A Post-Hoc Analysis of Emotional Lability With Delayed-Release/Extended-Release Methylphenidate in Children Aged 6 to 12 Years of Age Participating in Two Phase 3 Clinical Trials.

OBJECTIVE: DR/ER-MPH (formerly HLD200) is an evening-dosed delayed-release and extended-release methylphenidate approved for the treatment of ADHD in patients ≥6 years. Post hoc analyses of two pivotal Phase 3 trials: HLD200-107 (NCT02493777) and HLD200-108 (NCT02520388) evaluated emotional lability (EL) with DR/ER-MPH treatment. METHODS: Differences in Conners Global Index-Parent (CGI-P) EL subscale scores and age- and gender-adjusted T-scores over an open-label titration phase (HLD200-107) and between treatment and placebo groups at endpoint (HLD200-108) were evaluated. RESULTS: In HLD200-107 (N = 117) mean CGI-P EL subscale scores improved from 5.3 to 1.3 (p < .0001) after 6 weeks; in HLD200-108 significant improvements were observed in the treatment group (n = 81) versus placebo (n = 80; 3.11 vs. 4.08; p = .0053). T-scores showed an improvement with DR/ER-MPH treatment in both trials. Few emotional adverse events (AEs) were reported. CONCLUSION: DR/ER-MPH treatment resulted in statistically significant improvements in EL to the level of non-ADHD peers as contextualized by T-scores.

Effect of Delayed-Release and Extended-Release Methylphenidate on Caregiver Strain and Validation of Psychometric Properties of the Caregiver Strain Questionnaire: Results from a Phase 3 Trial in Children with Attention-Deficit/Hyperactivity Disorder.

Objectives: Inadequately controlled symptoms and associated impaired functioning have a significant negative impact on caregivers of children with attention-deficit/hyperactivity disorder (ADHD). This study aimed to assess the impact of evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) treatment on caregiver strain, measured by the Caregiver Strain Questionnaire (CGSQ), and present post hoc psychometric analyses assessing the reliability and validity of the CGSQ, its ability to detect change (responsiveness), and to derive responder definitions. Methods: The CGSQ was an exploratory efficacy endpoint in a phase 3, 3-week, randomized, double-blind, multicenter, placebo-controlled, forced-dose titration trial of DR/ER-MPH in children aged 6-12 years with ADHD (NCT02520388). Psychometric properties of the CGSQ evaluated post hoc included internal consistency using Cronbach's alpha; test/retest reliability using intraclass correlation coefficients (ICCs); construct validity (known groups and convergent/divergent validity); responsiveness to changes in assessments of ADHD severity (ADHD Rating Scale-IV [ADHD-RS-IV], Conners' Global Index-Parent [CGI-P], and Clinical Global Impression-Severity [CGI-S]/CGI-Improvement [CGI-I]); and meaningful change threshold (MCT) using receiver operating characteristic curves, which were used to compare response between DR/ER-MPH and placebo groups. Results: Randomized DR/ER-MPH (54.5) and placebo (54.9) groups had similar mean CGSQ scores at screening. Caregivers of children on DR/ER-MPH reported significant reductions in CGSQ scores after 3 weeks of DR/ER-MPH treatment versus placebo (least-squares mean: 41.2 vs. 49.1; p < 0.001). The CGSQ demonstrated strong internal consistency (Cronbach's alpha = 0.93) and good test/retest reliability (ICC = 0.72). Known groups, convergent/divergent validity, and responsiveness were demonstrated from relationships between the CGSQ and the CGI-S, ADHD-RS-IV, and CGI-P. The mean anchor-based MCT for CGSQ total score was estimated as -9.0 (DR/ER-MPH vs. placebo: 53.2% vs. 29.9% p = 0.003). Conclusions: CGSQ scores significantly decreased after 3 weeks of DR/ER-MPH treatment versus placebo, and the CGSQ was found to be a valid and reliable measure of strain in caregivers of children with ADHD. Clinical trial registration identification number: NCT02520388.

Efficacy and Safety of HLD200, Delayed-Release and Extended-Release Methylphenidate, in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Evening-dosed HLD200 is a delayed-release and extended-release methylphenidate (DR/ER-MPH) formulation consisting of uniform, dual-layered microbeads with an inner drug-loaded core. DR/ER-MPH is designed to delay the initial release of drug by 8-10 hours, and thereafter, provide a controlled, extended drug release to target onset of effect upon awakening that lasts into the evening. This phase 3 study evaluated the safety and efficacy of DR/ER-MPH on symptoms and temporal at-home functional impairment in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: This 3-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, forced-dose titration trial evaluated DR/ER-MPH (40-80 mg/day) in children aged 6-12 years with ADHD. Primary efficacy endpoint was the ADHD rating scale-IV (ADHD-RS-IV), and the key secondary endpoints were the Before-School Functioning Questionnaire (BSFQ), and Parent Rating of Evening and Morning Behavior-Revised, morning (PREMB-R AM) and evening (PREMB-R PM). Safety measures included spontaneously reported treatment-emergent adverse events (TEAEs) and two TEAEs of special interest, appetite suppression and insomnia (with direct questioning on sleep disturbance). RESULTS: One hundred sixty-one participants were included in the intent-to-treat population (DR/ER-MPH, n = 81; placebo, n = 80). After 3 weeks, DR/ER-MPH achieved significant improvements versus placebo in ADHD symptoms (least-squares [LS] mean ADHD-RS-IV: 24.1 vs. 31.2; p = 0.002), and at-home early morning (LS mean BSFQ: 18.7 vs. 28.4; p < 0.001; LS mean PREMB-R AM: 2.1 vs. 3.6; p < 0.001) and late afternoon/evening (LS mean PREMB-R PM: 9.4 vs. 12.2; p = 0.002) functional impairment. Commonly reported TEAEs (≥10%) were insomnia and decreased appetite. CONCLUSIONS: DR/ER-MPH was generally well tolerated and demonstrated significant improvements versus placebo in ADHD symptoms and at-home functional impairments in the early morning, late afternoon, and evening in children with ADHD.

ADHD Symptom Rebound and Emotional Lability With Lisdexamfetamine Dimesylate in Children Aged 6 to 12 Years.

OBJECTIVE: To describe symptom rebound in children with ADHD treated with lisdexamfetamine dimesylate (LDX) or placebo. METHOD: During a 4-week, randomized, double-blind, placebo-controlled trial of LDX, parents/caregivers completed the Conners' Parent Rating Scale-Revised: Short Form symptom rating scale throughout the day. Response, rebound, and emotional lability (EL) were assessed post hoc based on predefined criteria. RESULTS: Most participants given LDX ( n = 207) were responders throughout the day (50.7%-55.6%) versus placebo ( n = 72; 11.1%-22.2%). A total of seven (3.4%) LDX participants showed rebound in the afternoon and/or evening versus seven (9.7%) with placebo. In both groups, most incidences of rebound occurred in the evening. EL (mean) was higher in LDX rebounders and nonresponders (range = 4.2-9.0) versus LDX responders (range = 1.3-1.6) and versus placebo rebounders (range = 0.7-1.9). CONCLUSION: ADHD symptom rebound occurred in few participants (3.3%) given LDX (accompanied by clinically significant EL). Overall, more participants given LDX versus placebo responded throughout the day.

The effects of lisdexamfetamine dimesylate on emotional lability in children 6 to 12 years of age with ADHD in a double-blind placebo-controlled trial.

OBJECTIVE: To evaluate the effect of lisdexamfetamine dimesylate (LDX) on emotional lability (EL) in children with ADHD. METHOD: Post hoc analyses of a placebo-controlled trial of LDX-stratified children (aged 6-12 years) with ADHD to prominent and not prominent EL at baseline (score >3 or ≤3, respectively, on Conners' Parent Rating Scale [CPRS] items of anger, loss of temper, and irritability). Efficacy was assessed by change in CPRS EL scores and ADHD Rating Scale-IV (ADHD-RS-IV) total and subscale scores. Safety measures included treatment-emergent adverse events (TEAEs). RESULTS: LDX showed improvement versus placebo (p < .0005) for EL item least squares (LS) mean change scores at endpoint and throughout the day. At baseline, 138 and 73 participants randomized to LDX treatment and having baseline and endpoint CPRS scores were categorized with CPRS-derived prominent and not prominent baseline EL, respectively; 41 and 31 participants randomized to placebo were categorized with CPRS-derived prominent and not prominent baseline EL, respectively. ADHD-RS-IV total and subscale scores decreased with LDX regardless of baseline EL severity. TEAEs included decreased appetite, insomnia, upper abdominal pain, headache, and irritability. CONCLUSION: EL and ADHD symptoms improved with LDX regardless of baseline EL symptom severity. LDX demonstrated a safety profile consistent with long-acting psychostimulant use.

Guanfacine extended release: a novel treatment for attention-deficit/hyperactivity disorder in children and adolescents.

BACKGROUND: Guanfacine extended release (GXR) has reported efficacy for the treatment of attention-deficit/hyperactivity disorder (ADHD) as monotherapy and adjunctive therapy to psychostimulant medications. OBJECTIVE: The objective of this article was to review the efficacy, safety profile, mechanism of action, pharmacokinetics, and appropriate dosing of GXR in children and adolescents with ADHD. METHODS: Pertinent English-language literature was identified from searches of MEDLINE (1950-February 2012), BIOSIS (1969-February 2012), and EMBASE (1974-February 2012). Search terms included guanfacine, guanfacine extended release, attention deficit disorder with hyperactivity, ADHD, nonstimulant, and alpha-2 adrenergic receptor. Of the 49 publications identified, 12 are reviewed herein. Citations from identified articles were reviewed for additional references. Abstracts and posters presented at recent scientific meetings and data included in the prescribing information were also reviewed. RESULTS: Studies of GXR have demonstrated efficacy as once-daily monotherapy as well as adjunctive therapy to psychostimulants for ADHD in short-term trials. The safety profile of GXR is consistent with that of a centrally acting α2A-adrenoceptor agonist. Somnolence, sedation, and hypersomnia adverse events (AEs), although frequent, are typically mild to moderate and tend to diminish with continued treatment. However, 1 long-term, open-label study found that 22 serious treatment-emergent AEs occurred in 16 (6.2%) of 259 subjects, and another found that 26% of subjects discontinued therapy due to AEs. The cardiovascular effects, of GXR are consistent with guanfacine's known effects, and are generally modest in nature. The mechanism of action of GXR in ADHD is unknown. Because the pharmacokinetics of immediate-release guanfacine differ from GXR, dose substitution on a milligram-for-milligram basis is inappropriate. Clinical trials analyzed according to weight-adjusted doses suggest a dose-response relationship for efficacy. Doses >4 mg/d cannot be recommended due to lack of study data at those doses. CONCLUSIONS: Current evidence indicates that GXR is an effective treatment option for children and adolescents with ADHD. AEs are typically mild to moderate, although severe AEs and discontinuations due to AEs have been observed.

Long-acting stimulants for treatment of attention-deficit/hyperactivity disorder: a focus on extended-release formulations and the prodrug lisdexamfetamine dimesylate to address continuing clinical challenges.

Individuals with attention-deficit/hyperactivity disorder (ADHD) show pervasive impairments across family, peer, and school or work functioning that may extend throughout the day. Psychostimulants are highly effective medications for the treatment of ADHD, and the development of long-acting stimulant formulations has greatly expanded the treatment options for individuals with ADHD. Strategies for the formulation of long-acting stimulants include the combination of immediate-release and delayed-release beads, and an osmotic-release oral system. A recent development is the availability of the first prodrug stimulant, lisdexamfetamine dimesylate (LDX). LDX itself is inactive but is cleaved enzymatically, primarily in the bloodstream, to release d-amphetamine (d-AMP). Several clinical trials have demonstrated that long-acting stimulants are effective in reducing ADHD symptoms compared with placebo. Analog classroom and simulated adult workplace environment studies have shown that long-acting stimulants produce symptom reduction for at least 12 h. Long-acting stimulants exhibit similar tolerability and safety profiles to short-acting equivalents. While variations in gastric pH and motility can alter the availability and absorption of stimulants released from long-acting formulations, the systemic exposure to d-AMP following LDX administration is unlikely to be affected by gastrointestinal conditions. Long-acting formulations may also improve adherence and lower abuse potential compared with their short-acting counterparts. The development of long-acting stimulants provides physicians with an increased range of medication options to help tailor treatment for individuals with ADHD.

Physician perception of clinical improvement in children with attention-deficit/hyperactivity disorder: a post hoc comparison of lisdexamfetamine dimesylate and mixed amphetamine salts extended release in a crossover analog classroom study.

OBJECTIVE: To assess effects of lisdexamfetamine dimesylate (LDX) and mixed amphetamine salts extended release (MAS XR) on symptom improvement in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover analog-classroom environment was conducted. The primary efficacy outcome was the deportment subscale of the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP-D) rating scale. The secondary efficacy outcome was the investigator-rated Clinical Global Impressions-Improvement (CGI-I), a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), which assesses improvement over time from baseline. McNemar test was used to compare participants' responses to LDX and MAS XR on CGI-I scores dichotomized into 1 (very much improved) vs all other response scores (2 to 7) in a 2 × 2 table. RESULTS: Fifty-two children (aged 6 to 12 years) were enrolled, titrated, and randomized; 50 completed the study. Investigators rated 74% of LDX participants as either very much improved or much improved on the CGI-I scale relative to 72% of MAS XR participants and 18% of placebo participants. Of the 50 children who completed the study, 32% of LDX participants were very much improved vs 16% of MAS XR, and 2% of placebo participants relative to baseline. McNemar test indicated that 10 participants were very much improved with LDX, but not MAS XR; 2 participants were very much improved with MAS XR, but not LDX; 6 participants were very much improved with both, while 32 were not very much improved with either. Analysis showed that LDX had a significantly higher number of children with a very much improved score on the CGI-I than MAS XR (P = 0.0386). CONCLUSION: Treatment of children with LDX resulted in a higher number of participants with a very much improved score on the CGI-I than treatment with MAS XR or placebo.

Psychomotor functioning and alertness with guanfacine extended release in subjects with attention-deficit/hyperactivity disorder.

OBJECTIVES: To determine whether treatment with guanfacine extended release (GXR) in subjects with attention-deficit/hyperactivity disorder (ADHD) disrupted psychomotor functioning and alertness, or impacted daytime sleepiness. METHOD: This was a randomized, double-blind, placebo-controlled, multicenter, phase 2, dose-optimization, noninferiority, laboratory classroom study of GXR (1, 2, and 3 mg/day) in 182 subjects aged 6 to 17 years with ADHD. Psychomotor functioning and alertness were assessed through several measures, including the Choice Reaction Time (CRT) test from the Cambridge Neuropsychological Test Automated Battery. Sedative effects were examined via spontaneously reported adverse events of sedation, somnolence, and hypersomnia as well as fatigue and lethargy, and with two validated subject- and observer-rated sleepiness scales. Standard efficacy measures for ADHD also were included. Cardiovascular and laboratory parameters were assessed. RESULTS: There were no significant differences between the GXR and placebo groups on measures of psychomotor functioning or alertness from the CRT at endpoint (least-square mean difference: 2.5 [95% confidence interval (CI): -22.9, 28.0], p = 0.8 for CRT; 2.5 [95% CI: -21.5, 26.4], p = 0.84 for correct responses; 15.5 [95% CI: -45.1, 14.1], p = 0.30 for movement time; and -8.2 [95% CI: -54.1, 37.6] p = 0.72 for total time). Most sedative adverse events were mild to moderate, occurred during dose titration, decreased with dose maintenance, and resolved during the study period. One subject in the GXR group discontinued due to fatigue and somnolence. GXR was not associated with increased daytime sleepiness. GXR treatment was associated with significant improvement in ADHD symptoms (6.3 [95% CI: 2.7, 9.8], p = 0.001 for ADHD Rating Scale IV total scores at endpoint). CONCLUSIONS: At doses that resulted in significant improvement in ADHD symptoms, impairment on cognitive tasks was not observed. Daytime sleepiness did not differ with GXR compared with placebo. Results suggest that the beneficial effects of GXR on ADHD symptoms are independent of sedation.

Changes in emotions related to medication used to treat ADHD. Part I: literature review.

OBJECTIVE: To summarize the literature investigating changes in emotional expression (EE) as a function of pharmacotherapy in the treatment of ADHD and to differentiate emotional effects related to ADHD pharmacotherapy from emotional effects related to ADHD as a disorder. METHOD: English language articles published from January 1, 1988, through August 31, 2008 were identified through a PubMed literature search using the search terms attention, ADHD, hyperactive, hyperkinesis, and ADD cross-referenced with medication terms amphetamine, lisdexamfetamine, methylphenidate , guanfacine, atomoxetine, and clonidine. The search was limited to randomized, controlled trials. Abstracts from all identified articles were selected for further review if they met criteria including (a) presence of a placebo arm, (b) children ≤ 18 years of age, (c) ≥ 20 participants, and (b) study design elements that would allow reviewers to determine whether EE phenomena were specifically attributable to medication effects versus alternative explanations (e.g., time, maturation, baseline comorbidity, selection artifacts, or treatments other than the medication-placebo contrast). Qualifying full-text articles were reviewed for prespecified EE terms. RESULTS: Of 148 articles that met selection criteria, 47 reported varying types of EE. Eight of these included two active treatment arms. Hence, 55 data sets were identified. Patterns of change in EE in studies meeting search criteria are discussed. Data sets that reported accounts of EE by the percentage of patients were compiled and further analyzed for specific medication classes. The changes in EE are further discussed as (a) salutary or detrimental, (b) associated with time of day or circumscribed, and (c) presumed to be caused by pharmacological effects. CONCLUSIONS: Definitive methodologies for assessing the presence of changes in EE in clinical trials and guidelines for the evaluation of EE in clinical practice are yet to be established and are needed. Such guidelines could be used by clinicians to monitor positive and negative changes in emotion when patients are taking medications for their ADHD.

Changes in emotions related to medication used to treat ADHD. Part II: clinical approaches.

ADHD is one of the most common neurobehavioral disorders of childhood, and FDA-approved medications offer an efficacious treatment option. However, case reports and anecdotal sources suggest that children can have emotional responses, both salutary and detrimental, to these agents. We have previously conducted a comprehensive literature review and found very few research studies systematically examining changes in emotional expression (EE) associated with ADHD medication use. In addition, no empirical data pertaining to the management of these responses could be found. Although few methodologically stringent data are available for changes in EE, such changes should be recognized and measured to determine appropriate responses by clinicians and to maximize treatment benefits and reduce side effects. In this companion report, we draw on available research evidence and clinical experience to explore typical clinical manifestations, differential diagnosis, scales for monitoring, and management approaches of EE observed with pharmacologic treatment of ADHD. In the future, controlled clinical trials of ADHD pharmacotherapy should employ standardized ratings of EE at baseline, during and after treatment. In addition, future research studies should examine various management approaches of these EE changes, to ensure maximal treatment benefits and minimal risks to patients with ADHD who are treated with medication.

Effects of guanfacine extended release on oppositional symptoms in children aged 6-12 years with attention-deficit hyperactivity disorder and oppositional symptoms: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of guanfacine extended release (XR, Intuniv; Shire Development Inc., Wayne, PA, USA) in the treatment of oppositional symptoms in children aged 6-12 years with a diagnosis of attention-deficit hyperactivity disorder (ADHD) and the presence of oppositional symptoms. SUBJECTS AND METHODS: In this randomized, double-blind, placebo-controlled, multicentre, flexible-dose, dose-optimization study, children aged 6-12 years were randomized to receive guanfacine XR (1-4 mg/day) or placebo for 9 weeks. Screening and washout periods were followed by a 5-week dose-optimization period, a 3-week dose-maintenance period and a 1-week tapering period. The primary efficacy measure was change from baseline to endpoint in the oppositional subscale of the Conners' Parent Rating Scale-Revised: Long Form (CPRS-R:L) score. Change in ADHD Rating Scale IV (ADHD-RS-IV) total score was a secondary efficacy measure. Safety assessments included adverse events (AEs), vital signs, ECG readings and laboratory studies. RESULTS: A total of 217 children were enrolled: 138 were randomized to receive guanfacine XR and 79 to receive placebo. Least-squares mean reductions from baseline to endpoint in CPRS-R:L oppositional subscale scores were 10.9 in the guanfacine XR group compared with 6.8 in the placebo group (p < 0.001; effect size = 0.59). A significantly greater reduction in ADHD-RS-IV total score from baseline to endpoint was also seen in the guanfacine-treated group compared with the placebo group (23.8 vs 11.5, respectively; p < 0.001; effect size = 0.92). A post hoc correlation analysis between percentage reduction from baseline to endpoint in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores indicated that the decreases in oppositional symptoms and ADHD symptoms were highly correlated (r = 0.74). The most commonly reported, treatment-emergent AEs (TEAEs) in the guanfacine XR group were somnolence (50.7%), headache (22.1%), sedation (13.2%), upper abdominal pain (11.8%) and fatigue (11.0%) and most were mild or moderate in severity. TEAEs of sedation, somnolence or hypersomnia were experienced by 62.5% of subjects in the guanfacine XR group. These events were most common during the dose-titration period but most (63.5%) resolved prior to the taper period. TEAEs of fatigue, lethargy and asthenia were reported in 11.0%, 3.7% and 0.0% of subjects in the guanfacine XR group, respectively. Most subjects receiving guanfacine XR demonstrated modest changes in blood pressure, pulse rate and ECG readings that were not considered clinically significant. CONCLUSIONS: In this population of children aged 6-12 years with ADHD and the presence of oppositional symptoms, significant reductions in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores were observed with guanfacine XR treatment compared with placebo. Treatment with guanfacine XR at optimized doses was associated with mostly mild or moderate TEAEs. The findings of this study support the efficacy of guanfacine XR in the treatment of children with ADHD and the presence of oppositional symptoms. CLINICAL TRIAL REGISTRATION NUMBER: NCT00367835.

Duration of effect of oral long-acting stimulant medications for ADHD throughout the day.

OBJECTIVE: To examine duration of efficacy in long-acting stimulant treatment of attention-deficit/hyperactivity disorder (ADHD) in clinical trials using analog classroom protocols. RESEARCH DESIGN AND METHODS: Published reports of clinical trials examining duration of medication efficacy using analog classroom protocols were identified in a systematic literature search of PubMed, BIOSYS, and EMBASE, through June 2009 using combinations of terms: attention-deficit/hyperactivity disorder, ADHD, attention-deficit disorder with hyperactivity, stimulant, methylphenidate (MPH), amphetamine, laboratory school or classroom, analog classroom, math test, and Permanent Product Measure of Performance (PERMP). Reports of short-acting, nonoral or nonstimulant formulations, or inadequate data on duration of efficacy were excluded. MAIN OUTCOME MEASURES: Main outcomes examined were PERMP scores for number of math problems attempted (PERMP-A) and correctly answered (PERMP-C) based on a standard 10-minute math test given at regular intervals during the postdose period. RESULTS: Fifteen trials were included in the analysis. All except one trial in adults (18-55 years) were conducted in children with ADHD (6-15 years) and employed randomized, double- or single-blind, placebo-controlled designs. Duration of efficacy, based on PERMP-A/-C scores (vs. placebo), ranged from 8 hours with long-acting MPH to 14 hours with lisdexamfetamine dimesylate; most formulations exerted therapeutic effects for 12 hours after a single morning dose. Duration of efficacy assessment may be limited by duration of observation (12 hours postdose for most studies). Outcomes may have been influenced by differences in study designs, population characteristics, lack of comparable, equivalent dosages of different extended-release stimulants, and limited ability to extrapolate safety and tolerability from short-term studies to long-term clinical use. Results from cross-study comparisons must be interpreted with caution. CONCLUSIONS: Most long-acting stimulants exerted beneficial effects on ADHD symptoms for up to 12 hours as measured by the PERMP; the longest duration of efficacy versus placebo was seen with lisdexamfetamine dimesylate (14 hours postdose).

Assessing effects of treatment with lisdexamfetamine dimesylate for pediatric ADHD using a parental survey.

INTRODUCTION: Lisdexamfetamine dimesylate (LDX) is a prodrug stimulant approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults and children 6-12 years of age. Parent surveys provide valuable information regarding the impact of ADHD treatments. METHODS: Parents of children with ADHD beginning treatment with LDX voluntarily completed surveys through an automated telephone system or the Internet before and 6 weeks after LDX treatment initiation. Prescribing physicians received individual reports of the responses for each survey completed by their patients' parents. All patients whose parents completed both baseline and 6 week surveys were included in the analyses. Subgroup analyses were conducted for those previously treated with medications to treat ADHD, including mixed amphetamine salts-extended release. RESULTS: LDX treatment was associated with a significant decrease in ADHD symptom interference with school activities, family interactions, homework, and social interactions (P<.01; N=11,576). Parents rated satisfaction with LDX as significantly higher than with their child's previous treatment (P<.01). On average, global improvement, tolerability, convenience, and satisfaction with LDX were all highly rated. CONCLUSION: Patients treated with LDX showed significant symptom improvement and parents reported significantly greater satisfaction than with prior treatment.

Effects of once-daily oral and transdermal methylphenidate on sleep behavior of children with ADHD.

OBJECTIVE: Methylphenidate is a leading first-line treatment for ADHD (AD/HD). This stimulant has long been suspected to adversely affect sleeping patterns of treated individuals, especially children. There are few studies on the effects of recently developed longer-acting methylphenidate treatments, such as once-daily oral or transdermal formulations, on sleep. METHOD: The authors examined eight indices of sleep behavior among children treated with either of these two methylphenidate preparations or placebo in a randomized, double-blind, multicenter, parallel-group study. RESULTS: The main predictor of sleep problems was baseline numbers or severity of preexisting sleep problems, whereas the different treatments and placebo varied little in their propensity to elicit such problems. There was no significant relationship between dosage and severity or frequency of sleep problems. CONCLUSION: The authors found little evidence that methylphenidate treatment (at least in sustained-release forms) was a significant cause of sleep problems in treated children who were carefully titrated to an optimal dose.

Effect of lisdexamfetamine dimesylate on parent-rated measures in children aged 6 to 12 years with attention-deficit/hyperactivity disorder: a secondary analysis.

UNLABELLED: To evaluate the efficacy of lisdexamfetamine dimesylate (LDX) in school-aged children with attention-deficit/hyperactivity disorder (ADHD), using the Conners' Parent Rating Scale, Revised Short Version (CPRS-R:S) and its subscales. METHODS: This was a secondary post hoc analysis of data from a placebo-controlled, double-blind, parallel-group, forced dose-escalation trial. Boys and girls aged 6 to 12 years with a primary diagnosis of ADHD were randomly assigned to LDX (30, 50, or 70 mg/d) or placebo. Improvement on the CPRS-R:S and its subscales (ADHD Index, hyperactivity, oppositional, and cognition) at 10:00 AM, 2:00 PM, and 6:00 PM was analyzed. Safety assessments included the identification of adverse events and were conducted throughout the study. RESULTS: Of the 290 patients randomized, 285 were included in the intent-to-treat population. Parents noted significant improvements at all 3 assessment times on the CPRS-R:S total score and for the CPRS-R:S ADHD Index, hyperactivity, and cognition subscales, regardless of the subject baseline disease severity. For the CPRS-R:S oppositional subscale, significant improvement was noted at 10:00 AM and 2:00 PM (P < 0.01), and overall, significant improvement occurred in subjects who were more severely ill at baseline. The tolerability of LDX was comparable to that of other stimulants. CONCLUSION: Once-daily treatment with LDX was associated with significant improvement in parent-rated assessments of ADHD-related behavior throughout the day at approximately 10:00 AM, 2:00 PM, and 6:00 PM. Lisdexamfetamine dimesylate was effective and well tolerated in this study population of children aged 6 to 12 years with ADHD.

A randomized, double-blind, crossover study of once-daily dexmethylphenidate in children with attention-deficit hyperactivity disorder: rapid onset of effect.

BACKGROUND: Long-acting methylphenidate formulations provide control of attention-deficit hyperactivity disorder (ADHD) symptoms for up to 12 hours; however, not all formulations have rapid onset of therapeutic effect, which is essential for providing symptom control during morning hours. The primary objective of this randomized, double-blind, crossover study was to assess the efficacy of dexmethylphenidate extended release (ER) versus placebo by measuring the change from pre-dose to 0.5 hours post-dose on the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scale. METHODS: Eighty-six children (6-12 years) with ADHD diagnosed using the DSM-IV criteria were randomized to receive dexmethylphenidate ER 20 mg/day or placebo, sequentially, for 7 days, with the final dose administered in a laboratory classroom setting on day 7 of each treatment period. The primary efficacy comparison was change in the SKAMP-Combined score from pre-dose to 0.5 hours post-dose, with additional secondary assessments at 1, 2, 4, 6 and 8 hours post-dose. Secondary efficacy measures included change from pre-dose at all timepoints in the SKAMP-Attention and SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores, and change from baseline on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P). In an exploratory analysis, a daily diary card was completed by parents on the children's in-home behaviour before school. Safety was assessed by occurrence of adverse events, monitoring of vital signs and interpretation of ECGs. RESULTS: Significant improvements were noted at 0.5 hours and at all timepoints post-dose throughout the 8-hour laboratory classroom day for dexmethylphenidate ER vs placebo in the primary outcome measure of the SKAMP-Combined scores (p < 0.001), as well as SKAMP-Attention, SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores (p < 0.05). The changes from baseline in CADS-P scores were significantly greater with dexmethylphenidate ER than placebo (-16.382 vs -4.622; p < 0.001). Responses to all diary questions indicated significant improvement with dexmethylphenidate ER treatment versus placebo (all p < 0.001). The most common adverse events were abdominal pain (dexmethylphenidate ER 3.5%; placebo 4.7%), headache (dexmethylphenidate ER 3.5%; placebo 2.3%) and increased appetite (dexmethylphenidate ER 0%; placebo 3.5%). CONCLUSION: Compared with placebo, once-daily dexmethylphenidate ER 20 mg provided rapid and significant improvement at 0.5 hours post-dose in attention, deportment and academic performance, which was sustained for 8 hours post-dose. Overall, once-daily dexmethylphenidate ER 20 mg was well tolerated. In an analysis of parental assessment of diary responses, children appeared more organized, and morning preparation for school was smoother and less frustrating with once-daily dexmethylphenidate ER compared with placebo.

Varying the wear time of the methylphenidate transdermal system in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: Children with attention-deficit/hyperactivity disorder often have varying needs for coverage of their symptoms throughout the day. The objectives of this study were to determine the efficacy, duration of action, and safety of methylphenidate transdermal system worn for variable times by children (ages 6-12) diagnosed with ADHD. METHOD: Methylphenidate dose was optimized over 5 weeks using 10-, 15-, 20-, or 30-mg patches worn for 9 hours. The efficacy of 4- and 6-hour wear times was then assessed in an Analog Classroom setting during a randomized, placebo-controlled, double-blind, three-way crossover phase. The main efficacy measures were the Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale deportment scale and the Permanent Product Measure of Performance math test. RESULTS: All of the efficacy measures indicated that 4- and 6-hour wear times improved ADHD symptoms and that medication effects on the Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale deportment scale and Permanent Product Measure of Performance math test decreased between 2 and 4 hours after patch removal. The majority of adverse events were transient and mild to moderate in severity. CONCLUSIONS: These findings suggest that the duration of medication effect is related to the wear time of the patch and may be tailored to accommodate the schedules of patients.