Lurasidone Treatment Research Articles

Lurasidone in the Long-Term Treatment of Bipolar I Depression: A 28-week Open Label Extension Study

Lurasidone has demonstrated efficacy for short-term treatment of bipolar depression in a diverse ethnic population including Japanese. This study evaluated the long-term safety and effectiveness of open-label lurasidone treatment in these patients. Patients for this 28-week extension study were recruited from those who completed a 6-week double-blind study of lurasidone, 20-60 mg/day, lurasidone 80-120 mg/day, and placebo. In the extension study, lurasidone was flexibly dosed (20 to 120 mg/day). Safety was evaluated in terms of change from extension-phase baseline to endpoint including adverse events, vital signs, body weight, ECG, laboratory tests, and measures of suicidality and extrapyramidal symptoms. Effectiveness was determined by Montgomery Åsberg Depression Rating Scale (MADRS) and other measures. 303 of 413 (73.3%) subjects completed the extension study. Discontinuation due to a treatment-emergent adverse event occurred for 11.4% of those who received placebo, and 8.9% of those who received lurasidone, in the prior 6-week trial. The most common treatment-emergent adverse event was akathisia. Minimal changes were evident on body weight and metabolic parameters. Long-term treatment with lurasidone further reduced mean MADRS total scores from long-term baseline to week 28 (or endpoint) for both those who had received prior placebo (-11.3), and those who had receive prior lurasidone (-8.9), in the 6-week double-blind trial. There was no placebo control and treatment was not double-blind. Long-term treatment with lurasidone (20-120 mg/day) was well-tolerated with no new safety concerns and associated with continued improvement in depressive symptoms in this international sample of patients with bipolar depression. JapicCTI-132319, clinicaltrials.gov - NCT01986114.

P.608 Beneficial effects of lurasidone treatment during adolescence in rats exposed to stress during gestation

Leucine-rich repeat kinase 2 (LRRK2) is the causal gene of the autosomal dominant hereditary form of Parkinson’s disease (PD), PARK8. We have previously reported that induced pluripotent stem cells (iPSCs) from a PARK8 patient with I2020T LRRK2 mutation replicated to some extent the pathologic phenotype evident in the brain of PD patients. In the present study, we generated gene-corrected iPSCs line, KEIUi001-A, using TALEN-mediated genome editing. KEIUi001-A retained a normal karyotype and pluripotency, i.e. the capacity to differentiate into cell types of the three germ layers. This iPSCs will be valuable for clarifying various aspects of LRRK2-related pathology.

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

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. Patients aged from 13 to 17 who completed 6weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible dose (20-80mg/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. About 271 patients completed 6weeks 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 +3.3kg and+4.9kg, respectively, compared to an expected weight gain of +3.4kg and+5.7kg, 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. 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 2years of lurasidone treatment.

S212. LONG-TERM CHANGES OF MIRNA30A FOLLOWING EXPOSURE TO PRENATAL STRESS: MODULATORY EFFECTS OF LURASIDONE TREATMENT DURING ADOLESCENCE

BackgroundExposure to early life stress (ELS) represents a major risk factor for the development of psychiatric disorders, including depression and schizophrenia. The susceptibility associated with ELS may result from persistent changes in gene transcription, which can occur through epigenetic mechanisms, such as DNA methylation and miRNA expression. Animal models are particularly useful to identify the systems that are persistently affected as a consequence of ELS exposure and that may represent suitable targets for pharmacological intervention. On these bases, we performed genome-wide methylation analyses in rats exposed to gestational stress, a model associated with functional alterations relevant for psychiatric disorders, in order to identify systems that are persistently altered as a consequence of the adverse experience early in life.MethodsWe used MeDIP-chip to investigate changes in the prefrontal cortex and hippocampus of adult male and female rats exposed to chronic stress (immobilization under bright light) during the last week of gestation (PNS). After having identified the most promising candidates from this analysis, we investigated their expression profile during postnatal maturation, in order to establish potential changes in their developmental trajectories. We also investigated whether sub-chronic treatment with the antipsychotic drug lurasidone, given during the peripubertal period, could modulate the changes originating from PNS exposure.ResultsWe found that a large number of gene promoters were differentially methylated in the prefrontal cortex and hippocampus of adult male and female rats exposed to stress during gestation. An overlap of 138 differentially methylated genes around the transcription start site was observed among the two brain regions and genders. By restricting the overlap to genes that were modulated in the same direction, we identified two genes, miR-30a and NEUROD1, which interact with each other and that were both less methylated in PNS exposed rats. Using the miRWalk database, we found that miRNA30a is involved in the modulation of pathways related to axon guidance and neurotrophin signaling. Among the genes related to these two pathways, we validated CAMK2A, c-JUN, LIMK, MAP2K1, MAP2K2, PIK3CA and PLCG1 as miRNA30 targeted genes. We found that the cumulative score of their mRNA level modulation following PNS exposure supported the downregulation of the two identified pathways related to miRNA30a. Importantly, sub-chronic treatment with lurasidone was able to prevent, to a large extent, the up-regulation of miR30a, as well as the changes observed on its target genesDiscussionIn summary, our genome-wide approach allowed us to identify miR-30a as being persistently affected by PNS through epigenetic changes. This miRNA may represent a master regulator for the increased susceptibility to psychiatric disorders as a long-lasting consequence of ELS exposure. Furthermore, we show that chronic lurasidone treatment was able to prevent some of the changes produced by PNS, with a major effect on miRNA30a levels as well as on its target genes LIMK, MAP2K2 and PIK3CA.These effects may be particularly relevant in preventing some molecular alterations induced by ELS exposure, known to be involved in the development of stress-related psychiatric disorders, and thus be useful in minimizing the individual risk of vulnerability.

Switching to Lurasidone following 12\u2009months of treatment with Risperidone: results of a 6-month, open-label study

BackgroundPatients 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).MethodsThe 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.ResultsSix 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).ConclusionsIn 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 registrationClinicalTrials.gov NCT00641745 (Date of Registration: March 24, 2008).

Antipsychotic lurasidone: Behavioural and pharmacokinetic data in C57BL/6 mice

Lurasidone is an atypical antipsychotic that has been shown to be effective in reversing schizophrenia-related cognitive impairment. The development of new preclinical models of schizophrenia is a key for improving treatments of cognitive symptoms. This study investigated the effects of chronic lurasidone treatment in C57BL/6 male mice via intraperitoneal injection (1 mg/kg daily at 5 p.m. for 5 weeks). A large battery of behavioural tests was performed (between 9 a.m. and 5 p.m.), which is currently used to assess face validity in animal models of psychiatric diseases. Overall, lurasidone did not interfere with behavioural performances, which characterises very good tolerance to such a high dose. Moreover, pharmacokinetic parameters after i.p. and oral administration were measured. Mean transit time (MTT) values were 1.91 h (1 mg/kg acute i.p.) and 1.74 h (8.3 mg/kg acute oral), respectively, and relative bioavailability comparing these two routes of administration was of 19.8%. This last result gives important data to adapt oral chronic administration of lurasidone with a more ethical perspective in comparison with chronic i.p. injections. This study brings tools to improve pharmacological validity of preclinical models of psychiatric diseases, and to adapt dosage of antipsychotics according to the route used.

Chronic Lurasidone Treatment in Stress-Based Models of Psychiatric Disorders: From Prevention to Functional Normalization

Chronic Lurasidone Treatment in Stress-Based Models of Psychiatric Disorders: From Prevention to Functional Normalization

159 Safety and Efficacy of Lurasidone in Children and Adolescents with Bipolar Depression: Results from a 2-Year Open-label Extension Study

Bipolar I disorder frequently has an early onset, with an estimated prevalence rate of 1.8% in pediatric populations. Early onset is associated with a high degree of chronicity; however, limited data are available on the long-term efficacy of drug therapies in pediatric populations. The aim of the current study was to evaluate the long-term safety and efficacy of lurasidone in children and adolescents with bipolar depression. Patients 10-17 years with bipolar I depression were randomized to 6 weeks of double-blind (DB) treatment with lurasidone or placebo. Patients who completed the study were eligible to enroll in a 2-year, open-label (OL) extension study in which patients were continued on flexibly-dosed lurasidone (20-80 mg/d; LUR-LUR) or switched from placebo to lurasidone (PBO-LUR). The primary efficacy measure was the Children's Depression Rating Scale, Revised (CDRS-R); response was defined as ≥50% reduction from DB baseline in the CDRS-R total score. A total of 306 patients completed the 6-week DB study and entered the extension study; 195 (63.7%) completed 52 weeks, and 168 (54.9%) completed 104 weeks of treatment. Mean CDRS-R total score at DB baseline was 59.4 in patients treated with lurasidone, and 58.7 in patients treated with placebo; and mean CDRS-R total score at OL baseline (after 6 weeks of DB treatment) was 36.6 in the LUR-LUR group and 41.9 in the PBO-LUR group. For the total sample of patients in the OL study, mean change (from OL baseline) in the CDRS-R score was -13.4 at week 52 and -16.4 at week 104; and responder rates were 51.0% at OL baseline (64.5% for LUR-LUR; 36.9% for PBO-LUR), 88.4% at week 52, and 91.1% at week 104. During OL treatment with lurasidone, 31 patients (10.1%) discontinued due to an adverse event. The most commonly reported events 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 based on CDC normative data), and +6.75 kg at week 104 (vs. CDC expected weight gain of 6.67 kg). Two years of treatment with lurasidone in children and adolescents with bipolar depression was generally well-tolerated, with relatively low rates of study discontinuation. Lurasidone treatment was associated with few effects on weight, metabolic parameters, and prolactin. Patients also continued to experience improvement in depressive symptoms during long-term treatment with lurasidone.Clinicaltrials.gov identifier: NCT01914393. Supported by funding from Sunovion Pharmaceuticals Inc.

Effect of lurasidone treatment on chronic mild stress-induced behavioural deficits in male rats: The potential role for glucocorticoid receptor signalling

Stress represents one of the main precipitating factors for psychiatric diseases, characterised by an altered function of glucocorticoid receptors (GR), known to play a role in mood and cognitive function. We investigated the ability of the antipsychotic lurasidone to modulate the involvement of genomic and non-genomic GR signalling in the behavioural alterations due to chronic stress exposure. Male Wistar rats were exposed to seven weeks of chronic mild stress (CMS) and treated with lurasidone (3 mg/kg/day) starting from the second week of stress for more five weeks. Gene expression and protein analyses were conducted in dorsal hippocampus. Seven weeks of CMS induced anhedonia and cognitive impairment, which were normalised by lurasidone. At molecular level, CMS rats showed an increase of GR protein levels by 60% (p<0.001 vs. CTRL/VEH) in the membrane compartment, which was paralleled by an up-regulation of phosphoSINAPSYN Ia/b by 88% (p<0.01 vs. CTRL/VEH) and of the mitochondrial marker Cox3 by 21% (p<0.05 vs. CTRL/VEH). Moreover, while exposure to the novel object recognition test increased the nuclear translocation of GRs by 96% (p<0.01 vs. CTRL/VEH/Naïve) and their transcriptional activity in non-stressed rats, such mechanisms were impaired in CMS rats. Interestingly, the genomic and non-genomic alterations of GR, induced by CMS, were normalised by lurasidone. Our results further support the role of glucocorticoid signalling in the dysfunction associated with stress exposure. We provide novel insights on the mechanism of lurasidone, suggesting its effectiveness on different domains associated with psychiatric disorders.

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.

P.333 Multimodal neuroplastic mechanisms of lurasidone treatment in the chronic mild stress model

Today, most handheld devices including smartphones, tablets and notebooks are equipped with Wi-Fi, Bluetooth, LTE/4G radio interfaces that can allow connections to the Internet and other devices. However, given the properties changes of the radio environment and user mobility, an open question still lies in how to select the best access network interface, considering that the availability and characteristics of an access network will change in time. This paper describes a new intelligent interface selection mechanism based on analysis of contextual information obtained from the user, network environment, and device. To select the best available wireless network, the mechanism, named as CANS (Context-Aware Network Selection), allows for dynamic decision-making during the operation of a mobile device, taking into account different metrics such as price, local network capabilities, user preferences, and the mobile terminal capabilities. The evaluation of the proposed mechanism in a real environment shows that the adoption of selection strategies enables the best exploitation of the advantages on multiple access technologies, achieving a reduction in device power consumption and financial cost.

Stress regulates glucocorticoid-responsive genes expression in prefrontal cortex by altering DNA methylation: implication for lurasidone treatment

Stress regulates glucocorticoid-responsive genes expression in prefrontal cortex by altering DNA methylation: implication for lurasidone treatment

Chronic Stress Exposure Reduces Parvalbumin Expression in the Rat Hippocampus through an Imbalance of Redox Mechanisms: Restorative Effect of the Antipsychotic Lurasidone

BackgroundPsychiatric disorders are associated with altered function of inhibitory neurotransmission within the limbic system, which may be due to the vulnerability of selective neuronal subtypes to challenging environmental conditions, such as stress. In this context, parvalbumin-positive GABAergic interneurons, which are critically involved in processing complex cognitive tasks, are particularly vulnerable to stress exposure, an effect that may be the consequence of dysregulated redox mechanisms.MethodsAdult Male Wistar rats were subjected to the chronic mild stress procedure for 7 weeks. After 2 weeks, both control and stress groups were further divided into matched subgroups to receive chronic administration of vehicle or lurasidone (3 mg/kg/d) for the subsequent 5 weeks. Using real-time RT-PCR and western blot, we investigated the expression of GABAergic interneuron markers and the levels of key mediators of the oxidative balance in the dorsal and ventral hippocampus.ResultsChronic mild stress induced a specific decrease of parvalbumin expression in the dorsal hippocampus, an effect normalized by lurasidone treatment. Interestingly, the regulation of parvalbumin levels was correlated to the modulation of the antioxidant master regulator NRF2 and its chaperon protein KEAP1, which were also modulated by pharmacological intervention.ConclusionsOur findings suggest that the susceptibility of parvalbumin neurons to stress may represent a key mechanism contributing to functional and structural impairments in specific brain regions relevant for psychiatric disorders. Moreover, we provide new insights on the mechanism of action of lurasidone, demonstrating that its chronic treatment normalizes chronic mild stress-induced parvalbumin alterations, possibly by potentiating antioxidant mechanisms, which may ameliorate specific functions that are deteriorated in psychiatric patients.

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

BackgroundThis study compared hospital admission rates among adult patients with schizophrenia who switched to antipsychotic monotherapy with lurasidone or quetiapine.MethodsThis 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.ResultsQuetiapine (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).ConclusionsIn 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.

F60. INFLAMMATORY MARKERS AND COGNITIVE PERFORMANCE IN PATIENTS WITH SCHIZOPHRENIA TREATED WITH LURASIDONE

BackgroundRecent studies have linked inflammation, obesity, and lipid dysregulation with cognitive impairment, a core feature of schizophrenia. Elevated C-reactive protein concentration has been shown to be a reliable biomarker for inflammatory states. We conducted an exploratory analysis to investigate the potential influence of inflammation, obesity and lipid metabolism on changes in symptom severity and cognitive performance in patients with schizophrenia treated with lurasidone.MethodsPatients with acute exacerbation of schizophrenia were treated with one of two fixed doses of lurasidone (80 or 160 mg/day), placebo, or 600 mg/day quetiapine XR in a 6-week double-blind study. A wide-range CRP (wr-CRP) assay (equivalent to high sensitivity CRP assay) was used to assess levels of inflammation. CRP was evaluated as a logarithm transformed (log) continuous variable and as a categorical variable divided into low (≤ 2 mg/L), medium (> 2 mg/L and ≤ 5 mg/L) and high (> 5 mg/L) subgroups. Cognitive function was assessed with the CogState computerized cognitive battery at baseline and week 6 endpoint. Nonparametric bootstrap resampling method was applied to estimate the main and interactive effects of CRP on ranked cognitive scores.ResultsElevated level of wr-CRP (log) was associated with cognitive impairment at study baseline (P < 0.05), with significantly lower cognitive performance in the subgroup with high wr-CRP (> 5 mg/L) compared to those with low wr- CRP (< 2 mg/L) at study baseline (P < 0.05). Higher level of CRP (log) was also associated with significantly greater symptom severity as assessed by PANSS score, as well as higher BMI/body weight, and lower levels of high-density lipoprotein (HDL) and high hemoglobin A1c (HbA1c) at study baseline (P < 0.05). No significant associations were found for wr-CRP (log) with low-density lipoprotein (LDL) and total cholesterol at study baseline. High wr-CRP level (> 5 mg/L) at study baseline predicted less improvement of cognitive composite score at week 6 endpoint for all treatment groups, compared to those with low to medium wr-CRP levels (< 5 mg/L).The joint effect of wr-CRP (log) and HDL or HOMA-IR on moderating procognitive effects of lurasidone was significant (P<0.05), with greater lurasidone (vs. placebo) effect size in patients with either low wr-CRP and high HDL concentration or lower levels of both wr-CRP and HOMA-IR.Lurasidone treatment was associated with significant reduction in symptom severity as assessed by PANSS, CGI-S, and MADRS change scores from baseline to week 6, independent of wr-CRP, HDL and HOMA-IR levels at study baseline. Lurasidone had no significant effect on change in wr-CRP level from baseline to week 6 endpoint.DiscussionOur findings from this exploratory analysis of a placebo-controlled trial in patients with schizophrenia suggest that the joint effects of low wr-CRP level combined with either high HDL or low HOMA-IR can predict cognitive improvement in patients treated with lurasidone (vs. placebo). These findings suggest that inflammation and its interactive effects with insulin resistance and lipid parameters in patients with schizophrenia might impact cognition and response to treatment with antipsychotics.

T221. LURASIDONE DISPLAYS ANTIDEPRESSANT AND PRO-COGNITIVE EFFECTS IN THE CHRONIC MILD STRESS MODEL: A ROLE FOR REDOX MECHANISMS AND PARVALBUMIN EXPRESSION

BackgroundExposure of rodents to chronic stress is able to recapitulate a number of functional alterations that are associated with psychiatric disorders, including anhedonia and cognitive impairment. Stress-based experimental models are also useful to investigate the ability of pharmacological intervention in normalizing such defects as well as the molecular alterations associated with the behavioral phenotype. On these bases, the aim of the present study was to investigate the ability of a chronic treatment with the multi-receptor modulator lurasidone in normalizing behavioral changes produced by chronic mild stress (CMS) in rats. Moreover, we investigated the potential contribution of parvalbumin expression and of redox mechanisms in the alterations brought about by CMS exposure.MethodsAdult male Wistar rats were exposed to CMS for 2 weeks and sucrose consumption was used to identify rats that were susceptible to the stressful manipulation. Control and CMS-susceptible rats were then randomized to receive chronic vehicle or the multi-receptor modulator lurasidone (3 mg/kg/day) for 5 more weeks, while continuing the stress procedure. Animals were tested for anhedonia, using the sucrose intake test, and for cognitive impairment, using the novel object recognition (NOR) test. Rats were sacrificed at the end of the procedures and the brain regions of interest were dissected and used for the molecular analyses.ResultsExposure to CMS produced a persistent anhedonic phenotype as well as a significant deficit in the NOR test. Both behavioral abnormalities were normalized by chronic lurasidone treatment. Rats exposed to CMS display a marked and selective reduction in the expression of parvalbumin, which identifies a subpopulation of GABAergic interneurons, in dorsal (but not ventral) hippocampus, an effect that was normalized by chronic lurasidone administration. CMS rats also show a significant up-regulation of (NADPH) oxidase 2 (NOX2), which is critically involved in oxidative stress, as well as a down-regulation of Nrf-2, a master regulator of antioxidant defense. These alterations in dorsal hippocampus were normalized in animals that received chronic lurasidone treatment that was also capable of reducing the levels of Keap-1, an important player that exerts a repressive control over Nrf-2.DiscussionOur results demonstrate the ability of lurasidone in normalizing anhedonia and cognitive deficits associated with CMS exposure, suggesting its effectiveness on different ‘domains’ (RDoC) that characterize psychiatric disorders. Lurasidone was also able to normalize the effects produced by CMS exposure on parvalbumin expression, possibly through its ability in promoting anti-oxidative mechanisms within the dorsal hippocampus. All in all, these effects may promote resilience toward the alterations produced by adverse environmental conditions, such as stress, which represents a major vulnerability element in the etiology of psychiatric disorders.

F52. EFFICACY AND SAFETY OF LURASIDONE IN ADOLESCENTS WITH SCHIZOPHRENIA: INTERIM ANALYSIS OF A 24-MONTH, OPEN-LABEL EXTENSION STUDY

BackgroundLong-term efficacy and safety data from prospective studies in adolescents with schizophrenia are limited. Lurasidone is an atypical antipsychotic that has demonstrated efficacy in the treatment of schizophrenia in both adults and adolescents. The aim of the current open-label trial was to obtain long-term data on the safety and effectiveness of lurasidone in adolescents with schizophrenia.MethodsPatients ages 13–17 with schizophrenia were randomized to 6 weeks of double-blind (DB) treatment with lurasidone 40 mg/d, 80 mg/d or placebo. Patients who completed this study were eligible to enroll in a 2-year, open-label (OL), flexible-dose (20–80 mg/d) extension study in which patients were continued on lurasidone, or switched from placebo to lurasidone. These data are the results of an interim analysis of the 2-year study. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score (responder criteria, ≥20% reduction from double-blind baseline).ResultsA total of 271 patients completed 6 weeks of double-blind treatment and entered the 2-year extension study. At the time of the interim analysis, 132 patients had completed 52 weeks of treatment (24 patients were 2-year study completers; 96 patients were still ongoing; and 12 patients had discontinued after 52 weeks); 57 patients were still ongoing in the first 1-year of treatment; and 82 patients terminated prior to week 52 (28 patients due to withdrawal of consent; 23 due to adverse events; 9 due to lack of efficacy; and 22 for other reasons). Mean PANSS total score at double-blind baseline was 93.5. Overall mean change from double-blind to open-label baseline (after 6 weeks of treatment) was -17.5 (for patients assigned to lurasidone vs. placebo in the initial 6-week study, mean change was: -19.8 vs. -12.9). Overall mean change from double-blind baseline in the PANSS total score at weeks 28 (n=215), 52 (n=133), 76 (n=86), and 104 (n=24) was -29.2, -34.0, -35.0, and -34.1, respectively. Responder rates at week 52 and week 104 were 91.7% and 100%, respectively. During open-label treatment, the most common adverse events were headache (21.8%), nausea (11.8%), and anxiety (11.8%); 6.6% of patients reported an adverse event as severe. Median change in laboratory parameters from double-blind baseline to weeks 52 and 104, respectively, were: total cholesterol, -2.0 and -5.0 mg/dL; triglycerides, +3.5 and +3.0 mg/dL; hemoglobin A1c, 0.0 and 0.1%; prolactin in female, +0.5 and -0.5 ng/mL and males, +0.15 and +3.5 ng/mL; and mean change from DB baseline in weight at weeks 52 and 104 were 3.8 and 7.2 kg, vs. an expected weight gain of 3.3 and 5.1 kg, based on the gender-and-age specific CDC growth chart.DiscussionIn adolescents with schizophrenia, long-term treatment with lurasidone was associated with continued improvement in symptoms of schizophrenia. After one year of lurasidone treatment, minimal effects were observed on body weight, lipids, and glycemic indices.

Neuroprotective effect of lurasidone via antagonist activities on histamine in a rat model of cranial nerve involvement.

Cranial nerve involvement frequently involves neuron damage and often leads to psychiatric disorder caused by multiple inducements. Lurasidone is a novel antipsychotic agent approved for the treatment of cranial nerve involvement and a number of mental health conditions in several countries. In the present study, the neuroprotective effect of lurasidone by antagonist activities on histamine was investigated in a rat model of cranial nerve involvement. The antagonist activities of lurasidone on serotonin 5‑HT7, serotonin 5‑HT2A, serotonin 5‑HT1A and serotonin 5‑HT6 were analyzed, and the preclinical therapeutic effects of lurasidone were examined in a rat model of cranial nerve involvement. The safety, maximum tolerated dose (MTD) and preliminary antitumor activity of lurasidone were also assessed in the cranial nerve involvement model. The therapeutic dose of lurasidone was 0.32mg once daily, administered continuously in 14‑day cycles. The results of the present study found that the preclinical prescriptions induced positive behavioral responses following treatment with lurasidone. The MTD was identified as a once daily administration of 0.32mg lurasidone. Long‑term treatment with lurasidone for cranial nerve involvement was shown to improve the therapeutic effects and reduce anxiety in the experimental rats. In addition, treatment with lurasidone did not affect body weight. The expression of the language competence protein, Forkhead‑BOX P2, was increased, and the levels of neuroprotective SxIP motif and microtubule end‑binding protein were increased in the hippocampal cells of rats with cranial nerve involvement treated with lurasidone. Lurasidone therapy reinforced memory capability and decreased anxiety. Taken together, lurasidone treatment appeared to protect against language disturbances associated with negative and cognitive impairment in the rat model of cranial nerve involvement, providing a basis for its use in the clinical treatment of patients with cranial nerve involvement.

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

BackgroundSevere 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.MethodsA 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.ResultsAmong 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.ConclusionsLurasidone 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.

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

To evaluate the safety and effectiveness of 6 months of treatment with lurasidone in older adults with a diagnosis of bipolar I depression. Post-hoc analysis of a multicenter, 6-month, open-label extension study. Outpatient. 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). Flexible doses of lurasidone, 20 to 120 mg/day, either as monotherapy, or adjunctive with lithium or valproate. Effectiveness was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS; change from open-label-baseline to month-6, observed case analysis). 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. 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.