None of the mediators or moderators tested affected methylpheni date efficacy .
Academic improvements were small compared to symptom improvements ; qualitative changes limited to math .
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 .
A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (the Comacs Study).
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
None of the mediators or moderators tested affected methylpheni date efficacy .
Academic improvements were small compared to symptom improvements ; qualitative changes limited to math .
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 .