Researcher Database

Ichiro Kusumi
Faculty of Medicine Specialized Medicine Neurological Disorder
Professor

Researcher Profile and Settings

Affiliation

  • Faculty of Medicine Specialized Medicine Neurological Disorder

Job Title

  • Professor

Degree

  • M.D., Ph.D.

Research funding number

  • 30250426

J-Global ID

Profile

  • My major was psychopharmacology and the main research theme were the pathophysiology of mood disorders and mechanisms of action of psychotropic drugs. I have recently been interested in the neuroimaging and psychophysiology of schizophrenia.

Research Interests

  • valproate   SERCA   lithium   カルモジュリン   serotonin   dopamine D2 receptor   小胞体ストレス反応   bipolar disorder   protein kinase C   platelet   serotonin 5-HT2A receptor   atypical antipsychotics   psychopharmacology   molecular genetics   Calcium   SSRI   schizophrenia   

Research Areas

  • Life sciences / Psychiatry

Academic & Professional Experience

  • 2012/09 - Today Hokkaido University Graduate School of Medicine
  • 2008/04 - 2012/08 Hokkaido University Graduate School of Medicine
  • 1999/04 - 2008/03 北海道大学病院精神科神経科 講師
  • 1993/01 - 1999/03 Hokkaido University School of Medicine
  • 1989/08 - 1992/12 北海道大学医学部附属病院精神科神経科 医員
  • 1989/04 - 1989/07 市立室蘭総合病院祝津分院 常勤医師
  • 1988/10 - 1989/03 医療法人 啓生会病院 医師
  • 1987/07 - 1988/09 国立精神・神経センター 神経研究所 疾病研究第三部 流動研究員
  • 1985/07 - 1987/06 市立室蘭総合病院祝津分院 常勤医師
  • 1984/05 - 1985/06 北海道大学医学部附属病院精神科神経科 医員(研修医)

Education

  • 1978/04 - 1984/03  Hokkaido University  School of Medicine

Association Memberships

  • Society for Neuroscience(米国)   日本睡眠学会   日本生物学的精神医学会   日本神経化学会   日本心身医学会   日本精神科診断学会   JAPANESE SOCIETY MOOD DISORDERS   日本統合失調症学会   日本臨床精神薬理学会   THE JAPANESE SOCIETY OF NEUROPSYCHOPHARMACOLOGY   日本精神神経学会   

Research Activities

Published Papers

  • Ryo Okubo, Takeshi Inoue, Naoki Hashimoto, Akio Suzukawa, Hajime Tanabe, Matsuhiko Oka, Hisashi Narita, Koki Ito, Yuki Kako, Ichiro Kusumi
    PSYCHIATRY RESEARCH 257 126 - 131 0165-1781 2017/11 [Refereed][Not invited]
     
    Previous studies indicated that personality traits have a mediator effect on the relationship between childhood abuse and depressive symptoms in major depressive disorder and nonclinical general adult subjects. In the present study, we aimed to test the hypothesis that personality traits mediate the relationship between childhood abuse and depressive symptoms in schizophrenia. We used the following questionnaires to evaluate 255 outpatients with schizophrenia: the Child Abuse and Trauma Scale, temperament and character inventory, and Patients Health Questionnire-9. Univariate analysis, multiple regression analysis, and structured equation, modeling (SEM) were used to analyze the data. The relationship between neglect and sexual abuse and the severity of depressive symptoms was mostly mediated by the personality traits of high harm avoidance, low self-directedness, and low cooperativeness. This finding was supported by the results of stepwise multiple regression analysis and the acceptable fit indices of SEM. Thus, our results suggest that personality traits mediate the relationship between childhood abuse and depressive symptoms in schizophrenia. The present study and our previous studies also suggest that this mediator effect could occur independent of the presence or type of mental disorder. Clinicians should routinely assess childhood abuse history, personality traits, and their effects in schizophrenia.
  • Ryo Sawagashira, Hisashi Narita, Naoki Hashimoto, Tsugiko Kurita, Shin Nakagawa, Takuya Saitoh, Ichiro Kusumi
    EPILEPTIC DISORDERS 19 (3) 379 - 382 1294-9361 2017/09 [Refereed][Not invited]
     
    Transient lesions of the splenium of the corpus callosum are characterized by MRI findings. The lesions are very rare, but significant from a clinical standpoint as differential diagnoses include serious conditions such as encephalitis, meningitis, and neuroleptic malignant syndrome. In addition, it is reported that some are attributed to the withdrawal of antiepileptic drugs. Here, we present a case of transient lesions of the splenium of the corpus callosum following rapid withdrawal of levetiracetam alone. To the best of our knowledge, this is the first report of such a case. Moreover, it is reported that cases of incidental transient lesions of the splenium of the corpus callosum are detected in Japan more often than in other countries, and as a result are prone to over-triage. Taking this into consideration, in the event of transient lesions of the splenium of the corpus callosum, the utmost attention must be paid to clinical symptoms and history relating to any of the aforementioned serious conditions.
  • Tomiki Sumiyoshi, Atsuhito Toyomaki, Naoko Kawano, Tomoko Kitajima, Ichiro Kusumi, Norio Ozaki, Nakao Iwata, Kazuki Sueyoshi, Kazuyuki Nakagome
    FRONTIERS IN PSYCHIATRY 8 168  1664-0640 2017/09 [Refereed][Not invited]
     
    Backgrounds: Several domains of cognitive function, including learning memory and executive function, are impaired in mood disorders. Also, the relationship between disturbances of these two cognitive domains has been suggested. In line with the recent initiative to establish a standard measure of cognitive decline in bipolar disorder, the present study was conducted to (1) test the criterion-related validity and test-retest reliability of the California Verbal Learning Test (CVLT)-II Japanese version, and (2) determine if type of word learning tasks (i.e., with or without a category structure) affects severity of verbal memory deficits in patients with subsyndromal bipolar disorder. Methods: Thirty-six patients with bipolar disorder with mild symptoms and 42 healthy volunteers participated in the study. We first compared effect sizes for memory deficits in patients among the CVLT-II, Brief Assessment of Cognition in Schizophrenia (BACS), and Hopkins Verbal Memory Tests-Revised (HVLT-R). We next evaluated the correlations between scores of the CVLT-II vs. those of the BACS and HVLT-R. Bipolar patients were re-assessed with the same (standard) or alternate forms of the CVLT-II and HVLT-R 1 month later. Results: Scores on the CVLT-II 1-5 Free Recall and Long-delay Free Recall, as well as the HVLT-R Immediate Recall, but not the BACS List Learning were significantly lower for patients compared to control subjects. The effect sizes for cognitive decline due to the illness were comparable when measured by the CVLT-II and HVLT-R, ranging from 0.5 to 0.6. CVLT-II scores were significantly correlated with those of the HVLT-R and BACS. Test-retest reliability of the CVLT-II was acceptable, and no significant practice effect was observed when the alternate form was used. There was no consistent relationship between mood symptoms and performance on the CVLT-II. Conclusion: These results suggest the CVLT-II Japanese version is able to discriminate between bipolar disorder patients and healthy controls with good sensitivity and validity. Data in this study also indicate that the degree of verbal memory deficits in bipolar disorder may be influenced by memory organizational strategy.
  • Tomiki Sumiyoshi, Atsuhito Toyomaki, Naoko Kawano, Tomoko Kitajima, Ichiro Kusumi, Norio Ozaki, Nakao Iwata, Kazuki Sueyoshi, Kazuyuki Nakagome
    PSYCHIATRY AND CLINICAL NEUROSCIENCES 71 (8) 570 - U77 1323-1316 2017/08 [Refereed][Not invited]
  • Yasuyuki Ono, Yoshikazu Takaesu, Yukiei Nakai, Masahiko Ichiki, Jiro Masuya, Ichiro Kusumi, Takeshi Inoue
    JOURNAL OF AFFECTIVE DISORDERS 217 66 - 72 0165-0327 2017/08 [Refereed][Not invited]
     
    Background: The quality of parenting, neuroticism, and adult stressful life events are reportedly associated with depressive symptoms. However, previous studies have not examined the complex interaction between these three factors. In this study, we hypothesized that the quality of parenting (care and overprotection) acts on depressive symptoms through 'neuroticism' and the appraisal of adult stressful life events, and this hypothesis was verified by structural equation modeling. Methods: Four hundred one participants from the general adult population were studied using the following self-administered questionnaire surveys: Patient Health Questionnaire-9 (PHQ-9), Parental Bonding Instrument (PBI), neuroticism subscale of the short version of the Eysenck Personality Questionnaire-revised (EPQ-R), and Life Experiences Survey (LES). The data were analyzed with single and multiple regression analyses and covariance structure analyses. Results: In the covariance structure analysis, neuroticism scores and negative change scores on the LES acted on the depressive symptoms (PHQ-9 scores) directly, but care or overprotection in childhood on the PBI did not act on them directly. Low care and high overprotection of the PBI increased depressive symptoms and negative change scores on the LES through enhanced neuroticism, which is regarded as a mediator in these effects. Limitations: The subjects of this study were nonclinical volunteers; the findings might not be generalizable to psychiatric patients. Conclusions: This research showed that low care and high overprotection of maternal and paternal parenting in childhood influence depressive symptoms indirectly through enhanced neuroticism in general adults. These findings suggest that neuroticism mediates the long-term effect of the quality of parenting on depression in adulthood.
  • Takaoki Kasahara, Mizuho Ishiwata, Chihiro Kakiuchi, Satoshi Fuke, Nakao Iwata, Norio Ozaki, Hiroshi Kunugi, Yoshio Minabe, Kazuhiko Nakamura, Yasuhide Iwata, Kumiko Fujii, Shigenobu Kanba, Hiroshi Ujike, Ichiro Kusumi, Muneko Kataoka, Nana Matoba, Atsushi Takata, Kazuya Iwamoto, Takeo Yoshikawa, Tadafumi Kato
    PSYCHIATRY AND CLINICAL NEUROSCIENCES 71 (8) 518 - 529 1323-1316 2017/08 [Refereed][Not invited]
     
    Aim: Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. Methods: We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. Results: Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. Conclusion: Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.
  • Kuniyoshi Toyoshima, Yutaka Fujii, Nobuyuki Mitsui, Yuki Kako, Satoshi Asakura, Anabel Martinez-Aran, Eduard Vieta, Ichiro Kusumi
    PSYCHIATRY RESEARCH 254 85 - 89 0165-1781 2017/08 [Refereed][Not invited]
     
    In Japan, there are currently no reliable rating scales for the evaluation of subjective cognitive impairment in patients with bipolar disorder. We studied the relationship between the Japanese version of the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) and objective cognitive assessments in patients with bipolar disorder. We further assessed the reliability and validity of the COBRA. Forty-one patients, aged 16-64, in a remission period of bipolar disorder were recruited from Hokkaido University Hospital in Sapporo, Japan. The COBRA (Japanese version) and Frankfurt Complaint Questionnaire (FCQ), the gold standard in subjective cognitive assessment, were administered. A battery of neuropsychological tests was employed to measure objective cognitive impairment. Correlations among the COBRA, FCQ, and neuropsychological tests were determined using Spearman's correlation coefficient. The Japanese version of the COBRA had high internal consistency, good retest reliability, and concurrent validity as indicated by a strong correlation with the FCQ. A significant correlation was also observed between the COBRA and objective cognitive measurements of processing speed. These findings are the first to demonstrate that the Japanese version of the COBRA may be clinically useful as a subjective cognitive impairment rating scale in Japanese patients with bipolar disorder.
  • Akiyoshi Shimura, Yoshikazu. Takaesu, Yukiei Nakai, Akiko Murakoshi, Yasuyuki Ono, Yasunori Matsumoto, Ichiro Kusumi, Takeshi Inoue
    COMPREHENSIVE PSYCHIATRY 74 15 - 20 0010-440X 2017/04 [Refereed][Not invited]
     
    Introduction: The association between trait anxiety and parental bonding has been suggested. However, the mechanism remains uncertain and there is no study focused on general adult population. We investigated the association and the mechanism between childhood parental bonding and adulthood trait anxiety in the general adult population. Material and methods: A cross-sectional retrospective survey was conducted in 2014 with 853 adult volunteers from the general population. The Parental Bonding Instrument, Rosenberg Self-Esteem Scale, and State-Trait Anxiety Inventory Form Y (STAI-Y) were self-administered. Structural equation modelling was used for the analysis. Results: Childhood parental bonding affected adulthood trait anxiety indirectly mediated by self-esteem. Trait anxiety was decreased by parental care and increased by parental overprotection through self-esteem. This model explained 51.1% of the variability in STAI-Y trait anxiety scores. Conclusions: This study suggests an important role of self-esteem as a mediator between childhood parental bonding and adulthood trait anxiety. (C) 2016 Published by Elsevier Inc.
  • Transethnic replication study to assess the association between clozapine-induced agranulocytosis/granulocytopenia and genes at 12p12.2 in a Japanese population.
    Saito T, Ikeda M, Hashimoto R, Iwata N, Members of the Clozapine Pharmacogenomics Consortium of Japan are the following, Yamamori H, Yasuda Y, Fujimoto M, Kondo K, Shimasaki A, Kawase K, Miyata M, Mushiroda T, Ozeki T, Kubo M, Fujita K, Kida N, Nakai M, Otsuru T, Fukuji Y, Murakami M, Mizuno K, Shiratsuchi T, Numata S, Ohmori T, Ueno SI, Yada Y, Tanaka S, Kishi Y, Takaki M, Mamoto A, Taniguchi N, Sawa Y, Watanabe H, Noda T, Amano Y, Kimura T, Fukao T, Suwa T, Murai T, Kubota M, Ueda K, Tabuse H, Kanahara N, Kawai N, Nemoto K, Makinodan M, Nishihata Y, Hashimoto N, Kusumi I, Fujii Y, Miyata R, Hirakawa K, Ozaki N
    Biol Psychiatry 82 (1) e9 - e10 2017 [Refereed][Not invited]
  • Mediators of the effects of rice intake on health in individuals consuming a traditional Japanese diet centered on rice.
    Koga M, Toyomaki A, Miyazaki A, Nakai Y, Yamaguchi A, Kubo C, Suzuki J, Ohkubo I, Shimizu M, Musashi M, Kiso Y, Kusumi I
    PLoS One 12 (10) e0185816  2017 [Refereed][Not invited]
  • Ayano Otsuka, Yoshikazu Takaesu, Mitsuhiko Sato, Jiro Masuya, Masahiko Ichiki, Ichiro Kusumi, Takeshi Inoue
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 13 2559 - 2568 1178-2021 2017 [Refereed][Not invited]
     
    Background: Recent studies have suggested that multiple factors interact with the onset and prognosis of major depressive disorders. In this study, we investigated how child abuse, affective temperaments, and interpersonal sensitivity are interrelated, and how they affect depressive symptoms in the general adult population. Subjects and methods: A total of 415 volunteers from the general adult population completed the Patient Health Questionnaire-9, the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire version, the Child Abuse and Trauma Scale, and the Interpersonal Sensitivity Measure, which are all self-administered questionnaires. Data were subjected to structural equation modeling (Mplus), and single and multiple regression analyses. Results: The effect of child abuse on depressive symptoms was mediated by interpersonal sensitivity and 4 affective temperaments, including depressive, cyclothymic, anxious, and irritable temperaments. In addition, the effect of these temperaments on depressive symptoms was mediated by interpersonal sensitivity, indicating the indirect enhancement of depressive symptoms. In contrast to these 4 temperaments, the hyperthymic temperament did not mediate the effect of child abuse on depressive symptoms; its effect was not mediated by interpersonal sensitivity. However, a greater hyperthymic temperament predicted decreased depressive symptoms and interpersonal sensitivity, independent of any mediation effect. Limitations: Because this is a cross-sectional study, long-term prospective studies are necessary to confirm its findings. Therefore, recall bias should be considered when interpreting the results. As the subjects were adults from the general population, the results may not be generalizable towards all patients with major depression. Conclusion: This study suggests that child abuse and affective temperaments affect depressive symptoms partly through interpersonal sensitivity. Interpersonal sensitivity may have a major role in forming the link between abuse, affective temperament, and depression.
  • The relationship between a low grain intake dietary pattern and impulsive behaviors in middle-aged Japanese people.
    Toyomaki A, Koga M, Okada E, Nakai Y, Miyazaki A, Tamakoshi A, Kiso Y, Kusumi I
    PLoS ONE 12 (7) e0181057  2017 [Refereed][Not invited]
  • Neural responses to feedback information produced by self-generated or other-generated decision-making and their impairment in schizophrenia.
    Toyomaki A, Hashimoto N, Kako Y, Murohashi H, Kusumi I
    PLoS One 12 (8) e0183792  2017 [Refereed][Not invited]
  • Association between suicide-related ideations and affective temperaments in the Japanese general adult population.
    Mitsui N, Nakai Y, Inoue T, Udo N, Kitagawa K, Wakatsuki Y, Kameyama R, Toyomaki A, Ito YM, Kitaichi Y, Nakagawa S, Kusumi I
    PLoS One 12 (6) e0179952  2017 [Refereed][Not invited]
  • Reliability and validity of the California Verbal Learning Test-II - Japanese version.
    Sumiyoshi T, Toyomaki A, Kawano N, Kitajima T, Kusumi I, Ozaki N, Iwata N, Nakagome K
    Psychiatry Clin Neurosci 71 (6) 47 - 48 2017 [Refereed][Not invited]
  • Clinical pharmacokinetic interactions between lamotorigine and hormonal contraceptives in bipolar I disorders.
    Sawagashira R, Fujii Y, Kusumi I
    Psychiatry Clin Neurosci 71 (4) 290  2017 [Refereed][Not invited]
  • Kotaro Ono, Yoshikazu Takaesu, Yukiei Nakai, Akiyoshi Shimura, Yasuyuki Ono, Akiko Murakoshi, Yasunori Matsumoto, Hajime Tanabe, Ichiro Kusumi, Takeshi Inoue
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 13 477 - 482 1178-2021 2017 [Refereed][Not invited]
     
    Background: Recent studies have suggested that the interactions among several factors affect the onset, progression, and prognosis of major depressive disorder. This study investigated how childhood abuse, neuroticism, and adult stressful life events interact with one another and affect depressive symptoms in the general adult population. Subjects and methods: A total of 413 participants from the nonclinical general adult population completed the Patient Health Questionnaire-9, the Child Abuse and Trauma Scale, the neuroticism subscale of the shortened Eysenck Personality Questionnaire - Revised, and the Life Experiences Survey, which are self-report scales. Structural equation modeling (Mplus version 7.3) and single and multiple regressions were used to analyze the data. Results: Childhood abuse, neuroticism, and negative evaluation of life events increased the severity of the depressive symptoms directly. Childhood abuse also indirectly increased the negative appraisal of life events and the severity of the depressive symptoms through enhanced neuroticism in the structural equation modeling. Limitations: There was recall bias in this study. The causal relationship was not clear because this study was conducted using a cross-sectional design. Conclusion: This study suggested that neuroticism is the mediating factor for the two effects of childhood abuse on adulthood depressive symptoms and negative evaluation of life events. Childhood abuse directly and indirectly predicted the severity of depressive symptoms.
  • Chong Chen, Shin Nakagawa, Yan An, Koki Ito, Yuji Kitaichi, Ichiro Kusumi
    FRONTIERS IN NEUROENDOCRINOLOGY 44 83 - 102 0091-3022 2017/01 [Refereed][Not invited]
     
    Exercise is known to have beneficial effects on cognition, mood, and the brain. However, exercise also activates the hypothalamic-pituitary-adrenal axis and increases levels of the glucocorticoid cortisol (CORT). CORT, also known as the "stress hormone," is considered a mediator between chronic stress and depression and to link various cognitive deficits. Here, we review the evidence that shows that while both chronic stress and exercise elevate basal CORT levels leading to increased secretion of CORT, the former is detrimental to cognition/memory, mood/stress coping, and brain plasticity, while the latter is beneficial. We propose three preliminary answers to the exercise-CORT paradox. Importantly, the elevated CORT, through glucocorticoid receptors, functions to elevate dopamine in the medial prefrontal cortex under chronic exercise but not chronic stress, and the medial prefrontal dopamine is essential for active coping. Future inquiries may provide further insights to promote our understanding of this paradox. (C) 2016 Elsevier Inc. All rights reserved.
  • Tomiki Sumiyoshi, Keiichiro Nishida, Hidehito Niimura, Atsuhito Toyomaki, Tsubasa Morimoto, Masayuki Tani, Ken Inada, Taiga Ninomiya, Hikaru Hori, Jun Manabe, Asuka Katsuki, Takamitsu Kubo, Yosuke Koshikawa, Masanao Shirahama, Kentaro Kohno, Toshihiko Kinoshita, Ichiro Kusumi, Akira Iwanami, Takefumi Ueno, Toshi Kishimoto, Takeshi Terao, Kazuyuki Nakagome
    Schizophrenia research. Cognition 6 9 - 14 2016/12 [Refereed][Not invited]
     
    The Specific Levels of Functioning Scale (SLOF) has been reported to provide a measure of social function in patients with schizophrenia. The aim of this multi-center study was to determine convergent validity of the Japanese version of SLOF, and if cognitive insight would be associated with social function. Fifty-eight patients with schizophrenia participated in the study. Social function, neurocognition, and daily activity skills were evaluated by the Social Functioning Scale (SFS), Brief Assessment of Cognition in Schizophrenia (BACS) and UCSD Performance-based Skills Assessment-Brief (UPSA-B), respectively. We also assessed cognitive insight with the Beck Cognitive Insight Scale (BCIS). Significant relationships were noted between scores on the SLOF vs. those of the SFS, BACS, UPSA-B, and BCIS. Specifically, the correlation between performance on the UPSA-B and SLOF scores was significantly more robust compared to the correlation between performance on the UPSA-B and scores on the SFS. Similarly, the correlation between scores on the BACS and SLOF tended to be more robust than that between the BACS and SFS. Importantly, while the correlation between scores on the BCIS and SLOF reached significance, it was not so between scores on the BCIS and SFS. The SLOF Japanese version was found to provide a measure of social consequences in patients with schizophrenia. Importantly, this study is the first to indicate the relationship between cognitive insight and social function evaluated by the SLOF. This finding is consistent with the observation that SLOF scores were considerably associated with performances on objective functional measures.
  • Hisashi Narita, Khin K Tha, Naoki Hashimoto, Hiroyuki Hamaguchi, Shin Nakagawa, Hiroki Shirato, Ichiro Kusumi
    Progress in neuro-psychopharmacology & biological psychiatry 71 169 - 75 2016/11/03 [Refereed][Not invited]
     
    INTRODUCTION: Diffusion kurtosis imaging can provide a better understanding of microstructural white matter (WM) changes where crossing fibers exist, compared with conventional diffusion tensor imaging. Here, we aimed to examine the differences of mean kurtosis (MK) and fractional anisotropy (FA) values between patients with schizophrenia and control subjects using voxel-based analysis (VBA). Additionally, we examined the correlation between these values and severity of clinical symptoms in patients with schizophrenia. METHODS: MK and FA values were acquired with a 3.0T scanner from 31 patients with schizophrenia and 31 age-, handedness-, and sex-matched healthy controls. VBA was used to compare the MK and FA maps of the patients with schizophrenia and healthy controls. We also performed a correlation analysis between the MK and FA values of the regions with significant differences and the positive and negative syndrome scale scores in patients with schizophrenia. RESULTS: Compared to FA values, voxels with MK decrease were more widespread across bilateral cerebral the WM of patients with schizophrenia. The MK values of left superior longitudinal fasciculus were significantly negatively correlated with the severity of positive symptoms (r=-0.451, P=0.011). There was no significant correlation between MK and FA values and other clinical variables. CONCLUSION: The diffusion kurtosis indices are suitable for evaluating altered WM structures in the human brain as they may detect white matter alterations of crossing fibers alterations of WM in schizophrenia and assess the clinical state of patients.
  • Yan An, Chong Chen, Takeshi Inoue, Shin Nakagawa, Yuji Kitaichi, Ce Wang, Takeshi Izumi, Ichiro Kusumi
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 70 17 - 23 0278-5846 2016/10 [Refereed][Not invited]
     
    The functional role of serotonergic projections from the median raphe nucleus (MRN) to the dorsal hippocampus (DH) in anxiety remains understood poorly. The purpose of the present research was to examine the functional role of this pathway, using the contextual fear conditioning (CFC) model of anxiety. We show that intra-MRN microinjection of mirtazapine, a noradrenergic and specific serotonergic antidepressant, reduced freezing in CFC without affecting general motor activity dose-dependently, suggesting an anxiolytic-like effect. In addition, intra-MRN microinjection of mirtazapine dose-dependently increased extracellular concentrations of serotonin (5-HT) but not dopamine in the DH. Importantly, intra-DH pre-microinjection of WAY-100635, a 5-HT1A antagonist, significantly attenuated the effect of mirtazapine on freezing. These results, for the first time, suggest that activation of the MRN-DH 5-HT1A pathway exerts an anxiolytic-like effect in CFC. This is consistent with the literature that the hippocampus is essential for retrieval of contextual memory and that 5-HT1A receptor activation in the hippocampus primarily exerts an inhibitory effect on the neuronal activity. (C) 2016 Elsevier Inc. All rights reserved.
  • Yuka Shimizu, Shinsuke Yasuda, Yuki Kako, Shin Nakagawa, Masatoshi Kanda, Ryo Hisada, Kazumasa Ohmura, Sanae Shimamura, Haruki Shida, Yuichiro Fujieda, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Tetsuya Horita, Ichiro Kusumi, Tatsuya Atsumi
    AUTOIMMUNITY REVIEWS 15 (8) 786 - 794 1568-9972 2016/08 [Refereed][Not invited]
     
    In patients with systemic lupus erythematosus (SLE), neuropsychiatric (NP) symptoms sometimes occur after administration of corticosteroids, making differential diagnosis between NPSLE and steroid-induced psychosis challenging for clinicians. The aim of this study was to clarify the characteristics of post-steroid NP disease (PSNP) in patients with SLE. Clinical courses of 146 patients with SLE and 162 with other systemic autoimmune diseases, all in the absence of NP manifestations on admission, were retrospectively analyzed. Forty-three NPSLE patients on admission (de novo NPSLE) were also investigated. All patients were consecutively recruited and treated with 40 mg/day or more of prednisolone in Hokkaido University Hospital between April 2002 and March 2015. The prevalence of PSNP was strikingly higher in SLE patients than other systemic autoimmune diseases (24.7% vs. 7.4%, OR 4.09, 95% CI 2.04-8.22). As independent risk factors to develop PSNP in SLE patients, past history of mental disorder and the presence of antiphospholipid syndrome were identified using multiple logistic regression analysis. In patients with PSNP-SLE, mood disorder was significantly more frequent than in de novo NPSLE (47.2% vs. 20.9%, OR 3.38, 95% CI 126-9.04). Of PSNP-SLE patients, two-thirds were with one or more abnormal findings in cerebrospinal fluid, electroencephalogram, MRI or SPECT. Majority of our PSNP-SLE patients received intensified immunosuppressive treatments and experienced improvement in most cases. PSNP-SLE had better relapse-free survival than de novo NPSLE (p < 0.05, log rank test). In conclusion, PSNP frequently occurred in patients with SLE and treated successfully with immunosuppressive therapy, indicating that NPSLE is likely to harbor patients with PSNP-SLE. (C) 2016 Elsevier B.V. All rights reserved.
  • Takumi Nakamura, An-a Kazuno, Kazuo Nakajima, Ichiro Kusumi, Takashi Tsuboi, Tadafumi Kato
    PSYCHIATRY AND CLINICAL NEUROSCIENCES 70 (8) 342 - 350 1323-1316 2016/08 [Refereed][Not invited]
     
    AimThough genetic factors play a major role in the pathophysiology of psychoses including bipolar disorder (BD) and schizophrenia, lack of well-established causative genetic mutations hampers their neurobiological studies. Darier's disease, an autosomal dominant skin disorder caused by mutations of ATP2A2 on chromosome 12q23-24.1, encoding sarco/endoplasmic reticulum calcium transporting ATPase 2 (SERCA2), reportedly cosegregates with BD. A recent genome-wide association study showed an association of schizophrenia with ATP2A2. MethodsWe sequenced all coding regions of ATP2A2 in a newly identified patient with Darier's disease and BD. In addition, we performed a literature survey to examine whether likely gene disrupting (LGD) mutations are related to psychoses. ResultsWe identified a rare heterozygous mutation, c.1288-6A>G, at the 3 end of intron 10 in the patient. A minigene splicing assay showed that this mutation introduces a new splice site causing a frameshift and premature stop codon. A literature survey of case reports of patients with Darier's disease and psychoses revealed that the rate of LGD mutations causing frameshift, altered splicing, gain of stop codon, or loss of start codon was significantly higher among the mutations harbored by these cases (9 of 11) than that of ATP2A2 mutations for which comorbidity of psychosis was not reported (107 of 237, P=0.026). The only non-LGD mutation (p.C560R) reported in patients with Darier's disease and BD caused decreased ATP2A2 protein expression. ConclusionThese results suggest that psychoses in Darier's disease may be caused by a pleiotropic effect of loss-of-function mutations of ATP2A2.
  • Tsugiko Kurita, Kotaro Sakurai, Youji Takeda, Toru Horinouchi, Ichiro Kusumi
    PLOS ONE 11 (7) e0159464  1932-6203 2016/07 [Refereed][Not invited]
     
    Objective Surgical intervention can result in complete seizure remission rates of up to 80% in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). However, certain patients cannot be treated surgically for various reasons. We analyzed the very long-term clinical outcomes of patients with TLE-HS who could not be treated surgically. Methods Subjects were selected from among patients with TLE-HS who were actively followed up for > 10 years and treated with medication without surgical treatment. Patient medical records were used to retrospectively study seizure frequency, various clinical factors, and social adjustment. Patients who were seizure-free or had only aura were classified into Group 1; the others were classified into Group 2. Clinical factors including both patient and disease-specific factors were compared between the two groups. Current social adjustment, including the education, work, and economic status of each patient, was also investigated. Results Forty-one (41) subjects met the criteria for analysis, of which 12 (29%) were classified into Group 1. The average age of patients in Group 1 was higher than that of Group 2 (p = 0.0468). Group 2 included a significantly higher rate of patients who had more than one seizure per week at the onset (p = 0.0328), as well as a greater mean number of anti-epileptic drugs taken (p = 0.0024). Regarding social adjustment, Group 2 contained significantly fewer current jobholders than Group 1 (p = 0.0288). Conclusions After very long-term follow-up periods, 29% of patients with TLE-HS had a good outcome through treatment with anticonvulsant medications. Older patients tended to have fewer seizures, and seizure frequency at the onset was the only factor that predicted outcome.
  • Yan An, Takeshi Inoue, Yuji Kitaichi, Chong Chen, Shin Nakagawa, Ce Wang, Ichiro Kusumi
    EUROPEAN JOURNAL OF PHARMACOLOGY 783 112 - 116 0014-2999 2016/07 [Refereed][Not invited]
     
    Although preclinical and clinical studies have established the efficacy of lithium augmentation of antidepressant drugs, the mechanism of action of lithium augmentation is not fully understood. Our previous study reported that subchronic lithium treatment enhanced the anxiolytic-like effect of systemic mirtazapine. In the present study, we examined the effect of subchronic lithium in combination with acute local intracerebral injection of mirtazapine on fear-related behaviors in a contextual fear conditioning test in rats to clarify the target brain region of lithium augmentation of mirtazapine. After conditioning by footshock, diet (food pellets) containing Li2CO3 at a concentration of 0.2% was administered for 7 days. Ten min before testing and 7 days after conditioning, mirtazapine (3 mu g/site) in a volume of 0.5 mu l was acutely injected into the median raphe nucleus (MRN), hippocampus or amygdala. The combination of subchronic lithium and acute mirtazapine microinjection into the MRN but not the hippocampus or the amygdala reduced fear expression synergistically. These results suggest that intra-MRN mirtazapine treatment with subchronic lithium exerts the anxiolytic-like effect through the facilitation of the MRN-5HT pathway. (C) 2016 Elsevier B.V. All rights reserved.
  • Chong Chen, Shin Nakagawa, Yuji Kitaichi, Yan An, Yuki Omiya, Ning Song, Minori Koga, Akiko Kato, Takeshi Inoue, Ichiro Kusumi
    PSYCHONEUROENDOCRINOLOGY 69 1 - 9 0306-4530 2016/07 [Refereed][Not invited]
     
    Despite the well-documented beneficial effect of exercise on stress coping and depression treatment, its underlying neurobiological mechanism remains unclear. This is further complicated by a 'side effect' of exercise: it increases basal glucocorticoid (CURT), the stress hormone, which has been shown to be a mediator linking stress to depressive disorders. Here we show that three weeks of voluntary wheel running reduced rats' immobility in the forced swim test (FST), an antidepressant-like effect. Monitoring extracellular fluids in the medial prefrontal cortex PFC (mPFC) using microdialysis we found that, wheel running was associated with higher baseline CORT, but lower FST-responsive CORT. Further, wheel running resulted in a higher dopamine (DA) both at baseline and following FST. Interestingly, the antidepressant-like effect of wheel running was completely abolished by intra-mPFC pre-microinjection of a D2R (haloperidol) but not D1R (SCH23390) antagonist, at a dose that does not affect normal rats' performance in the FST. It suggests that exercise exerts antidepressant-like effect through upregulated DA and in a D2R dependent way in the mPFC. Importantly, the antidepressant-like effect of wheel running was also abolished by intra-mPFC pre-microinjection of a GR antagonist (RU486). Finally, intra-mPFC pre-microinjection of RU486 also downregulated the originally elevated basal and FST-responsive DA in the mPFC of exercise rats. These results suggest a causal pathway linking CURT, GR, DA, and D2R, to the antidepressant-like effect of exercise. In conclusion, exercise achieves antidepressant-like effect through the CORT-GR-DA-D2R pathway and that the increased basal CORT by exercise itself may be beneficial rather than detrimental. (C) 2016 Elsevier Ltd. All rights reserved.
  • Liping Hou, Urs Heilbronner, Franziska Degenhardt, Mazda Adli, Kazufumi Akiyama, Nirmala Akula, Raffaella Ardau, Barbara Arias, Lena Backlund, Claudio E. M. Banzato, Antoni Benabarre, Susanne Bengesser, Abesh Kumar Bhattacharjee, Joanna M. Biernacka, Armin Birner, Clara Brichant-Petitjean, Elise T. Bui, Pablo Cervantes, Guo-Bo Chen, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Scott R. Clark, Francesc Colom, David A. Cousins, Cristiana Cruceanu, Piotr M. Czerski, Clarissa R. Dantas, Alexandre Dayer, Bruno Etain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Janice M. Fullerton, Sebastien Gard, Julie S. Garnham, Fernando S. Goes, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Stefan Herms, Per Hoffmann, Andrea Hofmann, Stephane Jamain, Esther Jimenez, Jean-Pierre Kahn, Layla Kassem, Sarah Kittel-Schneider, Sebastian Kliwicki, Barbara Koenig, Ichiro Kusumi, Nina Lackner, Gonzalo Laje, Mikael Landen, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Carlos A. Lopez Jaramillo, Glenda MacQueen, Mirko Manchia, Lina Martinsson, Manuel Mattheisen, Michael J. McCarthy, Susan L. McElroy, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Noethen, Urban Oesby, Norio Ozaki, Roy H. Perlis, Andrea Pfennig, Daniela Reich-Erkelenz, Guy A. Rouleau, Peter R. Schofield, K. Oliver Schubert, Barbara W. Schweizer, Florian Seemueller, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Kazutaka Shimoda, Christian Simhandl, Claire M. Slaney, Jordan W. Smoller, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Julia Volkert, Stephanie Witt, Adam Wright, L. Trevor Young, Peter P. Zandi, James B. Potash, J. Raymond DePaulo, Michael Bauer, Eva Z. Reininghaus, Tomas Novak, Jean-Michel Aubry, Mario Maj, Bernhard T. Baune, Philip B. Mitchell, Eduard Vieta, Mark A. Frye, Janusz K. Rybakowski, Po-Hsiu Kuo, Tadafumi Kato, Maria Grigoroiu-Serbanescu, Andreas Reif, Maria Del Zompo, Frank Bellivier, Martin Schalling, Naomi R. Wray, John R. Kelsoe, Martin Alda, Marcella Rietschel, Francis J. McMahon, Thomas G. Schulze
    LANCET 387 (10023) 1085 - 1093 0140-6736 2016/03 [Refereed][Not invited]
     
    Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p= 1.37 x 10(-8); rs78015114, p= 1.31 x 10(-8); rs74795342, p= 3.31 x 10(-9); and rs75222709, p= 3.50 x 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p= 0.03268, hazard ratio 3.8, 95% CI 1.1-13.0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.
  • Hiroyuki Toda, Takeshi Inoue, Tomoya Tsunoda, Yukiei Nakai, Masaaki Tanichi, Teppei Tanaka, Naoki Hashimoto, Yoshikazu Takaesu, Shin Nakagawa, Yuji Kitaichi, Shuken Boku, Hajime Tanabe, Masashi Nibuya, Aihide Yoshino, Ichiro Kusumi
    PSYCHIATRY RESEARCH 236 142 - 147 0165-1781 2016/02 [Refereed][Not invited]
     
    Previous studies have shown that various factors, such as genetic and environmental factors, contribute to the development of major depressive disorder (MDD). The aim of this study is to clarify how multiple factors, including affective temperaments, childhood abuse and adult life events, are involved in the severity of depressive symptoms in MDD. A total of 98 participants with MDD were studied using the following self-administered questionnaire surveys: Patient Health Questionnaire-9 measuring the severity of depressive symptoms; Life Experiences Survey (LES) measuring negative and positive adult life events; Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego auto-questionnaire (TEMPS A) measuring affective temperaments; and the Child Abuse and Trauma Scale (CATS) measuring childhood abuse. The data were analyzed using single and multiple regression analyses and structural equation modeling (SEM). The neglect score reported by CATS indirectly predicted the severity of depressive symptoms through affective temperaments measured by TEMPS-A in SEM. Four temperaments (depressive, cyclothymic, irritable, and anxious) directly predicted the severity of depressive symptoms. The negative change in the LES score also directly predicted severity. This study suggests that childhood abuse, especially neglect, indirectly increases the severity of depressive symptoms through increased scores of affective temperaments in MDD. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
  • Yasuya Nakato, Takeshi Inoue, Shin Nakagawa, Yuji Kitaichi, Rie Kameyama, Yumi Wakatsuki, Kan Kitagawa, Yuki Omiya, Ichiro Kusumi
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 12 2173 - 2179 1178-2021 2016 [Refereed][Not invited]
     
    Background: The Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) is a 110-item questionnaire that assesses five affective temperaments. However, a valid shortened version is desired for large-scale investigations to enhance the compliance of respondents. Methods: A confirmatory factor analysis was conducted among 320 psychiatric patients and 61 general adults. The participants completed the Japanese 39-item short version of the TEMPS-A, and a portion of the participants completed the 110-item version. An exploratory factor analysis with the principal factor method and varimax rotation was conducted to identify a more suitable model of the short version of the TEMPS-A. Results: The confirmatory factor analysis revealed that the 39-item version exhibited a poor model fit. However, we found that the 18-item version exhibited a firm five-factor structure based on the exploratory factor analysis, and this model exhibited an acceptable model fit. It had good or acceptable internal consistency (Cronbach's as: 0.672-0.819). Limitations: The majority of the subjects in the present study were patients, and the temperament data may have been affected by psychiatric symptoms. Conclusion: A firm five-factor structure was not found in the 39-item short version of the Japanese TEMPS-A. Therefore, an 18-item version was proposed. This new 18-item version of the TEMPS-A might be useful for clinical applications and large-scale investigations.
  • Yoshiaki Kanai, Yoshikazu Takaesu, Yukiei Nakai, Masahiko Ichiki, Mitsuhiko Sato, Yasunori Matsumoto, Jun Ishikawa, Yasuyuki Ono, Akiko Murakoshi, Hajime Tanabe, Ichiro Kusumi, Takeshi Inoue
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 12 823 - 832 1178-2021 2016 [Refereed][Not invited]
     
    Background: Previous studies have shown the effects of childhood abuse, life events, and temperaments on well-being (positive affect) and ill-being (negative affect). We hypothesized that childhood abuse, affective temperaments, and adult life events interact with one another and influence positive and negative affects in the general adult population and tested this hypothesis using structural equation modeling. Methods: A total of 415 participants from the general, nonclinical adult population were studied using the following self-administered questionnaires: the Subjective Well-Being Inventory (SUBI); Life Experiences Survey (LES); Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A); and the Child Abuse and Trauma Scale (CATS). The data were analyzed with single and multiple regression analyses and structural equation modeling (Mplus). Results: Childhood abuse indirectly predicted the worsening of positive and negative affects through cyclothymic, anxious, and irritable temperaments as measured by the TEMPS-A in the structural equation model. The cyclothymic, anxious, and irritable temperaments directly worsened the positive and negative affects and the negative appraisal of life events that occurred during the past year, while the hyperthymic temperament had the opposite effects. Limitations: The subjects of this study were nonclinical volunteers. The findings might not be generalizable to psychiatric patients. Conclusion: This study demonstrated that childhood abuse, particularly neglect, indirectly worsened the well-being of individuals through cyclothymic, anxious, and irritable affective temperaments. An important "mediator" role of affective temperaments in the effect of childhood abuse on well-being was suggested.
  • Naoki Hashimoto, Yuriko Suzuki, Takahiro A Kato, Daisuke Fujisawa, Ryoko Sato, Kumi Aoyama-Uehara, Maiko Fukasawa, Satoshi Asakura, Ichiro Kusumi, Kotaro Otsuka
    Psychiatry and clinical neurosciences 70 (1) 62 - 70 2016/01 [Refereed][Not invited]
     
    AIMS: Suicide is a leading cause of death among Japanese college and university students. Gatekeeper-training programs have been shown to improve detection and referral of individuals who are at risk of suicide by training non-mental-health professional persons. However, no studies have investigated the effectiveness of such programs in university settings in Japan. The aim of this study was to investigate the effectiveness of the gatekeeper-training program for administrative staff in Japanese universities. METHODS: We developed a 2.5-h gatekeeper-training program based on the Mental Health First Aid program, which was originally developed for the general public. Seventy-six administrative staff at Hokkaido University participated in the program. Competence and confidence in managing suicide intervention, behavioral intention as a gatekeeper and attitude while handling suicidal students were measured by a self-reported questionnaire before, immediately after and a month after the program. RESULTS: We found a significant improvement in competence in the management of suicidal students. We also found improvements in confidence in management of suicidal students and behavioral intention as a gatekeeper after training, though questionnaires for those secondary outcomes were not validated. These improvements continued for a month. About 95% of the participants rated the program as useful or very useful and one-third of the participants had one or more chances to utilize their skills within a month. CONCLUSIONS: The current results suggest the positive effects of the training program in university settings in Japan. Future evaluation that includes comparison with standard didactic trainings and an assessment of long-term effectiveness are warranted.
  • Yukiei Nakai, Takeshi Inoue, Chong Chen, Hiroyuki Toda, Atsuhito Toyomaki, Yasuya Nakato, Shin Nakagawa, Yuji Kitaichi, Rie Kameyama, Yumi Wakatsuki, Kan Kitagawa, Hajime Tanabe, Ichiro Kusumi
    JOURNAL OF AFFECTIVE DISORDERS 187 203 - 210 0165-0327 2015/11 [Refereed][Not invited]
     
    Background: We recently demonstrated in the structural equation modeling that four of five affective temperaments, as measured by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego auto-questionnaire version (TEMPS-A), are strong mediators between childhood abuse and depressive symptoms in the nonclinical general adult population. In this study, we hypothesized that affective temperaments, childhood abuse, and adult life events have moderator effects that interact with one another on depressive symptoms. The hierarchical multiple regression analysis was used to analyze this interaction model. Methods: The 286 participants from the nonclinical general adult population were studied using the following self-administered questionnaire surveys: the Patient Health Questionnaire-9 (PHQ-9), Life Experiences Survey (LES), TEMPS-A, and Child Abuse and Trauma Scale (CATS). The data were analyzed using hierarchical multiple regressions with interactions. Results: Depressive temperament enhanced and hyperthymic temperament inhibited the depressogenic effects of childhood abuse, while irritable temperament enhanced and hyperthymic temperament inhibited the depressogenic effects of adult negative (stressful) life events. Adult positive life events had an inhibitory moderator effect on depressive symptoms that was increased by cyclothymic and anxious temperaments. Neglect, punishment, and total childhood abuse enhanced the effects of negative life events on depressive symptoms. Limitations: As the subjects of this study were nonclinical, the findings should not be generalized to patients with mood disorders. In this cross-sectional study, there may be interdependence between the measured variables. Conclusions: This study, using the hierarchical multiple regression analysis with interaction, demonstrated the positive and negative interactions between any two of affective temperaments, childhood abuse, and adult life events, and the influence on depressive symptoms in the nonclinical general adult population. Important moderator roles for affective temperaments, childhood abuse, and adult life events on depressive symptoms were suggested. (C) 2015 Elsevier B.V. All rights reserved,
  • Atsuhito Toyomaki, Naoki Hashimoto, Yuki Kako, Yoshiro Tomimatsu, Tsukasa Koyama, Ichiro Kusumi
    Schizophrenia Research: Cognition 2 (3) 166 - 169 2215-0013 2015/09/01 [Refereed][Not invited]
     
    The P50 is an early component of auditory evoked potentials and a measure of sensory gating deficits. This evoked potential component is thought to be an important endophenotype candidate for schizophrenia. Recent research suggests that instead of the P50 ratio, S1 and S2 amplitudes should be evaluated for sensory gating. However, no studies have focused on the relationship between cognitive dysfunction and P50 sensory gating deficits using S1 and S2 amplitudes. The purpose of the present study was to investigate the association between the P50 ratio (S2/S1), S1 and S2 amplitudes, and neuropsychological cognitive domains using stepwise multiple linear regression analyses. Results demonstrated a significant relationship between executive functioning and the P50 ratio and between sustained attention and S2 amplitude, respectively. Our findings suggest that the P50 ratio and S2 amplitude reflect distinct neurophysiological substrates associated with different cognitive functions.
  • Chong Chen, Taiki Takahashi, Shin Nakagawa, Takeshi Inoue, Ichiro Kusumi
    NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS 55 (55) 247 - 267 0149-7634 2015/08 [Refereed][Not invited]
     
    Despite being considered primarily a mood disorder, major depressive disorder (MDD) is characterized by cognitive and decision making deficits. Recent research has employed computational models of reinforcement learning (RL) to address these deficits. The computational approach has the advantage in making explicit predictions about learning and behavior, specifying the process parameters of RL, differentiating between model-free and model-based RL, and the computational model-based functional magnetic resonance imaging and electroencephalography. With these merits there has been an emerging field of computational psychiatry and here we review specific studies that focused on MDD. Considerable evidence suggests that MDD is associated with impaired brain signals of reward prediction error and expected value ('wanting'), decreased reward sensitivity ('liking') and/or learning (be it model-free or model-based), etc., although the causality remains unclear. These parameters may serve as valuable intermediate phenotypes of MDD, linking general clinical symptoms to underlying molecular dysfunctions. We believe future computational research at clinical, systems, and cellular/molecular/genetic levels will propel us toward a better understanding of the disease. (C) 2015 Elsevier Ltd. All rights reserved.
  • Ichiro Kusumi, Shuken Boku, Yoshito Takahashi
    PSYCHIATRY AND CLINICAL NEUROSCIENCES 69 (5) 243 - 258 1323-1316 2015/05 [Refereed][Not invited]
     
    The original definition of atypical antipsychotic drugs (APD) was drugs that are effective against positive symptoms in schizophrenia with no or little extrapyramidal symptoms (EPS). However, atypical APD have been reported to be more effective for cognitive dysfunction and negative symptoms in schizophrenia than typical APD, which expands the definition of atypicality'. This article provides a critical review of the pharmacology of atypical APD, especially from the viewpoint of receptor binding profiles and neurotransmitter regulations as well as neuroprotection and neurogenesis. A variety of serotonin (5-HT) receptors, such as 5-HT2A/2C, 5-HT1A, 5-HT6 and 5-HT7 receptors, may contribute to the mechanisms of action of atypicality'. The dopaminergic modulations, including a low affinity for dopamine D-2 receptors and a partial D-2 receptor agonistic action, and glutamatergic regulations may also be involved in the pharmacological backgrounds of atypicality'. Atypical APD, but not typical APD, may facilitate cortical neuroprotection and hippocampal neurogenesis, which might be a part of the action mechanisms of atypical APD. The facilitation of cortical neuroprotection and hippocampal neurogenesis induced by atypical APD might be mediated by an increase in the Ser9 phosphorylation of glycogen synthase kinase-3 (GSK-3). The stimulation of 5-HT1A receptors and/or the blockade of 5-HT2 receptors, which is characteristic of atypical APD, might increase Ser9 phosphorylation of GSK-3. Moreover, atypical APD increase brain-derived neurotrophic factor (BDNF) levels. BDNF increases Ser9 phosphorylation of GSK-3 and has neuroprotective and neurogenic effects, as in the case of atypical APD. These findings suggest that GSK-3 might play a role in the action mechanisms of atypical APD, in both the 5-HT-dependent and BDNF-dependent mechanisms.
  • Michio Nomura, Masayuki Kaneko, Yasunobu Okuma, Jun Nomura, Ichiro Kusumi, Tsukasa Koyama, Yasuyuki Nomura
    PLOS ONE 10 (3) e0119743  1932-6203 2015/03 [Refereed][Not invited]
     
    The serotonergic pathway has been implicated in the pathogenesis of impulsivity, and sensitivity to aversive outcomes may be linked to serotonin (5-HT) levels. Polymorphisms in the gene that encodes the serotonin transporter (5-HTT), which have differential effects on the level of serotonin transmission, display alternate responses to aversive stimuli. However, recent studies have shown that 5-HT does not affect motor function, which suggests that the functioning of the serotonin-transporter-linked polymorphic region (5-HTTLPR) does not directly affect the behavioral regulatory process itself, but instead exerts an effect via the evaluation of the potential risk associated with particular behavioral outputs. The aim of the present study was to examine the effect of specific 5-HTTLPR genotypes on the motor regulatory process, as observed during a Go/Nogo punishment feedback task. 5-HTT gene-linked promoter polymorphisms were analyzed by polymerase chain reaction, using lymphocytes from 61 healthy Japanese volunteers. Impulsivity was defined as the number of commission errors (responding when one should not) made during a Go/Nogo task. We found that the s/s genotype group made fewer impulsive responses, specifically under aversive conditions for committing such errors, compared to those in the s/l group, without affecting overall motor inhibition. These results suggest that 5-HTTLPRs do not directly affect the behavioral regulatory process itself, but may instead exert an effect on the evaluation of potential risk. The results also indicate that under such aversive conditions, decreased expression of 5-HTT may promote motor inhibitory control.
  • Yuki Omiya, Motokazu Uchigashima, Kohtarou Konno, Miwako Yamasaki, Taisuke Miyazaki, Takayuki Yoshida, Ichiro Kusumi, Masahiko Watanabe
    JOURNAL OF NEUROSCIENCE 35 (10) 4215 - 4228 0270-6474 2015/03 [Refereed][Not invited]
     
    Invaginating synapses in the basal amygdala are a unique type of GABAergic synapses equipped with molecular-anatomical organization specialized for 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling. Cholecystokinin (CCK)-positive basket cell terminals protrude into pyramidal cell somata and form invaginating synapses, where apposing presynaptic and postsynaptic elements are highly loaded with cannabinoid receptor CB1 or 2-AG synthetic enzyme diacylglycerol lipase-alpha (DGL alpha), respectively. The present study scrutinized their neurochemical and neuroanatomical phenotypes in adult mouse telencephalon. In the basal amygdala, vesicular glutamate transporter-3 (VGluT3) was transcribed in one-fourth of CB1-expressing GABAergic interneurons. The majority of VGluT3-positive CB1-expressing basket cell terminals apposed DGL alpha clusters, whereas the majority of VGluT3-negative ones did not. Importantly, VGluT3-positive basket cell terminals selectively constructed invaginating synapses. GABA(A) receptors accumulated on the postsynaptic membrane of invaginating synapses, whereas metabotropic glutamate receptor-5 (mGluR5) was widely distributed on the somatodendritic surface of pyramidal cells. Moreover, CCK2 receptor (CCK2R) was highly transcribed in pyramidal cells. In cortical regions, pyramidal cells equipped with such VGluT3/CB1/DGL alpha-accumulated invaginating synapses were found at variable frequencies depending on the subregions. Therefore, in addition to extreme proximity of CB1- and DGL alpha-loaded presynaptic and postsynaptic elements, tripartite transmitter phenotype of GABA/glutamate/CCK is the common neurochemical feature of invaginating synapses, suggesting that glutamate, CCK, or both can promote 2-AG synthesis through activating G alpha(q/11) protein-coupled mGluR5 and CCK2R. These molecular configurations led us to hypothesize that invaginating synapses might be evolved to provide some specific mechanisms of induction, regulation, and cooperativity for 2-AG-mediated retrograde signaling in particular cortical and cortex-like amygdaloid regions.
  • Ken Kazumata, Khin Khin Tha, Hisashi Narita, Ichiro Kusumi, Hideo Shichinohe, Masaki Ito, Naoki Nakayama, Kiyohiro Houkin
    STROKE 46 (2) 354 - 360 0039-2499 2015/02 [Refereed][Not invited]
     
    Background and Purpose-The mechanisms underlying frontal lobe dysfunction in moyamoya disease (MMD) are unknown. We aimed to determine whether chronic ischemia induces subtle microstructural brain changes in adult MMD and evaluated the association of changes with neuropsychological performance. Methods-MRI, including 3-dimensional T1-weighted imaging and diffusion tensor imaging, was performed in 23 adult patients with MMD and 23 age-matched controls and gray matter density and major diffusion tensor imaging indices were compared between them; any alterations in the patients were tested for associations with age, ischemic symptoms, hemodynamic compromise, and neuropsychological performance. Results-Decrease in gray matter density, associated with hemodynamic compromise (P<0.05), was observed in the posterior cingulate cortex of patients with MMD. Widespread reduction in fractional anisotropy and increases in radial diffusivity and mean diffusivity in some areas were also observed in bilateral cerebral white matter. The fractional anisotropy (r=0.54; P<0.0001) and radial diffusivity (r=-0.41; P<0.01) of white matter significantly associated with gray matter density of the cingulate cortex. The mean fractional anisotropy of the white matter tracts of the lateral prefrontal, cingulate, and inferior parietal regions were significantly associated with processing speed, executive function/attention, and working memory. Conclusions-In adult MMD, there were more white matter abnormalities than gray matter changes. Disruption of white matter may play a pivotal role in the development of cognitive dysfunction.
  • Shuken Boku, Hiroyuki Toda, Shin Nakagawa, Akiko Kato, Takeshi Inoue, Tsukasa Koyama, Noboru Hiroi, Ichiro Kusumi
    BIOLOGICAL PSYCHIATRY 77 (4) 335 - 344 0006-3223 2015/02 [Refereed][Not invited]
     
    BACKGROUND: Early life stress is thought to contribute to psychiatric disorders, but the precise mechanisms underlying this link are poorly understood. As neonatal stress decreases adult hippocampal neurogenesis, which, in turn, functionally contributes to many behavioral phenotypes relevant to psychiatric disorders, we examined how in vivo neonatal maternal separation (NMS) impacts the capacity of adult hippocampal neural precursor cells via epigenetic alterations in vitro. METHODS: Rat pups were separated from their dams for 3 hours daily from postnatal day (PND) 2 to PND 14 or were never separated from the dam (as control animals). We isolated adult neural precursor cells from the hippocampal dentate gyrus at PND 56 and assessed rates of proliferation, apoptosis, and differentiation in cell culture. We also evaluated the effect of DNA methylation at the retinoic acid receptor (RAR) promoter stemming from NMS on adult neural precursor cells. RESULTS: NMS attenuated neural differentiation of adult neural precursor cells but had no detectible effect on proliferation, apoptosis, or astroglial differentiation. The DNA methyltransferase (DNMT) inhibitor, 5-aza-dC, reversed a reduction by NMS of neural differentiation of adult neural precursor cells. NMS increased DNMT1 expression and decreased expression of RAR alpha. An RAR alpha agonist increased neural differentiation and an antagonist reduced retinoic acid-induced neural differentiation. NMS increased the methylated portion of RAR alpha promoter, and the DNMT inhibitor reversed a reduction by NMS of RAR alpha messenger RNA expression. CONCLUSIONS: NMS attenuates the capacity of adult hippocampal neural precursor cells to differentiate into neurons by decreasing expression of RAR alpha through DNMT1-mediated methylation of its promoter.
  • Simple Pulmonary Eosinophilia Associated With Clozapine Treatment
    Naoki Hashimoto, Tamaki Maeda, Ryo Okubo, Hisashi Narita, Ichiro Kusumi
    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY 35 (1) 99 - 101 0271-0749 2015/02 [Refereed][Not invited]
  • Takeshi Inoue, Kentaro Kohno, Hajime Baba, Minoru Takeshima, Hiroshi Honma, Yukiei Nakai, Toshihito Suzuki, Koji Hatano, Heii Arai, Shigehiro Matsubara, Ichiro Kusumi, Takeshi Terao
    JOURNAL OF AFFECTIVE DISORDERS 172 141 - 145 0165-0327 2015/02 [Refereed][Not invited]
     
    Background: Previously, we compared the hyperthymic scores of residents in Sapporo, Koshigaya, and Oita (which are located at latitudes of 43 degrees N, 36 degrees N, and 33 degrees N in Japan, respectively) using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A). We found that residents who lived at lower latitudes had higher hyperthymic temperament scores; however, the mechanism of the effect of latitude on hyperthymic temperament remained unclear. The current study examined the mediators of the latitude effect in additional regions with different annual temperatures and amounts of ambient sunshine. Methods: The Japanese archipelago stretches over 4000 km from north to south and has four large islands: Hokkaido, Honshu, Shikoku, and Kyushu. In addition to the TEMPS-A previously reported data collected at Sapporo (latitude 43 degrees N), Koshigaya (36 degrees N), and Oita (33 degrees N), we collected the TEMPS-A data of 189 and 106 residents from Takaoka (36 degrees N) and Obihiro (42 degrees N), respectively. Taken together, these five regions have different patterns (i.e., highs and lows) of annual ambient total sunshine (hours) and mean temperature (degrees C). The effect of latitude, sunshine, and temperature on affective temperaments was analyzed for five Japanese regions. Results: Multiple regression analyses revealed that latitude predicted significant variance in hyperthymic temperament. Ambient temperature, but not sunshine, significantly affected hyperthymic temperament. Limitations: The light exposure that residents actually received was not measured. The number of regions studied was limited. The findings might not generalize to residents across Japan or other countries. Conclusions: The present findings suggest that latitude affects hyperthymic temperament, and ambient temperature might mediate this effect. (C) 2014 Elsevier B.V. All rights reserved
  • Toda H, Inoue T, Tsunoda T, Nakai Y, Tanichi M, Tanaka T, Hashimoto N, Nakato Y, Nakagawa S, Kitaichi Y, Mitsui N, Boku S, Tanabe H, Nibuya M, Yoshino A, Kusumi I
    Neuropsychiatr Dis Treat 14 2079 - 2090 2015 [Refereed][Not invited]
  • Yan An, Takeshi Inoue, Yuji Kitaichi, Shin Nakagawa, Ce Wang, Chong Chen, Ning Song, Ichiro Kusumi
    EUROPEAN JOURNAL OF PHARMACOLOGY 747 13 - 17 0014-2999 2015/01 [Refereed][Not invited]
     
    Lithium not only has a mood-stabilizing effect but also the augmentation effect of an antidepressant, the mechanism of which remains unclear. Although lithium may augment the effect of mirtazapine, this augmentation has not been confirmed. Using a contextual fear conditioning test in rats, an animal model of anxiety or fear, we examined the effect of subchronic lithium carbonate (in diet) in combination with systemic mirtazapine on the expression of contextual conditioned fear. Mirtazapine (10 mg/kg) reduced freezing one day after fear conditioning dose-dependently, whereas the anxiolytic-like effect of mirtazapine (10 mg/kg) diminished seven days after fear conditioning. When the interval between fear conditioning and testing was seven days, only the combination of subchronic 0.2% Li2CO3 but not 0.05% Li2CO3 with acute mirtazapine (10 mg/kg) reduced freezing significantly. These results indicate that subchronic 0.2% Li2CO3 treatment enhanced the anxiolytic-like effect of systemic mirtazapine. This augmentation therapy might be useful for the treatment of anxiety disorders. (C) 2014 Elsevier B.V. All rights reserved,
  • Naoki Hashimoto, Atsuhito Toyomaki, Minoru Honda, Satoru Miyano, Nobuyuki Nitta, Hiroyuki Sawayama, Yasufumi Sugawara, Keiichi Uemura, Noriko Tsukamoto, Tsukasa Koyama, Ichiro Kusumi
    ANNALS OF GENERAL PSYCHIATRY 14 1  1744-859X 2015/01 [Refereed][Not invited]
     
    Background: While the frequency and importance of antipsychotic switching in patients with schizophrenia, there is insufficient evidence with regard to switching strategy. Quetiapine is one of the drugs of choice for switch because of its unique receptor profile. However, there were no data on the long-term clinical and neurocognitive effect of quetiapine in patients who had responded inadequately to prior antipsychotics. The purpose of this study is to examine the long-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response. We hypothesized that quetiapine would show long-term effectiveness in broad symptom dimensions including negative and neurocognitive symptoms while having good tolerability. Methods: Twenty-nine subjects with schizophrenia who did not respond to their current monotherapy of antipsychotic or who could not tolerate the treatment were switched to quetiapine and assessed at baseline and at 3, 6, and 12 months. The outcome measures included the brief assessment of cognition in schizophrenia (BACS), the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale (CGI), the Schizophrenia Quality of Life Scale Japanese version (JSQLS), the Athens Insomnia Scale (AIS), and the Drug Attitude Inventory with 30 items (DAI-30). The Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), HbA1c, prolactin (PRL), and body weight were also evaluated. Results: Statistically significant improvements were observed in all subscores of the PANSS, the GAF, and the symptoms and side effects subscale of the JSQLS, the DIEPSS, the AIS, and the PRL level, and nearly significant improvements were observed in the DAI-30. Quetiapine monotherapy was associated with significant improvement in the verbal memory test, even after controlling for the practice effect. Although quetiapine was well tolerated, three subjects dropped out because of the worsening of the psychotic symptoms and two additional subjects dropped out because of somnolence. Conclusion: In this open-label, single-arm study of 29 patients, quetiapine improved both the clinical symptoms and the neurocognitive impairment in chronic schizophrenia patients who failed to respond to prior antipsychotic treatment.
  • 古川 壽亮, 下寺 信次, 明智 龍男, 山田 光彦, 渡辺 範雄, 稲垣 正俊, 三木 和平, 米本 直裕, 小川 雄右, 田近 亜蘭, 竹島 望, 篠原 清美, 藤瀬 昇, 相澤 明憲, 池田 学, 安元 眞吾, 広田 進, 内村 直尚, 岡本 泰昌, 高石 佳幸, 萬谷 昭夫, 倉田 健一, 山脇 成人, 藤田 博一, 窪内 肇, 森信 繁, 近藤 真前, 加藤 正, 辻野 尚久, 茅野 分, 水野 雅文, 管 心, 杉下 和行, 笠井 清登, 井上 猛, 伊東 かほり, 久住 一郎, SUN-D臨床試験グループ
    精神医学 (株)医学書院 56 (6) 477 - 489 0488-1281 2014/06 [Refereed][Not invited]
  • Satoshi Okada, Shigeru Morinobu, Manabu Fuchikami, Masahiro Segawa, Kana Yokomaku, Tsutomu Kataoka, Yasumasa Okamoto, Shigeto Yamawaki, Takeshi Inoue, Ichiro Kusumi, Tsukasa Koyama, Kounosuke Tsuchiyama, Takeshi Terao, Yosuke Kokubo, Masaru Mimura
    JOURNAL OF PSYCHIATRIC RESEARCH 53 47 - 53 0022-3956 2014/06 [Refereed][Not invited]
     
    We examined the utility of DNA methylation profiles at the CpG island of SLC6A4 (DMS) as a diagnostic biomarker for major depression (MD). In addition, the relationship between DMS and the serotonin transporter gene-linked polymorphic region (5-HTTLPR) allele, the severity of symptoms, number of early adversities, and therapeutic responses to antidepressants were examined. Genomic DNA was extracted from peripheral blood of Japanese healthy controls and patients with MD before and after treatment. DMS was analyzed using a MassARRAY Compact System. The severity of depression was evaluated using the Hamilton Rating Scale for Depression, and early adversity was evaluated using the Early Trauma Inventory. We were unable to distinguish between and healthy controls, or between unmedicated patients and medicated patients using DMS. The 5-HTTLPR allele had no significant effect on DMS. The methylation rates for several CpGs differed significantly after treatment. Notably, the methylation rate of CpG 3 in patients with better therapeutic responses was significantly higher than that in patients with poorer responses. Although further studies examining the function of specific CpG units of SLC6A4 are required, these results suggest that the pre-treatment methylation rate of SLC6A4 is associated with therapeutic responses to antidepressants in unmedicated patients with MD. (C) 2014 Elsevier Ltd. All rights reserved.
  • Yukiei Nakai, Takeshi Inoue, Hiroyuki Toda, Atsuhito Toyomaki, Yasuya Nakato, Shin Nakagawa, Yuji Kitaichi, Rie Kameyama, Yoshiyuki Hayashishita, Yumi Wakatsuki, Koji Oba, Hajime Tanabe, Ichiro Kusumi
    Journal of affective disorders 158 101 - 7 2014/04 [Refereed][Not invited]
     
    BACKGROUND: Previous studies have shown the interaction between heredity and childhood stress or life events on the pathogenesis of major depression. We hypothesized that childhood abuse, affective temperaments, and adult stressful life events interact and influence depressive symptoms in the general adult population and tested this hypothesis in this study. METHODS: The 294 participants from the nonclinical general adult population were studied using the following self-administered questionnaire surveys: the Patient Health Questionnaire-9 (PHQ-9), Life Experiences Survey (LES), Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego auto-questionnaire (TEMPS-A), and Child Abuse and Trauma Scale (CATS). The data were analyzed with single and multiple regressions and structural equation modeling (Amos 20.0). RESULTS: Childhood abuse indirectly predicted the severity of the depressive symptoms through affective temperaments measured by TEMPS-A in the structural equation modeling. Four temperaments - depressive, cyclothymic, irritable, and anxious - directly predicted the severity of depressive symptoms and the negative appraisal of life events during the past year. The negative appraisal of life events during the past year mildly, but significantly, predicted the severity of depressive symptoms. LIMITATIONS: The subjects of this study were nonclinical. The findings might not be generalized to patients with mood disorders. CONCLUSIONS: This study suggests that childhood abuse, especially neglect, indirectly increased depressive symptoms through increased affective temperaments, which, in turn, increase the negative appraisal of stressful life events. An important role of affective temperaments in the effect of childhood abuse and stressful life events on depressive symptoms was suggested.
  • Kotaro Sakurai, Junko Yamamoto, Tsugiko Kurita, Youji Takeda, Ichiro Kusumi
    Epilepsy and Behavior Case Reports 2 (1) 24 - 25 2213-3232 2014/04 [Refereed][Not invited]
     
    A video event data recorder (VEDR) in a motor vehicle records images before and after a traffic accident. This report describes a taxi driver whose seizures were recorded by VEDR, which was extremely useful for the diagnosis of epilepsy. The patient was a 63-year-old right-handed Japanese male taxi driver. He collided with a streetlight. Two years prior to this incident, he raced an engine for a long time while parked. The VEDR enabled confirmation that the accidents depended on an epileptic seizure and he was diagnosed with symptomatic localization-related epilepsy. The VEDR is useful not only for traffic accident evidence it might also contribute to a driver's health care and road safety. © 2013 The Authors.
  • Naoki Takamura, Shin Nakagawa, Takahiro Masuda, Shuken Boku, Akiko Kato, Ning Song, Yan An, Yuji Kitaichi, Takeshi Inoue, Tsukasa Koyama, Ichiro Kusumi
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 50 116 - 124 0278-5846 2014/04 [Refereed][Not invited]
     
    Cumulative studies indicated that adult hippocampal neurogenesis might be involved in the action mechanism of antidepressant drugs and/or the pathophysiology of depression. Dopamine (DA) is involved in the regulation of motivation, volition, interest/pleasure, and attention/concentration, all of which are likely to be impaired in depressed patients. Several previous reports suggest that depression may often be accompanied by a relative hypodopaminergic state, and some DA receptor agonists are beneficial effects in the treatment for refractory and bipolar depression. In the present study, to clarify the direct effect of DA on neural progenitor cells, we examined the effect of DA on the proliferation of adult rat dentate gyrus-derived neural precursor cells (ADPs). In addition, we examined the effect of DA receptor agonists on adult rat hippocampal neurogenesis in vivo. Results showed that DA promoted the increase of ADPs via D1-like receptor and D1-like receptor agonist promoted the survival of newborn cells in the adult hippocampus. On the contrary, D2-like receptor agonist did not affect both proliferation and survival. These results suggested that DA might play, at least in part, a role in adult hippocampal neurogenesis via D1-like receptor and the activation of D1-like receptor has a therapeutic potential for depression. (C) 2013 Elsevier Inc. All rights reserved.
  • The consortium on lithium genetics
    N Engl J Med 370 (19) 1857 - 1859 2014 [Refereed][Not invited]
  • Takahiro Masuda, Takeshi Inoue, Yan An, Naoki Takamura, Shin Nakagawa, Yuji Kitaichi, Tsukasa Koyama, Ichiro Kusumi
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 10 289 - 295 1176-6328 2014 [Refereed][Not invited]
     
    Background: Mirtazapine, a noradrenergic and specific serotonergic antidepressant, which blocks the alpha(2)-adrenergic autoreceptors and heteroreceptors, has shown anxiolytic properties in clinical trials and preclinical animal experiments. The addition of mirtazapine to selective serotonin reuptake inhibitors (SSRIs) is clinically suggested to be more effective for anxiety disorders. In this study, we examined the combined effects of mirtazapine and citalopram, an SSRI, on the freezing behavior of rats, which was induced by contextual conditioned fear as an index of anxiety or fear. Methods: Male Sprague Dawley rats individually received footshocks in a shock chamber, and 24 hours later, they were given citalopram and/or mirtazapine injections. One hour after citalopram and 30 minutes after mirtazapine administration, freezing behavior was analyzed in the same shock chamber without shocks. Results: Mirtazapine decreased freezing in a dose-dependent manner, which is consistent with a previous report; it also enhanced an anxiolytic-like effect at a high dose (30 mg/kg) of citalopram. Because mirtazapine blocks alpha(2)-adrenoreceptors, the combined effect of atipamezole, a selective alpha(2) receptor antagonist, with citalopram was also examined. Similar to mirtazapine, atipamezole reduced freezing dose-dependently, but the enhancement of citalopram's effects by atipamezole was not clear when compared with mirtazapine. Conclusion: The present findings suggest that mirtazapine has an anxiolytic-like effect and may enhance the anxiolytic-like effect of SSRIs, but this enhancement may not be explained by its anti-alpha(2) property alone.
  • Shuken Boku, Shin Nakagawa, Takahiro Masuda, Hiroyuki Nishikawa, Akiko Kato, Naoki Takamura, Yuki Omiya, Yuji Kitaichi, Takeshi Inoue, Ichiro Kusumi
    EUROPEAN JOURNAL OF PHARMACOLOGY 723 425 - 430 0014-2999 2014/01 [Refereed][Not invited]
     
    Neurogenesis in the adult dentate gyrus (DC) is decreased in rodent models for mood disorders. Mood stabilizers including lithium (Li) and valproate (VPA) increase it. These increasing effects of Li and VPA on neurogenesis in adult DG are considered to be one of the therapeutic actions of Li and VPA, but their molecular mechanism remains unclear. We have already reported that Li recovers the inhibitory effects of dexamethasone (DEX), an agonist of glucocorticoid receptor, on the proliferation of adult rat DG-derived neural precursor cells (ADP) via GSK-3 beta and beta-catenin pathway. Following it, here we investigated the mechanism underlying the recovery effects of VPA on DEX-induced decrease of ADP proliferation. VPA is an inhibitor of histone deacetylase (HDAC). However, Trichostatin A, a HDAC inhibitor, had no effect on ADP proliferation. In contrast, SB415286, a specific GSK-3 beta inhibitor, recovered DEX-induced decrease of ADP proliferation. In addition, quercetin (Que), a beta-catenin pathway inhibitor, abolished such a recovery effect of VPA. Moreover, nuclear p-catenin and the expression of cyclin D1 were altered by DEX. VPA and Que like the proliferation. Moreover, VPA increased the phosphorylation of Ser(9), which is known as the inhibitory phosphorylation site of GSK-3 beta. These suggest that HDAC is not involved in the recovery effect of VPA on ADP proliferation and that VPA recovers the inhibitory effects of DEX via increasing the phosphorylation of Ser9 on GsK-3 beta and following up-regulation of beta-catenin pathway. Therefore, GSK-3 beta and beta-catenin pathway might play a role in the increasing effects of VPA on neurogenesis on adult DC. (C) 2013 Elsevier B.V. All rights reserved,
  • Yusuke Shimizu, Nobuki Kitagawa, Nobuyuki Mitsui, Yutaka Fujii, Atsuhito Toyomaki, Naoki Hashimoto, Yuki Kako, Teruaki Tanaka, Satoshi Asakura, Ichiro Kusumi
    Psychiatry Research 210 (3) 913 - 918 0165-1781 2013/12/30 [Refereed][Not invited]
     
    Quality of life (QOL) has been reported to be impaired in patients with major depressive disorder (MDD), even after remission according to symptom rating scales. Although a relationship between QOL and neurocognitive dysfunction has been reported during depressive episodes, little is known about this relationship in remitted MDD patients. The aim of the present study was to investigate the relationship between QOL and neurocognitive dysfunction in patients with remitted MDD while controlling for confounding factors. Forty-three remitted MDD patients were assessed with neuropsychological tests and QOL, which was measured by a short-form 36-item health survey. The neurocognitive performances of the patients were compared with those of 43 healthy controls. We next evaluated the relationships between neurocognitive impairments, clinical factors, and QOL. Remitted MDD patients had poorer neurocognitive performances than healthy controls for psychomotor speed, attention, and verbal memory. Residual depressive symptoms were strongly associated with QOL. Delayed verbal recall was associated with general health perceptions, which are part of the QOL assessment, even after the effects of the residual depressive symptoms were considered. The results may indicate that clinicians should try to detect neurocognitive dysfunctions that may interfere with QOL using neurocognitive assessments in their daily practice. © 2013 Elsevier Ireland Ltd.
  • Yan An, Takeshi Inoue, Yuji Kitaichi, Takeshi Izumi, Shin Nakagawa, Ning Song, Chong Chen, Xiaobai Li, Tsukasa Koyama, Ichiro Kusumi
    European Journal of Pharmacology 720 (1-3) 192 - 197 0014-2999 2013/11/15 [Refereed][Not invited]
     
    Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), blocks the α2-adrenergic autoreceptors and heteroreceptors, which are responsible for controlling noradrenaline and 5-hydroxytryptamine (5-HT) release. Though preclinical and clinical studies have shown that mirtazapine exerts an anxiolytic action, its precise brain target sites remain unclear. In the present study, we investigated the brain area(s) in which mirtazapine exerts its anxiolytic-like effects on the expression of contextual conditioned freezing in rats. Mirtazapine (3 μg/site) was directly injected into three brain structures, the median raphe nucleus (MRN), hippocampus and amygdala. Freezing behavior tests were carried out 10 min after injections. Our results showed that the intra-MRN injection of mirtazapine reduced freezing significantly, whereas injections into the hippocampus or the amygdala did not. In addition, the intra-MRN injection of mirtazapine did not affect locomotor activity. These results suggest that the anxiolytic-like effect of mirtazapine might be mediated by its action on the MRN. © 2013 Elsevier B.V. All rights reserved.
  • Shuken Boku, Kazue Hisaoka-Nakashima, Shin Nakagawa, Akiko Kato, Naoto Kajitani, Takeshi Inoue, Ichiro Kusumi, Minoru Takebayashi
    PLOS ONE 8 (11) e79371  1932-6203 2013/11 [Refereed][Not invited]
     
    Antidepressants increase the proliferation of neural precursors in adult dentate gyrus (DG), which is considered to be involved in the therapeutic action of antidepressants. However, the mechanism underlying it remains unclear. By using cultured adult rat DG-derived neural precursors (ADP), we have already shown that antidepressants have no direct effects on ADP. Therefore, antidepressants may increase the proliferation of neural precursors in adult DG via unknown indirect mechanism. We have also shown that amitriptyline (AMI), a tricyclic antidepressant, induces the expressions of GDNF, BDNF, FGF2 and VEGF, common neurogenic factors, in primary cultured astrocytes (PCA). These suggest that AMI-induced factors in astrocytes may increase the proliferation of neural precursors in adult DG. To test this hypothesis, we examined the effects of AMI-induced factors and conditioned medium (CM) from PCA treated with AMI on ADP proliferation. The effects of CM and factors on ADP proliferation were examined with BrdU immunocytochemistry. AMI had no effect on ADP proliferation, but AMI-treated CM increased it. The receptors of GDNF, BDNF and FGF2, but not VEGF, were expressed in ADP. FGF2 significantly increased ADP proliferation, but not BDNF and GDNF. In addition, both of a specific inhibitor of FGF receptors and anti-FGF2 antibody significantly counteracted the increasing effect of CM on ADP proliferation. In addition, FGF2 in brain is mainly derived from astrocytes that are key components of the neurogenic niches in adult DG. These suggest that AMI may increase ADP proliferation indirectly via PCA and that FGF2 may a potential candidate to mediate such an indirect effect of AMI on ADP proliferation via astrocytes.
  • Nobuyuki Mitsui, Satoshi Asakura, Yusuke Shimizu, Yutaka Fujii, Yuki Kako, Teruaki Tanaka, Koji Oba, Takeshi Inoue, Ichiro Kusumi
    Comprehensive psychiatry 54 (8) 1215 - 21 2013/11 [Refereed][Not invited]
     
    OBJECTIVE: The aim of our study was to reveal the personality traits of individuals with major and other depressive episodes among the young adult population. Furthermore, character traits of individuals with ideas of suicide or self-harm were also investigated in this study. METHODS: The subjects of this study were 1421 university students who completed the Patient Health Questionnaire (PHQ-9) and the Temperament and Character Inventory (TCI). The subjects were divided into three separate groups: the major depressive episode group (N = 41), the other depressive episode group (N = 97), and the non-depressive controls (N = 1283). This separation was achieved using the PHQ-9 algorithm diagnosis. We compared the TCI scores using an analysis of variance. Moreover, the Cochran-Armitage trend test was used to determine the diagnosis, ideas of suicide or self-harm, and analysis of character profiles. RESULTS: The major depressive episode group had significantly higher HA (P < 0.001), lower RD (P < 0.001), lower SD (P < 0.001), and lower C (P < 0.001) scores than non-depressive controls. The other depressive episode group had significantly higher HA scores (P < 0.001) and lower SD scores (P < 0.001) than non-depressive controls. The Cochran-Armitage trend test revealed that the prevalence of depressive episodes decreased as the character profiles matured (χ(2)(trend) = 57.2, P < 0.0001). The same tendency was observed in individuals who had ideas of suicide or self-harm (χ(2)(trend) = 49.3, P < 0.0001). CONCLUSION: High HA and low SD scores were common personality traits among young adults with major depressive episodes. Furthermore, the immaturity of character profiles was clearly associated with depressive episodes and ideas of suicide or self-harm.
  • Yuji Kitaichi, Takeshi Inoue, Nobuyuki Mitsui, Shin Nakagawa, Rie Kameyama, Yoshiyuki Hayashishita, Tohru Shiga, Ichiro Kusumi, Tsukasa Koyama
    Neuropsychiatric Disease and Treatment 9 1591 - 1594 1176-6328 2013/10/16 [Refereed][Not invited]
     
    We report a case in which selegiline, an irreversible monoamine oxidase B (MAO-B) inhibitor, greatly improved depressive symptoms in an adult with stage 5 treatment-resistant major depressive disorder. Four antidepressants and four augmentation therapies had previously been ineffective or intolerable, and electroconvulsive therapy had only a temporary effect. After 20 weeks of treatment with selegiline (10 mg/day), the patient's score on the 17-item Hamilton Depression Rating Scale (HDRS) had decreased from 19 to 4 points. [18F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) showed increased glucose metabolism in the bilateral basal ganglia after initiating selegiline treatment blood dopamine levels were also increased after selegiline treatment. These results raise the possibility that selegiline enhances dopaminergic neural transmission in treatment-resistant depression, thus leading to an improvement in depressive symptoms. © 2013 Kitaichi et al.
  • Rie Kameyama, Takeshi Inoue, Mai Uchida, Teruaki Tanaka, Yuji Kitaichi, Yasuya Nakato, Yoshiyuki Hayashishita, Yukiei Nakai, Shin Nakagawa, Ichiro Kusumi, Tsukasa Koyama
    JOURNAL OF AFFECTIVE DISORDERS 150 (2) 546 - 550 0165-0327 2013/09 [Refereed][Not invited]
     
    Background: We developed a self-reported questionnaire, the Manic Episode Screening Questionnaire (MES), based on the eight diagnostic criteria items of DSM-IV-TR (hypo)manic episodes. This study was designed to determine the optimal screening methods to identify bipolar disorders among mood disorder patients of a psychiatric specialty clinic. Methods: In 95 mood disorder patients, we assessed the operational characteristics of the MES as a screening and diagnostic instrument using a DSM-IV-TR diagnosis by a trained psychiatrist as a reference standard. The reference criteria were bipolar disorders. MES was used with two methods: the diagnostic algorithm and the one-question method (question #1 only). The diagnostic algorithm was regarded as fulfilled if the answers to question #1 and three or more of questions #2 to #8 were "yes", corresponding to the DSM-IV-TR (hypo)manic episode criteria. In different subjects, the test-retest reliability of the MES was examined. Results: The two methods of the MES showed high specificity (0.93-0.94), high positive predictive value (0.81-0.83) and high negative predictive value (0.88-0.90), but the sensitivity scored lower (0.68-0.75). The test-retest reliability was moderate: 0.75 for the diagnostic algorithm and 0.68 for the one-question method. Limitations: This study includes a small number of bipolar l patients. The findings might not be generalized to patients outside of this patient population. Conclusions: The MES is useful for the screening and diagnosis of bipolar disorders among mood disorder patients in psychiatric specialty clinics. The one question method of the MES is more convenient to use than prior questionnaires and is here recommended. (C) 2013 Elsevier B.V. All rights reserved.
  • Tsugiko Kurita, Kotaro Sakurai, Youji Takeda, Ichiro Kusumi
    Epilepsy and Behavior Case Reports 1 (1) 142 - 145 2213-3232 2013/08 [Refereed][Not invited]
     
    Piloerection is a rare ictal manifestation of temporal lobe epilepsy. The case is a 38-year-old man with acute onset of repetitive pilomotor seizures. Lacking other symptoms implicating epileptic seizures, a month passed before he was diagnosed with epilepsy. Ictal electroencephalography revealed rhythmic waves in the right temporal area. Reversible magnetic resonance imaging (MRI) abnormalities were visible in the right hippocampus, right uncus, and right amygdala. The appropriate antiepileptic drug therapy made him seizure-free, but following MRI, he showed right hippocampal atrophy one year after seizure cessation. This case is significant in that we can follow sequential MRI from onset, and it is meaningful for considering the mesial temporal area as involved with piloerection. © 2013 The Authors.
  • Nobuyuki Mitsui, Satoshi Asakura, Takeshi Inoue, Yusuke Shimizu, Yutaka Fujii, Yuki Kako, Teruaki Tanaka, Nobuki Kitagawa, Ichiro Kusumi
    COMPREHENSIVE PSYCHIATRY 54 (5) 556 - 561 0010-440X 2013/07 [Refereed][Not invited]
     
    Objective: The aims of this study were to investigate the personality traits of suicide completers using the Temperament and Character Inventory (TCI) scale. Methods: Newly enrolled students who enrolled at Hokkaido University in 1999-2002 and 2004-2007 completed the TCI. Among these students, twenty subjects (2 females and 18 males) later completed suicide. We compared the TCI scales of these subjects with those of 60 (6 females and 54 males) well-matched controls. The controls were matched for age, gender, university department and year of enrollment in the university. Because the number of females was too small, the statistical analyses for the TCI subscales and logistic regression analysis were performed only with the 18 males. Results: A univariate analysis of seven personality dimensions on the TCI revealed higher scores of harm avoidance (HA) in subjects with suicide completion (P=0.034). Analysis of the male subjects showed that suicide completers had higher scores for anticipatory worry (HA1 P=0.007) and fear of uncertainty (HA2, P=0.036) and lower scores for spiritual acceptance (ST3, P=0.038) than did the controls. A multivariate analysis, which was performed to adjust confounding factors, demonstrated significantly higher scores for HA1 among suicide completers (P=0.01, OR=1.32). Conclusions: These results suggest that higher HA scores may predict suicide completion. (C) 2013 Elsevier Inc. All rights reserved.
  • Mirko Manchia, Mazda Adli, Nirmala Akula, Raffaella Ardau, Jean-Michel Aubry, Lena Backlund, Claudio E. M. Banzato, Bernhard T. Baune, Frank Bellivier, Susanne Bengesser, Joanna M. Biernacka, Clara Brichant-Petitjean, Elise Bui, Cynthia V. Calkin, Andrew Tai Ann Cheng, Caterina Chillotti, Sven Cichon, Scott Clark, Piotr M. Czerski, Clarissa Dantas, Maria Del Zompo, J. Raymond DePaulo, Sevilla D. Detera-Wadleigh, Bruno Etain, Peter Falkai, Louise Frisen, Mark A. Frye, Jan Fullerton, Sebastien Gard, Julie Garnham, Fernando S. Goes, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Rebecca Hoban, Liping Hou, Stephane Jamain, Jean-Pierre Kahn, Layla Kassem, Tadafumi Kato, John R. Kelsoe, Sarah Kittel-Schneider, Sebastian Kliwicki, Po-Hsiu Kuo, Ichiro Kusumi, Gonzalo Laje, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Carlos A. Lopez Jaramillo, Mario Maj, Alain Malafosse, Lina Martinsson, Takuya Masui, Philip B. Mitchell, Frank Mondimore, Palmiero Monteleone, Audrey Nallet, Maria Neuner, Tomas Novak, Claire O'Donovan, Urban Osby, Norio Ozaki, Roy H. Perlis, Andrea Pfennig, James B. Potash, Daniela Reich-Erkelenz, Andreas Reif, Eva Reininghaus, Sara Richardson, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Oliver K. Schubert, Barbara Schweizer, Florian Seemueller, Maria Grigoroiu-Serbanescu, Giovanni Severino, Lisa R. Seymour, Claire Slaney, Jordan W. Smoller, Alessio Squassina, Thomas Stamm, Jo Steele, Pavla Stopkova, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Naomi R. Wray, Adam Wright, Peter P. Zandi, David Zilles, Michael Bauer, Marcella Rietschel, Francis J. McMahon, Thomas G. Schulze, Martin Alda
    PLOS ONE 8 (6) e65636  1932-6203 2013/06 [Refereed][Not invited]
     
    Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (kappa)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (kappa = 0.66 and kappa = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
  • Yutaka Fujii, Nobuki Kitagawa, Yusuke Shimizu, Nobuyuki Mitsui, Atsuhito Toyomaki, Naoki Hashimoto, Yuki Kako, Teruaki Tanaka, Satoshi Asakura, Tsukasa Koyama, Ichiro Kusumi
    Neuroscience Letters 543 42 - 46 0304-3940 2013/05/24 [Refereed][Not invited]
     
    To evaluate neurocognitive functions of patients with social anxiety disorder (SAD) without comorbidity using neuropsychological assessments and to investigate the relation between neurocognitive functions and clinical severity of SAD, this study assessed 30 SAD patients (10 female, 20 male) without comorbidity and 30 healthy subjects matched on gender, education level, and age. The neuropsychological assessment consisted of the Wisconsin card sorting test (WCST), the continuous performance test, the trail-making test, the word fluency test, and the auditory verbal learning test. On the WCST, patients showed lower performance than healthy controls did. The Liebowitz Social Anxiety Scale score correlated significantly with the numbers of perseverative errors of the WCST, although the State anxiety score of State-Trait Anxiety Inventory and the Beck Depression Inventory - Second Edition score showed no correlation with neuropsychological test scores. Results show that the executive functioning of patients with SAD was low and that the low functioning correlates with the SAD symptom severity. © 2013 Elsevier Ireland Ltd.
  • Shuken Boku, Shin Nakagawa, Naoki Takamura, Akiko Kato, Minoru Takebayashi, Kazue Hisaoka-Nakashima, Yuki Omiya, Takeshi Inoue, Ichiro Kusumi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 434 (4) 779 - 784 0006-291X 2013/05 [Refereed][Not invited]
     
    While the pro-neurogenic actions of antidepressants in the adult hippocampal dentate gyrus (DG) are thought to be one of the mechanisms through which antidepressants exert their therapeutic actions, antidepressants do not increase proliferation of neural precursor cells derived from the adult DG. Because previous studies showed that antidepressants increase the expression and secretion of glial cell line-derived neurotrophic factor (GDNF) in C6 glioma cells derived from rat astrocytes and GDNF increases neurogenesis in adult DG in vivo, we investigated the effects of GDNF on the proliferation, differentiation and apoptosis of cultured neural precursor cells derived from the adult DG. Data showed that GDNF facilitated the differentiation of neural precursor cells into astrocytes but had no effect on their proliferation or apoptosis. Moreover, GDNF increased the phosphorylation of STAT3, and both a specific inhibitor of STAT3 and lentiviral shRNA for STAT3 decreased their differentiation into astrocytes. Taken together, our findings suggest that GDNF facilitates astrogliogenesis from neural precursor cells in adult DG through activating STAT3 and that this action might indirectly affect neurogenesis. (C) 2013 Elsevier Inc. All rights reserved.
  • Kotaro Sakurai, Tsugiko Kurita, Youji Takeda, Hideaki Shiraishi, Ichiro Kusumi
    Epilepsy and Behavior Case Reports 1 (1) 74 - 76 2213-3232 2013 [Refereed][Not invited]
     
    Akinetopsia is a rare syndrome in which a patient specifically loses the ability to perceive visual motion following bilateral cortical lesions outside the striate cortex. We describe a patient who showed akinetopsia recurrently as epileptic seizures.The patient was a 61-year-old man. At age 46, a cerebral arteriovenous malformation in the right parietal lobe was discovered. At age 58, he began to have a recurrent visual symptom by which smooth movements of objects suddenly appeared, resembling freeze frames in a motion picture. This symptom was paroxysmal and recurrent. Both EEG and magnetoencephalography showed repetitive right temporal spikes. We diagnosed his visual symptom as akinetopsia, which was aroused by hyperexcitability of the right temporal and parietal cortices, including area MT/V5. We administered carbamazepine 200. mg/day, which suppressed his akinetopsic symptom completely. © 2013 The Authors.
  • Hiromi Kimura, Akemi Osaki, Rui Kawashima, Takeshi Inoue, Shin Nakagawa, Katsuji Suzuki, Satoshi Asakura, Teruaki Tanaka, Yuji Kitaichi, Takuya Masui, Nobuki Kitagawa, Yuki Kako, Tomohiro Abekawa, Ichiro Kusumi, Hiroyoshi Yamanaka, Kenzo Denda, Tsukasa Koyama
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 9 619 - 627 1178-2021 2013 [Refereed][Not invited]
     
    Background: The bipolar-unipolar distinction in patients with a major depressive episode is the most important issue related to the diagnosis and treatment of mood disorders, but remains unresolved. This study was undertaken to compare bipolar and unipolar depression on Rorschach testing using the Comprehensive System with reference to healthy Japanese controls. Methods: Patients with bipolar or unipolar depression who had undergone the Rorschach test for routine clinical purposes were followed up naturalistically for a long period. Based on diagnostic confirmation after long-term follow-up, scores on this test for patients with bipolar and unipolar depression were compared with those published elsewhere for healthy Japanese controls. Results: The bipolar depression group showed significantly higher scores or positive findings in five variables of the Rorschach test, ie, WSum6, DR2 > 0, (CF + C) > FC + 2, PureC > 1, and Populars > 7, as assessed using the Comprehensive System, than did the unipolar depression group and healthy controls. These scores did not differ between the unipolar depression and control groups. Conclusion: The results of this study show thought disorder or cognitive slippage and marked laxness in modulating emotion in bipolar depression, indicating the psychopathological characteristics of bipolar disorder.
  • 藤井 泰, 賀古 勇輝, 久住 一郎
    精神科 科学評論社 21 (4) 444 - 447 1347-4790 2012/10 [Not refereed][Not invited]
  • Maki Miyajima, Atsuhito Toyomaki, Naoki Hashimoto, Ichiro Kusumi, Harumitsu Murohashi, Tsukasa Koyama
    NEUROREPORT 23 (11) 642 - 646 0959-4965 2012/08 [Refereed][Not invited]
     
    Task switching is a well-known cognitive paradigm to explore task-set reconfiguration processes such as rule shifting. In particular, endogenous task switching is thought to differ qualitatively from stimulus-triggered exogenous task switching. However, no previous study has examined the neural substrate of endogenous task switching. The purpose of the present study is to explore the differences between event-related potential responses to exogenous and endogenous rule switching at cue stimulus. We modified two patterns of cued switching tasks: exogenous (bottom-up) rule switching and endogenous (top-down) rule switching. In each task cue stimulus was configured to induce switching or maintaining rule. In exogenous switching tasks, late positive deflection was larger in the switch rule condition than in the maintain rule condition. However, in endogenous switching tasks late positive deflection was unexpectedly larger in the maintain-rule condition than in the switch-rule condition. These results indicate that exogenous rule switching is explicit stimulus-driven processes, whereas endogenous rule switching is implicitly parallel processes independent of external stimulus. NeuroReport 23:642-646 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
  • R. Shimazawa, I. Kusumi, M. Ikeda
    JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS 37 (3) 348 - 351 0269-4727 2012/06 [Refereed][Not invited]
     
    What is known and Objective: The lag in the approval and development of psychiatric drugs between Japan and other countries has been a major issue both for patients with psychiatric diseases and for psychiatrists. The objective of this study was to analyse factors contributing to delays in launching new psychiatric drugs in Japan. Methods: We analysed data from Japan, the USA, and the UK for the approval of 23 standard psychiatric drugs and examined potential factors that might have contributed the delay of their launch. Results: Of the 23 standard psychiatric drugs, all of which were approved in the USA and the UK, only 13 were introduced in Japan between September 2000 and July 2011. None of their development strategies adopted the ICH E5 guideline on simultaneous development of drugs on a global scale. Twelve of the 13 drugs (not including atomoxetine) were approved in Japan after their approval in the USA and the UK. The median review time (from approval application to approval) of these 13 drugs in Japan was 23 months, which was considerably longer than those of the US Food and Drug Administration and European Medicines Agency (10.0 and 13.5 months, respectively). The 1013-month difference in review time cannot explain the overall 87- and 51-month delay in Japan after approval in the USA or UK. What is new and Conclusion: There remains a large gap between Japan and Western countries, such as the USA and the UK, with regard to access to standard psychiatric drugs, despite several important reforms in the Japanese drug approval system.
  • Noko Matsuda, Naoki Hashimoto, Ichiro Kusumi, Koki Ito, Tsukasa Koyama
    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY 32 (2) 297 - 298 0271-0749 2012/04 [Refereed][Not invited]
  • Ichiro Kusumi, Minoru Honda, Keiichi Uemura, Yasuhumi Sugawara, Masako Kohsaka, Akihiko Tochigi, Tsukasa Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 36 (2) 313 - 317 0278-5846 2012/03 [Refereed][Not invited]
     
    Olanzapine has frequently been reported to induce substantial weight gain, which is associated with an increased prevalence of dyslipidemia and type 2 diabetes. Several reports have described that olan rapine orally disintegrating tablets (ODT) induce less weight gain than oral standard tablets (OST) do, although both forms have equal bioavailability. We tried to clarify whether or not body weight change differed between olanzapine ODT and OST treatments in olanzapine-naive schizophrenia patients. An open-label, 12-month, multi-center, randomized, flexible-dose study was conducted for direct comparison of the effects of OST (mean dosage, 15.7 mg; N = 57) and ODT (mean dosage, 15.2 mg; N = 61) on body weight and metabolic measures such as blood glucose, hemoglobinmc(A1c), total cholesterol and HDL-cholesterol, and triglycerides in olanzapinenaive patients with schizophrenia. Outcome measures included Positive and Negative Syndrome Scale (PANSS), Global Assessment of Function (GAF), The World Health Organization Quality of Life 26 (WHO-QO126), Drug Attitude Inventory (DAI)-10, and tolerability assessed by the UKU side-effect rating scale. This study was conducted between June 2007 and April 2010. No significant difference was found in the weight gain between the two forms of olanzapine. No significant difference was found between the two groups in any metabolic measure, efficacy, tolerability. WHO-QO126, or DAI-10 score. Previous reports describing that olanzapine ODT induced less weight gain than OST were not supported by results of this randomized study. (C) 2011 Elsevier Inc. All rights reserved.
  • Ichiro Kusumi, Minoru Honda, Keiichi Uemura, Yasuhumi Sugawara, Masako Kohsaka, Akihiko Tochigi, Tsukasa Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 36 (2) 313 - 317 0278-5846 2012/03 [Refereed][Not invited]
     
    Olanzapine has frequently been reported to induce substantial weight gain, which is associated with an increased prevalence of dyslipidemia and type 2 diabetes. Several reports have described that olan rapine orally disintegrating tablets (ODT) induce less weight gain than oral standard tablets (OST) do, although both forms have equal bioavailability. We tried to clarify whether or not body weight change differed between olanzapine ODT and OST treatments in olanzapine-naive schizophrenia patients. An open-label, 12-month, multi-center, randomized, flexible-dose study was conducted for direct comparison of the effects of OST (mean dosage, 15.7 mg; N = 57) and ODT (mean dosage, 15.2 mg; N = 61) on body weight and metabolic measures such as blood glucose, hemoglobinmc(A1c), total cholesterol and HDL-cholesterol, and triglycerides in olanzapinenaive patients with schizophrenia. Outcome measures included Positive and Negative Syndrome Scale (PANSS), Global Assessment of Function (GAF), The World Health Organization Quality of Life 26 (WHO-QO126), Drug Attitude Inventory (DAI)-10, and tolerability assessed by the UKU side-effect rating scale. This study was conducted between June 2007 and April 2010. No significant difference was found in the weight gain between the two forms of olanzapine. No significant difference was found between the two groups in any metabolic measure, efficacy, tolerability. WHO-QO126, or DAI-10 score. Previous reports describing that olanzapine ODT induced less weight gain than OST were not supported by results of this randomized study. (C) 2011 Elsevier Inc. All rights reserved.
  • Satoshi Asakura, Takeshi Inoue, Nobuki Kitagawa, Mifumi Hasegawa, Yutaka Fujii, Yuki Kako, Yasuya Nakato, Naoki Hashimoto, Koki Ito, Teruaki Tanaka, Shin Nakagawa, Ichiro Kusumi, Tsukasa Koyama
    PSYCHOPATHOLOGY 45 (2) 96 - 101 0254-4962 2012 [Refereed][Not invited]
     
    Background: Taijin-kyofu (TK), especially the 'convinced' subtype of TK (c-TK; also known as the 'offensive' subtype of TK), is described as a Japanese culture-bound syndrome similar to social anxiety disorder (SAD). Recently, in Western countries, the symptoms of c-TK have been investigated in patients with SAD. We developed the Social Anxiety/Taijin-Kyofu Scale (SATS), a 12-item structured clinician-rated instrument designed to rate the severity of TK symptoms, and examined its reliability and validity. Methods:The SATS was administered to 15 patients with c-TK diagnosed using the traditional Japanese TK criteria. Interviews used to score patients' symptoms were recorded on videotape. Additionally, the Clinical Global Impression-Severity Scale (CGI-S) was administered to assess convergent validity. Interrater reliability was assessed on 15 videotaped interviews; the interviews were independently rated by 10 other raters. Test-retest reliability was assessed on 15 videotaped interviews by the same rater at an interval of more than 4 weeks. Results: The SATS had high internal consistency (Cronbach's alpha = 0.97) and good interrater reliability (ICC = 0.88-0.93) and test-retest reliability (ICC = 0.94-0.99). The SATS total score correlated with the CGI-S scores (r = 0.77, p < 0.0001). Conclusion: The SATS appears to be a reliable and valid measure of the symptoms of TK. Copyright (C) 2012 S. Karger AG, Basel
  • Yuji Kitaichi, Takeshi Inoue, Shin Nakagawa, Shuken Boku, Akiko Kato, Ichiro Kusumi, Tsukasa Koyama
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 8 501 - 507 1176-6328 2012 [Refereed][Not invited]
     
    Background: Up to 30% of depressed patients are partially or totally resistant to antidepressant therapy. The administration of triiodothyronine (T-3) to antidepressant nonresponders can be an effective augmentation strategy, although the mechanism is not fully understood. Methods: In vivo microdialysis was used to examine the effect of T-3 augmentation of the antidepressant, milnacipran. Basal extracellular serotonin, norepinephrine, and dopamine levels were measured before and after acute milnacipran administration in the medial prefrontal cortex and amygdala of rats which had received subchronic (7 days) T-3 treatment or control saline. Results: Subchronic administration of T3 at 0.1 mg/kg significantly increased basal extracellular levels of serotonin in the medial prefrontal cortex, but not in the amygdala. In contrast, subchronic administration of T-3 at 0.2 mg/kg did not alter basal extracellular serotonin levels in the medial prefrontal cortex. Basal extracellular levels of norepinephrine and dopamine were not modified by either dose of T-3 in either region. Acute administration of milnacipran, a serotonin-norepinephrine reuptake inhibitor, to control animals resulted in a significant increase of extracellular levels of serotonin, norepinephrine, and dopamine. When administered to animals treated subchronically with T-3 at 0.1 mg/kg, milnacipran produced an additional increase in extracellular serotonin levels but not in levels of norepinephrine or dopamine in the medial prefrontal cortex of rats. Conclusion: These results suggest that the mechanism of the augmentation effect of milnacipran by T-3 administration occurs via enhancement of serotonergic neurotransmission, but not through noradrenergic or dopaminergic neurotransmission.
  • Ichiro Kusumi, Koki Ito, Keiichi Uemura, Minoru Honda, Tadayuki Hayashishita, Kazuko Miyamoto, Hiroyuki Sawayama, Yuki Kako, Shoichiro Tsuchida, Naoki Hashimoto, Tsukasa Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 35 (8) 1922 - 1926 0278-5846 2011/12 [Refereed][Not invited]
     
    Second-generation antipsychotics (SGAs) tend to induce weight gain, dyslipidemia and diabetes mellitus. For those reasons, patients treated with SGAs should receive appropriate monitoring to avoid morbidity and mortality associated with cardiovascular disease. We conducted a one-year follow-up study using Japanese blood glucose monitoring guidance in schizophrenia patients treated with SGAs to evaluate the detection capability of the guidance in real clinical settings and to assess the importance of longitudinal monitoring. This retrospective cohort study included schizophrenia patients receiving at least one SGA, who were enrolled during June 2008-January 2009 at multiple sites and who had both baseline data and follow-up monitoring data at month 12. After one-year follow-up, the probable diabetes type (fasting blood glucose is higher than 125 mg/dL, casual blood glucose is higher than 179 mg/dL, or glycosylated hemoglobin (Hb(A1c)) is greater than 6.4%) was detected in 30(8%) of the patients, and the pre-diabetes type (fasting blood glucose is 110-125 mg/dL, or casual blood glucose is 140-179 mg/dL, or Hb(A1c) is 6.0-6.4%) in 65 (17.4%) out of the total of 374 patients. During the follow-up period, 1.5% of patients had advanced from the normal (fasting blood glucose is less than 110 mg/dL, casual blood glucose is less than 140 mg/dL, or Hb(A1c) is less than 6.0%) to probable diabetes type and 42.4% had progressed from the pre-diabetes to probable diabetes type. Predictive factors for worsening of the diabetic state were a family history of diabetes, and high serum total-cholesterol and triglyceride levels at baseline. Not only cross-sectional baseline screening but also longitudinal follow-up screening is important to detect glucose abnormalities in patients treated with SGAs. (C) 2011 Elsevier Inc. All rights reserved.
  • Ichiro Kusumi, Koki Ito, Keiichi Uemura, Minoru Honda, Tadayuki Hayashishita, Kazuko Miyamoto, Hiroyuki Sawayama, Yuki Kako, Shoichiro Tsuchida, Naoki Hashimoto, Tsukasa Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 35 (8) 1922 - 1926 0278-5846 2011/12 [Refereed][Not invited]
     
    Second-generation antipsychotics (SGAs) tend to induce weight gain, dyslipidemia and diabetes mellitus. For those reasons, patients treated with SGAs should receive appropriate monitoring to avoid morbidity and mortality associated with cardiovascular disease. We conducted a one-year follow-up study using Japanese blood glucose monitoring guidance in schizophrenia patients treated with SGAs to evaluate the detection capability of the guidance in real clinical settings and to assess the importance of longitudinal monitoring. This retrospective cohort study included schizophrenia patients receiving at least one SGA, who were enrolled during June 2008-January 2009 at multiple sites and who had both baseline data and follow-up monitoring data at month 12. After one-year follow-up, the probable diabetes type (fasting blood glucose is higher than 125 mg/dL, casual blood glucose is higher than 179 mg/dL, or glycosylated hemoglobin (Hb(A1c)) is greater than 6.4%) was detected in 30(8%) of the patients, and the pre-diabetes type (fasting blood glucose is 110-125 mg/dL, or casual blood glucose is 140-179 mg/dL, or Hb(A1c) is 6.0-6.4%) in 65 (17.4%) out of the total of 374 patients. During the follow-up period, 1.5% of patients had advanced from the normal (fasting blood glucose is less than 110 mg/dL, casual blood glucose is less than 140 mg/dL, or Hb(A1c) is less than 6.0%) to probable diabetes type and 42.4% had progressed from the pre-diabetes to probable diabetes type. Predictive factors for worsening of the diabetic state were a family history of diabetes, and high serum total-cholesterol and triglyceride levels at baseline. Not only cross-sectional baseline screening but also longitudinal follow-up screening is important to detect glucose abnormalities in patients treated with SGAs. (C) 2011 Elsevier Inc. All rights reserved.
  • Taiki Takahashi, Hidemi Oono, Takeshi Inoue, Shuken Boku, Yuki Kako, Yuji Kitaichi, Ichiro Kusumi, Takuya Masui, Shin Nakagawa, Katsuji Suzuki, Teruaki Tanaka, Tsukasa Koyama, Mark H, B. Radford
    Neuro Endocrinol Lett. 2008, 29(3):351-358 2011/11 [Refereed][Not invited]
     
    Depression has been associated with impaired neural processing of reward and
    punishment. However, to date, little is known regarding the relationship
    between depression and intertemporal choice for gain and loss. We compared
    impulsivity and inconsistency in intertemporal choice for monetary gain and
    loss (quantified with parameters in the q-exponential discount function based
    on Tsallis' statistics) between depressive patients and healthy control
    subjects. This examination is potentially important for advances in
    neuroeconomics of intertemporal choice, because depression is associated with
    ...
  • Manabu Fuchikami, Shigeru Morinobu, Masahiro Segawa, Yasumasa Okamoto, Shigeto Yamawaki, Norio Ozaki, Takeshi Inoue, Ichiro Kusumi, Tsukasa Koyama, Kounosuke Tsuchiyama, Takeshi Terao
    PLOS ONE 6 (8) e23881  1932-6203 2011/08 [Refereed][Not invited]
     
    Major depression, because of its recurring and life-threatening nature, is one of the top 10 diseases for global disease burden. Major depression is still diagnosed on the basis of clinical symptoms in patients. The search for specific biological markers is of great importance to advance the method of diagnosis for depression. We examined the methylation profile of 2 CpG islands (I and IV) at the promoters of the brain-derived neurotrophic factor (BDNF) gene, which is well known to be involved in the pathophysiology of depression. We analyzed genomic DNA from peripheral blood of 20 Japanese patients with major depression and 18 healthy controls to identify an appropriate epigenetic biomarker to aid in the establishment of an objective system for the diagnosis of depression. Methylation rates at each CpG unit was measured using a MassArray (R) system (SEQUENOM), and 2-dimensional hierarchical clustering analyses were undertaken to determine the validity of these methylation profiles as a diagnostic biomarker. Analyses of the dendrogram from methylation profiles of CpG I, but not IV, demonstrated that classification of healthy controls and patients at the first branch completely matched the clinical diagnosis. Despite the small number of subjects, our results indicate that classification based on the DNA methylation profiles of CpG I of the BDNF gene may be a valuable diagnostic biomarker for major depression.
  • Naoki Hashimoto, Mie Matsui, Ichiro Kusumi, Atsuhito Toyomaki, Koki Ito, Yuki Kako, Tsukasa Koyama
    PSYCHIATRY RESEARCH 188 (2) 289 - 290 0165-1781 2011/07 [Refereed][Not invited]
     
    After random assignment of 20 schizophrenia patients to either an explicit or normal instruction group, the Japanese Verbal Learning Test was administered to them. Results reveal that explicit instruction group patients demonstrated more improved memory performance using semantic clustering, suggesting that explicit and direct teaching facilitates patients' learning of information. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
  • 久住 一郎, 村下 眞理, 小山 司
    Journal of Japanese Association of Psychiatric Hospitals 日本精神科病院協会 30 (3) 201 - 205 1347-4103 2011/03 [Not refereed][Not invited]
  • Ichiro Kusumi, Minoru Honda, Koichi Ito, Keiichi Uemura, Yukie Kumazawa, Tomohito Ishikane, Yasushi Niide, Tsukasa Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 35 (2) 537 - 540 0278-5846 2011/03 [Refereed][Not invited]
     
    The time required to attain the maximum plasma level of risperidone (RIS) is shorter for RIS oral solution (OS) than for RIS standard tablets (ST), although both forms have equal bioavailability. The objective of this study was to clarify whether RIS-OS shows a faster onset of efficacy and lower adverse events than RIS-ST. The two forms of risperidone were compared with respect to effectiveness including a speed of response, efficacy and tolerability. An open-label, 24-week, multicentre, randomized, flexible-dose study comparing the RIS-OS (mean dose, 3.7 mg; N = 44) to the RIS-ST (mean dose, 3.7 mg; N = 37) in acutely ill patients with schizophrenia showed no differences. Outcome measures included psychopathology, tolerability (extrapyramidal symptoms and serum prolactin), and Drug Attitude Inventory. This study was conducted between October 2006 and October 2008. Both RIS-OS- and RIS-ST-treated patients showed statistically significant reductions from the baseline in the mean scores of the Positive and Negative Syndrome Scale (PANSS)-total and PANSS-excite component, with no statistically significant differences between the treatment groups. The accumulated treatment response ratio was similar between the two groups. There was no significant difference in the Drug-Induced Extrapyramidal Symptom Scale score or serum prolactin increase between the treatment groups, but RIS-OS appeared to induce less serum prolactin increase than RIS-ST in drug-naive female patients. Because there is no theoretical reason why this should be so, these results will require confirmation from a double-blind study in a larger sample. No significant difference was observed in the subjective drug attitude between the two groups. The original hypothesis that RIS-OS shows an earlier onset of efficacy or less adverse events than RIS-ST was not supported in this study. Subsequent studies should carefully establish the differences among various forms of antipsychotic drugs. (C) 2010 Elsevier Inc. All rights reserved.
  • Ichiro Kusumi, Koki Ito, Minoru Honda, Tadayuki Hayashishita, Keiichi Uemura, Naoki Hashimoto, Mitsukuni Murasaki, Yoshihito Atsumi, Takashi Kadowaki, Tsukasa Koyama
    PSYCHIATRY AND CLINICAL NEUROSCIENCES 65 (4) 349 - 355 1323-1316 2011 [Refereed][Not invited]
     
    Aim: The Japanese blood glucose monitoring guidance for patients receiving second-generation anti-psychotics has been newly developed. We aimed to report a cross-sectional study using the baseline data of the Japanese monitoring guidance to find undiagnosed hyperglycemia systematically as a routine clinical practice and to quantify the frequency of glucose abnormalities in schizophrenia patients treated with second-generation antipsychotics. Methods: Data for 537 patients with schizophrenia, who had not been diagnosed as having diabetes prior to baseline screening and started the monitoring between June 2008 and January 2009, were collected from medical records in 25 hospitals. Blood glucose (fasting or casual), hemoglobin(A1c), serum lipids, height/weight, clinical diabetic symptoms, and family history of diabetes were assessed. Patients were classified into normal, pre-diabetic or probable diabetic type based on their values of blood glucose or hemoglobin(A1c), and various background characteristics and serum lipid values were compared among the three types. Results: Out of 537 patients, 13 (2.4%) met criteria for probable diabetic type, 51 (9.5%) for pre-diabetic type, and 473 (88.1%) for normal type. Individuals categorized as probable diabetic type had a higher body mass index and higher frequency of family history of diabetes mellitus than those with normal type. Conclusion: Glucose abnormalities were newly detected in 11.9% of schizophrenia patients treated with second-generation antipsychotics by the baseline monitoring. To assess the detective power and usefulness of the guidance, longitudinal investigations are necessary.
  • Thomas G. Schulze, Martin Alda, Mazda Adli, Nirmala Akula, Raffaella Ardau, Elise T. Bui, Caterina Chillotti, Sven Cichon, Piotr Czerski, Maria Del Zompo, Sevilla D. Detera-Wadleigh, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Rebecca Hoban, Nakao Iwata, Layla Kassem, Tadafumi Kato, Sarah Kittel-Schneider, Sebastian Kliwicki, John R. Kelsoe, Ichiro Kusumi, Gonzalo Laje, Susan G. Leckband, Mirko Manchia, Glenda MacQueen, Takuya Masui, Norio Ozaki, Roy H. Perlis, Andrea Pfennig, Paola Piccardi, Sara Richardson, Guy Rouleau, Andreas Reif, Janusz K. Rybakowski, Johanna Sasse, Johannes Schumacher, Giovanni Severino, Jordan W. Smoller, Alessio Squassina, Gustavo Turecki, L. Trevor Young, Takeo Yoshikawa, Michael Bauer, Francis J. McMahon
    NEUROPSYCHOBIOLOGY 62 (1) 72 - 78 0302-282X 2010 [Refereed][Not invited]
     
    For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic 'fashions', and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health, lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts. Copyright (C) 2010 S. Karger AG, Basel
  • Depressive patients are more impulsive and inconsistent in intertemporal choice behavior for monetary gain and loss than healthy subjects - An analysis based on Tsallis' statistics
    Taiki Takahashi, Hiderni Oono, Takeshi Inoue, Shuken Boku, Yuki Kako, Yuji Kitaichi, Ichiro Kusumi, Takuya Masui, Shidn Nakagawa, Katsuji Suzuki, Teruaki Tanaka, Tsukasa Koyama, Mark H. B. Radford
    NEUROENDOCRINOLOGY LETTERS 29 (3) 351 - 358 0172-780X 2008/06 [Refereed][Not invited]
     
    OBJECTIVES: Depression has been associated with impaired neural processing of reward and punishment. However, to date, little is known regarding the relationship between depression and intertemporal choice (delay discounting) for gain and loss. This examination is potentially important for advances in neuroeconomics of intertemporal choice, because depression is associated with reduced serotonergic activities in the brain. DESIGN AND SETTING: We compared impulsivity and inconsistency in intertemporal choice for monetary gain and loss between depressive patients and healthy control subjects. METHODS: We conducted delay discounting tasks for gain and loss in depressed and healthy control subjects. We then quantified impulsivity and inconsistency in the delay discounting with parameters in the q-exponential discount function based on Tsallis' statistics. RESULTS: We observed that depressive patients were more impulsive and time-inconsistent in intertemporal choice action for gain and loss, in comparison to healthy controls. MAIN FINDINGS: Depressed patients were more irrational in temporal discounting. Conclusions: The usefulness of the q-exponential discount function for assessing the impaired decision-making by depressive patients was demonstrated. Furthermore, biophysical mechanisms underlying the altered intertemporal choice by depressive patients are discussed in relation to impaired serotonergic neural systems.
  • G. Kuratomi, K. Iwamoto, M. Bundo, I. Kusumi, N. Kato, N. Iwata, N. Ozaki, T. Kato
    MOLECULAR PSYCHIATRY 13 (4) 429 - 441 1359-4184 2008/04 [Refereed][Not invited]
     
    To search DNA methylation difference between monozygotic twins discordant for bipolar disorder, we applied a comprehensive genome scan method, methylation-sensitive representational difference analysis (MS-RDA) to lymphoblastoid cells derived from the twins. MS-RDA isolated 10 DNA fragments derived from 50 region of known genes/ESTs. Among these 10 regions, four regions showed DNA methylation differences between bipolar twin and control co-twin confirmed by bisulfite sequencing. We performed a case-control study of DNA methylation status of these four regions by pyrosequencing. Two regions, upstream regions of spermine synthase (SMS) and peptidylprolyl isomerase E-like (PPIEL) (CN265253), showed aberrant DNA methylation status in bipolar disorder. SMS, a gene on X chromosome, showed significantly higher DNA methylation level in female patients with bipolar disorder compared with control females. However, there was no difference of mRNA expression. In PPIEL, DNA methylation level was significantly lower in patients with bipolar II disorder than in controls. The expression level of PPIEL was significantly higher in bipolar II disorder than in controls. We found strong inverse correlation between gene expression and DNA methylation levels of PPIEL. These results suggest that altered DNA methylation statuses of PPIEL might have some significance in pathophysiology of bipolar disorder.
  • Ichiro Kusumi, Takuya Masui, Tsukasa Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 32 (2) 520 - 522 0278-5846 2008/02 [Refereed][Not invited]
     
    Perospirone, a serotonin 5-HT2A and dopamine D-2 receptor antagonist, is metabolized to ID-15036 by CYP3A4 and the elimination half-life (T-1/2) for the latter is longer than the former. The active metabolite ID-15036 is an 8-times weaker D-2 antagonist than perospirone, although it has a high affinity for 5-HT2A receptor. In this study, we measured the plasma concentrations of perospirone and ID-15036 in the long-term stable schizophrenic patients with a single dose of perospirone at bedtime. The mean level of perospirone at 11-15 h after a last dosing was much lower (0.49 ng/ml) than that of ID-15036 (2.89 ng/ml). These results show that a long-term perospirone monotherapy with a single dose at bedtime is effective for the maintenance treatment of chronic schizophrenia and also suggest the possibility that intermittent D-2 receptor blockade may be sufficient for effective relapse prevention. (c) 2007 Elsevier Inc. All rights reserved.
  • 統合失調症急性期症例におけるolanzapine口腔内崩壊錠の使用経験?多施設共同研究の結果からー
    伊藤耕一, 久住一郎, 上村恵一, 岡崎大介, 塚本典子, 藤井 泰, 武重宏呂修, 千秋 勉, 三枝英之, 池田輝明, 本田 稔, 関口奈緒, 新出泰士, 坂井陽子, 臼窪幸恵, 栃木昭彦, 甲野智也, 橋本直樹, 白木淳子, 掛川優紀子, 臼居礼子, 細川嘉之, 松山哲晃, 伊藤侯輝, 小山 司
    精神科治療学 23 613 - 622 2008 [Refereed][Not invited]
  • Atsuhito Toyomaki, Ichiro Kusumi, Testsuaki Matsuyama, Yuki Kako, Koki Ito, Tsukasa Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 32 (1) 95 - 99 0278-5846 2008/01 [Refereed][Not invited]
     
    Impairment in mismatch negativity (MMN) potentials is a robust finding in schizophrenia. There are few studies which examined the correlation between MMN deficits and neuropsychological performances. The purpose of this study was to investigate the relationship between deficits of tone duration MMN and various neuropsychological measures in schizophrenic patients (n = 23). The results demonstrated a significant correlation between low MMN amplitude and poor performances of executive function in Wisconsin Card Sorting Test, Stroop Test and Trail Making Test. Our finding suggests MMN deficits in schizophrenia predict deficits of executive function and might reflect ongoing functional abnormality of fronto-temporal interaction. (c) 2007 Elsevier Inc. All rights reserved.
  • Takuya Masui, Ryota Hashimoto, Ichiro Kusumi, Katsuji Suzuki, Teruaki Tanaka, Shin Nakagawa, Tatsuyo Suzuki, Nakao Iwata, Norio Ozaki, Tadalunii Kato, Masatoshi Takeda, Hiroshi Kunugi, Tsukasa Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 32 (1) 204 - 208 0278-5846 2008/01 [Refereed][Not invited]
     
    Lithium is one of the most commonly used drugs for the treatment of bipolar disorder. To prescribe lithium appropriately to patients, predictors of response to this drug were explored, and several genetic markers are considered to be good candidates. We previously reported a significant association between genetic variations in the breakpoint cluster region (BCR) gene and bipolar disorder. In this study, we examined a possible relationship between response to maintenance treatment of lithium and Asn796Ser single-nucleotide polymorphism in the BCR gene. Genotyping was performed in 161 bipolar patients who had been taking lithium for at least 1 year, and they were classified into responders for lithium monotherapy and non-responders. We found that the allele frequency of Ser796 was significantly higher in non-responders than in responders. Further investigation is warranted to confirm our findings. (c) 2007 Elsevier Inc. All rights reserved.
  • Mari Murashita, Ichiro Kusumi, Hiroshi Hosoda, Kenji Kangawa, Tsukasa Koyama
    PSYCHONEUROENDOCRINOLOGY 32 (7) 777 - 784 0306-4530 2007/08 [Refereed][Not invited]
     
    Objective: Among antipsychotics, clozapine ranks highest in terms of the risk for weight gain and developing diabetes. However, the mechanism by which clozapine induces weight gain and diabetes remains unclear. The aim of this study was to determine the mechanism of ctozapine-induced weight gain and hyperglycemia, and to clarify whether ctozapine-induced hyperglycemia results from impairment of the system regulating appetite. Methods: Circulatory glucose, insulin, leptin and ghrelin levels were analyzed after acute administration of clozapine in rats. Clozapine (10 mg/kg) or a vehicle was injected intraperitoneally and blood samples were collected at 0, 15, 30, and 60 min after the injection. Clozapine(5, 10 or 20 mg/kg) or the vehicle was given, and blood samples were collected at 30 min after the injection. Since clozapine has receptor affinity for multiple neurotransmitters, selective antagonists of it, including dopamine, serotonin, alpha-adrenergic, muscarine and histamine were administered to clarify the pathway of ctozapine-induced blood glucose and changes in plasma ghrelin. Results: Clozapine administration increased the blood glucose level at all time points (p < 0.05) compared to controls. Plasma ghrelin was elevated at 30 min (p = 0.0124) and 60 min (p=0.00152). Blood glucose was increased in rats given 5 (p=0.0344), 10 (p < 0.0001), or 20 mg/kg (p < 0.0001) clozapine, white plasma ghrelin was increased in rats treated with 10 mg/kg (p = 0.0009) or 20 mg/kg (p = 0.0059) clozapine. Blood glucose was increased in rats treated with a selective alpha(1)-adrenergic receptor antagonist (p < 0.0001), white plasma ghrelin was significantly increased in rats given a selective alpha(1)-(p = 0.025) or alpha(2)-adrenergic receptor antagonist (p = 0.0003). Conclusions: Clozapine impairs glucose metabolism and the appetite-regulation system. Clozapine increases blood glucose independent of insulin. The antagonistic action of alpha-adrenergic receptors is one of the mechanisms that induces both hyperglycemia and elevation of ghrelin. (C) 2007 Elsevier Ltd. All rights reserved.
  • Mari Murashita, Takeshi Inoue, Ichiro Kusumi, Shin Nakagawa, Kouichi Itoh, Teruaki Tanaka, Takeshi Izumi, Hiroshi Hosoda, Kenji Kangawa, Tsukasa Koyama
    PSYCHIATRY AND CLINICAL NEUROSCIENCES 61 (1) 54 - 58 1323-1316 2007/02 [Refereed][Not invited]
     
    Risperidone has a relatively low risk of causing obesity and diabetes mellitus and is a first-line treatment for schizophrenia. The aim of the present study was to investigate glucose and lipid metabolism, and feeding-control parameters in schizophrenia patients treated with long-term risperidone monotherapy. Fifteen patients with paranoid-type schizophrenia who had been treated with risperidone and had Global Assessment of Function (GAF) scores > 70 were selected and compared with healthy volunteers (n = 25). Single assessments of psychotic symptoms, side-effects, Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) score, bodyweight, body fat percentage and blood sampling were performed. Fasting blood glucose, insulin, hemoglobin A1c, homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol, triglyceride, high density lipoprotein (HDL)-, low density lipoprotein-cholesterol, adiponectin, prolactin and feeding-control parameters (ghrelin and leptin) were analyzed. The body fat percentage (P = 0.0018), body mass index (BMI) (P = 0.0150), fasting blood glucose (P = 0.0358), triglyceride (P = 0.0377), leptin (P = 0.0243), total ghrelin (P = 0.0067), active ghrelin (P = 0.0241) and prolactin (P < 0.0001) levels of patients treated with risperidone were significantly higher than those of healthy volunteers, while the HDL-cholesterol level (P = 0.0222) was significantly lower. Although the patients had very mild psychiatric symptoms and maintained functionally high levels, the glucose and lipid parameters were significantly impaired compared to healthy volunteers. A high level of plasma ghrelin might increase appetite, leading to exacerbation of metabolic impairment.
  • Tatsuyuki Akimoto, Chiro Kusumi, Katsuji Suzuki, Tsukasa Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 31 (1) 136 - 141 0278-5846 2007/01 [Refereed][Not invited]
     
    Disturbed intracellular calcium (Ca2+) homeostasis has been implicated in bipolar disorder, which mechanisms may be involved in the dysregulation of protein kinase C (PKC) and calmodulin systems. In this study, we investigated a transient intracellular Ca2+ increase induced by thapsigargin, an inhibitor of sarco/endoplasinic reticulum Ca2+-ATPase pump (SERCA), and a capacitative Ca2+ entry followed by addition of extracellular Ca, in the presence or absence of PKC/calmodulin modulators in the platelets of healthy subjects in order to elucidate the role of SERCA in Ca2+ homeostasis and to assess how both PKC and calmodulin systems regulate the two Ca2+ responses. Moreover, we also examined the thapsigargin-elicited transient Ca2+ increase and capacitative Ca2+ entry in patients with mood disorders. PKC and calmodulin systems have opposite regulatory effects on the transient Ca2+ increase and capacitative Ca2+ entry in the platelets of normal subjects. The inhibitory effect of PKC activation on capacitative Ca2+ entry is significantly increased and the stimulatory effect of PKC inhibition is significantly decreased in bipolar disorder compared to major depressive disorder and normal controls. These results suggest the possibility that increased PKC activity may activate the inhibitory effect of capacitative Ca2+ entry in bipolar disorder. However, this is a preliminary study using a small sample, thus further studies are needed to examine the PKC and calmodulin modulators on the capacitative Ca2+ entry in a larger sample. (c) 2006 Elsevier Inc. All rights reserved.
  • Effects of valproate on serotonin-induced intracellular calcium mobilization in human platelets
    Akimoto T, Kusumi I, Suzuki K, Masui T, Koyama T
    J Psychiat Neurosci 321 17 - 22 2007 [Refereed][Not invited]
  • Tomoya Kohno, Tohru Shiga, Ichiro Kusumi, Tetsuaki Matsuyama, Hiroyuki Kageyama, Chietsugu Katoh, Tsukasa Koyama, Nagara Tamaki
    PSYCHIATRY RESEARCH-NEUROIMAGING 147 (2-3) 163 - 171 0925-4927 2006/10 [Refereed][Not invited]
     
    We evaluated the relationship between regional cerebral blood flow (rCBF) and clinical symptoms in patients with schizophrenia. Single photon emission computed tomography with N-isopropyl-p-[ (123)]iodoamphetamine (I-123-IMP) was used to study 29 patients with schizophrenia. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). We examined the correlation between rCBF and each BPRS item score using Statistical Parametric Mapping software. Corrected P-values < 0.05 were considered as statistically significant. The suspiciousness score on the BPRS was positively correlated with rCBF in the left inferior temporal gyrus. There was no significant correlation between rCBF and any other items of the BPRS. There was no significant correlation between rCBF and chlorpromazine-equivalent dosage. This analysis permits the quantitative assessment of the severity of persecutory delusions in relation to left temporal perfusion in patients with schizophrenia. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
  • Takeshi Inoue, Shin Nakagawa, Yuji Kitaichi, Takeshi Izurni, Teruaki Tanaka, Takuya Masui, Ichiro Kusumi, Kenzo Denda, Tsukasa Koyama
    JOURNAL OF AFFECTIVE DISORDERS 95 (1-3) 61 - 67 0165-0327 2006/10 [Refereed][Not invited]
     
    Background: The long-term outcome of antidepressant-refractory depression is not well known. Therefore, the present study investigated the long-term outcome of 26 antidepressant-refractory patients with depression, whom we had studied and treated in 1995. Methods: Before being classified as nonresponse, these patients had been treated adequately with at least two tricyclic or heterocyclic antidepressants (a minimum of the equivalent of 150mg of imipramine for 4weeks). In 1995, 21 of 26 patients were diagnosed with unipolar depression, while 5 were diagnosed with bipolar depression. Mean follow-up was 5.7 years (range: 1-7years) and changes in diagnosis, remission and treatment efficacy were evaluated. Results: Following the long-term follow-up, 13 patients achieved full remission and demonstrated high social functioning (mean GAF score, 91). A further four depressed patients experienced full remission; however, subsequent recurrence was observed. In total, 17 of 26 patients experienced remission at least once during the long-term follow-up period despite the chronic depressive episodes observed at study entry. Adjuvant treatment with lithium, dopamine receptor agonists or thyroid hormone was effective for promoting full remission. Among the 21 patients initially diagnosed with unipolar depression in 1995, diagnoses were changed to bipolar disorder in 5 cases. Limitations: This naturalistic study had a relatively small sample size and treatment was not controlled. Conclusions: Long-term follow-up revealed that a substantial proportion of antidepressant-refractory depression is comprised of bipolar disorders. In addition, augmentation therapies are effective for promoting full remission among chronically depressed patients without a risk of serious side effects. (c) 2006 Elsevier B.V. All rights reserved.
  • Takuya Masui, Ichiro Kusumi, Yoshito Takahashi, Tsukasa Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 30 (7) 1330 - 1333 0278-5846 2006/09 [Refereed][Not invited]
     
    Perospirone is a serotonin 5-HT2A and dopamine D-2 receptor antagonist which originated in Japan. It has been shown that perospirone is metabolized to ID-15036 mainly by CYP3A4 based on an in vitro study. To investigate the metabolism of perospirone in humans, the authors measured the concentration of perospirone and ID-15036 after a single oral dose of perospirone (8 mg) in 10 healthy male subjects, before and during coadministration of carbamazepine, known as a potent inducer of CYP3A4. Before carbamazepine coadministration, the peak plasma concentrations +/- SD of perospirone and ID-15036 were 4.0 +/- 4.3 and 11.7 +/- 7.1 ng/ml, respectively. During carbamazepine coadministration, the concentration of perospirone was decreased below the detection limit, and that of ID-15036 was 6.0 +/- 1.7 ng/ml. The concentrations of perospirone and ID-15036 were influenced significantly by the treatment with carbamazepine, and this was probably attributable to the induction of CYP3A4. This study provided an in vivo evidence of involvement of CYP3A4 in the metabolism of perospirone. (c) 2006 Elsevier Inc. All rights reserved.
  • Michio Nomura, Ichiro Kusumi, Masayuki Kaneko, Takuya Masui, Makoto Daiguji, Takeji Ueno, Tsukasa Koyama, Yasuyuki Nomura
    PSYCHOPHARMACOLOGY 187 (1) 30 - 35 0033-3158 2006/07 [Refereed][Not invited]
     
    Rationale and objective: Impulsive behavior has been suggested to occur due to a dysfunction of serotonergic 5-HT neurotransmission. After evaluation by a self-reporting measure, a polymorphism in the promoter of the 5-HT2A receptor gene has been proposed to underlie the impulsive behavior; however, this hypothesis is not convincing. In this study, we examined whether this 5-HT2A receptor gene polymorphism is involved in impulsive aggression by evaluating a behavioral task (go/no-go task) in normal volunteers. Materials and methods: The polymorphism of the 5-HT2A receptor gene promoter was analyzed by polymerase chain reaction using lymphocytes from 71 volunteers. Impulsivity was defined as the number of commission errors (responding when one should not) made during a go/no-go task (a larger number of commission errors indicates greater difficulty in inhibiting the behavior). Results: The subjects in the group with the A-1438A allele of the 5-HT2A receptor gene (A-1438A group) made more commission errors under the punishment-reward condition in a go/no-go task than those in the G-1438G group. Conclusions: These results suggest the possible involvement of the A-1438A polymorphism of the 5-HT2A receptor gene in impulsive behavior; this was evaluated using a behavioral task measure that can directly reveal the traits of human impulsive behavior.
  • 村下 真理, 久住 一郎, 小山 司
    精神科 科学評論社 8 (4) 320 - 324 1347-4790 2006/04 [Not refereed][Not invited]
  • T Masui, R Hashimoto, Kusumi, I, K Suzuki, T Tanaka, S Nakagawa, H Kunugi, T Koyama
    INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY 9 (1) 83 - 88 1461-1457 2006/02 [Refereed][Not invited]
     
    Bipolar disorder (BPD) is a severe, chronic, and life-threatening illness, and its pathogenesis remains unclear. Recently, a functional polymorphism (-116C/G) of the X-box binding protein 1 (XBP1) gene was reported to be a genetic risk factor for BPD. Moreover, the endoplasmic reticulum stress responses were impaired in cultured lymphocytes from BPD patients with the -116G allele and only valproate rescued such impairment among three major mood stabilizers. In this context, we hypothesized that BPD patients with different genotypes respond differently to mood stabilizers. We investigated the association between the -116C/G polymorphism of the XBP1 gene and lithium response in Japanese patients with BPD. We found that lithium treatment is more effective among BPD patients with the -116C allele carrier than in patients homozygous for the -116G allele. The association between the -116C/G polymorphism and clinical efficacy of mood stabilizers should be further investigated in a prospective study with a larger sample.
  • L Masui, Kusumi, I, Y Takahashi, T Koyama
    THERAPEUTIC DRUG MONITORING 28 (1) 73 - 75 0163-4356 2006/02 [Refereed][Not invited]
     
    Perospirone is an atypical antipsychotic agent originated and clinically used in Japan. Based on an in vitro Study, it is reported that perospirone is mainly metabolized to ID-15036 by cytochrorne P450 (CYP) 3A4. In this study, the authors investigated the effects of itraconazole, which is a specific inhibitor of CYP3A4, or tandospirone, which is inainly metabolized by CYP3A4 and is expected to competitively inhibit the activity of this enzyme, on single oral dose pharmacokinetics of perospirone. After pretreatment with 200 mg daily of itraconazole or 10 mg daily of tandospirone for 5 days, 9 healthy male subjects received 8 mg of perospirone. Plasma concentrations of perospirone and ID-15036 tip to 10 hours after perospirone dosing were measured by high-performance liquid chromatography (HPLC). The metabolism of perospirone was significantly inhibited by treatment with itraconazole but not by tandospirone. The present study suggests that CYP3A4 is significantly involved in metabolism of perospirone in humans.
  • Lithium response and Val66Met polymorphism of the BDNF genein Japanese patients with bipolar disorder
    Masui T, Hashimoto R, Kusumi I, Suzuki K, Tanaka T, Nakagawa S, Suzuki T, Iwata N, Ozaki N, Kato T, Kunugi H, Koyama T
    Psychiat Genet 16 49 - 50 2006 [Refereed][Not invited]
  • A Takano, T Suhara, Kusumi, I, Y Takahashi, Y Asai, F Yasuno, T Ichimiya, M Inoue, Y Sudo, T Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 30 (1) 75 - 81 0278-5846 2006/01 [Refereed][Not invited]
     
    Most antipsychotics were thought to induce antipsychotic action at an excess of 70% striatal dopamine D, receptor occupancy, while the clinical dose of clozapine was reported to show less than 60% occupancy. High-dose clozapine could occupy as high as 80% of striatal dopamine D-2 receptor in monkey PET studies. Although the time course of dopamine D-2 receptor occupancy is an important property of antipsychotics, that by clozapine has not been investigated in a clinical setting. We measured the time course of extrastriatal dopamine D-2 receptor occupancy with different doses of clozapine and evaluated whether the measured occupancies fitted the binding theory. Three consecutive PET scans with [C-11]FLB 457 were performed for two patients with schizophrenia, chronically taking 600 mg/day and 200 mg/ day of clozapine, respectively. Series of occupancies were also measured in combination with fluvoxamine or paroxetine in one patient. Dopamine D2 receptor occupancies were also simulated using individual clozapine plasma data and previously determined in vivo ED50 value. The occupancy of one patient with high plasma concentration (1207 ng/ml at peak time) was around 75% at peak and around 60% after 26 h. Another patient with medium plasma concentration (649 ng/ml at peak time) showed less than 50% occupancy at peak, decreasing to 15% after 25 h. The measured occupancy values fitted well with the simulated occupancy values. At high plasma concentration, clozapine can induce high extrastriatal dopamine D2 receptor occupancy in the human brain, and this finding fitted well with the theoretical estimation. (c) 2005 Elsevier Inc. All rights reserved.
  • 第二世代抗精神病薬治療中に発症した糖尿病症例の長期経過
    村下真理, 久住一郎, 井上 猛, 増井拓哉, 小山 司
    臨床精神薬理 9 1591 - 1603 2006 [Refereed][Not invited]
  • L Kusumi, T Masui, C Kakiuchi, K Suzuki, T Akimoto, R Hashimoto, H Kunugi, T Kato, T Koyama
    NEUROSCIENCE LETTERS 391 (1-2) 7 - 10 0304-3940 2005/12 [Refereed][Not invited]
     
    There have been several researches on the role of personality in the pathophysiology of bipolar disorder. Recently, a polymorphism of XBPI, a pivotal gene in the endoplasmic reticulum (ER) stress response, was shown to contribute to the genetic risk factor for bipolar disorder. Therefore, in this study, we examined the relationship between the XBPI gene polyrnorphism and the personality traits assessed by two self-rating scales, a shortened version of Temperament and Character Inventory (TCI) and NEO-Five Factor Inventory (NEO-FFI) in healthy subjects. The present results suggested that the XBPI gene polymorphism was associated with the NEO-FFI score of neuroticism in female subjects. However, no significant differences in the other personality scale scores of both assessments were observed among normal subjects with - 116C/C, C/G and G/G genotypes. Further investigations are necessary to examine the relationship in patients with bipolar disorder, or use full version of various self-rating personality assessments. (C) 2005 Elsevier Ireland Ltd. All rights reserved.
  • H Toda, Kusumi, I, Y Sasaki, K Ito, T Koyama
    INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY 20 (6) 331 - 333 0268-1315 2005/11 [Refereed][Not invited]
     
    The present study aimed to examine the relationship between plasma concentration levels of risperidone and clinical effects in the treatment of delirium. We conducted a prospective, open-label, flexible-dose study of risperidone oral solution. Ten patients with delirium were assessed using Delirium Rating Scales. Plasma concentration levels of risperidone were measured 30 min after the first administration of a 0.5 mg dose. Two patients with high plasma levels had adverse effects and one patient with the lowest plasma level did not achieve remission; the remaining seven patients achieved remission without any adverse effects. A highly significant negative correlation was observed in these responders without adverse effects between the plasma levels and durations of treatment until remission (r = -0.861, P = 0.0095). The plasma concentration level of risperidone at 30 min after the first 0.5 mg dose may be a favourable response predictor in the treatment of delirium. Further studies in larger samples are needed to verify this preliminary finding.
  • 久住 一郎, 小山 司
    医学のあゆみ 医歯薬出版 213 (7) 683 - 688 0039-2359 2005/05/14 [Not refereed][Not invited]
  • T Masui, Kusumi, I, Y Takahashi, T Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 29 (2) 343 - 346 0278-5846 2005/02 [Refereed][Not invited]
     
    Neuroleptic-induced akathisia is a distressing side effect of antipsychotics, and it is unmanageable in some cases. The authors report three cases of schizophrenia whose neuroleptic-induced akathisia did not respond to representative anti-akathisia drugs such as beta-adrenergic antagonists, anticholinergic agents, benzodiazepines and antihistaminergics, and they showed a marked improvement of it without worsening of psychotic symptoms dining a combination treatment with carbamazepine and perospirone, a serotonin-dopamine antagonist developed in Japan. As the mechanism of current observation, we assumed that carbamazepine affected the pharmacokinetics of perospirone, and change in the proportion of perospirone and its major active metabolite (ID-15036). Further investigations including the monitoring pharmacokinetics of perospirone and ID-15036 under concomitant use of carbamazepine should be carried out to explain the mechanism of the current experience. (C) 2004 Elsevier Inc. All rights reserved.
  • M Murashita, Kusumi, I, T Inoue, Y Takahashi, H Hosoda, K Kangawa, T Koyama
    PSYCHONEUROENDOCRINOLOGY 30 (1) 106 - 110 0306-4530 2005/01 [Refereed][Not invited]
     
    Objective: Increased appetite and weight gain are frequently reported in treatment with olanzapine. However, the mechanism behind this appetite gain remains unclear. Ghrelin is a newly discovered appetite-stimulating peptide that has a role in the regulation of feeding behavior. Ghrelin is synthesized principally in the stomach, and the concentration of circulating ghrelin is negatively correlated with leptin and body fat mass. To elucidate the mechanism of appetite and weight gain during olanzapine treatment, we investigated the circulating ghrelin levels. Methods: Seven patients with schizophrenia were examined before and after 6-month administration of olanzapine. The concentrations of circulating ghrelin, leptin, glucose and lipid metabolic parameters were measured. Results: Body fat percentage (P = 0.0121) and serum leptin (P = 0.0284) were significantly increased after 6-month administration of olanzapine. Both plasma total ghrelin (P = 0.0188) and active ghrelin levels (P = 0.0057) were significantly increased. Six of the seven patients reported increased appetite during olanzapine treatment. Other glucose and lipid parameters were not altered significantly. Conclusions: Although, the leptin level and body fat percentage were significantly increased, the concentration of circulating ghrelin was also significantly increased. Olanzapine may directly act on the secretion of ghrelin and induce appetite, resulting in weight gain. (C) 2004 Elsevier Ltd. All rights reserved.
  • Arinami T, Ohtsuki T, Ishiguro H, Ujike H, Tanaka Y, Morita Y, Takeichi M, Yamada S, Imamura A, Ohara K, Shibuya H, Ohara K, Suzuki Y, Muratake T, Kaneko N, Someya T, Inada T, Yoshikawa T, Toyota T, Yamada K, Kojima T, Takahashi S, Ohmori O, Shinkai T, Nakamura M, Fukuzako H, Hashiguchi T, Niwa S, Ueno T, Tachikawa H, Hori T, Asada T, Nanko S, Kunugi H, Hashimoto R, Ozaki N, Iwata N, Harano M, Arai H, Ohnuma T, Kusumi I, Koyama T, Yoneda H, Fukumaki Y, Shibata H, Kaneko S, Higuchi H, Yasui-Furukori N, Numachi Y, Itokawa M, Okazaki
    Am J Hum Genet 77 937 - 945 2005 [Refereed][Not invited]
  • Clozapine投与により社会復帰に至った治療不耐性統合失調症の1例
    田中輝明, 松山哲晃, 久住一郎, 村下真理, 小山 司
    臨床精神薬理 8 1984 - 1988 2005 [Not refereed][Not invited]
  • 持続的な幻聴、体系的な妄想に左右されて二度の腹部刺傷を行った後、clozapine導入により就労可能となった妄想型統合失調症の1例
    久住一郎, 高橋義人, 高田秀樹, 小山 司
    臨床精神薬理 8 2104 - 2107 2005 [Not refereed][Not invited]
  • Clozapine治療により単身生活が可能となった治療抵抗性統合失調症の1例
    久住一郎, 高橋義人, 小山 司
    臨床精神薬理 8 2100 - 2103 2005 [Not refereed][Not invited]
  • 遅発性ジストニアに対してclozapineが著効した統合失調症の1例
    田中輝明, 長尾智美, 久住一郎, 村下真理, 小山 司
    臨床精神薬理 8 1979 - 1983 2005 [Not refereed][Not invited]
  • Kusumi, I, T Masui, C Kakiuchi, K Suzuki, T Akimoto, R Hashimoto, H Kunugi, T Kato, T Koyama
    NEUROSCIENCE LETTERS 369 (1) 1 - 3 0304-3940 2004/10 [Refereed][Not invited]
     
    Dysregulations of calcium (Ca) homeostasis may be involved in the pathophysiology of bipolar disorder. Enhanced Ca response to various agonists in peripheral blood cells is one of a few confirmed biological markers for bipolar disorder. Recently, a polymorphism of XBP1, a pivotal gene in the endoplasmic reticulum (ER) stress response, was shown to contribute to the genetic risk factor for bipolar disorder. Thus, in this study, we examined the relationship between the XBP1 gene polymorphism and the Ca signaling in the platelets of healthy controls. The present results suggest no significant difference in the basal Ca level or 5-HT-induced Ca mobilization among normal subjects with -116C/C, C/G, and G/G genotypes. Further investigations are necessary to examine the relationship in the different peripheral blood cells and/or in larger samples from patients with bipolar disorder. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
  • 豊巻 敦人, 久住 一郎, 小山 司
    精神科 科学評論社 4 (4) 262 - 265 1347-4790 2004/04 [Not refereed][Not invited]
  • 戸田裕之, 佐々木幸哉, 伊藤耕一, 仲唐安哉, 賀古勇輝, 伊藤侯輝, 増井拓哉, 久住一郎, 小山 司
    『精神医学』 46 1163 - 1167 2004 [Refereed][Not invited]
  • 「非定型抗精神病薬使用患者における糖尿病発症頻度の検討」
    村下真理, 久住一郎, 井上 猛, 高橋義人, 佐々木幸哉, 賀古勇輝, 鈴木克治, 田中輝明, 北市雄士, 榊原則寛, 小山 司
    『臨床精神薬理』 7 991 - 998 2004 [Refereed][Not invited]
  • K Suzuki, Kusumi, I, T Akimoto, Y Sasaki, T Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 28 (1) 67 - 72 0278-5846 2004/01 [Refereed][Not invited]
     
    Serotonin (5-HT)- or thrombin-stimulated platelet intracellular calcium (Ca) mobilization has been reported to be enhanced in patients with bipolar disorders. However, the mechanism of this enhancement is unknown. As a preliminary study, the authors examined the effects of a myosin light chain kinase (MLCK) inhibitor, 1-(5-chloronaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML-9), and two drugs that are mainstays of treatment for bipolar disorder, lithium and valproate, on 5-HT- or thrombin-induced Ca increase in the platelets of normal subjects. When preincubated with 30 muM ML-9, Ca responses to both agonists were enhanced. Valproate showed a dose-dependent attenuation of agonist-induced intracellular Ca rise, both in the absence and presence of ML-9. Although lithium alone had no significant effect on the Ca increase, a high concentration of lithium significantly decreased Ca mobilization only in the presence of ML-9. These results suggest that the enhanced Ca response observed in bipolar disorder might be relevant to decreased function of MLCK and that the mechanism of action of lithium may include a compensatory effect on MLCK modulation. (C) 2003 Elsevier Inc. All rights reserved.
  • "A case of tardive dystonia successfully managed with quetiapine"
    Sasaki Y, Kusumi I, Koyama T
    J. Clin. Psychiatry 65 583  2004 [Refereed][Not invited]
  • C Kakiuchi, K Iwamoto, M Ishiwata, M Bundo, T Kasahara, Kusumi, I, T Tsujita, Y Okazaki, S Nanko, H Kunugi, T Sasaki, T Kato
    NATURE GENETICS 35 (2) 171 - 175 1061-4036 2003/10 [Refereed][Not invited]
     
    The pathophysiology of bipolar disorder is still unclear, although family, twin and linkage studies implicate genetic factors(1). Here we identified XBP1, a pivotal gene in the endoplasmic reticulum ( ER) stress response, as contributing to the genetic risk factor for bipolar disorder. Using DNA microarray analysis of lymphoblastoid cells derived from two pairs of twins discordant with respect to the illness, we found downregulated expression of genes related to ER stress response in both affected twins. A polymorphism (-116C-->G) in the promoter region of XBP1, affecting the putative binding site of XBP1, was significantly more common in Japanese patients ( odds ratio = 4.6) and overtransmitted to affected offspring in trio samples of the NIMH Bipolar Disorder Genetics Initiative. XBP1-dependent transcription activity of the -116G allele was lower than that of the -116C allele, and in the cells with the G allele, induction of XBP1 expression after ER stress was markedly reduced. Valproate, one of three mood stabilizers, rescued the impaired response by inducing ATF6, the gene upstream of XBP1. These results indicate that the -116C--> G polymorphism in XBP1 causes an impairment of its positive feedback system and increases the risk of bipolar disorder.
  • 久住 一郎, 小山 司
    精神科 科学評論社 3 (4) 340 - 344 1347-4790 2003/10 [Not refereed][Not invited]
  • K Suzuki, Kusumi, I, T Akimoto, Y Sasaki, T Koyama
    NEUROPSYCHOPHARMACOLOGY 28 (6) 1210 - 1214 0893-133X 2003/06 [Refereed][Not invited]
     
    We have reported that the platelet intracellular calcium (Ca) mobilization after stimulation by serotonin (5-HT) is specifically enhanced in bipolar disorder among various psychiatric disorders, compared with that in normal control. To explore the mechanisms of enhanced Ca response to 5-HT in the platelets, we first examined the relation between the 5HT-elicited Ca mobilization and 5-HT2A receptor density using the platelets from 13 normal subjects. From this study, we found no significant correlation between two measures. Then, we investigated the effects of staurosporine, a protein kinase C (PKC) inhibitor, on Ca response to 5-HT in platelets from patients with major depressive disorder (unipolar), bipolar disorder, and normal controls. While 5-HT-induced Ca mobilization, in the presence of 100 nM staurosporine, was significantly attenuated in normal controls and patients with major depressive disorder, the inhibitory effect of staurosporine was not observed in bipolar disorder. These results suggest that the failure in inhibiting the platelet intracellular Ca response to 5-HT in bipolar disorder may be related to increased activity of PKC rather than increased 5-HT2A receptor number. Moreover, the trend of the Ca response towards staurosporine may become a specific biological marker for unipolar-bipolar dichotomy.
  • 久住 一郎, 亀田 謙介, 鈴木 克治
    分子精神医学 先端医学社 3 (2) 94 - 98 1345-9082 2003/04 [Not refereed][Not invited]
  • Initial genome-wide scan for linkage with schizophrenia in the Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) families.
    Japanese Schizophrenia Sib-Pair Linkage Group
    Am J Med Genet 120B 22 - 28 2003 [Refereed][Not invited]
  • 久住 一郎, 鈴木 克治, 中川 伸
    精神科 科学評論社 1 (6) 460 - 464 1347-4790 2002/12 [Not refereed][Not invited]
  • 中川 伸, 久住 一郎, 小山 司
    精神科 科学評論社 1 (3) 256 - 260 1347-4790 2002/09 [Not refereed][Not invited]
  • Kusumi, I, K Suzuki, Y Sasaki, K Kameda, T Sasaki, T Koyama
    JOURNAL OF AFFECTIVE DISORDERS 68 (2-3) 235 - 241 0165-0327 2002/04 [Refereed][Not invited]
     
    Background: Central serotonin-2A (5-HT2A) receptor dysfunction is regarded as an important factor in the etiology of affective disorders. The relations between some personality traits and the vulnerability of affective disorders are also implicated. Moreover, there are several reports which describe the association between 5-HT2A receptor gene polymorphisms and mental disorders. We therefore examined the relationship between personality traits, the 5-HT2A receptor function, and 5-HT2A receptor gene polymorphisms. Methods: 5-HT-induced intraplatelet calcium (Ca) mobilization, 5-HT2A receptor gene polymorphisms (A-1438G, T102C, T516C, C1340T, C1354T), and Temperament and Character Inventory (TCI) scores were examined in 133 healthy subjects. Results: Neither 5-HT-induced Ca mobilization nor 5-HT2A receptor gene polymorphisms (A-1438G, T102C) appear to be associated with seven personality dimensions including Harm Avoidance. There was no significant difference in the Ca. response among the subjects with - 1438A/A, A/G and G/G genotypes. Since the appearance of the other types of the 5-HT2A receptor gene polymorphisms (T516C, C1340T and C1354T) was quite rare in our sample, we were unable to examine the relationship between these polymorphisms, and the TCI score or the Ca response, Limitations: Our failure to find a significant association may reflect the false negative results due to the small sample size and low statistical power. Further studies in depressed patients may clarify the complicated relationship between personality traits and the vulnerability of affective disorders. Conclusions: Personality traits detected by TCI may not be directly related to the 5-HT2A receptor function or 5-HT2A receptor gene polymorphism which may be involved in the vulnerability of affective disorders. (C) 2002 Elsevier Science BY All rights reserved.
  • 北川信樹, 朝倉 聡, 久住一郎, 傳田健三, 小山 司
    『精神医学』 44 381 - 389 2002 [Refereed][Not invited]
  • 「従来型あるいは非定型抗精神病薬からquetiapineへの切り替え症例の検討」
    久住一郎, 高橋義人, 本田 稔, 三浦 淳, 井上 猛, 小山 司
    『臨床精神薬理』 5 (増刊) 335 - 342 2002 [Refereed][Not invited]
  • 「無為・自閉、抑うつ症状にクエチアピンが著効した一例」
    久住一郎, 小山 司
    『精神分裂病における私の処方 ―クエチアピンを中心に―』 32 - 34 2002 [Not refereed][Not invited]
  • K Kameda, T Tanaka, J Miura, Kusumi, I, T Koyama
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 25 (8) 1583 - 1595 0278-5846 2001/11 [Refereed][Not invited]
     
    1. Previously the authors have shown that acute citalopram. treatment increased the dopamine D2 receptor expression in rat brain striatum (Kameda et al., 2000), In the present study, the authors attempted to determine whether these effects of citalopram influence the methamphetamine-induced locomotor activity. 2. The pretreatment with a single administration of citalopram (10mg/kq, i.p.) resulted in the significant enhancement of the locomotor activity induced by methamphetamine treatment (1mg/kg, i.p.). The enhancement was observed 30 min, 12 hours, 24 hours, but not 7 days after withdrawal of citalopram administration. 3. Then the authors determined the methamphetamine concentration in rat brain striatum by gas chromatography-mass spectrometry (GC-MS) The results showed that the concentration of methamphetamine was significantly higher in the rats 24 hours, and also 7 days after withdrawal of citalopram. administration, compared to the control rats. 4. These results emphasized the involvement of the high methamphetamine concentration, caused by the pretreatment with citalopram, in the enhancement of the methamphetamine-induced locomotor activity. However high methamphetamine concentration alone could not account for this enhancement, since the high concentration of methamphetamine observed 7 days after withdrawal of citalopram administration did not appear to enhance the methamphetamine-induced locomotor activity. Another mechanism through which the pretreatment with citalopram. enhanced the methamphetamine-induced locomotor activity, such as the increased expression of the dopamine D2 receptors, could not be excluded.
  • K Fujimaki, S Morinobu, J Takahashi, S Yamawaki, N Kato, M Kanno, N Okuyama, S Kawakatsu, K Otani, Kusumi, I, T Koyama
    JOURNAL OF AFFECTIVE DISORDERS 65 (2) 139 - 143 0165-0327 2001/07 [Not refereed][Not invited]
     
    Pharmacological studies of bipolar disorder suggest that dysfunction of calcium mobilization via phosphatidylinositol-mediated transduction may be involved in its pathogenesis. The present study tests the hypothesis that dysfunction of calcium mobilization in bipolar disorder is due to the mutation of the nucleotide sequence in the FKBP12 binding site on the inositol 1,4,5-trisphosphate type-1 receptor (IP(3)R1). Nucleotide sequence analysis of the FKBP12 binding site on IP(3)R1 was performed using reverse transcription-polymerase chain reaction and DNA sequencing. The nucleotide sequence in this region was preserved in all subjects. This finding suggests that IP(3)R1 dysfunction through the FKBP12 binding site is not involved in the pathogenesis of bipolar disorder. (C) 2001 Elsevier Science B.V. All rights reserved.
  • K Suzuki, Kusumi, I, Y Sasaki, T Koyama
    JOURNAL OF AFFECTIVE DISORDERS 64 (2-3) 291 - 296 0165-0327 2001/05 [Refereed][Not invited]
     
    Background: Serotonin (5-HT)-stimulated platelet intracellular calcium (Ca) mobilization has been reported to be enhanced in unmedicated depressive patients compared to those of normal healthy subjects, which suggests increased 5-HT2A receptor function in these patients. It has not been ascertained whether this enhanced response is specific to some type of affective disorders among various mental disorders. Methods: We examined 5-HT-induced platelet intracellular Ca response in 152 unmedicated outpatients with various psychiatric disorders including bipolar disorder (BD), major depressive disorder with melancholia (DM), major depressive disorder without melancholia (DN), schizophrenia (SCH), panic disorder (PD), obsessive-compulsive disorder (OCD), social phobia (SP) and bulimia nervosa (BN), and 30 normal controls. Results: We observed no significant differences in basal intracellular Ca concentration among all patient subgroups and normal controls. While the 5-HT-induced Ca response was significantly and specifically higher in patients with ED than in normal controls, no significant differences were found in the Ca response to 5-HT between patients with DM, DN, SCH, PD, OCD, SP and BN, and normal controls. Limitations: The sample sizes of each group are still small. Therefore, they have to be enlarged in the continuation of the study so as to increase the power of the statistical tests. Conclusion: These results indicate the possibility that enhanced signal transduction, mediated by the 5-HT2A receptor, may be specific to bipolar disorder. (C) 2001 Elsevier Science B;V. All rights reserved.
  • K Kameda, J Miura, K Suzuki, Kusumi, I, T Tanaka, T Koyama
    JOURNAL OF NEURAL TRANSMISSION 108 (3) 321 - 334 0300-9564 2001 [Refereed][Not invited]
     
    Effects of lithium on the dopamine D2 receptor expression in the rat brain striatum were studied. Feeding the chow containing 0.2% LiCO3 for 6 days increased the level of the dopamine D2 receptor mRNA, and the transcription rate of the dopamine D2 receptor gene, indicating the stimulatory effects of lithium on the transcription of the dopamine D2 receptor gene. [H-3] Spiperone binding to the striatal membranes increased in the rats treated with lithium, while the Western blotting analysis showed no change of the amount of the dopamine D2 receptors. These results suggested that lithium might induce the conformational changes of the dopamine D2 receptors. The methamphetamine-induced locomotor activity was enhanced by the pretreatment with lithium, whereas simultaneous increase in the methamphetamine concentration in the striatum was also observed. These observations suggested that the stimulation of methamphetamine-induced locomotor activity by lithium might be, at least partly, due to either increased sensitivity of the dopamine receptors, or increased concentration of methamphetamine in brain, or combination of both.
  • 双極性感情障害に対するバルプロ酸の有効性と血中濃度について
    鈴木克治, 田中輝明, 井上 猛, 安部川智浩, 高橋義人, 久住一郎, 傳田健三, 小山 司
    精神科治療学 16 1077 - 1084 2001 [Refereed][Not invited]
  • Kusumi, I, K Suzuki, Y Sasaki, K Kameda, T Koyama
    NEUROPSYCHOPHARMACOLOGY 23 (6) 690 - 696 0893-133X 2000/12 [Refereed][Not invited]
     
    Serotonin (5-HT)-stimulated intraplatelet calcium (Ca) mobilization has been shown to be enhanced in nonmedicated depressive patients by many studies. However, there has not been any longitudinal follow-up study of this parameter. We examined the relationship between treatment response and pretreatment valve of tie 5-HT-induced Ca response. The 5-HT(10 muM)-induced intraplatelet Ca mobilization was measured in 98 nonmedicated depressive patients (24 bipolar disorders, 51 melancholic major depressive disorders, and 23 non-melancholic major depressive disorders). These patients were followed tip prospectively for a further period of five years. The depressed patients with enhanced Ca response to 5-HT in bipolar disorders exhibited a good response to mood stabilizers brit those with major depressive disorders showed,ed a poor response to antidepressants. These findings suggest the possibility that the 5-HT-induced intraplatelet Cn response may be a good predictor of treatment response in depressed patients. Longer longitudinal follow-up studies are needed in larger samples to examine if this parameter may De a specific biological marker for unipolar-bipolar dichotomy. (C) 2000 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.
  • T Izumi, T Inoue, N Kitagawa, N Nishi, S Shimanaka, Y Takahashi, Kusumi, I, Y Odagaki, K Denda, T Ohmori, T Koyama
    JOURNAL OF AFFECTIVE DISORDERS 61 (1-2) 127 - 132 0165-0327 2000/12 [Refereed][Not invited]
     
    Background: Recently, a dopamine hypothesis of depression was put forward, and several studies have demonstrated that direct and indirect dopamine agonists have antidepressant effects. Methods: Using Clinical Global Impressions, we evaluated the efficacy of 4-week treatment of pergolide as an antidepressant adjuvant involving 20 unipolar depressed patients who were refractory to standard treatment with antidepressants. Results: One patients (5%) were very much improved, seven (35%) much improved, four (20%) minimally improved, six (30%) no change or worse, and two (10%) not assessed. There was no significant difference in any clinical factors between the pergolide responder and non-responder group. Limitations: This study was a non-blind open trial, and pergolide was added to tricyclic and heterocyclic antidepressants. Conclusion: Pergolide may be useful as an antidepressant adjuvant. suggesting a potential role for dopamine-2 stimulation in the antidepressant response. (C) 2000 Elsevier Science B.V. All rights reserved.
  • 久住 一郎, 高橋 義人, 小山 司
    神経研究の進歩 医学書院 44 (6) 958 - 964 0001-8724 2000/12 [Not refereed][Not invited]
  • 久住 一郎, 小山 司
    医学のあゆみ 医歯薬出版 195 (8) 519 - 522 0039-2359 2000/11/25 [Not refereed][Not invited]
  • K Narita, T Sasaki, R Akaho, Y Okazaki, Kusumi, I, T Kato, O Hashimoto, R Fukuda, T Koyama, K Matsuo, Y Okabe, S Nanko, H Hohjoh, K Tokunaga
    AMERICAN JOURNAL OF PSYCHIATRY 157 (7) 1173 - 1175 0002-953X 2000/07 [Refereed][Not invited]
     
    Objective: Five Japanese studies, to the authors' knowledge, without exception, have consistently shown an increased frequency of human leukocyte antigen (HLA)-DR1 in patients with schizophrenia. This suggests an association between HLA-DR1 and schizophrenia in the Japanese population. The mechanism of the association is unknown; however, prenatal infections may be involved. The present study explored factors, including winter birth, that might correlate with this mechanism. Age at onset and gender were also studied. Method: Factors were compared between Japanese patients with schizophrenia with and in those without HLA-DR1 (N=60 and N=307, respectively). Results: A significantly higher incidence of births in February and March was observed in patients with (31.7%) than those without (15.6%) HLA-DR1. No association was found between the presence of HLA-DR1 and other variables. Conclusions: Although this result is preliminary, it may suggest an interaction between HLA and winter birth in the development of schizophrenia in the Japanese population.
  • Effects of citalopram on dopamine D2 receptor expression in the rat brain striatum
    K Kameda, Kusumi, I, K Suzuki, J Miura, Y Sasaki, T Koyama
    JOURNAL OF MOLECULAR NEUROSCIENCE 14 (1-2) 77 - 86 0895-8696 2000/02 [Refereed][Not invited]
     
    Effects of citalopram on dopamine D2 receptor expression in the rat brain striatum were studied. Repeated administration of citalopram increased the amount of dopamine D2 receptors, the level of dopamine D2 receptor mRNA, and the transcription rate of the dopamine D2 receptor gene. Single administration of citalopram also increased the level of dopamine D2 receptor mRNA with a maximum effect in 2-4 h after the treatment, and the transcription rate of the dopamine D2 receptor gene. The administration of 5-hydroxytryptophan (5-HTP) also increased the level of dopamine D2 receptor mRNA. These results suggest that the increase in the dopamine D2 receptor expression induced by citalopram may be owing, at least partially, to the stimulation of the dopamine D2 receptor gene transcription, and that serotonin (5-HT) may mediate the effects of citalopram in the induction of dopamine D2 receptor expression.
  • 「気分障害発症脆弱性の生物学的背景と気質・性格特性」
    久住一郎, 鈴木克治, 小山 司
    『精神科診断学』 11 135 - 145 2000 [Not refereed][Not invited]
  • Differential effects of subchronic treatments with atypical antipsychotic drugs on dopamine D-2 and serotonin 5-HT2A receptors in the rat brain
    Kusumi, I, Y Takahashi, K Suzuki, K Kameda, T Koyama
    JOURNAL OF NEURAL TRANSMISSION 107 (3) 295 - 302 0300-9564 2000 [Refereed][Not invited]
     
    The effects of 3-week treatment with a typical antipsychotic drug chlorpromazine and three atypical antipsychotic drugs (risperidone, olanzapine and perospirone) on the binding to dopamine D-2 and serotonin 5-HT2A receptors were examined in the rat stratum and frontal cortex, respectively. Subchronic treatment with chlorpromazine (10 mg/kg) and perospirone (1 mg/kg) significantly increased D-2 receptors, while no increase was observed with lower dose of chlorpromazine (5 mg/kg), perospirone (0.1 mg/kg), risperidone (0.25, 0.5 mg/kg) or olanzapine (1, 2 mg/kg). On the other hand, 3-week administration of chlorpromazine (5, 10 mg/kg) and olanzapine (1, 2 mg/kg) significantly decreased 5-HT2A receptors, but risperidone (0.25, 0.5 mg/kg) or perospirone (0.1, 1 mg/kg) had no effect. The measurement of in vivo drug occupation for D-2 and 5-HT2A receptors using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)) suggested that high occupation of 5-HT2A receptors with lower D-2 receptor occupancy might be involved in the absence of up-regulation of D-2 receptors after subchronic treatment with some atypical antipsychotic drugs.
  • 久住 一郎, 小山 司, 高橋 義人
    秋山記念生命科学振興財団研究成果報告集 秋山記念生命科学振興財団 66 - 69 1999/03 [Not refereed][Not invited]
  • 「セロトニン5-HT2A受容体機能ならびに遺伝子多型性、人格特性分類に基づく気分障害発症機構と薬物反応性に関する研究」
    久住一郎, 鈴木克治, 亀田謙介, 佐々木由紀, 小山 司
    『精神薬療基金研究年報』 31 110 - 117 1999 [Not refereed][Not invited]
  • M. Sato, N. Nakane, M. Hayashida, Y. Koshino, H. Uchimura, T. Tsutsumi, T. Koyama, I. Kusumi, K. Akiyama, H. Saito, T. Saijo, C. Ito, Y. Kubota, T. Nishikawa, Y. Kuroda, T. Hamamura, Y. Fujiwara, T. Higuchi, S. Yamawaki
    International Journal of Psychiatry in Clinical Practice 3 (4) 271 - 276 1365-1501 1999 [Not refereed][Not invited]
     
    Evidence-based psychopharmacological algorithms for the treatment of patients with schizophrenia have been developed in many countries in the last decade. While it would be of interest to consider a common algorithm based on international consensus, algorithms and information on antipsychotics available in each country are limited. Inspired by the algorithm generated by the International Psychopharmacology Algorithm (IPA) Project, this algorithm for the treatment of schizophrenia has been developed by the Japan Psychopharmacology Algorithm (JPA) Project. New antipsychotics, such as clozapine, olanzapine and quetiapine, are excluded from this algorithm, being currently unavailable in Japan. In the end there was no essential difference between the algorithms for the treatment of acute schizophrenic episodes. However, combined use of antipsychotics appears to be more common in Japan and the adjunctive use of L-DOPS or thyrotropin-releasing hormone is included in the JPA algorithm for the treatment of drug-refractory schizophrenia.
  • 鈴木克治, 久住一郎, 小山 司
    『精神医学』 41 947 - 957 1999 [Refereed][Not invited]
  • "Algorithms for the treatment of acute side effects induced by neuroleptics"
    Psychiat. Clin. Neurosci. 53 (suppl.) S19-S22  1999 [Not refereed][Not invited]
  • 久住 一郎, 小山 司, 西川 徹
    モレキュラ-メディシン 中山書店 35 (12) 1452 - 1461 0918-6557 1998/12 [Not refereed][Not invited]
  • The human serotonin-7 receptor pseudogene: variation and chromosome location
    D Nam, IHP Qian, Kusumi, I, C Ulpian, T Tallerico, ISC Liu, P Seeman
    JOURNAL OF PSYCHIATRY & NEUROSCIENCE 23 (4) 214 - 216 1180-4882 1998/09 [Refereed][Not invited]
     
    We report a variation of the pseudogene for the serotonin-7 receptor in human DNA. Human genomic DNA was amplified, using the polymerase chain reaction method and degenerate oligonucleotide primers for serotonin receptor-like genes. A novel gene DNA sequence of 1325 bp was found. Based on nucleotides, this gene is 88% identical to the serotonin-7 receptor coding sequence. Compared with the previously known serotonin-7 receptor pseudogene, this pseudogene has I nucleotide deletion and 4 nucleotide mutations. The gene is located on human chromosome 12 at 12p 12.3-p13.2.
  • In vivo occupation of dopamine D-1, D-2 and serotonin (5-HT)(2A) receptors by sertindole in the rat brain
    Y Takahashi, Kusumi, I, T Ishikane, S Matsubara, T Koyama
    JOURNAL OF PSYCHIATRY & NEUROSCIENCE 23 (3) 157 - 162 1180-4882 1998/05 [Refereed][Not invited]
     
    Objective: To determine the in vivo occupation of dopamine D-1, D-2 and serotonin (5-MT)(2A) receptors by novel antipsychotic agent sertindole using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible antagonist at these receptor sites. Design: Animal study. interventions: Intraperitoneal administration to Wistar rats of I of 4 test compounds: a control compound of 0.15% tartaric acid, or a compound of either sertindole (0.5 mg/kg or 2.0 mg/kg) or clozapine (20 mg/kg) dissolved in 0.15% tartaric acid I hour before intraperitoneal administration of EEDQ (0 mg/kg) or ethanol/water solution. Results: Sertindole exhibited little or no effect on D and D, binding sites in vivo. On the other hand, sertindole occupied 5-HT2A receptors more extensively and firmly than EEDQ. This study indicates that sertindole is characterized by high occupancy of 5-HT2A receptors and by low or minimum occupancy of D-1 and D-2 receptors. Conclusions: These characteristics are very similar to atypical antipsychotic agents such as clozapine. Sertindole's low liability to cause extrapyramidal side effects (EPS) may be related to greater long-term binding for 5-HT2A receptors relative to D-2 receptors.
  • Y Takahashi, Kusumi, I, T Ishikane, T Koyama
    JOURNAL OF NEURAL TRANSMISSION 105 (2-3) 181 - 191 0300-9564 1998 [Refereed][Not invited]
     
    In vivo occupation of dopamine D-1, D-2 and serotonin (5-MT)(2A) receptors by a novel antipsychotic drug, SM-9018 (perospirone hydrochloride cis-N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]cyclohexane-1,2-dicarboximide monohydrochloride) and its major metabolite (ID-15036; N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1-hydroxy-1, 2-cyclohexanedicarboximide) was measured in rat brain using N-ethoxycarbonyl-2-ethoxy-1 ,2-dihydroquinoline (EEDQ), an irreversible antagonist, at these receptor sites. SM-9018 and its metabolite, ID-15036, dose-dependently reversed EEDQ-induced 5-MT2A and D-2 receptor inactivation, but not D-1 receptor inactivation. At lower doses (0.1 mg/kg i.p.), SM-9018 showed a preferential occupation of the 5-MT2A receptors, with only a small effect on the D-2 receptors; while at higher doses (1.0 and 5.0 mg/kg i.p.): it was nearly equipotent in its occupation of both the D-2 (77.8%) and the 5-HT2A receptors (78.6%). On the other hand, ID-15036 was more potent in occupying the 5-MT2A than the D-2 receptors even at higher doses (1.0 and 5.0 mg/kg i.p.). We previously reported that atypical antipsychotic drugs, such as clozapine, were characterized by a high occupancy of the 5-MT2A receptors, with a low or minimum occupancy of the D-2 receptors in vivo. The present study suggests that SM-9018 and its metabolite ID-15036 show a preferential tendency to occupy 5-MT2A receptors, and that the clozapine-like atypical properties of SM-9018 may be due to some pharmacological action of both the SM-9018 itself and its metabolite, ID-15063.
  • ISC Liu, Kusumi, I, C Ulpian, T Tallerico, P Seeman
    MOLECULAR BRAIN RESEARCH 53 (1-2) 98 - 103 0169-328X 1998/01 [Refereed][Not invited]
     
    During a search for new G-protein-linked receptors for dopamine and serotonin, we found a serotonin-4 receptor-like pseudogene. This receptor-like pseudogene is intronless, contains an in-frame stop codon following transmembrane-3, and has two one-nucleotide insertions between transmembrane-5 and -6 regions which alter the reading frame. The predicted amino acid sequence of the human pseudogene is about 35% identical with that of the rat serotonin-4 receptor. (C) 1998 Elsevier Science B.V.
  • IHP Qian, Kusumi, I, C Ulpian, T Tallerico, D Nam, ISC Liu, MV Seeman, P Seeman
    MOLECULAR BRAIN RESEARCH 53 (1-2) 339 - 343 0169-328X 1998/01 [Refereed][Not invited]
     
    Although the serotonin-7 receptor was cloned several years ago, its localization in brain tissues remains confusing because of the existence of a related expressed pseudogene, the sequence of which has not hitherto been reported. During the course of searching for related receptor genes, we also searched for this pseudogene to determine its sequence. Human genomic DNA was screened for dopamine and serotonin receptor-like genes, using the polymerase chain reaction method and degenerate oligonucleotide primers based on the similar sequences in the transmembrane-6 and -7 regions of the serotonin-5A, the serotonin-7, and the dopamine D2, D3 and D4 receptors. This resulted in one of the clones having a 115 bp fragment, of which 89% of the bases were identical to the transmembrane-6 and -7 regions of the serotonin-7 receptor sequence. The fragment was radiolabelled and used to screen a human fetal brain cDNA library. A. novel cDNA clone of 1326 bp was isolated. Based on the nucleotide sequence, 88% of the bases in this sequence of the pseudogene are identical to the human serotonin-7 receptor coding sequence. However, compared to the serotonin-7 receptor DNA sequence, the pseudogene sequence has nucleotide deletions and insertions, resulting in frame-shifts and stop codons. It was concluded that this sequence represented a pseudogene related to the serotonin-7 receptor gene. (C) 1998 Elsevier Science B.V.
  • Risperidoneとpimozideの併用療法が著効したGilles de la Tourette症候群の1症例
    佐々木幸哉, 小林理子, 久住一郎, 傳田健三, 小山 司
    臨床精神医学 27 1149 - 1155 1998 [Refereed][Not invited]
  • 精神医学 40 1209 - 1212 1998 [Not refereed][Not invited]
  • T Ishikane, Kusumi, I, R Matsubara, S Matsubara, T Koyama
    EUROPEAN JOURNAL OF PHARMACOLOGY 321 (2) 163 - 169 0014-2999 1997/02 [Refereed][Not invited]
     
    We examined the modulatory effect of serotonergic activities on haloperidol-induced up-regulation of dopamine D-2 receptors in rat striatum. Chronic treatment with haloperidol (0.1, 0.5 mg/kg, i.p., 3 weeks) increased the number of dopamine D-2 receptors, while no increase was observed with the atypical antipsychotic drugs clozapine (10 mg/kg) and trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrolidine maleate (ORG 5222; 0.25 mg/kg). Chronic treatment with 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), a nonselective serotonin (5-hydroxytryptamine, 5-HT) receptor agonist (2.5 mg/kg), or with citalopram, a 5-HT reuptake inhibitor (10 mg/kg), potentiated the haloperidol (0.1 mg/kg)-induced up-regulation of dopamine D-2 receptors, while that with (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist (0.1 mg/kg) had no influence on the dopamine D-2 receptor up-regulation. Coadministration of ritanserin (1 mg/kg), a 5-HT2A/2C receptor antagonist, with a low dose of haloperidol (0.1 mg/kg), but not with a high dose of the agent (0.5 mg/kg) attenuated the dopamine D-2 receptor up-regulation. Drug occupation of 5-HT2A and dopamine D-2 receptors in vivo examined using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was 69.8% and 45.1%, respectively, after the acute administration of haloperidol (0.1 mg/kg) plus ritanserin (1 mg/kg). This profile, that 5-HT2A receptors are highly occupied compared with dopamine D-2 receptors, was similar to that of clozapine or ORG 5222. These results suggest that potent 5-HT2A receptor antagonism versus weak dopamine D-2 receptor blockade may be involved in the absence of up-regulation of dopamine D-2 receptors after chronic treatment with clozapine or ORG 5222.
  • セロトニンと感情障害
    久住一郎, 小山 司
    医学のあゆみ 183 512 - 513 1997 [Not refereed][Not invited]
  • 『精神医学』 39 1145 - 1152 1997 [Not refereed][Not invited]
  • 「感情障害とセロトニン−2受容体機能」
    『精神神経学雑誌』 98 915 - 920 1996 [Not refereed][Not invited]
  • CHRONOBIOLOGICAL APPROACH FOR TREATMENT-RESISTANT RAPID-CYCLING AFFECTIVE-DISORDERS
    KUSUMI, I, T OHMORI, M KOHSAKA, M ITO, H HONMA, T KOYAMA
    BIOLOGICAL PSYCHIATRY 37 (8) 553 - 559 0006-3223 1995/04 [Refereed][Not invited]
  • 薬物治療抵抗性躁うつ病に対する時間生物学的アプローチ. —光パルス療法併用の奏効した非季節性感情障害2症例の検討
    久住一郎, 大森哲郎, 香坂雅子, 伊藤ますみ, 本間裕士, 小山 司
    臨床精神医学 24 81 - 91 1995 [Refereed][Not invited]
  • 多彩な精神症状を呈し治療的対応が困難であった末期カルチノイド腫瘍の1症例
    久住一郎, 笠原敏彦, 傳田健三, 中村一朗, 築島 健, 小山 司
    臨床精神医学 24 183 - 190 1995 [Refereed][Not invited]
  • 鈴木克治, 久住一郎, 井上 猛, 土屋 潔, 松倉真弓, 越前谷則子, 松原良次, 大森哲郎, 松原繁広, 小山 司
    精神医学 37 477 - 484 1995 [Refereed][Not invited]
  • Characterization of [3H]clozapine binding sites in rat brain
    I. Kusumi, S. Matsubara, Y. Takahashi, T. Ishikane, T. Koyama
    J. Neural Transm.(Gen) 101 51 - 64 1995 [Refereed][Not invited]
  • LONG-TERM TREATMENT WITH HALOPERIDOL OR CLOZAPINE DOES NOT AFFECT DOPAMINE D-4 RECEPTORS IN RAT FRONTAL-CORTEX
    KUSUMI, I, T ISHIKANE, S MATSUBARA, T KOYAMA
    JOURNAL OF NEURAL TRANSMISSION-GENERAL SECTION 101 (1-3) 231 - 235 0300-9564 1995 [Refereed][Not invited]
     
    We examined the effects of long-term treatment with haloperidol and clozapine on dopamine D-4 receptors in rat frontal cortex. Dopamine D-4 receptor binding sites were indirectly determined from the displacement experiments of [H-3]clozapine binding using nemonapride. Three-weeks administration of haloperidol (0.5 mg/kg) or clozapine (10 mg/kg) did not significantly affect the D-4 receptors in the frontal cortex. The density of D-2 receptors, determined by [H-3]spiperone binding to striatum, was increased by long-term treatment with haloperidol, but it was not significantly changed by that with clozapine.
  • 慢性期精神分裂病に対 するブロモクリプチン投与の影響
    久住一郎, 岡 五百理, 安田素次, 宮野 悟, 和田千里, 小山 司
    臨床精神医学 24 1231 - 1241 1995 [Refereed][Not invited]
  • 気分障害におけるリチウム反応性
    久住一郎, 小山 司
    神経精神薬理 17 857 - 864 1995 [Not refereed][Not invited]
  • EFFECT OF MOOD STABILIZING AGENTS ON AGONIST-INDUCED CALCIUM MOBILIZATION IN HUMAN PLATELETS
    KUSUMI, I, T KOYAMA, YAMASHITA, I
    JOURNAL OF PSYCHIATRY & NEUROSCIENCE 19 (3) 222 - 225 1180-4882 1994/05 [Refereed][Not invited]
     
    The effect of mood stabilizing agents such as lithium, carbamazepine, valproic acid and clonazepam on serotonin(5-HT)-or thrombin-induced intracellular calcium (Ca) mobilization was studied in the platelets of healthy subjects using the fluorescent Ca indicator fura-2. After incubating platelet-rich plasma with these drugs for one or four hours, there was no significant difference in either basal Ca2+ concentration or 5-HT-stimulated Ca response between each agent treatment and control. 5-HT- or thrombin-induced Ca mobilization was not altered by four weeks of lithium carbonate administration in healthy volunteers. These results indicate that these mood stabilizers fail to affect the agonist-stimulated intracellular Ca mobilizing pathway either in vitro or ex vivo in the platelets of healthy subjects.
  • SEROTONIN-INDUCED PLATELET INTRACELLULAR CALCIUM MOBILIZATION IN DEPRESSED-PATIENTS
    KUSUMI, I, T KOYAMA, YAMASHITA, I
    PSYCHOPHARMACOLOGY 113 (3-4) 322 - 327 0033-3158 1994/01 [Refereed][Not invited]
     
    Serotonin(S-HT)-stimulated intracellular calcium(Ca) mobilization was measured in the platelets of depressed patients to assess 5-HT2 receptor function. The 5-HT-induced Ca response was significantly higher in unmedicated patients with bipolar depression and melancholic major depression than in those with nonmelancholic major depression and normal controls. The enhanced Ca response to 5-HT failed to correlate with severity of depressive symptoms. In patients with bipolar disorder and melancholic major depression, there was no significant difference in 5-HT-stimulated Ca response between the unmedicated group and those in remission. These results suggest that 5-HT2 receptor function is increased in some types of depression, and raise the possibility that the enhanced Ca response to 5-HT may be trait dependent rather than state dependent.
  • DOPAMINE-D(1), DOPAMINE-D(2) AND SEROTONIN(2) RECEPTOR OCCUPATION BY TYPICAL AND ATYPICAL ANTIPSYCHOTIC-DRUGS INVIVO
    S MATSUBARA, R MATSUBARA, KUSUMI, I, T KOYAMA, YAMASHITA, I
    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 265 (2) 498 - 508 0022-3565 1993/05 [Refereed][Not invited]
     
    In vivo occupation of dopamine D1 and D2 and serotonin (5-HT)2 receptors by typical and atypical antipsychotic drugs (APD) was examined using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, which nonselectively and irreversibly inactivates these receptor sites. APD were classified as typical or atypical based on their capacity to induce extrapyramidal side effect in humans and/or catalepsy in laboratory rodents. Pretreatment of rats with typical APD (haloperidol, 0.25-3 mg/kg; chlorpromazine, 5-10 mg/kg; cis-flupenthixol, 1 mg/kg; zotepine, 5 mg/kg; nemonapride, 0.5-2 mg/kg) potently reversed the N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline-induced D2 receptor inactivation in rat striatum. In contrast, some atypical APD or its candidates (clozapine, 5-30 mg/kg; fluperlapine, 10 mg/kg; risperidone, 0.25-3 mg/kg; setoperone, 0.025-0.25 mg/kg; ORG 5222, 0.25 mg/kg) showed considerable occupation of 5-HT2 receptors in cerebral cortex with smaller or negligible occupation of D2 and D1 receptors. Pretreatment with the other atypical APD (sulpiride, 30 mg/kg; amperozide, 1 mg/kg) had no effect on these three receptors, although at higher doses, sulpiride (60 mg/kg) and amperozide (5 mg/kg) slightly but significantly reversed D2 and 5-HT2 receptor inactivation, respectively. It was concluded that a certain group of atypical APD is characterized by high occupancy of 5-HT2 receptor with lower or minimal occupancy of D2 and D1 receptors in vivo. The relevance of these characteristics of atypical APD was discussed in relation to extrapyramidal side effects and the therapeutic effects on schizophrenia.
  • セロトニン−2受容体を介する血小板内カルシウム動員を指標とした感情障害の 成因に関する研究
    久住一郎
    北海道医学雑誌 68 325 - 336 1993 [Refereed][Not invited]
  • THROMBIN-INDUCED PLATELET CALCIUM MOBILIZATION IS ENHANCED IN BIPOLAR DISORDERS
    KUSUMI, I, T KOYAMA, YAMASHITA, I
    BIOLOGICAL PSYCHIATRY 32 (8) 731 - 734 0006-3223 1992/10 [Refereed][Not invited]
  • SEROTONIN-STIMULATED CA2+ RESPONSE IS INCREASED IN THE BLOOD-PLATELETS OF DEPRESSED-PATIENTS
    KUSUMI, I, T KOYAMA, YAMASHITA, I
    BIOLOGICAL PSYCHIATRY 30 (3) 310 - 312 0006-3223 1991/08 [Refereed][Not invited]
  • INCREASED 5-HT-2 RECEPTOR FUNCTION AS MEASURED BY SEROTONIN-STIMULATED PHOSPHOINOSITIDE HYDROLYSIS IN PLATELETS OF DEPRESSED-PATIENTS
    M MIKUNI, KUSUMI, I, A KAGAYA, Y KURODA, H MORI, K TAKAHASHI
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 15 (1) 49 - 61 0278-5846 1991 [Refereed][Not invited]
     
    1. The present study was undertaken to examine whether or not 5-HT-induced inositol monophosphate (IP-1) accumulation in human platelets is mediated by 5-HT-2 receptors and to assess 5-HT-2 receptor function as measured by 5-HT-stimulated IP-1 accumulation in platelets from normal controls and depressed patients before drug treatment. 2. In platelets prelabeled with 3H-myo-inositol, in Ca ion free HEPES buffer containing 10mM LiCl, 5-HT caused a dose-dependent accumulation of IP-1 during 15min incubation. A maximal increase in IP-1 formation was observed at 30-mu-M of 5-HT and its EC50 value was 4-mu-M 3. Ketanserin, a selective 5-HT-2 antagonist, was a potent inhibitor of 5-HT-stimulated IP-1 accumulation with a Ki value of 12nM, but (-)propranolol (10-mu-M), a 5-HT-1 antagonist, failed to block the 5-HT response. 4. The potencies of various compounds tested to inhibit 5-HT-stimulated IP-1 accumulation in human platelets correlated positively with the affinities to 5-HT-2 receptor as defined by radioligand binding in rat cerebral cortex. 5. In a group of unmedicated patients with major depressive disorder matched for age with normal control group, we found a significant increase in 5-HT(100-mu-M)-induced accumulation of IP-1(150+/-7% of basal for depressed patients, 132+/-3% for controls).
  • EFFECT OF SUBCHRONIC ANTIDEPRESSANTS ADMINISTRATION ON SEROTONIN-STIMULATED PHOSPHOINOSITIDE HYDROLYSIS IN PARA-CHLOROPHENYLALANINE-TREATED RAT HIPPOCAMPAL SLICES
    KUSUMI, I, M MIKUNI, K TAKAHASHI
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 15 (3) 393 - 403 0278-5846 1991 [Refereed][Not invited]
     
    1. This study examines the effect of subchronic para-chlorophenylalanine(PCPA) treatment upon serotonin(5-HT)-stimulated inositol monophosphate(IP-1) accumulation in rat hippocampal slices and also the effect of antidepressants upon this 5-HT response in the hippocampus from rats treated with or without concurrent administration of PCPA. 2. For high dose PCPA treatment, animals were injected intraperitoneally with 300 mg/kg daily for the first 5 days and then 100 mg/kg for 5 days, while for low dose PCPA treatment animals were injected for 10 days at a dose of 100 mg/kg. Imipramine or iprindole (15 mg/kg i.p.) was given once daily for 10 consecutive days. 3. 10-Day treatment with high dose of PCPA resulted in a significant increase in 5-HT-stimulated IP-1 accumulation, whereas low dose of PCPA had no significant effect upon the 5-HT response as compared to vehicle. 5-HT-stimulated IP-1 accumulation in rat hippocampus was not affected by subchronic treatment with imipramine or iprindole. The enhancement of the 5-HT response induced by high dose of PCPA was not attenuated by repeated antidepressants treatment.
  • KUSUMI, I, T KOYAMA, YAMASHITA, I
    LIFE SCIENCES 48 (25) 2405 - 2412 0024-3205 1991 [Refereed][Not invited]
     
    Serotonin (5-HT)-stimulated intracellular Ca2+ concentration change was studied in the platelets of healthy subjects, using fluorescent Ca indicator fura-2. 5-HT increased the Ca2+ response in a concentration-dependent manner. 10-mu-M of 5-HT induced the maximal response and its EC50 value was 0.4-mu-M. This response was potently inhibited by selective 5-HT2 antagonists, suggesting that 5-HT-induced Ca2+ mobilization in human platelets is mediated by 5-HT2 receptors. This 5-HT2-mediated Ca2+ response was not significantly affected by the time of blood sampling, gender, meal or exercise. However, this response declined with time after blood drawing, suggesting that it must be measured as soon as possible after sampling. These results indicate that 5-HT-stimulated Ca2+ response in human platelets is a stable parameter and that it will be suitable for assessing 5-HT2 receptor function in depressed patients.
  • SEROTONIN-INDUCED ACUTE DESENSITIZATION OF SEROTONIN-2 RECEPTORS IN HUMAN PLATELETS VIA A MECHANISM INVOLVING PROTEIN-KINASE-C
    A KAGAYA, M MIKUNI, KUSUMI, I, H YAMAMOTO, K TAKAHASHI
    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 255 (1) 305 - 311 0022-3565 1990/10 [Refereed][Not invited]
  • SUBCHRONIC ADMINISTRATION OF PARA-CHLOROPHENYLALANINE ENHANCES SEROTONIN-STIMULATED PHOSPHOINOSITIDE HYDROLYSIS IN RAT HIPPOCAMPAL SLICES
    KUSUMI, I, M MIKUNI, Y KURODA, K TAKAHASHI
    JOURNAL OF NEURAL TRANSMISSION-GENERAL SECTION 80 (3) 181 - 188 0300-9564 1990 [Refereed][Not invited]
  • 向精神薬連用のよる頻脈とCa拮抗薬. —β遮断薬からの切り替えによる検討—
    久住一郎, 浅野 裕, 加沢鉄士, 林下忠行, 菊入 剛
    臨床精神医学 17 637 - 644 1988 [Refereed][Not invited]
  • 久住一郎, 浅野 裕, 加沢鉄士, 林下忠行
    精神医学 30 899 - 906 1988 [Refereed][Not invited]
  • 久住一郎, 浅野 裕, 加沢鉄士, 林下忠行
    精神医学 30 1333 - 1338 1988 [Refereed][Not invited]

Books etc

  • 今日の治療指針2017
    久住一郎 (Contributor抗うつ薬の副作用)
    医学書院 2017
  • 今日の精神疾患治療指針第2版
    賀古勇輝, 久住一郎 (Contributor適応障害)
    医学書院 2016
  • 精神科研修ノート改訂第2版
    久住一郎 (Contributor精神科研修でマスターすべきこと/薬物療法:抗精神病薬)
    診断と治療社 2016
  • デュロキセチンのすべて
    仲唐安哉, 井上 猛, 久住一郎 (Contributorデュロキセチンによる難治性うつ病のアプローチ)
    先端医学社 2014
  • クロザピン 100のQ&A
    久住一郎 (Contributorクロザピン治療と高血糖・ケトアシドーシスについて教えて下さい)
    星和書店 2014
  • 今日の治療指針2014
    久住一郎 (Contributor抗精神病薬の副作用)
    医学書院 2014
  • 今日の治療指針 2012 私はこう治療している
    久住一郎 (Contributor統合失調症圏障害)
    医学書院 2012
  • 抗精神病薬完全マスター
    久住一郎 (Contributor新規抗精神病薬の薬理、臨床応用:クエチアピン)
    医学書院 2012
  • 服薬支援とケアプランに活かす 非定型抗精神病薬Q&A
    久住一郎, 大熊恵子 (Contributor各非定型抗精神病薬の効果と副作用の特徴:ペロスピロン塩酸塩水和物)
    医学書院 2012
  • 統合失調症治療の新たなストラテジー―非定型抗精神病薬によるアプローチ―
    久住一郎, 小山 司 (Contributor非定型抗精神病薬の特徴)
    先端医学社 2011
  • 専門医のための精神科臨床リュミエール25 向精神薬のリスク・ベネフィット
    久住一郎, 小山 司 (Contributorクロザピン時代の薬物療法)
    中山書店 2011
  • 精神科研修ノート
    久住一郎 (Contributor精神科研修でマスターすべきこと/薬物療法:抗精神病薬)
    診断と治療社 2011
  • 脳とこころのプライマリケア 8 幻覚と妄想
    久住一郎 (Contributorカタトニア(緊張病)症候群)
    株式会社シナジー 2011
  • 今日の治療指針 2009
    久住一郎 (Contributor双極性障害、うつ状態)
    医学書院 2009
  • 老年期うつ病ハンドブック
    久住一郎, 小山 司 (Contributor薬物療法—新しい抗うつ薬)
    診断と治療社 2009
  • 精神疾患と認知機能
    久住一郎, 豊巻敦人, 小山 司 (Contributor認知機能とその改善—抗うつ薬)
    新興医学出版社 2009
  • 統合失調症の薬物療法 100のQ & A
    久住一郎 (ContributorQ2初発の統合失調症患者に対しては、それぞれの第二世代抗精神病薬の優劣の比較は検討されているのですか?)
    星和書店 2008
  • 気分障害
    鈴木克治, 久住一郎 (Contributorラピッドサイクラー)
    医学書院 2008
  • ガイドライン外来診療2008
    久住一郎 (Contributor統合失調症)
    日経メディカル開発 2008
  • KEY WORD 精神 第4版
    久住一郎, 小山 司 (ContributorDarier病遺伝子と気分障害)
    先端医学社 2007
  • 統合失調症の治療—臨床と基礎
    久住一郎, 小山 司 (Contributor治療計画策定と治療の実際—安定期:薬物の選択・用量・投与法)
    朝倉書店 2007
  • EBM 精神疾患の治療 2006-2007
    久住一郎, 小山 司 (Contributor第一世代抗精神病薬は認知障害を引き起こすのか?)
    中外医学社 2006
  • 統合失調症の薬物治療アルゴリズム
    久住一郎, 小山 司 (Contributor錐体外路症状と悪性症候群に対する治療アルゴリズム)
    医学書院 2006
  • 新規抗精神病薬のすべて
    久住一郎, 小山 司 (Contributor新規抗精神病薬の薬理学的プロフィール—ドパミンD2受容体遮断作用)
    先端医学社 2004
  • 新世紀の精神科治療2 気分障害の診療学 —初診から治療終了まで
    久住一郎, 小山 司 (Contributor診断の概説—DSM-IV-TRを中心に)
    中山書店 2004
  • 双極性障害の治療スタンダード
    鈴木克治, 久住一郎, 小山 司 (Contributor双極性障害の治療に用いられる薬剤の特徴 —Sodium valproate—)
    星和書店 2002
  • 臨床精神医学講座2 精神分裂病 I
    久住一郎, 小山 司 (Contributor病態・病理—神経化学)
    中山書店 1999
  • Signal Transduction in Affective Disorders
    Kusumi I, Koyama T (ContributorSerotonin-2A receptor function in affective disorders)
    Springer 1998
  • 精神分裂病と気分障害 の治療手順
    久住一郎, 小山 司 (Contributor精神分裂病のアルゴリズム—急性の副作用)
    星和書店 1998
  • 臨床精神医学講座3 精神分裂病 II
    久住一郎, 小山 司 (Contributor薬物療法—今後の展望)
    中山書店 1997
  • 抗うつ薬の科学 —基礎と臨床的検証—
    久住一郎, 小山 司 (Contributorリチウムの抗うつ作用)
    星和書店 1995
  • Serotonin in the Central Nervous System and Periphery
    Koyama T, Kusumi I (ContributorRole of serotonin (5-HT)2 receptor function: Implication for theetiology and treatment of depression)
    Elsevier Science B.V. 1995
  • リチウム療法の実際
    久住一郎, 浅野 裕 (Contributorリチウム反応性と非反応性)
    医歯薬出版 1990

Research Grants & Projects

  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2011 -2013 
    Author : 久住 一郎
  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2010 -2011 
    Author : 鈴木 克治, 久住 一郎
     
    本研究の目的は、気分障害患者のアラキドン酸(AA)カスケードに関わる蛋白の機能と躁転に代表されるスイッチングプロセスあるいは血小板カルシウム反応などの生物学的指標との関連を明らかにすることである。平成22年度は、AAカスケードの中核をなすCox-2のウェスタンブロットによる定量の確立を目指す一方で、気分障害患者を研究にエントリーし、カルシウム反応を測定するとともに質問紙を用いて気質などの臨床背景のデータを集積した。Cox-2の定量は、ヒト血小板で実施する前に培養細胞(SH-SY5Y細胞)で確立させたが、ヒト血小板では未実施であり来年度に繰り越しとなった。エントリー患者の縦断的採血は、躁転時に実施する予定であったが今年度は対象となる状態像を呈するエントリー患者がなく、来年度へ繰り越しとなった。平成22年度にエントリーされた患者は25例、健常対照者は59例であった。これらのうち、年齢と性をマッチさせた19例ずつを抽出し気質と血小板カルシウム反応の関連について検討した結果を研究成果として報告した。TEMPS-Aで測定される気質では発揚気質を除く4気質(抑うつ気質、循環気質、焦燥気質、不安気質)で患者群の方が有意に高得点であった。カルシウム反応の大きさと各気質の得点は両群とも相関は認めなかったが、静止時カルシウム濃度は患者群で循環気質のみ有意に正の相関を認めた(r=0.46,p<0....
  • Ministry of Education, Culture, Sports, Science and Technology:Grants-in-Aid for Scientific Research(基盤研究(C))
    Date (from‐to) : 2008 -2010 
    Author : Ichiro KUSUMI, Katsuji SUZUKI, Nobuki KITAGAWA, Naoki HASHIMOTO, Atsuhito TOYOMAKI
     
    It is possible that depressive patients have dysregulation of cognitive processes due to hyperactivity of anterior cingulate cortex. We measured feedback negativity, one of event-related brain potential and functional MRI during imposing decision-making and reward prediction problems, respectively. The amplitude of feedback negativity was decreased in schizophrenia patients compared to controls. Reward prediction induced increased neuronal activities in the dorsal anterior cingulate cortex and ventral striatum of healthy subjects using a functional MRI. Further studies are ongoing to evalua...
  • Ministry of Education, Culture, Sports, Science and Technology:Grants-in-Aid for Scientific Research(基盤研究(C))
    Date (from‐to) : 2005 -2006 
    Author : Ichiro KUSUMI, 鈴木 克治
     
    Recently, a functional polymorphism (-116C/G) of the XBP1 gene was reported to contribute to the genetic risk factor for bipolar disorder (BPD). Moreover, the endoplasmic reticulum (ER) stress response were impaired in cultured lymphocytes from BPD patients with G allele and only valproate rescued the impairment of the ER stress response among three major mood stabilizers. In this context, it is likely that BPD patients with different genotype respond differently to mood stabilizers. Therefore, we investigated the association of-116C/G polymorphism and lithium response in patients with BPD....
  • Ministry of Education, Culture, Sports, Science and Technology:Grants-in-Aid for Scientific Research(基盤研究(C))
    Date (from‐to) : 2003 -2005 
    Author : Tomohiro ABEKAWA, 久住 一郎
     
    We can use an NMDA receptor dysfunction model for the treatment-resistant schizophrenia, and methamphetamine model for the treatment-responsive model for schizophrenia. We hypothesized that increased glutamate levels in the medial prefrontal cortex(mPFC) and the nucleus accumbens(NA) induced by high dose of methamphetamine play an important role for the development of behavioral cross-sensitization to an NMDA receptor antagonist. We have shown that a protein kinase C inhibitor, staurosporine and a GABA stimulant, valproate block the development of the cross-sensitization to dizocilpine. Val...
  • Ministry of Education, Culture, Sports, Science and Technology:Grants-in-Aid for Scientific Research(基盤研究(C))
    Date (from‐to) : 2003 -2004 
    Author : Ichiro KUSUMI, 鈴木 克治
     
    We examined thapsigargin (microsomal Ca-ATPase inhibitor)-induced transient intraplatelet calcium increase (TCI) and capcitative calcium entry (CCE) in the patients with bipolar disorder and major depressive disorder, and normal controls. There was no significant difference in thapsigargin-induced TCI or CCE among the three groups. However, in bipolar disorders, the inhibitory effect of proteinkinase C (PKC) stimulator on CCE was increased, and the stimulatory effect of PKC inhibitor on CCE was decreased. No significant differences in the effect of calmodulin inhibitor were observed among t...
  • Ministry of Education, Culture, Sports, Science and Technology:Grants-in-Aid for Scientific Research(基盤研究(B))
    Date (from‐to) : 2002 -2004 
    Author : Tsukasa KOYAMA, 安部川 智浩, 久住 一郎
     
    Clarifying the pathogenesis and the mechanism for the treatment of cognitive dysfunction of schizophrenia is important, because this dysfunction induces serious social dysfunction in patients with schizophrenia.Phencyclidine-induced increases in glutamate levels in the prefrontal cortex and hyperlocomotion were blocked by 5-HT2A receptor antagonist, an atypical antipsychotic, dozapine. Lesioning the mediodortsal thalamus, which projects the glutamatengic neuronal terminals to the prefrontal cortex, enhanced the behavioral and neurochemical changes of NMDA receptor antagonist, MK-801. Chroni...
  • Ministry of Education, Culture, Sports, Science and Technology:Grants-in-Aid for Scientific Research(基盤研究(C))
    Date (from‐to) : 2002 -2003 
    Author : Tsukasa SASAKI, 今村 明, 久住 一郎, 岡崎 祐士
     
    Specification of Factors that Cause Seasonality of Birth in Schizophrenia: a Study for a Clue to the Preventive Measure Seasonality of births (winter increase and/or summer decrease) in schizophrenia has consistently been observed in a number of studies. Specification of the factors that cause the seasonality may provide a clue to elucidation of causal factors and development of preventive measures of the disease. We investigated several groups of schizophrenia patients born in different areas of Japan to obtain a clue to the specification. Also, a review of previous studies on the seasonal...
  • Ministry of Education, Culture, Sports, Science and Technology:Grants-in-Aid for Scientific Research(基盤研究(C))
    Date (from‐to) : 2001 -2002 
    Author : Ichiro KUSUMI, 高橋 義人
     
    The effects of 3-week treatment with haloperidol (HPD 0.1 mg/kg), HPD/fluvoxamine (FLV 25 mg/kg) and risperidone (RIS 0.5mg/kg)/FLV on the binding to D_2 receptors were examined in the rat striatum. Subchronic treatment with HPD/FLV significantly enhanced D_2 receptor up-regulation induced by HPD alone, while no increase was observed with RIS/FLV compared to controls. These findings suggest that 5-HT_<2A> receptor blockade prevents the enhanced D_2 receptor up-regulation induced by coadministration of SSRI with HPD and that the frequency of extrapyramidal symptoms and tardive dyskinesia may...
  • Ministry of Education, Culture, Sports, Science and Technology:Grants-in-Aid for Scientific Research(基盤研究(C))
    Date (from‐to) : 1997 -2000 
    Author : Yuji ODAGAKI, 久住 一郎
     
    The assay method for agonist-induced stimulation of high-affinity GTPase activity was developed and applied to membranes prepared from rat brain, postmortem human brain, and human blood platelets to investigate the functional interaction between some receptors and their coupled G proteins. This method was shown to be suitable for detection of the functional activation of the G proteins that are negatively coupled to adenylyl cyclase, i.e.G_i family. Indeed, it has been shown that glutamate-stimulated high-affintiy GTPase activity in rat cerebral cortical, striatal, and hippocampal membranes...
  • 文部科学省:科学研究費補助金(萌芽的研究)
    Date (from‐to) : 1998 -1999 
    Author : 小山 司, 久住 一郎
     
    胎児にたいするTNF-αの影響を調べるために、妊娠2日目より出産まで毎日、体重1kgあたり1μgのTNF-αをラットに腹空内投与した。この母ラットより生まれた仔ラットが、3週齢に達した時点で行動観察を行った。オープンフィールドテストとして歩行、毛繕い、立ち上がりについてはそれぞれ有意差は認められなかったが歩行と立ち上がりについてはTNF-α投与群が、また毛繕いについてはTNF-α非投与群がその回数が多く認められた。学習能力や空間認知能力を調べるための強制水泳実験では、有意差は認められなかったがTNF-α投与群では水中の到達目標に達するまでにより多くの時間を必要とする傾向が認められた。TNF-α投与群 TNF-α非投与群歩行(回/10分) 77.4±30.3 61.2±23.6毛繕い(回/10分) 3.3±1.1 5.2±1.5立ち上がり(回/10分) 19.1±10.2 15.6±5.0強制水泳試験(秒)1回目 7.3±3.1 5.7±2.22回目 6.7±3.9 4.1±3.33回目 4.5±2.7 2.3±0.6これらの結果よりTNF-αの胎児への投与が情動性を不安定とし、学習能力を低下させる傾向があることが示唆された。更に行動観察を詳細に行い、これらの結果を確認する必要があるものと思われる。また実験動物より採取した大脳組織切片を、アポトーシスの検索などの組織学的な解析を...
  • Ministry of Education, Culture, Sports, Science and Technology:Grants-in-Aid for Scientific Research(基盤研究(C))
    Date (from‐to) : 1997 -1999 
    Author : Ichiro KUSUMI, 井上 猛
     
    The effect of non-competitive NMDA receptor antagonist phencyclidine (PCP) on the binding to dopamine DィイD22ィエD2 and serotonin 5-HTィイD22AィエD2 receptor was examined in the rat striatum and frontal cortex, respectively. Neither acute or 3-week treatment with 5 mg/kg PCP had any significant effect on DィイD22ィエD2 and 5-HTィイD22AィエD2 receptors. Acute or 8-day footshock stress (1 series: 2.5 mA for 30 sec, randam interval; mean 30 sec, 30 times) did not significantly affect the D2 and 5-HTィイD22AィエD2 receptors in both saline- and PCP (5 mg/kg)-treated rats. However, stress-induced changes in the Dィイ...
  • Ministry of Education, Culture, Sports, Science and Technology:Grants-in-Aid for Scientific Research(一般研究(B))
    Date (from‐to) : 1993 -1994 
    Author : Tsukasa KOYAMA, 久住 一郎, 大森 哲郎
     
    A series of experiments was conducted to clarify the mode of action mechanisms of atypical antipsychotic drugs (APDs)(1) A certain group of atypical APD was characterized by high occupancy of serotonin (5-HT) _<2A> receptor with lower or minimal occupancy of dopamine D_2 receptor in vivo.(2) The treatment of clozapine or ziprasidone induced the significantly greater increases in dopamine release in the prefrontal cortex, when compared to the treatment of other APDs.(3) Only clozapine and ziprasidone inhibited the reuptake of noradrenaline in the synaptosomes from the prefrontal cortex. The ...

Educational Activities

Teaching Experience

  • 研究発表技法Ⅰ
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
  • Master's Thesis Research in Medical Sciences
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 「精神医学」、「精神病理学」、「分子遺伝学」、「精神行動薬理学」、「神経画像学」、「神経生理学」
  • 研究発表技法Ⅱ
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
  • Basic Principles of Medicine
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 「統合失調症」、「気分障害」、「不安障害」、「向精神薬」、「病態モデル」
  • 研究発表技法Ⅰ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • Advanced Social and behavioral Sciences
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 「精神医学」、「気分障害」、「認知症」、「統合失調症」、「神経症」、「メンタルヘルス」「自殺」「精神保健行政」「評価尺度」
  • 研究発表技法Ⅱ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • Principles of Medicine
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 「精神疾患」、「向精神薬」、「機能画像」、「脳磁図」、「心理社会的治療法」
  • 基盤医学研究Ⅱ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • Dissertation Research in Medical Sciences
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 「精神医学」、「精神病理学」、「分子遺伝学」、「精神行動薬理学」、「神経画像学」、「神経生理学」
  • 基盤医学研究Ⅰ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • Dissertation Research in Clinical Medicine
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 「精神医学」、「臨床研究」、「クリニカル・クエスチョン」、「リサーチ・クエスチョン」、「プロトコール」
  • 臨床医学研究Ⅱ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • Principles of Medicine
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 児童思春期精神疾患、神経発達障害、自殺、インターネット依存、向精神薬、機能画像、脳磁図、心理社会的治療法 Child and adolescent psychiatric disorders, Suicide, Internet Addiction, neurodevelopmental disorders, neurotrophic drugs, functional imaging, magnetic encephalography, psychosocial treatment
  • 臨床医学研究Ⅰ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • Principles of Medicine
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 児童思春期精神疾患、神経発達障害、向精神薬、機能画像、脳磁図、心理社会的治療法、 新規知見 Child and adolescent psychiatric disorders, neurodevelopmental disorders, Suicide, Internet addiction, neurotrophic drugs, functional imaging, magnetic encephalography, psychosocial treatment, up to date
  • 医学総論
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • Psychiatry
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 「統合失調症」、「双極性障害」、「うつ病」、「神経症性障害」、「器質性・症状性精神障害」、「睡眠障害」、「薬物・アルコール関連障害」、「人格障害」「てんかん」、「リエゾン精神医学」、「緩和ケア」、「自殺」「児童・青年期精神医学」、「老年期精神医学」
  • 研究発表技法Ⅰ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
  • PsychiatryⅢ
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 精神障害、精神科面接、統合失調症、感情障害
  • 研究発表技法Ⅱ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
  • 精神医学
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部
  • 選択実習Ⅰ
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部
  • 選択実習Ⅱ
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部
  • 臨床基礎講義
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部
  • 歯科学
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部
  • 診断学実習
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部
  • 全科臨床実習
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部
  • 臨床特別講義Ⅱ
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部
  • 診療参加型コア科臨床実習
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部
  • 診療参加型選択科臨床実習
    開講年度 : 2018
    課程区分 : 学士課程
    開講学部 : 医学部


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