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 Novel Atypical Antipsychotic Lurasidone Affects Cytochrome P450 Expression in the Liver and Peripheral Blood Lymphocytes.

Lurasidone is a novel atypical antipsychotic drug acting on dopaminergic, serotonergic and noradrenergic receptors; it is applied for the long-term treatment of schizophrenia and depression in patients with bipolar disorders. We aimed at performing a comparative study on the influence of chronic treatment with lurasidone on the expression of cytochrome P450 enzymes in the liver and in peripheral blood lymphocytes, and to evaluate the relationship between changes in the expression of CYP enzymes in the two experimental models. The obtained results show a fairly similar expression pattern of the main CYP enzymes in the rat livers and lymphocytes, and they indicate that in the liver, lurasidone exerts an inhibitory effect on the activity, protein and mRNA levels of CYP2B1/2 (not CYP2B2 mRNA), CYP2C11 and CYP2E1, while in the case of CYP3A1 and CYP3A2, it causes enzyme induction. At the same time, lurasidone decreases the expression of CYP2B, CYP2C11 (CYP2C11 protein only) and CYP2E1 but increases that of CYP3A2 (not CYP3A1) in lymphocyte cells. In conclusion, chronic treatment with lurasidone simultaneously and in the same way influences the expression and activity of CYP2B, CYP2C11, CYP2E1 and CYP3A2 in the liver and peripheral blood lymphocytes of rats. Thus, the lymphocyte cytochrome P450 profile may be utilized as an indicator of the hepatic cytochrome P450 profile in further clinical studies with lurasidone, and lymphocytes may serve as easily available surrogates for examining the impact of new drugs and chronic in vivo treatments on CYP enzyme expression, as well as to estimate drug-drug interactions and toxicity risk.

In Silico Drug Repurposing of FDA-Approved Drugs Highlighting Promacta as a Potential Inhibitor of H7N9 Influenza Virus.

Influenza virus infections continue to be a significant and recurrent public health problem. Although vaccine efficacy varies, regular immunisation is the most effective method for suppressing the influenza virus. Antiviral drugs are available for influenza, although two of the four FDA-approved antiviral treatments have resulted in significant drug resistance. Therefore, new treatments are being sought to reduce the burden of flu-related illness. The time-consuming development of treatments for new and re-emerging diseases such as influenza and the high failure rate are increasing concerns. In this context, we used an in silico-based drug repurposing method to repurpose FDA-approved drugs as potential therapies against the H7N9 virus. To find potential inhibitors, a total of 2568 drugs were screened. Promacta, tucatinib, and lurasidone were identified as promising hits in the DrugBank database. According to the calculations of MM-GBSA, tucatinib (-54.11 kcal/mol) and Promacta (-56.20 kcal/mol) occupied the active site of neuraminidase with a higher binding affinity than the standard drug peramivir (-49.09 kcal/mol). Molecular dynamics (MD) simulation studies showed that the C-α atom backbones of the complexes of tucatinib and Promacta neuraminidase were stable throughout the simulation period. According to ADME analysis, the hit compounds have a high gastrointestinal absorption (GI) and do not exhibit properties that allow them to cross the blood-brain barrier (BBB). According to the in silico toxicity prediction, Promacta is not cardiotoxic, while lurasidone and tucatinib show only weak inhibition. Therefore, we propose to test these compounds experimentally against the influenza H7N9 virus. The investigation and validation of these potential H7N9 inhibitors would be beneficial in order to bring these compounds into clinical settings.

Stress Modifies the Expression of Glucocorticoid-Responsive Genes by Acting at Epigenetic Levels in the Rat Prefrontal Cortex: Modulatory Activity of Lurasidone.

Epigenetics is one of the mechanisms by which environmental factors can alter brain function and may contribute to central nervous system disorders. Alterations of DNA methylation and miRNA expression can induce long-lasting changes in neurobiological processes. Hence, we investigated the effect of chronic stress, by employing the chronic mild stress (CMS) and the chronic restraint stress protocol, in adult male rats, on the glucocorticoid receptor (GR) function. We focused on DNA methylation specifically in the proximity of the glucocorticoid responsive element (GRE) of the GR responsive genes Gadd45ß, Sgk1, and Gilz and on selected miRNA targeting these genes. Moreover, we assessed the role of the antipsychotic lurasidone in modulating these alterations. Chronic stress downregulated Gadd45ß and Gilz gene expression and lurasidone normalized the Gadd45ß modification. At the epigenetic level, CMS induced hypermethylation of the GRE of Gadd45ß gene, an effect prevented by lurasidone treatment. These stress-induced alterations were still present even after a period of rest from stress, indicating the enduring nature of such changes. However, the contribution of miRNA to the alterations in gene expression was moderate in our experimental conditions. Our results demonstrated that chronic stress mainly affects Gadd45ß expression and methylation, effects that are prolonged over time, suggesting that stress leads to changes in DNA methylation that last also after the cessation of stress procedure, and that lurasidone is a modifier of such mechanisms.

Effects of Subchronic Administrations of Vortioxetine, Lurasidone, and Escitalopram on Thalamocortical Glutamatergic Transmission Associated with Serotonin 5-HT7 Receptor.

The functional suppression of serotonin (5-HT) type 7 receptor (5-HT7R) is forming a basis for scientific discussion in psychopharmacology due to its rapid-acting antidepressant-like action. A novel mood-stabilizing atypical antipsychotic agent, lurasidone, exhibits a unique receptor-binding profile, including a high affinity for 5-HT7R antagonism. A member of a novel class of antidepressants, vortioxetine, which is a serotonin partial agonist reuptake inhibitor (SPARI), also exhibits a higher affinity for serotonin transporter, serotonin receptors type 1A (5-HT1AR) and type 3 (5-HT3R), and 5-HT7R. However, the effects of chronic administration of lurasidone, vortioxetine, and the selective serotonin reuptake inhibitor (SSRI), escitalopram, on 5-HT7R function remained to be clarified. Thus, to explore the mechanisms underlying the clinical effects of vortioxetine, escitalopram, and lurasidone, the present study determined the effects of these agents on thalamocortical glutamatergic transmission, which contributes to emotional/mood perception, using multiprobe microdialysis and 5-HT7R expression using capillary immunoblotting. Acute local administration of a 5-HT7R agonist and antagonist into the mediodorsal thalamic nucleus (MDTN) enhanced and reduced thalamocortical glutamatergic transmission, induced by N-methyl-D-aspartate (NMDA)/glutamate receptor inhibition in the reticular thalamic nucleus (RTN). Acute local administration of a relevant therapeutic concentration of vortioxetine and lurasidone into the MDTN suppressed the thalamocortical glutamatergic transmission via 5-HT7R inhibition, whereas that of escitalopram activated 5-HT7R. Subchronic administration of effective doses of vortioxetine and lurasidone (for 7 days) reduced the thalamocortical glutamatergic transmission, but escitalopram did not affect it, whereas subchronic administration of these three agents attenuated the stimulatory effects of the 5-HT7R agonist on thalamocortical glutamatergic transmission. Subchronic administration of effective doses of vortioxetine, lurasidone, and escitalopram downregulated the 5-HT7R expression of the plasma membrane in the MDTN; the 5-HT7R downregulation induced by vortioxetine and lurasidone was observed at 3 days, but that induced by escitalopram required a longer duration of 7 days. These results indicate that chronic administration of vortioxetine, escitalopram, and lurasidone generate downregulation of 5-HT7R in the thalamus; however, the direct inhibition of 5-HT7R associated with vortioxetine and lurasidone generates more rapid downregulation than the indirect elevation of the extracellular serotonin level via serotonin transporter inhibition by escitalopram.

Asenapine and iloperidone decrease the expression of major cytochrome P450 enzymes CYP1A2 and CYP3A4 in human hepatocytes. A significance for drug-drug interactions during combined therapy.

Antipsychotics are often used in combination with other psychotropic drugs to treat a variety of psychiatric disorders, as well as in combination with other drugs taken by patients with co-morbidities. When these drugs are combined, the potential for drug-drug interaction increases, leading to side-effects, in addition to the predicted increase in effectiveness. The present study aimed at examining the effects of the three atypical neuroleptics asenapine, lurasidone and iloperidone on cytochrome P450 (CYP) expression in the human liver. The study was carried out on cryopreserved human hepatocytes. The hepatotoxicity of the tested drugs was assessed after exposure to the neuroleptics (LDH cytotoxicity assay). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A1/2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19) and testosterone 6ß-hydroxylation (CYP3A4). Parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. Asenapine significantly decreased the mRNA level and activity of CYP1A2, while iloperidone potently diminished the mRNA level and activity of CYP3A4 in the cultures of human hepatocytes. Lurasidone did not affect the expression and activity of any of the investigated human CYP enzymes. The presented findings may have clinical implications for the prediction of potential drug-drug interactions involving the asenapine-induced inhibition of metabolism of CYP1A2 substrates (e.g. caffeine, theophylline, melatonin, tricyclic antidepressants, phenacetin, propranolol) and iloperidone-induced inhibition of CYP3A4 substrates (e.g. antidepressants, benzodiazepines, atorvastatin, macrolide antibiotics, calcium channel antagonists).

Chemical puzzles in the search for new, flexible derivatives of lurasidone as antipsychotic drugs.

In the pharmacotherapy of schizophrenia, there is a lack of effective drugs, and currently used agents cause a large number of side effects. The D2, 5-HT1A, 5-HT2A receptors are among the most important receptor targets in the treatment of schizophrenia, but antagonism at 5-HT6 and 5-HT7 receptors may bring about additional improvement of cognitive functions. However, doubt exists regarding the importance of 5-HT7R in the pharmacotherapy. In 2010, lurasidone (with high affinity for D2, D3, 5-HT1A, 5-HT2A, 5-HT7 receptors) was approved for the treatment of schizophrenia. Due to the efficacy of the mentioned drug and doubts related to the role of 5-HT7R, we decided to obtain compounds with an activity profile similar to that of lurasidone, but with the reduced affinity for 5-HT7R and increased affinity for 5-HT6R. For this purpose, we chose aflexible hexyl derivative of lurasidone (2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 1a) as a hit structure. After molecular modeling, we modified it, in the area of the arylpiperazine and imide group, using the moieties found in other known CNS drugs. We received the compounds in accordance with the previously developed method of ecological synthesis in the microwave radiation field. Among the obtained compounds, N-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)naphthalene-sulfonamides 1v and 1w were distinguished as multifunctional ligands showing increased affinity for 5-HT6R, and 2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 1i - a multifunctional ligand showing moderate affinity for 5-HT6R and threefold lower for 5-HT7R. In the paper, we discuss some of the observed dependencies regarding 5-HT6/5-HT7R affinity using molecular docking methods.

Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia.

AIM: The aim of the present study was to evaluate the efficacy and safety of lurasidone for the treatment of Chinese schizophrenic patients. METHODS: Hospitalized schizophrenia patients aged 18-65 were randomized to 6 weeks of double-blind, double-dummy, flexible-dose treatment with lurasidone (40 or 80 mg/day) or risperidone (2, 4 or 6 mg/day). Efficacy was evaluated using a non-inferiority comparison of lurasidone relative to risperidone based on week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score. Safety assessments included adverse events, clinical laboratory measures, and electrocardiograms. RESULTS: Four hundred and forty-four patients were screened to obtain an intent-to-treat sample of 384 patients, of whom 54 patients discontinued treatment prior to 6 weeks. Lurasidone met the criteria for non-inferiority versus risperidone on the PANSS total score. Adjusted mean (SE) change at week 6 on the PANSS total score was -31.2 (1.0) and -34.9 (1.0) in the lurasidone and risperidone group, respectively. The mean difference score was 3.7, and the upper boundary of the 95%-confidence interval (1.0-6.3) was less than the prespecified margin of 7.0. No clinically meaningful between-treatment group differences were evident on secondary efficacy measures, including PANSS positive, PANSS negative, Clinical Global Impression scale - Severity, and Calgary Depression Scale for Schizophrenia scales. The incidence of adverse events was lower for lurasidone vs risperidone for extrapyramidal symptoms (17.0% vs 38.2%), akathisia (7.2% vs 13.6%), prolactin increase (3.1% vs 14.1%), and weight increase (0.5% vs 5.2%). CONCLUSION: Lurasidone was found to be non-inferior to risperidone on the primary endpoint with minimal effects on weight, metabolic parameters, or prolactin levels.

Double-blind, placebo-controlled study of lurasidone monotherapy for the treatment of bipolar I depression.

AIM: Previous studies conducted primarily in the USA and Europe have demonstrated the efficacy and safety of lurasidone 20-120 mg/day for the treatment of bipolar I depression. The aim of the current study was to evaluate the efficacy and safety of lurasidone monotherapy for the treatment of bipolar I depression among patients from diverse ethnic backgrounds, including those from Japan. METHODS: Patients were randomly assigned to double-blind treatment for 6 weeks with lurasidone, 20-60 mg/day (n = 184) or 80-120 mg/day (n = 169), or placebo (n = 172). The primary end-point was change from baseline to Week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Lurasidone treatment significantly reduced mean MADRS total scores from baseline to Week 6 for the 20-60-mg/day group (-13.6; adjusted P = 0.007; effect size = 0.33), but not for the 80-120-mg/day group (-12.6; adjusted P = 0.057; effect size = 0.22) compared with placebo (-10.6). Treatment with lurasidone 20-60 mg/day also improved MADRS response rates, functional impairment, and anxiety symptoms. The most common adverse events associated with lurasidone were akathisia and nausea. Lurasidone treatments were associated with minimal changes in weight, lipids, and measures of glycemic control. CONCLUSION: Monotherapy with once daily doses of lurasidone 20-60 mg, but not 80-120 mg, significantly reduced depressive symptoms and improved functioning in patients with bipolar I depression. Results overall were consistent with previous studies, suggesting that lurasidone 20-60 mg/day is effective and safe in diverse ethnic populations, including Japanese.

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.

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

Background: Psychiatric 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. Methods: Adult 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. Results: Chronic 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. Conclusions: Our 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.

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.

A case series on the effectiveness of lurasidone in patients with stuttering.

BACKGROUND: The prevalence of stuttering is approximately 1% of the population, affecting an estimated 3 million individuals in the United States. The dopamine hypothesis of stuttering explains that abnormally increased cerebral dopamine affects the balanced levels that maintain the basal ganglia circuits, which helps with timing cues in initiating speech. This is especially significant when considering treatment strategies. We report a reduction in stuttering with lurasidone, a potent D2 receptor antagonist with a relatively favorable adverse effects profile. METHODS: We conducted a non-randomized, open-label study of lurasidone in patients with stuttering (N = 7). Patients self-reported stuttering severity, locus of control, and avoidance using the Subjective Screening of Stuttering (SSS) scale and were assessed with the Clinical Global Impression (CGI) Scale. RESULTS: We observed a notable, statistically significant improvement in all areas of stuttering, as rated by the SSS scale. According to the CGI-Improvement Scale, 2 patients were scored as "very much improved" and 5 were scored as "much improved." CONCLUSIONS: This open-label study of lurasidone in patients with stuttering showed improvement in subjective symptoms, in CGI scores, and on the SSS scale.

Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: Restorative effect of pharmacological intervention.

Major depression is a complex disease that originates from the interaction between a genetic background of susceptibility and environmental factors such as stress. At molecular level, it is characterized by dysfunctions of multiple systems including neurotransmitters, hormones, signalling pathways, neurotrophic and neuroplastic molecules and - more recently - inflammatory mediators. Accordingly, in the present study we used the chronic mild stress (CMS) paradigm in the rat to elucidate to what extent brain inflammation may contribute to the development and/or the maintenance of an anhedonic phenotype and how pharmacological intervention may interfere with such behavioral and molecular stress-induced alterations. To this aim, adult male rats were exposed to CMS for 2 weeks and the cerebral expression of several mediators of the inflammatory system was evaluated in the hippocampus and prefrontal cortex of both stressed and control animals in parallel with the sucrose intake. Next, the animals that showed a decreased sucrose consumption were exposed to five further weeks of CMS and treated with the antidepressants imipramine or agomelatine, or the antipsychotic lurasidone. Our results demonstrate that only the stressed animals that were characterized by a deficit in sucrose intake showed increased expression of the pro-inflammatory cytokines IL-1ß, IL-6 and up-regulation of markers and mediators of microglia activation such as CD11b, CX3CL1 and its receptor CX3CR1 in comparison with stress-resilient animals. Some of these molecular alterations persisted also after longer stress exposure and were modulated, similarly to the behavioral effects of CMS, by chronic pharmacological treatment. These data suggest that neuroinflammation may have a key role in the pathological consequences of stress exposure, thus contributing to the subject's vulnerability for depression.

Chronic mild stress-induced alterations of clock gene expression in rat prefrontal cortex: modulatory effects of prolonged lurasidone treatment.

Disruptions of biological rhythms are known to be associated with depressive disorders, suggesting that abnormalities in the molecular clock may contribute to the development of these disorders. These mechanisms have been extensively characterized in the suprachiasmatic nucleus, but little is know about the role exerted by individual clock genes in brain structures that are important for depressive disorders. Using the chronic mild stress model we found a significant reduction of BMAL1 and CLOCK protein levels in the nuclear compartment of the prefrontal cortex of CMS rats, which was paralleled by a down-regulation of the expression of several target genes, including Pers and Crys but also Reverbß and Pparα. Interestingly, chronic treatment with the multi receptor modulator lurasidone (3mg/kg for 5 weeks) was able to normalize the molecular changes induced by CMS exposure in prefrontal cortex, but it was also able to regulate some of these genes within the hippocampus. We believe that changes in clock genes expression after CMS exposure may contribute to the disturbances associated with depressive disorders and that the ability of chronic lurasidone to normalize such alterations may be relevant for its therapeutic properties in ameliorating functions that are deteriorated in patients with major depression and other stress-related disorders.

The sleep effects of lurasidone: a placebo-controlled cross-over study using a 4-h phase-advance model of transient insomnia.

BACKGROUND: Lurasidone, an atypical antipsychotic, is a potent 5-HT7 antagonist and D2 , 5-HT2A antagonist, and 5-HT1A partial agonist. As such, lurasidone would be expected to modulate sleep and circadian function but there have been no human studies of the sleep effects of a 5-HT7 antagonist. The purpose of this study was to assess effects of lurasidone on sleep. METHODS: This was a cross-over, polysomnographic study involving 54 healthy volunteers who underwent two treatment periods (order randomized) each consisting of two nights in the laboratory: Night 1-lights out at usual bedtime; Night 2-4-h advance of sleep phase and randomization to either lurasidone 40 mg or placebo. The next morning impairment testing was carried out. RESULTS: Lurasidone significantly (p < 0.05) increased total sleep time by an average of 28.4 min versus placebo, decreased wake time after sleep onset and wake time after the final awakening, and increased sleep efficiency. No other effects were found. CONCLUSIONS: Lurasidone had a sleep maintenance effect without effects on sleep onset, rapid eye movement, or slow-wave sleep. Lurasidone is likely to be beneficial to patients with disturbed sleep, particularly those with sleep maintenance problems. Copyright © 2016 John Wiley & Sons, Ltd.

Lurasidone exerts antidepressant properties in the chronic mild stress model through the regulation of synaptic and neuroplastic mechanisms in the rat prefrontal cortex.

BACKGROUND: Major depression is associated with several alterations, including reduced neuronal plasticity and impaired synaptic function, which represent an important target of pharmacological intervention. METHODS: In the present study, we have investigated the ability of the antipsychotic drug lurasidone to modulate behavioral and neuroplastic alterations in the chronic mild stress model of depression. RESULTS: Rats that show reduced sucrose consumption after 2 weeks of chronic mild stress have reduced expression of the pool of Bdnf transcripts with the long 3' untranslated region (3'-UTR) that may be targeted to the synaptic compartment, suggesting the contribution of the neurotrophin to the behavioral dysfunction produced by chronic mild stress. The downregulation of Bdnf expression persisted also after 7 weeks of chronic mild stress, whereas chronic lurasidone treatment improved anhedonia in chronic mild stress rats and restored Bdnf mRNA levels in the prefrontal cortex. Moreover, chronic lurasidone treatment was able to normalize chronic mild stress-induced defects of Psd95 and Gfap as well as changes in molecular regulators of protein translation at the synapse, including mTOR and eEF2. CONCLUSIONS: These results demonstrate that lurasidone shows antidepressant properties in the chronic mild stress model through the modulation of synaptic and neuroplastic proteins. Such changes may contribute to the amelioration of functional capacities, which are deteriorated in patients with major depression and stress-related disorders.

Transcriptomic analyses of rats exposed to chronic mild stress: Modulation by chronic treatment with the antipsychotic drug lurasidone.

Exposure to stressful experiences accounts for almost half of the risk for mental disorders. Hence, stress-induced alterations represent a key target for pharmacological interventions aimed at restoring brain function in affected individuals. We have previously demonstrated that lurasidone, a multi-receptor antipsychotic drug approved for the treatment of schizophrenia and bipolar depression, can normalize the functional and molecular impairments induced by stress exposure, representing a valuable tool for the treatment of stress-induced mental illnesses. However, the mechanisms that may contribute to the therapeutic effects of lurasidone are still poorly understood. Here, we performed a transcriptomic analysis on the prefrontal cortex (PFC) of adult male rats exposed to the chronic mild stress (CMS) paradigm and we investigated the impact of chronic lurasidone treatment on such changes. We found that CMS exposure leads to an anhedonic phenotype associated with a down-regulation of different pathways associated to neuronal guidance and synaptic plasticity within the PFC. Interestingly, a significant part of these alterations (around 25%) were counteracted by lurasidone treatment. In summary, we provided new insights on the transcriptional changes relevant for the therapeutic intervention with lurasidone, which may ultimately promote resilience.