Efficacy and Safety of Adding Lurasidone to Ongoing Therapy With Lithium or Valproate for the Treatment of an Acute Bipolar Depressive Episode: A Post Hoc Analysis of 2 Placebo-Controlled Trials.

PURPOSE: The aim of this study was to compare the efficacy and safety profile of lurasidone combined with either lithium or valproate, in the short-term treatment of patients with bipolar depression. METHODS: Data were pooled from two 6-week, double-blind, placebo-controlled trials of patients with bipolar depression on stable doses of lithium or valproate randomized to lurasidone (20-120 mg/d) or placebo. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, Clinical Global Impressions Bipolar Scale, and the Quick Inventory of Depressive Symptomatology via self-assessment and were analyzed using a mixed model for repeated measures approach. RESULTS: Notably larger week 6 effect sizes were observed when lurasidone was added to lithium, compared with when lurasidone was added to valproate, on 2 of the 3 depression outcome measures, Montgomery-Åsberg Depression Rating Scale total score (d = 0.45 vs 0.22) and Quick Inventory of Depressive Symptomatology via self-assessment (d = 0.63 vs 0.29); the efficacy advantage was smaller on the Clinical Global Impressions Bipolar Scale depression score (d = 0.34 vs 0.29). Similar adverse event profiles were observed for lurasidone treatment in combination with either lithium or valproate. The most frequently reported events (≥5%) in both groups were nausea, parkinsonism, somnolence, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone combined with either lithium or valproate. CONCLUSIONS: Lurasidone added to either lithium or valproate was found to be an effective treatment for bipolar depression, with a larger antidepressant effect observed when lurasidone was combined with lithium. There were no clinically meaningful differences in the safety or tolerability of lurasidone when used adjunctively with lithium or valproate.

The Effect of Lurasidone on Anxiety Symptoms in Patients With Bipolar Depression: A Post Hoc Analysis.

Objective: To assess the effects of lurasidone on anxiety symptoms and sleep disruption, and their moderating and mediating roles on treatment response in bipolar depression.Methods: This post hoc analysis included pooled data from 2 previously published 6-week placebo-controlled trials of lurasidone for bipolar I depression conducted between April 2009 and February 2012. Hamilton Anxiety Rating Scale (HAM-A) "psychic anxiety" (items 1-6, 14) and "somatic anxiety" (items 7-13) subscores were calculated. Functional outcome was assessed by the Sheehan Disability Scale.Results: All subjects (n = 824) had at least 1 psychic anxiety and 729 (88.5%) had at least 1 somatic anxiety symptom at baseline. 594 subjects (72.1%) experienced baseline sleep disturbance. Lurasidone, as monotherapy (20-60 mg/d and 80-120 mg/d pooled dose groups vs placebo) and adjunctive therapy (20 to 120 mg/d flexibly dosed vs placebo) with lithium or valproate, significantly reduced HAM-A psychic anxiety (-4.82 vs -2.97, P < .001, monotherapy; -5.56 vs -4.26, P = .009, adjunctive therapy) and somatic anxiety (-1.89 vs -1.37, P = .048, monotherapy; -2.22 vs -1.47, P = .006, adjunctive therapy) subcomponents. Improvement in anxiety symptoms mediated reduction in depressive symptoms and functional impairment. Decrease in sleep at baseline predicted change in anxiety symptoms with lurasidone treatment at week 6.Conclusions: Lurasidone was superior to placebo in reducing psychic and somatic anxiety in the short-term treatment of bipolar depression. Improvement in depressive symptoms and reduction in functional impairment were associated with reduction in anxiety symptoms moderated by baseline sleep disturbance during lurasidone treatment.Trial Registration: ClinicalTrials.gov identifiers: NCT00868699 and NCT00868452.

Lurasidone and risk of metabolic syndrome: results from short and long-term studies in patients with bipolar depression.

OBJECTIVE: The elevated prevalence of metabolic syndrome (MetS) in patients with depression has been associated with increased mortality. This post hoc analysis assessed the effect of treatment with lurasidone on risk of MetS in patients with bipolar depression. METHODS: Data used in the current analyses consisted of 3 double-blind (DB), placebo-controlled, 6-week studies in adults with bipolar I depression (N = 1192), consisting of 1 monotherapy, and 2 adjunctive trials (lithium or valproate). Also analyzed was a 6-month open-label (OL) extension study (monotherapy, N = 316; adjunctive therapy, N = 497); and a 5-month, OL, stabilization phase followed by randomization to a 28-week DB, placebo-controlled, adjunctive therapy study with lurasidone (N = 490). MetS was defined based on NCEP ATP III criteria (2005 revision). RESULTS: The proportion of patients with new-onset MetS was similar for lurasidone vs placebo in the short-term studies (monotherapy, 13.9% vs 15.3%; adjunctive therapy, 13.6% vs 11.0%); and remained stable during both the 6-month extension phase study (monotherapy, 15.2%; adjunctive therapy, 16.9%), and the 5-month stabilization study (adjunctive therapy, 12.2%). After 28 weeks of DB treatment (following 5-month treatment in the stabilization study), new onset MetS was observed at endpoint (OC) in 26.2% of the lurasidone group, and 30.8% of the placebo group. CONCLUSIONS: This post hoc analysis found that both short and long-term treatment with lurasidone was associated with a relatively low risk for the development of MetS in patients with bipolar I disorder. These findings are consistent with similar analyses in patients with schizophrenia.

Sleep Disturbance, Irritability, and Response to Lurasidone Treatment in Children and Adolescents with Bipolar Depression.

BACKGROUND: The presence of mixed (subsyndromal hypomanic) symptoms may influence treatment outcomes in pediatric bipolar depression. This post-hoc analysis investigated "bridge" symptoms that have cross-sectional and predictive associations with depressive and manic symptom clusters in youth with bipolar depression. METHODS: The moderating effects of these bridge symptoms on the response to flexibly dosed lurasidone 20-80 mg/d compared to placebo treatment was analyzed in children and adolescents with bipolar I depression in a six-week, placebo-controlled, double-blind study followed by a 2-year, openlabel extension study of lurasidone. RESULTS: Sleep disturbances, assessed by "difficulty with sleep" (Children's Depression Rating Scale, Revised [CDRS-R] item 4) and "decreased need for sleep" (Young Mania Rating Scale [YMRS] item 4), and "irritability" (CDRS-R item-8, YMRS item 5) were identified as "bridge" symptoms and found to have replicable causal associations with depressive (CDRS-R total) and manic symptom clusters (YMRS total) at baseline and week-6. A greater improvement in overall depression severity at week 6 with lurasidone (vs. placebo) treatment was observed in the presence (vs. absence) of decreased need for sleep at study baseline, mediated in part by significant reductions from study baseline in decreased need for sleep and manic symptom severity. The absence of sleep disturbance and irritability in patients at open-label extension study baseline was associated with higher rates of sustained recovery (symptomatic and functional remission) over 6 months compared to patients with those symptoms at baseline (68% vs. 50%, Number Needed to Treat=6). CONCLUSION: Our findings suggest that sleep disturbance and irritability are cardinal symptoms that "bridge" between depressive and manic symptom clusters and influence treatment outcomes in youth with bipolar depression.

Impact of lurasidone on health-related quality of life in adults with bipolar depression: a post-hoc analysis.

OBJECTIVE: The objective of this post-hoc analysis was to assess the impact of lurasidone monotherapy on health-related quality of life (HRQoL) in adults with bipolar depression. METHODS: Data were analyzed from a 6-week randomized, double-blind (DB), placebo-controlled trial of lurasidone monotherapy (NCT00868699) and a 6-month open label extension (OLE; NCT00868959). Patients who received lurasidone monotherapy or placebo during the DB trial were eligible to continue or switch to lurasidone monotherapy during the OLE. The 16-item Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) was collected at DB baseline, DB week 6/OLE baseline, OLE month 3, and OLE month 6. Effect size (ES) and mean changes from baseline were reported for Q-LES-Q-SF total and item scores during the DB trial and OLE, respectively. RESULTS: Of 485 patients in the DB trial (lurasidone monotherapy: n = 323; placebo: n = 162), 316 patients continued or switched to lurasidone monotherapy during the OLE. Significant improvements in Q-LES-Q-SF scores in lurasidone vs. placebo were reported for 13 of 16 items (all p < .05) at DB week 6. The greatest improvements were overall life satisfaction (ES = 0.57), social relationships (0.55), medication satisfaction (0.48), family relationships (0.46), and ability to function in daily life (0.45, all p < .001). Improvements in Q-LES-Q-SF total and item scores were sustained at OLE month 6. CONCLUSIONS: Treatment with lurasidone provided a significant improvement across HRQoL items including overall life satisfaction, social and family relationships, medication satisfaction, and ability to function in daily life. Improvements were sustained during the 6-month OLE.

Efficacy and safety of lurasidone in schizophrenia: pooled analysis of European results from double-blind, placebo-controlled 6-week studies.

The objective of this study is to confirm the efficacy and safety of lurasidone in the acute treatment of schizophrenia in European patients. Data were pooled from three studies of patients randomized to 6 weeks of double-blind, placebo-controlled, fixed-dose (40/80 mg and 120/160 mg) lurasidone. The primary efficacy endpoint was a week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score and secondary endpoints included the Clinical Global Impression, Severity scale (CGI-S). In total 328 safety patients were enrolled; 72.6% were completers. Endpoint change was significantly greater in patients treated with 40-80 mg/d and 120-160 mg/d compared to placebo on the PANSS total score ( P < 0.001) and the CGI-Severity score ( P < 0.001) for all comparisons. For PANSS total scores, endpoint effect sizes for lurasidone 40-80 mg/d and 120-160 mg/d were 0.68 to 0.77, respectively. Adverse events with a frequency ≥5% (and were greater than for combined lurasidone) were insomnia (11.7%), akathisia (11.3%), headache (7.4%), Parkinsonism (6.5%) and nausea (5.7%). Median changes (in mg/dL) at endpoint were minimal for total cholesterol (-8.0); triglycerides (-8.5) and glucose (-2.0) and in mean weight (-0.2 kg). In European patients with schizophrenia, short-term treatment with lurasidone in doses of 40-160 mg/d was generally safe, well-tolerated and effective with minimal effects on weight and metabolic parameters.

Long-term safety and effectiveness of open-label lurasidone in antipsychotic-Naïve versus previously treated adolescents with Schizophrenia: A post-hoc analysis.

BACKGROUND: There is a relative lack of long-term, prospective data evaluating the safety and effectiveness of treatment in early-onset adolescent patients with schizophrenia who are treatment-naïve. The aim of this post-hoc analysis was to examine the long-term safety and effectiveness of lurasidone in adolescents with schizophrenia who were antipsychotic treatment-naïve (TN; at the time of enrolment in the initial study) compared to adolescents treated previously (TP) with an antipsychotic. METHODS: Patients aged 13-17 who completed 6 weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible-dose (20-80 mg/day) lurasidone study. RESULTS: The long-term analysis sample consisted of 50 TN and 221 TP patients, of whom 40% and 43%, respectively, discontinued prematurely. The three most common adverse events for TN and TP patients, respectively, were headache (26.0%, 23.5%); schizophrenia (14.0%, 12.2%), dizziness (16.0%, 4.1%), and nausea (16.0%, 11.8%). At endpoint, mean increase in weight was similar to expected weight gain based on growth charts for both TN (+4.5 kg vs. + 5.7 kg) and TP (+4.6 kg vs. + 6.6 kg) patients. Minimal changes were observed for each group in metabolic parameters and prolactin. Mean improvement was consistently greater in the TN vs. TP group (-19.2 vs. -15.9; effect size of 0.33) for between-group change in PANSS total score at Week 104. CONCLUSIONS: In both TN and TP adolescents with schizophrenia, long-term treatment with lurasidone was associated with minimal effects on body weight, lipids, glycemic indices, and prolactin, with generally small differences noted in rates of reported AEs. Continued improvement in symptoms of schizophrenia was evident for both the TN and TP groups. These data indicate that lurasidone is a safe and efficacious treatment option for treatment-naïve youth with schizophrenia, who are generally most sensitive to antipsychotic adverse effects.

The impact of lurasidone on functioning and indirect costs in adults with bipolar depression: a post-hoc analysis.

OBJECTIVE: The aim of this post-hoc analysis was to assess the impact of lurasidone monotherapy on functional impairment, productivity, and associated indirect costs in patients with bipolar depression. METHODS: Data were analyzed from a 6-week randomized, double-blind (DB; NCT00868699), placebo-controlled trial of lurasidone monotherapy and a 6-month open label extension (OLE; NCT00868959) study. Patients with bipolar depression who completed the 6-week DB trial were subsequently enrolled in the OLE. Analysis of the OLE was limited to patients who either continued lurasidone (LUR-LUR) or switched from placebo to lurasidone monotherapy (PBO-LUR). The Sheehan Disability Scale (SDS), which measures functional impairment and productivity, was collected at DB baseline, DB week 6/OLE baseline, OLE month 3, and OLE month 6. Annual indirect costs were calculated based on days lost or unproductive from work/school due to symptoms. Effect sizes (ES) in functioning and days lost/unproductive were reported for the DB trial and mean changes for the OLE. RESULTS: A total of 485 patients were enrolled in the DB trial (lurasidone: n = 323; placebo: n = 162) and 316 were in the lurasidone monotherapy group during the OLE (LUR-LUR: n = 210; PBO-LUR: n = 106). In the DB trial, improvements in functioning (work: ES = 0.36, p = .0071; social: ES = 0.55, p < .0001; family: ES = 0.50, p < .0001) were significantly greater for lurasidone compared to placebo. Reductions in days lost (ES = 0.33, p = .0050) and unproductive (ES = 0.45, p = .0001) were significantly higher for lurasidone vs. placebo. This resulted in a greater reduction in indirect costs for lurasidone vs. placebo (least squares mean (standard error) = -$32,322 ($2,100) vs. -$20,091 ($2,838)). Improvements in functioning and productivity were sustained during the 6-month OLE for both LUR-LUR and PBO-LUR. CONCLUSIONS: Lurasidone monotherapy for the treatment of bipolar depression significantly improved functioning and reduced indirect costs vs. placebo at week 6. Significant improvements in functioning and productivity were sustained for 6 months for both LUR-LUR and PBO-LUR.

Safety and effectiveness of lurasidone in adolescents with schizophrenia: results of a 2-year, open-label extension study.

BACKGROUND: Minimal long-term benefit: Risk data are available regarding antipsychotic treatments for schizophrenia in pediatric populations. This study evaluated the long-term safety, tolerability, and effectiveness of lurasidone in adolescents with schizophrenia. METHODS: Patients aged from 13 to 17 who completed 6 weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible dose (20-80 mg/day) lurasidone treatment study. Safety was assessed via spontaneous reporting, rating scales, body weight measurement, metabolic, and prolactin testing. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score. RESULTS: About 271 patients completed 6 weeks of DB treatment and entered the 2-year OL extension study. Altogether, 42.4% discontinued prematurely, 10.7% due to adverse events. During OL treatment, the most common adverse events were headache (24.0%); anxiety (12.9%), schizophrenia, and nausea (12.5%); sedation/somnolence (12.2%); and nasopharyngitis (8.9%). Minimal changes were observed on metabolic parameters and prolactin. Mean change from DB baseline in weight at week 52 and week 104 was +3.3 kg and + 4.9 kg, respectively, compared to an expected weight gain of +3.4 kg and + 5.7 kg, respectively, based on the sex- and age-matched US Center for Disease Control normative data. Continued improvement was observed in PANSS total score, with mean change from OL baseline of -15.6 at week 52 and -18.4 at week 104. CONCLUSION: In adolescents with schizophrenia, long-term lurasidone treatment was associated with minimal effects on body weight, lipids, glycemic indices, and prolactin. Continued improvement in symptoms of schizophrenia was observed over 2 years of lurasidone treatment.

Tolerability, Safety, and Effectiveness of Two Years of Treatment with Lurasidone in Children and Adolescents with Bipolar Depression.

Objectives: To evaluate long-term safety and effectiveness of lurasidone in children and adolescents with bipolar depression. Methods: Participants, ages 10-17 years, with bipolar depression, who completed 6 weeks of double-blind (DB) treatment with lurasidone or placebo were enrolled in a 2-year, open-label (OL) extension study of lurasidone (20-80 mg/d). The primary effectiveness measure was the Children's Depression Rating Scale, Revised (CDRS-R). Results: A total of 306 participants entered the 2-year extension study; 195 (63.7%) completed 52 weeks, and 168 (54.9%) completed 104 weeks of treatment. For all participants entering the extension study, mean change in CDRS from OL baseline was -13.4 at week 52, and -16.4 at week 104 (-11.3 at last observation carried forward [LOCF]-endpoint). Overall, 31 participants (10.1%) discontinued due to an adverse event (AE); the three most common AEs were headache (23.9%), nausea (16.4%), and somnolence (9.8%). OL treatment with lurasidone was associated with few effects on metabolic parameters or prolactin. Mean change from DB baseline in weight was +4.25 kg at week 52 (vs. an expected weight gain of +3.76 kg), and +6.75 kg at week 104 (vs. an expected weight gain of +6.67 kg), based on the sex- and age-matched United States Center for Disease Control normative data. Conclusions: For youth with bipolar depression, up to 2 years of treatment with lurasidone was generally well tolerated, safe, and effective with relatively low rates of discontinuation due to AEs, minimal effects on weight, metabolic parameters or prolactin, and continued improvement in depressive symptoms. Clinical Trial Registration number: NCT01914393.

Hospitalization Risk for Adults with Bipolar I Disorder Treated with Oral Atypical Antipsychotics as Adjunctive Therapy with Mood Stabilizers: A Retrospective Analysis of Medicaid Claims Data.

Background: Atypical antipsychotics (AAPs) with mood stabilizers are recommended as a first-line treatment for patients with bipolar disorder. No studies have compared the inpatient health care resource utilization for patients with bipolar disorder treated with lurasidone as adjunctive therapy with mood stabilizers compared with other oral AAPs. Objective: To compare the risk of hospitalization for adult Medicaid beneficiaries with bipolar I disorder when treated with lurasidone compared with other oral AAPs as adjunctive therapy with mood stabilizers. Methods: This retrospective cohort study used the MarketScan Research Databases Multi-State Medicaid Database (IBM, Armonk, NY) claims data to assess patients with bipolar I disorder between January 1, 2014, and June 30, 2019. Adult patients who initiated oral AAP treatment with mood stabilizers (index date) and who were continuously enrolled 12 months before (pre-index) and 24 months after (post-index) the index date were included. Treatment categories assigned by patient-month included lurasidone, aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone with mood stabilizers; no/minimal treatment; AAP monotherapy; and other. Marginal structural models were performed to estimate the all-cause and psychiatric hospitalization rates and hospital length of stay associated with each adjunctive AAP therapy by controlling for both time-invariant and time-varying confounders. Results: Adults with bipolar I disorder (N = 11,426; mean age = 39.4 years; female=73%) treated with an adjunctive oral AAP with mood stabilizers during the index month were categorized into lurasidone (12%), aripiprazole (17%), olanzapine (7%), quetiapine (32%), risperidone (11%), ziprasidone (7%), or other (15%) treatment groups. The adjusted odds of all-cause and psychiatric hospitalization were significantly higher for olanzapine (all causes: adjusted odds ratio [aOR] = 1.59; 95% CI, 1.13-2.25; psychiatric: aOR = 1.61, 95% CI, 1.12-2.32), quetiapine (all-causes: aOR = 1.27, 95% CI, 1.01-1.58; psychiatric: aOR = 1.28, 95% CI, 1.02-1.59), and ziprasidone (all-causes: aOR = 1.68, 95% CI, 1.05-2.66; psychiatric: aOR = 1.55, 95% CI, 1.02-2.35) compared with lurasidone with mood stabilizers. The adjusted odds of all-cause and psychiatric hospitalizations were numerically lower for lurasidone compared with aripiprazole. The all-cause hospital length of stay per 100 patient-months was significantly higher for olanzapine (20.3 days) and quetiapine (16.0 days) compared with lurasidone (12.2 days, both P values < 0.05). Conclusions: In a Medicaid population, adults with bipolar I disorder treated with lurasidone as adjunctive therapy with mood stabilizers had significantly lower all-cause and psychiatric hospitalization rates compared with olanzapine, quetiapine, and ziprasidone. Fewer hospitalizations may reduce the economic burden associated with bipolar disorder. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX).

Efficacy and safety of lurasidone in adolescents and young adults with schizophrenia: A pooled post hoc analysis of double-blind, placebo-controlled 6-week studies.

BACKGROUND: The aim of this pooled analysis was to evaluate the efficacy and safety of lurasidone in the treatment of an acute exacerbation of schizophrenia in adolescents and young adults. METHODS: The six pooled studies in this analysis used similar study designs and outcome measures. Patients (aged 13-25 years) were randomized to 6 weeks of double-blind, placebo-controlled treatment with lurasidone in fixed doses of 40, 80, 120, or 160 mg. The primary efficacy endpoint was Week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score; secondary efficacy endpoints included Week 6 change in the Clinical Global Impression-Severity scale. RESULTS: The safety population consisted of 537 patients (mean age: 18.1 years); 82.6% of patients completed the studies. Treatment with lurasidone was significantly better than placebo at all doses (p < 0.001) for change in the PANSS total score at Week 6. Placebo-adjusted PANSS scores ranged from -9.4 to -16.1 (effect sizes: 0.53-0.90), with effect sizes increasing at higher doses. For lurasidone (combined doses), three adverse events occurred with a frequency of ≥5% (nausea: 13.5%; somnolence: 12.1%; akathisia: 10.1%). At last observation carried forward (LOCF)-endpoint weight gain of ≥7% was similar for lurasidone versus placebo (3.6 vs. 4.7%). Minimal median changes were observed at endpoint in cholesterol, -2.0 mg/dL; triglycerides, 0.0 mg/dL; and glucose, 0.0 mg/dL. CONCLUSIONS: In adolescents and young adults with schizophrenia, treatment with lurasidone in doses of 40-160 mg/d was a safe, well-tolerated, and effective treatment. Short-term treatment with lurasidone was associated with minimal effects on weight and metabolic parameters.

Improvement in Lung Function and Patient-Reported Outcomes in Patients with COPD with Comorbid Anxiety and Depression Receiving Nebulized Glycopyrrolate in the GOLDEN 3 and 4 Studies.

BACKGROUND: Anxiety and depression (A/D) are common in patients with chronic obstructive pulmonary disease (COPD) and are often associated with lower adherence to treatment and worse patient-related outcomes. However, studies on the impact of comorbid A/D on responses to bronchodilators are limited. METHODS: This post hoc analysis of pooled data (N=861) from the GOLDEN 3 and 4 studies compared the efficacy and safety of nebulized glycopyrrolate (GLY) 25 µg in patients with moderate-to-very-severe COPD, grouped by self-reported A/D. Changes in forced expiratory volume in 1 second (FEV1) and health-related quality of life determined by St George's Respiratory Questionnaire (SGRQ) scores in patients with or without comorbid A/D (A/D [+] or A/D [-]) were examined following 12 weeks of GLY 25 µg twice-daily (BID) or placebo treatment. RESULTS: A/D (+) patients were predominantly female, younger, included a higher proportion of current smokers, and had higher baseline SGRQ scores compared with the A/D (-) group. At 12 weeks, GLY resulted in placebo-adjusted improvements from baseline in FEV1 of 46.9 mL (p=0.19; not significant) and 106.7 mL (p<0.0001), in the A/D (+) and A/D (-) groups, respectively. Improvements were observed with GLY compared to placebo in SGRQ scores, regardless of baseline A/D status; the placebo-adjusted least squares mean change from baseline in SGRQ total scores was -3.16 (p>0.05) and -3.34 (p<0.001), for the A/D (+) and A/D (-) groups, respectively. Despite numerical improvements in SGRQ scores with GLY in the A/D (+) group, a higher response to placebo was observed. GLY was generally well tolerated throughout 12 weeks of treatment; incidence of adverse events was higher in the A/D (+) group compared with the A/D (-) group in both treatment arms. CONCLUSION: GLY 25 µg BID resulted in numerical improvements in FEV1, SGRQ total scores and SGRQ responder rates in patients with moderate-to-very-severe COPD, regardless of A/D status at baseline; significant improvements were noted only in the A/D (+) group. The results emphasize the importance of considering underlying comorbidities including A/D when evaluating the efficacy of COPD treatments.

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).

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 in Children and Adolescents with Bipolar Depression Presenting with Mixed (Subsyndromal Hypomanic) Features: Post Hoc Analysis of a Randomized Placebo-Controlled Trial.

Objectives: To evaluate the efficacy and safety of lurasidone in the treatment of children and adolescents with bipolar depression presenting with mixed (subsyndromal hypomanic) features. Methods: Patients, 10-17 years of age, with a Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5), diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with once-daily flexible doses of lurasidone 20-80 mg or placebo. The presence of mixed (subsyndromal hypomanic) features in this pediatric bipolar depression trial was defined as a Young Mania Rating Scale score of 5 or greater at study baseline. Key efficacy measures included change from baseline to week 6 in the Children's Depression Rating Scale-Revised (CDRS-R) score (primary endpoint) and Clinical Global Impressions-Bipolar Severity (CGI-BP-S) score, using a mixed model for repeated measures analysis. Results: At baseline, subsyndromal hypomanic features were present in 54.2% of patients. Treatment with lurasidone (vs. placebo) was associated with significantly greater reductions in CDRS-R scores at week 6, independent of the presence (-21.5 vs. -15.9, p < 0.01; effect size d = 0.43) or absence (-20.5 vs. -14.9, p < 0.01; d = 0.44) of subsyndromal hypomanic features. Likewise, lurasidone (vs. placebo) was associated with significantly greater reductions in CGI-BP-S scores at week 6, independent of the presence (-1.6 vs. -1.1, p < 0.001, d = 0.51) or absence (-1.3 vs. -1.0, p = 0.05; d = 0.31) of these subsyndromal hypomanic features. Rates of protocol-defined treatment-emergent hypomania or mania were similar for lurasidone and placebo in patients with (lurasidone 8.2% vs. placebo 9.0%) or without subsyndromal hypomanic features (lurasidone 1.3% vs. placebo 3.7%). Conclusions: In this post hoc analysis of a randomized placebo-controlled trial, lurasidone was found to be efficacious in the treatment of child and adolescent patients with bipolar depression who presented with mixed (subsyndromal hypomanic) features. No differences in safety profile, including the risk of treatment-emergent mania, were observed in patients with or without subsyndromal hypomanic features in this study.

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).

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.