Short-term effects of an elimination diet and healthy diet in children with attention-deficit/hyperactivity disorder: a randomized-controlled trial.

An Elimination Diet (ED) may be effective in reducing symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD), but has never been compared to an active control condition [i.e., Healthy Diet (HD)]. In a two-armed RCT, a total of N = 165 children (5-12 years) with ADHD were randomized by means of minimization (1:1) to either an ED (N = 84) or HD (N = 81) within two Dutch child and adolescent psychiatry centers. The design included a non-randomized comparator arm including N = 58 children being treated with Care as Usual (CAU). Treatment allocation was unblinded. The primary outcome was a 5-point ordinal measure of respondership based on a combination of parent and teacher ratings on ADHD and emotion regulation, determined after 5 weeks of treatment. Ordinal regression analyses were done on an intention-to-treat basis. Fewer ED (35%) than HD (51%) participants showed a partial to full response, despite overall good-to-excellent treatment adherence (> 88%) and comparable high parental prior believes. A younger age and higher problem severity predicted a better respondership. CAU-preferring participants responded more often favorably (56%) compared to ED-but not HD-participants. Small-to-medium improvements in physical health (blood pressure, heart rate, and somatic complaints) were found in response to ED/HD versus decrements in response to CAU (74% received psychostimulants). The lack of superiority of the ED versus HD suggests that for the majority of children, dietary treatment response is not rooted in food-allergies/-sensitivities. The comparable results for treatment with HD and CAU are remarkable given that CAU participants were probably 'easier to treat' than HD (and ED) participants with proportionally fewer with a (suboptimal/non-response to) prior treatment with medication (4% versus 20%). Further assessment of long-term effects is needed to evaluate the potential place of dietary treatment within clinical guidelines. The trial is closed and registered in the Dutch trial registry, number NL5324 ( https://www.onderzoekmetmensen.nl/en/trial/25997 ).

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.

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.

A two arm randomized controlled trial comparing the short and long term effects of an elimination diet and a healthy diet in children with ADHD (TRACE study). Rationale, study design and methods.

BACKGROUND: Food may trigger Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms. Therefore, an elimination diet (ED) might be an effective treatment for children with ADHD. However, earlier studies were criticized for the nature of the control group, potential confounders explaining the observed effects, unsatisfactory blinding, potential risks of nutritional deficiencies and unknown long term and cost-effectiveness. To address these issues, this paper describes the rationale, study design and methods of an ongoing two arm randomized controlled trial (RCT) comparing the short (5 week) and long term (1 year) effects of an elimination diet and a healthy diet compared with care as usual (CAU) in children with ADHD. METHODS: A total of N = 162 children (5-12 years) with ADHD will be randomized to either an ED or a healthy diet. A comparator arm including N = 60 children being solely treated with CAU (e.g. medication) is used to compare the effects found in both dietary groups. The two armed RCT is performed in two youth psychiatry centers in the Netherlands, with randomization within each participating center. The primary outcome measure is response to treatment defined as a ≥ 30% reduction on an ADHD DSM-5 rating scale (SWAN) and/or on an emotion dysregulation rating scale (SDQ: dysregulation profile). This is assessed after 5 weeks of dietary treatment, after which participants continue the diet or not. Secondary outcome measures include the Disruptive Behavior Diagnostic Observational Schedule (DB-DOS), parent and teacher ratings of comorbid symptoms, cognitive assessment (e.g. executive functions), school functioning, physical measurements (e.g. weight), motor activity, sleep pattern, food consumption, nutritional quality of the diet, adherence, parental wellbeing, use of health care resources and cost-effectiveness. Assessments take place at the start of the study (T0), after five weeks (T1), four months (T2), eight months (T3) and 12 months of treatment (T4). T0, T1 and T4 assessments take place at one of the psychiatric centers. T2 and T3 assessments consist of filling out online questionnaires by the parents only. DISCUSSION: This RCT will likely contribute significantly to clinical practice for ADHD by offering insight into the feasibility, nutritional quality, (cost-)effectiveness and long term effects of dietary treatments for ADHD. TRIAL REGISTRATION: www.trialregister.nl, NTR5434. Registered at October 11th, 2015.

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.

To stop or not to stop? How long should medication treatment of attention-deficit hyperactivity disorder be extended?

ADHD is a common neuropsychiatric disorder with a strong persistence over time. Medication is frequently used in the clinical management of ADHD. After response, medication is typically prescribed for months to years. It is unclear whether extended medication treatment provides long-term benefits and how long it should be continued. Furthermore, there is concern about the long-term safety of ADHD medication. The aim of this systematic review is to address these issues and provide recommendations about the decision to stop or not to stop ADHD medication. We performed a search in PubMed and focused on medication studies with a treatment longer than 12weeks in subjects 6-18years old. Extended placebo-controlled double-blind parallel studies are not available. Placebo-controlled discontinuation studies and prospective long-term observational treatment studies provide evidence that medication management leads to a substantial reduction of ADHD symptoms and less impairment of functioning for a period of about 2years. There is limited and inconsistent evidence for long-term advantage of medication treatment beyond symptom control, such as improved social functioning, academic achievement, employment status and less adverse psychiatric outcome. In terms of safety, long-term effects of medication on growth, blood pressure and heart rate are limited and the occurrence of suicidal, psychotic and manic symptoms is rare. Animal data about neurotoxic effects of psycho stimulants cannot be directly extrapolated to humans. Therefore, clinical decisions about starting, continuing, and stopping of ADHD medication should be made on an individual basis. Medication free periods should be implemented at regular times to investigate the need for an ongoing benefit of medication. Unfounded assumptions about continuing benefit of medication use should be abandoned. Careful monitoring of side effects is necessary and must be able to detect early alarming signals.