Joyce Tsai

Efficacy of Lurasidone in Adults Aged 55 Years and Older With Bipolar Depression: Post Hoc Analysis of 2 Double-Blind, Placebo-Controlled Studies.

OBJECTIVE The aim of this post hoc analysis was to evaluate the efficacy of lurasidone in patients aged 55 years and older with bipolar depression. METHODS A post hoc analysis was performed on the older adult subgroup (n = 142) of outpatients meeting DSM-IV-TR criteria for bipolar I depression in 2 placebo-controlled, 6-week, randomized, double-blind studies conducted from 2009-2012: a monotherapy study comparing fixed flexible-dose ranges of lurasidone 20-60 mg/d or 80-120 mg/d with placebo and an adjunctive therapy study comparing flexible doses of lurasidone 20-120 mg/d with placebo adjunctive to either lithium or valproate. The primary endpoint was mean change at week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. RESULTS In the randomized sample, the proportion of older adults was 88/505 (17.4%) in the monotherapy study and 54/348 (15.5%) in the adjunctive therapy study. In the older adult subgroup in the monotherapy study, mean change at week 6 in the MADRS was significantly greater for lurasidone versus placebo (-14.8 vs -7.1; P = .003; effect size, 0.83; pooled doses), and in the adjunctive therapy study, mean change for lurasidone was not significantly different from placebo (-13.9 vs -11.1; P = .398; effect size, 0.26). Discontinuation rates due to adverse events for lurasidone versus placebo were similar for the monotherapy (6.8% vs 6.9%) and adjunctive therapy (3.8% vs 7.1%) studies. Lurasidone had minimal effects on metabolic laboratory values. CONCLUSIONS The results of these post hoc analyses, which assessed the efficacy of lurasidone in older adults with bipolar disorder, found that monotherapy was significantly effective while adjunctive therapy was not associated with significant improvement. Both monotherapy and adjunctive therapy with lurasidone were safe and well-tolerated in this older adult population. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT00868699, NCT00868452.

Lurasidone for major depressive disorder with mixed features and anxiety: a post-hoc analysis of a randomized, placebo-controlled study

OBJECTIVE The aim of this post-hoc analysis was to evaluate the efficacy of lurasidone in treating patients with major depressive disorder (MDD) with mixed features who present with mild and moderate-to-severe levels of anxiety. METHODS The data in this analysis were derived from a study of patients meeting the DSM-IV-TR criteria for unipolar MDD, with a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26, presenting with two or three protocol-defined manic symptoms, who were randomized to 6 weeks of double-blind treatment with either lurasidone 20-60 mg/day (n=109) or placebo (n=100). Anxiety severity was evaluated using the Hamilton Anxiety Rating Scale (HAM-A). To evaluate the effect of baseline anxiety on response to lurasidone, the following two anxiety groups were defined: mild anxiety (HAM-A≤14) and moderate-to-severe anxiety (HAM-A≥15). Change from baseline in MADRS total score was analyzed for each group using a mixed model for repeated measures. RESULTS Treatment with lurasidone was associated with a significant week 6 change versus placebo in MADRS total score for patients with both mild anxiety (-18.4 vs. -12.8, p<0.01, effect size [ES]=0.59) and moderate-to-severe anxiety (-22.0 vs. -13.0, p<0.001, ES=0.95). Treatment with lurasidone was associated with a significant week 6 change versus placebo in HAM-A total score for patients with both mild anxiety (-7.6 vs. -4.0, p<0.01, ES=0.62), and moderate-to-severe anxiety (-11.4 vs. -6.1, p<0.0001, ES=0.91). CONCLUSIONS In this post-hoc analysis of an MDD with mixed features and anxiety population, treatment with lurasidone was associated with significant improvement in both depressive and anxiety symptoms in subgroups with mild and moderate-to-severe levels of anxiety at baseline.

Safety and Effectiveness of Long-Term Treatment with Lurasidone in Older Adults with Bipolar Depression: Post-Hoc Analysis of a 6-Month, Open-Label Study

OBJECTIVE To evaluate the safety and effectiveness of 6 months of treatment with lurasidone in older adults with a diagnosis of bipolar I depression. DESIGN Post-hoc analysis of a multicenter, 6-month, open-label extension study. SETTING Outpatient. PARTICIPANTS Patients aged 55 to 75 years with a DSM-IV-TR diagnosis of bipolar I depression who had completed 6 weeks of double-blind, placebo-controlled treatment with either lurasidone monotherapy (1 study) or adjunctive therapy with lithium or valproate (2 studies). INTERVENTION Flexible doses of lurasidone, 20 to 120 mg/day, either as monotherapy, or adjunctive with lithium or valproate. MEASUREMENTS Effectiveness was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS; change from open-label-baseline to month-6, observed case analysis). RESULTS A total of 141 older adults entered the extension study (monotherapy, N = 55; 39%; adjunctive therapy, N = 86; 61%). At the end of 6 months of open-label treatment with lurasidone, as monotherapy or adjunctive therapy, minimal changes were observed in the older adult sample in mean weight (-1.0 kg and -0.4 kg, respectively); and median total cholesterol (-2.0 mg/dL and +6.0 md/dL, respectively), triglycerides (+2.5 mg/dL and +6.0 mg/dL, respectively), and HbA1c (0.0% and -0.1%, respectively). Patients treated with 6 months of lurasidone showed a mean improvement on the MADRS in both the monotherapy (-6.2) and adjunctive therapy (-6.7) groups. CONCLUSIONS Results of these post-hoc analyses found that up to 7.5 months of lurasidone treatment for bipolar depression in older adults was associated with minimal effects on weight and metabolic parameters, with low rates of switching to hypomania or mania, and was well tolerated. The antidepressant effectiveness of lurasidone in this age group was maintained over the 6-month treatment period.

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.

C-reactive protein and response to lurasidone in patients with bipolar depression

Prior studies suggest that the inflammatory biomarker c-reactive protein (CRP) holds promise for predicting antidepressant response in patients with major depressive disorder. The objective of this study was to evaluate whether CRP might similarly predict antidepressant responses to lurasidone in patients with bipolar I depression. Serum CRP concentration was measured prior to, and following, 6 weeks of treatment in 485 outpatients with bipolar I depression. Patients were randomized to receive monotherapy with lurasidone 20-60 mg/day (N = 161), lurasidone 80-120 mg/day (N = 162) or placebo (N = 162). CRP was assessed using the wide-range CRP assay (wr-CRP). The primary efficacy endpoint was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Mixed models and statistical interaction tests were applied to investigate the moderating effects of pre-treatment wr-CRP on clinical endpoints. CRP was evaluated as a log-transformed continuous variable and by clinically-relevant cut-points. Increasing pre-treatment wr-CRP level predicted a larger overall antidepressant response to lurasidone, as well as an increased response for a number of individual depressive symptoms. These moderating effects of pre-treatment wr-CRP remained significant after adjustment for potential confounds (e.g. baseline BMI and weight change). Treatment with lurasidone did not affect serum concentrations of CRP compared to placebo during the study. Elevated CRP level prior to treatment was associated with an enhanced clinical response to lurasidone in patients with bipolar I depression. If confirmed in future studies, CRP may represent a clinically useful diagnostic and predictive biomarker supporting a precision medicine approach to the treatment of bipolar depression.

Efficacy and Tolerability of Lurasidone in Older Adults with Bipolar Depression: Analysis of Two 6-week Double-blind, Placebo-controlled Studies

Introduction The acute treatment of bipolar depression in the elderly has not been well-studied. Objectives/Aims To evaluate the acute efficacy and tolerability of lurasidone in older adults (age ≥55 years) with bipolar I depression (BPD). Methods The older adult sample was analyzed from two, randomized, double-blind, 6-week studies of BPD patients with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥20: a monotherapy trial (lurasidone 18.5-56 mg/d vs 74-111 mg/d vs placebo); and an adjunctive trial (with lithium or valproate; lurasidone 18.5-111 mg/d vs placebo). Results The older adult sample consisted of 83 patients (17.1%) on monotherapy, and 53 patients (15.6%) on adjunctive therapy. At Week 6, mean change in MADRS was significantly greater for lurasidone 18.5-56 mg (-15.4; P P Conclusions Results of these analyses suggest that lurasidone, in doses of 18.5-111 mg, was an efficacious and well-tolerated acute treatment for bipolar depression in older adults. Significance vs placebo was achieved with lurasidone monotherapy, however, adjunctive therapy with lurasidone did not reach statistical significance. NCT00868699, NCT00868452. Sponsored by Sunovion Pharmaceuticals Inc.

Effect of Lurasidone On Metabolic Parameters in Patients with Bipolar Depression

Introduction Patients with bipolar disorder are at a higher risk of metabolic complications and associated mortality than the general population. Objective/Aims To evaluate the extent to which treatment with lurasidone was associated with clinically relevant shifts in key weight and metabolic parameters in patients with bipolar I depression (BPD). Methods Data were from 3 short-term studies in patients with BPD who were randomized to 6 weeks of double-blind, placebo-controlled treatment with lurasidone (18.5-111 mg/d), either as monotherapy (one study, N=499), or adjunctive therapy with lithium or valproate (2 studies, N=694). Patients completing the 6-week trials continued in a 6 month open-label extension study (N=494). The proportion of patients with shifts in metabolic parameters were analyzed at the 6 week and 6 month end-points, and are reported descriptively. Shifts were defined as changes in weight (≥7% change), BMI category, triglycerides (increase ≥50 mg/dL), total cholesterol (increase ≥40 mg/dL), LDL (increase ≥30 mg/dL), and glucose (shift to ≥110 mg/dL). Results At Week 6 in the monotherapy study, a similar proportion of patients treated with lurasidone vs placebo, respectively, had shifts in weight (2.0% vs 0.6%), triglycerides (15.7% vs 10.1%), total cholesterol (5.5% vs 3.4%), LDL (6.4% vs 3.4%), and glucose (11.3% vs 9.5%). Results were similar for lurasidone vs placebo in the adjunctive therapy study. At Month 6 of the extension study, a relatively low proportion of the patients on lurasidone met shift criteria. Conclusions These data add to the substantial and growing body of information regarding the metabolic safety of lurasidone. NCT00868699, NCT01284517, NCT00868452, NCT00868959. Sponsored by Sunovion Pharmaceuticals Inc.

Long-term Treatment with Lurasidone in Older Adults with Bipolar Depression: Results of a 6 Month Open-label Study

Introduction Long-term treatment of bipolar depression in the elderly has not been well-studied. Objectives/Aims To evaluate the long-term safety and tolerability of lurasidone in older adults (age ≥55 years) with bipolar I depression (BPD). Methods The older adult sample was analyzed from an extension study in which patients who completed one of three 6 week, double-blind, placebo-controlled trials received 6 months of open-label treatment with flexible doses of lurasidone 18.5-111 mg/d, either as monotherapy, or adjunctive to lithium or valproate. Results The older adult sample consisted of 55 patients (17.4% of total) on lurasidone monotherapy and 86 patients (17.3%) on adjunctive lurasidone. At the end of 6 months of treatment with lurasidone, monotherapy and adjunctive therapy, respectively, minimal changes were observed in mean weight (-1.0 kg; -0.4 kg); and median total cholesterol (-2.0 mg/dL; +6.0 md/dL), triglycerides (+2.5 mg/dL; +6.0 mg/dL), and HbA1c (0.0%; -0.1%). The 3 most common adverse events were fatigue (18.4%), insomnia (18.4%), headache (15.8%) in the monotherapy group, and akathisia (31.7%), insomnia (22.0%), tremor (19.5%) in the adjunctive group. Discontinuation due to adverse events was low in both groups (monotherapy, 7.3%; adjunctive, 9.3%). Improvement in depression was maintained during 6 months of treatment, with a mean change in MADRS scores of -15.7 for the monotherapy group, and -17.8 for the adjunctive therapy group (from acute study baseline). Conclusions Results of these secondary analyses suggest that lurasidone, in doses of 18.5-111 mg/day, was a safe and well-tolerated long-term treatment for bipolar depression in older adults. NCT00868959. Sponsored by Sunovion Pharmaceuticals Inc.