Pharmacotherapy of the Preschool ADHD Treatment Study (PATS) Children Growing Up

ObjectiveTo describe the long-term psychopharmacological treatment of children first diagnosed with attention-deficit/hyperactivity disorder (ADHD) as preschoolers.MethodIn a systematic, prospective, naturalistic follow-up, 206 (68.0%) of the 303 children who participated in the Preschool ADHD Treatment Study (PATS) were reassessed 3 years (mean age 7.4 years) and 179 (59.1%) were reassessed 6 years (mean age 10.4 years) after completion of the controlled study. Pharmacotherapy and clinical data were obtained from the parents. Pharmacotherapy was defined as use of a specific class of medication for at least 50% of the days in the previous 6 months.ResultsAt year 3, a total of 34.0% of the participants were on no pharmacotherapy, 41.3% were on stimulant monotherapy, 9.2% were on atomoxetine alone or with a stimulant, 8.3% were on an antipsychotic usually together with a stimulant, and the remaining 7.2% were on other pharmacotherapy; overall, 65.0% were on an indicated ADHD medication. At year 6, a total of 26.8% of the participants were on no pharmacotherapy, 40.2% were on stimulant monotherapy, 4.5% were on atomoxetine alone or with a stimulant, 13.4% were on an antipsychotic, and 15.1% were on other pharmacotherapy; overall, 70.9% were on an indicated ADHD medication. Antipsychotic treatment was associated with more comorbidity, in particular disruptive behavior disorders and pervasive development disorders, and a lower level of functioning.ConclusionIn this study, the long-term pharmacotherapy of preschoolers with ADHD was heterogeneous. Although stimulant medication continued to be used by most children, about 1 child in 4 was off medication, and about 1 in 10 was on an antipsychotic

A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (The Comacs Study)

The objective of this study was to evaluate differences in the pharmacodynamic (PD) profile of 2 second-generation extended-release (ER) formulations of methylphenidate (MPH): Metadate CD (MCD; methylphenidate HCl, US Pharmacopeia) extended-release capsules, CII, and Concerta (CON; methylphenidate 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 randomized 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 &gt; MCD CON (PLA superiority) immediately after dosing; 2) MCD &gt; CON &gt; PLA during the morning (MCD superiority); 3) MCD CON &gt; PLA during the afternoon (PD equivalence of MCD and CON); and 4) CON &gt; MCD 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 .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 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.<br/

The ecological validity of delay aversion and response inhibition as measures of impulsivity in AD/HD: a supplement to the NIMH multimodal treatment study of AD/HD

Impulsivity is a primary symptom of the combined type of Attention Deficit/Hyperactivity Disorder (AD/HD). The Stop Signal Paradigm is premised upon a primary deficit in inhibitory control in AD/HD, whereas the Delay Aversion Hypothesis, by contrast, conceptualizes impulsivity in AD/HD, not as an inability to inhibit a response, but rather as a choice to avoid delay. This study compared the ecological validity of the Stop Signal Task (SST) and Choice-Delay Task (C-DT) measure of delay aversion, with respect to their relative utility in discriminating AD/HD children from normal control participants, and their correlations with classroom observations and with ratings of impulsivity and other core AD/HD symptoms on the Conners and SNAP-IV checklists. The tasks exhibited modest discriminant validity when used individually and excellent discriminant validity when used in combination. The C-DT correlated with teacher ratings of impulsivity, hyperactivity, and conduct problems, and with observations of gross motor activity, physical aggression, and an AD/HD composite score. The SST correlated with the observations only. These results suggest that delay aversion is associated with a broad range of AD/HD characteristics whereas inhibitory failure seems to tap a more discrete dimension of executive contro