Lurasidone

Lurasidone in the treatment of schizophrenia: Results of a double-blind, placebo-controlled trial in Asian patients.[Pubmed:30950208]

Asia Pac Psychiatry. 2019 Apr 4:e12352.

INTRODUCTION: To evaluate efficacy and safety of Lurasidone for the treatment of Asian patients with schizophrenia. METHODS: Patients with schizophrenia from Japan, South Korea, Malaysia, and Taiwan were randomly assigned to 6 weeks of double-blind treatment with 40 or 80 mg/d of Lurasidone or placebo. The primary efficacy measure was change from baseline to week 6 on the Positive and Negative Syndrome Scale (PANSS) total score. Efficacy was evaluated using a mixed-model repeated-measures (MMRM) analysis in the modified intention-to-treat (mITT) population. RESULTS: On the basis of the analysis for the mITT population, the estimated difference score for Lurasidone 40 and 80 mg/d vs placebo was -4.8 (P = 0.050) and -4.2 (P = 0.080). For the full intention-to-treat (ITT) population, the difference score for Lurasidone 40 and 80 mg/d vs placebo was -5.8 (P = 0.017) and -4.2 (P = 0.043). The most frequent adverse events in the Lurasidone 40 and 80 mg/d and placebo groups, respectively, were akathisia (7.3%, 10.4%, 3.3%), somnolence (6.0%, 2.6%, 0.7%), and vomiting (6.0%, 5.8%, 2.0%). The proportion of patients experiencing clinically significant weight gain (>/=7%) was 5.3% for Lurasidone 40 mg/d, 1.3% for 80 mg/d, and 1.4% for placebo. End point changes in metabolic parameters and prolactin were comparable for both Lurasidone groups and placebo. CONCLUSIONS: In the ITT (but not the mITT) population, treatment with Lurasidone was associated with significant improvement in the PANSS total score in patients with schizophrenia. Lurasidone was generally well tolerated with minimal impact on weight and metabolic parameters.

Effects of Temperature and Ionic Strength of Dissolution Medium on the Gelation of Amorphous Lurasidone Hydrochloride.[Pubmed:30915636]

Pharm Res. 2019 Mar 26;36(5):72.

PURPOSE: Amorphous Lurasidone hydrochloride (LH) showed decreased dissolution behavior in comparison to crystalline LH owing to gelation during dissolution as reported in our previous study. The current study aims to investigate external factors including temperature and ionic strength on the gelation and hence the dissolution of amorphous LH. METHODS: Dissolution tests of amorphous LH were performed under different temperatures and buffer ionic strengths. The formed gels were characterized by rheology study, texture analysis, PLM, SEM, DSC, XRPD and FTIR. RESULTS: With the increase of temperature and ionic strength of medium, the dissolution of amorphous LH decreased, while the strength, hardness and adhesiveness of in situ formed gel enhanced. Amorphous LH converted into its crystalline state during dissolution and the crystallization rate was affected by medium conditions. With medium temperature increasing from 30 degrees C to 45 degrees C, the gel microstructure changed from interconnecting fibrillar network to spherical particle aggregate. On the other hand, the formed spherulitic gel aggregate exhibited increased particle size when increasing the ionic strength of medium. CONCLUSIONS: With increase of temperature and ionic strength, the gel strength of in situ formed gel from amorphous LH enhanced with more compact microstructure, subsequently leading to decreased dissolution profiles.

Randomized, double-blind, placebo, and risperidone-controlled study of lurasidone in the treatment of schizophrenia: Results of an inconclusive 6-week trial.[Pubmed:30912222]

Asia Pac Psychiatry. 2019 Mar 25:e12354.

OBJECTIVE: The efficacy and safety of Lurasidone in schizophrenia has been demonstrated in multiple controlled trials, primarily in US and European populations. The aim of the current study was To evaluate Lurasidone for the treatment of schizophrenia among patients in Japan, Korea, and Taiwan. METHODS: Hospitalized patients (N = 460) with schizophrenia were randomized to 6 weeks of fixed-dose Lurasidone 40 mg/d, Lurasidone 80 mg/d, risperidone 4 mg/d, or placebo. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). RESULTS: No significant endpoint differences in PANSS total score were found for Lurasidone or risperidone vs placebo. Lurasidone was safe and well tolerated, with minimal effects on weight and metabolic parameters. DISCUSSION: The current study was inconclusive regarding the efficacy of Lurasidone in schizophrenia but further confirmed its safety and tolerability.

Adjunctive Lurasidone Suppresses Food Intake and Weight Gain Associated with Olanzapine Administration in Rats.[Pubmed:30905132]

Clin Psychopharmacol Neurosci. 2019 May 31;17(2):314-317.

Objective: : Lurasidone is an antipsychotic drug that shows a relative lack of weight gain common to many antipsychotics. Aripiprazole and ziprasidone also show little weight gain and can reduce olanzapine-induced food intake and weight gain in animals, paralleling some clinical findings. We hypothesized that Lurasidone would have similar actions. Methods: : Female Lister-hooded rats received intraperitoneal injection either 2x vehicle (saline), Lurasidone (3 mg/kg) and vehicle, olanzapine (1 mg/kg) and vehicle, or olanzapine and Lurasidone. Following drug administration food intake was measured for 60min. A further series of rats underwent a seven-day regime of once-daily administration of the above doses and free access to food and water. Weight gain over the course of the study was monitored. Results: : Olanzapine induced a significant increase in food intake while Lurasidone showed no significant effect. Co-administration of Lurasidone with olanzapine suppressed the increase in food intake. Repeated dosing showed an increase in body weight after seven days with olanzapine, and no significant effect observed with Lurasidone, while repeated administration of Lurasidone with olanzapine reduced the effect of olanzapine on the increase in body weight. Conclusion: : These findings support our hypotheses in that Lurasidone, in addition to a lack of effect on acute food intake and short term weight gain, can reduce olanzapine-induced food intake and weight gain in rats. This indicates the drug to have an active anti-hyperphagic mechanism, rather than solely the absence of a drug-induced weight gain that is such a severe limitation of drugs such as olanzapine.

Modulation of anterior cingulate cortex reward and penalty signalling in medication-naive young-adult subjects with depressive symptoms following acute dose lurasidone.[Pubmed:30606271]

Psychol Med. 2019 Jan 4:1-13.

BACKGROUND: Aberrations in reward and penalty processing are implicated in depression and putatively reflect altered dopamine signalling. This study exploits the advantages of a placebo-controlled design to examine how a novel D2 antagonist with adjunctive antidepressant properties modifies activity in the brain's reward network in depression. METHODS: We recruited 43 medication-naive subjects across the range of depression severity (Beck's Depression Inventory-II score range: 0-43), including healthy volunteers, as well as people meeting full-criteria for major depressive disorder. In a double-blind placebo-controlled cross-over design, all subjects received either placebo or Lurasidone (20 mg) across two visits separated by 1 week. Functional magnetic resonance imaging with the Monetary Incentive Delay (MID) task assessed reward functions via neural responses during anticipation and receipt of gains and losses. Arterial spin labelling measured cerebral blood flow (CBF) at rest. RESULTS: Lurasidone altered fronto-striatal activity during anticipation and outcome phases of the MID task. A significant three-way Medication-by-Depression severity-by-Outcome interaction emerged in the anterior cingulate cortex (ACC) after correction for multiple comparisons. Follow-up analyses revealed significantly higher ACC activation to losses in high- v. low depression participants in the placebo condition, with a normalisation by Lurasidone. This effect could not be accounted for by shifts in resting CBF. CONCLUSIONS: Lurasidone acutely normalises reward processing signals in individuals with depressive symptoms. Lurasidone's antidepressant effects may arise from reducing responses to penalty outcomes in individuals with depressive symptoms.

Lurasidone (SM-13496) is an antagonist of both dopamine D2 and 5-HT7 with IC50s of 1.68 and 0.495 nM, respectively. Lurasidone (SM-13496) is also a partial agonist of 5-HT1A receptor with an IC50 of 6.75 nM.

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