Michael Tocco

F60. INFLAMMATORY MARKERS AND COGNITIVE PERFORMANCE IN PATIENTS WITH SCHIZOPHRENIA TREATED WITH LURASIDONE

Abstract Background Recent studies have linked inflammation, obesity, and lipid dysregulation with cognitive impairment, a core feature of schizophrenia. Elevated C-reactive protein concentration has been shown to be a reliable biomarker for inflammatory states. We conducted an exploratory analysis to investigate the potential influence of inflammation, obesity and lipid metabolism on changes in symptom severity and cognitive performance in patients with schizophrenia treated with lurasidone. Methods Patients with acute exacerbation of schizophrenia were treated with one of two fixed doses of lurasidone (80 or 160 mg/day), placebo, or 600 mg/day quetiapine XR in a 6-week double-blind study. A wide-range CRP (wr-CRP) assay (equivalent to high sensitivity CRP assay) was used to assess levels of inflammation. CRP was evaluated as a logarithm transformed (log) continuous variable and as a categorical variable divided into low (≤ 2 mg/L), medium (> 2 mg/L and ≤ 5 mg/L) and high (> 5 mg/L) subgroups. Cognitive function was assessed with the CogState computerized cognitive battery at baseline and week 6 endpoint. Nonparametric bootstrap resampling method was applied to estimate the main and interactive effects of CRP on ranked cognitive scores. Results Elevated level of wr-CRP (log) was associated with cognitive impairment at study baseline (P < 0.05), with significantly lower cognitive performance in the subgroup with high wr-CRP (> 5 mg/L) compared to those with low wr- CRP (< 2 mg/L) at study baseline (P < 0.05). Higher level of CRP (log) was also associated with significantly greater symptom severity as assessed by PANSS score, as well as higher BMI/body weight, and lower levels of high-density lipoprotein (HDL) and high hemoglobin A1c (HbA1c) at study baseline (P < 0.05). No significant associations were found for wr-CRP (log) with low-density lipoprotein (LDL) and total cholesterol at study baseline. High wr-CRP level (> 5 mg/L) at study baseline predicted less improvement of cognitive composite score at week 6 endpoint for all treatment groups, compared to those with low to medium wr-CRP levels (< 5 mg/L). The joint effect of wr-CRP (log) and HDL or HOMA-IR on moderating procognitive effects of lurasidone was significant (P<0.05), with greater lurasidone (vs. placebo) effect size in patients with either low wr-CRP and high HDL concentration or lower levels of both wr-CRP and HOMA-IR. Lurasidone treatment was associated with significant reduction in symptom severity as assessed by PANSS, CGI-S, and MADRS change scores from baseline to week 6, independent of wr-CRP, HDL and HOMA-IR levels at study baseline. Lurasidone had no significant effect on change in wr-CRP level from baseline to week 6 endpoint. Discussion Our findings from this exploratory analysis of a placebo-controlled trial in patients with schizophrenia suggest that the joint effects of low wr-CRP level combined with either high HDL or low HOMA-IR can predict cognitive improvement in patients treated with lurasidone (vs. placebo). These findings suggest that inflammation and its interactive effects with insulin resistance and lipid parameters in patients with schizophrenia might impact cognition and response to treatment with antipsychotics.

T5. LURASIDONE AND RISK FOR METABOLIC SYNDROME IN PATIENTS WITH SCHIZOPHRENIA: A COMPREHENSIVE DATABASE ANALYSIS

Abstract Background Patients with schizophrenia are at increased risk for developing metabolic syndrome, with an estimated prevalence of approximately 35–50% (Correll et al. Psychiatr Serv 2010;61:892–98; Vancampfort et al. World Psychiatry 2015;14:339–47). Treatment with atypical antipsychotic medications have been shown to increase rates of metabolic syndrome, with differences observed among antipsychotic agents, most notably in propensity for weight gain: higher for olanzapine, clozapine, and iloperidone; intermediate for quetiapine, risperidone, and paliperidone; and lower for amisulpride, aripiprazole, asenapine, lurasidone, and ziprasidone (Leucht et al. Lancet 2013;382:951–62). Independent of weight gain, atypical antipsychotics also appear to have direct effects on lipid metabolism and glucose regulation. The aim of this safety analysis was to assess the effects of treatment with lurasidone on metabolic syndrome risk in patients with schizophrenia. Methods Changes in the rate of metabolic syndrome during treatment with lurasidone (40–160 mg/d) versus active comparators (olanzapine, quetiapine, risperidone) were analyzed using pooled short-term data from 3 randomized, double-blind, placebo-controlled studies; long-term data from 2 active-controlled studies; and switch data from 2 open-label extension studies. Metabolic syndrome was defined based on the National Cholesterol Education Program criteria (NCEP ATP III; 2005 revision). Results In short-term studies, risk of treatment-emergent metabolic syndrome was similar for patients in the lurasidone and placebo groups (odds ratio [OR]=0.97; week 6 LOCF-endpoint); and was significantly greater for patients in the olanzapine (OR=2.68; P<0.001) and quetiapine (OR=3.70; P<0.001) groups compared to placebo. In long-term studies, risk of treatment-emergent metabolic syndrome after 12 months was significantly lower for lurasidone compared with risperidone (OR=0.374; 95% CI, 0.180–0.774; P<0.01) and non-significantly lower for lurasidone compared with quetiapine XR (OR=0.267; 95% CI, 0.040–1.806; P>0.05). In open-label switch studies, the rate of metabolic syndrome decreased in patients switched to lurasidone after 6 weeks of treatment with olanzapine or 12 months of treatment with risperidone. Discussion In this comprehensive analysis of the lurasidone clinical trial data base, treatment with lurasidone (40–160 mg/d) was not associated with the development of metabolic syndrome in patients with schizophrenia. Rates of metabolic syndrome increased in patients treated with olanzapine, risperidone, and quetiapine XR.

108 Lurasidone in Children and Adolescents With Bipolar Depression Presenting With Mixed Features

Objective: To evaluate the efficacy and safety of lurasidone in the treatment of children and adolescents with bipolar depression presenting with mixed features. METHODS: Patients 10 to 17 years of age, inclusive, with a DSM-IV-TR diagnosis of bipolar I depression, were randomized to 6 weeks of double-blind treatment with once-daily, flexible doses of lurasidone 20-80 mg or placebo. The presence of mixed features (subthreshold hypomanic symptoms) was defined as a YMRS score > 5 at study baseline. Efficacy analyses included change from baseline to week 6 in Children Depression Rating Scale, Revised (CDRS-R) score (the primary outcome), and Clinical Global Impressions, Bipolar Severity of Depression Score (CGI-BP-S), using mixed model for repeated measures (MMRM) analysis. RESULTS: At baseline, mixed features were present in 54.2% of patients (lurasidone, n= 97/173; placebo, n=89/170). Treatment with lurasidone (vs placebo) was associated with significantly greater reductions in CDRS-R scores at week 6 in the mixed features group (-21.5 vs -15.9; P<0.01; effect size, 0.45), and in the group without mixed features (-20.4 vs -14.8; P<0.01; effect size, 0.45). Likewise, lurasidone was associated with greater effect size (vs placebo) for reductions inCGIBP-S scores at week 6 in the mixed features group (-1.6 vs -1.1; P< 0.001; effect size 0.57), and in the group without mixed features (-1.3 vs -1.0; P=0.05; effect size 0.30). Rates of protocol-defined treatment-emergent hypomania or mania were similar for lurasidone and placebo in patients with mixed features(lurasidone 8.2% vs. placebo 9.0%) and without mixed features (lurasidone 1.3% vs. placebo 3.7%). CONCLUSIONS: In this post-hoc analysis, lurasidone was found to be efficacious for treating child and adolescent patients with bipolar depression presenting with mixed features(assessed cross-sectionally at study baseline). There was no increased risk of treatment-emergent mania observed in patients with or without mixed features. FUNDING ACKNOWLEDGEMENTS: Sunovion Pharmaceuticals Inc. 109 Comparative Efficacy and Tolerability of Lurasidone Versus Other Oral Atypical Antipsychotics for Pediatric Schizophrenia: A Network Meta Analysis Celso Arango, MD, PhD; Daisy Ng-Mak, PhD; Elaine Finn, MPharm, MSc; Aidan Byrne, MSc; Krithika Rajagopalan, PhD; and Antony Loebel, MD 1 Chair Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, Universidad Complutense, IBERSAM, Madrid, Spain 2 Senior Director, Global Health Economics & Outcomes Research, Sunovion Pharmaceuticals Inc, Marlborough, MA, USA 3 QuintilesIMS, London, United Kingdom Head of Global HEOR, Global Health Economics and Outcomes Research, Sunovion Pharmaceuticals, Marlborough, MA 5 Executive Vice President, Chief Medical Officer, Research & Development, Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA ABSTRACT: Study Objective: This analysis assessed the relative efficacy and tolerability of lurasidone versus other atypical antipsychotics in the treatment of pediatricschizophrenia. Study Objective: This analysis assessed the relative efficacy and tolerability of lurasidone versus other atypical antipsychotics in the treatment of pediatricschizophrenia. METHODS: A systematic literature review identified 13 randomized-controlled trials for the treatment of pediatric schizophrenia. A Bayesian network meta-analysis compared the efficacy and tolerability of the following atypical antipsychotics: aripiprazole, asenapine, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, andziprasidone. Patients were 7-17 years old and trial duration ranged from 6-12 weeks. Outcomes included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), weight gain, all-cause treatment discontinuation, and extrapyramidal symptoms. Results from the fixed effect models 70 ABSTRACTS https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852918000081 Downloaded from https://www.cambridge.org/core. IP address: 178.57.67.30, on 11 Apr 2019 at 22:31:17, subject to the Cambridge Core terms of use, available at

Effects of Lurasidone On Hostility in Patients with an Acute Exacerbation of Schizophrenia: a Pooled Post HOC Analysis of 5 Short-term Studies

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.