Examination of the comprehensive gene expression in the SK-S-SH cell by the LTG dosage
Yoichiro Tanabe1,2. Shizen Yu1. Chiaki Ono1. Ai Hatou1. Hiroo Matsuoka2. Ichiro Sora,1. Hiroaki Tomita,1.
Effi cacies of a low dose atypical antipsychotic drug addition to an antidepressant and its effects on plasma brain-derived neurotrophic factor levels in refractory depression
○Reiji Yoshimura, Atsuko Ikenouchi-Sugita, Hikaru Hori, Wakako Umene-Nakano, Asuka Katsuki, Kenji Hayashi,
According to the meta-analysis of Nelson and Papakostas (2009), addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we examined the effects of various atypical antipsychotic drugs as adjuvant to antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors, tricyclic antidepressants and mood stabilizers, on plasma BDNF levels
in refractory depressed patients. Forty-five patients who met the DSMIV criteria for major depressive disorder (n=31) or bipolar disorder (10 with bipolar I, 4 with bipolar II) were enrolled in the study. Twentyone were male and 24 were female, and their ages ranged from 28 to 71 (mean±SD=49±12) years. Plasma BDNF levels were measured using a sandwich ELISA. The plasma BDNF levels in responders (those showing a decline in HAM-D scores of 50% or more) were significantly increased 4
weeks after the administration of each atypical antipsychotic drug, while the levels in non-responders were not changed. Furthermore, there was a significant correlation between the changes in HAM-D scores and the changes in plasma BDNF levels. These results indicate that adding an atypical antipsychotic drug to ongoing treatment with an antidepressant or mood stabilizer is useful and well-tolerated for refractory depressed patients, and the efficacy of atypical antipsychotics as an adjuvant might
Benefi ts of Switching Antidepressants Following Early Nonresponse
○Shinichiro Nakajima1,3. Takefumi Suzuki1,2. Kei Funaki1,8. Takashi Tsuboi1,9. Ryosuke Kitahata1,7. Norifusa Sawada1,3.
1. Background: The guidelines for major depressive disorder (MDD) recommend the continuous use of antidepressants for 4 to 8 weeks based on delayed onset hypothesis. Contrary to the conventional belief, recent meta-analyses show that antidepressants start to exert their efficacy within a couple of weeks. In addition, early outcomes at week 2 could predict subsequent outcomes. In this study, we examined the benefits of switching antidepressants following early nonresponse in patients with MDD. 2. Methods Patients: with a MDD who had not been treated for the current episode were included. Sertraline was initiated at 25 mg, increased to 50 mg on day 3, and maintained until day 14. If subjects showed an early response (i.e. a 20% improvement in the MADRS) at week 2, it was titrated at 50-100 mg. In case of early nonresponse, they were randomly divided into two groups. In one group, sertraline was titrated at 50-100 mg, whereas in the other group it was switched to paroxetine 20-40 mg. The regular assessments included MADRS and QIDS. 3. Results: Among 123 participants, both Switching group (n=18, 2 dropouts) and Continuing group (n=18, 4 dropouts) showed significant improvement at week 8. However, the Switching group showed superior results, compared to the Continuing group, in the number of remitters (11 vs. 3), MADRS (-18 vs. -6), and QIDSSR (-7 vs. -2). 4. Conclusion Our findings suggest that patients with MDD who fail to show early response may deserve benefits from switching antidepressants at the early stage. 5. Source of funding This study is partially funded by Pfizer.
How long to wait before reducing antipsychotic dosage in stabilized patients with schizophrenia? A retrospective chart review
○Hiroyoshi Takeuchi1. Hiroyuki Uchida1,2. Toshiaki Kikuchi1. Shinichiro Nakajima1. Hiroshi Manki1,3. Koichiro Watanabe1. Haruo Kashima1. Takefumi Suzuki1,2,4.
[Objective]Antipsychotic dose reduction is generally recommended to occur after six months of clinical stabilization despite inadequate evidence. This timing issue was addressed in this retrospective chart review.[Methods]Inclusion criteria were (1) diagnosis of schizophrenia (DSM-IV), (2) being acutely psychotic at their first outpatient visit from May 1, 2002 to April 30, 2003, (3) having responded to antipsychotics and achieved stabilization of acute symptoms, indexed as a fixation of regimen for four or more weeks, and (4) one or more years of follow-up. Patients who had their antipsychotic doses reduced were then identified, and they were divided into two groups based on the waiting period before dose reduction: ＜24 weeks (Early Group) and≧24 weeks (Standard Group). The rate of dose escalation for≧20% within the follow-up period was investigated as a proxy of clinical worsening.[Results]After excluding stable patients at baseline, 211 of 922 cases met the inclusion criteria. The rates of dose escalation were comparable between patients whose dose was reduced (N=83) and those who was not (N=128) (57.8% vs. 59.4%). The dose was increased again in 48 of the former patients: 36 in the Early Group (61.0%) and 12 in the Standard Group (50.0%). This difference failed to reach statistical significance although the reduction rate in antipsychotic dosage was significantly greater in the Early Group (58.7% vs. 43.3%). [Conclusion]The timeline until antipsychotic dose reduction in stable patients with schizophrenia could be shorter than currently recommended.
Predicting Antipsychotic Plasma Concentrations Before Titrating The Dose: A Population Pharmacokinetic Study
○Hiroyuki Uchida1,2. David Mamo2,3. Bruce Pollock2,3. Mulsant Benoit2,3. Takefumi Suzuki1,2,3. Koichiro Watanabe1. Robert Bies4.
Background: Due to a high interindividual variability in peripheral pharmacokinetic parameters, robustly predicting antipsychotic plasma concentrations before changing a dose for each individual has been a challenge. Methods: Two plasma samples for the measurement of risperidone (RIS) and 9-hydroxyrisperidone (9-OH-RIS) concentrations were collected at two separate given time points from 29 patients with schizophrenia (DSM-IV) and assessed, using LC/MS/MS. Subsequently, we collected another sample, following a dosage change. A plasma concentration associated with the dosage change was predicted in a blinded fashion, using the two samples collected at the baseline dose and subjects'demographic information with a previously established population pharmacokinetic model for RIS, using NONMEM. Accuracy of the predictions was then evaluated. This study was approved by the Institutional Review Board, and all subjects provided written informed consent. No information that could indentify subjects was collected. Results: The mean prediction errors and root squared prediction errors (ng/ml) were as low as 0.8 and 4.4 for RIS and 2.7 and 7.1 for 9-OH-RIS. The observed and predicted concentrations of RIS and 9-OH-RIS were highly correlated (r=0.93 and r=0.92, respectively). Conclusions: Antipsychotic plasma concentrations could be predicted before a dosage change. Taken together with the close relationship among plasma concentration, D2 receptor occupancy, and clinical effects, individualized dosing with the measurement of antipsychotic plasma concentrations could become a real potential clinical application.
Glucocorticoid-induced inhibition of astrocytic proliferation by the decrease of the expression of glucocorticoid receptor in cortical culture
○Kazuhiro Unemura. Toshiaki Kume. Minami Kondo. Yasuhiko Izumi. Akinori Akaike.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan Glucocorticoids are hypersecreted in depression/stress disorder, which is one of the most consistent findings in both clinical patients and animal models. In addition, it is reported that the number of astrocytes was reduced in the post-mortem prefrontal cortex from patients with depression. Glucocorticoid receptor (GR) deficient in forebrain has been reported to induce depression-like behavior in mice. Here, we investigated the relationship between astrocyte proliferation and GR expression change after GR stimulation. Cortical astrocytes were prepared from postnatal day 0-1 pups of Wistar rats. Cell proliferation was measured by MTT assay. GR expression level was determined by Western blotting analysis. Astrocytic proliferation was reduced by treatment of corticosterone or dexamethasone for 72 hr. The effects of corticosterone and dexamethasone on the proliferation were inhibited by RU486, a GR antagonist, but not eplerenone, a mineralcorticoid receptor antagonist. These results suggested that glucocorticoids reduced astrocyte proliferation via GR. Next, we investigated the involvement of GR expression level in astrocytic proliferation. GR expression was transiently increased at 3 hr after treatment with corticosterone or dexamethasone, subsequently decreased at 24 hr. The reduction of GR expression by glucocorticoids was inhibited by RU486. Furthermore, knockdown of GR resulted in reduction of astrocyte proliferation. Taken together, our results suggest glucocorticoids reduce astrocytic proliferation by glucocorticoid-induced reduction of GR.
Roles of prostaglandin E2 and its receptor EP1 in adaptive selection of emotional behaviors
○Tomoyuki Furuyashiki1. Kohei Tanaka1. Shiho Kitaoka1,2. Shuh Narumiya1.
An animal chooses an adaptive behavior among several behavioral strategies, "flight-or-fight" or social coping, upon encounter to a novel individual. In addition, chronic stress alters the selection of emotional behaviors. However, the mechanism for behavioral selection and plasticity remains elusive. Prostaglandin (PG) E2, a bioactive lipid, is derived from arachidonic acid by sequential actions of cyclooxygenase (COX) and PGE synthase, and binds to EP1, EP2, EP3, or EP4 for its actions. We previously reported that EP1-deficient mice show reduced social interaction and elevated aggression through hyperdopaminergic activity. Here we examined the role of PGE2-EP1 signaling in plasticity of emotional behavior. After repeated social defeat, wild-type mice acquired social withdrawal from a novel individual. In contrast, mice treated with SC-560, a COX-1 selective inhibitor, did not show the social withdrawal. Further, EP1-deficient mice abnormally showed social interaction even after social defeat, indicating the role of PGE2-EP1 signaling in the acquisition of social withdrawal after repeated social defeat. Behavioral evidence suggested that this lack of social withdrawal was not due to impaired perception or memory of social defeat. Consistent with a previous report on EP1 expression in the nucleus accumbens, EP1 deficiency abolished an increase in GSK-3β phosphorylation in these neurons after repeated social defeat. Thus, PGE2-EP1 signaling modulates social interaction in distinct ways without or with chronic stress.
Crisis in CNS Drug Development: Current Challenges and Possible Solutions
○Amir H Kalali
Central Nervous System disorders are a major cause of morbidity and mortality. While neuroscience discoveries are bringing us ever closer to understanding the etiology of these complex disorders, CNS drug development is a high risk, high cost endeavor compared to other therapeutic areas. Recently, several pharmaceutical companies have left the CNS drug development area, seeing it as being too risky, while others see this as an opportunity to meet the huge unmet need.This talk will discuss the unique issues and challenges in CNS drug development, and bringing new CNS treatments to market. Also the talk will discuss future trends such as increased globalization of drug development, personalized medicine, and the impact of financial constraints brought about by expiring patents on branded medications. These issues have implications for patients, health care providers, regulators, and governments.
A dibenzoylmethane derivative inhibits lipopolysaccharide-induced NO production in cultured rat astrocytes
○Katsura Takano1. Kumiko Sugita1. Mitsuaki Moriyama1. Koji Hashida2. Satoshi Hibino3. Tominari Choshi3. Rika Murakami4. Masashi Yamada5. Hiroto Suzuki5. Osamu Hori2,6. Yoichi Nakamura1.
[Introduction]Activation of glia has been observed in various neurodegenerative diseases. The enhancement of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress has been also implicated in several neurodegenerative disorders. During a search for compounds that regulate ER stress, we identified a dibenzoylmethane derivative, 2,2'-dimethoxydibenzoylmethane (DBM14-26) as a novel neuroprotective agent. In this study, we examined the effects of DBM14-26 on astrocyte's functions. [Methods]Cultured astrocytes were prepared from brain cortex dissected from Wistar rat embryo 19-20. The concentration of nitrite in the medium was measured by fluorescent assay with DAN reagent. iNOS expression was detected by western blotting with specific antibody. [Results]We found that DBM14-26 protected cultured astrocytes from H2O2- induced cytotoxicity. DBM14-26 prevented the production of reactive oxygen species in the cells exposed with H2O2 evaluated by fluorescent intensity of dichlorofluorescein. Further examination revealed that DBM14-26 inhibited lipopolysaccharide (LPS)-induced iNOS expression and NO production. DBM14-26 suppressed LPS-stimulated nuclear factor (NF)-κB activation evaluated by gel retardation electrophoresis.[Conclusion]These results indicate that DBM14-26 suppresses astrocyte's activation via inhibition of NF-κB activation. Functional regulation of astrocytes by DBM14-26 could be a therapeutic candidate for the treatment of neurodegenerative diseases.