A laboratory school comparison of mixed amphetamine salts extended release (Adderall XR) and atomoxetine (Strattera) in school-aged children with attention deficit/hyperactivity disorder

Mixed amphetamine salts extended release (MAS XR; Adderall XR) and atomoxetine (Strattera) were compared in children 6 to 12 years old with attention deficit/hyperactivity disorder (ADHD) combined or hyperactive/impulsive type in a randomized, double-blind, multicenter, parallel-group, forced-dose-escalation laboratory school study. Primary efficacy measure was the SKAMP (Swanson, Kotkin, Agler, M-Flynn, and Pelham) behavioral rating scale. Changes in mean SKAMP deportment scores from baseline were significantly greater for MAS XR (n = 102) than for atomoxetine (n = 101) overall (-0.56 and -0.13, respectively; p < .0001) and at each week (p < .001). Adverse events were similar for both treatment groups. The extended time course of action and greater therapeutic efficacy of MAS XR suggests that it is more effective than atomoxetine in children with ADHD.     

Methylphenidate enhances extinction of contextual fear

Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show that MPH, administered before or immediately following extinction of contextual fear, will enhance extinction retention in C57BL/6 mice. Animals that received MPH (2.5-10 mg/kg) before an extinction session showed decreased freezing response during extinction, and the effect of the 10 mg/kg dose on freezing persisted to the next day. When MPH (2.5-40 mg/kg) was administered immediately following an extinction session, mice that received MPH showed dose-dependent decreases in freezing during subsequent tests. MPH administered immediately after a 3-min extinction session or 4 h following the first extinction session did not cause significant differences in freezing. Together, these findings demonstrate that MPH can enhance extinction of fear and that this effect is sensitive to dose, time of injection, and duration of the extinction session. Because MPH is widely used in clinical treatments, these experiments suggest that the drug could be used in combination with behavioral therapies for patients with fear disorders.     

Ethical Evaluation Bias

The objective of this study was to determine whether Ritalin (methylphenidate, MPH) affects cognitive flexibility and creativity in children with Attention Deficit Hyperactivity Disorder (ADHD). Measures administered included the Wisconsin Card Sorting Test-Revised (WCST-R), the Test of Divergent Thinking (TDT), and the Conners' ADHD rating scale, for both on and off MPH conditions. Comparison of on and off MPH data indicated that MPH administration significantly decreased symptoms of ADHD, as rated by parents on the Conners'. No significant differences were found on the WCST-R as a function of MPH administration. The Elaboration subscale of the TDT was the only scale to show a significant decrease in scores with MPH administration.     

Time Course of Treatment Effect of OROS(R) Methylphenidate in Children With ADHD

Objective: The authors evaluated the time course of the treatment effect of Osmotic-Release Oral System methylphenidate (OROS(?) MPH) HCl (Concerta(?), Raritan, NJ) CII in children with ADHD. Method: Data were combined from two double-blind, randomized, placebo-controlled, cross-over, analog classroom studies in children (9-12 years) with ADHD. Participants received an individualized dose of placebo or OROS(?) MPH on two laboratory school days. Permanent Product Math Test and Swanson, Kotkin, Agler, M-Flynn, and Pelham scores were evaluated 0.5 hr before dosing and 1, 2, 4, 10, 11, and 12.5 hr post dose. Analysis used a repeated-measures mixed model. Results: Treatment effects were present at all postdose assessment points (p < .0001 for all comparisons, n = 139). Adverse events were similar to previous reports for OROS(?) MPH. Conclusion: A robust treatment effect occurred with OROS(?) MPH; onset was at 1 hr and persisted for at least 12.5 hr after dosing.     

Stimulant Treatment Reduces Lapses in Attention among Children with ADHD: The Effects of Methylphenidate on Intra-Individual Response Time Distributions

Recent research has suggested that intra-individual variability in reaction time (RT) distributions of children with ADHD is characterized by a particularly large rightward skew that may reflect lapses in attention. The purpose of the study was to provide the first randomized, placebo-controlled test of the effects of the stimulant methylphenidate (MPH) on this tail and other RT distribution characteristics. Participants were 49 9- to 12-year-old children with ADHD. Children participated in a 3-day double-blind, placebo-controlled medication assessment during which they received long-acting MPH (Concerta®), with the nearest equivalents of 0.3 and 0.6 mg/kg t.i.d. immediate-release MPH. Children completed a simple two-choice speeded discrimination task on and off of medication. Mode RT and deviation from the mode were used to examine the peak and skew, respectively, of RT distributions. MPH significantly reduced the peak and skew of RT distributions. Importantly, the two medication effects were uncorrelated suggesting that MPH works to improve both the speed and variability in responding. The improvement in variability with stimulant treatment is interpreted as a reduction in lapses in attention. This, in turn, may reflect stimulant enhancement of self-regulatory processes theorized to be at the core of ADHD.     

Attention-Deficit/Hyperactivity Disorder and methylphenidate: a dose-response analysis and parent-child comparison of somatic complaints

The authors examined parent and child ratings of somatic complaints in 65 children with Attention-Deficit/Hyperactivity Disorder (ADHD) who received four doses (5 mg, 10 mg, 15 mg, 20 mg) of methylphenidate (MPH) in the context of a double-blind, placebo controlled, within-subject (crossover) experimental design. Results indicated that parent and child ratings of somatic complaints decreased in a linear fashion from baseline levels as a function of increasing MPH dose and showed minimal variation across MPH conditions. Statistical comparisons of specific somatic complaints indicated minimal agreement between parents and children in contrast to the nearly identical parent-child dose-response curves. The paradoxical findings of fewer somatic complaints associated with MPH, importance of obtaining children's perceptions of MPH treatment, and implications for measuring somatic complaints are discussed.     

RITALIN VS. RESPONSE COST IN THE CONTROL OF HYPERACTIVE CHILDREN: A WITHIN-SUBJECT COMPARISON

A within-subject comparison was made of the effects of methylphenidate (Ritalin) and response cost in reducing the off-task behavior of two boys, 7 and 8 years of age, who had been diagnosed as having an attentional deficit disorder with hyperactivity. Several dosages of Ritalin (5 to 20 mg/day) were evaluated with the results indicating varying effects of the drug for both children. Response cost (with free-time as the reinforcer) was superior to Ritalin in raising levels of on-task behavior and in improving academic performance.     

Effects of methylphenidate on inhibitory control in hyperactive children

This study investigated the effects of methylphenidate (MPH) on inhibitory control in hyperactive children. A double-blind, placebo-control, within-subject (crossover) design was used in which 12 children, between 6 and 11 years of age, were each tested four times in each drug condition: 0.3 mg/kg and 1.0 mg/kg of methylphenidate, and placebo. Dependent measures included (a) the probability of inhibiting responses to a primary choice reaction time task given a stop signal, on the Stopping Task, and (b) response latency and errors on the Matching Familiar Figures Test (MFFT). MPH improved the efficiency of the central inhibitory mechanism by speeding the inhibitory process, thereby affording the children greater control over their actions and enabling them to increase the probability with which they inhibited responses given a stop signal. MPH increased response latency but did not reduce errors on the MFFT, and observation of the children's task performance highlighted the interpretive problems associated with this task. Performance on both tasks was better at a dosage of 1.0 mg/kg than at 0.3 mg/kg.     

Efficacy of Adderall for Attention-Deficit/Hyperactivity Disorder: a meta-analysis

Stimulant medication has, for many years, been the pharmacological treatment of choice for children and adults with Attention-Deficit/Hyperactivity Disorder (ADHD). Several studies have shown Adderall , to be efficacious for measures of inattention, hyperactivity-impulsivity, aggression, disruptive behavior, and academic productivity. Although these studies provide useful information for clinicians treating ADHD children and adults, the variability in efficacy among the different types of measures used within each study has not been comprehensively examined. Thus, to provide a clearer picture of what conclusions can be drawn from these studies, we performed a meta-analysis. Data from the six available studies of standard release Adderall show it to be efficacious for symptoms of inattention, hyperactivity-impulsivity, and aggression, as well as global ratings. Its efficacy was significant for clinician, parent, and teacher ratings, and for both fixed- and best-dose designs.     

The effect of methylphenidate on three forms of response inhibition in boys with AD/HD

The current study was aimed at (a) investigating the effect of three doses methylphenidate (MPH) and placebo on inhibition of a prepotent response, inhibition of an ongoing response, and interference control in Attention Deficit/Hyperactivity Disorder (AD/HD), and (b) studying dose-response relations for the three forms of response inhibition. To meet these aims, the following tasks were selected: two versions of the Stop Paradigm for inhibition of a prepotent response, a Circle Tracing Task and a recently developed Follow Task for inhibition of an ongoing response, and the Stroop Color-Word Test and an Eriksen Flanker Task for interference control. These tasks were administered to 23 boys with AD/HD during four treatment conditions: 5 mg MPH, 10 mg MPH, 20 mg MPH, and placebo. A pseudorandomized, multiple-blind, placebo-controlled, within-subject design was used. As hypothesized, inhibitory control in children with AD/HD improved under MPH compared to placebo. However, this effect was only significant for inhibition of a prepotent response and inhibition of an ongoing response (as measured by the Follow Task), but not for interference control. The relation between treatment condition and response was linear. However, this linear relation was due to improved inhibitory control under MPH compared to placebo, because no effects of MPH dose were observed for any of the response inhibition measures.     

Improving Working Memory in Children with Attention-Deficit/Hyperactivity Disorder: The Separate and Combined Effects of Incentives and Stimulant Medication

Working memory (WM) is considered a core deficit in Attention-Deficit/ Hyperactivity Disorder (ADHD), with numerous studies demonstrating impaired WM among children with ADHD. We tested the degree to which WM in children with ADHD was improved by performance-based incentives, an analog of behavioral intervention. In two studies, WM performance was assessed using a visuo-spatial n-back task. Study 1 compared children (ages 9-12?years) with ADHD-Combined type (n?=?24) to a group of typically developing (TD) children (n?=?32). Study 1 replicated WM deficits among children with ADHD. Incentives improved WM, particularly among children with ADHD. The provision of incentives reduced the ADHD-control group difference by approximately half but did not normalize WM. Study 2 examined the separate and combined effects of incentives and stimulant medication among 17 children with ADHD-Combined type. Both incentives and a moderate dose of long-acting methylphenidate (MPH; ~0.3?mg/kg t.i.d. equivalent) robustly improved WM relative to the no-incentive, placebo condition. The combination of incentives and medication improved WM significantly more than either incentives or MPH alone. These studies indicate that contingencies markedly improve WM among children with ADHD-Combined type, with effect sizes comparable to a moderate dose of stimulant medication. More broadly, this work calls attention to the role of motivation in studying cognitive deficits in ADHD and in testing multifactorial models of ADHD.     

A horse of a different color: how formulation influences medication effects

A medication's pharmacokinetic properties can be as important as its efficacy in determining how successful a treatment is. Formulation plays a critical role in absorption, distribution, and elimination of a drug, which in turn can influence the clinical profile of a medication, including onset and duration of action, consistency of plasma levels, ability to cross the blood-brain barrier, and other factors. Advances in drug delivery technology mean that formulation is now an integral component in the development of a drug. Likewise, formulation is one of the factors that may influence selection of a medication to suit the needs of a particular patient. This article briefly reviews the technologies commonly applied in the development of psychotropic medications, with emphasis on the various oral modified-release formulations, and discusses how formulation can be used to optimize the efficacy and tolerability of psychotropic drugs.     

Attention deficit disorder with hyperactivity and methylphenidate: The effects of dose and mastery level on children's learning performance

This investigation examined the relationship between methylphenidate (MPH) and the learning and recall of paired associations by children with attention deficit disorder with hyperactivity (ADDH). Forty-five children with ADDH were randomly assigned to one of three groups (novel, partial mastery, and mastery learning) that varied in the amount of previous learning of paired associations and participated in a double-blind, placebo-control, repeated-measures-across-dose (crossover) design. Each child received four doses of MPH (5 mg, 10 mg, 15 mg, and 20 mg) and a placebo in a random, counterbalanced sequence. The results indicated that both the rate of acquisition and accuracy in learning paired associations were significantly, but differentially, affected by MPH dose and the degree of learning mastery. The implications of these results for psychopharmacological research and the monitoring of psychostimulant effects on children's learning performance in academic settings are discussed.The authors wish to acknowledge and express their sincere appreciation to the graduate and undergraduate student members of the Children's Learning Clinic.     

Single and combined effects of methylphenidate and behavior therapy on the classroom performance of children with attention-deficit hyperactivity disorder

Twenty-four boys with attention deficit-hyperactivity disorder (ADHD) participating in an intensive summer treatment program each received b.i.d. placebo and two doses of methylphenidate (MPH, 0.3 mg/kg and 0.6 mg/kg) crossed with two classroom settings: a behavior modification classroom including a token economy system, time out and daily home report card, and a regular classroom setting not using these procedures. Dependent variables included classroom observations of on-task and disruptive behavior, academic work completion and accuracy, and daily self-ratings of performance. Both MPH and behavior modification alone significantly improved children's classroom behavior, but only MPH improved children's academic productivity and accuracy. Singly, behavior therapy and 0.3 mg/kg PMH produced roughly equivalent improvements in classroom behavior. Further, the combination of behavior therapy and 0.3 mg/kg MPH resulted in maximal behavioral improvements, which were nearly identical to those obtained with 0.6 mg/kg MPH alone.The authors gratefully acknowledge the assistance of Patricia Donovan, Michelle Berry, Mary Ingram, Patricia Wells, Beth Gnagy, Karen Greenslade, Mary Hamilton, and the entire staff of the Western Psychiatric Institute and Clinic ADHD Summer Treatment Program.     

Music and Video as Distractors for Boys with ADHD in the Classroom: Comparison with Controls,Individual Differences,and Medication Effects

This study examined the effects of music and video on the classroom behavior and performance of boys with and without attention deficit hyperactivity disorder (ADHD) and examined the effects of 0.3 mg/kg methylphenidate (MPH). In one study, 41 boys with ADHD and 26 controls worked in the presence of no distractor, music, or video. Video produced significant distraction, particularly for the boys with ADHD, and MPH improved the performance of boys with ADHD across distractor conditions.There were individual differences in response to the music such that some boys were adversely affected and others benefited relative to no-distractor.In a second study, music and MPH were assessed in an additional 86 boys with ADHD to examine further the music results. In the presence or absence of music, MPH improved performance relative to placebo. Similar individual differences were found as in Experiment 1.     

Methodological Issues in the Assessment of Medication Effects in Children Diagnosed with Attention Deficit Hyperactivity Disorder (ADHD)

Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed disorders in school-aged children and is usually treated with stimulant medications, including methylphenidate (MPH; Ritalin®, Ritalin-LA®, Concerta®, Metadate®, or Focalin®) and other drug compounds (e.g., Adderall®, Adderall-XR®, or Dexedrine). Assessment of school behavior and performance is a critical component in determining the safety and efficacy of these medications. This paper reviews methodological issues in assessing drug effects in school settings by considering features of the independent variable (the medication), the dependent variables (the endpoints selected for assessment), and the design (the structure of the assessment). In addition, we consider recent conceptual advances in understanding the behavioral mechanisms of action of drugs used to treat ADHD that may influence the structure and interpretation of medication assessments.     

THE RELATIVE EFFICACY OF METHYLPHENIDATE (RITALIN) AND BEHAVIOR-MODIFICATION TECHNIQUES IN THE TREATMENT OF A HYPERACTIVE CHILD

Drug versus placebo effects were contrasted with those of contingency management in the treatment of a hyperactive child. Several criterion behaviors were monitored in two different settings to gauge the breadth and generalizability of drug and behavior-management effects. Medication and contingency management effects were both found to be situation specific. No interaction effects were found. Accuracy of task performance, amount of eye contact with the experimenters, frequency of repetitive hand movements, and distractible behavior were apparently unaffected by medication (Ritalin versus placebo) within the clinic. A multiple-baseline design incorporating contingency reversals revealed the reinforcement contingencies to be the crucial variable controlling behavior within the clinic. Medication effects were shown to be significant within the home setting where reinforcement contingencies were not changed. While aggressive behavior decreased as a function of Ritalin, repetitive hand movements increased.     

Further analysis of the separate and interactive effects of methylphenidate and common classroom contingencies

We evaluated separate and interactive effects between common classroom contingencies and methylphenidate (MPH) on disruptive and off-task behaviors for 4 children with a diagnosis of attention deficit hyperactivity disorder. Analogue conditions consisting of contingent teacher reprimands, brief time-out, no interaction, and alone were conducted in a multielement design. Medication status (MPH or placebo) was alternated across days in a superordinate multielement design. Results indicate that (a) the behavioral effects of MPH were influenced by one or more of the analogue conditions for each participant, and (b) time-out was associated with zero or near-zero levels of both disruptive and off-task behavior for 3 of the 4 participants during MPH and placebo conditions. Implications for the clinical effectiveness of MPH and possible behavioral mechanisms of action of MPH in applied settings are discussed.     

Selective inhibition in children with attention-deficit hyperactivity disorder off and on stimulant medication

Selective inhibition requires discrimination between auditory signals and is assessed using a modification of the stop-signal task. Selective inhibition was assessed in a group of 59 clinic-referred, DSM-IV-diagnosed children with attention-deficit hyperactivity disorder (ADHD) and compared to that of a community sample of 59 children. Methylphenidate (MPH) effects on selective inhibition were assessed in a subset of the ADHD sample that participated in an acute, randomized, placebo-controlled, crossover trial with 3 fixed doses of MPH. Children with ADHD performed more poorly than controls on the majority of selective stop-signal task parameters: they exhibited more anticipatory (invalid) responses, with less accurate and more variable responses on the response execution task, as well as a slower selective inhibition process. MPH improved speed of both inhibition and response execution processes; it also reduced variability of response execution and decreased nonselective inhibition. On the one hand, findings are consistent with purported inhibition deficit in ADHD, but on the other hand, suggest that neither the impairment itself, nor MPH effects, were restricted to inhibition.