Effects of methylphenidate on executive functioning in children and adolescents with ADHD after long-term use: a randomized, placebo-controlled discontinuation study.

BACKGROUND: Methylphenidate may improve executive functioning in children with attention-deficit/hyperactivity disorder (ADHD). However, it is unclear if there are still acute effects of methylphenidate on executive functioning after long-term use. METHODS: In a randomized double-blind, placebo-controlled discontinuation study, 94 children and adolescents (ages 8-18 years) who used methylphenidate beyond two years were either assigned to seven weeks of continued treatment with 36 or 54 mg of extended-release methylphenidate or to gradual withdrawal over three weeks to placebo for four weeks. Performance on neuropsychological tasks, measuring working memory, response inhibition, attentional flexibility and psychomotor speed was compared between both groups using mixed models for repeated measures. Additionally, we investigated within the discontinuation group if a deterioration on the investigator-rated Clinical Global Impressions Improvement scale after withdrawing to placebo was related to a worse performance on the neuropsychological tasks. This study was registered in the Netherlands Trial Register (www. Trialregister.nl) with identifier 5252. RESULTS: After withdrawal of methylphenidate, the discontinuation group made more errors on working memory (ß = -1.62, SD = 0.56, t = -2.88, p = .01, Cohen's f2 = .14), independent from reaction time compared to baseline, in contrast to the continuation group. We did not find differences in changes in response inhibition, attentional flexibility and psychomotor speed between the two groups. Also, there were no significant differences in task measures between the participants who deteriorated clinically and those who did not. CONCLUSIONS: Our study shows that methylphenidate has a beneficial effect on working memory after two years of use. Future studies should explore whether cognitive outcomes may aid clinical decision-making on the continued use of methylphenidate, given dissociation between cognitive and behavioural effects of stimulant medication.

Adherence to Clinical Guidelines for Dose Finding and Monitoring Methylphenidate Use: A Medical Record Audit in Child and Adolescent Mental Health Care and Pediatric Settings.

Background: Guideline adherence is important to ensure optimal and safe use of methylphenidate for children and adolescents with attention-deficit/hyperactivity disorder (ADHD). We investigated adherence to Dutch guidelines regarding dosing and monitoring of methylphenidate in child and adolescent mental health care and pediatric treatment settings. Methods: Five hundred six medical records of children and adolescents were investigated in 2015 and 2016. We assessed adherence to the following guideline recommendations: (1) at least four visits during the dose-finding phase; (2) monitoring thereafter at least every 6 months; (3) measuring height and weight at least annually; and (4) the use of validated questionnaires to assess treatment response. Pearson's chi-squared test statistics were used to examine differences between settings. Results: Only a small portion of patients had at least four visits during the dose-finding phase (5.1% in the first 4 weeks to 12.4% in the first 6 weeks). Also, less than half of the patients (48.4%) were seen at least every 6 months. Height was recorded at least annually in 42.0% of patients, weight in 44.9%, and both recorded in a growth chart in 19.5%. Questionnaires to assess treatment response were only used in 2.3% of all visits. When comparing both settings, more patients in the pediatric settings were seen every 6 months, although height and weight were recorded more often in the mental health care setting. Conclusion: Overall, guideline adherence was low. Training of clinicians and adding guideline recommendations to electronic medical records templates may improve adherence. Additionally, we should aim to close the gap between guidelines and clinical practice by looking critically at the feasibility of guidelines.

Withdrawing methylphenidate in relation to serum levels of ferritin and zinc in children and adolescents with attention-deficit/hyperactivity disorder.

Iron and zinc have been associated with attention-deficit/hyperactivity disorder (ADHD), executive functioning, and response to methylphenidate, given their link with the dopaminergic system. This study aimed to investigate the effect of withdrawing methylphenidate after long-term treatment on serum levels of ferritin and zinc; and if baseline (pre-discontinuation) serum levels of these nutritional markers moderated the effects of withdrawing methylphenidate on ADHD and oppositional defiant disorder (ODD) symptoms, and working memory. Blood samples were collected from 63 children and adolescents who participated in a randomized, placebo-controlled methylphenidate discontinuation study. They were assigned to either seven weeks of continued treatment with methylphenidate or to gradual withdrawal to placebo. With mixed models for repeated measures we (i) compared changes in ferritin and zinc serum levels between both groups, and (ii) investigated moderating effects of ferritin and zinc on the effects of discontinuation on ADHD and ODD symptoms, and working memory. We additionally explored correlations of baseline and change serum levels with respective symptom scores. Withdrawing methylphenidate led to a decrease in ferritin levels. Higher baseline ferritin was associated with a larger increase (i.e., worsening) of teacher-rated hyperactivity-impulsivity and ODD symptoms after withdrawal; and higher baseline zinc with a larger increase in number of errors on the working memory task after withdrawal. Serum levels did not correlate with ADHD and ODD symptoms. Our preliminary results suggest that ferritin and zinc may be potential biomarkers for the effectiveness of long-term treatment with methylphenidate.

Clinicians' Adherence to Guidelines When Initiating Methylphenidate Treatment.

Aims: Between 2008 and 2012, the number of children and adolescents in the Netherlands who received methylphenidate prescriptions increased by 35.6%. We determined guideline adherence regarding the assessment of attention-deficit/hyperactivity disorder (ADHD) and rates of off-label use in those 2 years. We also compared adherence to guidelines between mental health and pediatrics settings. Methods: We conducted a medical file audit of 506 children or adolescents who had received a first methylphenidate prescription in 2008 (n = 208) or 2012 (n = 298) across mental health (n = 333) and pediatrics outpatient clinics (n = 173) in the Netherlands and assessed adherence to seven guideline recommendations. Results: We did not find significant differences between 2008 and 2012 regarding the mean adherence to the seven recommendations (43% vs. 45%) or the percentage of off-label use (35% vs. 30%). Best adherence rates (over the years 2008 and 2012 combined) concerned the assessment of comorbidities (89%) and the involvement of teachers in the diagnostic process (75%). Least frequently adhered to were assessing ADHD severity (1%), the use of a (semi-)structured parent interview (16%), and providing psycho-education to parents (42%) or teachers (1%). Mental health settings showed better adherence than pediatrics settings (over the years 2008 and 2012 combined) concerning the use of (semi-)structured parent interviews (22% vs. 3.1%), having a separate diagnostic session directed at the child (81% vs. 63%), assessment of comorbidities (95% vs. 76%), and providing psycho-education to parents (51% vs. 24%). Conclusions: There was neither a decrease in adherence to guidelines nor an increase in off-label use between 2008 and 2012. However, there is ample room for improvement regarding guideline adherence.

Effects of Discontinuing Methylphenidate on Strengths and Difficulties, Quality of Life and Parenting Stress.

Objectives: To study the effects of discontinuation of long-term methylphenidate use on secondary outcome measures of strengths and difficulties, quality of life (QoL), and parenting stress. Methods: Ninety-four children and adolescents aged 8 to 18 years who had used methylphenidate for over 2 years were randomly assigned to double-blind continuation of treatment for 7 weeks (36 or 54 mg extended release methylphenidate) or to gradual withdrawal over 3 to 4 weeks placebo. We used mixed models for repeated measures to investigate effects on parent, teacher, and child ratings of hyperactivity/inattention and comorbid symptoms with the Strengths and Difficulties Questionnaire (SDQ), investigator- and teacher-rated oppositional symptoms (Conners Teacher Rating Scale-Revised: short form [CTRS-R:S]), and parent-rated aggression with the Retrospective Modified Overt Aggression Scale. QoL was assessed with the Revised Questionnaire for Children and Adolescents to record health-related quality of life and parenting stress with the Nijmegen Parental Stress Index. Results: Hyperactivity/inattention scores from the parent- and teacher-rated SDQ (difference in mean change over time of respectively: -1.1 [95% confidence interval, CI, -2.0 to -0.3]; p = 0.01; -2.9 [95% CI -2.9 to -0.7; p = 0.01]) and oppositional scores of the teacher-rated CTRS-R:S (difference in mean change -1.9 95% CI [-3.1 to -0.6; p < 0.01]) deteriorated to a significantly larger extent in the discontinuation group than in the continuation group. We did not find effects on other symptom domains, aggression, QoL, and parenting stress after discontinuation of methylphenidate. Conclusion: Our study suggests beneficial effects of long-term methylphenidate use beyond 2 years for oppositional behaviors in the school environment. Similarly, beneficial effects were found on hyperactivity-inattention symptoms as rated by parent and teacher scales, confirming our primary study on investigator ratings of attention-deficit/hyperactivity disorder. However, discontinuation of methylphenidate did not appear to have impact on other comorbid problems or aspects of the child's or parental functioning.

Continued Benefits of Methylphenidate in ADHD After 2 Years in Clinical Practice: A Randomized Placebo-Controlled Discontinuation Study.

OBJECTIVE: The benefits of long-term use of methylphenidate treatment in children and adolescents with attention deficit hyperactivity disorder (ADHD), as frequently prescribed in clinical practice, are unclear. The authors investigated whether methylphenidate remains beneficial after 2 years of use. METHODS: Ninety-four children and adolescents (ages 8-18 years) who had been treated in regular care with methylphenidate for more than 2 years were randomly assigned to double-blind continuation of treatment for 7 weeks (36 or 54 mg/day of extended-release methylphenidate) or gradual withdrawal over 3 weeks, to 4 weeks of placebo. The primary outcome measure was the investigator-rated ADHD Rating Scale (ADHD-RS); secondary outcome measures were the investigator-rated Clinical Global Impressions improvement scale (CGI-I) and the Conners' Teacher Rating Scale-Revised: Short Form (CTRS-R:S). Continuous ratings were analyzed with mixed model for repeated measures analyses, and the CGI-I with a chi-square test. RESULTS: The mean ADHD-RS scores at baseline for the continuation and discontinuation groups, respectively, were 21.4 (SD=9.7) and 19.6 (SD=8.9); after 7 weeks, the mean scores were 21.9 (SD=10.8) and 24.7 (SD=11.4), with a significant between-group difference in change over time of -4.6 (95% CI=-8.7, -0.56) in favor of the group that continued methylphenidate treatment. The ADHD-RS inattention subscale and the CTRS-R:S ADHD index and hyperactivity subscale also deteriorated significantly more in the discontinuation group. The CGI-I indicated worsening in 40.4% of the discontinuation group, compared with 15.9% of the continuation group. CONCLUSIONS: Continued treatment with methylphenidate remains effective after long-term use. Some individual patients may, however, be withdrawn from methylphenidate without deterioration. This finding supports guideline recommendations that patients be assessed periodically to determine whether there is a continued need for methylphenidate treatment.