Placebo-related improvement with methylphenidate treatment in children with ADHD.

Non-specific effects of methylphenidate treatment, including expectancy and regression to the mean effects, contribute to the overall effect of methylphenidate on attention-deficit/hyperactivity disorder (ADHD) symptoms. Knowledge on the extent to which non-specific effects contribute to the overall effect and whether regression to the mean explains part of the non-specific effects, is currently lacking. A double-blind, randomized, placebo-controlled, cross-over trial was used to compare parent and teacher ratings of child ADHD symptoms at baseline and during treatment with placebo and 5, 10, 15 and 20 mg of methylphenidate, twice daily. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). The extent to which non-specific effects contributed to the effects of methylphenidate was determined by ADHD symptom reductions observed with placebo versus reductions observed with active doses of methylphenidate. The influence of regression to the mean was examined by estimating the contribution of baseline ADHD symptom severity to the effects observed with placebo treatment. Data were analyzed using multilevel analyses. We observed significant non-specific effects of methylphenidate for parent-rated ADHD symptoms, but not for teacher-rated symptoms. For parent reported hyperactive/impulsive symptoms, higher baseline symptoms predicted larger effects with placebo, indicating regression to the mean effects. For parent-reports, a significant part of the overall effect of methylphenidate treatment is explained by non-specific effects. Our findings stress the importance of taking non-specific effects into account when evaluating methylphenidate treatment, by including teacher-reports and using a double baseline assessment during titration. Comparing active medication with a placebo in the titration trial has the potential to identify non-specific effects.

Improving Methylphenidate Titration in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): A Randomized Controlled Trial Using Placebo-Controlled Titration Implemented in Clinical Practice.

BACKGROUND AND OBJECTIVES: Concerns exist regarding the rising use of methylphenidate. A double-blind, placebo-controlled methylphenidate titration (PCT) for children with attention-deficit/hyperactivity disorder (ADHD) has shown potential to improve titration (i.e., detection of placebo responders and larger ADHD symptom improvement) in experimental settings. This study aims to determine if these advantages can be transferred to clinical settings. METHOD: Children (aged 5-13 years) with an ADHD diagnosis and an indication to start methylphenidate (MPH) treatment were recruited. Participants were randomized to PCT or care as usual (CAU) in a 1:1 ratio followed by a 7-week randomized controlled trial (T1) and 6-month, naturalistic, open-label follow-up (T2). Parents, teachers, and physicians rated ADHD symptoms, ADHD medication use, MPH dosing, and treatment satisfaction using questionnaires. RESULTS: A total of 100 children were enrolled and randomized to PCT (n = 49) or CAU (n = 51). In the PCT group, we found 8.2% placebo responders, 16.3% non-responders, and 65.3% responders to MPH. With PCT compared with CAU, a significantly larger number of children discontinued MPH (T1: 24.5 vs 5.9%, p = 0.009; T2: 41.7 vs 10.4%, p < 0.001) and refrained from using other pharmacological treatment (T1: 20.4 vs 3.9%, p = 0.013; T2: 20.83 vs 6.25%, p = 0.002). At both timepoints, there were no significant differences between the groups in the average dose of MPH, ADHD symptoms, or treatment satisfaction. CONCLUSIONS: PCT can be used to improve detection of children who do not benefit from MPH, and may therefore potentially reduce overtreatment of ADHD with MPH.

Methylphenidate dose-response in children with ADHD: evidence from a double-blind, randomized placebo-controlled titration trial.

Methylphenidate (MPH) is highly efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) in children. Generally increased doses are found to result in better symptom control; however, it remains unclear whether this pattern can be observed at the individual level, given the large heterogeneity in individual dose-response relationships and observed placebo responses. A double-blind, randomized, placebo-controlled cross-over trial was used to compare weekly treatment with placebo and 5, 10, 15 and 20 mg of MPH twice daily on parent and teacher ratings of child ADHD symptoms and side effects. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). MPH response was assessed at group and individual levels and predictors of individual dose-response curves were examined. Mixed model analysis showed positive linear dose-response curves at group level for parent and teacher rated ADHD symptoms and parent rated side effects, but not for teacher rated side effects. Teachers reported all dosages to improve ADHD symptoms compared to placebo, while parents only reported > 5 mg/dose as effective. At the individual level, most (73-88%) children, but not all, showed positive linear dose-response curves. Higher severity of hyperactive-impulsive symptoms and lower internalizing problems, lower weight, younger age and more positive opinions towards diagnosis and medication partly predicted steeper linear individual dose-response curves. Our study confirms that increased doses of MPH yield greater symptom control at a group level. However, large interindividual variation in the dose-response relationship was found and increased doses did not lead to greater symptom improvement for all children. This trial was registered in the Netherlands trial register (# NL8121).

[A scientifically grounded pharmacological treatment of ADHD]. / Medicamenteuze behandeling van ADHD bij kinderen en jongeren.

Methylphenidate is the first-choice pharmaceutical treatment for children and adolescents with attention deficit/hyperactivity disorder (ADHD). Concerns have been raised regarding unnecessary or suboptimal prescription of this medicine. Based on the results of three recently conducted Dutch studies - the Medication Optimization for ADHD study (MOVA), the Methylphenidate Discontinuation Study in Children (MASK), and the Discontinuation Trials Study - we advocate for an evidence-based approach to the treatment of children and adolescents with methylphenidate. The studies highlight that careful assessment of the effects of methylphenidate using placebo-controlled titration and systematically evaluating long-term treatment through placebo-controlled discontinuation trials can be beneficial in reducing unnecessary prescriptions of methylphenidate.

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

OBJECTIVE: Neurocognitive deficits are at the heart of explanatory models of attention-deficit/hyperactivity disorder (ADHD), and lead to significant impairments in daily life. Determining the dosing effects of methylphenidate (MPH) on a broad range of neurocognitive functions and investigating possible impairing effects of high doses is therefore important. METHOD: Placebo-controlled trials were included that investigated MPH dosing effects on neurocognitive functions in children and adolescents (aged 5-18 years) diagnosed with ADHD. Effect sizes (standardized mean differences [SMDs]) were calculated for different neurocognitive functions (baseline speed, variability in responding, nonexecutive memory and executive memory, inhibitory control, and cognitive flexibility) and, if available, for ADHD symptoms. Meta-regression analysis were used to investigate linear effects of dose (mg/kg/dose), and separate meta-analyses compared SMDs for 3 MPH dose ranges: low (0.10-0.30 mg/kg/dose), medium (0.31-0.60 mg/kg/dose), and high (0.61-1.00 mg/kg/dose). RESULTS: A total of 31 studies fulfilled inclusion criteria, comprising 804 children with ADHD. Methylphenidate had beneficial effects on all neurocognitive functions (d = 0.20-0.73). Significant linear dosing effects were found for ADHD symptoms and lower-order neurocognitive functions (baseline speed, variability in responding, nonexecutive memory), with greater enhancement of functioning with increasing dose. No dosing effects were found for higher-order neurocognitive functions (executive memory, inhibitory control, and cognitive flexibility). No detrimental effects of MPH were found on any of the investigated functions. CONCLUSION: Methylphenidate was superior to placebo in improving ADHD symptoms and a broad range of neurocognitive functions; however, effects sizes regarding the effects of dose vary substantially between functions. Our data highlight the importance of considering both neurocognitive and symptomatic aspects of ADHD in clinical practice.

The Validity of Teacher Rating Scales for the Assessment of ADHD Symptoms in the Classroom: A Systematic Review and Meta-Analysis.

Objective: To assess attention-deficit/hyperactivity disorder (ADHD) symptoms in the classroom, most often teacher rating scales are used. However, clinical interviews and observations are recommended as gold standard assessment. This systematic review and meta-analysis evaluates the validity of teacher rating scales. Method: Twenty-two studies (N = 3,947 children) assessing ADHD symptoms using teacher rating scale and either semi-structured clinical interview or structured classroom observation were meta-analyzed. Results: Results showed convergent validity for rating scale scores, with the strongest correlations (r = .55-.64) for validation against interviews, and for hyperactive-impulsive behavior. Divergent validity was confirmed for teacher ratings validated against interviews, whereas validated against observations this was confirmed for inattention only. Conclusion: Teacher rating scales appear a valid and time-efficient measure to assess classroom ADHD; although validated against semi-structured clinical interviews, there were only a few studies available. Low correlations between ratings and structured observations of inattention suggest that observations could add information above rating scales.

Effects of physical activity interventions on cognitive outcomes and academic performance in adolescents and young adults: A meta-analysis.

The aim was to provide a meta-analysis of studies investigating the effects of physical activity interventions on cognitive outcomes and academic performance in adolescents or young adults. A systematic review with meta-analysis was performed using the following databases: Embase, ERIC, MEDLINE, PsycINFO and Web of Science. Studies had to meet the following criteria: controlled study design, investigating the effects of physical activity interventions on cognitive outcomes and academic performance in healthy adolescents or young adults (12-30 years). Results showed that acute interventions (n=44) significantly improved processing speed (ES=0.39), attention (ES=0.34) and, inhibition (ES=0.32). In a subsequent meta-regression, shorter duration of intervention was significantly associated with greater improvements in attention (ß=-0.02) and cognitive flexibility (ß=-0.04), whereas age, percentage of boys, intensity and dose were not. Chronic interventions (n=27) significantly improved processing speed (ES=0.30), attention (ES=0.50), cognitive flexibility (ES=0.19), working memory (ES=0.59) and language skills (ES=0.31). In the meta-regression, higher percentage of boys was significantly associated with greater improvements in attention (ß=0.02) and working memory (ß=0.01) whereas age, duration, frequency, dose and load were not. In conclusion, acute and chronic physical activity interventions might be a promising way to improve several cognitive outcomes and language skills in adolescents and young adults.