Functional Impairment in Youth With ADHD: Normative Data and Norm-Referenced Cutoff Points for the Before School Functioning Questionnaire and the Parent Rating of Evening and Morning Behavior Scale, Revised.

OBJECTIVE: Children with attention-deficit/hyperactivity disorder (ADHD) frequently manifest behavioral difficulties in the morning prior to school and in the afternoons and evenings. We sought to establish norms for 2 time-specific measures of functioning: the Before School Functioning Questionnaire (BSFQ) and the Parent Rating of Evening and Morning Behavior Scale, Revised (PREMB-R), which includes Morning (AM) and Evening (PM) subscales. METHODS: The normative online survey of a representative US sample of 1,200 primary caregivers of children and adolescents aged between 6 and 17 years was conducted in June 2016. A quota system was used whereby caregivers of 50 male and 50 female children or adolescents were recruited in each age group, ie, 100 parents for each of the 12 age groups. Diagnosis of ADHD relied on a caregiver's report that his or her child was so diagnosed by a health professional. RESULTS: Across all items of the BSFQ, youth with current untreated ADHD or a history of ADHD were rated as more severely ill than those without ADHD (all unadjusted P values < .001), even after adjustment for psychiatric comorbidity (all adjusted P values < .001). A similar pattern was observed for the PREMB-R AM (all unadjusted P values < .001; all adjusted P values < .001, except for item 1 [P = .01]) and PREMB-R PM (all unadjusted P values < .001; all adjusted P values < .001). The use of a large population sample allowed for computation of age-stratified norms for 4 thresholds of risk: screening risk (80th percentile), mild functional impairment (90th percentile), moderate functional impairment (93rd percentile), and severe functional impairment (98th percentile). CONCLUSIONS: The norms generated by this study can guide clinicians in the use of the BSFQ and PREMB-R for identifying those ADHD youth who may be experiencing difficulties in the early morning and late afternoon/evening. Such tools are needed given the availability of treatments that can target ADHD symptoms and impairments at these extremes of the daily routine.

An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations.

Introduction: Long-acting stimulant formulations are recommended as first-line pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Over the past 20 years, extended-release (ER) methylphenidate (MPH) and amphetamine (AMP) formulations have evolved to include varying drug delivery technologies, enantiomers/salts, and dosage forms. All formulations are characterized by a unique pharmacokinetic profile that is closely mirrored by pharmacodynamic response allowing clinicians to individualize therapy based on their patient's clinical needs and dosing preferences.Areas covered: This review provides an update on the pharmacokinetic properties of approved and investigational ER MPH and AMP formulations and highlights pharmacokinetic features that clinicians should consider when selecting a long-acting stimulant.Expert opinion: Since there are no reliable biomarkers that can predict individualized response to long-acting stimulants, clinicians need to consider their distinctive pharmacokinetic properties, including the pharmacokinetic profile, rate and extent of absorption, variability, dose proportionality, bioequivalence, and potential for accumulation. Clinicians also need to understand that certain factors can contribute to increased variability in pharmacokinetics and potentially affect outcomes. Less invasive, high-throughput techniques and novel time-based scales are being developed to advance research on the pharmacokinetic-pharmacodynamic relationships of stimulants. Model-based pharmacokinetic-pharmacodynamic approaches can be applied to aid the development of novel formulations and individualize therapy with existing drugs.

Reliability and Validity of the Daily Parent Rating of Evening and Morning Behavior Scale, Revised.

OBJECTIVE: Children with ADHD frequently manifest behavioral difficulties in the morning prior to school. We sought to assess the reliability and validity of the Daily Parent Rating of Evening and Morning Behavior Scale, Revised (DPREMB-R) morning score as a measure of morning behaviors impaired by ADHD. METHOD: We used data from a clinical trial of HLD200 treatment in pediatric participants with ADHD to address our objectives. RESULTS: The DPREMB-R morning score showed significant internal homogeneity, test-retest reliability ( r = .52-.45), and good concurrent validity ( r = .50-.71). CONCLUSION: The DPREMB-R morning score could be a useful instrument for assessing treatment efficacy in the morning before school.

Early Morning Functional Impairments in Stimulant-Treated Children with Attention-Deficit/Hyperactivity Disorder Versus Controls: Impact on the Family.

OBJECTIVE: Children with attention-deficit/hyperactivity disorder (ADHD) frequently manifest early morning functional (EMF) impairments before school. We conducted a quantitative research survey to assess the impact of these EMF impairments on the family unit (caregiver, spouse/partner, and siblings). STUDY DESIGN: We developed an online survey questionnaire to collect data from 300 primary caregivers of children with ADHD and 50 primary caregivers of children who did not have ADHD. RESULTS: Although the ADHD children we surveyed were currently treated with stable doses of stimulants as their primary ADHD medication for at least 3 months, their parents reported high levels of EMF impairments in the child, which had a substantial negative effect on the emotional well-being of parents, on parents' functioning during the early morning routine, and on the level of conflict with siblings. The impact of EMF impairments on family functioning was mediated by the severity of the index child's impairments. CONCLUSIONS: EMF impairments exert a pervasive and significantly negative emotional and functional burden on not only the primary caregiver but also on the spouse/partner and siblings. This work suggests that adequate ADHD symptom control during the early morning period may be an unmet need for school-age children with ADHD being treated with stimulants. More work is needed to confirm this finding and determine the degree to which symptom control at other times of day is also an unmet need.

Single-dose pharmacokinetics of NWP06, an extended-release methylphenidate suspension, in children and adolescents with ADHD.

BACKGROUND: Extended-release formulations of stimulants provide once-daily treatment options for patients with attention-deficit/hyperactivity disorder (ADHD). Such preparations are more convenient and may improve compliance, and thus, improve outcomes. Currently, there is no extended-release liquid oral preparation of any stimulant. As such, there is a medical need for a liquid extended-release preparation of methylphenidate for the management of ADHD in children who are unable or unwilling to swallow solid formulations. OBJECTIVE: To evaluate the single-dose pharmacokinetics of an extended-release oral liquid formulation of methylphenidate (NWP06) in pediatric subjects with ADHD. METHODS: Subjects with ADHD received a single oral dose of NWP06 20 or 60 mg. Serial blood samples were obtained before and after drug administration for determination of plasma methylphenidate concentrations and standard pharmacokinetic parameters. Dose- and weight-corrected pharmacokinetic parameters were presented by age group (9-12 years and 13-15 years). RESULTS: A total of 14 youths (7 children aged 9-12 years and 7 adolescents aged 13-15 years) were enrolled and completed the study. Body mass index ranged from 12.08 to 34.08 kg/m(2). Mean values of dose and body weight-adjusted maximum plasma concentration (Cmax) (23.8, 22.3, 22.1, 25.7 [ng/mL]/mg) and area under the concentration-time curve (AUC) (208, 199, 239, 210 [hr·ng/mL]/[mg/kg]) were similar among all age/dose groups, suggesting dose proportionality and a similar rate and extent of absorption in children and adolescents. Values for Cmax were observed between 2 and 4 hours after the dose. The elimination half-life and body weight-adjusted clearance also appeared to be independent of dose and age. NWP06 was well tolerated with no serious adverse events and no adverse event-related treatment discontinuations. CONCLUSION: There were no age-related pharmacokinetic differences after oral administration of NWP06 to children or adolescents in this small sample. Over the dose range of methylphenidate used in this study (0.45-3.3 mg/kg), the pharmacokinetics of NWP06 were linear and dose proportional.

Effects of clonidine and methylphenidate on family quality of life in attention-deficit/hyperactivity disorder.

OBJECTIVE: The aim of this study was to determine the effect on family quality of life (QOL) of clonidine (CLON) and methylphenidate (MPH), used alone and in combination, in treating attention-deficit/hyperactivity disorder (ADHD). METHODS: Two proxy QOL measures were used in a multicenter, double-blind, placebo-controlled 16-week trial of 122 children, ages 7-12 years, with ADHD. Children were randomized to one of four groups in which they received MPH, CLON, a combination of drugs, or placebo. QOL was measured with the Daily Hassles Scale and the Impact on Family Scale at baseline and at 16 weeks. RESULTS: In a general linear model repeated measures analysis, treatment groups improved over a 16-week period compared to placebo for Daily Hassles and Impact on Family, as well as in symptoms measured by the ADHD Rating Scale. QOL measures correlated moderately with efficacy and symptom measures. CONCLUSION: This study provides evidence that measures of QOL for the family are sensitive to pharmacological treatment of ADHD. The correlation pattern of the QOL measures with symptom and efficacy variables supported family QOL as a related but separate construct. Clonidine for Attention-Deficit/Hyperactivity Disorder Treatment Study (CAT) Trial Registry Name: Clinicaltrials.gov; ID Number, NCT00031395; URL, http://clinicaltrials.gov/ct/show/NCT00031395?order=8/ .

Atomoxetine treatment of ADHD in children with comorbid Tourette syndrome.

OBJECTIVE: This study examines changes in severity of tics and ADHD during atomoxetine treatment in ADHD patients with Tourette syndrome (TS). METHOD: Subjects (7-17 years old) with ADHD (Diagnostic and Statistical Manual of Mental Disorders, DSM-IV) and TS were randomly assigned to double-blind treatment with placebo (n = 56) or atomoxetine (0.5-1.5 mg/kg/day, n = 61) for approximately 18 weeks. RESULTS: Atomoxetine subjects showed significantly greater improvement on ADHD symptom measures. Treatment was also associated with significantly greater reduction of tic severity on two of three measures. Significant increases were seen in mean pulse rate and rates of treatment-emergent nausea, decreased appetite, and decreased body weight. No other clinically relevant treatment differences were observed in any other vital sign, adverse event, laboratory parameter, or electrocardiographic measure. CONCLUSION: Atomoxetine is efficacious for treatment of ADHD and its use appears well tolerated in ADHD patients with comorbid TS.

Atomoxetine treatment of ADHD in Tourette syndrome: reduction in motor cortex inhibition correlates with clinical improvement.

OBJECTIVE: In children with attention deficit hyperactivity disorder (ADHD), clinical responses to the selective norepinephrine reuptake inhibitor atomoxetine (ATX) vary. We sought to determine in children with Tourette Syndrome (TS) whether clinical responses correlate with changes in short interval cortical inhibition (SICI). METHODS: Fourteen children, ages 8-16, with ADHD and TS were treated open-label with ATX for one month. ADHD rating scale scores and SICI, measured with paired-pulse transcranial magnetic stimulation (pTMS), were assessed blindly and independently at treatment onset and one month later. RESULTS: Eleven children, mean ADHD rating scale scores 31.8 (SD 8.2) at onset, completed the study. After one month, ADHDRS changes ranged from an increase of 4 points to a decrease (improvement) of 24 points (mean change -9.6, SD 9.1). The changes in ADHDRS scores correlated with reduction in SICI (r=.74, p=.010). CONCLUSIONS: In children with TS, one month of atomoxetine treatment appears to induce correlated improvements in ADHD and, paradoxically, further reductions in cortical inhibition. SIGNIFICANCE: PTMS-evoked SICI in ADHD with TS may be a biomarker of both deficiency and compensatory changes within cortical interneuronal systems. Effective atomoxetine treatment may augment compensatory processes and thereby reduce SICI.

Parent-proxy EQ-5D ratings of children with attention-deficit hyperactivity disorder in the US and the UK.

BACKGROUND: The symptoms of attention-deficit hyperactivity disorder (ADHD) are associated with impairment in multiple domains of health-related quality of life (HR-QOL). HR-QOL of children with ADHD has been assessed by relatively long multidimensional questionnaires. A review of the literature found no studies using the brief, well established EuroQoL Five-Dimension Questionnaire (EQ-5D) to estimate the HR-QOL of children with ADHD. The objective of this study was to assess the HR-QOL of children with ADHD using parents' responses to the proxy version of the EQ-5D. METHODS: Participants were recruited in the midwestern US and in the vicinity of London, England. All parents completed three questionnaires: the EQ-5D proxy version; a measure of ADHD symptoms based on Diagnostic and Statistical Manual of Mental Disorders (4th Edition) [DSM-IV] criteria (the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV - Parent Version [ADHD-RS]); and either the Child Health Questionnaire - Parent Form 50 (CHQ-PF50) or the Child Health and Illness Profile - Child Edition (CHIP-CE), which are both generic multidimensional paediatric HR-QOL questionnaires. RESULTS: A total of 126 parents of children with ADHD participated in the study: 43 in the US and 83 in the UK. On the EQ-5D, participants indicated that 78.6% of their children experienced some problems or extreme problems performing usual activities, while 64.8% believed their child demonstrated some or extreme anxiety or depression. The mean EQ-5D index score was 0.75 and the mean visual analogue scale (VAS) score was 73.9. The EQ-5D index and VAS scores were found to be significantly correlated (p < 0.05) with several domains of the CHQ-PF50 (e.g. Mental Health, Self-Esteem, Family Activities, Psychosocial Summary Score) and the CHIP-CE (e.g. Satisfaction, Comfort, Academic Performance, Peer Relations). The EQ-5D scales were also significantly correlated with the ADHD-RS scales (p < 0.001). CONCLUSION: The proxy version of the EQ-5D, completed by parents, was able to detect impairment in children diagnosed with ADHD in the US and the UK. Furthermore, the EQ-5D index and VAS scores demonstrated construct validity among this sample through significant correlations with an ADHD symptom measure and previously validated multidimensional QOL instruments. These results suggest that parent-proxy EQ-5D ratings are feasible and valid for use as part of an overall health outcomes assessment in clinical studies of childhood ADHD.

Assessment of health state utilities for attention-deficit/hyperactivity disorder in children using parent proxy report.

This study used standard gamble (SG) utility interviews to assess parent preferences for health states of childhood attention-deficit/hyperactivity disorder (ADHD). Health state utilities are needed to calculate quality-adjusted life years (QALYs), a critical outcome measure in cost-effectiveness studies of new treatments. Parents (n = 43) of children diagnosed with ADHD completed SG utility interviews, rating their child's current health and 11 hypothetical health states describing untreated ADHD and ADHD treated with a stimulant or non-stimulant. Parents completed questionnaires on their children's symptoms and health-related quality of life (HRQL). Parents' SG rating of their child's current health state (mean of 0.74 on a utility scale ranging from 0 to 1) was significantly correlated with inattentive, hyperactive, and overall ADHD symptoms (r = 0.37, 0.36, and 0.40 respectively; p < 0.05) and psychosocial HRQL domains. Hypothetical health state utilities ranged from 0.48 (severe untreated ADHD) to 0.88 (effective and tolerable non-stimulant treatment). Comparisons between health states found expected differences between untreated mild, moderate, and severe ADHD health states. When both treatments were effective and tolerable, parents preferred the non-stimulant health state over the stimulant health state (p < 0.03). Results suggest that parent SG interviews are a feasible and useful method for obtaining utility scores that can be used in cost-effectiveness models of ADHD treatment.

Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study.

OBJECTIVE: The authors assessed the efficacy of once-daily atomoxetine administration in the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). METHOD: In a double-blind study, children and adolescents with ADHD (N=171, age range=6-16 years) were randomly assigned to receive 6 weeks of treatment with either atomoxetine (administered once daily) or placebo. RESULTS: Outcomes among atomoxetine-treated patients were superior to those of the placebo treatment group as assessed by investigator, parent, and teacher ratings. The treatment effect size (0.71) was similar to those observed in previous atomoxetine studies that used twice-daily dosing. Parent diary ratings suggested that drug-specific effects were sustained late in the day. Discontinuations due to adverse events were low (less than 3%) for both treatment groups, and no serious safety concerns were observed. CONCLUSIONS: Once-daily administration of atomoxetine is an effective treatment for children and adolescents with ADHD.