Placebo-controlled Trial Of Methylphenidate Research Articles

Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1: a study protocol for a randomised placebo-controlled crossover trial

IntroductionDopamine dysregulation has been identified as a key modulator of behavioural impairment in neurofibromatosis type 1 (NF1) and a potential therapeutic target. Preclinical research demonstrates reduced dopamine in the brains...

How do stimulant treatments for ADHD work? Evidence for mediation by improved cognition.

Stimulant medications such as methylphenidate (MPH) are the frontline treatment for Attention-Deficit/Hyperactivity Disorder (ADHD). Despite their well-documented efficacy, the mechanisms by which stimulants improve clinical outcomes are not clear. The current study evaluated whether MPH effects on classroom behavior were mediated by improved cognitive functioning. Children with ADHD (n=82; 9-12years old) participated in a week-long summer research camp, consisting of cognitive testing, classroom periods, and recreational activities. After a baseline day, participants completed a 3-day randomized, double-blind, placebo-controlled trial of MPH (at doses approximating 0.3 and 0.6mg/kg of immediate-release MPH dosed TID). Cognitive domains included inhibitory control (Stop Signal Task and prepulse inhibition of startle), attention (Continuous Performance Task and reaction time variability), and working memory (forward and backward spatial span). Clinical outcomes included math seatwork productivity and teacher-rated classroom behavior. A within-subjects path-analytic approach was used to test mediation. MPH-placebo and dose-response contrasts were used to evaluate drug effects. Methylphenidate improved seatwork productivity and teacher ratings (ds=1.4 and 1.1) and all domains of cognition (ds=0.3-1.1). Inhibitory control (Stop Signal Task, SST) and working memory backward uniquely mediated the effect of MPH (vs. placebo) on productivity. Only working memory backward mediated the impact of MPH on teacher-rated behavior. The dose-response (0.6 vs. 0.3mg/kg) effects were more modest for clinical outcomes (ds=0.4 and 0.2) and cognition (ds=0-0.3); there was no evidence of cognitive mediation of the clinical dose-response effects. These findings are novel in demonstrating that specific cognitive processes mediate clinical improvement with stimulant treatment for ADHD. They converge with work on ADHD theory, neurobiology, and treatment development in suggesting that inhibitory control and working memory may be mechanisms of stimulant treatment response in ADHD. More work is necessary to evaluate the degree to which these findings generalize to chronic treatment, a broader array of clinical outcomes, and nonstimulant treatments.

Is the Inattentive Subtype of ADHD Different From the Combined/Hyperactive Subtype?

Objective: To compare the ADHD combined/hyperactive subtype (ADHD/CH) to the ADHD inattentive subtype (ADHD/I) on the level of comorbidity, treatment response, and possible etiological factors. Method: A total of 371 clinically referred children diagnosed with ADHD aged between 6 and 12 years are recruited for a double-blind, placebo-controlled trial of methylphenidate. Comorbidity, treatment response, and stress during pregnancy are assessed for each participant. Genotyping is done for the DAT, DRD4, and 5-HTT genes. Mothers report smoking or alcohol consumption during their pregnancy and their child’s birth weight. Results: The ADHD/CH children show both a higher frequency of conduct disorder and good response to treatment, are exposed to more moderate stress during their mothers’ pregnancy, and show a higher frequency of L/L genotype for the 5-HTT-linked polymorphic region. Conclusion: The significant differences found between the ADHD/CH and the ADHD/I subtypes raise the possibility that the two may be separate disorders.

Methylphenidate improves response inhibition but not reflection–impulsivity in children with attention deficit hyperactivity disorder (ADHD)

RationaleImpulsivity is a cardinal feature of attention deficit hyperactivity disorder (ADHD), which is thought to underlie many of the cognitive and behavioural symptoms associated with the disorder. Impairments on some measures of impulsivity have been shown to be responsive to pharmacotherapy. However, impulsivity is a multi-factorial construct and the degree to which different forms of impulsivity contribute to impairments in ADHD or respond to pharmacological treatments remains unclear.ObjectivesThe aims of the study were to assess the effects of methylphenidate (MPH) on the performance of children with ADHD on measures of reflection–impulsivity and response inhibition and to compare with the performance of healthy volunteers.MethodsTwenty-one boys (aged 7–13 years) diagnosed with ADHD underwent a double-blind, placebo-controlled trial of MPH (0.5 mg/kg) during which they performed the Information Sampling Task (IST) and the Stop Signal Task. A healthy age- and education-matched control group was tested on the same measures without medication.ResultsChildren with ADHD were impaired on measures of response inhibition, but did not demonstrate reflection–impulsivity on the IST. However, despite sampling a similar amount of information as their peers, the ADHD group made more poor decisions. MPH improved performance on measures of response inhibition and variability of response, but did not affect measures of reflection–impulsivity or quality of decision-making.ConclusionsMPH differentially affected two forms of impulsivity in children with ADHD and failed to ameliorate their poor decision-making on the information sampling test.

The Effects of Methylphenidate on Decision Making in Attention-Deficit/Hyperactivity Disorder

BackgroundChildren with attention-deficit/hyperactivity disorder (ADHD) frequently display poor judgment and risk taking in their everyday behavior, but there are little empirical data on decision-making cognition in this disorder. The objectives of the study were to assess the effects of stimulant medication on decision making in ADHD and compare performance on the Cambridge Gamble Task between boys with and without ADHD.MethodsTwenty-one boys (aged 7–13) diagnosed with ADHD underwent a double-blind, placebo-controlled trial of methylphenidate (.5 mg/kg) during which they performed the Cambridge Gamble Task (CGT). A healthy age-matched control group was tested on two occasions off drug.ResultsThe ADHD group bet more conservatively on the methylphenidate session than on the placebo session. In comparison with healthy control subjects, the ADHD group made more poor decisions, placed their bets more impulsively, and adjusted their bets less according to the chances of winning. Poor decision making was correlated with parent-reported symptoms and disruptive behavior in the ADHD group.ConclusionsMethylphenidate reduced risk-prone betting behavior on the CGT. Compared with control subjects, children with ADHD display a number of decision-making deficits on the task, and the measure of rational decision making may serve as an ecologically valid neuropsychological marker of impairment.

A randomized, double-blind, placebo-controlled trial of methylphenidate for attentional problems in survivors of childhood cancer

A randomized, double-blind, placebo-controlled trial of methylphenidate for attentional problems in survivors of childhood cancer

Stimulant medication effects on learning in children with mental retardation and ADHD

Forty four children (ages 6–13 years) with moderate mental retardation to borderline intellectual functioning participated in a double-blind, placebo-controlled trial of methylphenidate (Ritalin) involving .3 and .6 mg/kg medication doses and a placebo. Sixty six percent of subjects were found to be responders to medication based upon weekday school reports or data obtained while attending a weekly Saturday laboratory classroom. The assessment of medication effects on learning was conducted via a daily work task (number of problems completed and work accuracy) and a short-term auditory memory task. Results indicated beneficial medication effects on work output during the weekday and Saturday program, but gains in work accuracy in the weekday classroom only. No significant medication effects were noted on the short-term auditory memory task. Results are consistent with previous research and suggest that children with mental retardation and ADHD require supplemental programming, such as the teaching of specific learning strategies or behavioral interventions, to take full advantage of gains resulting from medication.

Prediction of Clinical Response to Methylphenidate in Children with Attention-Deficit Hyperactivity Disorder

To examine the pattern of individual responses to to methylphenidate (MPH) in children with attention-deficit hyperactivity disorder and to examine factors that predict drug response. Individual drug response was defined on the basis of changes on the Abbreviated Conners Rating Scales completed by parents and teachers. These scales were the main outcome measures in a double-blind, placebo-controlled trial of MPH. Response prediction was examined in stepwise discriminant analyses, in which baseline variables and the response to a single, 10-mg dose of MPH were entered. Predictors of a strong MPH response were a high IQ, considerable inattentiveness, young age, low severity of disorder, and low rates of anxiety. A positive response to a single dose of MPH significantly improved the prediction of less stringently defined levels of MPH response. Only strong levels of response could be predicted by baseline characteristics. Severity of disorder based on clinical judgment and improvement after a single dose of MPH are found to be important contributors to response prediction.

Cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid in adults with attention deficit disorder, residual type

Following the hypothesis that attention deficit disorder in adults (attention deficit disorder, residual type; ADD, RT), as well as in children, is associated with decreased central dopaminergic activity, the authors measured lumbar cerebrospinal fluid monoamine metabolites in a group of adults with ADD, RT and matched control subjects. Patients were then entered into a double-blind, placebo-controlled trial of methylphenidate. It was predicted that the patients would have lower levels of homovanillic acid (HVA), the major dopamine metabolite in humans. Patients who had a significant response to methylphenidate showed a trend in this direction. Nonresponding patients had significantly higher levels of HVA than controls.

Methylphenidate in severely retarded residents and the clinical significance of stereotypic behavior.

An attempt was made to evaluate a model predicting stimulant drug response based on attentional characteristics of the participants. Twenty-eight severely and profoundly mentally retarded residents took part in a double blind, placebo controlled trial of methylphenidate (Ritalin). Methylphenidate was administered, for one week each, in a low dose of 0.3 mg/kg and a high dose of 0.6 mg/kg. The results failed to show any clinically relevant differences between placebo and active drug conditions with the exception that methylphenidate caused a significant reduction in food consumption. A variety of subject characteristics, including level of stereotypy, hyperactivity, and IQ were unrelated to drug effect. One positive finding, unrelated to drug effects, was that subdivision of the group by degree of stereotypy provided substantial clinical information about individual subjects.