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HLD200 is the first evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) designed to delay initial release of MPH and provide treatment effects throughout the day and into the evening for individuals with attention-deficit/hyperactivity disorder (ADHD). Because DR/ER-MPH is uniquely absorbed in the colon, it cannot be substituted for other ADHD medications on a milligram-per-milligram basis. To provide clinicians with a target dose range for DR/ER-MPH when transitioning patients from a prior ADHD medication, dose conversion ratios (DCRs) between prior medication doses and optimized doses of DR/ER-MPH were determined post hoc from a pivotal Phase III study of children (aged 6–12 years) with ADHD. DR/ER-MPH doses were optimized over a 6-week open-label period. DCRs were calculated between optimized doses of DR/ER-MPH at week 6 and prior stable doses of ADHD medication. Mean DCRs ranged from 1.8 to 4.3 for optimized DR/ER-MPH dose versus previous stable dose for individuals taking an extended-release stimulant monotherapy. DCRs for those taking an immediate-release stimulant monotherapy ranged from 4.7 to 6.0. In a Phase III trial of children with ADHD, optimized doses of DR/ER-MPH were higher than doses of prior ADHD medications, but the adverse event profile was consistent with that of other MPHs. Higher DCRs compared with those predicted by bioavailability differences are consistent with a predicted dose-dependent duration of effect for DR/ER-MPH: with increasing doses, absorption is extended but with an attenuated increase in Cmax compared with MPH formulations absorbed in the upper bowel. These data may help guide clinicians to optimize DR/ER-MPH doses. ClinicalTrials.gov identifier: NCT02493777.

We examined real-world evidence on whether Lumosity, a remote digital health technology designed to deliver cognitive training to healthy adults, can improve cognition and reduce inattention in adults who reported having received a prior (lifetime) diagnosis of ADHD. Over the course of Lumosity training, this cohort of commercial users was assessed repeatedly online with a neuropsychological test battery (NCPT) and a scale of attention and mood in real-world contexts (BAMS-7). More Lumosity training between successive assessments led to greater improvements on the NCPT composite measure and the attentional subscale of the BAMS-7. This positive dose-response relation was found for six of eight NCPT subtests and three of four BAMS-7 attentional items. Additional findings support the participants’ clinical status and sensitivity of the assessments to ADHD symptoms. These findings provide evidence of cognitive and attentional benefits in a real-world cohort of adults reporting a lifetime diagnosis of ADHD from training with Lumosity under real-world conditions.

Methylphenidate hydrochloride extended-release chewable tablet (MPH ERCT) is approved for treatment of attention deficit hyperactivity disorder in patients aged 6 years and older. This article evaluates the pharmacokinetic parameters and relative bioavailability of MPH ERCT when chewed versus swallowed whole. In this open-label, single-dose, 3-period, 3-treatment crossover study, 12 healthy adult volunteers were randomly assigned to treatment sequence. In each period, subjects received a single 40-mg dose of the assigned treatment (MPH ERCT chewed, MPH ERCT swallowed whole, or methylphenidate extended-release oral suspension [MEROS]). Blood samples for pharmacokinetic analysis were collected for 24 hours postdose. Key pharmacokinetic parameters included Cmax, AUC0–t, and AUC0–∞. The geometric mean values for AUC0–t, AUC0–∞, and Cmax were similar for MPH ERCT chewed, MPH ERCT swallowed whole, and MEROS. In all pairwise between-treatment comparisons, the 90% CIs of the geometric mean ratios for AUC0–t, AUC0–∞, and Cmax were fully contained within the bioequivalence range of 80% to 125%. Early exposure over the first 4 hours after dosing (AUC0–4) was similar for MPH ERCT chewed versus swallowed whole; AUC0–4 was approximately 15% lower for MPH ERCT, either chewed or swallowed, compared with MEROS. Each treatment was generally well tolerated. There was no difference in overall rate or extent of exposure of methylphenidate when MPH ERCT was chewed versus swallowed whole by healthy volunteers.

Attention-deficit/hyperactivity disorder (ADHD) is a common and impairing mental disorder. Individuals with ADHD typically experience symptoms from awakening throughout the entire day, contributing to impaired function at home, at school, and in the workplace. Treatment is available to address the symptoms of ADHD; however, the extent to which treatments afford improved function remains less clear. Impaired function in children and adolescents, particularly in the early morning where multiple tasks must be completed, from getting out of bed, and having breakfast to leaving for school on time, is common even among stimulant-treated children, and can increase stress upon caregivers and family members. Herein, we present a narrative review on early morning functioning impairment in children and adolescents with ADHD, its impact on caregivers, the rating scales available for clinicians to identify the degree of early morning functioning impairment, and the efficacy of currently available treatments in providing functional improvements to patients with ADHD during the early morning, identifying that only treatments that are available upon awakening have been shown to statistically separate from placebo for early morning functioning improvement.

Objectives: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder defined as a persistent pattern of inactivity and/or hyperactivity that interferes with behavioral function or development. Diagnosis and treatment of ADHD in the preschool-aged population (children 3–5 years old) is more complicated compared with older children because of developmental and physiological differences. This article reviews the available literature regarding the challenges associated with ADHD diagnosis and treatment in preschool-aged children, as well as the unmet needs of preschool-aged children with ADHD. Methods: Key considerations for ADHD diagnosis and treatment patterns in preschool-aged children are summarized in this review, including the need for early intervention, the association with comorbidities, and the differences in pharmacokinetic profiles between preschool-aged children and older children. Results: Efficacy and safety data are lacking, as clinical trial design and execution pose unique challenges in this population. Preschool-aged children often have difficulty with pill swallowing and tolerating phlebotomy necessary for the collection of pharmacokinetic and safety data. However, early diagnosis and treatment are essential to mitigate ADHD symptoms and comorbidities that may develop during childhood and adolescence in patients with persistent ADHD. Conclusion: This review describes the established diagnostic and treatment modalities, along with the unmet needs of preschool-aged children with ADHD.

Background Lisdexamfetamine dimesylate (LDX) is indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children 6 to 12 years of age and in adults. In a previous laboratory school study, LDX demonstrated efficacy 2 hours postdose with duration of efficacy through 12 hours. The current study further characterizes the time course of effect of LDX. Methods Children aged 6 to 12 years with ADHD were enrolled in a laboratory school study. The multicenter study consisted of open-label, dose-optimization of LDX (30, 50, 70 mg/d, 4 weeks) followed by a randomized, placebo-controlled, 2-way crossover phase (1 week each). Efficacy measures included the SKAMP (deportment [primary] and attention [secondary]) and PERMP (attempted/correct) scales (secondary) measured at predose and at 1.5, 2.5, 5, 7.5, 10, 12, and 13 hours postdose. Safety measures included treatment-emergent adverse events (AEs), physical examination, vital signs, and ECGs. Results A total of 117 subjects were randomized and 111 completed the study. Compared with placebo, LDX demonstrated significantly greater efficacy at each postdose time point (1.5 hours to 13.0 hours), as measured by SKAMP deportment and attention scales and PERMP ( P < .005). The most common treatment-emergent AEs during dose optimization were decreased appetite (47%), insomnia (27%), headache (17%), irritability (16%), upper abdominal pain (16%), and affect lability (10%), which were less frequent in the crossover phase (6%, 4%, 5%, 1%, 2%, and 0% respectively). Conclusion In school-aged children (6 to 12 years) with ADHD, efficacy of LDX was maintained from the first time point (1.5 hours) up to the last time point assessed (13.0 hours). LDX was generally well tolerated, resulting in typical stimulant AEs. Trial registration Official Title: A Phase IIIb, Randomized, Double-Blind, Multi-Center, Placebo-Controlled, Dose-Optimization, Cross-Over, Analog Classroom Study to Assess the Time of Onset of Vyvanse (Lisdexamfetamine Dimesylate) in Pediatric Subjects Aged 6–12 With Attention-Deficit/Hyperactivity Disorder. ClinicalTrials.gov Identifier: NCT00500149 http://clinicaltrials.gov/ct2/show/NCT00500149

Attention-deficit/hyperactivity disorder, or ADHD, is the most frequently occurring neurobiological disorder in childhood and is defined by symptoms of inattention and/or hyperactivity and impulsivity that are excessive when compared with other individuals at the same developmental level. ADHD can be successfully treated pharmacologically and stimulant medications are considered a first-line treatment. However, 20–35 % of subjects in clinical trials may have an inadequate response to initial stimulant treatment. There is no standard definition of inadequate response. In many clinical trials, response is defined as a percentage improvement on the Attention-Deficit/Hyperactivity Disorder Rating Scale alone, while in others the change in Clinical Global Impression-Improvement score has also been employed. Other outcome measures have also been used. A more meaningful definition for inadequate response is one that does not produce sufficient reduction of symptoms to produce functional improvement. The literature reveals many factors that may contribute to inadequate response to treatment. Among these are poor adherence, severity and/or complexity of ADHD, inadequate stimulant dosing and/or dose-limiting adverse effects. The reasons for poor adherence should be determined. Common factors include adverse effects, lack of effectiveness, concerns about addictive potential, difficulty ingesting the medication and cost. For patients with inadequate dosing, medication optimization should be tried. For those with dose-limiting adverse effects, switching to another stimulant class or a non-stimulant is an option. For patients who are partial responders to stimulants, despite adequate adherence and dose optimization, the addition of atomoxetine or guanfacine extended release or clonidine extended release may help them achieve adequate response.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder beginning in childhood and often continuing into adulthood. A wealth of data shows that ADHD symptoms respond well to pharmacological treatment. Stimulant medications, including amphetamine and methylphenidate, are most commonly used to treat ADHD. However, with the approval of atomoxetine (Strattera(®), [ATX]) by the US Food and Drug Administration in late 2002, an effective non-stimulant option became available. The US Food and Drug Administration approved ATX for the treatment of ADHD in children, adolescents, and adults. Although the effect size of ATX is generally lower than that of stimulants, the American Academy of Child and Adolescent Psychiatry Practice Parameter for the treatment of ADHD lists ATX as a first-line treatment option. ATX is widely prescribed and accounted for 6% of the prescriptions of ADHD visits in the US in 2010. Numerous trials have found that ATX improves quality of life and emotional lability in addition to core ADHD symptoms. Although some improvement may be seen in a patient as early as one week after the initiation of treatment, ATX generally takes longer to have a full effect. The median time to response using 25% improvement in ADHD symptoms in pooled trials was 3.7 weeks. Data from these trials indicate that the probability of symptom improvement may continue to increase up to 52 weeks after treatment is initiated. ATX has been shown to be safe and effective in combination with stimulants. It has also been studied systematically in subjects with ADHD and comorbid oppositional defiant disorder, anxiety, depression, and substance use disorders. The mechanism of action of ATX, its efficacy, and adverse events reported in trials is reviewed.

Background Psychostimulants are considered first-line pharmacotherapy for youth with attention-deficit/hyperactivity disorder (ADHD), but questions remain regarding the comparative efficacy of amphetamine- and methylphenidate-based agents. Objective Our objective was to describe two acute randomized, double-blind, placebo-controlled, head-to-head studies of lisdexamfetamine dimesylate (LDX) and osmotic-release oral system methylphenidate (OROS-MPH) in adolescents with ADHD. Methods Adolescents (13–17 years) diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision ( DSM-IV-TR ) criteria were enrolled in an 8-week flexible-dose study [LDX 30–70 mg/day ( n  = 186 randomized); OROS-MPH 18–72 mg/day ( n  = 185 randomized); placebo ( n  = 93 randomized)] or a 6-week forced-dose study [LDX 70 mg/day ( n  = 219 randomized); OROS-MPH 72 mg/day ( n  = 220 randomized); placebo ( n  = 110 randomized)]. Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) total score changes from baseline (primary endpoint) at week 8 (flexible-dose study) or week 6 (forced-dose study) were assessed with mixed-effects models for repeated measures. Secondary endpoints included improvement on the dichotomized Clinical Global Impressions–Improvement scale (CGI-I; key secondary endpoint) and changes from baseline on the ADHD-RS-IV subscales. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. Results Least squares (LS) mean ± standard error of the mean (SEM) ADHD-RS-IV total score changes from baseline to end of treatment were −17.0 ± 1.03 with placebo, −25.4 ± 0.74 with LDX, and −22.1 ± 0.73 with OROS-MPH in the forced-dose study and −13.4 ± 1.19 with placebo, −25.6 ± 0.82 with LDX, and −23.5 ± 0.80 with OROS-MPH in the flexible-dose study. LS mean ± SEM treatment difference for the change from baseline significantly favored LDX over OROS-MPH in the forced-dose [−3.4 ± 1.04, p  = 0.0013, effect size (ES) −0.33] but not the flexible-dose (−2.1 ± 1.15, p  = 0.0717, ES −0.20) study. The percentage of improved participants on the dichotomized CGI-I at end of treatment was significantly greater with LDX than with OROS-MPH in the forced-dose study (81.4 vs. 71.3%, p  = 0.0188) but not the flexible-dose study (LDX 83.1%, OROS-MPH 81.0%, p  = 0.6165). The LS mean ± SEM treatment differences for change from baseline on the ADHD-RS-IV hyperactivity/impulsivity and inattentiveness subscales nominally favored LDX in the forced-dose study (hyperactivity/impulsivity subscale −1.3 ± 0.49, nominal p  = 0.0081, ES −0.27; inattentiveness subscale −2.0 ± 0.63, nominal p  = 0.0013, ES −0.33), but there were no significant differences between active treatments in the flexible-dose study. In both studies, LDX and OROS-MPH were superior to placebo for all efficacy-related endpoints (all nominal p  < 0.0001; ES range −0.43 to −1.16). The overall frequency of TEAEs for LDX and OROS-MPH, respectively, were 66.5 and 58.9% in the forced-dose study and 83.2 and 82.1% in the flexible-dose study. TEAEs occurring in ≥ 5% of participants that were also reported at two or more times the rate of placebo were decreased appetite, decreased weight, insomnia, initial insomnia, dry mouth, and nasopharyngitis (LDX and OROS-MPH), irritability and dizziness (LDX only), and increased heart rate (OROS-MPH only) in the forced-dose study and decreased appetite, decreased weight, insomnia, and dizziness (LDX and OROS-MPH) and dry mouth and upper abdominal pain (LDX only) in the flexible-dose study. Mean ± standard deviation (SD) increases from baseline in vital signs (systolic and diastolic blood pressure, pulse) were observed in the forced-dose study [LDX 1.6 ± 9.65 and 3.3 ± 8.11 mmHg, 6.7 ± 12.78 beats per minute (bpm); OROS-MPH 2.6 ± 10.15 and 3.3 ± 9.13 mmHg, 7.6 ± 12.47 bpm] and the flexible-dose study (LDX 2.4 ± 9.46 and 2.8 ± 8.41 mmHg, 4.7 ± 11.82 bpm; OROS-MPH 0.4 ± 9.90 and 2.2 ± 8.64 mmHg, 6.0 ± 10.52 bpm) at the last on-treatment assessment. Conclusions LDX was superior to OROS-MPH in adolescents with ADHD in the forced-dose but not the flexible-dose study. Safety and tolerability for both medications was consistent with previous studies. These findings underscore the robust acute efficacy of both psychostimulant classes in treating adolescents with ADHD. ClinicalTrials.gov registry numbers NCT01552915 and NCT01552902.

Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder in children and adolescents, consisting of developmentally inappropriate levels of inattention and/or hyperactivity and impulsivity. The majority of children with ADHD will continue to experience significant ADHD symptoms as teens. ADHD in adolescents can result in significant functional impairment and poorer quality of life. Children and adolescents with ADHD are at higher risk of developing other psychiatric illnesses such as mood, conduct and substance abuse disorders. Stimulants (amphetamines and methylphenidates) and nonstimulants (atomoxetine, guanfacine extended-release (XR) and clonidine XR) have been found to be effective and are approved by the US FDA for the treatment of ADHD in adolescents in the US. Of the agents approved in the US, only guanfacine XR and clonidine XR are not approved in any other countries. There is growing evidence that treatment of ADHD with stimulants reduces the risk of development of other psychiatric co-morbidities, including substance abuse disorders. To date, all FDA-approved stimulants and nonstimulants that have been adequately studied have been demonstrated to be safe and effective in treating ADHD in both children and adolescents. Therefore, clinical decisions used in selecting pharmacotherapy to treat ADHD in children aged 6–12 years can be applied in the adolescent population.