (Cohen, 1988).

The same stepwise model comparison procedure was performed in individuals from the methylphenidate discontinuation group, to explore differences in change scores of task measures (between baseline and seven-week follow-up) between the children who deteriorated (i.e. CGI-I ≥ 6) compared to children who did not deteriorate after withdrawal of methylphenidate, with age, sex and IQ included as covariates. We also used here an alpha level of .00714.

Finally, we additionally included reaction time variability (i.e. the standard deviation) of working memory, response inhibition, attentional flexibility and baseline speed to our models. We considered this as exploratory given the scattered and preliminary evidence of methylphenidate reducing reaction time variability across various cognitive measures (Coghill, Seth, et al., 2014; Epstein et al., 2011).

Sensitivity analyses

To check whether a large difference in the timepoint of assessment of the baseline and follow-up visit (median = 28 min; SD = 112; range = 0–449 min) may have impacted the results, we repeated the analyses including only the participants with a difference smaller than 60 min (n = 66) and again including only participants with a difference smaller than 120 min (n = 75) between the timepoint of the baseline and follow-up assessment. We also repeated the analyses within the discontinuation group with the definition of deteriorated of CGI ≥ 5. To investigate whether a possible dose effect (35 or 54 mg) had an influence on the withdrawal effects, we also repeated the analyses including dosage as a covariable.

Results Sample characteristics

See Table 1 for group characteristics at baseline. The methylphenidate discontinuation and continuation groups did not differ regarding age, sex, IQ, and start, duration, and dosage of methylphenidate use, ADHD severity, co-medication use and use of psychosocial treatments. Table 2 presents the neuropsychological task measures for both groups at baseline and seven weeks. Figure 1 summarizes the flow of participants throughout the study.

Table 1. Group characteristics of children and adolescents in a randomized, placebo-controlled discontinuation trial of methylphenidate at baseline: comparing a discontinuation group (withdrawal to placebo) and continuation group (continued methylphenidate use)

Discontinuation group

n = 47

Continuation group

n = 47

Age in years, M (SD)[range]a 13.65 (2.17) [8.5–17.9] 13.77 (2.05) [10.3–17.9] Methylphenidate start age, M (SD)[range]a 9.2 (2.3) [3.6–14.1] 9.3 (2.2) [5.3–14.1] Duration of methylphenidate use, M (SD)[range]a 4.5 (1.7) [2.0–8.5] 4.5 (1.4) [2.0–7.2] Methylphenidate dosage, mg/kg per day (SD)a 0.91 (0.29) 0.93 (0.31) Study methylphenidate dosage, n (%)b 36 mg/day 23 (48.9%) 26 (55.3%) 54 mg/day 24 (51.1%) 21 (44.7%) Male sex, n (%)b 34 (72.3%) 39 (83.0%) IQ, M (SD)a 94.9 (10.7) 93.1 (13.0) ADHD-RS, M (SD) Total score 19.6 (8.9) 21.4 (9.7) Inattention score 12.0 (5.7) 13.8 (6.2) Hyperactivity–impulsivity score 7.6 (5.0) 7.6 (5.2) Comorbidities, n (%)b ODDb 0 (0) 2 (4.3) ASDb 7 (14.9) 8 (17) Otherb 4 (8.5) 1 (2.1) Co-medication, n (%) 22 (46.8%) 13 (27.7%) Antipsychotic medicationb 1 (2.1%) 0 (0.0%) Psychosocial treatment n (%) For externalizing problemsb 4 (8.5%) 5 (10.6%) For internalizing problemsb 1 (2.1%) 3 (6.4%) ADHD-RS, Attention-Deficit/Hyperactivity Disorder-Rating Scale; ASD, Autism Spectrum Disorder; ODD, Oppositional Defiant Disorder. Between-group differences were tested by a aMann–Whitney U test, or bPearson’s chi-squared test. There were no significant group differences (p < .05). Table 2. Task measures at baseline and 7 weeks in children and adolescents treated with methylphenidate for >2 years, comparing a discontinuation group (withdrawal to placebo) and a continuation group (continued methylphenidate use) Measure

Discontinuation group

n = 47

deltaa

Continuation group

n = 47

deltaa Δ Change between groupsb 95% CI Cohen’s f2 Baseline 7 weeks Baseline 7 weeks Mean SD Mean SD Mean SD Mean SD Working memory RT 386 272 422 287 35.8 378 267 535 319.83 157 121 38.9, 203 ER 1.02 2.06 2.28 2.07 1.26 1.81 1.79 1.44 1.65 −0.37 1.63* 1.09, 2.17 .14 Response inhibition RT 195 121 127 103 −68.2 186 132 154 124.26 −32.3 35.9 −66.7, 2.15 ER 1.50 2.10 1.12 1.54 −0.38 0.67 1.98 0.70 1.22 0.03 0.41 −0.09, 0.91 Attentional flexibility RT 542 249 395 237 −146 542 255 383 162.28 −159 13.0 −52.4, 78.4 ER 3.26 3.15 2.81 3.10 −0.45 2.70 2.96 2.31 2.81 −0.39 0.06 −0.80, 0.92 Psychomotor speed RT 320 49.7 328 41.2 8.10 322 41.0 332 40.35 10.4 2.27 −10.1, 14.6 RT, reaction time in milliseconds; ER, error rate; working memory by the Memory Search Letters task; response inhibition and attentional flexibility by the Shifting Attentional Set—Visual (SSV) task, and psychomotor speed by the Baseline Speed task (De Sonneville, 1999). a The difference between seven weeks and baseline. b The difference in mean change from baseline to seven weeks between the discontinuation and continuation group, by mixed models analyses. * p < .0074 using Bonferroni correction for multiple testing.

CONSORT flow diagram of participants in the randomized, placebo-controlled discontinuation study of methylphenidate

Task results between the methylphenidate discontinuation and continuation groups Working memory

We found an interaction effect between group and time with a near-medium effect size (β = −1.62, SD = 0.56, t = −2.88, p = .01, Cohen’s f2 = .14), indicating that the continuation group using methylphenidate made fewer errors at the follow-up visit compared to the baseline visit, whereas the discontinuation group made more errors at the follow-up visit compared to the baseline visit. Thus, withdrawal of methylphenidate led to making more errors regarding working memory compared to continuing with methylphenidate use, independent from working memory reaction time. No significant differences were observed in changes in working memory reaction time between both groups (β = 58.16, SD = 70.78, t = .82, p = .42).

Response inhibition

We did not find significant differences in changes in response inhibition reaction time (β = 50.12, SD = 31.35, t = 1.60, p = .12) or error rate (β = −.13, SD = 0.67, t = −.20, p = .84) between the two groups from baseline to seven weeks.

Attentional flexibility

There were also no significant differences in changes in attentional flexibility reaction time (β = −26.94, SD = 38.76, t = −.07, p = .49) and error rate (β = −.49, SD = 0.81, t = .61, p = .55) between the two groups from baseline to seven weeks.

Psychomotor speed

We did not find a significant difference in changes in mean reaction time between the two groups from baseline to seven weeks (β = −4.29, SD = 7.94, t = −.54, p = .59).

Reaction time variability

None of the variability measures were significant (all p’s > .10).

Task results in relation to clinical deterioration within the discontinuation group

We did not find significant differences in changes in cognitive measures between children and adolescents who worsened in clinical functioning after discontinuation of methylphenidate (n = 19) versus those who did not deteriorate (n = 28) regarding working memory reaction time (β = 137.41, SD = 105.89, t = 1.30, p = .21) and error rate (β = −1.40, SD = 0.97, t = −1.44, p = .16), response inhibition reaction time (β = −7.16, SD = 47.31, t = −0.15, p = .88) and error rate (β = 1.82, SD = 1.02, t = 1.79, p = .08), attentional flexibility reaction time (β = −.15, SD = 0.16, t = −0.92, p = .36) and error rate (β = −.42, SD = 0.96, t = −0.44, p = .67), psychomotor speed reaction time (β = 18.89, SD = 10.80, t = 1.75, p = .09) and reaction time variability measures (all p’s > .36), see Table 3.

Table 3. Task measures within the discontinuation group at baseline and seven weeks of youth who deteriorated clinically versus those who did not Measure

Not deteriorateda

n = 28

deltab

Deteriorateda

n = 19

deltab Δ Change between groupsc Δ 95% CI Baseline 7 weeks Baseline 7 weeks Mean SD Mean SD Mean SD Mean SD Working memory RT 380 280 390 297 9.67 396 267 496 262 100 90.8 9.50, 172 ER 1.07 1.96 2.73 2.21 1.66 0.94 2.26 1.30 1.34 0.36 1.30 0.73, 1.87 Response inhibition RT 186 124 112 111 −74.0 189 79.5 160 78.3 −28.4 45.6 17.0, 74.2 ER 1.61 2.15 0.91 1.44 −0.70 1.33 2.09 1.60 1.71 0.38 1.2 0.67, 1.73 Attentional flexibility RT 519 276 398 258 −121 576 203 390 199 −186 64.7 −2.89, 132 ER 3.31 3.20 2.50 2.26 −0.81 2.20 1.66 1.92 2.43 −0.28 0.53 −0.17, 1.23 Psychomotor speed RT 317 52.5 309 34.5 −7.86 326 45.6 364 26.3 37.7 45.6 33.9, 57.3 RT, reaction time in milliseconds; ER, error rate; tasks see Table 2. p < .0074 using Bonferroni correction for multiple testing: none of the Δ changes between groups were significant.