A Novel Assessment Tool for Impulsive Aggression in Children with Attention-Deficit/Hyperactivity Disorder.

Objective: To establish the validity and reliability of a provisional 30-item impulsive aggression (IA) diary in children (ages 6-12 years, inclusive) with attention-deficit/hyperactivity disorder (ADHD). Methods: The provisional 30-item IA diary was administered for 14 days to parents of children with ADHD and IA symptoms (n = 103). Key inclusion criteria: confirmed ADHD diagnosis; signs of IA as measured by a Retrospective-Modified Overt Aggression Scale (R-MOAS) score ≥20 and an Aggression Questionnaire score of -2 to -5. Analyses included inter-item correlations, exploratory factor analysis (EFA), item response theory (IRT) modeling, internal consistency, test-retest reliability (TRT), concurrent validity (estimated by correlation between the IA diary and the R-MOAS/Nisonger Child Behavior Rating Form), and known-groups methods. Results: The prevalence rates of 15 (50.0%) items were found to be too low (<1%) for analysis; three items with prevalence rates ≤1% were retained, as content validity was deemed high by clinical experts. The remaining 12 behavior items had prevalence rates of 2.7%-73.6%. EFA and IRT models confirmed two subdomains in the IA diary included within a general domain of IA behavior frequency, yielding a single total behavioral frequency score (TBFS). Internal consistency was high for this TBFS (marginal reliability = 0.86 and α = 0.73). TRT for the TBFS, based on the intraclass correlation coefficient, was 0.8. Concurrent validity of TBFS with R-MOAS ranged from r = 0.49 to r = 0.62. Conclusion: The final 15-item IA diary is a reliable, psychometrically validated IA measurement tool that will allow clinicians and researchers to assess the frequency of IA behavior.

Application of the Impulsive Aggression Diary in Adolescents with Attention-Deficit/Hyperactivity Disorder.

Objective: Impulsive aggression (IA) is a maladaptive form of aggressive behavior that is an associated feature of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). As one of the most common forms of aggressive behavior, IA is a serious clinical concern. Recognition, monitoring, and management of IA symptoms are complicated by the lack of IA-specific psychometric instruments and evidence-based treatments. A recently developed electronic observer-reported outcome instrument has been validated in children for monitoring the frequency of 15 IA-related behaviors in the context of ADHD. This study seeks to first determine if the behaviors included in the pediatric IA diary are applicable to adolescents with ADHD, and second, compare the reliability of adolescent versus parent reporters. Methods: We evaluated the utility of the pediatric IA diary through concept elicitation and cognitive interviews with 17 pairs of parents and adolescents (aged 13-17 years) with IA and ADHD, supplemented with 15 new behaviors potentially applicable to adolescents. Results: The behaviors most frequently reported by adolescents included arguing (93.8%), raising their voice/shouting/yelling (93.8%), hitting others (87.5%), slamming (87.5%), pushing/shoving (81.3%), breaking (75.0%), fighting (75.0%), throwing (75.0%), and cursing (68.8%). The behaviors most commonly reported by parents included raising their voice/shouting/yelling (94.1%), arguing (88.2%), being disrespectful/mean/rude (88.2%), slamming (88.2%), throwing (88.2%), cursing (82.4%), hitting others (82.4%), pushing/shoving (82.4%), breaking (76.5%), name-calling (76.5%), and threatening (70.6%). Of all commonly reported behaviors, only being "disrespectful/mean/rude" and "breaking" are not part of the pediatric IA diary, likely due to the imprecision of these terms. No significant usability issues were found for the IA diary device. Conclusions: These findings suggest that the 15-item pediatric IA diary should be applicable to adolescent populations to appropriately characterize IA behaviors in individuals with ADHD. Furthermore, this study indicated that parents may be more reliable reporters of IA behavior than adolescents.

Use of computer simulations to test the concept of dose forgiveness in the era of extended-release (XR) drugs.

"Forgiveness" - the difference between a drug's postdose duration of action and its prescribed dosing interval - estimates the margin of therapeutic effect following a missed dose. Because this margin presumably decreases as dosing becomes less frequent, QD dosing of an antiepileptic drug (AED) is expected to be less forgiving than more frequent (e.g., BID) dosing of that same AED. However, if the AED is reformulated as an extended-release (XR) preparation, drug input may be prolonged relative to its immediate-release (IR) counterpart. It therefore stands to reason that forgiveness could be increased by an XR AED that extends the period during which therapeutic plasma concentrations are maintained if a dose is missed. Computer simulation was used to estimate forgiveness for an IR formulation of a hypothetical AED and its XR counterparts reformulated for less frequent dosing. Simulations determined forgiveness when the hypothetical IR AED was dosed TID, BID, and QD and when suitably designed XR formulations were dosed BID and QD. Simulations showed that forgiveness for an XR formulation can equal or exceed that for an IR formulation dosed more frequently.

Pharmacokinetic simulations of topiramate plasma concentrations following dosing irregularities with extended-release vs. immediate-release formulations.

BACKGROUND: Once-daily extended-release (XR) antiepileptic drugs (AEDs) offer potential adherence and tolerability advantages over their BID immediate-release (IR) counterparts. However, patients with epilepsy will inevitably be at least occasionally nonadherent with a prescribed dosing regimen, regardless of formulation. Although perturbations in plasma concentrations due to dosing irregularities may have clinical consequences for AEDs with concentration-response relationships, clinical studies that deliberately expose patients to specific dosing irregularities in order to assess the effect on plasma concentrations and determine appropriate corrective actions would be unethical. METHODS: Computer simulation was used to assess the impact of irregular dosing on topiramate (TPM) concentrations in noninduced (monotherapy/neutral cotherapy) and induced (adjunctive therapy with enzyme-inducing AEDs) states using a population pharmacokinetic (PK) model developed to predict steady-state plasma concentration-time profiles produced by once-daily Trokendi XR (extended-release topiramate capsules, Supernus Pharmaceuticals) and BID TPM-IR. RESULTS: Computer simulations predicted that, relative to adherent dosing, delaying a dose 4 to 24h in noninduced patients would decrease trough (Cmin) levels 9% to 31% in the case of TPM-IR and 6% to 27% with Trokendi XR; a single omitted dose would reduce Cmin by 21% (TPM-IR) and 27% (Trokendi XR). After dose recovery to correct for a delayed or omitted dose, simulated peak concentration (Cmax) was higher than steady-state Cmax, regardless of formulation, although the magnitude of "overshoot" was consistently lower with Trokendi XR vs. TPM-IR. Doubling of a dose would increase Cmax by 26% and 28%, respectively. Predicted changes for nonadherent vs. adherent dosing were greater in the induced vs. noninduced state but were generally comparable for the two TPM formulations. Because the long half-life of TPM has been cited as a justification for QD dosing of TPM-IR, simulations also compared steady-state PK profiles of once-daily Trokendi XR and QD TPM-IR. Predicted TPM plasma concentration-time profiles were markedly different, as demonstrated by peak-trough fluctuation (QD TPM-IR, 64%; QD Trokendi XR, 18%) and 34% lower Cmin with QD TPM-IR. CONCLUSIONS: Based on these simulations, dosing irregularities with once-daily Trokendi XR should pose no greater risk than with BID TPM-IR. In the event of a delayed or omitted Trokendi XR dose, TPM concentrations can be restored in noninduced and induced states by administering the delayed/omitted dose at any time during the next dosing interval or by adding the missed dose to the next scheduled dose.