Floyd R. Sallee

Objectives: Aripiprazole modulates dopaminergic and serotonergic pathways that may play a role in the pathogenesis of Tourette's disorder (TD). This trial evaluated the efficacy and safety of oral aripiprazole in the suppression of tics in children and adolescents with TD. Methods: This phase 3, randomized, double-blind, placebo-controlled trial ( ClinicalTrials.gov , NCT01727700) recruited patients who were 7–17 years old with a diagnosis of TD from hospitals, private practices, and research clinics at 76 sites in the United States, Canada, Hungary, and Italy. Patients were randomized in a 1:1:1 ratio by using an interactive voice/web-response system to low-dose aripiprazole (5 mg/day if n = 44), high-dose aripiprazole ( n = 45), or placebo ( n = 44). Least-squares mean treatment differences versus placebo in change from baseline to week 8 in the YGTSS-TTS were statistically significant (high dose, −9.9 [95% confidence interval, CI, −13.8 to −5.9], low dose, −6.3 [95% CI, −10.2 to −2.3]). At week 8, 69% (29/42) of patients in the low-dose and 74% (26/35) of patients in the high-dose aripiprazole groups demonstrated a Clinical Global Impression–Tourette's Syndrome improvement score of 1 (very much improved) or 2 (much improved) compared with 38% (16/42) in the placebo group. The most common adverse events (AEs) were sedation (low dose, 8/44 [18.2%], high dose, 4/45 [8.9%], placebo, 1/44 [2.3%]), somnolence (low dose, 5/44 [11.4%], high dose, 7/45 [15.6%], placebo, 1/44 [2.3%]), and fatigue (low dose, 3/44 [6.8%], high dose, 7/45 [15.6%], placebo, 0). No serious AEs or deaths occurred. Conclusions: This study indicates that oral aripiprazole is a safe and effective treatment for tics in children and adolescents with TD.

We conducted an open‐label, single‐dose, randomized, crossover study in healthy adults to assess the impact of food on the bioavailability of 60 mg methylphenidate extended‐release oral suspension (MEROS; Quillivant XR™)—a long‐acting stimulant for the treatment of attention deficit hyperactivity disorder—by comparing the pharmacokinetic parameters under fed and fasting conditions. When MEROS 60 mg was administered under fed conditions compared with fasting conditions, the exposure of methylphenidate (denantiomer) was higher, with a mean area under the plasma concentration‐vs‐time curve (AUC)_0–tof 160.2 ng·h/mL vs 140.4 ng·h/mL, and a mean AUC_0–infof 163.2 ng·h/mL vs 143.7 ng·h/mL, respectively. The ratios of the ln‐transformed geometric means for methylphenidate for AUC_0–tand AUC_0–infwere 119.5% (90%CI, 115.7% to 123.5%) and 119.0% (90%CI, 115.2% to 122.8%), respectively, within the standard 80% to 125% bioequivalence acceptance range indicating no food effect on the overall exposure (rate and extent). There was a small increase in the peak plasma concentration (127.6% [90%CI, 119.9% to 135.8%]). However, this effect was small and not likely to be clinically significant. Overall, MEROS 60 mg was safe in both the fed and fasting condition when administered to healthy volunteers in this study.

Objective: The purpose of this study was to examine the temporal occurrence and severity of inadequate attention-deficit/hyperactivity disorder (ADHD) symptom control throughout the day, and, more specifically, the frequency and severity of associated functional impairments and their apparent emotional impact on parents and caregivers during the early morning routine before school, in children and adolescents with ADHD currently treated with stable doses of stimulant medications. Methods: Information was obtained from 201 primary caregivers of children and adolescents with ADHD using a self-administered, on-line quantitative research survey. Results: Inadequately controlled ADHD symptoms were rated as most severe during the evening homework time and the early morning routine. The majority of caregivers reported early morning ADHD symptoms and impairment of early morning functioning (EMF) as moderate to severe. Caregiver reactions to their child's early morning ADHD symptoms and unwanted behaviors included feeling overwhelmed, exhausted, and constantly stressed. Conclusions: Control of EMF impairments from inadequately controlled ADHD symptoms is a significant unmet need in children and adolescents with ADHD treated with stable morning doses of stimulant medications. Current orally administered stimulant treatment options have not addressed this challenge.

Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder defined by persistent inattention and/or hyperactivity and impulsivity. These symptoms occur more frequently and are more severe in individuals with ADHD compared with those at a similar developmental level without ADHD, and can be conceptualized as deficits in executive functioning (EF). EF includes domains of metacognition and inhibition, which influence the ability to regulate responses elicited by emotional stimuli. EF deficits can lead to emotional lability (EL), which is characterized by sudden changes in emotion and behaviors of inappropriately high intensity that may include sudden bouts of anger, dysphoria, sadness, or euphoria. EL is common and estimated to occur in about 3.3–10 % of the population. Recent estimates of EL prevalence in children and adolescents with ADHD range from 38 to 75 %. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition does not include EL in diagnostic criteria for ADHD, but does include ADHD-associated features of low frustration tolerance, irritability, or mood lability. The neurobiological basis of EL is not well understood, but brain imaging studies support dividing EF into “cool” cognitive networks encompassing attention and planning activities, and “hot” motivational networks involved in temporal discounting, reward processing, and reward anticipation. Dysfunction in “hot” networks is thought to be related to EL. EL symptoms are associated with more severe ADHD and co-morbidities, have significant impact on functioning, and may respond to treatment with medications frequently used to treat ADHD. Treatment outcomes and areas for future research are discussed.

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.

Objective: Interest in the potential role for the α₂-adrenoceptor agonists clonidine and guanfacine as treatments for attention-deficit/hyperactivity disorder (ADHD) has driven additional clinical studies as well as development of new formulations of these agents. This article reviews the published data that supported United States Food and Drug Administration approval and subsequent clinical use of α₂-adrenoceptor agonists in the treatment of ADHD, and identifies promising directions for future research. Methods: Electronic searches were performed in PubMed through October 2012 using the base terms ADHD or attention deficit hyperactivity disorder and alpha agonists, as well as the following limits: humans, clinical trial, meta-analysis, practice guideline, randomized controlled trial, review, English. The electronic searches were complemented with reference lists from the articles retrieved by informal search of the literature, producing a qualitative review of published, pertinent drug-class preclinical and clinical data. Articles were selected for greater exposition based on hierarchy of evidence (e.g., randomized controlled trials), relevance, and quality of individual studies, as well as generalizability to clinical practice. Results: Results of clinical studies of immediate-release and extended-release formulations of α₂-adrenoceptor agonists and basic science investigations of cognitive effects of these drugs are discussed. Studies of both clonidine and guanfacine extended-release formulations as monotherapy and adjunctive therapy with psychostimulants for the treatment of ADHD are also reviewed. Conclusions: Large, randomized, placebo-controlled clinical trials support the efficacy and safety of α₂-adrenoceptor agonists as monotherapy and adjunctive therapy with psychostimulants for the symptomatic treatment of ADHD. Future research could reveal whether there are cognitive benefits associated with this drug class and thus further define the role of α₂-adrenoceptor agonists in the treatment of ADHD.

Background: Extended-release guanfacine (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6–17 years. This post-hoc analysis further examines the effects of GXR on hyperactivity-impulsivity and inattentiveness. Method: Data from two large double-blind placebo-controlled pivotal trials of GXR in the treatment of ADHD were analyzed. Using the pooled population to provide sufficient sample size and associated statistical power, the impact of GXR treatment on core ADHD symptoms was examined by comparing ADHD Rating Scale IV (ADHD-RS-IV) total scores in the overall GXR and placebo groups in subjects with each of the three ADHD subtypes. ADHD-RS-IV Hyperactivity-Impulsivity and Inattentiveness subscale scores in the overall study population by randomized dose group (vs. placebo) were also examined. Results: The full analysis set included 631 subjects aged 6–17 years (GXR: n =490; placebo: n =141). Among subjects with the predominantly inattentive subtype of ADHD, differences in least squares (LS) mean reductions from baseline in ADHD-RS-IV total scores were significantly greater in GXR-treated subjects ( n =127) than in placebo-treated subjects ( n =38) at treatment weeks 3 through 5 and end point ( p ≤0.020). Among subjects with combined type ADHD, differences in LS mean ADHD-RS-IV total score reductions from baseline were significantly greater in the GXR group ( n =354) than in the placebo group ( n =100) at treatment weeks 1 through 5 and end point ( p ≤0.011). The dearth of predominantly hyperactive-impulsive type subjects ( n =12) precluded analysis of this subgroup. Each randomized GXR dose group in each trial demonstrated significantly greater reductions from baseline in ADHD-RS-IV Hyperactivity-Impulsivity and Inattentiveness subscale scores than did the respective placebo group at end point ( p ≤0.05 for all). Conclusions: The results support the use of GXR in the treatment of core ADHD symptoms as defined in the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision , including hyperactivity, impulsivity, and inattention.

Attention-deficit hyperactivity disorder (ADHD) treatment options include pharmacological and nonpharmacological approaches. In North America, psychostimulants (amphetamine and methylphenidate) are considered first-line pharmacological treatments for patients (children, adolescents and adults) with ADHD. However, in the UK, National Institute for Health and Clinical Excellence (NICE) guidelines have placed short-acting d-amphetamine as a third-line treatment option due to a lack of contemporary, published clinical trials on its efficacy and the concerns from clinical and patient experts regarding the potential for increased abuse and/or misuse compared with methylphenidate. These guidelines do not account for some of the more recent amphetamine products that have been developed to alleviate some of these concerns, but that are not currently approved in the UK or other European countries. The purpose of this review is to describe the pharmacology and clinical efficacy of various amphetamine compositions, as well as to explore the apparent differences in these compositions and their associated risks and benefits. A PubMed literature search was conducted to investigate amphetamine pharmacology, clinical efficacy and safety and ADHD outcomes in the published literature from 1980 through March 2011. Search terms included the keywords ‘ADHD’ or ‘ADD’ or ‘hyperkinetic disorder’ and any of the following keywords combined with ‘or’: ‘amphetamine’, ‘dexamphetamine’, ‘mixed amphetamine salts’, ‘lisdexamfetamine’ and ‘methamphetamine’. The search included English-language primary research articles and review articles but excluded editorial articles and commentaries. The literature search resulted in 330 articles. Pertinent articles relating to amphetamine pharmacology, compositions, clinical efficacy and safety, effectiveness and tolerability, ADHD outcomes and abuse liability were included in this review. The different delivery profiles of amphetamine compositions result in pharmacological and pharmacokinetic differences that contribute to varying effects in the clinical treatment of ADHD, ADHD outcomes and abuse liability. The efficacy and safety of amphetamine compositions for the treatment of ADHD have been demonstrated in clinical trials and meta-analyses, and the long-acting amphetamine compositions have been widely studied and found efficacious without increased adverse effects. Long-acting amphetamine compositions offer the obvious advantage of enhanced duration of action over short-acting amphetamine compositions, and lisdexamfetamine has been shown to have reduced abuse liability compared with short-acting amphetamine.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder characterized by developmentally inappropriate levels of inattention, hyperactivity and impulsivity. Although much evidence supports the use of psychostimulants as a first-line treatment in children and adolescents, up to 30% of patients may have an inadequate response to these medications. For these patients, addition of an alpha(2)-adrenoceptor agonist can further improve ADHD symptoms. The alpha(2)-adrenoceptor agonists may work in a synergistic fashion with stimulants through regulation of prefrontal cortex function. Early studies were completed with immediate-release clonidine (CLON-IR), which requires multiple daily doses and achieves a higher maximum concentration more rapidly than the more recently developed extended-release clonidine (CLON-XR). Pharmacokinetic properties of CLON-XR may be responsible for differences in efficacy and tolerability between the CLON-IR and CLON-XR formulations. Recent double-blind, placebo-controlled trials have shown that extended-release alpha(2)-adrenoceptor agonists are safe and effective, both as monotherapy and as adjunctive treatment with stimulants. This review will focus on clonidine used in conjunction with stimulants to optimize treatment of ADHD.