Serdexmethylphenidate/dexmethylphenidate effects on sleep in children with attention-deficit/hyperactivity disorder.

Introduction: Sleep-related problems are common in children with attention-deficit/hyperactivity disorder (ADHD). Sleep disorders are also side effects of all stimulant ADHD medications. Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is a once-daily treatment approved for patients age 6 years and older with ADHD. In this analysis, sleep behavior was assessed during SDX/d-MPH treatment in children with ADHD. Methods: In a 12-month, dose-optimized, open-label safety study in 6- to 12-year-old participants (NCT03460652), a secondary endpoint was assessment of sleep behavior based on the Children's Sleep Habits Questionnaire (CSHQ) consisting of 8 sleep domains (bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep-disordered breathing, and daytime sleepiness). This post hoc analysis examined the individual sleep domains in the 12-month safety study. Results: Of 282 participants enrolled, 238 were included in the sleep analysis. At baseline, mean (SD) CSHQ total sleep disturbance score was 53.4 (5.9). After 1 month of treatment, the mean (SD) CSHQ total score significantly decreased to 50.5 (5.4); least-squares mean change from baseline was -2.9 (95% CI: -3.5 to -2.4; p < 0.0001) and remained decreased up to 12 months. Mean sleep-score improvements from baseline to 12 months were statistically significant (p < 0.0001) for 5 of 8 sleep domains, including bedtime resistance, sleep anxiety, night wakings, parasomnias, and daytime sleepiness. Parasomnias and daytime sleepiness sleep domains showed the greatest mean improvement from baseline to 12 months. Sleep onset delay and sleep duration scores increased from baseline to 12 months. No statistically significant worsening occurred from baseline in sleep duration and sleep-disordered breathing domains; however, worsening of sleep onset delay was statistically significant. Conclusion: In this analysis of children taking SDX/d-MPH for ADHD, sleep problems did not worsen based on the mean CSHQ total sleep disturbance score. Statistically significant improvements in most CSHQ sleep domains were observed after 1 month and lasted for up to 12 months of treatment.

Do We Need a New Nomenclature for Atypical Antipsychotics? A Survey of Health Care Professionals and Patients.

Objective: The current nomenclature for atypical antipsychotics does not indicate that they are used to treat nonpsychotic conditions (eg, bipolar disorder, major depressive disorder), which could have negative implications for both health care providers (HCPs) and patients. The objective of this study was to evaluate how the atypical antipsychotic class name affects HCPs who treat bipolar disorder and patients who receive the diagnosis.Methods: Nationwide surveys of primary care and psychiatric HCPs (n = 200) and patients with bipolar disorder (n = 200) were conducted to assess perspectives regarding current atypical antipsychotic nomenclature. HCP opinion about a change in class name was also evaluated. The self-administered electronic surveys were completed by HCPs from May 22, 2020, to June 1, 2020, and by patients from August 25, 2020, to September 7, 2020.Results: Compared with the mood stabilizer class name, the atypical antipsychotic name elicited stronger negative feelings from both HCPs and patients. Most HCPs avoided bringing up the atypical antipsychotic name with patients (72%), often due to fear of negative reactions. Despite being approved for bipolar mania and depression, only 48% and 39% of HCPs indicated that atypical antipsychotics were appropriate for these disorders, respectively. If an appropriate alternative for the term atypical antipsychotic was available for bipolar disorder, 71% of HCPs said they were likely to change their class-related behaviors. Most patients had never heard of the atypical antipsychotic class name (69%). Significantly more patients had negative reactions (eg, worry, fear, confusion) to the idea of their HCP prescribing an atypical antipsychotic versus a mood stabilizer (25% vs 6%). Compared with mood stabilizers, patients were less likely to take an atypical antipsychotic immediately as prescribed.Conclusions: Significantly more HCPs and patients had negative reactions to atypical antipsychotic nomenclature compared with mood stabilizer nomenclature for treating bipolar disorder. The broad descriptive atypical antipsychotic class name may not support the standard of care for the treatment of bipolar disorder.

Individualization of attention-deficit/hyperactivity disorder treatment: pharmacotherapy considerations by age and co-occurring conditions.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that manifests in childhood and can persist into adolescence and adulthood. Impairments associated with ADHD can impact quality of life, social interactions, and increase the risk of morbidity and mortality; however, for many patients, effective treatment can lessen these effects. Pharmacotherapy with stimulants or nonstimulants is recommended in conjunction with psychosocial therapy for most patients. Determining the optimal pharmacotherapy can be complex, and the clinician needs to consider many factors such as the patient's age, comorbidities, and lifestyle. Furthermore, the needs of the patient with ADHD will change over time, with specific challenges to consider at each stage of life. A variety of Food and Drug Administration (FDA)-approved stimulant and nonstimulant formulations are available with different modes of delivery and durations of effect. This armamentarium of ADHD medications can be used to individualize ADHD treatment for each patient's needs. This article combines current information from the literature and the first-hand experience of the authors to provide guidance on ADHD treatment options for patients of different ages and for some of the more common comorbidities.

A Phase 3, Randomized Double-Blind Study of the Efficacy and Safety of Low-Dose SHP465 Mixed Amphetamine Salts Extended-Release in Children with Attention-Deficit/Hyperactivity Disorder.

Objectives: In a previous pivotal study of children and adolescents (aged 6-17 years) with attention-deficit/hyperactivity disorder (ADHD), dose-optimized SHP465 mixed amphetamine salts (MAS) extended-release (12.5-25 mg once daily) was superior to placebo in reducing ADHD symptoms. This study evaluated the efficacy, tolerability, and safety of 6.25 mg SHP465 MAS once daily (one-half the lowest approved dose for adolescents and adults) versus placebo in children aged 6-12 years with ADHD. Methods: Children (aged 6-12 years) with Diagnostic and Statistical Manual of Mental Disorders, Fifth edition-defined ADHD; baseline ADHD-Rating Scale, Fifth Edition, Child, Home Version total scores (ADHD-RS-5-HV-TS) ≥28; and baseline Clinical Global Impressions-Severity scores ≥4 were eligible. Participants received 6.25 mg SHP465 MAS once daily or placebo for 4 weeks. The primary (ADHD-RS-5-HV-TS change from baseline at week 4) and key secondary (Clinical Global Impressions-Improvement [CGI-I] score at week 4) efficacy end points were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and vital sign changes. Results: Of 89 randomized participants, 83 completed the study (placebo, n = 41; SHP465 MAS, n = 42). At week 4, the least squares mean (95% confidence interval) treatment differences (SHP465 MAS-placebo) were not statistically significant for ADHD-RS-5-HV-TS change (-1.9 [-6.8 to 3.1], p = 0.451; effect size [ES] = 0.17) or CGI-I score (-0.1 [-0.5 to 0.3], nominal p = 0.597; ES = 0.12). The percentage of participants reporting TEAEs was 16.3% with placebo and 24.4% with SHP465 MAS. The most frequently reported TEAEs (placebo; SHP465 MAS) were headache (7.0%; 4.4%) and decreased appetite (4.7%; 2.2%). Minimal increases in blood pressure were observed with SHP465 MAS at the final on-treatment assessment. Conclusions: SHP465 MAS 6.25 mg once daily (one-half the lowest dose approved for adolescents and adults) was well tolerated in children aged 6-12 years but was not superior to placebo in reducing ADHD symptoms, suggesting that this dose of SHP465 MAS was subtherapeutic in this age group. The Clinical Trial Registration number: NCT03325881.

Randomized Controlled Crossover Trials of the Pharmacokinetics of PRC-063, a Novel Multilayer Extended-Release Formulation of Methylphenidate, in Healthy Adults.

PURPOSE/BACKGROUND: PRC-063 is a once-daily, extended-release oral formulation of methylphenidate hydrochloride developed to provide early and prolonged symptom improvement in patients with attention-deficit/hyperactivity disorder. METHODS/PROCEDURES: We conducted 3 randomized, open-label crossover studies of the pharmacokinetics of PRC-063 in healthy, nonobese men and women aged 18 to 45 years. PRC-063 (100 mg/d) was compared with immediate-release methylphenidate (20 mg, 3 times daily) when administered on a single day under fasted and fed conditions and at steady state (day 5 of repeat dosing under fasted conditions). The pharmacokinetics of PRC-063 administered as capsule contents sprinkled on apple sauce, yoghurt, or ice cream were also investigated. FINDINGS/RESULTS: PRC-063 demonstrated biphasic absorption, with 2 distinct peak plasma concentrations. Intake of a high-fat, high-calorie meal did not increase the peak plasma methylphenidate concentration (Cmax) or extent of absorption (area under the curve), however; it resulted in slower uptake versus a fasted state. During repeated dosing, steady state was reached with no further accumulation of methylphenidate from day 3. At steady state, PRC-063 gave higher evening and trough plasma methylphenidate levels than immediate-release methylphenidate (3 times daily). The pharmacokinetics of PRC-063 sprinkled on food were comparable to that of intact capsules. Reported adverse events (AEs) were consistent with the established safety profile of methylphenidate. There were no serious AEs, but 3 subjects discontinued the repeat-dosing study because of AEs assessed as possibly related to study treatment. IMPLICATIONS/CONCLUSIONS: Our data indicate that PRC-063 can be taken with or without food or by sprinkling capsule contents on food.

Switching to Lurasidone following 12 months of treatment with Risperidone: results of a 6-month, open-label study.

BACKGROUND: Patients with a diagnosis of schizophrenia are at an increased risk for developing metabolic syndrome, which is associated with greater cardiovascular morbidity and mortality. Treatment with some commonly used antipsychotic medications may increase the risk of developing metabolic syndrome. The aim of the study was to evaluate the safety of lurasidone in patients who continued lurasidone or switched from risperidone to lurasidone. A secondary aim was assessment of the effect of long-term lurasidone on the Positive and Negative Syndrome Scale (PANSS). METHODS: The treatment sample in the current study consisted of clinically stable patients with schizophrenia (N = 223) who had completed a 12-month, double-blind study of lurasidone vs. risperidone. In the current extension study, all patients received 6 months of open-label treatment with lurasidone, either continuing lurasidone assigned during the preceding double-blind trial, or switching from double-blind risperidone to lurasidone. Safety and tolerability parameters included body weight, prolactin, and metabolic laboratory tests. RESULTS: Six months of OL treatment with lurasidone was generally well-tolerated, with a low incidence of parkinsonism (4.5%) and akathisia (3.1%). Overall, few adverse events were rated as severe (4.9%), and discontinuation due to an adverse event was low in the lurasidone continuation vs. risperidone switch groups (3.7% vs. 6.9%). In the lurasidone continuation versus risperidone switch groups, change from OL baseline to 6-month endpoint (observed case) was observed in mean body weight (- 0.6 vs. -2.6 kg), median total cholesterol (- 4.0 vs. + 4.5 mg/dL), triglycerides (- 4.5 vs. -5.5 mg/dL), glucose (0.0 vs. -3.0 mg/dL) and prolactin (males, + 0.15 vs. -11.2 ng/mL; females, + 1.3 vs. -30.8 ng/mL). Improvement in PANSS total score was maintained, from OL baseline to endpoint in the continuation vs. switch groups (+ 1.0 vs. -1.0; OC). CONCLUSIONS: In this 6-month extension study, lurasidone treatment was generally well-tolerated and associated with minimal effects on weight, metabolic parameters, and prolactin levels. Patients who switched from risperidone to lurasidone experienced reductions in weight, metabolic parameters and prolactin levels commensurate with increases in these safety parameters experienced during the previous 12 months of treatment with risperidone. TRIAL REGISTRATION: ClinicalTrials.gov NCT00641745 (Date of Registration: March 24, 2008).

Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Titration Study of Methylphenidate Hydrochloride Extended-Release Capsules (Aptensio XR) in Preschool Children with Attention-Deficit/Hyperactivity Disorder.

Objectives: To assess the efficacy and safety of a methylphenidate hydrochloride extended-release capsule (MPH-MLR) formulation in treating attention-deficit/hyperactivity disorder (ADHD) in preschool children. Methods: Children aged 4 to <6 years with qualifying ADHD Rating Scale Fourth Edition (ADHD-RS-IV) Preschool Version scores (≥90th percentile for age/gender) participated in four behavior management training (BMT) sessions or immediately entered (based on investigator assessment of symptom severity or previous participation) into a 6-week, open-label, flexible MPH-MLR dose optimization phase. After BMT, children with <30% improvement in ADHD-RS-IV score and ≥3 score on the Clinical Global Impression-Improvement (CGI-I) scale also entered the open-label period. All children began the open-label period with MPH-MLR 10 mg once daily; weekly adjustments permitted once-daily maximum of up to 40 mg. Children with ≥30% improvement in ADHD-RS-IV total score and a CGI-I score of 1-2 at open-label completion were randomized to their optimized dose of MPH-MLR or placebo for 2 weeks (double blind [DB]). Safety measures included adverse events (AEs), vital signs, and electrocardiograms. Results: Open-label enrollment was 119 children. Mean (SD) ADHD-RS-IV total scores at open-label start and open-label end was 40.8 (10.4) and 19.5 (11.1), respectively. Ninety children were enrolled in the DB phase. Mean (SD) ADHD-RS-IV total scores for the MPH-MLR and placebo group were similar at DB beginning and was 25.8 (14.6) and 34.9 (14.1), respectively, at DB end. Mean change from baseline in ADHD-RS-IV total score during DB was significantly greater in children randomized to placebo compared with MPH-MLR; least squares mean change difference from baseline was -11.2, p = 0.002. During open-label dosing, the most common AEs (≥10%) were decreased appetite, decreased weight, insomnia, hypertension, emotional disorder, and affect lability. Conclusion: Results demonstrate MPH-MLR efficacy in preschool children and a safety profile consistent with known AEs of methylphenidate when used for ADHD.

Modelling resilience in adolescence and adversity: a novel framework to inform research and practice.

Recent conceptualisations of resilience have advanced the notion that it is a dynamic and multifaceted construct. However, its adaptive components, especially those forged by adversity, have not been fully realised, and its neurobiological and psychosocial underpinnings are yet to be meaningfully integrated. In part, this is because a developmental perspective is often neglected in the formulation of resilience. In this review, we consider the findings of resilience research, with a specific emphasis on the developmental period of adolescence. To bridge the gaps in our current understanding, we propose a model of resilience that is predicated on experiencing adversity. Specifically, our model provides a sophisticated insight into the components of resilience, which, together with intrinsic features, involves facilitation of, and skill acquisition via strengthening processes we term tempering and fortification. The model also points to the potential trajectories of adversity-driven resilience and forms the basis of a framework that allows for individual variance in resilience, and the identification of both neurobiological and psychosocial targets for prevention and therapeutic interventions.

Characteristics of ADHD Symptom Response/Remission in a Clinical Trial of Methylphenidate Extended Release.

Clinical trials in attention-deficit/hyperactivity disorder (ADHD) have typically measured outcome using clinician ratings on the Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Remission has been defined as an endpoint score of less than or equal to 18 on the ADHD-RS-IV (or a mean score of 1). Responders have been defined as patients who achieve a CGI-I score of much or very much improved (1 or 2). There is a lack of agreement in the literature on what percent change in symptoms on the ADHD-RS-IV should be used to define improvement or remission. This study uses data from a clinical trial of a methylphenidate extended release (MPH-MLR; Aptensio XR®) phase III clinical trial to attempt to determine the percent change of symptoms that best corresponds with improvement and remission. Symptom remission at endpoint (ADHD-RS-IV total score ≤18) was most closely aligned with a ≥46% reduction in ADHD-RS-IV total score. Clinical improvement was most closely aligned with a ≥40% reduction in ADHD-RS-IV total score. The three different measures of outcome were strongly aligned during double blind and open label treatment, and were independent of subtype status. Our data suggest that at least 40% improvement in symptoms is needed to achieve a robust response at endpoint.

Relationship Between Symptomatic and Functional Improvement and Remission in a Treatment Response to Stimulant Trial.

OBJECTIVE: To evaluate the relationship between symptom and functional improvement and remission in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) enrolled in an 11-week open-label dose-optimization phase of an methylphenidate extended release (MPH-MLR) pivotal study. METHODS: Assessments included the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) and ADHD Rating Scale, Fourth Edition (ADHD-RS-IV). Definitions included the following: symptom improvement (≥30% decrease in ADHD-RS-IV total score); symptom remission (ADHD-RS-IV total score ≤18); functional improvement (decrease in WFIRS-P total score ≥0.25 [minimally important difference]); and functional remission (WFIRS-P total score ≤0.65). RESULTS: Two hundred children completed the open-label phase. At initial assessment, functional impairment was evident across all WFIRS-P domains and similar between children and adolescents. Those who were treatment naive had more functional impairment (WFIRS-P total: 0.82 vs. 0.70, p = 0.02). Significant improvements in all WFIRS-P domains were noted at open-label end (p < 0.001), with the largest improvement in Learning. At open-label end, 94% of children and adolescents demonstrated symptom improvement, of which 57% also showed functional improvement, and 75% of children and adolescents showed symptom remission, of which 81% also showed functional remission. CONCLUSIONS: Children and adolescents treated with MPH-MLR showed moderate-to-large improvement in functioning during 3 months of treatment, both overall and in specific domains. However, a significant number of those who would be considered symptomatic responders failed to show improvement in functioning or continue to have significant functional impairment. Treatment with MPH-MLR showed that both symptomatic and functional remission are achievable goals. Identification of children and adolescents who have been successfully treated for their symptoms, but continue to suffer functional impairment, will allow us to offer additional targeted treatment interventions over and above medication to address residual difficulties.

Effect of Aptensio XR (Methylphenidate HCl Extended-Release) Capsules on Sleep in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: To evaluate measures of sleep (exploratory endpoints) in two pivotal studies of a multilayer bead extended-release methylphenidate (MPH-MLR) treatment of attention-deficit/hyperactivity disorder in children. METHODS: Study 1 evaluated the time course of response to MPH-MLR (n = 26) patients in an analog classroom setting through four phases: screening (≤28 days), open label (OL) dose optimization (4 weeks), double-blind (DB) crossover (2 weeks; placebo vs. optimized dose), and follow-up call. Study 2 was a forced-dose parallel evaluation of MPH-MLR (n = 230) in four phases: screening (≤28 days), DB (1 week; placebo or MPH-MLR 10, 15, 20, or 40 mg/day), OL dose optimization (11 weeks), and follow-up call. Sleep was evaluated by parents using the Children's or Adolescent Sleep Habits Questionnaire (CSHQ or ASHQ) during the DB and OL phases. DB analysis: Study 1 (crossover), analysis of variance; Study 2, analysis of covariance. OL analysis: paired t-test. RESULTS: DB: treatments were significantly different in Study 1 only for CSHQ Sleep Onset Delay (MPH-MLR, 1.90 vs. placebo, 1.34; p = 0.0046, placebo was better), and Study 2 for CSHQ Parasomnias (treatment, p = 0.0295), but no MPH-MLR treatment was different from placebo (pairwise MPH-MLR treatment to placebo, all p ≥ 0.170). OL: CSHQ total and Bedtime Resistance, Sleep Duration, Sleep Anxiety, Night Wakings, Parasomnias, and Sleep-disordered Breathing subscales decreased (improved, Study 1) significant only for CSHQ Night Wakings (p < 0.05); in Study 2 CSHQ total and Bedtime Resistance, Sleep Duration, Night Wakings, Parasomnias, and Daytime Sleepiness, and ASHQ total, Bedtime, Sleep Behavior, and Morning Waking all significantly improved (p < 0.05). CONCLUSIONS: In both studies, there was minimal negative impact of MPH-MLR on sleep during the brief DB phase and none during the longer duration OL phase. Some measures of sleep improved with optimized MPH-MLR dose.

Aiming for remission in adults with attention-deficit/hyperactivity disorder: The primary care goal.

Attention-deficit/hyperactivity disorder (ADHD) is often undiagnosed and undertreated in adults, resulting in wide-ranging problems and functional deficits in patients' lives. In addition, psychiatric comorbidities unrelated to symptom severity may be present. However, effective treatment that can alleviate symptoms and bring about meaningful improvements in functionality is available. Primary care providers can play a crucial role in recognizing and diagnosing ADHD, initiating and monitoring treatment, and obtaining consultations or arranging referrals when necessary, all with the goal of achieving and maintaining remission. Fulfillment of this role requires a practical understanding of the diverse clinical manifestations of ADHD in patients stratified by age and sex, and familiarity with current treatment guidelines. Although there is no absolute consensus on the criteria by which remission is defined, treatment response may be guided by objective ratings of global symptom severity and patients' self-reports of changes in their ability to cope with routine daily tasks, academic and vocational responsibilities, and social relationships. Although there has been much research into the genetic and neurophysiologic basis of ADHD, it is more important for primary care providers to appreciate that ADHD is a chronic condition requiring lifelong follow-up and that clinical presentation and response to treatment can vary widely among patients and over time in the same patients. Such variability makes the management of ADHD challenging, but the opportunity to bring about dramatic improvement in patients' lives makes it imperative for primary care providers to be competent in this area. This review provides primary care clinicians with a practical definition of remission in adults with ADHD, to emphasize that symptom reduction does not necessarily mean intact functionality, and to suggest a multidisciplinary approach aimed at achieving the greatest possible reduction of symptoms and normalization of functionality.

Switching to iloperidone: An omnibus of clinically relevant observations from a 12-week, open-label, randomized clinical trial in 500 persons with schizophrenia.

OBJECTIVE: To describe secondary analyses from a 12-week, randomized, open-label trial where adult schizophrenia outpatients receiving risperidone, olanzapine, or aripiprazole were switched to iloperidone. METHODS: Patients were randomized into two groups: one where the antecedent antipsychotic dose was titrated downwards to zero over 2 weeks (n=240), and the other group where the antecedent antipsychotic was abruptly stopped (n=260). Adaptations of the Clinical Global Impression scale were used to evaluate clinical changes. Other assessments included the reporting of adverse events (AEs), study discontinuation, body weight, and metabolic variables. RESULTS: Improvement was steady throughout the study for both gradual- and immediate-switch groups starting at Week 1 and continuing through Week 12. Discontinuations due to AEs in the first 2 weeks of treatment were higher for the immediate-switch group compared with the gradual-switch group (10.8% vs. 5.4%, NNT 19, 95% CI 10-151). Fewer patients in the gradual-switch group experienced dizziness as an AE, whereas a higher percentage of patients in the immediate-switch group exhibited earlier onset of a therapeutic response within the first 2 weeks; both groups were comparable thereafter with low rates of dizziness and similar efficacy outcomes. CONCLUSIONS: Switching to iloperidone can be accomplished either with a gradual crossover or immediate discontinuation of the prior antipsychotic; however, the immediate-switch method is associated with greater proportion of initial dizziness. The observed outcomes are consistent with what has been previously reported regarding iloperidone's favorable akathisia/EPS profile and modest impact on somnolence/sedation, body weight, and metabolic variables.

A trial evaluating gradual- or immediate-switch strategies from risperidone, olanzapine, or aripiprazole to iloperidone in patients with schizophrenia.

In a 12-week randomized open-label trial, adults diagnosed with schizophrenia experiencing inadequate efficacy and/or poor tolerability on risperidone, olanzapine, or aripiprazole were randomized to switch to iloperidone either gradually (ie, down-titration of current therapy over the first 2weeks [to 50% on Day 1, 25% by Week 1, 0% by Week 2]) or immediately. All patients were titrated on iloperidone to 6mg BID by Day 4, then flexibly dosing between 6 and 12mg BID, as needed. The primary variable was the Integrated Clinical Global Impression of Change (I-CGI-C) and the primary analysis time point was Week 12. A total of 500 patients were randomized and received iloperidone (gradual switch, 240; immediate switch, 260), with 175, 155, and 170 patients switched from risperidone, olanzapine, and aripiprazole, respectively. I-CGI-C Results confirmed improved outcomes at Week 12, with scores that were similar between the gradual- and immediate-switch groups, respectively, for risperidone, 2.82 and 2.67 (95% CI: -0.229, 0.511); olanzapine, 2.87 and 3.03 (95% CI: -0.548, 0.235); and aripiprazole, 2.79 and 2.81 (95% CI: -0.405, 0.368). Incidence of adverse events (AEs) was similar in both switch groups, with the most frequently reported (≥10%) being dizziness, dry mouth, somnolence, and weight increase. In conclusion, switching to iloperidone by either a gradual or an immediate method did not reveal any clinically significant differences in ratings of overall efficacy and safety/tolerability outcomes, based on the I-CGI-C at 12weeks. Similar overall safety/AE profiles were observed regardless of the specific agent from which patients were switched.

Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: Despite the overall high degree of response to pharmacotherapy, consensus is lacking on how to judge clinical response or define optimal treatment/remission when treating adults with attention-deficit/hyperactivity disorder (ADHD). This study examined clinical response and symptomatic remission in analyses of 2 studies of lisdexamfetamine dimesylate (LDX) in adults with ADHD. METHODS: In a 4-week, double-blind, forced-dose trial, adults with ADHD were randomized to LDX 30, 50, and 70 mg/day (mg/d) or placebo. In a second, open-label, follow-up trial, adults entering from the 4-week study were titrated to an "optimal" LDX dose (30 mg/d [n=44], 50 mg/d [n=112], and 70 mg/d [n=171]) over 4 weeks, and maintained for 11 additional months. The ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions-Improvement (CGI-I) scale assessed efficacy. Clinical response was defined, post hoc, as ≥30% reduction from baseline in ADHD-RS-IV and CGI-I rating of 1 or 2; symptomatic remission was defined as ADHD-RS-IV total score ≤18. Log rank analysis examined overall significance among the treatment groups in time to response or remission. RESULTS: Four hundred and fourteen participants in the 4-week study and 345 in the open-label, extension study were included in the efficacy populations. All LDX groups improved by ADHD-RS-IV and CGI-I scores in both studies. In the 4-week study (n=414), 69.3% responded and 45.5% achieved remission with LDX (all doses); 37.1% responded and 16.1% achieved remission with placebo; time (95% CI) to median clinical response (all LDX doses) was 15.0 (15.0, 17.0) days and to remission was 31.0 (28.0, 37.0) days (P<.0001 overall). In the open-label study, with LDX (all doses), 313 (95.7%) and 278 (85.0%) of 327 participants with evaluable maintenance-phase data met criteria for response and remission, respectively. Of participants who completed dose optimization, 75.2% remained responders and 65.7% remained in remission in the 12-month study. Overall, 285 (82.6%) and 227 (65.8%) of 345 participants were responders and remitters, respectively, at their final visits. CONCLUSION: In the long-term study, with open-label, dose-optimized LDX treatment, most adults with ADHD achieved clinical response and/or symptomatic remission; almost two-thirds maintained symptomatic remission over the remaining 11 months. TRIAL REGISTRATION: Clinical Trial Numbers: NCT00334880 and NCT01070394CLINICAL TRIAL REGISTRY: clinicaltrials.gov.

Long-term safety and tolerability of iloperidone: results from a 25-week, open-label extension trial.

INTRODUCTION/OBJECTIVE: Long-term use of the atypical antipsychotic iloperidone has not been investigated at doses above 16 mg/d. This article describes safety and tolerability results from the 25-week open-label extension of a 4-week placebo- and ziprasidone-controlled clinical trial of iloperidone. METHODS: Patients received a dose of 24 mg/d (given as 12 mg twice daily; mean dose = 21.6 mg) that could be reduced to 12 mg/d (given once daily at bedtime) any time after day 35 at the investigator's discretion. RESULTS: A total of 72/173 patients (41.6%) completed the open-label extension. Treatment-emergent adverse events (TEAEs), most mild to moderate in severity, included headache (13.9%), weight increase (9.2%), dizziness (6.9%), nausea (6.4%), sedation (6.4%), and insomnia (5.2%). The only notable dose-related TEAEs were increased weight and headache. Levels of serum glucose, lipids, and prolactin were essentially unchanged or decreased during treatment. In general, akathisia and extrapyramidal symptoms (EPS) improved or were unchanged during treatment. There was no signal of worsening of efficacy based on changes from baseline in the Positive and Negative Syndrome Scale-Total. DISCUSSION/CONCLUSION: This study further supports the long-term safety and tolerability of iloperidone for the treatment of schizophrenia, including iloperidone's favorable effect on metabolic laboratory parameters and low propensity to cause akathisia or EPS.

Attention deficit hyperactivity disorder subtypes and symptom response in adults treated with lisdexamfetamine dimesylate.

OBJECTIVE: To evaluate the efficacy of lisdexamfetamine dimesylate in adults with attention deficit hyperactivity disorder symptom subtypes who exhibit predominantly inattention, hyperactivity/ impulsivity, or combined symptom clusters. DESIGN/SETTING/PARTICIPANTS: This is a post-hoc analysis from a multicenter, one-year, open-label lisdexamfetamine dimesylate study in adults with attention deficit hyperactivity disorder previously completing two weeks or more in a four-week, randomized, placebo-controlled lisdexamfetamine dimesylate study, using Attention Deficit Hyperactivity Disorder Rating Scale IV symptom ratings as an attention deficit hyperactivity disorder subtype proxy (N=349). MEASUREMENTS: Attention Deficit Hyperactivity Disorder Rating Scale IV was measured at baseline of prior study and throughout the open-label study. Proxy subtypes were based on item scores of 2 (moderate) or 3 (severe), representing endorsement of at least six of nine symptoms on respective subscales; predominantly combined type endorsed at least six of nine symptoms on each subscale. Overall safety evaluations included treatment-emergent adverse events. RESULTS: At baseline, 93 of 345 participants exhibited predominantly inattention, 13 predominantly hyperactivity/ impulsivity, 236 combined symptom clusters, and three were unassigned. For the three subgroups, respectively, mean (standard deviation) Attention Deficit Hyperactivity Disorder Rating Scale IV total scores at baseline were 34.5 (4.02), 33.8 (3.27), and 43.6 (5.24); change from baseline to endpoint scores were -19.3 (9.48), -24.0 (7.22), and -27.3 (11.78). Mean (standard deviation) end-of-study lisdexamfetamine dimesylate dose was 57.7 (14.75), 53.1 (16.01), and 56.9 (14.94)mg/day, respectively.Treatment-emergent adverse events (>5%) were upper respiratory tract infection (21.8%), insomnia (19.5%), headache (17.2%), dry mouth (16.6%), decreased appetite (14.3%), irritability (11.2%), anxiety (8.3%), nasopharyngitis (7.4%), sinusitis (6.6%), decreased weight (6.0%), back pain (5.4%), and muscle spasms (5.2%). CONCLUSIONS: Lisdexamfetamine dimesylate was effective in participants with predominantly inattention, hyperactivity/ impulsivity, and combined attention deficit hyperactivity disorder symptom clusters. Groups exhibiting specific predominant subtype symptoms did not differ in clinical response to lisdexamfetamine dimesylate.

Improving Communication in ADHD Care: Results from In-office Linguistic Research.

UNLABELLED: IntroductionAn in-office linguistic study was conducted to help improve understanding of how to better evaluate and treat attention-deficit/hyperactivity disorder (ADHD). METHODS: Naturally occurring interactions were recorded among 7 psychiatrists and 23 patients and 8 pediatricians along with 22 patients and their parents. Participants were interviewed separately post-visit. Transcripts of interactions and interviews were analyzed using sociolinguistic techniques. RESULTS: Visits were variable in length and lacked concrete treatment plans. In the pediatric setting, children were typically excluded from dialogues, accounting for only 8% of words spoken. School was the primary metric used to evaluate symptoms. Pediatricians allayed parents' concerns about stimulant therapy by promising to prescribe the lowest possible dose, rather than discussing titrating to an optimal dose. Adults were evaluated idiosyncratically without the use of scales or tools. Stimulants were positioned as short-term "trials" without strong physician recommendations.DiscussionConversations about stimulant therapy lacked goal- and expectation-setting. Also missing from conversations was a definitive treatment plan based on the core symptoms of ADHD. Incorporating open-ended questions and tools or rating scales may result in a more effective and efficient in-office dialogue. CONCLUSION: Further research is warranted to assess the efficacy of communication strategies to enhance in-office discussions of ADHD and stimulant therapy.

Long-term safety and effectiveness of lisdexamfetamine dimesylate in adults with attention-deficit/ hyperactivity disorder.

OBJECTIVE: To evaluate the long-term safety and effectiveness of lisdexamfetamine dimesylate (LDX) in the treatment of adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: Following a 4-week, placebo-controlled, double-blind trial, 349 adults with ADHD were enrolled into an open-label, single-arm study for up to 12 months. Treatment was initiated at 30 mg/day and titrated up to 70 mg/day at subsequent visits to achieve optimal effectiveness and tolerability. Safety assessments included adverse events inquiries, vital signs, and electrocardiograms while the primary effectiveness assessment was the ADHD Rating Scale (ADHD-RS) total score. RESULTS: A total of 191 (54.7%) subjects completed the study. The most common treatment-emergent adverse events (TEAEs) were upper respiratory tract infection (21.8%), insomnia (19.5%), headache (17.2%), dry mouth (16.6%), decreased appetite (14.3%), and irritability (11.2%). Most TEAEs were mild to moderate in severity. At endpoint, small but statistically significant increases in pulse and blood pressure were noted. Significant improvements in mean ADHD-RS total scores were observed at week 1 and sustained throughout the study (P < .0001 at all postbaseline visits). At endpoint, the mean improvement from baseline ADHD-RS total score was 24.8 (P < .0001). CONCLUSIONS: LDX demonstrated a safety profile consistent with long-acting stimulant use and provided continued effectiveness in adults with ADHD for up to 12 months.