Faculty Bibliography

OBJECTIVE: The authors explored genetic moderators of symptom reduction and side effects in methylphenidate-treated preschool-age children diagnosed with attention-deficit/hyperactivity disorder (ADHD). METHOD: DNA was isolated from 81 subjects in a double-blind, placebo-controlled, crossover methylphenidate titration. Parents and teachers completed ADHD symptom scales and side effect ratings for each of five randomly administered weekly conditions that included immediate-release methylphenidate 1.25, 2.5, 5.0, 7.5 mg and placebo given three times daily. Candidate genes hypothesized to influence stimulant effects or individual risks for ADHD were genotyped. RESULTS: Although the primary analysis did not indicate significant genetic effects, secondary analyses revealed associations between symptom response and variants at the dopamine receptor (DRD4) promoter (p=.05) and synaptosomal-associated protein 25 (SNAP25) allelesT1065G (p=.03) andT1069C (p=.05). SNAP25 variants were also associated with tics (p=.02), buccal-lingual movements (p=.01), and irritability (p=04). DRD4 variants were also associated with picking (p=.03). Increasing dose predicted irritability (p=.05) and social withdrawal (p=.03) with DRD4 variants. There were no significant effects for the dopamine transporter (DAT1). CONCLUSIONS: Emerging evidence suggests the potential for understanding the individual variability of response to and side effects of ADHD medications from the study of genetics, although additional research is required before these findings are proven to have clinical utility

OBJECTIVE: To report on the safety and tolerability of methylphenidate (MPH) 3- to 5-year-old children with attention-deficit/hyperactivity disorder (ADHD) during 1 year of treatment. METHOD: Exactly 183 children (3-5 years old) entered a treatment study of MPH, consisting of a 1-week open-label lead-in (n=183); a 5-week placebo-controlled, double-blind phase (n=165); a 5-week double-blind, parallel phase (n=114); and 10 months of open-label maintenance (n=140 entered, 95 completed). Mean total daily MPH doses rose from the titration trial best dose, 14.1 (+/-8.1) mg/day, to 20.5 (+/-9.7) mg/day mean total daily dose at the end of maintenance. Pulse, blood pressure, and the presence of treatment emergent adverse events (AEs), parent and teacher AE ratings, and vital signs were recorded in each phase. RESULTS: Thirty percent of parents spontaneously reported moderate to severe AEs in all study phases after baseline. These included emotional outbursts, difficulty falling asleep, repetitive behaviors/thoughts, appetite decrease, and irritability. During titration, decreased appetite (chi=5.4, p<.03), trouble sleeping (chi=5.4, p<.03), and weight loss (chi=4.0, p<.05) occurred statistically more often on MPH than on placebo. During maintenance, trouble sleeping and appetite loss persisted and other MPH-related AEs decreased. There were transient, one-time pulse and blood pressure elevations in five children. Twenty-one children (11%) discontinued because of drug-attributed AEs. CONCLUSIONS: Eleven percent of preschoolers discontinued treatment because of intolerable MPH AEs. Of the serious AEs reported, one occurred in baseline, two in lead-in, three in titration, one in parallel, and one in maintenance. Only one was possibly related to MPH

BACKGROUND: While studies have increasingly investigated deficits in reaction time (RT) and RT variability in children with attention deficit/hyperactivity disorder (ADHD), few studies have examined the effects of stimulant medication on these important neuropsychological outcome measures. METHODS: 316 children who participated in the Multimodal Treatment Study of Children with ADHD (MTA) completed the Conners' Continuous Performance Test (CPT) at the 24-month assessment point. Outcome measures included standard CPT outcomes (e.g., errors of commission, mean hit reaction time (RT)) and RT indicators derived from an Ex-Gaussian distributional model (i.e., mu, sigma, and tau). RESULTS: Analyses revealed significant effects of medication across all neuropsychological outcome measures. Results on the Ex-Gaussian outcome measures revealed that stimulant medication slows RT and reduces RT variability. CONCLUSIONS: This demonstrates the importance of including analytic strategies that can accurately model the actual distributional pattern, including the positive skew. Further, the results of the study relate to several theoretical models of ADHD

OBJECTIVE: This study evaluates the efficacy, duration of action, and tolerability of methylphenidate transdermal system (MTS) in children with ADHD. METHOD: Participants were dose optimized over 5 weeks utilizing patch doses of 10, 16, 20, and 27 mg applied in the morning and worn for 9 hours. Following optimization, 80 participants were randomized to 1 week of MTS or placebo followed by 1 week of the opposite treatment. Laboratory classroom sessions conducted after each randomized week included blinded ratings of attention, behavior, and academic performance. RESULTS: MTS was well tolerated and displayed significant improvement compared with placebo. Improvements were seen at the first postdose time point measured and continued through 12 hours. CONCLUSIONS: Treatment with MTS resulted in statistically significant improvements on all efficacy measures. Time course and therapeutic effects of MTS suggest that this novel methylphenidate delivery system is an efficacious once-daily treatment for ADHD

Peer-assessed outcomes were examined at the end of treatment (14 months after study entry) for 285 children (226 boys, 59 girls) with attention deficit hyperactivity disorder (ADHD) who were rated by their classmates (2,232 classmates total) using peer sociometric procedures. All children with ADHD were participants in the Multimodal Treatment Study of Children with ADHD (MTA). Treatment groups were compared using the orthogonal treatment contrasts that accounted for the largest amount of variance in prior MTA outcome analyses: Medication Management + Combined Treatment versus Behavior Therapy + Community Care; Medication Management versus Combined Treatment; Behavior Therapy versus Community Care. There was little evidence of superiority of any of the treatments for the peer-assessed outcomes studied, although the limited evidence that emerged favored treatments involving medication management. Post hoc analyses were used to examine whether any of the four treatment groups yielded normalized peer relationships relative to randomly selected-classmates. Results indicated that children from all groups remained significantly impaired in their peer relationships

Significant ethnic differences have been consistently documented on attention-deficit/hyperactivity disorder (ADHD) teacher rating scales. Whether these ethnic differences result from a teacher rating bias or reflect actual classroom behavior patterns is unknown. Ethnic differences between Caucasian and African American (AA) elementary schoolchildren on teacher ratings and codings of observed classroom behavior were examined with latent variables. In structural equation models, correlations between teacher ratings and observed classroom behavior suggested nonbiased teacher ratings of AA schoolchildren with diagnosed ADHD. Ethnic differences were documented for both teacher ratings of ADHD and classroom behavior. Differences in classroom behavior were attenuated when the behavior of an average child in the classroom was taken into account. Multiple explanations for this pattern of results are discussed

(from the journal abstract) This preliminary study examined intervention effects of a universal prevention program offered by classroom teachers to public elementary school students. The Unique Minds School Program (M.B. Stern, 1999) is a teacher-led program designed to promote cognitive-social-emotional (CSE) skills, including student self-efficacy, problem solving, social-emotional competence, and a positive classroom climate, with the dual goal of preventing youth behavioral problems and promoting academic learning. During 2 consecutive school years, 119 students and their teachers were assessed in the fall and spring of Grade 4 and again in the spring of Grade 5. As compared to students in the comparison school, students in the intervention showed gains in student self-efficacy, problem solving, social-emotional competencies, and math grades. Incremental gains within CSE domains were found after 1 and 2 years of intervention.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by clinically significant anxiety, but few empirical data guide treatment of children meeting full DSM-IV criteria for ADHD and anxiety disorders (ADHD/ANX). This study examined the efficacy of sequential pharmacotherapy for ADHD/ANX children. METHOD: Children, age 6 to 17 years, with ADHD/ANX were titrated to optimal methylphenidate dose and assessed along with children who entered the study on a previously optimized stimulant. Children with improved ADHD who remained anxious were randomly assigned to 8 weeks of double-blind stimulant + fluvoxamine (STIM/FLV) or stimulant + placebo (STIM/PL). Primary efficacy measures were the Swanson, Nolan, Atkins, and Pelham IV Parent and Teacher Rating Scale ADHD score and the Pediatric Anxiety Rating Scale total score. ADHD, ANX, and overall Clinical Global Impressions-Improvement scores were also obtained. RESULTS: Of the 32 medication-naive children openly treated with methylphenidate, 26 (81%) improved as to ADHD. Twenty-five children entered the randomized trial. Intent-to-treat analysis indicated no differences between the STIM/FLV (n = 15) and STIM/PL groups on the Pediatric Anxiety Rating Scale or Clinical Global Impressions-Improvement-defined responder rate. Medications in both arms were well tolerated. CONCLUSIONS: Children with ADHD/ANX have a response rate to stimulants for ADHD that is comparable with that of children with general ADHD. The benefit of adding FLV to stimulants for ANX remains unproven