title: Mediators of Methylphenidate Effects on Math Performance in Children with Attention-Deficit Hyperactivity Disorder Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings. Relative efficacy of long-acting stimulants on children with attention deficit-hyperactivity disorder: a comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dextroamphetamine, and pemoline. A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (the Comacs Study). Effects of OROS Methylphenidate on Academic, Behavioral, and Cognitive Tasks in Children 9 to 12 Years of Age With Attention-Deficit/Hyperactivity Disorder A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Reliability and validity of the SKAMP rating scale in a laboratory school setting. Stimulant Medication and Reading Performance A dose-response analysis of the effects of methylphenidate on the peer interactions and simulated classroom performance of ADD children with and without conduct problems. A longitudinal examination of neuropsychological and clinical functioning in boys with attention deficit hyperactivity disorder (ADHD): improvements in executive functioning do not explain clinical improvement. Differential Effects of Stimulant Medication on Reading Performance of Boys With Hyperactivity With and Without Conduct Disorder Comparative efficacy of once–a–day
  extended–release methylphenidate,
  two–times–daily immediate–release
  methylphenidate, and placebo in a
  laboratory school setting The Effects of Methylphenidate on Word Decoding Accuracy in Boys With Attention-Deficit/Hyperactivity Disorder Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder. Short term effects of methylphenidate on the cognitive, learning and academic performance of children with attention deficit disorder in the laboratory and the classroom. Pharmacokinetics and therapeutic effect of OROS methylphenidate under different breakfast conditions in children with attention-deficit/hyperactivity disorder. Methylphenidate in Children With ADHD With or Without Learning Disability Methylphenidate and children with attention deficit disorder. Dose effects on classroom academic and social behavior. Comparative effects of methylphenidate on ADD girls and ADD boys. Time Course of Treatment Effect of OROS® Methylphenidate in Children With ADHD Childhood hyperactivity and psychostimulants: a review of extended treatment studies.
abstract: Objective : Stimulant medications , such as methylpheni date ( MPH ) , improve the academic performance of children with attention-deficit hyperactivity disorder ( ADHD ) . However , the mechanism by which MPH exerts an effect on academic performance is unclear . We examined MPH effects on math performance and investigated possible mediation of MPH effects by changes in time on-task , inhibitory control , selective attention , and reaction time variability . Methods : Children with ADHD aged 7 to 11 years ( N = 93 ) completed a timed math worksheet ( with problems tailored to each individual 's level of proficiency ) and 2 neuropsychological tasks ( Go/No-Go and Child Attention Network Test ) at baseline , then participated in a 4-week , r and omized , controlled , titration trial of MPH . Children were then r and omly assigned to their optimal MPH dose or placebo for 1 week ( administered double-blind ) and repeated the math and neuropsychological tasks ( posttest ) . Baseline and posttest videorecordings of children performing the math task were coded to assess time on-task . Results : Children taking MPH completed 23 more math problems at posttest compared to baseline , whereas the placebo group completed 24 fewer problems on posttest versus baseline , but the effects on math accuracy ( percent correct ) did not differ . Path analyses revealed that only change in time on-task was a significant mediator of MPH 's improvements in math productivity . Conclusions : MPH-derived  math productivity improvements may be explained in part by increased time spent on-task , rather than improvements in neurocognitive parameters , such as inhibitory control , selective attention , or reaction time variability OBJECTIVE Methylpheni date ( MPH ) , the most commonly prescribed drug for attention-deficit/hyperactivity disorder ( ADHD ) , has a short half-life , which necessitates multiple daily doses . The need for multiple doses produces problems with medication administration during school and after-school hours , and therefore with compliance . Previous long-acting stimulants and preparations have shown effects equivalent to twice-daily dosing of MPH . This study tests the efficacy and duration of action , in natural and laboratory setting s , of an extended-release MPH preparation design ed to last 12 hours and therefore be equivalent to 3-times-daily dosing . METHODS Sixty-eight children with ADHD , 6 to 12 years old , participated in a within-subject , double-blind comparison of placebo , immediate-release ( IR ) MPH 3 times a day ( tid ) , and Concerta , a once-daily MPH formulation . Three dosing levels of medication were used : 5 mg IR MPH tid/18 mg Concerta once a day ( qd ) ; 10 mg IR MPH tid/36 mg Concerta qd ; and 15 mg IR MPH tid/54 mg Concerta qd . All children were currently medicated with MPH at enrollment , and each child 's dose level was based on that child 's  MPH dosing before the study . The doses of Concerta were selected to be comparable to the daily doses of MPH that each child received . To achieve the ascending rate of  MPH delivery determined by initial investigations to provide the necessary continuous coverage , Concerta doses were 20 % higher on a daily basis than a comparable tid regimen of IR MPH . Children received each medication condition for 7 days . The investigation was conducted in the context of a background clinical behavioral intervention in both the natural environment and the laboratory setting . Parents received behavioral parent training and teachers were taught to establish a school-home daily report card ( DRC ) . A DRC is a list of individual target behaviors that represent a child 's most salient areas of impairment . Teachers set daily goals for each child 's impairment targets , and parents provided rewards at home for goal attainment . Each weekday , teachers completed the DRC , and it was used as a dependent measure of individualized medication response . Teachers and parents also completed weekly st and ardized ratings of behavior and treatment effectiveness . To evaluate the time course of medication effects , children spent 12 hours in a laboratory setting on Saturdays and medication effects were measured using procedures and methods adapted from our summer treatment program . Measures of classroom behavior and academic productivity/accuracy were taken in a laboratory classroom setting during which children completed independent math and reading worksheets . Measures of social behavior were taken in structured , small-group board game setting s and unstructured recess setting s. Measures included behavior frequency counts , academic problems completed and accuracy , independent observations , teacher and counselor ratings , and individualized behavioral target goals . Reports of adverse events , sleep quality , and appetite were collected . RESULTS On virtually all measures in all setting s , both drug conditions were significantly different from placebo , and the 2 drugs were not different from each other . In children 's regular school setting s , both medications improved behavior as measured by teacher ratings and individualized target behaviors ( the DRC ) ; these effects were seen into the evening as measured by parent ratings . In the laboratory setting , effects of Concerta were equivalent to tid MPH and lasted at least through 12 hours after dosing . Concerta was significantly superior to tid MPH on 2 parent rating scores , and when asked , more parents preferred Concerta than preferred tid IR MPH or placebo . Side effects on children 's sleep and appetite were similar for the 2 preparations . In the lab setting , both medications improved productivity and accuracy on arithmetic seatwork assignments , disruptive and on-task behavior , and classroom rule following . Both medications improved children 's rule following and negative behavior in small group board games , as well as in unstructured recess setting s. Individual target behaviors also showed significant improvement with medication across domains in the laboratory setting . Children 's behavior across setting s deteriorated across the laboratory day , and the primary effect of medication was to prevent this deterioration as the day wore on . Results support the use of background behavioral treatment in clinical trials of stimulant medication , and illustrate the utility of a measure of individualized daily target goals ( ie , the DRC ) as an objective measure of medication response in both the laboratory and natural school setting s. CONCLUSION This investigation clearly supports the efficacy of the Concerta long-acting formulation of MPH for parents who desire to have medication benefits for their child throughout the day and early evening . ( ABSTRACT TRUNCATED Twenty-two children with attention deficit-hyperactivity disorder underwent a double-blind , placebo-controlled , crossover evaluation of the efficacy of st and ard methylpheni date twice a day and comparable doses every morning of a sustained-release preparation of methylpheni date ( SR-20 Ritalin ) , a sustained-release form of dextroamphetamine ( Dexedrine Spansule ) , and pemoline . The children were participating in a summer treatment program in which they engaged in recreational and classroom activities . Dependent measures include evaluations of social behavior during group recreational activities , classroom performance , and performance on a continuous performance task . Results revealed generally equivalent and beneficial effects of all four medications . Dexedrine Spansule and pemoline tended to produce the most consistent effects and were recommended for 10 of the 15 children who were responders to medication . The continuous performance task results showed that all four medications had an effect within 2 hours of ingestion , and the effects lasted for 9 hours . The implication s of these results for the use of long-acting stimulant medication in children with attention deficit-hyperactivity disorder are discussed OBJECTIVE The objective of this study was to evaluate differences in the pharmacodynamic ( PD ) profile of 2 second-generation extended-release ( ER ) formulations of methylpheni date ( MPH ) : Meta date CD ( MCD ; methylpheni date HCl , US Pharmacopeia ) extended-release capsules , CII , and Concerta ( CON ; methylpheni date HCl ) extended-release tablets , CII . Little empirical information exists to help the clinician compare the PD effects of the available ER formulations on attention and behavior . Previous studies have shown that the near-equal doses of MCD and CON provide equivalent , total exposure to MPH as measured by area under the plasma concentration time curve , yet their pharmacokinetic ( PK ) plasma concentration versus time profiles are different . We previously offered a theoretical PK/PD account of the similarities and differences among available ER formulations based on the hypothesis that all formulations produce effects related to MPH delivered by 2 processes : 1 ) an initial bolus dose of immediate-release ( IR ) MPH that is expected to achieve peak plasma concentration in the early morning and have rapid onset of efficacy within 2 hours of dosing , which for the MCD capsule is delivered by 30 % of the total daily dose as uncoated beads and for the CON tablet is delivered by an overcoat of 22 % of the total daily dose ; and 2 ) an extended , controlled delivery of ER MPH that is expected to achieve peak plasma concentrations in the afternoon to maintain efficacy for a programmed period of time after the peak of the initial bolus , which for the MCD capsule is delivered by polymer-coated beads and for the CON tablet by an osmotic-release oral system . According to this PK/PD model , clinical superiority is expected at any point in time for the formulation with the highest MPH plasma concentration . METHODS This was a multisite , double-blind , double-dummy , 3-way crossover study of 2 active treatments ( MCD and CON ) and placebo ( PLA ) . Children with confirmed diagnoses of attention-deficit/hyperactivity disorder were stratified to receive bioequivalent doses of MCD and CON that were considered to be low ( 20 mg of MCD and 18 mg of CON ) , medium ( 40 mg of MCD and 36 mg of CON ) , or high ( 60 mg of MCD and 54 mg of CON ) , and in a r and omized order each of the study treatments was administered once daily in the morning for 1 week . On the seventh day of each treatment week , children attended a laboratory school , where surrogate measures of response were obtained by using teacher ratings of attention and deportment and a record of permanent product of performance on a 10-minute math test at each of the 7 classroom sessions spread across the day at 1.5-hour intervals . Safety was assessed by patient reports of adverse events , parent ratings on a stimulant side-effects scale , and measurement of vital signs . RESULTS The analyses of variance revealed large , statistically significant main effects for the within-subject factor of treatment for all 3 outcome measures ( deportment , attention , and permanent product ) . The interactions of treatment x session were also highly significant for all 3 outcome measures . Inspection of the PD profiles for the treatment x session interactions suggested 4 patterns of efficacy across the day : 1 ) PLA > MCD approximately CON ( PLA superiority ) immediately after dosing ; 2 ) MCD > CON > PLA during the morning ( MCD superiority ) ; 3 ) MCD approximately CON > PLA during the afternoon ( PD equivalence of MCD and CON ) ; and 4 ) CON > MCD approximately PLA in the early evening ( CON superiority ) . The effect of site was significant , because some study centers had low and some high scores for behavior in the lab classroom , but both the low- and high-scoring sites showed similar PD patterns across the day . The interaction of dose x treatment was not significant , indicating that the pattern of treatment effects was consistent across each dose level . There were no statistically significant overall differences among the 3 treatments for the frequency of treatment-emergent adverse events , ratings of side effects , or vital signs . Two additional PK/PD questions were addressed : 1 . The a priori hypothesis called for a comparison of the average of sessions ( removing session as a factor ) during a time period that corresponds to the length of a typical school day ( from 1.5 through 7.5 hours after dosing ) . For the planned contrast of the 2 treatment conditions ( MCD versus CON ) , the difference was significant , confirming the a priori hypothesis of superiority of near-equal daily doses of MCD over CON for this predefined postdosing period . 2 . In the design of the study , the dose factor represented the total daily dose , consisting of 2 components : the initial bolus doses of IR MPH , which differ for the near-equal total daily doses of MCD and CON , and the reservoir doses of ER MPH , which were the same for the 2 formulations . To evaluate the moderating effects of the bolus component of dose on outcome , average effect size ( ES ) was calculated for the efficacy outcomes at the time of expected peak PK concentration times of the initial bolus component for each formulation at the 3 dose levels . The correlation ( r ) of ES with IR MPH bolus dose was significant for each of the 3 outcome measures ( r approximately .9 ) , indicating that the magnitude of effects in the early morning may be attributed to the dose administered by the IR MPH bolus of each formulation . For the 2 dose conditions with equal 12-mg IR MPH boluses ( MCD 40 and CON 54 ) , the ESs were large and indistinguishable ( eg , deportment ES approximately 0.75 for both ) . CONCLUSIONS Once-daily doses of MCD and CON produced statistically significantly different PD effects on surrogate measures of behavior and performance among children with attention-deficit/hyperactivity disorder in the laboratory school setting . As predicted by the PK/PD model , superiority at any point in time was achieved by the formulation with the highest expected plasma MPH concentration Objective . To assess effects of OROS methylpheni date on cognitive and academic tasks in 9 to 12 year olds with attention-deficit/hyperactivity disorder ( ADHD ) . Methods . A double-blind , within-subject , crossover design was used to compare OROS methylpheni date with placebo in a laboratory classroom setting on several cognitive and academic tasks for 68 children who met r and omization criteria . Results . Performance on the following measures was significantly better when children received individually optimized OROS methylpheni date than placebo :  math fluency and accuracy measured by the Permanent Product Math Test , ADHD symptoms observed in the laboratory setting , computerized indices of attention and impulsivity as measured by the Test of Variables of Attention ( TOVA ) , and visual — spatial working memory ( Finger Windows Backwards ) . Study medication was well tolerated ; adverse events were generally consistent with previous reports . Conclusions . OROS methylpheni date improves performance on measures of attention and vigilance , behavior , and working memory in a laboratory school setting in 9 to 12 year olds with ADHD BACKGROUND Previous studies have demonstrated the short-term efficacy of pharmacotherapy and behavior therapy for attention-deficit/hyperactivity disorder ( ADHD ) , but no longer-term ( i.e. , > 4 months ) investigations have compared these 2 treatments or their combination . METHODS A group of 579 children with ADHD Combined Type , aged 7 to 9.9 years , were assigned to 14 months of medication management ( titration followed by monthly visits ) ; intensive behavioral treatment ( parent , school , and child components , with therapist involvement gradually reduced over time ) ; the two combined ; or st and ard community care ( treatments by community providers ) . Outcomes were assessed in multiple domains before and during treatment and at treatment end point ( with the combined treatment and medication management groups continuing medication at all assessment points ) . Data were analyzed through intent-to-treat r and om-effects regression procedures . RESULTS All 4 groups showed sizable reductions in symptoms over time , with significant differences among them in degrees of change . For most ADHD symptoms , children in the combined treatment and medication management groups showed significantly greater improvement than those given intensive behavioral treatment and community care . Combined and medication management treatments did not differ significantly on any direct comparisons , but in several instances ( oppositional/aggressive symptoms , internalizing symptoms , teacher-rated social skills , parent-child relations , and reading achievement )  combined treatment proved superior to intensive behavioral treatment and /or community care while medication management did not . Study medication strategies were superior to community care treatments , despite the fact that two thirds of community-treated subjects received medication during the study period . CONCLUSIONS For ADHD symptoms , our carefully crafted medication management was superior to behavioral treatment and to routine community care that included medication . Our combined treatment did not yield significantly greater benefits than medication management for core ADHD symptoms , but may have provided modest advantages for non-ADHD symptom and positive functioning outcomes In children with attention deficit hyperactivity disorder ( ADHD ) , the effects of methylpheni date were investigated in a pharmacodynamic comparison of placebo and the st and ard b.i.d . administration of methylpheni date . In each of these conditions , teachers completed ratings in classroom setting s at times chosen to coincide with expected " peaks " and " troughs " of serum concentrations in the b.i.d . condition . Analyses of variance ( ANOVAs ) revealed the expected differences between the two conditions in the laboratory classroom setting using st and ard rating scales ( Conners and the IOWA Conners ) and a new rating scale ( the SKAMP ) , which specifically measures the classroom manifestation of ADHD . The psychometric properties of the SKAMP were evaluated by calculating test-retest reliability and by calculating correlations with the st and ard rating scales to establish concurrent validity The study examined the sustained effects of methylpheni date on reading performance in a sample of 42 boys , ages 8 to 11 , with attention deficit-hyperactivity disorder ( ADHD ) . Two subgroups were formed based on the presence or absence of co-occurring conduct disorders . Subjects were selected on the basis of their positive response to methylpheni date as determined in a series of original medication trials ( Forness , Cantwell , Swanson , Hanna , & Youpa , 1991 ) . For the purpose of this study , subjects were placed on their optimal dose of medication for a 6-week period and then tested on measures of oral reading and reading comprehension equivalent to those used in the original trials , retested after a week without medication ( placebo ) , then tested again the following week after return to medication . Only the subgroup with conduct disorders responded , and this response was limited to reading comprehension improvement in only those subjects who also demonstrated improvement in oral reading on original trials . No response differences were found between subjects with or without learning disabilities To examine the social effects of methylpheni date , groups of 15 attention-deficit disordered boys with ( ADD ) and 15 ADD boys without conduct problems ( ADD/CP ) were paired with normal peers . ADD and ADD/CP children showed a different pattern of responses to methylpheni date . While on task behavior in ADD/CP dyads increased at 0.15 mg/kg doses , increases in ADD dyads were not observed until doses reached 0.50 mg/kg . Although controlling interaction in ADD children decreased at 0.15 mg/kg , the controlling behavior of ADD/CP children did not decline at either dose . Peers of both ADD and ADD/CP children showed reciprocal declines in controlling behavior . In both free play and cooperative task situations , 0.15 mg/kg increased social interaction in ADD boys and decreased social interaction in ADD/CP boys BACKGROUND Attention deficit hyperactivity disorder ( ADHD ) often , but not always , persists into adulthood . Investigations of the associations between clinical and biological markers of persistence can shed light on causal pathways . It has been proposed that compensatory improvements in executive neuropsychological functioning are associated with clinical improvements . This is the first study to test this hypothesis prospect ively . METHOD The clinical and neuropsychological functioning of 17 boys with ADHD ( mean age 10.45 years at time 1 ; 14.65 years at time 2 ) and 17 typically developing ( TYP ) boys ( mean age 10.39 years at time 1 ; 14.47 years at time 2 ) was tested on two occasions , 4 years apart . This was done using a battery of st and ardized neuropsychological tests that included tasks with high and low executive dem and s. RESULTS Clinical improvements were observed over time . Neuropsychological performance improvements were also evident , with ADHD boys developing with a similar pattern to TYP boys , but with a developmental lag . Whilst there was an association between reduced symptoms and superior performance at retest for one task with a high executive dem and ( spatial working memory ) , this was not seen with two further high executive dem and tasks [ Stockings of Cambridge and intra-dimensional extra-dimensional ( ID/ED ) set shifting ] . Also , there was no association between change in executive functioning and change in symptoms . Baseline performance on the ID/ED set-shifting task predicted better clinical outcome . Only change in performance on the low executive dem and delayed matching-to- sample task predicted better clinical outcome . CONCLUSIONS These data highlight the importance of longitudinal measurements of cognition , symptoms and treatment response over time in children and adolescents with ADHD Controversy surrounding stimulant medication , particularly its effects on reading performance , continues to obscure the issue of the use of this drug in classroom situations . The present study emphasized careful differential diagnosis , double-blind and placebo approaches , and curriculum-based dependent measures to address these concerns . Methylpheni date was administered to two groups of boys , ages 8 through 11 . The two groups included 27 subjects meeting criteria for attention deficit-hyperactivity disorder but not conduct disorder , known as hyperactive disorder ( HD ) , and 28 subjects meeting criteria for both diagnostic categories , known as hyperactive-aggressive ( HA ) . Only four subjects in each group met a discrepancy criterion for learning disabilities ( LD ) . Methylpheni date was administered to both groups at three levels of dosage , along with baseline and placebo conditions . Dependent measures involved both reading recognition and reading comprehension , equivalent across all conditions . No significant results were found for the group with HD in either reading recognition or comprehension , due largely to unusual placebo reactions . Results were generally in the direction predicted for the group with HA , but only significantly so in reading comprehension , and no dose effect was found on this variable . Implication s for reading as a dependent measure of medication effects are discussed Abstract Background Given the dosing limitations of methylpheni date short – acting preparations in treating ADHD , galenics with longer release of the substance were developed mainly to avoid drug intake during school hours . Objectives This investigation was conducted to assess the efficacy and the duration of action of a new extended-release formulation of methylpheni date ( Medikinet ® retard ) as a once – daily treatment for children with attention – deficit hyperactivity disorder ( ADHD ) . Method This was a r and omized , double – blind , crossover multicentre study with three treatment conditions : once – daily extended – release methylpheni date , twice – daily immediate – release methylpheni date and placebo given to 79 children ( 8–14 years old ) with ADHD . Daily assessment s in an analogue classroom setting included blind ratings of attention and deportment and a performance measure ( math test ) obtained 5 times over an 8–hour period . Secondary measures included an ADHD rating scale , based on DSMIV/ ICD–10 separately rated for the morning and the afternoon . Results Both active treatment conditions displayed significant time course effects and were superior to placebo in improving all efficacy measures . Once a day extended – release methylpheni date was not different from the same dose of twice daily immediate – release methylpheni date . Conclusions These data provide support for the benefit of this novel , once-daily methylpheni date preparation in the treatment of ADHD . The longer duration of action of Medikinet Retard has the potential to simplify psychostimulant treatment , thus reducing dose diversion and eliminating the need for in – school administration The investigation aim ed to delineate the immediate effect of methylpheni date on decoding in the comorbid condition of attention-deficit/hyperactivity disorder and reading disorder . Boys with attention-deficit/hyperactivity and reading disorders ( n = 25 ) between the ages of 7.9 and 11.7 years , with at least average intelligence and verbal processing abilities participated in a double-blind , acute , r and omized , placebo-controlled crossover trial with a single dose of methylpheni date 0.3 to 0.4 mg/kg with weekly intervals between testing sessions . The test battery included tasks of attention/control functions and reading domain functions . Paired comparisons and first trial group comparison comparing performance under placebo and under methylpheni date were used . Methylpheni date selectively improved strategy /set shift ( P = 0.004 ) and facilitated improvement both in rapid naming ( P = 0.043 ) and word/nonword accuracy ( P = 0.028/P = 0.035 ) . These findings lend support to a possible influence of methylpheni date on cognitive attention functions related to reading skills in the comorbid group Two studies were conducted to investigate the relative effects of sustained release methylpheni date ( Ritalin [ SR-20 ] ) and st and ard methylpheni date ( Ritalin , 10 mg , administered twice daily ) . In the first study , 13 boys with attention deficit disorder participating in a summer treatment program went through a double-blind , within-subject trial of each form of methylpheni date and placebo . Measures of social and cognitive behavior were gathered in classroom and play setting s. Although group analyses of the data showed that both drugs were effective and there were few differences between them , st and ard methylpheni date was superior to SR-20 on several important measures of disruptive behavior . Furthermore , analyses of individual responsivity showed clearly that most boys responded more positively to st and ard methylpheni date than to SR-20 . The second study involved a partially overlapping group of nine boys with attention deficit disorder participating in the same summer treatment program . Also double-blind , within-subject , and placebo controlled , this study tracked the time courses of the two forms of methylpheni date . Both were shown to have similar time courses on the Abbreviated Conners Rating Scale and other measures , but SR-20 had a slower onset than did the st and ard drug form on a continuous performance task . Effects of SR-20 were still evident eight hours after ingestion Sixteen children meeting diagnostic criteria for Attention Deficit Disorder with Hyperactivity ( ADD-H ) were tested on methylpheni date ( 0.3 mg/kg ) and placebo on cognitive , learning , academic and behavioral measures in a double-blind study . Assessment s were carried out in the laboratory and in the children 's regular classrooms . Results indicate methylpheni date -induced improvements on a majority of the measures . Drug-induced changes reflected increased output , accuracy and efficiency and improved learning acquisition . There was also evidence of increased effort and self-correcting behaviours . It is argued that review ers have underestimated the potential of stimulants to improve the performance of ADD-H children on academic , learning and cognitive tasks OBJECTIVE To examine the pharmacokinetics ( PKs ) and pharmacodynamics ( PDs ) of OROS methylpheni date ( OROS MPH ) dosed once daily ( QD ) versus an early st and ard regimen ( immediate-release [ IR ] MPH dosed three times daily [ TID ] ) under various breakfast conditions . METHODS This single-center , double-blind , double-dummy , r and omized , crossover study of OROS MPH ( NCT00269815 ) in children aged 6 to 12 years with attention-deficit/hyperactivity disorder evaluated the PKs and PDs of MPH given with different breakfast conditions : OROS MPH administered after a high-fat breakfast , after a normal breakfast , or after fasting and IR MPH administered after a normal breakfast or after fasting in the morning and at two subsequent time points during the day . To maximize information , patients were divided into two groups , each receiving three of the five treatments for 1 day in a three-period , r and omized , crossover design . Patients were assigned to 1 of 3 dosage levels ( OROS MPH 18 , 36 , and 54 mg QD , and an assumed equivalent regimen of IR MPH 5 , 10 , and 15 mg given TID ) based on their pre study established clinical dose of IR MPH . PD measurements included Combined-Attention and Deportment scores on a rating scale of school behavior ( the Swanson , Kotkin , Agler , M-Flynn , and Pelham ) , global assessment s of efficacy , and activity monitor levels during academic seatwork . Serial blood sample s for PK analysis were taken predose , and then every 60 to 90 minutes until 11.5 hours postdose . Vital signs were assessed predose , and then every 1.5 to 2.5 hours until 11.5 hours postdose . RESULTS Of the 32 patients enrolled , 31 completed the study . The PK profiles for MPH after OROS MPH administration were similar under all conditions ( with normal , high-fat breakfast , or fasting ) . No bioequivalence tests of OROS MPH and IR MPH under various breakfast conditions were done because there were so few patients in each dose level of treatment . The two IR MPH conditions ( after normal breakfast and fasting ) were not compared . The drug-to-metabolite ratios ( area under the curve ) for all OROS MPH and IR MPH treatments were similar . OROS MPH and IR MPH provided a similar therapeutic effect , irrespective of breakfast conditions , as demonstrated by the Swanson , Kotkin , Agler , M-Flynn , and Pelham Attention and Deportment measures and global assessment s. No serious adverse events , no deaths , and no clinical ly significant changes in vital signs were reported , except for one patient who was discontinued early because of repeated systolic blood pressure elevations on study day 1 . CONCLUSIONS The results of this study demonstrate that in children with attention-deficit/hyperactivity disorder , administering OROS MPH with or without food produces similar PK and PD profiles Objective : To explore treatment response to Osmotic Release Oral System ® ( OROS ) methylpheni date in children with ADHD with and without comorbid learning disability ( LD ) . Method : Data were analyzed from two 6-week , double-blind , r and omized , placebo-controlled , crossover studies evaluating individually determined doses of OROS methylpheni date versus placebo in 135 children ( ages 9 to 12 years ) with ADHD with or without an LD in reading , math , or both . The sample was demographically diverse , with 31 % females and more than 40 % minority , predominantly African American and Hispanic . On two laboratory school days , participants received either OROS methylpheni date or placebo and were given a battery of cognitive and behavioral tests . Results : Treatment with OROS methylpheni date led to improvement in ADHD Rating Scale scores for participants with or without comorbid LD . Both groups performed better during treatment with OROS methylpheni date than placebo on measures of cognitive skills ( i.e. , Test of Variables of Attention , Finger Windows Backwards ) , academically related tasks ( i.e. , Dynamic Indicators of Basic Early Literacy Skills , Test of H and writing Skills – Revised , Permanent Product Math Test ) , and observed classroom behavior ( i.e. , Swanson , Kotkin , Alger , M-Flynn , and Pelham Scale ) . Conclusion : In children with ADHD with or without comorbid LD  , behavior and performance improved during treatment with OROS methylpheni date The short-term , dose-response effects of methylpheni date hydrochloride were evaluated on academic and social classroom measures in 29 children with attention deficit disorder . In a double-blind , cross-over design with order r and omized , children received a placebo for two weeks and three doses of methylpheni date hydrochloride ( 0.15 mg/kg , 0.3 mg/kg , and 0.6 mg/kg ) for one week each . Dependent measures included the output and accuracy of performance in grade -appropriate reading comprehension workbooks and arithmetic problems , spelling word acquisition , and observations of disruptive and on-task behavior . Beneficial drug effects and linear dose-response curves on all dependent measures were found . The results suggest that beneficial methylpheni date effects on classroom behavior may be accompanied by enhanced academic achievement in some hyperactive children The effects of 0.3 mg/kg methylpheni date were compared for 12 ADD boys and 12 ADD girls participating in a summer treatment program for children with behavior and /or learning problems . Previous investigations have suggested that ADD girls may differ from ADD boys in some important respects . No information exists regarding whether the effects of the most common treatment for these children , methylpheni date , has comparable effects on boys and girls . The boys and girls were matched for age and IQ . The results revealed equivalent and beneficial effects of methylpheni date for both boys and girls . Methylpheni date therefore would appear to be as useful a treatment for ADD girls as for ADD boys Objective : The authors evaluated the time course of the treatment effect of Osmotic-Release Oral System methylpheni date ( OROS ® MPH ) HCl ( Concerta ® , Raritan , NJ ) CII in children with ADHD . Method : Data were combined from two double-blind , r and omized , 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 ABSTRACT Clinical trials with a treatment duration of at least 3 months were review ed to determine the effect of psychostimulants on the core symptoms of attention-deficit hyperactivity disorder ( ADHD ) and on its commonly associated features . Eighteen studies were identified : 17 were studies of  methylpheni date  , 1 was a study of dextroamphetamine , and none involved  pemoline  or  slow-release stimulants . Eleven of these studies were r and omized controlled trials , whereas seven employed quasi-experimental design s without r and omization . The results of r and omized controlled trials showed that psychostimulants provided greater benefit than did the nonr and omized trials , suggesting that the efficacy of extended treatment may have been underestimated because more seriously disturbed children were assigned to medication treatment than to control treatments in nonr and omized trials . Evidence from the more definitive r and omized controlled trials indicates that stimulants are more effective in ameliorating the core behavioral symptoms of ADHD ( restlessness , inattentiveness , impulsiveness ) than placebos , nonpharmacological therapies , or no treatment-at least in 3 - 7-month trials . During extended psychostimulant treatment , few children become symptom-free , clinical effects may diminish with time , and improvement dissipates rapidly upon discontinuation of medication . There is minimal evidence that extended stimulant treatment improves cognitive deficits or associated problems such as conduct disturbance , low self-esteem , poor peer relationships , or academic underachievement . The belief that stimulants do not improve the long-term prognosis of  children with ADHD  may be based on weakly design ed studies that focus on associated rather than core symptoms . A failure to assign patients of similar clinical severity to different treatment conditions may also have contributed to obscuring the efficacy of extended psychostimulant treatments
target: None of the mediators or moderators tested affected methylpheni date efficacy .
  Academic improvements were small compared to symptom improvements ; qualitative changes limited to math .
background: Academic improvement is amongst the most common treatment targets when prescribing stimulants to children with ADHD .
  Previous review s on stimulant-related academic improvements are inconclusive and focus on task engagement .
  Recent literature suggests outcome -domain-specific medication effects that are larger for productivity than for accuracy .
  The aims of this study are quantifying methylpheni date effects on academic productivity and accuracy for math , reading , spelling ; exploring the mediating or moderating effects of symptom improvements , demographic- , design - and disorder-related variables .