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There is a relative lack of long-term, prospective data evaluating the safety and effectiveness of treatment in early-onset adolescent patients with schizophrenia who are treatment-naïve. The aim of this post-hoc analysis was to examine the long-term safety and effectiveness of lurasidone in adolescents with schizophrenia who were antipsychotic treatment-naïve (TN; at the time of enrolment in the initial study) compared to adolescents treated previously (TP) with an antipsychotic.Patients aged 13-17 who completed 6 weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible-dose (20-80 mg/day) lurasidone study.The long-term analysis sample consisted of 50 TN and 221 TP patients, of whom 40% and 43%, respectively, discontinued prematurely. The three most common adverse events for TN and TP patients, respectively, were headache (26.0%, 23.5%); schizophrenia (14.0%, 12.2%), dizziness (16.0%, 4.1%), and nausea (16.0%, 11.8%). At endpoint, mean increase in weight was similar to expected weight gain based on growth charts for both TN (+4.5 kg vs. + 5.7 kg) and TP (+4.6 kg vs. + 6.6 kg) patients. Minimal changes were observed for each group in metabolic parameters and prolactin. Mean improvement was consistently greater in the TN vs. TP group (-19.2 vs. -15.9; effect size of 0.33) for between-group change in PANSS total score at Week 104.In both TN and TP adolescents with schizophrenia, long-term treatment with lurasidone was associated with minimal effects on body weight, lipids, glycemic indices, and prolactin, with generally small differences noted in rates of reported AEs. Continued improvement in symptoms of schizophrenia was evident for both the TN and TP groups. These data indicate that lurasidone is a safe and efficacious treatment option for treatment-naïve youth with schizophrenia, who are generally most sensitive to antipsychotic adverse effects.

In a previous study, dasotraline demonstrated efficacy at a dose of 8 mg/day in adults with attention deficit hyperactivity disorder (ADHD). The aim of the current study was to evaluate the efficacy and safety of dasotraline in doses of 4 and 6 mg/day. Adults meeting Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria for ADHD were randomized to 8 weeks of double-blind, once-daily, fixed-dose treatment with dasotraline 4 mg/day, 6 mg/day, or placebo. The primary efficacy endpoint was changed in the ADHD Rating Scale, Version IV (ADHD RS-IV) total score. Secondary efficacy endpoints included the Clinical Global Impression, Severity (CGI-S) Scale. Least squares mean reduction at week 8 in the ADHD RS-IV HV total score was not significantly greater (vs. placebo) in the dasotraline 4 mg/day group (-15.0 vs. -13.9; n.s.; or in the dasotraline 6 mg/day group (-16.5 vs. -13.9; P = 0.074; Hochberg correction). Treatment with dasotraline 6 mg/day was significant at week 8 (uncorrected) on the ADHD RS-IV total score (P = 0.037) and the CGI-S score (P = 0.011). Treatment with the 4 mg/day dose of dasotraline was NS. Treatment with dasotraline was generally well tolerated. The results provide additional evidence that supports the potential efficacy of dasotraline, in doses of 6 mg/day, in adults with ADHD.

Introduction A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia. Methods In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression–Severity scale, and Montgomery–Åsberg Depression Rating Scale. Results In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE. Conclusion Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone’s long-term effectiveness and favourable metabolic profile in patients with schizophrenia. Trial Registration ClinicalTrials.gov identifier NCT00641745.

Objective: To evaluate the efficacy and safety of dasotraline for treatment of ADHD in children. Method: Children (ages 6-12 years; N = 112) with ADHD were randomized, double-blind, to 14 days of once-daily evening doses of dasotraline 4 mg or placebo. ADHD symptom severity was measured at baseline and Day 15 in seven, 30-min classroom sessions using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) and the Permanent Product Measure of Performance (PERMP) math test. Results: Significant improvement was observed for dasotraline versus placebo in the SKAMP-combined score (−3.2 vs. +2.0; p < .001; effect size = 0.85) and SKAMP and PERMP subscale scores. The three most common adverse events for dasotraline (vs. placebo) were insomnia (19.6% vs. 3.6%), headache (10.7% vs. 8.9%), and decreased appetite (10.7% vs. 3.6%). Conclusion: In this laboratory classroom study, dasotraline 4 mg was found to be an efficacious and generally well-tolerated treatment for ADHD in children aged 6 to 12 years.

Background The aim of this pooled analysis was to evaluate the efficacy and safety of lurasidone in the treatment of an acute exacerbation of schizophrenia in adolescents and young adults. Methods The six pooled studies in this analysis used similar study designs and outcome measures. Patients (aged 13–25 years) were randomized to 6 weeks of double-blind, placebo-controlled treatment with lurasidone in fixed doses of 40, 80, 120, or 160 mg. The primary efficacy endpoint was Week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score; secondary efficacy endpoints included Week 6 change in the Clinical Global Impression–Severity scale. Results The safety population consisted of 537 patients (mean age: 18.1 years); 82.6% of patients completed the studies. Treatment with lurasidone was significantly better than placebo at all doses (p Conclusions In adolescents and young adults with schizophrenia, treatment with lurasidone in doses of 40–160 mg/d was a safe, well-tolerated, and effective treatment. Short-term treatment with lurasidone was associated with minimal effects on weight and metabolic parameters.

Background:Early-onset schizophrenia is characterized by greater severity and more functional impairment than adult-onset schizophrenia. Few studies have prospectively evaluated short- or long-term antipsychotic efficacy in treatment-naïve (vs. previously treated) first-episode schizophrenia. The aim of this post-hoc analysis was to evaluate the long-term efficacy of lurasidone in antipsychotic-naïve adolescents with schizophrenia.Method:Patients aged 13-17 years with schizophrenia were randomized to 6 weeks of double-blind (DB), fixed-dose treatment with lurasidone (40 mg/day or 80 mg/day) or placebo. Six-week completers were eligible to enroll in an open-label (OL), flexible dose 2-year lurasidone treatment study. Efficacy over 104 weeks of OL treatment with lurasidone was evaluated for 2 patient groups based on treatment status prior to entering the initial DB study (treatment-naïve [TN] vs. treated previously [TP]). Treatment-naïve was defined as never having received antipsychotic treatment prior to randomization. Efficacy measures included the PANSS total score and the Clinical Global Impressions-Severity (CGI-S) score. Treatment response was defined as ≥20% reduction from baseline in PANSS total score.Results:A total of 50 TN and 221 TP patients completed the 6-week DB study and entered the extension study; and 30 (60.0%) TN and 126 (57.0%) TP patients completed 104 weeks. In the ITT population of the initial DB study, treatment with lurasidone (vs. placebo) yielded larger effects at DB endpoint on the PANSS total score in the TN group (-25.0 vs. -14.4; PConclusion:In this post-hoc analysis of a 2-year OL extension study, antipsychotic-naïve adolescents with schizophrenia responded well to treatment with lurasidone at doses of 40 mg/day or 80 mg/day. TN patients achieved greater improvement than TP patients during acute treatment; and these greater treatment effects were largely maintained during 2 years of continued treatment with lurasidone.Funding Acknowledgements:Supported by funding from Sunovion Pharmaceuticals Inc

Dasotraline is a potent inhibitor of presynaptic dopamine and norepinephrine reuptake with a pharmacokinetic profile characterized by slow absorption and a long elimination half-life. The aim of this study was to evaluate the efficacy and safety of dasotraline in children with attention-deficit/hyperactivity disorder (ADHD).Children aged 6-12 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD were randomized to 6 weeks of double-blind once-daily treatment with dasotraline (2 or 4 mg) or placebo. The primary efficacy endpoint was change from baseline in the ADHD Rating Scale Version IV-Home Version (ADHD RS-IV HV) total score at week 6.A total of 342 patients were randomized to dasotraline or placebo (mean age 9.1 years, 66.7% male). Treatment with dasotraline was associated with significant improvement at study endpoint in the ADHD RS-IV HV total score for the 4 mg/day dose versus placebo (-17.5 vs. -11.4; p 0.001; effect size [ES], 0.48), but not for the 2 mg/day dose (-11.8 vs. -11.4; ns; ES, 0.03). A regression analysis confirmed a significant linear dose-response relationship for dasotraline. Significant improvement for dasotraline 4 mg/day dose versus placebo was also observed across the majority of secondary efficacy endpoints, including the Clinical Global Impression (CGI)-Severity score, the Conners Parent Rating Scale-Revised scale (CPRS-R) ADHD index score, and subscale measures of hyperactivity and inattentiveness. Discontinuation rates due to adverse events (AEs) were higher in the dasotraline 4 mg/day group (12.2%) compared with the 2 mg/day group (6.3%) and placebo (1.7%). The most frequent AEs associated with dasotraline were insomnia, decreased appetite, decreased weight, and irritability. Psychosis-related symptoms were reported as AEs by 7/219 patients treated with dasotraline in this study. There were no serious AEs or clinically meaningful changes in blood pressure or heart rate on dasotraline.In this placebo-controlled study, treatment with dasotraline 4 mg/day significantly improved ADHD symptoms and behaviors, including attention and hyperactivity, in children aged 6-12 years. The most frequently reported AEs observed on dasotraline included insomnia, decreased appetite, decreased weight, and irritability.

BackgroundFew studies have examined treatment response in adolescents with schizophrenia who are treatment-naive; and there is no placebo-controlled study that we are aware of in first episode treatment-naive patients with schizophrenia. The aim of this analysis was to evaluate the long-term efficacy of lurasidone in antipsychotic-naive adolescents with schizophrenia.MethodPatients aged 13–17 years with schizophrenia, and a PANSS total score ≥70 and ResultsA total of 50 TN and 221 TP patients completed the 6-week DB study and entered the extension study; and 30 (60.0%) TN and 126 (57.0%) TP patients completed 104 weeks. During the initial 6 weeks of DB treatment, mean change in PANSS total score at endpoint was greater for lurasidone vs. placebo in both the TN group (−25.0 vs. −14.4; PConclusionsIn this post-hoc analysis of a 2-year study, adolescents with schizophrenia who had received no previous antipsychotic therapy showed greater improvement compared to previously treated patients during both short- and long-term treatment with lurasidone.FundingSunovion Pharmaceuticals Inc.

ObjectiveTo evaluate the safety and effectiveness of lurasidone in the long-term treatment of patients with schizophrenia.MethodsPatients who completed a 6-week, double-blind (DB), placebo-controlled trial continued in a 22-month, open-label (OL) study during which they received once-daily, flexible-doses of lurasidone, 40–120 mg. Change in the Positive and Negative Syndrome Scale (PANSS) was analyzed using both observed case (OC) and last observation carried forward (LOCF) analyses.ResultsOf the 251 patients who entered the OL extension, 51.4% completed 6 months, 36.7% completed 12 months, and 26.7% completed 22 months of OL treatment. Treatment with lurasidone was associated with a mean change from DB baseline, in weight of +0.4 kg at Month 12 (n=99), and +0.8 kg at Month 24 (n=67; OC analyses). Median change from DB baseline to Month 12 and Month 24, respectively, was -1.0 and -9.0 mg/dL for total cholesterol; 0.0 and -1.0 mg/dL for LDL; +1.0 and -11.0 mg/dL for triglycerides; and 0.0 and +0.1/% for HbA1c (OC analyses). The mean PANSS total score was 96.5 at DB baseline and 69.5 at OL baseline. The mean change from DB baseline in the PANSS total score at Month 24 was -43.6 (OC) and -28.4 (LOCF). Thirty-seven patients (14.7%) discontinued due to an adverse event (AE) during OL treatment. Three AEs occurred in ≥10% of patients: schizophrenia (12.4%), akathisia (10.8%), and somnolence (10.8%); and 19.2% reported at least one movement disorder–related AE. Discontinuations due to AEs occurred in 14.8% of patients.ConclusionsIn this 22-month, open-label extension study, treatment with lurasidone was associated with minimal effects on weight, glucose, lipids, and prolactin. Patients demonstrated sustained improvement in the PANSS total score for up to 24 months of lurasidone treatment.

BACKGROUND: Onset of schizophrenia commonly occurs during late adolescence or early adulthood. Earlier onset (before age 18) is often characterized by greater symptom severity and higher rates of chronic functional impairment. Few studies have examined treatment response in adolescents with schizophrenia who are treatment-naïve, and no placebo-controlled study in first episode treatment-naïve patients with schizophrenia exists at any age. The aim of the current post-hoc analysis was to evaluate the efficacy of lurasidone in antipsychotic-naïve adolescents with a diagnosis of schizophrenia. METHODS: Patients aged 13–17 years with a DSM-IV-TR diagnosis of schizophrenia, and a Positive and Negative Symptom Scale (PANSS) total score ≥70 and

Bipolar disorder is a chronic, recurrent illness that ranks among the top 10 causes of disability in the developed world. As the illness progresses, major depressive episodes increasingly predominate. However, few treatment options are available that have demonstrated efficacy in the treatment of bipolar depression, either as monotherapy or adjunctive therapy in combination with mood stabilizers. Lurasidone is an atypical antipsychotic drug that was initially developed for the treatment of schizophrenia. Since no previous atypical antipsychotic development program had proceeded directly from work on schizophrenia to bipolar depression, the decision to focus on this indication represented an innovation in central nervous system drug development and was designed to address a clinically significant unmet need. The current review summarizes key results of a clinical development program undertaken to characterize the efficacy and safety of lurasidone in patients diagnosed with bipolar depression. Lurasidone is currently the only treatment for bipolar depression approved in the United States as both a monotherapy and an adjunctive therapy with lithium or valproate. The approval of lurasidone expands available treatment options for patients with bipolar depression and provides a therapy with an overall favorable risk-benefit profile.

ObjectivesOnce-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours with once-daily dosing. This study evaluated dasotraline in children aged 6–12 years (NCT02428088).MethodsPatients were randomized 1:1:1 to 6 weeks of once-daily, fixed-dose dasotraline 2 or 4 mg/day, or placebo. The primary efficacy endpoint was change from baseline (CFB) at Week 6 in ADHD Rating Scale Version IV – Home Version (ADHD RS-IV HV) total score, using a mixed model for repeated measures (MMRM) in the intent-to-treat (ITT) population. Secondary endpoints included Clinical Global Impression-Severity (CGI-S) score and safety endpoints.ResultsThe mean age of 342 randomized patients was 9.1 [SD: 1.9] years; 66.7% were male. Overall, 79% of patients completed the study. In the ITT population (N=336), ADHD RS-IV HV total score improved significantly with dasotraline 4 mg/day vs placebo(least squares [LS] mean [SE] CFB at Week 6: –17.53 [±1.31] vs –11.36 [±1.29], respectively, pConclusionsCompared with placebo, dasotraline 4 mg/day significantly improved ADHD symptoms in children, as assessed by ADHD RS-IV HV total score and inattentiveness and hyperactivity/impulsivity subscale scores. Dasotraline was generally well tolerated; most common AEs were insomnia, decreased appetite, weight loss and irritability.Funding AcknowledgementsStudy sponsored by Sunovion Pharmaceuticals Inc.

ObjectiveTo evaluate the long-term safety and tolerability of lurasidone in schizophrenia and schizoaffective disorder patients switched to lurasidone.MethodPatients in this multicenter, 6-month open-label, flexible-dose, extension study had completed a core 6-week randomized trial in which clinically stable, but symptomatic, outpatients with schizophrenia or schizoaffective disorder were switched to lurasidone. Patients started the extension study on treatment with the same dose of lurasidone taken at study endpoint of the 6-week core study; following this, lurasidone was flexibly dosed (40–120 mg/day), if clinically indicated, starting on Day 7 of the extension study. The primary safety endpoints were the proportion of patients with treatment emergent adverse events (AEs), serious AEs, or who discontinued due to AEs. Secondary endpoints included metabolic variables and measures of extrapyramidal symptoms and akathisia, as well as the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), and the Calgary Depression Scale for Schizophrenia (CDSS). The study was conducted from August 2010 to November 2011.ResultsOf the 198 patients who completed the 6-week core study, 149 (75.3%) entered the extension study and 148 received study medication. A total of 98 patients (65.8%) completed the 6-month extension study. Lurasidone 40, 80, and 120 mg were the modal daily doses for 19 (12.8%), 65 (43.9%), and 64 (43.2%) of patients, respectively. Overall mean (SD) daily lurasidone dose was 102.0 mg (77.1). The most commonly reported AEs were insomnia (13 patients [8.8%]), nausea (13 patients [8.8%]), akathisia (12 patients [8.1%]), and anxiety (9 patients [6.1%]). A total of 16 patients (10.8%) had at least one AE leading to discontinuation from the study. Consistent with prior studies of lurasidone, there was no signal for clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin. Movement disorder rating scales did not demonstrate meaningful changes. Treatment failure (defined as any occurrence of discontinuation due to insufficient clinical response, exacerbation of underlying disease, or AE) was observed for 19 patients (12.8% of patients entering) and median time to treatment failure was 58 days (95% CI 22–86). The discontinuation rate due to any cause was 50/148 (33.8%), and median time to discontinuation was 62 days (95% CI 30–75). The mean PANSS total score, mean CGI-S score, and mean CDSS score decreased consistently from core study baseline across extension visits, indicating an improvement in overall condition.ConclusionsIn this 6-month, open-label extension study, treatment with lurasidone was generally well-tolerated with sustained improvement in efficacy measures observed in outpatients with schizophrenia or schizoaffective disorder who had switched to lurasidone from a broad range of antipsychotic agents.

Despite the availability of established antipsychotic agents for the treatment of schizophrenia, continued unmet needs exist for effective medications with lower adverse-effect burden. The present study evaluated the efficacy, safety, and tolerability of treatment with the atypical antipsychotic lurasidone for patients with an acute exacerbation of schizophrenia. Patients were randomized to 6 weeks of double-blind treatment with lurasidone 40 mg/day, 80 mg/day, or 120 mg/day, or placebo. Changes in Positive and Negative Syndrome Scale (PANSS) scores were evaluated using mixed-model repeated-measures (MMRM) analysis. Vital signs, laboratory parameters, extrapyramidal symptoms, and electrocardiogram were assessed. Treatment with lurasidone 80 mg/day resulted in significantly greater improvement in PANSS total score compared with placebo (-23.4 versus -17.0; p < 0.05) at study endpoint (MMRM); lurasidone 40 mg/day and 120 mg/day achieved clinically meaningful overall PANSS score reductions from baseline (-19.2 and -20.5), but not significant separation from placebo. Differences between all lurasidone groups and placebo for changes in laboratory parameters and electrocardiographic measures were minimal. Weight gain ≥ 7% occurred in 8.2% of patients receiving lurasidone and 3.2% receiving placebo. Modest increases in prolactin (median increase, 0.7 ng/mL) and extrapyramidal symptoms were observed following treatment with lurasidone compared with placebo. Akathisia was the most commonly reported adverse event with lurasidone (17.6%, versus 3.1% with placebo). In this study, in which a large placebo response was observed, lurasidone 80 mg/day, but not 40 mg/day or 120 mg/day, was statistically superior to placebo in treating acute exacerbation of chronic schizophrenia. All lurasidone doses were generally well tolerated.

Objective: The primary objective was to evaluate the safety and tolerability of lurasidone, a new atypical antipsychotic agent, in the longer-term treatment of schizophrenia (DSM-IV). Persistence of symptom improvement was assessed as a secondary outcome. Method: Patients who completed a 6-week, doubleblind, placebo-controlled study evaluating the efficacy of fixed doses of once-daily lurasidone (40 or 120 mg) or olanzapine 15 mg (to confirm assay sensitivity) were eligible to receive flexibly dosed lurasidone 40 to 120 mg/d in this 6-month, open-label extension study (conducted from March 2008 to December 2009). Assessments of safety and tolerability were conducted at open-label baseline, at day 10, and monthly thereafter. Results: Of 254 enrolled patients, 113 (44.5%) completed 6 months of open-label treatment. During the open-label study (month 6 observed cases), small decreases were observed in mean weight (−0.1 kg) and median lipid levels (total cholesterol, −6.5 mg/dL; lowdensity lipoprotein, 0.0 mg/dL; high-density lipoprotein, 0.0 mg/dL; triglycerides, −8.5 mg/dL). Patients previously treated with olanzapine (n = 69) experienced decrease in weight and improvement in lipid levels, whereas patients previously treated with lurasidone (n = 115) or placebo (n = 62) experienced minimal changes. No clinically meaningful changes were observed in median prolactin levels. The 2 most commonly reported adverse events were akathisia (13.0%) and insomnia (11.0%). Persistent antipsychotic efficacy of lurasidone was shown for patients who had previously received lurasidone, olanzapine, or placebo; further reductions from open-label baseline to final visit were observed in mean PANSS total score (−8.7) for all patients. Conclusions: Open-label treatment with flexibly dosed lurasidone (40–120 mg/d) was generally safe, well tolerated, and effective over a 6-month period in patients who had completed a preceding 6-week, double-blind study. Trial Registration: ClinicalTrials.gov identifier: NCT00615433

Objective To examine the effectiveness of switching patients to lurasidone using 3 different dosing strategies. Method Adults with DSM-IV-defined schizophrenia or schizoaffective disorder in a nonacute phase of illness were randomized to 1 of 3 lurasidone dosing regimens for the initial 2 weeks of the study: (1) 40 mg/d for 2 weeks; (2) 40 mg/d for 1 week, increased to 80 mg/d on day 8 for week 2 (up-titration group); and (3) 80 mg/d for 2 weeks. Lurasidone was then flexibly dosed (40-120 mg/d) for the subsequent 4 weeks of the study. The preswitch antipsychotic agent was tapered by day 7 to 50% of the original dose and discontinued by the end of week 2. Subjects were stratified on the basis of whether the primary preswitch antipsychotic medication was classified as "sedating" (olanzapine or quetiapine) or "nonsedating" (all other antipsychotics). The primary outcome measure was time to treatment failure, defined as any occurrence of insufficient clinical response, exacerbation of underlying disease, or discontinuation due to an adverse event. The study was conducted from June 2010 to May 2011. Results Of 240 subjects treated in this study, 86 (35.8%) were treated with an antecedent sedating antipsychotic, and 154 (64.2%) were treated with an antecedent nonsedating antipsychotic. Nineteen (7.9%) of the 240 patients experienced treatment failure. No clinically relevant differences were observed when the 3 randomized switch groups were compared. Treatment failure rates were 10/86 (11.6%) versus 9/154 (5.8%) among subjects who had been receiving a preswitch sedating versus nonsedating antipsychotic medication, respectively. Consistent with prior studies of lurasidone, there was no signal for clinically relevant adverse changes in body weight, glucose, insulin, lipids, or prolactin; mean improvements in weight and lipids were observed. Movement disorder rating scales did not demonstrate meaningful changes. The incidence of akathisia as an adverse event was 12.5%; only 1 subject (0.4%) discontinued due to akathisia. Conclusions Switching patients to lurasidone can be successfully accomplished by starting at 40 mg/d for 2 weeks, or 80 mg/d for 2 weeks, or 40 mg/d for 1 week followed by 80 mg/d the second week. Trial registration ClinicalTrials.gov identifier: NCT01143077.

This post hoc analysis evaluated the effect of lurasidone on agitation in acutely ill patients with schizophrenia.Patient-level data were pooled from five 6-week, randomized, double-blind, placebo-controlled studies of fixed-dose, once-daily, oral lurasidone (40, 80, 120, or 160 mg/d). Agitation was assessed with the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score, utilizing a mixed model for repeated measurement analysis.In patients with higher levels of agitation at baseline (PANSS-EC score≥14; n=773), lurasidone was associated with significantly greater improvement in least-squares (LS) mean PANSS-EC scores versus placebo at Day 3/4 (-1.6 vs -1.0; p0.05), Day 7 (-2.3 vs -1.6; p0.05), and at Week 6 endpoint (-5.5 vs -3.8; p0.001; effect size=0.43). In patients with lower agitation at baseline (PANSS-EC score14; n=754), LS mean PANSS-EC score change was significantly greater for lurasidone compared with placebo at Day 7 (-0.8 vs -0.1; p0. 01) through Week 6 endpoint (-1.9 vs -0.9; p0.001; effect size=0.31). Higher doses of lurasidone were notably more effective than lower doses in patients with more severe agitation at study baseline.In this pooled analysis of 5 short-term studies, lurasidone provided early and sustained reduction in agitation, assessed using the PANSS-EC score, in patients with an acute exacerbation of schizophrenia. Higher doses of lurasidone were particularly effective in patients with more severe agitation at study baseline. Overall, these results suggest that lurasidone may be a useful treatment option for patients exhibiting agitation associated with acute psychotic symptoms of schizophrenia. ClinicalTrials.gov Identifiers: NCT00088634 (Study D1050196); NCT00549718 (Study D1050229), NCT00615433 (Study D1050231); NCT00790192 (Study D1050233). Study D1050006 was completed prior to the requirement to register trials.

Long-term improvement of health-related quality of life (HRQoL) in schizophrenia may improve adherence and reduce relapse and rehospitalization. This analysis examines long-term changes in HRQoL among patients with schizophrenia switched to lurasidone from other antipsychotics. Patients who completed an open-label 6-week switch study continued on lurasidone for an additional 24-weeks. HRQoL was measured using the self-reported Personal Evaluation of Transitions in Treatment (PETiT) scale and Short-Form 12 (SF-12) questionnaire. The PETiT assessed HRQoL via total and domain scores (adherence-related attitude and psychosocial functioning). The SF-12 assessed patients’ mental and physical component summary scores (MCS and PCS). Mean changes from the initial baseline were calculated at extension baseline and extension endpoint using analysis of covariance models. Analyses were further stratified by prior antipsychotic medication and responder status; responders were defined as having a ≥20 % improvement in Positive and Negative Syndrome Scale during the first 6-weeks of treatment. The analysis included 144 patients with PETIT or SF-12 data who received ≥1 dose of lurasidone. Mean (standard deviation) PETiT total score improved significantly from 34.9 (9.3) at baseline to 39.5 (8.9) at extension baseline and 39.1 (9.0) at extension endpoint, representing improvements of 4.5 (7.9) and 5.1 (7.2) points, respectively (both p

ObjectivesOnce-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours. This phase 3 study evaluated the efficacy and safety of dasotraline in children with attention deficithyperactivity disorder (ADHD) throughout the day, in a laboratory classroom setting (NCT02734693).MethodsChildren (6–12 years) meeting DSM-5 criteria for ADHD were randomized to 2 weeks of dasotraline or placebo (dosed daily at home at approximately 8 PM). Following an abbreviated practice day, laboratory classroom evaluations took place at baseline and on Day 15. The primary endpoint was mean change from baseline at Day 15 in ADHD symptoms, as measured by the Swanson, Kotkin, Agler, M-Flynn, and Pelham Combined Score (SKAMP-CS), obtained from the average of 7 assessments collected across the 12-hour laboratory classroom day (12–24 hours post-dose). Secondary endpoints included SKAMP scores obtained throughout the day at individual timepoints from 8 AM through 8 PM (12–24 hours post-dose), and measures of safety and tolerability.ResultsThe ITT population comprised 112 patients. Mean age was 9.5 years, 68.8% were male; 92% completed the study. Dasotraline 4 mg/day significantly improved mean SKAMP-CS versus placebo (pConclusionsIn this 2-week, randomized, double-blind, laboratory classroom study in children with ADHD, once-daily dasotraline significantly improved ADHD symptoms (including deportment and attention), compared with placebo, and demonstrated sustained efficacyup to 24 hours post-dose. The most common adverse events were insomnia, decreased appetite, and headache.Funding AcknowledgementsStudy sponsored by Sunovion Pharmaceuticals Inc.

A 4-MB L2 data cache was implemented for a 64-bit 1.6-GHz SPARC(r) RISC microprocessor. Static sense amplifiers were used in the SRAM arrays and for global data repeaters, resulting in robust and flexible timing operation. Elimination of the global clock grid over the SRAM array saves power, enabled by combining the clock information with array select signals. Redundancy was implemented flexibly, with shift circuits outside the main data array for area efficiency. The chip integrates 315 million transistors and uses an 8-metal-layer 90-nm CMOS process.

This quad-issue processor achieves 1-GHz operation through improved dynamic circuit techniques in critical paths and a more extensive on-chip memory system which scales in both bandwidth and latency. Critical logic paths use domino, delayed clocked domino, and logic embedded in dynamic flip-flops for minimum delay. A 64-KB sum-addressed memory data cache combines the address offset add with the cache decode, allowing the average memory latency to scale by more than the clock ratio. Memory bandwidth is improved by using wave pipelined SRAM designs for on-chip caches and a write cache for store traffic. Memory power is controlled without increased latency by use of delayed-reset logic decoders. The chip operates at 1000 MHz and dissipates less than 80 W from a 1.6-V supply. It contains 23 million transistors (12 million in RAM cells) on a 244 mm/sup 2/ die.

This double-blind study evaluated change in cognitive performance and functional capacity in lurasidone and quetiapine XR-treated schizophrenia patients over a 6-week, placebo-controlled study, followed by a 6-month, double-blind extension. Cognitive performance and functional capacity were assessed with the CogState computerized cognitive battery and the UPSA-B. Analyses were conducted for all subjects, as well as the subsample whose test scores met prespecified validity criteria. No statistically significant differences were found for change in the composite neurocognitive score for lurasidone (80 mg/day and 160 mg/day) groups, quetiapine XR and placebo in the full sample at week 6. For the evaluable sample (N = 267), lurasidone 160 mg was superior to both placebo and quetiapine on the neurocognitive composite, while lurasidone 80 mg, quetiapine XR, and placebo did not differ. UPSA-B scores were superior to placebo at 6 weeks for all treatments. In the double-blind extension study, analysis of the full sample showed significantly better cognitive performance in the lurasidone (40-160 mg) group compared to the quetiapine XR (200-800 mg) group at both 3 and 6 months. Cognitive and UPSA-B total scores were significantly correlated at baseline and for change over time. This is the first study to date where the investigational treatment was superior to placebo on both cognitive assessments and a functional coprimary measure at 6 weeks, as well as demonstrated superiority to an active comparator on cognitive assessments at 6 weeks and at 6 months of extension study treatment. These findings require replication, but are not due to practice effects, because of the placebo and active controls.

Introduction Lurasidone has demonstrated efficacy in the treatment of schizophrenia. Objective To evaluate the effect of lurasidone on hostility in patients with an acute exacerbation of schizophrenia. Aims To assess the efficacy of lurasidone for reducing hostility. Methods Data were pooled from 5 double-blind, placebo-controlled, 6-week studies of lurasidone (40-160 mg/d) in patients with evidence of hostility at study baseline (Positive and Negative Syndrome Scale [PANSS] hostility item score ≥2). Lurasidone was compared with placebo using mixed-model repeated-measures analysis, with and without adjustment for positive symptoms of schizophrenia and somnolence as covariates. Results A total of 1148 patients met criteria for hostility at baseline (lurasidone, n=775; placebo, n=373). Lurasidone was significantly superior to placebo in reducing the PANSS hostility item score from Week 1 (P=0.002) through Week 6 (P>0.001). After adjusting for change in positive symptoms, lurasidone significantly decreased hostility compared with placebo from Week 2 (P=0.014) through Week 6 (P>0.05). After adjusting for the presence of somnolence, lurasidone significantly reduced hostility relative to placebo beginning at Week 2 and every assessment thereafter (P>0.05), except for Week 6. Overall, 63.1% of lurasidone-treated patients demonstrated any improvement (≥1 point change) on the PANSS hostility item at study endpoint compared with 55.0% of patients taking placebo (number needed to treat=13; 95% confidence interval, 8-49). Conclusions Lurasidone showed a specific antihostility effect in this post hoc analysis; improvement in hostility was significantly greater with lurasidone than placebo and was independent of change in other positive symptoms or somnolence. Funding Sunovion Pharmaceuticals Inc.

Primary sensory neurons of the C and Aδ subtypes express the vanilloid capsaicin receptor TRPV1 and contain proinflammatory peptides such as substance P (SP) that mediate neurogenic inflammation. Pancreatic injury stimulates these neurons causing the release of SP in the pancreas resulting in pancreatic edema and neutrophil infiltration that contributes to pancreatitis. Axons of primary sensory neurons innervating the pancreas course through the celiac ganglion. We hypothesized that disruption of the celiac ganglion by surgical excision or inhibition of C and Aδ fibers through blockade of TRPV1 would reduce the severity of experimental pancreatitis by inhibiting neurogenic inflammation. Resiniferatoxin (RTX) is a specific TRPV1 agonist that, in high doses, selectively destroys C and Aδ fibers. Sprague-Dawley rats underwent surgical ganglionectomy or application of 10 μg RTX (vs. vehicle alone) to the celiac ganglion. One week later, pancreatitis was induced by six hourly intraperitoneal injections of caerulein (50 μg/kg). The severity of pancreatitis was assessed by serum amylase, pancreatic edema, and pancreatic myeloperoxidase (MPO) activity. SP receptor (neurokinin-1 receptor, NK-1R) internalization in acinar cells, used as an index of endogenous SP release, was assessed by immunocytochemical quantification of NK-1R endocytosis. Caerulein administration caused significant increases in pancreatic edema, serum amylase, MPO activity, and NK-1R internalization. RTX treatment and ganglionectomy significantly reduced pancreatic edema by 46% ( P < 0.001) and NK-1R internalization by 80% and 51% ( P < 0.001 and P < 0.05, respectively). RTX administration also significantly reduced MPO activity by 47% ( P < 0.05). Neither treatment affected serum amylase, consistent with a direct effect of caerulein. These results demonstrate that disruption of or local application of RTX to the celiac ganglion inhibits SP release in the pancreas and reduces the severity of acute secretagogue-induced pancreatitis. It is possible that selectively disrupting TRPV1-bearing neurons could be used to reduce pancreatitis severity.

The sensitivity analysis results are of fundamental importance to the VLSI design because it provides the information to identify a set of critical parameters for each fabrication technology. We have formulated a new sensitivity function to select the critical MOS parameters for digital and analog circuit designs using various MOSIS fabrication technologies. The most sensitive parameters with respect to the drain current have been found to be the gate-oxide thickness, threshold voltage, mobility, and body-effect coefficient. As for the transistor output conductance, the channel-length modulation coefficient and saturated carrier velocity are the most sensitive parameters in addition to those parameters mentioned above. The set of critical parameters plays an important role in the statistical circuit analysis where the worst/best-case parameter files have to be established and in the extreme-temperature circuit simulation.

A next-generation 1.6GHz 4-issue CPU supports high-end servers and has a 4MB L2 cache. The chip uses 315M transistors in a 90nm 8M CMOS process with an area of 234mm/sup 2/.

Luminescence efficiency of ultraviolet light-emitting diodes (UV-LEDs) is investigated using electroluminescence measurements. The effects of thermal and layer structure on the external quantum efficiency at different current densities are discussed and clarified.

In this paper, we have conduced a series of measurements to investigate the luminescence efficiency of UV-LEDs with emission wavelength of 400 nm. Injection current-dependent characteristics are analysed to clarify the dominant factors affecting the luminescence efficiency of UV-LEDs.

This 3rd-generation, superscalar processor, implementing the SPARC V9 64 b architecture, improves performance over previous processors by improvements in the on-chip memory system and circuit designs enhancing the speed of critical paths beyond the process entitlement. In the on-chip memory system, both bandwidth and latency are scaled. Keys to scaling memory latency are a sum-addressed memory data cache, which allows the average memory latency to scale by more than the clock ratio, and the use of a prefetch data cache. Memory bandwidth is improved by using wave-pipelined SRAM designs for on-chip caches and a write cache for store traffic. The chip operates at 800 MHz and dissipates

Introduction Clinically significant depressive symptoms are common in schizophrenia, and are associated with greater functional impairment and worse outcomes. Objectives To evaluate the effect of lurasidone in patients with a DSM-IV-TR diagnosis of schizophrenia who presented with significant depressive symptoms. Methods Pooled data were analyzed from 4, six-week, double-blind, placebo-controlled schizophrenia trials, with available MADRS data. Patients with an acute exacerbation of schizophrenia were randomized to fixed, 40–160 mg (n=902) once-daily doses of lurasidone, or placebo (n=439). LOCF-endpoint data were analyzed using ANCOVA. MADRS remission was defined as an endpoint score Results At baseline, 45.0% and 24.5% of subjects had a MADRS score of ≥12, and ≥16 respectively. Treatment with lurasidone was associated with significantly greater improvement in the MADRS at LOCF-endpoint compared with placebo in the total sample (-2.8 vs. -1.4; p Conclusions In this pooled, post-hoc analysis, 40-160 mg once-daily doses of lurasidone significantly reduced the severity of depressive symptoms in patients with schizophrenia. Daily doses of 160 mg demonstrated the largest effect size. These results warrant further evaluation of lurasidone in patients with schizophrenia and co-morbid depression.

The heterogeneous group of oral bacteria within the sanguinis (sanguis) streptococci comprise members of the indigenous biota of the human oral cavity. While the association of Streptococcus sanguinis with bacterial endocarditis is well described in the literature, S. sanguinis is thought to play a benign, if not a beneficial, role in the oral cavity. Little is known, however, about the natural history of S. sanguinis and its specific relationship with other oral bacteria. As part of a longitudinal study concerning the transmission and acquisition of oral bacteria within mother-infant pairs, we examined the initial acquisition of S. sanguinis and described its colonization relative to tooth emergence and its proportions in plaque and saliva as a function of other biological events, including subsequent colonization with mutans streptococci. A second cohort of infants was recruited to define the taxonomic affiliation of S. sanguinis . We found that the colonization of the S. sanguinis occurs during a discrete “window of infectivity” at a median age of 9 months in the infants. Its colonization is tooth dependent and correlated to the time of tooth emergence; its proportions in saliva increase as new teeth emerge. In addition, early colonization of S. sanguinis and its elevated levels in the oral cavity were correlated to a significant delay in the colonization of mutans streptococci. Underpinning this apparent antagonism between S. sanguinis and mutans streptococci is the observation that after mutans streptococci colonize the infant, the levels of S. sanguinis decrease. Children who do not harbor detectable levels of mutans streptococci have significantly higher levels of S. sanguinis in their saliva than do children colonized with mutans streptococci. Collectively, these findings suggest that the colonization of S. sanguinis may influence the subsequent colonization of mutans streptococci, and this in turn may suggest several ecological approaches toward controlling dental caries.