Yongcai Mao

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).

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.

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.

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.

Efficacy of lurasidone across five symptom dimensions of schizophrenia: Pooled analysis of short-term, placebo-controlled studies

OBJECTIVE To evaluate the efficacy of lurasidone for schizophrenia using an established five-factor model of the Positive and Negative Syndrome Scale (PANSS). METHODS Patient-level data were pooled from five randomized, double-blind, placebo-controlled, 6-week studies of lurasidone (fixed doses, 40-160mg/d) for patients with an acute exacerbation of schizophrenia. Changes in five established PANSS factors were assessed using mixed-model repeated measures analysis. RESULTS Compared with placebo (n=496), lurasidone (n=1029, dose groups pooled) significantly improved the PANSS total score at Week 6 (-22.6 vs. -12.8; P<0.001; effect size, 0.45), as well as all factor scores (P<0.001 for each): positive symptoms (-8.4 vs. -6.0; effect size, 0.43), negative symptoms (-5.2 vs. -3.3; effect size, 0.33), disorganized thought (-4.9 vs. -2.8; effect size, 0.42), hostility/excitement (-2.7 vs. -1.6; effect size, 0.31), and depression/anxiety (-3.2 vs. -2.3; effect size, 0.31). Separation from placebo occurred at Week 1 for the positive symptoms, disorganized thought, and hostility/excitement factors and at Week 2 for the other factors. CONCLUSIONS In this pooled analysis of short-term studies in patients with acute schizophrenia, lurasidone demonstrated significant improvement for each of the five PANSS factor scores, indicating effectiveness across the spectrum of schizophrenia symptoms.

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.

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.

Lurasidone in post-menopausal females with major depressive disorder with mixed features: Post-hoc analysis of a placebo-controlled trial

Background: Several studies have found that depressed, post‐menopausal females may respond differently to antidepressants compared to pre‐menopausal females. The atypical antipsychotic lurasidone, whose mechanism of action differs from SSRIs and other standard antidepressants, was shown in a 6‐week randomized, flexible‐dose, placebo‐controlled study (n = 209), to be effective in treating major depressive disorder (MDD) with mixed features (subthreshold hypomanic symptoms). This post‐hoc analysis assessed the efficacy of lurasidone in this study by menopausal status. Methods: The main outcome measure for this post‐hoc analysis was change in MADRS score from baseline to week 6 endpoint for two lurasidone‐treated subgroups: presumptive pre‐menopausal (< 52 years) and presumptive post‐menopausal (≥ 52 years) patients, compared to placebo treatment, using a mixed‐model for repeated‐measures analysis, and calculation of the effect size for each subgroup. Additional efficacy assessments included the CGI‐S, HAM‐A and YMRS. An exploratory analysis was also conducted removing presumptive peri‐menopausal women (ages 45–51 years) to allow for clearer definition of pre‐ and post‐menopausal status. Results: A total of 56 lurasidone‐treated and 47 placebo‐treated pre‐menopausal females, and 17 lurasidone‐treated and 25 placebo‐treated post‐menopausal females were available from the larger study for comparison on key outcome measures. The pre‐ and post‐menopausal subgroups had similar demographic and clinical characteristics at study baseline (other than age), including number of past major depressive episodes as well as depressive and manic symptom severity. Mean daily lurasidone dose was similar for each subgroup during the study. Both the primary and exploratory analyses showed that both lurasidone‐treated post‐menopausal and pre‐menopausal females responded significantly compared to placebo (p = 0.016 or less) on the MADRS, and that post‐menopausal patients had a numerically larger response (effect size = 0.96) than pre‐menopausal patients (effect size = 0.64). All other secondary outcome measures for lurasidone compared with placebo treatment were significant (p = 0.045 or less) for both subgroups. Conclusions: In this post‐hoc analysis, lurasidone was found to be effective in treating post‐menopausal MDD patients with mixed features (subthreshold hypomanic symptoms). HIGHLIGHTSWe performed post‐hoc analysis to assess efficacy of lurasidone by menopausal status.Post‐menopausal and younger females responded significantly versus placebo on MADRS.Post‐menopausal patients had better response than younger patients.Lurasidone effectively treated MDD in both post‐menopausal and younger females.