A Non-D2-Receptor-Binding Drug for the Treatment of Schizophrenia.

BACKGROUND: An oral compound, SEP-363856, that does not act on dopamine D2 receptors but has agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) receptors, may represent a new class of psychotropic agent for the treatment of psychosis in schizophrenia. METHODS: We performed a randomized, controlled trial to evaluate the efficacy and safety of SEP-363856 in adults with an acute exacerbation of schizophrenia. The patients were randomly assigned in a 1:1 ratio to receive once-daily treatment with SEP-363856 (50 mg or 75 mg) or placebo for 4 weeks. The primary end point was the change from baseline in the total score on the Positive and Negative Symptom Scale (PANSS; range, 30 to 210; higher scores indicate more severe psychotic symptoms) at week 4. There were eight secondary end points, including the changes from baseline in the scores on the Clinical Global Impressions Severity (CGI-S) scale and the Brief Negative Symptom Scale (BNSS). RESULTS: A total of 120 patients were assigned to the SEP-363856 group and 125 to the placebo group. The mean total score on the PANSS at baseline was 101.4 in the SEP-363856 group and 99.7 in the placebo group, and the mean change at week 4 was -17.2 points and -9.7 points, respectively (least-squares mean difference, -7.5 points; 95% confidence interval, -11.9 to -3.0; P = 0.001). The reductions in the CGI-S and BNSS scores at week 4 were generally in the same direction as those for the primary outcome, but the results were not adjusted for multiple comparisons. Adverse events with SEP-363856 included somnolence and gastrointestinal symptoms; one sudden cardiac death occurred in the SEP-363856 group. The incidence of extrapyramidal symptoms and changes in the levels of lipids, glycated hemoglobin, and prolactin were similar in the trial groups. CONCLUSIONS: In this 4-week trial involving patients with an acute exacerbation of schizophrenia, SEP-363856, a non-D2-receptor-binding antipsychotic drug, resulted in a greater reduction from baseline in the PANSS total score than placebo. Longer and larger trials are necessary to confirm the effects and side effects of SEP-363856, as well as its efficacy relative to existing drug treatments for patients with schizophrenia. (Funded by Sunovion Pharmaceuticals; ClinicalTrials.gov number, NCT02969382.).

Efficacy and safety of dasotraline in adults with binge-eating disorder: a randomized, placebo-controlled, fixed-dose clinical trial.

OBJECTIVE: The aim of this fixed-dose study was to evaluate the efficacy and safety of dasotraline in the treatment of patients with binge-eating disorder (BED). METHODS: Patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for BED were randomized to 12 weeks of double-blind treatment with fixed doses of dasotraline (4 and 6 mg/d), or placebo. The primary efficacy endpoint was change in number of binge-eating (BE) days per week at week 12. Secondary efficacy endpoints included week 12 change on the BE CGI-Severity Scale (BE-CGI-S) and the Yale-Brown Obsessive-Compulsive Scale Modified for BE (YBOCS-BE). RESULTS: At week 12, treatment with dasotraline was associated with significant improvement in number of BE days per week on the dose of 6 mg/d (N = 162) vs placebo (N = 162; -3.47 vs -2.92; P = .0045), but not 4 mg/d (N = 161; -3.21). Improvement vs placebo was observed for dasotraline 6 and 4 mg/d, respectively, on the BE-CGI-S (effect size [ES]: 0.37 and 0.27) and on the YBOCS-BE total score (ES: 0.43 and 0.29). The most common adverse events on dasotraline were insomnia, dry mouth, headache, decreased appetite, nausea, and anxiety. Changes in blood pressure and pulse were minimal. CONCLUSION: Treatment with dasotraline 6 mg/d (but not 4 mg/d) was associated with significantly greater reduction in BE days per week. Both doses of dasotraline were generally safe and well-tolerated and resulted in global improvement on the BE-CGI-S, as well as improvement in BE related obsessional thoughts and compulsive behaviors on the YBOCS-BE. These results confirm the findings of a previous flexible dose study.

Efficacy and tolerability of atypical antipsychotics for acute bipolar depression: a network meta-analysis.

BACKGROUND: While clinical trial evidence has firmly established the efficacy of several atypical antipsychotics (AAPs) for treating bipolar depression, no randomized controlled trials (RCT's) comparing AAPs have been conducted. This Bayesian network meta-analysis (NMA) compared the relative efficacy and tolerability of AAP monotherapy in adults with bipolar depression. METHODS: Efficacy measures included change in Montgomery Åsberg Depression Rating Scale (MADRS), Clinical Global Improvement - Bipolar Disorder (CGI-BP), response, and remission. Multiple tolerability outcomes were examined. Results from random effects models were reported as difference in change from baseline for continuous variables or odds ratios for dichotomous variables. Treatments were ranked using the surface under the curve cumulative ranking probabilities. Number needed to treat (NNT) and harm (NNH) were calculated. RESULTS: Eighteen RCT's met inclusion criteria of the systematic literature review. On change in MADRS, lurasidone (- 4.71 [95% Crl - 6.98, - 2.41]), quetiapine (- 4.80 [- 5.93, - 3.72]), olanzapine (- 4.57 [- 5.92, - 3.20]), and cariprazine (- 2.29 [- 3.47, - 1.09]) were more efficacious than placebo. Lurasidone was associated with a significantly greater odds of response (≥50% improvement in MADRS) compared to cariprazine (1.78 [95% Crl 1.08, 2.77]), aripiprazole (2.38 [1.38, 3.85]), and ziprasidone (2.47 [1.41, 3.98]), but was similar to olanzapine (1.68 [0.99,2.65]) and quetiapine (1.25 [0.78, 1.90]). For change in CGI-BP-S-overall score, lurasidone was significantly better than cariprazine (- 0.38 [95% Crl - 0.66,-0.10]) and ziprasidone (- 0.58 [- 0.91,-0.26]), but similar to quetiapine (- 0.08 [- 0.36, 0.19])and olanzapine (- 0.04 [- 1.41, 1.46]). Lurasidone (0.34 kg [95% Crl - 0.22, 0.89]) and aripiprazole (0.20 kg [- 0.59, 1.00]) had a similar weight change compared to placebo, but olanzapine (2.88 kg [2.40, 3.36]), quetiapine (1.17 kg [0.84, 1.49]), and cariprazine (0.65 kg [0.34, 0.96]) were associated with greater weight gain. The NNT for response was the lowest for lurasidone (NNT = 5) followed by quetiapine (NNT = 6), olanzapine (NNT = 10) and cariprazine (NNT = 12). CONCLUSIONS: In this NMA in adults with bipolar depression, which evaluated change in depressive symptoms (assessed by MADRS) across short-term trials, the largest improvement versus placebo was observed for lurasidone, olanzapine and quetiapine with cariprazine, showing a smaller treatment effect. Aripiprazole and ziprasidone were ineffective for the treatment of bipolar depression. Improvement in CGI-BP-S score for lurasidone was larger than cariprazine and ziprasidone but similar to quetiapine and olanzapine. Based on short term studies lurasidone and aripiprazole had similar weight gain compared to placebo.

C-reactive protein and response to lurasidone treatment in children and adolescents with bipolar I depression: Results from a placebo-controlled trial.

This study sought to investigate associations between levels of high-sensitivity c-reactive protein (hsCRP) prior to treatment and change in depressive symptoms and cognition in a short-term, double-blind, placebo-controlled study of lurasidone in children and adolescents with bipolar I depression. Patients 10-17 years of age with a DSM-5 diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with flexibly dosed lurasidone (20-80 mg/day) (n = 173) or placebo (n = 170). The primary efficacy measure was change from baseline to week 6 in the Children's Depression Rating Scale, Revised (CDRS-R). Treatment response was defined as 50% or greater improvement on the CDRS-R from baseline to week 6. Cognitive function was evaluated with the computerized Brief Cogstate Battery at baseline and week 6. Analyses were adjusted for baseline BMI, as well as age. HsCRP was evaluated as a logarithmically transformed continuous variable and as a categorical variable dichotomized into lower (<1 mg/L) and higher (≥1 mg/L) subgroups. A significant interaction was found between baseline hsCRP and treatment group for change in CDRS-R score at study endpoint, with larger placebo-corrected effect sizes for lurasidone in the higher baseline hsCRP group (≥1 mg/L). A significant BMI-by-hsCRP-by-treatment interaction was found for response rate with higher baseline hsCRP levels associated with greater antidepressant response to lurasidone (vs. placebo) in the normal BMI range subgroup (NNT = 2 in higher hsCRP vs. NNT = 5 in lower hsCRP groups) but not in the overweight/obese patients (NNT = 6 in higher hsCRP vs. NNT = 5 in lower hsCRP). Similarly, a significant interaction effect was observed for the combination of hsCRP and BMI on the procognitive effect of lurasidone, with higher baseline hsCRP levels being associated with improvement in cognitive function for lurasidone (vs placebo) in the normal BMI range subgroup but not in overweight/obese patients. These results suggest that young patients with bipolar depression with normal weight and higher levels of pre-treatment CRP may show a greater placebo-adjusted improvement in depressive symptoms and cognitive performance when treated with lurasidone. If these findings are confirmed in future prospective studies, CRP and BMI may prove to be useful diagnostic and predictive biomarkers in the treatment with lurasidone of children and adolescents with bipolar depression.

Lurasidone and risk for metabolic syndrome: results from short- and long-term clinical studies in patients with schizophrenia.

OBJECTIVE: To assess the effects of treatment with lurasidone on risk for metabolic syndrome (MetS) in patients with schizophrenia. METHODS: Rates of metabolic syndrome during treatment with lurasidone (40-160 mg/d) were analyzed using pooled, short-term data from three randomized, double-blind, placebo-controlled studies (vs olanzapine and quetiapine XR); long-term data from two active-comparator-controlled studies (vs risperidone and quetiapine XR); and data from two open-label studies in which patients were switched from olanzapine or risperidone to lurasidone. RESULTS: MetS was defined based on the National Cholesterol Education Program criteria. In short-term studies, the odds of meeting criteria for MetS at week 6 LOCF (adjusted for baseline metabolic syndrome status) was similar for the lurasidone and placebo groups (OR = 1.18; [95% CI, 0.81-1.71]; P = .39), but the odds (vs placebo) were significantly greater for olanzapine (OR = 2.81; [95% CI, 1.53-5.15]; P < .001) and quetiapine (OR = 3.49; [95% CI, 1.93-6.29]; P < .0001). No dose effect was observed for lurasidone across the dose range of 40-160 mg/d. In long-term studies, the odds of MetS after 12 months of treatment was significantly higher for risperidone compared with lurasidone (OR = 2.12; 95% CI, 1.15-3.90; P = .016) and for quetiapine XR compared with lurasidone (OR = 3.92; 95% CI, 1.15-13.40; P = .029). In open-label extension studies, the rate of MetS decreased in patients switched to lurasidone after 6 weeks of treatment with olanzapine or 12 months of treatment with risperidone. CONCLUSION: In this analysis of lurasidone clinical trials, the odds of developing metabolic syndrome were minimal during short- and long-term treatment with lurasidone (40-160 mg/d).

Switching to Lurasidone following 12 months of treatment with Risperidone: results of a 6-month, open-label study.

BACKGROUND: Patients with a diagnosis of schizophrenia are at an increased risk for developing metabolic syndrome, which is associated with greater cardiovascular morbidity and mortality. Treatment with some commonly used antipsychotic medications may increase the risk of developing metabolic syndrome. The aim of the study was to evaluate the safety of lurasidone in patients who continued lurasidone or switched from risperidone to lurasidone. A secondary aim was assessment of the effect of long-term lurasidone on the Positive and Negative Syndrome Scale (PANSS). METHODS: The treatment sample in the current study consisted of clinically stable patients with schizophrenia (N = 223) who had completed a 12-month, double-blind study of lurasidone vs. risperidone. In the current extension study, all patients received 6 months of open-label treatment with lurasidone, either continuing lurasidone assigned during the preceding double-blind trial, or switching from double-blind risperidone to lurasidone. Safety and tolerability parameters included body weight, prolactin, and metabolic laboratory tests. RESULTS: Six months of OL treatment with lurasidone was generally well-tolerated, with a low incidence of parkinsonism (4.5%) and akathisia (3.1%). Overall, few adverse events were rated as severe (4.9%), and discontinuation due to an adverse event was low in the lurasidone continuation vs. risperidone switch groups (3.7% vs. 6.9%). In the lurasidone continuation versus risperidone switch groups, change from OL baseline to 6-month endpoint (observed case) was observed in mean body weight (- 0.6 vs. -2.6 kg), median total cholesterol (- 4.0 vs. + 4.5 mg/dL), triglycerides (- 4.5 vs. -5.5 mg/dL), glucose (0.0 vs. -3.0 mg/dL) and prolactin (males, + 0.15 vs. -11.2 ng/mL; females, + 1.3 vs. -30.8 ng/mL). Improvement in PANSS total score was maintained, from OL baseline to endpoint in the continuation vs. switch groups (+ 1.0 vs. -1.0; OC). CONCLUSIONS: In this 6-month extension study, lurasidone treatment was generally well-tolerated and associated with minimal effects on weight, metabolic parameters, and prolactin levels. Patients who switched from risperidone to lurasidone experienced reductions in weight, metabolic parameters and prolactin levels commensurate with increases in these safety parameters experienced during the previous 12 months of treatment with risperidone. TRIAL REGISTRATION: ClinicalTrials.gov NCT00641745 (Date of Registration: March 24, 2008).

Association of C-reactive protein and metabolic risk with cognitive effects of lurasidone in patients with schizophrenia.

BACKGROUND: Accumulating evidence has implicated insulin resistance and inflammation in the pathophysiology of cognitive impairments associated with neuropsychiatric disorders. This post-hoc analysis based on a placebo-controlled trial investigated the effect of inflammation (indexed by CRP) and metabolic risk factors on cognitive performance in patients with schizophrenia treated with lurasidone. METHODS: Acutely exacerbated patients with schizophrenia were randomized to lurasidone (80 or 160 mg/day), quetiapine XR 600 mg/day, or placebo. A wide range CRP test and a cognitive assessment using the CogState computerized battery were performed at baseline and week 6 study endpoint. Associations between log-transformed CRP, high density lipoprotein (HDL), homeostatic model assessment of insulin resistance (HOMA-IR) and treatment response were evaluated. RESULTS: CRP combined with HDL, triglyceride-to-HDL (TG/HDL) ratio, or HOMA-IR at study baseline were significant moderators of the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment (p < .05). Greater placebo-corrected treatment effect size on the CogState composite score was observed for patients in the lurasidone 160 mg/day treatment group who had either low CRP and high HDL (d = 0.43), or low CRP and low HOMA-IR (d = 0.46). Interactive relationships between CRP, HDL, TG/HDL, HOMA-IR and the antipsychotic efficacy of lurasidone or quetiapine XR were not significant. There were no significant associations between antipsychotic treatment and changes in CRP level at study endpoint. CONCLUSIONS: Findings of this post-hoc analysis based on a placebo-controlled trial in patients with schizophrenia suggest that baseline CRP level combined with measures of metabolic risk significantly moderated the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment. Our findings underscore the importance of maintaining a low metabolic risk profile in patients with schizophrenia.

Lurasidone compared to other atypical antipsychotic monotherapies for adolescent schizophrenia: a systematic literature review and network meta-analysis.

This network meta-analysis assessed the efficacy and tolerability of lurasidone versus other oral atypical antipsychotic monotherapies in adolescent schizophrenia. A systematic literature review identified 13 randomized controlled trials of antipsychotics in adolescents with schizophrenia-spectrum disorders. A Bayesian network meta-analysis compared lurasidone to aripiprazole, asenapine, clozapine, olanzapine, paliperidone extended-release (ER), quetiapine, risperidone, and ziprasidone. Outcomes included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), weight gain, all-cause discontinuation, extrapyramidal symptoms (EPS), and akathisia. Results were reported as median differences for continuous outcomes and odds ratios (ORs) for binary outcomes, along with 95% credible intervals (95% CrI). Lurasidone was significantly more efficacious than placebo on the PANSS (- 7.95, 95% CrI - 11.76 to - 4.16) and CGI-S (- 0.44, 95% CrI - 0.67 to - 0.22) scores. Lurasidone was associated with similar weight gain to placebo and statistically significantly less weight gain versus olanzapine (- 3.62 kg, 95% CrI - 4.84 kg to - 2.41 kg), quetiapine (- 2.13 kg, 95% CrI - 3.20 kg to - 1.08 kg), risperidone (- 1.16 kg, 95% CrI - 2.14 kg to - 0.17 kg), asenapine (- 0.98 kg, 95% CrI - 1.71 kg to - 0.24 kg), and paliperidone ER (- 0.85 kg, 95% CrI - 1.57 kg to - 0.14 kg). The odds of all-cause discontinuation were significantly lower for lurasidone than aripiprazole (OR = 0.28, 95% CrI 0.10-0.76) and paliperidone ER (OR = 0.25, 95% CrI 0.08-0.81) and comparable to other antipsychotics. Rates of EPS and akathisia were similar for lurasidone and other atypical antipsychotics. In this network meta-analysis of atypical antipsychotics in adolescent schizophrenia, lurasidone was associated with similar efficacy, less weight gain, and lower risk of all-cause discontinuation compared to other oral atypical 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.

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.

Hospitalization outcomes in patients with schizophrenia after switching to lurasidone or quetiapine: a US claims database analysis.

BACKGROUND: This study compared hospital admission rates among adult patients with schizophrenia who switched to antipsychotic monotherapy with lurasidone or quetiapine. METHODS: This retrospective cohort study used U.S.-based Truven Health MarketScan® Medicaid Multi-State Database (April 2010 through December 2012) and MarketScan® Commercial Claims and Encounters Database (April 2010 through October 2013). Continuous enrollment for 6-months before and after medication initiation was required. Treatment episodes ended after 6-months post lurasidone or quetiapine initiation, a 60-day treatment gap, or initiation of another antipsychotic. Length of treatment episodes (i.e., treatment duration) was compared using a t-test. All-cause, mental-health, and schizophrenia-related hospitalization rates, as well as costs, were compared between lurasidone- and quetiapine-treated patients using multivariable generalized linear models that adjusted for background characteristics. RESULTS: Quetiapine (n = 435) compared to lurasidone (n = 238) treatment was associated with increased all-cause (21% vs 13%, p < 0.05) and mental health-related hospitalizations (20% vs 12%, p < 0.05), but similar rates of schizophrenia-related hospitalizations (14% vs. 10%, p = 0.14). After adjusting for baseline covariates, quetiapine had 64% higher likelihood of all-cause hospitalizations (OR [odds ratio] = 1.64, 95% confidence interval [CI] 1.05-2.57, p = 0.03), 74% higher likelihood of mental health-related hospitalizations (OR = 1.74, 95% CI 1.11-2.75, p = 0.02), and a similar likelihood of schizophrenia-related hospitalization (OR = 1.35, 95% CI 0.82-2.22, p = 0.24). For those with hospital admissions, adjusted all-cause admission costs were higher for quetiapine when compared with lurasidone in both the Medicaid ($22,036 vs. $15,424, p = 0.17) and commercial populations ($23,490 vs. $20,049, p = 0.61). These differences were not significant. The length of treatment episodes was significantly shorter for quetiapine than lurasidone (115.4 vs 123.1 days, p < 0.05). CONCLUSIONS: In this retrospective claims database study, patients with schizophrenia who were switched to lurasidone had significantly fewer all-cause and mental health-related hospitalizations and similar rates of schizophrenia-related hospitalization compared with those switched to quetiapine. Patients switching to lurasidone had a significantly longer treatment duration rate than those switching to quetiapine. These results may reflect differences in efficacy or tolerability between lurasidone and quetiapine.

Socioeconomic Disparities and Metabolic Risk in Veterans with Serious Mental Illness.

Socioeconomic disparities were assessed in predicting metabolic risk among veterans with serious mental illness. Veterans with schizophrenia, schizoaffective, or bipolar disorders were identified in VISN 4 facilities from 10/1/2010 to 9/30/2012. Differences between patients with and without metabolic syndrome were compared using t-tests, Chi square tests and multivariate logistic regressions. Among 10,132 veterans with mental illness, 48.8% had metabolic syndrome. Multivariate logistic regression analysis confirmed that patients with metabolic syndrome were significantly more likely to be older, male, African-American, married, and receiving disability pensions but less likely to be homeless. They were more likely to receive antipsychotics, antidepressants, or anticonvulsants. Bivariate cross-sectional analysis revealed that patients with metabolic syndrome had higher rates of coronary artery disease, cerebrovascular disease, and mortality, and that metabolic syndrome was more often associated with emergency visits and psychiatric or medical hospitalizations. Demographics, socioeconomic status and medications are independent predictors of metabolic syndrome and should be considered in broader screening of risk factors in order to provide preventive interventions for metabolic syndrome.

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 for major depressive disorder with mixed features and irritability: a post-hoc analysis.

OBJECTIVE: The aim of this post-hoc analysis was to evaluate the efficacy of lurasidone in treating major depressive disorder (MDD) with mixed features including irritability. METHODS: The data in this analysis were derived from a study of patients meeting 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, and who were randomized to 6 weeks of double-blind treatment with either lurasidone 20-60 mg/d (n=109) or placebo (n=100). We defined "irritability" as a score ≥2 on both the Young Mania Rating Scale (YMRS) irritability item (#5) and the disruptive-aggressive item (#9). Endpoint change in the MADRS and YMRS items 5 and 9 were analyzed using a mixed model for repeated measures for patients with and without irritability. RESULTS: Some 20.7% of patients met the criteria for irritability. Treatment with lurasidone was associated with a significant week 6 change vs. placebo in MADRS score in both patients with (-22.6 vs. -9.5, p<0.0001, effect size [ES]=1.4) and without (-19.9 vs. -13.8, p<0.0001, ES=0.7) irritability. In patients with irritable features, treatment with lurasidone was associated with significant week 6 changes vs. placebo in both the YMRS irritability item (-1.4 vs. -0.3, p=0.0012, ES=1.0) and the YMRS disruptive-aggressive item (-1.0 vs. -0.3, p=0.0002, ES=1.2). CONCLUSIONS: In our post-hoc analysis of a randomized, placebo-controlled, 6-week trial, treatment with lurasidone significantly improved depressive symptoms in MDD patients with mixed features including irritability. In addition, irritability symptoms significantly improved in patients treated with lurasidone.

Remission and recovery associated with lurasidone in the treatment of major depressive disorder with subthreshold hypomanic symptoms (mixed features): post-hoc analysis of a randomized, placebo-controlled study with longer-term extension.

OBJECTIVE: This post-hoc analysis assessed rates of symptomatic and functional remission, as well as recovery (combination of symptomatic and functional remission), in patients treated with lurasidone for major depressive disorder (MDD) associated with subthreshold hypomanic symptoms (mixed features). METHOD: Patients with MDD plus two or three manic symptoms (defined as per the DSM-5 mixed-features specifier) were randomly assigned to flexible-dose lurasidone 20-60 mg/day (n=109) or placebo (n=100) for 6 weeks, followed by a 3-month open-label, flexible-dose extension study for U.S. sites only (n=48). Cross-sectional recovery was defined as the presence of both symptomatic remission (Montgomery-Åsberg Depression Rating Scale score ≤ 12) and functional remission (all Sheehan Disability Scale [SDS] domain scores ≤3) at week 6, and at both months 1 and 3 of the extension study ("sustained recovery"). RESULTS: A significantly higher proportion of lurasidone-treated patients (31.3%) achieved recovery (assessed cross-sectionally) compared to placebo (12.2%, p=0.002) at week 6. The number of manic symptoms at baseline moderated the effect size for attaining cross-sectional recovery for lurasidone treatment (vs. placebo) (p=0.028). Sustained recovery rates were higher in patients initially treated with lurasidone (20.8%) versus placebo (12.5%). CONCLUSIONS: In this post-hoc analysis of a placebo-controlled study with open-label extension that involved patients with MDD and mixed features, lurasidone was found to significantly improve the rate of recovery at 6 weeks (vs. placebo) that was sustained at month 3 of the extension study. The presence of two (as opposed to three) manic symptoms moderated recovery at the acute study endpoint.

Weight changes before and after lurasidone treatment: a real-world analysis using electronic health records.

BACKGROUND: Severe and persistent mental illnesses, such as schizophrenia and bipolar disorder, are associated with increased risk of obesity compared to the general population. While the association of lurasidone and lower risk of weight gain has been established in short and longer-term clinical trial settings, information about lurasidone's association with weight gain in usual clinical care is limited. This analysis of usual clinical care evaluated weight changes associated with lurasidone treatment in patients with schizophrenia or bipolar disorder. METHODS: A retrospective, longitudinal analysis was conducted using de-identified electronic health records from the Humedica database for patients who initiated lurasidone monotherapy between February 2011 and November 2013. Weight data were analyzed using longitudinal mixed-effects models to estimate the impact of lurasidone on patient weight trajectories over time. Patients' weight data (kg) were tracked for 12-months prior to and up to 12-months following lurasidone initiation. Stratified analyses were conducted based on prior use of second-generation antipsychotics with medium/high risk (clozapine, olanzapine, quetiapine, or risperidone) versus low risk (aripiprazole, ziprasidone, first-generation antipsychotics, or no prior antipsychotics) for weight gain. RESULTS: Among the 439 included patients, the mean age was 42.2 years, and 69.7% were female. The average duration of lurasidone treatment across all patients was 55.2 days and follow-up duration after the index date was 225.1 days. The estimated impact of lurasidone on weight was - 0.77 kg at the end of the 1-year follow-up. Patients who had received a prior second-generation antipsychotic with medium/high risk for weight gain were estimated to lose an average of 1.68 kg at the end of the 1-year follow-up. CONCLUSIONS: Lurasidone was associated with a reduction in weight at 1 year following its initiation in patients with schizophrenia or bipolar disorder. Stratified analyses indicated that weight reduction was more pronounced among patients who had received second-generation antipsychotics associated with a higher risk of weight gain prior to lurasidone treatment. These findings are consistent with the results of prior short- and long-term prospective studies and suggest that lurasidone is associated with low risk for weight gain in patients with schizophrenia or bipolar disorder.

Cardiometabolic comorbidities, readmission, and costs in schizophrenia and bipolar disorder: a real-world analysis.

BACKGROUND: Serious mental illnesses are associated with increased risk of cardiometabolic comorbidities. The objective of this study was to evaluate the prevalence of cardiometabolic comorbidity and its association with hospitalization outcomes and costs among inpatients with schizophrenia or bipolar disorder. METHODS: This retrospective database analysis reviewed patients with an inpatient diagnosis of schizophrenia or bipolar disorder from the Premier Perspective® Database (4/1/2010-6/30/2012). Patients were categorized into 4 cohorts based on the number of ICD-9-CM cardiometabolic comorbidities (i.e., 0, 1, 2, or 3+). Outcomes included length of stay, mortality during the index hospitalization, healthcare costs, and 30-day all-cause readmission rates. RESULTS: Of 57,506 patients with schizophrenia, 66.1% had at least one cardiometabolic comorbidity; 39.3% had two or more comorbidities. Of 124,803 patients with bipolar disorder, 60.5% had at least one cardiometabolic comorbidity; 33.4% had two or more. Average length of stay was 8.5 (for patients with schizophrenia) and 5.2 (for patients with bipolar disorder) days. Each additional cardiometabolic comorbidity was associated with an increase in length of stay for patients with bipolar disorder (p < .001) but not for patients with schizophrenia. Mortality rates during the index hospitalization were 1.2% (schizophrenia) and .7% (bipolar disorder). Each additional cardiometabolic comorbidity was associated with a significant increase in mortality for patients with bipolar disorder (OR 1.218, p < .001), and a numerical increase in mortality for patients with schizophrenia (OR 1.014, p = .727). Patients with more cardiometabolic comorbidities were more likely to have a 30-day readmission (schizophrenia = 9-13%; bipolar disorder = 7-12%), and to incur higher costs (schizophrenia = $10,606-15,355; bipolar disorder = $7126-13,523) (all p < .01). CONCLUSIONS: Over 60% of inpatients with schizophrenia or bipolar disorder had cardiometabolic comorbidities. Greater cardiometabolic comorbidity burden was associated with an increased likelihood of readmission and higher costs among patients with schizophrenia or bipolar disorder, and an increase in length of stay and mortality for patients with bipolar disorder.

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.

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.

Long-term health-related quality of life improvements among patients treated with lurasidone: results from the open-label extension of a switch trial in schizophrenia.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 < 0.001). Significant improvements in adherence-related attitude and psychosocial functioning were observed at extension baseline and extension endpoint (all p < 0.001). Improvement in SF-12 MCS score was observed at extension baseline and endpoint, and PCS score at extension endpoint (all p < 0.01). Patients who switched from quetiapine and aripiprazole showed significant improvement of PETiT total score and adherence-related attitude at extension baseline and extension endpoint. In addition, patients who switched from quetiapine, risperidone, aripiprazole, or ziprasidone showed significant improvement in MCS scores from baseline to extension endpoint. Responders to lurasidone demonstrated greater improvement in PETiT total, psychosocial functioning, and MCS scores at extension baseline than nonresponders. CONCLUSIONS: After switching to lurasidone, patients with schizophrenia experienced HRQoL improvements that were sustained for an additional 24 weeks of treatment. Further study is warranted to understand the implications of these improvements in terms of employment, adherence, relapse, and rehospitalization. TRIAL REGISTRATION: Clinical trials.gov identifier NCT01143090 (June 10th, 2010).