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.

Efficacy and Safety of Lurasidone in Children and Adolescents With Bipolar I Depression: A Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To evaluate the efficacy and safety of lurasidone in children and adolescents with bipolar depression. METHOD: Patients 10 to 17 years old with a DSM-5 diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with flexible doses of lurasidone 20 to 80 mg/day. The primary endpoint was change from baseline to week 6 in the Children's Depression Rating Scale-Revised (CDRS-R) total score, evaluated by a mixed-model repeated-measures analysis. RESULTS: A total of 347 patients were randomized and received at least 1 dose of lurasidone (n = 175; mean age 14.2 years; mean dose 33.6 mg/day) or placebo (n = 172; mean age 14.3 years). At week 6, treatment with lurasidone was associated with statistically significant improvement compared with placebo in CDRS-R total score (-21.0 versus -15.3; p < .0001; effect size 0.45). Lurasidone also was associated with statistically significant improvement in the Clinical Global Impression-Bipolar Severity depression score (key secondary measure) and in measures of anxiety, quality of life, and global functioning. Study completion rates were 92.0% in the lurasidone group and 89.7% in the placebo group; discontinuation rates due to adverse events were the same for the 2 groups (1.7%). The 2 most common adverse events on lurasidone were nausea and somnolence. Treatment with lurasidone was associated with few effects on weight and metabolic parameters. CONCLUSION: In this placebo-controlled study, monotherapy with lurasidone, in the dose range of 20 to 80 mg/day, significantly decreased depressive symptoms in children and adolescents with bipolar depression. Lurasidone was well tolerated, with minimal effects on weight and metabolic parameters. Clinical trial registration information-Lurasidone Pediatric Bipolar Study; http://Clinicaltrials.gov; NCT02046369.

Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder.

Lurasidone (DS-RAn) has demonstrated efficacy in the acute treatment of bipolar depression, both as monotherapy, and as combination therapy with lithium or valproate. To evaluate the recurrence prevention efficacy of lurasidone for the maintenance treatment of bipolar I disorder, patients received up to 20 weeks of open-label lurasidone (20-80mg/d) combined with lithium or valproate during an initial stabilization phase. A total of 496 patients met stabilization criteria and were randomized to 28 weeks of double-blind treatment with lurasidone (20-80mg/d) or placebo, in combination with lithium or valproate. Based on a Cox proportional hazard model, treatment with lurasidone reduced the probability of recurrence of any mood episode by 29% (primary endpoint), however, the reduction did not achieve statistical significance. Probability of recurrence on lurasidone was significantly lower in patients with an index episode of depression (HR, 0.57; P=0.039), in patients with any index episode who were not rapid-cycling (HR, 0.69; P=0.046), and when recurrence was based on MADRS, YMRS, or CGI-BP-S severity criteria (HR, 0.53; P=0.025; sensitivity analysis). Long-term treatment with lurasidone combined with lithium or valproate was found to be safe and well-tolerated, with minimal effects on weight or metabolic parameters.

Efficacy and Safety of Lurasidone in Adolescents with Schizophrenia: A 6-Week, Randomized Placebo-Controlled Study.

OBJECTIVE: To evaluate the efficacy and safety of lurasidone in acutely symptomatic adolescent patients with schizophrenia. METHODS: Patients aged 13-17 years were randomly assigned to 6 weeks of double-blind, fixed-dose lurasidone (40 or 80 mg/day) or placebo. Primary and key secondary efficacy measures were change from baseline to week 6 in the Positive and Negative Symptom Scale (PANSS) total score and Clinical Global Impressions-Severity (CGI-S) score, respectively, using mixed model for repeated measurement (MMRM) analysis. The proportion of patients achieving treatment response at endpoint, based on ≥20% reduction in PANSS total score, was analyzed using a logistic regression model. RESULTS: Least-squares (LS) mean change in PANSS total score from baseline to week 6 was -18.6 with lurasidone 40 mg/day (N = 108; p < 0.001 vs. placebo; effect size = 0.51), -18.3 with lurasidone 80 mg/day (N = 106; p < 0.001 vs. placebo; effect size = 0.48), and -10.5 with placebo (N = 112). Similarly, LS mean change in CGI-S score from baseline to week 6 was significantly greater with lurasidone 40 mg/day (-1.0; p < 0.001; effect size = 0.49) and 80 mg/day (-0.9; p = 0.0015; effect size = 0.45) compared with placebo (-0.5). A significantly higher proportion of patients met responder criteria on lurasidone 40 and 80 mg/day versus placebo (63.9% and 65.1% vs. 42.0%; p < 0.001 for both comparisons). The rate of study discontinuation was 10.3% in lurasidone-treated and 17.7% in placebo-treated patients. The most common adverse events (incidence ≥5% in either lurasidone dose group and at least twice the rate of placebo) for lurasidone 40 mg/day, 80 mg/day, and placebo, respectively, were nausea (12.7%, 14.4%, and 2.7%), somnolence (9.1%, 11.5%, and 5.4%), akathisia (9.1%, 8.7%, and 1.8%), vomiting (8.2%, 6.7%, and 1.8%), and sedation (5.5%, 1.9%, and 1.8%). Treatment with lurasidone was not associated with clinically meaningful effects on body weight, lipids, measures of glycemic control, or prolactin. CONCLUSIONS: In this 6-week study, lurasidone at doses of 40 and 80 mg/day demonstrated statistically significant and clinically meaningful symptom improvement in adolescent patients with schizophrenia. Lurasidone was generally well tolerated with few effects on weight and metabolic parameters, consistent with findings in adult patients with schizophrenia.

Long-term use of lurasidone in patients with bipolar disorder: safety and effectiveness over 2 years of treatment.

BACKGROUND: Bipolar disorder is a chronic illness with a 2-year recurrence rate of approximately 50% among individuals receiving treatment in the community. The aim of this 18-month, open-label, continuation study was to evaluate the long-term safety and effectiveness of lurasidone in patients who initially presented with a major depressive episode associated with bipolar disorder, and who had completed at least 6 months of initial treatment with lurasidone. METHODS: Patients with bipolar I depression were enrolled in one of three 6-week, double-blind, placebo-controlled trials (monotherapy with lurasidone, 1 study; adjunctive therapy with lurasidone; and lithium or valproate, 2 studies). Study completers were eligible for a 6-month, open-label extension study of lurasidone utilizing flexible daily doses of 20-120 mg; extension completers were then eligible for an additional 18 months of continuation treatment with flexible, once-daily doses of lurasidone in the range of 20-80 mg. Concomitant therapy with mood stabilizers was permitted throughout the open-label extension and continuation studies. RESULTS: A total of 1199 patients entered, and 941 (78.5%) completed initial, double-blind, acute treatment, of whom 817/941 (86.8%) entered, and 559 (68.4%) completed the 6-month extension study; 122/559 patients (21.8%) entered the 18-month continuation study, of whom 19.7% of discontinued, including 6.6% due to adverse events and 1.6% due to insufficient efficacy. The mean dose of lurasidone during the 18-month continuation study was 61.8 mg/day, and the modal dose was 60 mg/day. Mean change in weight, from acute baseline to 18-month continuation endpoint was +0.8 kg (completers, n = 55); median changes in cholesterol and triglycerides were -3.0 mg/dL and +26.0 mg/dL, respectively. Based on a Kaplan-Meier analysis, the probability of relapse during 18 months of continuation treatment with lurasidone was estimated to be 18.3% in the monotherapy group and 29.1% in the adjunctive therapy group. Improvement in global illness severity was also maintained during 18 months of continuation therapy (CGI-S at continuation baseline, 2.1; 18-month completers, 1.7; LOCF-endpoint, 1.9). CONCLUSIONS: Up to 2 years of treatment with lurasidone was safe and well tolerated in this bipolar disorder population presenting with an index episode of depression. Improvement in depressive symptoms was maintained in the majority of patients treated with lurasidone, with relatively low rates of relapse, and with minimal effects on weight and metabolic parameters.

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 Dose Escalation in Early Nonresponding Patients With Schizophrenia: A Randomized, Placebo-Controlled Study.

OBJECTIVE: To assess the effect of dose increase in adult patients with schizophrenia who demonstrate inadequate initial response to standard-dose lurasidone and to evaluate the efficacy of low-dose lurasidone in adult patients with schizophrenia. METHODS: In this randomized, double-blind, placebo-controlled study conducted between May 2013 and June 2014, hospitalized patients with acute schizophrenia (DSM-IV-TR criteria) were randomly assigned to double-blind treatment with lurasidone 20 mg/d (n = 101), lurasidone 80 mg/d (n = 199), or placebo (n = 112). Nonresponders to lurasidone 80 mg/d (Positive and Negative Syndrome Scale [PANSS] score decrease < 20%) at 2 weeks were re-randomized to lurasidone 80 mg/d or 160 mg/d for the remaining 4 weeks of the study. The primary outcome measure was change from baseline to week 6 in PANSS total score. RESULTS: In nonresponders to lurasidone 80 mg/d (n = 95), dose increase to 160 mg/d at week 2 significantly reduced PANSS total score at week 6 study endpoint compared with continuing 80 mg/d (-16.6 vs -8.9; P < .05 [effect size = 0.52]). While a comparable magnitude of improvement was observed in Clinical Global Impression-Severity (CGI-S) score from week 2 to week 6 endpoint for lurasidone 160 mg/d versus 80 mg/d (-1.0 vs -0.6; effect size = 0.44), the difference was not statistically significant (P = .052). Patients receiving lurasidone 20 mg/d did not demonstrate significant improvement compared with placebo at week 6 in PANSS total (-17.6 vs -14.5; P = .26) or CGI-S (-0.93 vs -0.73; P = .17) scores. Few dose-related adverse effects associated with lurasidone were observed. CONCLUSIONS: In adult patients with schizophrenia demonstrating nonresponse to 2 weeks of treatment with lurasidone 80 mg/d, dose increase to 160 mg/d resulted in significant symptom improvement compared with continuing lurasidone 80 mg/d. Lurasidone 20 mg/d was not associated with significant improvement in psychotic symptoms in adult patients with schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01821378.

Long-term safety and effectiveness of lurasidone in schizophrenia: a 22-month, open-label extension study.

OBJECTIVE: To evaluate the safety and effectiveness of lurasidone in the long-term treatment of patients with schizophrenia. METHODS: Patients 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. RESULTS: Of 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. CONCLUSIONS: In 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.

LURASIDONE IN THE LONG-TERM TREATMENT OF PATIENTS WITH BIPOLAR DISORDER: A 24-WEEK OPEN-LABEL EXTENSION STUDY.

BACKGROUND: The aim of this study was to evaluate the safety and tolerability of 6 months of open-label, uncontrolled extension treatment with lurasidone in patients with a diagnosis of bipolar depression who completed 6 weeks of acute treatment. METHODS: Patients completing 6 weeks of double-blind placebo-controlled treatment with either lurasidone monotherapy (one study) or adjunctive therapy with lithium or valproate (two studies), were treated for 6 months with flexible doses of lurasidone, 20-120 mg/day, in an open-label, uncontrolled extension study (N = 813; monotherapy, 38.9%; adjunctive therapy, 61.1%). Changes in safety parameters were calculated from double-blind, acute-phase baseline to month 6 of the extension phase, using a last observation carried forward (LOCF endpoint) analysis. RESULTS: Five hundred fifty-nine of 817 (68.4%) patients completed the extension study. In the monotherapy and adjunctive therapy groups, 6.9 and 9.0%, respectively, discontinued due to an adverse event. For the monotherapy and adjunctive therapy groups, respectively, changes from double-blind baseline to month 6 were +0.8 and +0.9 kg for weight (mean), 0.0 and +2.0 mg/dL for total cholesterol (median), +5.0 and +5.0 mg/dL for triglycerides (median), -1.0 and 0.0 mg/dL for glucose (median); -22.6 and -21.7 for Montgomery-Asberg Depression Rating Scale (MADRS; mean); whereas change from open-label baseline to month 6 were +0.85 and +0.88 kg for weight (mean), and -6.9 and -6.5 for MADRS (mean). CONCLUSIONS: Six months of treatment with open-label lurasidone was safe and well tolerated with minimal effect on weight and metabolic parameters; continued improvement in depressive symptoms was observed.

Major depressive disorder with subthreshold hypomania (mixed features): Clinical characteristics of patients entered in a multiregional, placebo-controlled study.

Major depressive disorder (MDD) associated with subthreshold hypomanic symptoms (mixed features), has been identified as a distinct nosological entity in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We identified the predominant manic symptoms present at baseline in a multiregional, placebo-controlled trial involving 211 patients with MDD with mixed features (Clinicaltrials.govNCT01421134). Patients with 2 or 3 DSM-5 criteria defined manic symptoms were eligible for the study. At study baseline, increased talkativeness (pressure to keep talking) and flight of ideas (racing thoughts) were endorsed by approximately 65% of patients and a decreased need for sleep was endorsed by 40% of patients. Approximately 60% of patients also endorsed irritability and distractibility at baseline although these symptoms are not generally counted as part of the "mixed" depression diagnosis as they may overlap with criteria for MDD. Thus, five clinical symptoms characterized the manic presentation in the majority of patients diagnosed as having MDD with "mixed" features in this first placebo-controlled trial examining the use of a psychotropic medication (lurasidone) in this population. Our findings support the designation of MDD with mixed features specifier and suggest that this subpopulation of depressed patients may warrant additional medication beyond antidepressants.

Lurasidone Dose Response in Bipolar Depression: A Population Dose-response Analysis.

PURPOSE: Characterization of dose-response relationships for psychotropic agents may be difficult to determine based on results of individual clinical studies, particularly those with a flexible dose design. The goal of this pharmacometric analysis was to characterize the dose-response profile for lurasidone in patients with bipolar depression. METHODS: The statistical modeling and simulation analyses reported here were derived from 2 randomized, 6-week, double-blind, placebo-controlled, flexible-dose studies (20-60 mg/d or 80-120 mg/d of lurasidone as monotherapy or 20-120 mg/d adjunct to lithium or valproate) in patients with bipolar depression. Pooled data included 5245 Montgomery-Åsberg Depression Rating Scale (MADRS) observations from 825 patients who had received lurasidone or placebo treatments, with or without lithium or valproate background medication. FINDINGS: The time course of placebo effect on the MADRS score was adequately described by an exponential asymptotic placebo model. A linear dose-response model best described the effect of lurasidone. The net improvement in MADRS score due to lurasidone treatment (the drug effect) was significant (P < 0.001), and a positive dose response was detected. Net drug effect after 6 weeks of treatment was estimated to be a 6.0-point decrease in MADRS score per 100 mg of lurasidone. Covariate effects (for age and lithium or valproate use) were significant only for placebo effect parameters; thus, no dose adjustment was necessary related to demographic covariates. IMPLICATIONS: This population dose-response modeling analysis indicates that higher doses of lurasidone are likely to produce greater therapeutic effects in patients with bipolar depression. The linear dose response was consistent for both lurasidone monotherapy and adjunctive therapy in patients with bipolar depression. ClinicalTrials.gov identifiers: NCT00868452, NCT00868699.

Lurasidone for the Treatment of Major Depressive Disorder With Mixed Features: A Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: Accumulating evidence indicates that manic symptoms below the threshold for hypomania (mixed features) are common in individuals with major depressive disorder. This form of depression is often severe and is associated with an increased risk for recurrence, suicide attempts, substance abuse, and functional disability. This study evaluated the efficacy and safety of lurasidone in major depressive disorder with mixed features. METHODS: Patients meeting DSM-IV-TR criteria for major depressive disorder who presented with two or three protocol-defined manic symptoms were randomly assigned to 6 weeks of double-blind treatment with either lurasidone at 20-60 mg/day (N=109) or placebo (N=100). Changes from baseline in Montgomery-Åsberg Depression Rating Scale score (MADRS; primary outcome measure) and Clinical Global Impressions severity subscale score (CGI-S; key secondary outcome measure) were evaluated using a mixed model for repeated-measures analysis. RESULTS: Lurasidone significantly improved depressive symptoms and overall illness severity, assessed by least squares mean change at week 6 in the MADRS and CGI-S scores: -20.5 compared with -13.0 (effect size, 0.80) and -1.8 compared with -1.2 (effect size, 0.60), respectively. Significant improvement in manic symptoms, assessed by the Young Mania Rating Scale, was also observed, in addition to other secondary efficacy endpoints. Rates of discontinuation due to adverse events were low. The most common adverse events were nausea (6.4% and 2.0% in the lurasidone and placebo groups, respectively) and somnolence (5.5% and 1.0%). CONCLUSIONS: Lurasidone was effective and well tolerated in this study involving patients with major depressive disorder associated with subthreshold hypomanic symptoms (mixed features).

A double-blind, placebo-controlled, randomized withdrawal study of lurasidone for the maintenance of efficacy in patients with schizophrenia.

OBJECTIVE: To evaluate the effectiveness of lurasidone as maintenance treatment for schizophrenia. METHOD: Adults experiencing an acute exacerbation of schizophrenia initially received 12-24 weeks of open-label treatment with lurasidone (40-80 mg/d, flexibly dosed). Patients who maintained clinical stability for ⩾12 weeks were randomized in double-blind fashion to placebo or lurasidone (40-80 mg/d, flexibly dosed) for an additional 28-week treatment period. The primary efficacy endpoint was time to relapse (based on Kaplan-Meier survival analysis). RESULTS: A total of 676 patients enrolled in the open-label phase; 285 met protocol-specified stabilization criteria and were randomized to lurasidone (N=144) or placebo (N=141). During the open-label phase, mean Positive and Negative Syndrome Scale total score decreased from 90.1 to 54.4 in patients who met clinical stability criteria and were randomized. In the double-blind phase, lurasidone significantly delayed time to relapse compared with placebo (log-rank test, p=0.039), reflecting a 33.7% reduction in risk of relapse (Cox hazard ratio (95% confidence interval), 0.663 (0.447-0.983); p=0.041). Probability of relapse at the double-blind week 28 endpoint (based on Kaplan-Meier analysis) was 42.2% in the lurasidone group and 51.2% in the placebo group. Minimal changes in weight, lipid, glucose, and prolactin were observed throughout the study. CONCLUSIONS: This multicenter, placebo-controlled, randomized withdrawal study demonstrated the efficacy of lurasidone for the maintenance treatment of patients with schizophrenia.

Treatment of early non-response in patients with schizophrenia: assessing the efficacy of antipsychotic dose escalation.

BACKGROUND: Early non-response to antipsychotic treatment in patients with schizophrenia has been shown in multiple studies to predict poor response at short-term trial endpoint. Therefore, strategies to address the challenge of non-improvement early in the course of treatment are needed. A novel trial design was developed to assess the potential utility of antipsychotic dose escalation in patients with an inadequate initial treatment response. This design was embedded in a study intended to assess the efficacy of low dose lurasidone in patients with schizophrenia. The purpose of this report is to describe the background, rationale and design of this study that included a novel method for the assessment of the potential for dose-response in early non-responding patients with schizophrenia. METHODS/DESIGN: In this 6-week, international, multicenter, double-blind trial, eligible adults with acute schizophrenia were randomized to receive fixed doses of lurasidone 20 mg/day, 80 mg/day (active control), or placebo in a 1:2:1 ratio. Patients initially randomized to lurasidone 80 mg/day who did not have a Positive and Negative Syndrome Scale total score improvement ≥ 20% at Week 2 were re-randomized on a 1:1 basis to receive either lurasidone 80 mg/day or lurasidone 160 mg/day for the remainder of the trial. All other groups remained on their initially assigned treatment. The formal primary objective of the study was to evaluate the efficacy of low-dose lurasidone (20 mg/day) compared to placebo; secondary objectives included evaluating the efficacy of lurasidone 80 mg/day versus 160 mg/day in early non-responders, and evaluating the efficacy of lurasidone in all subjects initially randomized to 80 mg/day versus placebo. DISCUSSION: Since a lack of early improvement predicts poor response to short-term antipsychotic treatment in patients with schizophrenia, several treatment strategies have been proposed to enhance treatment outcome in early non-responders. A novel clinical trial design involving a placebo arm and re-randomization of early non-responders to increased or maintained antipsychotic dose was developed. The study design described in this report provides a robust method to assess the value of antipsychotic dose escalation in patients with schizophrenia who demonstrate poor initial treatment response. TRIAL REGISTRATION: ClinicalTrials.gov NCT01821378; initial registration March 22, 2013.

Recovery in bipolar depression: Post-hoc analysis of a placebo-controlled lurasidone trial followed by a long-term continuation study.

BACKGROUND: In this post-hoc analysis, rates of remission and recovery were evaluated in patients with bipolar depression treated with lurasidone. METHODS: Outpatients meeting DSM-IV-TR criteria for bipolar I depression, were randomized to 6 weeks of once-daily, double-blind treatment with lurasidone 20-60mg, lurasidone 80-120mg or placebo, followed by a 6-month, open-label, flexible-dose, lurasidone continuation study. Recovery was defined as meeting criteria for combined symptomatic remission (Montgomery-Asberg Depression Rating Scale total score ≤12) and functional remission (all Sheehan Disability Scale domain scores ≤3) sustained for at least 3 months in the 6-month continuation study. RESULTS: A significantly higher proportion of lurasidone-treated patients met criteria for combined symptomatic remission and functional remission (33.3%, 91/273) compared to the placebo group (21.0%, 30/143, p<0.05, NNT=9) at the 6-week study endpoint. In the 6-month continuation study, the proportion of lurasidone-treated patients achieving sustained recovery was 60.7% (85/140) and 44.9% (31/69), for patients who continued lurasidone treatment and who switched from placebo to lurasidone, respectively. LIMITATIONS: The definition of recovery used has not been previously validated and the analysis was post hoc. Lack of a control group in the continuation study limits data interpretation. CONCLUSIONS: Recovery in patients with bipolar depression was assessed based on rates of combined symptomatic and functional remission sustained over time. A majority of patients initially treated with lurasidone in the acute phase achieved recovery status in the continuation study. Treatment with lurasidone (vs. placebo) earlier in the course of the bipolar depressive episode increased the likelihood of subsequent recovery.

Weight change during long-term treatment with lurasidone: pooled analysis of studies in patients with schizophrenia.

The objective of this analysis was to evaluate the effect of 12 months of treatment with lurasidone on weight in patients with schizophrenia. Post-hoc, observed-case analysis included pooled data from six studies on 40-160 mg/day lurasidone; two studies included active comparators (2-6 mg/day risperidone or 200-800 mg/day quetiapine XR). Overall, 593 patients completed 12 months of treatment (N=471 lurasidone, N = 89 risperidone, N = 33 quetiapine XR). The mean baseline weight was 72.8, 80.8, and 72.4 kg in the lurasidone, risperidone, and quetiapine XR groups, respectively. The mean weight change at month 12 was -0.4 kg with lurasidone, +2.6 kg with risperidone, and +1.2 kg with quetiapine XR. Weight gain of at least 7% from study baseline was observed in 16.0, 25.8, and 15.2% of patients, and weight loss of at least 7% was seen in 18.5, 6.7, and 9.1% of patients treated with lurasidone, risperidone, and quetiapine XR, respectively. A shift from normal/underweight baseline BMI status to overweight/obese at month 12 occurred in 10.2, 27.6, and 15.0% of patients in the lurasidone, risperidone, and quetiapine XR groups, respectively. Conversely, 14.3, 1.7, and 7.7% of patients, respectively, shifted from overweight/obese to normal/underweight. In summary, a low potential for clinically significant weight gain was observed in patients with schizophrenia treated continuously with lurasidone for 12 months.

Lurasidone in the treatment of bipolar depression with mixed (subsyndromal hypomanic) features: post hoc analysis of a randomized placebo-controlled trial.

OBJECTIVE: Mixed (subsyndromal hypomanic) features are prevalent in patients with bipolar depression and are associated with more severe and complex illness, including increased risk for suicide attempts, higher switch to mania during antidepressant therapy, and a higher rate of recurrence. The aim of this post hoc analysis was to evaluate the efficacy and safety of lurasidone in the treatment of patients with bipolar depression presenting with mixed features. METHOD: Patients with a DSM-IV-TR diagnosis of major depressive episode associated with bipolar I disorder, with or without rapid cycling, and with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 20 and a Young Mania Rating Scale (YMRS) score ≤ 12 were randomly assigned to 6 weeks of double-blind, once-daily treatment with lurasidone 20-60 mg, lurasidone 80-120 mg, or placebo. The presence of mixed features was defined as a YMRS score ≥ 4 at study baseline. Efficacy analyses included change in MADRS total score from baseline to week 6 (the primary outcome in the original study, conducted between April 2009 and February 2012). RESULTS: At baseline, mixed features were present in 56% of patients (lurasidone, n = 182/323; placebo, n = 90/162). Treatment with lurasidone (vs placebo) was associated with significantly greater reductions in MADRS scores in the mixed features group (-15.7 vs -10.9; P = .001; week 6; mixed model for repeated measures [MMRM]; effect size, 0.48) and in the group without mixed features (-15.2 vs -10.8; P = .002; week 6; MMRM; effect size, 0.48). Rates of protocol-defined treatment-emergent hypomania or mania were similar for patients with mixed features (lurasidone, 2.2%; placebo, 3.2%) and without mixed features (lurasidone, 3.4%; placebo, 0.0%). CONCLUSIONS: Lurasidone was found in this post hoc analysis to be efficacious in the treatment of patients with bipolar depression who present with mixed features (assessed cross-sectionally at study baseline). No increased risk of treatment-emergent mania was observed in either group. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00868699.

The development of lurasidone for bipolar depression.

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.

Lurasidone for the treatment of depressive symptoms in schizophrenia: analysis of 4 pooled, 6-week, placebo-controlled studies.

OBJECTIVE: Depressive symptoms are common in schizophrenia and can worsen outcomes and increase suicide risk. Lurasidone is an atypical antipsychotic agent indicated for the treatment of schizophrenia and for the treatment of major depressive episodes associated with bipolar I disorder. This post hoc analysis evaluated the effect of lurasidone on depressive symptoms in patients with schizophrenia. METHODS: Patient-level data were pooled from 4 similarly designed, double-blind, placebo-controlled, 6-week registration studies of lurasidone (40-160 mg/d) in adult patients with an acute exacerbation of schizophrenia. Changes in depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), were analyzed for the overall sample and for subgroups of patients stratified by baseline MADRS scores. RESULTS: MADRS assessments at baseline and endpoint (day 42 or last observation carried forward [LOCF]) were available for 1330 patients. Patients receiving lurasidone experienced significantly greater decreases in MADRS score (-2.8, least-squares [LS] mean change, LOCF) compared with patients receiving placebo (-1.4, P < .001, effect size 0.24). Analysis of change in MADRS score (LOCF) by baseline symptom severity (MADRS score of ≥12, ≥14, ≥16, ≥18) showed significantly greater improvement for lurasidone-treated patients across all severity groups; effect sizes ranged from 0.25 to 0.34. Among patients with a baseline MADRS score of ≥12, depressive symptom remission (defined as MADRS score <10 at LOCF endpoint) was attained by 45.0% of lurasidone-treated patients and 36.3% of patients receiving placebo (P < .05). CONCLUSIONS: In a pooled analysis of short-term, placebo-controlled studies, lurasidone significantly improved depressive symptoms in patients with schizophrenia.

Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: The authors evaluated the efficacy and safety of lurasidone in the treatment of patients with major depressive episodes associated with bipolar I disorder. METHOD: Patients were randomly assigned to receive double-blind treatment with lurasidone (20-60 mg/day [N=166] or 80-120 mg/day [N=169]) or placebo (N=170) for 6 weeks. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively. RESULTS: Lurasidone treatment significantly reduced mean MADRS total scores at week 6 for both the 20-60 mg/day group (-15.4; effect size=0.51) and the 80-120 mg/day group (-15.4; effect size=0.51) compared with placebo (-10.7). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores for both the 20-60 mg/day group (-1.8; effect size=0.61) and the 80-120 mg/day group (-1.7; effect size=0.50) compared with placebo (-1.1). Both lurasidone groups also experienced significant improvements compared with placebo in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were similar in the 20-60 mg/day (6.6%), 80-120 mg/day (5.9%), and placebo (6.5%) groups. The most frequent adverse events associated with lurasidone were nausea, headache, akathisia, and somnolence. Minimal changes in weight, lipids, and measures of glycemic control were observed with lurasidone. CONCLUSION: Monotherapy with lurasidone in the dosage range of 20-120 mg/day significantly reduced depressive symptoms in patients with bipolar I depression. Lurasidone was well tolerated, with few changes in weight or metabolic parameters.