Hirotaka Yamagata, Ryouichi Tsunedomi, Toshiharu Kamishikiryo, Ayumi Kobayashi, Tomoe Seki, Masaaki Kobayashi, Kosuke Hagiwara, Norihiro Yamada, Chong Chen, Shusaku Uchida, Hiroyuki Ogihara, Yoshihiko Hamamoto, Go Okada, Manabu Fuchikami, Junichi Iga, Shusuke Numata, Makoto Kinoshita, A Takahiro Kato, Ryota Hashimoto, Hiroaki Nagano, Shuichi Ueno, Yasumasa Okamoto, Tetsuro Ohmori and Shin Nakagawa : Interferon signaling and hypercytokinemia-related gene expression in the blood of antidepressant non-responders., Heliyon, Vol.9, No.1, e13059, 2023.
(要約)
Only 50% of patients with depression respond to the first antidepressant drug administered. Thus, biomarkers for prediction of antidepressant responses are needed, as predicting which patients will not respond to antidepressants can optimize selection of alternative therapies. We aimed to identify biomarkers that could predict antidepressant responsiveness using a novel data-driven approach based on statistical pattern recognition. We retrospectively divided patients with major depressive disorder into antidepressant responder and non-responder groups. Comprehensive gene expression analysis was performed using peripheral blood without narrowing the genes. We designed a classifier according to our own discrete Bayes decision rule that can handle categorical data. Nineteen genes showed differential expression in the antidepressant non-responder group (n = 15) compared to the antidepressant responder group (n = 15). In the training sample of 30 individuals, eight candidate genes had significantly altered expression according to quantitative real-time polymerase chain reaction. The expression of these genes was examined in an independent test sample of antidepressant responders (n = 22) and non-responders (n = 12). Using the discrete Bayes classifier with the
Tomoki Ozaki, Yuta Yoshino, Ayumi Tachibana, Hideaki Shimizu, Takaaki Mori, Tomohiko Nakayama, Kazuaki Mawatari, Shusuke Numata, Junichi Iga, Akira Takahashi, Tetsuro Ohmori and Shu-ichi Ueno : Metabolomic alterations in the blood plasma of older adults with mild cognitive impairment and Alzheimer's disease (from the Nakayama Study)., Scientific Reports, Vol.12, No.1, 15205, 2022.
(要約)
Alzheimer's disease (AD) is a progressive disease, and the number of AD patients is increasing every year as the population ages. One of the pathophysiological mechanisms of AD is thought to be the effect of metabolomic abnormalities. There have been several studies of metabolomic abnormalities of AD, and new biomarkers are being investigated. Metabolomic studies have been attracting attention, and the aim of this study was to identify metabolomic biomarkers associated with AD and mild cognitive impairment (MCI). Of the 927 participants in the Nakayama Study conducted in Iyo City, Ehime Prefecture, 106 were selected for this study as Control (n = 40), MCI (n = 26), and AD (n = 40) groups, matched by age and sex. Metabolomic comparisons were made across the three groups. Then, correlations between metabolites and clinical symptoms were examined. The blood mRNA levels of the ornithine metabolic enzymes were also measured. Of the plasma metabolites, significant differences were found in ornithine, uracil, and lysine. Ornithine was significantly decreased in the AD group compared to the Control and MCI groups (Control vs. AD: 97.2 vs. 77.4; P = 0.01, MCI vs. AD: 92.5 vs. 77.4; P = 0.02). Uracil and lysine were also significantly decreased in the AD group compared to the Control group (uracil, Control vs. AD: 272 vs. 235; P = 0.04, lysine, Control vs. AD: 208 vs. 176; P = 0.03). In the total sample, the MMSE score was significantly correlated with lysine, ornithine, thymine, and uracil. The Barthel index score was significantly correlated with lysine. The instrumental activities of daily living (IADL) score were significantly correlated with lysine, betaine, creatine, and thymine. In the ornithine metabolism pathway, the spermine synthase mRNA level was significantly decreased in AD. Ornithine was decreased, and mRNA expressions related to its metabolism were changed in the AD group compared to the Control and MCI groups, suggesting an association between abnormal ornithine metabolism and AD. Increased betaine and decreased methionine may also have the potential to serve as markers of higher IADL in elderly persons. Plasma metabolites may be useful for predicting the progression of AD.
Toshiharu Kamishikiryo, Go Okada, Eri Itai, Yoshikazu Masuda, Satoshi Yokoyama, Masahiro Takamura, Manabu Fuchikami, Atsuo Yoshino, Kazuaki Mawatari, Shusuke Numata, Akira Takahashi, Tetsuro Ohmori and Yasumasa Okamoto : Left DLPFC activity is associated with plasma kynurenine levels and can predict treatment response to escitalopram in major depressive disorder., Psychiatry and Clinical Neurosciences, Vol.76, No.8, 367-376, 2022.
(要約)
Blood metabolite levels and resting-state brain activity were measured in patients with moderate to severe depression (n = 65) before and after 6-8 weeks of treatment with escitalopram, and these were compared between Responders and Nonresponders to treatment. We then examined the relationship between blood metabolites and brain activity related to treatment responsiveness in patients and healthy controls (n = 36).
Hirotaka Yamagata, Ayumi Kobayashi, Ryouichi Tsunedomi, Tomoe Seki, Masaaki Kobayashi, Kosuke Hagiwara, Chong Chen, Shusaku Uchida, Go Okada, Manabu Fuchikami, Toshiharu Kamishikiryo, Junichi Iga, Shusuke Numata, Makoto Kinoshita, A Takahiro Kato, Ryota Hashimoto, Hiroaki Nagano, Yasumasa Okamoto, Shuichi Ueno, Tetsuro Ohmori and Shin Nakagawa : Optimized protocol for the extraction of RNA and DNA from frozen whole blood sample stored in a single EDTA tube., Scientific Reports, Vol.11, No.1, 17075, 2021.
(要約)
Cryopreservation of whole blood is useful for DNA collection, and clinical and basic research. Blood samples in ethylenediaminetetraacetic acid disodium salt (EDTA) tubes stored at - 80 °C are suitable for DNA extraction, but not for high-quality RNA extraction. Herein, a new methodology for high-quality RNA extraction from human blood samples is described. Quickly thawing frozen whole blood on aluminum blocks at room temperature could minimize RNA degradation, and improve RNA yield and quality compared with thawing the samples in a 37 °C water bath. Furthermore, the use of the NucleoSpin RNA kit increased RNA yield by fivefold compared with the PAXgene Blood RNA Kit. Thawing blood samples on aluminum blocks significantly increased the DNA yield by ~ 20% compared with thawing in a 37 °C water bath or on ice. Moreover, by thawing on aluminum blocks and using the NucleoSpin RNA and QIAamp DNA Blood kits, the extraction of RNA and DNA of sufficient quality and quantity was achieved from frozen EDTA whole blood samples that were stored for up to 8.5 years. Thus, extracting RNA from frozen whole blood in EDTA tubes after long-term storage is feasible. These findings may help advance gene expression analysis, as well as biomarker research for various diseases.
(キーワード)
Blood Chemical Analysis / Blood Preservation / Cryopreservation / DNA (DNA) / Edetic Acid / Humans / RNA (RNA)
Shabeesh Balan, Tetsuo Ohnishi, Akiko Watanabe, Hisako Ohba, Yoshimi Iwayama, Manabu Toyoshima, Tomonori Hara, Yasuko Hisano, Yuki Miyasaka, Tomoko Toyota, Chie Shimamoto-Mitsuyama, Motoko Maekawa, Shusuke Numata, Tetsuro Ohmori, Tomomi Shimogori, Yoshiaki Kikkawa, Takeshi Hayashi and Takeo Yoshikawa : Role of an Atypical Cadherin Gene, Cdh23 in Prepulse Inhibition, and Implication of CDH23 in Schizophrenia., Schizophrenia Bulletin, Vol.47, No.4, 1190-1200, 2021.
(要約)
We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.
Chise Ueoka, Masahito Nakataki, Yoshinori Ueoka, Atsuko Miyazaki, Saki Taniguchi and Tetsuro Ohmori : An attempt to analyze the longitudinal psychological state of cancer patients in the active treatment stage., The Journal of Medical Investigation : JMI, Vol.68, No.1.2, 148-153, 2021.
(要約)
The psychological state and changes over time of cancer patients in the active treatment stage were classified into emotions by the speech and behavior of the patient described in the medical record article of the cancer psychological interview record, and the analysis of the "emotional state map" was attempted. In all cases, positive / negative emotions were mixed and appeared with variation, but a relatively large number of positive emotions, including <joy>, <relief>, and <liking>, were manifested, and the same was true in patients who experienced stressful treatment events. In the background, the existence of appropriate support from medical professionals and psychological characteristics peculiar to the stage of active treatment was inferred, such as the active treatment of the target patient, the hospitalization environment in which mental and physical pain promptly appealed to medical professionals, and the influence of psychological interviews. Cancer patients during active treatment perceived and expressed changes in the body and pain caused by the disease, and after responses from medical professionals and family members, they were conscious of their physical condition and emotions. It is suggested that this analysis method helps to objectively understand and explain the invisible and ever-changing psychological state of cancer patients in the active treatment stage. J. Med. Invest. 68 : 148-153, February, 2021.
Chigusa Uchiumi, Hiroshi Kato, Motohiro Ishida, Masahito Nakataki and Tetsuro Ohmori : Peritraumatic reactions, PTSD symptoms, and pain : A study of train disasters in Japan., The Journal of Medical Investigation : JMI, Vol.68, No.1.2, 85-89, 2021.
(要約)
Objective : The purpose of this study was to examine the relationship between peritraumatic reactions, posttraumatic stress disorder (PTSD) symptoms, and pain in people injured in train disasters. Methods : The participants were injured in a train crash in Japan that left more than 100 dead. There were 218 participants in the analysis, with a mean age of 37.50 ± 14.67 years. Peritraumatic reactions were assessed using the Peritraumatic Distress Inventory. PTSD symptoms were evaluated using the Impact of Event Scale-Revised Japanese-language version. Pain was measured using the Visual Analog Scale. Results : Peritraumatic reactions did not directly affect PTSD symptoms but were found to be associated via latent variables. Regarding pain and PTSD symptoms, intrusive memories were more associated with pain than other symptoms were. There was an associative path from intrusion to pain, but no such path from pain to intrusion. Conclusions : Our results suggest that a therapeutic approach to intrusion may be effective in ameliorating the pain caused by injury. Future research should examine integrated treatment approaches for both PTSD and pain, rather than just for aspects of PTSD. J. Med. Invest. 68 : 85-89, February, 2021.
Yukiko Tomioka, Makoto Kinoshita, Hidehiro Umehara, Tomohiko Nakayama, Shinya Watanabe, Masahito Nakataki, Shusuke Numata and Tetsuro Ohmori : Association between serum folate levels and schizophrenia based on sex., Psychiatry and Clinical Neurosciences, Vol.74, No.9, 466-471, 2020.
(要約)
Our findings suggest that: (i) a low serum folate level may be associated with schizophrenia regardless of sex; and (ii) folate administration may be beneficial for the treatment of schizophrenia. In schizophrenic patients with low serum folate levels, folate administration might result in improvements in high tHcy and an increase in low vitamin B6 levels.
Satoshi Okazaki, Shusuke Numata, Ikuo Otsuka, Tadasu Horai, Makoto Kinoshita, Ichiro Sora, Tetsuro Ohmori and Akitoyo Hishimoto : Decelerated epigenetic aging associated with mood stabilizers in the blood of patients with bipolar disorder., Translational Psychiatry, Vol.10, No.1, 129, 2020.
(要約)
There is high mortality among patients with bipolar disorder (BD). Studies have reported accelerated biological aging in patients with BD. Recently, Horvath and Hannum et al. independently developed DNA methylation (DNAm) profiles as "epigenetic clocks," which are the most accurate biological age estimate. This led to the development of two accomplished measures of epigenetic age acceleration (EAA) using blood samples, namely, intrinsic and extrinsic EAA (IEAA and EEAA, respectively). IEAA, which is based on Horvath's clock, is independent of blood cell counts and indicates cell-intrinsic aging. On the other hand, EEAA, which is based on Hannum's clock, is associated with age-dependent changes in blood cell counts and indicates immune system aging. Further, Lu et al. developed the "GrimAge" clock, which can strongly predict the mortality risk, and DNAm-based telomere length (DNAmTL). We used a DNAm dataset from whole blood samples obtained from 30 patients with BD and 30 healthy controls. We investigated Horvath EAA, IEAA, Hannum EAA, EEAA, Grim EAA, DNAmTL, and DNAm-based blood cell composition. Compared with controls, there was a decrease in Horvath EAA and IEAA in patients with BD. Further, there was a significant decrease in Horvath EAA and IEAA in patients with BD taking medication combinations of mood stabilizers (including lithium carbonate, sodium valproate, and carbamazepine) than in those taking no medication/monotherapy. This study provides novel evidence indicating decelerated epigenetic aging associated with mood stabilizers in patients with BD.
Yosuke Suga, Keiichiro Yoshimoto, Shusuke Numata, Shinji Shimodera, Shogo Takamura, Naoto Kamimura, Ken Sawada, Hiromitsu Kazui, Tetsuro Ohmori and Shigeru Morinobu : Structural variation in the glycogen synthase kinase 3β and brain-derived neurotrophic factor genes in Japanese patients with bipolar disorders., Neuropsychopharmacology Reports, Vol.40, No.1, 46-51, 2020.
(要約)
Lithium is the first-line drug for the treatment of bipolar disorders (BDs); however, not all patients responded. Glycogen synthase kinase (GSK) 3β and brain-derived neurotrophic factor (BDNF) play a role in the therapeutic action of lithium. Since structural variations were reported in these genes, it is possible that these genomic variations may be involved in the therapeutic responses to lithium. Fifty patients with BDs and 50 healthy subjects (mean age 55.0 ± 15.0 years; M/F 19/31) participated. We examined structural variation of the GSK3β and BDNF genes by real-time PCR. We examined the influence of structural variation of these genes on the therapeutic responses to lithium and the occurrence of antidepressant-emergent affective switch (AEAS). The efficacy of lithium was assessed using the Alda scale, and AEAS was evaluated using Young Mania Rating Scale. Although we examined structural variations within intron II and VII of the GSK3 gene and from the end of exon IV to intron IV and within exon IX of the BDNF gene, no structural variation was found in BDs. Whereas 5 of 50 patients exhibited three copies of the genomic region within exon IV of the BDNF gene, all healthy subjects had two copies. No difference in the therapeutic efficacy of lithium was found between patients with three and two copies. No difference in the occurrence of AEAS was found between the two groups. The amplification of the BDNF gene influenced neither the therapeutic responses to lithium nor the occurrence of AEAS.
Takeo Tominaga, Masahito Tomotake, Tomoya Takeda, Yoshinori Ueoka, Tsunehiko Tanaka, Shinya Watanabe, Naomi Kameoka, Masahito Nakataki, Shusuke Numata, Yumiko Izaki, Satsuki Sumitani, Hiroko Kubo, Yasuhiro Kaneda and Tetsuro Ohmori : Predictors of life skills in people with schizophrenia, The Journal of Medical Investigation : JMI, Vol.67, No.1,2, 75-82, 2020.
(要約)
Objective : The purpose of the present study is to examine clinical factors related to life skills in people with schizophrenia. Method : The participants were 51 stabilized outpatients with schizophrenia. Their mean age was 38.91 (SD = 10.73) years. Life skills were assessed using the Life skills profile (LSP). Cognitive function was evaluated with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). Clinical symptoms were assessed using the Positive and Negative Syndrome scale (PANSS), the Calgary Depression Scale for Schizophrenia (CDSS) and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Results : Cognitive function was not correlated with the LSP scores at all. Among clinical symptoms, scores of the PANSS positive and negative syndrome scales, the CDSS, and the DIEPSS had negative correlations with the LSP total score and the subscales. Stepwise regression analyses showed that the CDSS and PANSS negative syndrome scale scores were independent predictors of the LSP total score and two of the subscales. Conclusions : These results indicate that cognitive function is not associated with life skills but clinical symptoms such as depressive and negative symptoms have considerable impacts on life skills in people with schizophrenia. J. Med. Invest. 67 : 75-82, February, 2020.
K Yamazaki, Y Yoshino, K Kawabe, T Ibuki, S Ochi, Y Mori, Y Ozaki, Shusuke Numata, Junichi Iga, Tetsuro Ohmori and Shu-ichi Ueno : ABCA7 Gene Expression and Genetic Association Study in Schizophrenia., Neuropsychiatric Disease and Treatment, Vol.16, 441-446, 2020.
(要約)
Although ATP-binding cassette sub-family A member 7 gene () is known to be associated with Alzheimer's disease, the relationship between and schizophrenia has been unknown. Schizophrenia patients (n = 50; 24 males, 62.1 ± 0.50 years old) and age- and sex-matched healthy controls (n = 50) were recruited for the mRNA analysis. Additionally, a case-control study for the rs3764650 genotypes was performed with 1308 samples (control subjects; n = 527, schizophrenia patients; n = 781). All participants were Japanese, unrelated to each other, and living in the same area. The distributions of the rs3764650 genotypes in schizophrenia patients were not different from that of controls. However, the mRNA expression levels in schizophrenia patients were significantly higher than those in controls by a logistic regression analysis. Additionally, the mRNA expression levels in schizophrenia patients were correlated with the rs3764650 genotypes in a dose-dependent manner. The mRNA expression levels in peripheral blood with the rs3764650 genotypes may be related to pathological mechanisms in schizophrenia and may be a biological marker for schizophrenia.
N Kudo, H Yamamori, T Ishima, K Nemoto, Y Yasuda, M Fujimoto, H Azechi, T Niitsu, Shusuke Numata, M Ikeda, M Iyo, Tetsuro Ohmori, M Fukunaga, Y Watanabe, K Hashimoto and R Hashimoto : Plasma levels of matrix metalloproteinase-9 (MMP-9) are associated with cognitive performance in patients with schizophrenia., Neuropsychopharmacology Reports, Vol.40, No.2, 150-156, 2020.
(要約)
Matrix metalloproteinase-9 (MMP-9) has been shown to modulate synaptic plasticity and may contribute to the pathophysiology of schizophrenia. This study investigated the peripheral levels of MMP-9 and its association with cognitive functions in patients with schizophrenia to see the possible involvement of MMP-9 in pathophysiology of schizophrenia, especially in cognitive decline. We measured the plasma levels of MMP-9 in 257 healthy controls and 249 patients with schizophrenia, including antipsychotic drug-free patients. We also explored the possible association between plasma MMP-9 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition (WAIS- III), the Wechsler Memory Scale-Revised (WMS-R), and the Rey Auditory Verbal Learning Test (AVLT). We found that the plasma levels of MMP-9 were significantly higher in patients with schizophrenia, including antipsychotic drug-free patients, than in healthy controls. We found a significant negative association between plasma MMP-9 levels and cognitive performance in controls and patients with schizophrenia. Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased MMP-9 levels are associated with cognitive impairment.
Naoki Yamada, Yoshihiro Nakadoi, Ryosuke Fukuma and Tetsuro Ohmori : Two children exhibiting social withdrawal, school refusal, and underlying generalized anxiety disorder successfully treated using a selective serotonin reuptake inhibitor., The Journal of Medical Investigation : JMI, Vol.67, No.3.4, 355-357, 2020.
(要約)
Generalized anxiety disorder (GAD) sometimes exists in the background of social withdrawal and school refusal. Although clinical evidence suggests that selective serotonin reuptake inhibitors (SSRIs) are an effective treatment for GAD, they are not officially approved for GAD in Japan. In addition, it has been established that the use of SSRIs increases the risk for suicide and activation syndrome among young individuals. As such, there is currently little domestic clinical experience in prescribing SSRIs to young patients with GAD. The authors report two cases involving 10-year-old patients with GAD who were treated successfully with escitalopram and experienced subsequent improvement in social withdrawal and school refusal. One patient had autistic spectrum disorder and exhibited self-harm associated with anxiety symptoms, requiring careful use of SSRIs under hospitalization. The other patient was treated at an outpatient clinic without any side effects. In each case, improvement of anxiety symptoms with the use of SSRIs facilitated the introduction of psychoeducation and psychotherapy. It is important to accurately diagnose GAD, which may exist in the background of patients exhibiting social withdrawal and school refusal, and to treat the disorder appropriately. J. Med. Invest. 67 : 355-357, August, 2020.
Naomi Kameoka, Satsuki Sumitani and Tetsuro Ohmori : Behavioral and psychological symptoms of dementia (BPSD) and care burden : Examination in the facility staff for elderly residents., The Journal of Medical Investigation : JMI, Vol.67, No.3.4, 236-239, 2020.
(要約)
Purpose : We investigated the cognitive function, behavioral and psychological symptoms of dementia (BPSD), and activities of daily living (ADLs) of elderly individuals admitted in care facilities. Moreover, the factors affecting the care burden experienced by facility staffs were examined. Method : 24 care facilities for elderly individuals participated in the study. The Revised Hasegawa Dementia Scale (HDS-R), Japanese version of the Neuropsychiatric Inventory (NPI), and Crichton Geriatric Behavioral Rating Scale (CGBRS) were used to evaluate cognitive function, BPSD, and ADL, respectively. The short Japanese version of the Zarit Burden Interview was used to assess the care burden. A multiple regression analysis was conducted with data obtained from 464 elderly individuals who fulfilled all the scales. Results : The care burden was correlated to the scores of HDS-R, but not with those of dysphoria/depression and disinhibition of NPI, restlessness of CGBRS, and subjective mood of CGBRS (R2 = 0.309, p < 0.005). Conclusion : Dysphoria/depression, disinhibition, restlessness, and subjective mood, but not cognitive decline, have an effect on the care burden experienced by facility staffs who manage elderly individuals. These results indicated that the appropriate diagnosis and treatment of BPSD are important in reducing the burden of facility staffs. J. Med. Invest. 67 : 236-239, August, 2020.
Chikako Kane, Masahito Tomotake, Hamatani Sayo, Shin-ichi Chiba, Naomi Kameoka, Shinya Watanabe, Masahito Nakataki, Shusuke Numata and Tetsuro Ohmori : Clinical factors influencing resilience in patients with anorexia nervosa, Neuropsychiatric Disease and Treatment, Vol.15, 391-395, 2019.
(要約)
This study was to elucidate clinical factors influencing resilience in anorexia nervosa (AN) patients. Twenty female patients with AN (median age =30.0 years, quartile deviation =6.8) and 40 female healthy controls (HCs) (median age =30.0 years, quartile deviation =8.6) participated in the present study. Resilience was assessed with the Connor- Davidson resilience scale (CD-RISC). Clinical symptoms were evaluated with the structured interview guide for the Hamilton depression rating scale (SIGH-D) and the eating disorder inventory-2 (EDI-2). Scores of the CD-RISC in the AN group were lower than those in the HC group, and the SIGH-D score in the AN group was higher than that in the HC group. Scores of interoceptive confusion, interpersonal difficulty and negative self-image subscales of the EDI-2 negatively correlated with the CD-RISC score. Moreover, stepwise regression analysis showed that negative self-image score was an independent predictor of the CD-RISC score. These results suggest that among these clinical factors including psychopathologies, self-dissatisfaction and feeling of being rejected by others are the most important influencing factors on an AN patients' resilience.
Tomoya Takeda, Masahito Nakataki, Masashi Ohta, S Hamatani, K Matsuura, R Yoshida, Naomi Kameoka, Takeo Tominaga, Hidehiro Umehara, Makoto Kinoshita, Shinya Watanabe, Shusuke Numata, Satsuki Sumitani and Tetsuro Ohmori : Negative and positive self-thoughts predict subjective quality of life in people with schizophrenia., Neuropsychiatric Disease and Treatment, Vol.15, 293-301, 2019.
(要約)
Recently, cognitive variables such as negative and positive self-belief and thoughts have attracted much attention because they are associated with functional outcomes and quality of life (QOL). However, it is unclear how cognitive variables affect subjective and objective QOL. This study aimed to investigate the relationship of negative and positive self-belief and thoughts with subjective and objective QOL. Thirty-six people with schizophrenia participated in this study. Subjective and objective QOL were assessed with the Schizophrenia Quality of Life Scale (SQLS) and Quality of Life Scale (QLS), respectively. Neurocognitive function was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Clinical symptoms were assessed with the Positive and Negative Syndrome Scale and Calgary Depression Scale for Schizophrenia. Side effects were assessed with the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS). Negative and positive self-belief and thoughts were assessed with the Defeatist Performance Belief Scale and Automatic Thoughts Questionnaire-Revised. A generalized linear model was tested, with subjective and objective QOL as the response variable and symptoms, neurocognitive function, and cognitive variables that were significantly correlated with subjective and objective QOL as explanatory variables. In the schizophrenia group, the common objects score on the QLS was predicted by the composite BACS score, and the total QLS score was predicted by the DIEPSS score. Motivation and Energy, Psychosocial, and Symptoms and Side effects scores on the SQLS were predicted by depression and by negative automatic thought (NAT) and positive automatic thought (PAT). Our results indicated that key targets for improving objective and subjective QOL in people with schizophrenia are side effects, neurocognitive function, depression, and NAT and PAT.
Makoto Kinoshita, Masahito Nakataki, Ryoma Morigaki, Satsuki Sumitani, Satoshi Goto, Ryuji Kaji and Tetsuro Ohmori : Turning on the Left Side Electrode Changed Depressive State to Manic State in a Parkinson's Disease Patient Who Received Bilateral Subthalamic Nucleus Deep Brain Stimulation: A Case Report., Clinical Psychopharmacology and Neuroscience, Vol.16, No.4, 494-496, 2018.
(要約)
No previous reports have described a case in which deep brain stimulation elicited an acute mood swing from a depressive to manic state simply by switching one side of the bilateral deep brain stimulation electrode on and off. The patient was a 68-year-old woman with a 10-year history of Parkinson's disease. She underwent bilateral subthalamic deep brain stimulation surgery. After undergoing surgery, the patient exhibited hyperthymia. She was scheduled for admission. On the first day of admission, it was clear that resting tremors in the right limbs had relapsed and her hyperthymia had reverted to depression. It was discovered that the left-side electrode of the deep brain stimulation device was found to be accidentally turned off. As soon as the electrode was turned on, motor impairment improved and her mood switched from depression to mania. The authors speculate that the lateral balance of stimulation plays an important role in mood regulation. The current report provides an intriguing insight into possible mechanisms of mood swing in mood disorders.
N Yamaki, I Otsuka, Shusuke Numata, M Yanagi, K Mouri, S Okazaki, S Boku, T Horai, Tetsuro Ohmori, O Shirakawa, I Sora and A Hishimoto : Mitochondrial DNA copy number of peripheral blood in bipolar disorder: The present study and a meta-analysis., Psychiatry Research, Vol.269, 115-117, 2018.
(要約)
Numerous evidence indicated mitochondrial abnormalities in the pathophysiology of bipolar disorder (BD); however, it remains unclear whether aberrant mitochondrial DNA (mtDNA) copy number (cn) occur in BD due to the conflicting results in previous studies. Here, peripheral blood mtDNAcn in 69 BD patients and 54 controls were analysed via qPCR. BD patients had significantly lower mtDNAcn compared to controls (regardless of their BD type [BD I or II]). Meta-analysis for all previous BD-mtDNAcn studies combining our results with previously published studies failed to identify any significant association. Meanwhile, Asian-specific meta-analysis remarkably revealed lower mtDNAcn in BD patients.
Shusuke Numata, Hidehiro Umehara, Tetsuro Ohmori and R. Hashimoto : Clozapine Pharmacogenetic Studies in Schizophrenia: Efficacy and Agranulocytosis., Frontiers in Pharmacology, Vol.9, 1049, 2018.
(要約)
Clozapine is an efficacious atypical antipsychotic for treatment-refractory schizophrenia. Clinical response and appearance of adverse events vary among individual patients receiving clozapine, with genetic and non-genetic factors potentially contributing to individual variabilities. Pharmacogenetic studies investigate associations between genetic variants and drug efficacy and toxicity. To date, most pharmacogenetic studies of clozapine have been conducted through candidate gene approaches. A recent advance in technology made it possible to perform comprehensive genetic mapping underlying clinical phenotypes and outcomes, which allow novel findings beyond biological hypotheses based on current knowledge. In this paper, we will summarize the studies on clozapine pharmacogenetics that have extensively examined clinical response and agranulocytosis. While there is still limited evidence on clozapine efficacy, recent genome-wide studies provide further evidence of the involvement of the human leukocyte antigen (HLA) region in clozapine-induced agranulocytosis.
I Kushima, B Aleksic, M Nakatochi, T Shimamura, T Okada, Y Uno, M Morikawa, K Ishizuka, T Shiino, H Kimura, Y Arioka, A Yoshimi, Y Takasaki, Y Yu, Y Nakamura, M Yamamoto, T Iidaka, S Iritani, T Inada, N Ogawa, E Shishido, Y Torii, N Kawano, Y Omura, T Yoshikawa, T Uchiyama, T Yamamoto, M Ikeda, R Hashimoto, H Yamamori, Y Yasuda, T Someya, Y Watanabe, J Egawa, A Nunokawa, M Itokawa, M Arai, M Miyashita, A Kobori, M Suzuki, T Takahashi, M Usami, M Kodaira, K Watanabe, T Sasaki, H Kuwabara, M Tochigi, F Nishimura, H Yamasue, Y Eriguchi, S Benner, M Kojima, W Yassin, T Munesue, S Yokoyama, R Kimura, Y Funabiki, H Kosaka, M Ishitobi, Tetsuro Ohmori, Shusuke Numata, T Yoshikawa, T Toyota, K Yamakawa, T Suzuki, Y Inoue, K Nakaoka, YI Goto, M Inagaki, N Hashimoto, I Kusumi, S Son, T Murai, T Ikegame, N Okada, K Kasai, S Kunimoto, D Mori, N Iwata and N Ozaki : Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights., Cell Reports, Vol.24, No.11, 2838-2856, 2018.
(要約)
Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders.
(キーワード)
Adolescent / Adult / Autism Spectrum Disorder / Child / DNA Copy Number Variations / Female / Genetic Predisposition to Disease / Genome-Wide Association Study / Genotype / Humans / Male / Middle Aged / Oxidative Stress / Schizophrenia / Young Adult
Takeo Tominaga, Masahito Tomotake, Tomoya Takeda, Yoshinori Ueoka, Tsunehiko Tanaka, Shinya Watanabe, Naomi Kameoka, Masahito Nakataki, Shusuke Numata, Yumiko Izaki, Satsuki Sumitani, hiroko Kubo, Yasuhiro Kaneda and Tetsuro Ohmori : Relationship between social and cognitive functions in people with schizophrenia, Neuropsychiatric Disease and Treatment, Vol.14, 2215-2224, 2018.
(要約)
The purpose of the present study was to examine clinical factors related to social function in people with schizophrenia. The participants were 55 stabilized outpatients with schizophrenia. Their mean age was 39.36 (SD =10.65) years. Social function was assessed using the Quality of Life Scale (QLS). Cognitive function was evaluated with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia, and the Drug-Induced Extrapyramidal Symptoms Scale. Neither the MCCB cognitive domain score nor composite score was correlated with the QLS scores. However, of the 10 MCCB subtests, the Trail Making Test Part A and the Brief Assessment of Cognition in Schizophrenia-Symbol Coding (BACS-SC) scores were positively correlated with the QLS scores. Among clinical variables, especially the PANSS negative syndrome scale score had a strong negative correlation with the QLS scores. Stepwise regression analyses showed that the PANSS negative syndrome scale score was an independent predictor of the QLS scores, and although the BACS-SC score predicted the QLS common objects and activities subscale score, the association was not so strong compared to the PANSS negative syndrome scale score. These results indicate that speed of processing evaluated by BACS-SC could predict some aspect of social function but negative symptoms have a much stronger impact on global social function in people with schizophrenia.
Y Zhang, A Hishimoto, I Otsuka, Y Watanabe, Shusuke Numata, H Yamamori, S Boku, T Horai, T Someya, Tetsuro Ohmori, R Hashimoto and I Sora : Longer telomeres in elderly schizophrenia are associated with long-term hospitalization in the Japanese population., Journal of Psychiatric Research, Vol.103, 161-166, 2018.
(要約)
Several previous studies have investigated an association between leukocyte telomere length (LTL) and schizophrenia (SCZ). However, results have been largely inconsistent, partially due to the relatively small sample sizes in each study and heterogeneity caused by various uncontrolled confounders (e.g., duration of illness or hospitalization, lifetime antipsychotic dose, and LTL assay methods). Here, we investigate the association of LTL with SCZ with the quantitative polymerase chain reaction method in independent cohorts consisting of 1241 patients with SCZ and 1042 controls (the largest independent sample in this field). Furthermore, we examined whether duration of hospitalization and lifetime antipsychotic dose had an effect on LTL in SCZ. In all samples, we observed significantly longer LTL in patients with SCZ relative to controls. In subgroup analyses, we observed that longer telomeres in SCZ were only visible in elderly patients and not in patients under 50 years old. Moreover, significantly longer LTL in elderly patients with SCZ was only specific to those with long-term hospitalization, but not outpatients or those with short-term hospitalization. This may be because the former received more appropriate lifestyle management. Meanwhile, lifetime antipsychotic dose had no effect on LTL. Our findings suggest that consideration of the effect of age and duration of hospitalization on LTL may improve our understanding of controversial results obtained in previous studies of telomeres in SCZ.
Noriko Kudo, Hidenaga Yamamori, Tamaki Ishima, Kiyotaka Nemoto, Yuka Yasuda, Michiko Fujimoto, Hirotsugu Azechi, Tomihisa Niitsu, Shusuke Numata, Manabu Ikeda, Masaomi Iyo, Tetsuro Ohmori, Masaki Fukunaga, Yoshiyuki Watanabe, Kenji Hashimoto and Ryota Hashimoto : Plasma Levels of Soluble Tumor Necrosis Factor Receptor 2 (sTNFR2) are Associated with Hippocampal Volume and Cognitive Performance in Patients with Schizophrenia., The International Journal of Neuropsychopharmacology, Vol.21, No.7, 631-639, 2018.
(要約)
An imbalance in the inflammatory tumor necrosis factor system, including soluble tumor necrosis factor receptor 2 (sTNFR2), may contribute to the pathophysiology of schizophrenia. We measured the plasma levels of sTNFR2 in 256 healthy controls and 250 patients with schizophrenia including antipsychotic drug-free patients and treatment-resistant patients. We also explored the possible association between plasma sTNFR2 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition, the Wechsler Memory Scale-Revised, and the Rey Auditory Verbal Learning Test. An association between plasma sTNFR2 levels and hippocampal volume in controls and patients with schizophrenia was also investigated via MRI. We found that the plasma levels of sTNFR2 were significantly higher in patients with schizophrenia, including both antipsychotic drug-free patients and treatment-resistant patients. We found a significant negative association between plasma sTNFR2 levels and cognitive performance in controls and patients with schizophrenia. Hippocampal volume was also negatively associated with plasma sTNFR2 levels in patients with schizophrenia. Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased sTNFR2 levels are associated with a smaller hippocampal volume and cognitive impairment.
Masashi Ohta, Masahito Nakataki, Tomoya Takeda, Shusuke Numata, Takeo Tominaga, Naomi Kameoka, Hiroko Kubo, Makoto Kinoshita, K Matsuura, M Otomo, N Takeichi, Masafumi Harada and Tetsuro Ohmori : Structural equation modeling approach between salience network dysfunction, depressed mood, and subjective quality of life in schizophrenia: an ICA resting-state fMRI study., Neuropsychiatric Disease and Treatment, Vol.14, 1585-1597, 2018.
(要約)
Quality of life (QOL) is an important clinical outcome for patients with schizophrenia, and recent studies have focused on subjective QOL. We evaluated the causal relationship between psychosocial aspect of subjective QOL, symptoms, cognitive functions, and salience network (SN) dysfunction in schizophrenia using structural equation modeling (SEM). We performed a cross-sectional study of 21 patients with symptomatically stabilized schizophrenia and 21 age-, sex-, and education level-matched healthy controls who underwent resting-state functional magnetic resonance imaging. We evaluated SN dysfunction in schizophrenia using independent component analysis (ICA). We rated participant psychopathology using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), and the Calgary Depression Scale for Schizophrenia (CDSS). We rated psychosocial aspect of subjective QOL using the Schizophrenia Quality of Life Scale (SQLS) psychosocial subscale. We applied SEM to examine the relationships between SN dysfunction, PANSS positive and negative scores, CDSS total scores, BACS composite scores, and SQLS psychosocial subscale scores. In second-level analysis after group ICA, patient group had significant lower right pallidum functional connectivity (FC) within the SN than the controls did (Montreal Neurological Institute [MNI] [] = [22 -2 -6]) ( = 0.027, family-wise error [FWE] corrected). In SEM, we obtained a good fit for an SEM model in which SN dysfunction causes depressed mood, which in turn determines psychosocial aspect of subjective QOL (chi-squared = 0.9, root mean square error of approximation (RMSEA) < 0.001, comparative fit index [CFI] = 1.00, and standardized root mean square residual [SRMR]= 0.020). We found a continuous process by which SN dysfunction causes depressed moods that determine psychosocial aspect of subjective QOL in schizophrenia. This is the first report that offers a unified explanation of functional neuroimaging, symptoms, and outcomes. Future studies combining neuroimaging techniques and clinical assessments would elucidate schizophrenia's pathogenesis.
Tomoya Takeda, Masahito Nakataki, Masashi Ohta, Sayo Hamatani, Kanae Matsuura and Tetsuro Ohmori : Effect of cognitive function on jumping to conclusion in patients with schizophrenia., Schizophrenia Research. Cognition, Vol.12, 50-55, 2018.
(要約)
The "jumping to conclusion" (JTC) bias is related to the formation and maintenance of delusions. Higher JTC bias can be based on both neurocognitive dysfunction and social cognitive dysfunction in patients with schizophrenia. The aim of this study was to assess the relationship between JTC bias, neurocognition, and social cognition in patients with schizophrenia. A total of 22 patients with schizophrenia and 21 controls participated in this study. Neurocognition and social cognition were assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) and Social Cognition Screening Questionnaire (SCSQ), respectively. The JTC bias and the decision confidence were assessed using the beads task. The patients were classified into the JTC group (with higher JTC bias; n = 10) and JTC-non group (n = 12). The JTC group scored significantly lower on verbal memory, working memory, and motor speed sub-scores of BACS than the JTC-non group. No difference in social cognition was observed between the two groups. The decision confidence was predicted by metacognition, which is an SCSQ sub-score. Similarly to the patients, the controls were classified into the JTC group (higher JTC bias; n = 9) and the JTC-non group (n = 12). There were no significant differences in neurocognition and social cognition between the control JTC and JTC-non groups. The present results indicated that JTC bias is related to neurocognition and decision confidence is related to social cognition in patients with schizophrenia. These findings may bridge the gaps between psychotic symptom and cognitive dysfunction in schizophrenia.
Yukiko Tomioka, Shusuke Numata, Makoto Kinoshita, Hidehiro Umehara, Shinya Watanabe, Masahito Nakataki, Y Iwayama, T Toyota, M Ikeda, H Yamamori, S Shimodera, A Tajima, R Hashimoto, N Iwata, T Yoshikawa and Tetsuro Ohmori : Decreased serum pyridoxal levels in schizophrenia: meta-analysis and Mendelian randomization analysis., Journal of Psychiatry & Neuroscience, Vol.43, No.3, 194-200, 2018.
(要約)
Alterations in one-carbon metabolism have been associated with schizophrenia, and vitamin B6 is one of the key components in this pathway. We first conducted a case-control study of serum pyridoxal levels and schizophrenia in a large Japanese cohort ( = 1276). Subsequently, we conducted a meta-analysis of association studies ( = 2125). Second, we investigated whether rs4654748, which was identified in a genome-wide association study as a vitamin B6-related single nucleotide polymorphism, was genetically implicated in patients with schizophrenia in the Japanese population ( = 10 689). Finally, we assessed the effect of serum pyridoxal levels on schizophrenia risk using a Mendelian randomization (MR) approach. Serum pyridoxal levels were significantly lower in patients with schizophrenia than in controls, not only in our cohort, but also in the pooled data set of the meta-analysis of association studies (standardized mean difference -0.48, 95% confidence interval [CI] -0.57 to -0.39, = 9.8 × 10-24). We failed to find a significant association between rs4654748 and schizophrenia. Furthermore, an MR analysis failed to find a causal relationship between pyridoxal levels and schizophrenia risk (odds ratio 0.99, 95% CI 0.65-1.51, = 0.96). Food consumption and medications may have affected serum pyridoxal levels in our cross-sectional study. Sample size, number of instrumental variables and substantial heterogeneity among patients with schizophrenia are limitations of an MR analysis. We found decreased serum pyridoxal levels in patients with schizophrenia in this observational study. However, we failed to obtain data supporting a causal relationship between pyridoxal levels and schizophrenia risk using the MR approach.
S Okazaki, A Hishimoto, I Otsuka, Y Watanabe, Shusuke Numata, S Boku, N Shimmyo, Makoto Kinoshita, E Inoue, Tetsuro Ohmori, T Someya and I Sora : Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia., Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol.83, 33-41, 2018.
(要約)
Numerous studies have suggested that an immune system imbalance plays an important role in schizophrenia. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine. It plays multiple roles in various biological processes, including inflammation and neurogenesis. Furthermore, several exhaustive serum proteomic profiling studies have identified MIF as a potential biomarker of schizophrenia. Here, we investigate MIF protein levels in serum and postmortem prefrontal cortex in patients with schizophrenia and controls. Moreover, we investigate the association of two functional polymorphisms in the MIF gene promoter region (MIF-794CATT microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) with schizophrenia. We measured serum MIF levels with an enzyme-linked immunosorbent assay (ELISA) (51 patients vs. 86 controls) and postmortem brain MIF levels with a western blotting assay (18 patients vs. 22 controls). Subsequently, we genotyped the MIF-794CATT microsatellite with a fluorescence-based fragment assay and the MIF-173G/C SNP with a TaqMan SNP genotyping assay (1483 patients vs. 1454 controls). Serum MIF levels were significantly higher in patients with schizophrenia than in controls (p=0.00118), and were positively correlated with antipsychotic dose (Spearman's r=0.222, p=0.0402). In addition, an earlier age of onset was observed in patients with a high serum MIF level (≥40ng/mL) than those with a low serum MIF level (<40ng/mL) (p=0.0392). However, postmortem brain MIF levels did not differ between patients with schizophrenia and controls. The association study revealed that the CATT-G haplotype was nominally significantly associated with schizophrenia (p=0.0338), and that the CATT allele and CATT-G haplotype were significantly associated with female adolescent-onset schizophrenia (AsOS) (corrected p=0.0222 and p=0.0147, respectively). These results suggest that serum MIF level is a potential pharmacodynamic and/or monitoring marker of schizophrenia, and is related to a novel antipsychotic effect beyond dopamine antagonism. Furthermore, the MIF gene polymorphisms are associated with the risk for schizophrenia especially in adolescent females, and are potential stratification markers of schizophrenia. Further studies of MIF are warranted to elucidate the pathophysiology of schizophrenia and the effects of antipsychotics.
Masatoshi Inoshita, Hidehiro Umehara, Shinya Watanabe, Masahito Nakataki, Makoto Kinoshita, Yukiko Tomioka, Atsushi Tajima, Shusuke Numata and Tetsuro Ohmori : Elevated peripheral blood glutamate levels in major depressive disorder., Neuropsychiatric Disease and Treatment, Vol.14, 945-953, 2018.
(要約)
There is growing evidence that glutamatergic signaling may be involved in major depressive disorder (MDD). In regard to peripheral blood glutamate changes in MDD, inconsistent findings have been reported. The purpose of the present study was to evaluate whether blood glutamate levels differed between MDD patients and control participants. We conducted a systematic review and meta-analysis of 12 association studies between blood glutamate levels and MDD in a total of 529 MDD patients and 590 controls. Subsequently, we conducted subgroup analyses and a meta-regression analysis to examine the sources of potential heterogeneity. A random effects model showed that blood glutamate levels were significantly higher in MDD patients than in controls (standardized mean difference=0.54, 95% CI=0.27-0.82, =8.5×10) with high heterogeneity (=75.0%, <0.05). Subgroup analyses showed elevated glutamate levels in MDD patients compared with controls in plasma, but not serum studies, and in studies using high-performance liquid chromatography but not with mass spectrometry for glutamate assay. A meta-regression analysis showed no effects of age, gender, medication use, sample size, and published year on blood glutamate levels. Our findings suggest that altered glutamate levels may be implicated in MDD, which provides further evidence of glutamatergic dysfunction in MDD.
M Ikeda, A Takahashi, Y Kamatani, Y Okahisa, H Kunugi, N Mori, T Sasaki, Tetsuro Ohmori, Y Okamoto, H Kawasaki, S Shimodera, T Kato, H Yoneda, R Yoshimura, M Iyo, K Matsuda, M Akiyama, K Ashikawa, K Kashiwase, K Tokunaga, K Kondo, T Saito, A Shimasaki, K Kawase, T Kitajima, K Matsuo, M Itokawa, T Someya, T Inada, R Hashimoto, T Inoue, K Akiyama, H Tanii, H Arai, S Kanba, N Ozaki, I Kusumi, T Yoshikawa, M Kubo and N Iwata : A Genome-Wide Association Study Identifies Two Novel Susceptibility Loci and Trans Population Polygenicity Associated With Bipolar Disorder., Molecular Psychiatry, Vol.23, No.3, 639-647, 2018.
(要約)
Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (P=5.8 × 10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (P=1.9 × 10), TRANK1 (P=2.1 × 10) and ODZ4 (P=3.3 × 10). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', P~10, R~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' P~10, R~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.
(キーワード)
Adult / Bipolar Disorder / Cell Cycle Proteins / Cytokines / Fatty Acid Desaturases / Female / Genetic Predisposition to Disease / Genome-Wide Association Study / Humans / Japan / Male / Membrane Glycoproteins / Middle Aged / Multifactorial Inheritance / NFI Transcription Factors / Nuclear Proteins / Polymorphism, Single Nucleotide
Chikako Kane, Masahito Tomotake, Sayo Hamatani, Shin-ichi Chiba and Tetsuro Ohmori : Clinical factors influencing quality of life in anorexia nervosa patients, Open Journal of Psychiatry, Vol.8, 50-60, 2018.
Objective : The aim of the present study is to explore clinical factors associated with basic ability of social life in schizophrenia inpatients. Methods : The subjects were 50 inpatients with schizophrenia (DSM‐IV). Their mean age was 53.08 (SD＝12.08) years. Social life functioning was evaluated using the Functional Independence Measure (FIM). Cognitive function was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS) and clinical symptoms with the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia (CDSS) and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Results : FIM motor subscale score showed a significant correlation with the DIEPSS score (r＝0.33, p<0.05). The FIM cognitive subscale score showed significant correlations with the PANSS positive syndrome score (r＝-0.30, p<0.05), the PANSS negative syndrome score (r＝-0.37, p<0.01) and the DIEPSS score (r＝-0.40, p<0.01). Conclusion : These results suggest that positive and negative symptoms and drug-induced extrapyramidal symptoms are much more important factors related to lowered basic ability of social life of schizophrenia inpatients than cognitive function.
Sayo Hamatani, Masahito Tomotake, Tomoya Takeda, Naomi Kameoka, Masashi Kawabata, Hiroko Kubo, Masashi Ohta, Yukio Tada, Yukiko Tomioka, Shinya Watanabe, Masatoshi Inoshita, Makoto Kinoshita and Tetsuro Ohmori : Impaired central coherence in patients with anorexia nervosa, Psychiatry Research, Vol.259, 77-80, 2017.
(要約)
The purpose of this study was to investigate the characteristics of central coherence in patients with anorexia nervosa (AN). 22 female patients with AN (median age = 31.50 (QD = 8.13) years) and 33 female healthy controls (HC) (median age = 28.00 (QD = 8.50) years) participated in the study. Their central coherence was assessed with the Rey Complex Figure Task (RCFT). Clinical symptoms were evaluated with the Beck Depression Inventory-II and the State-Trait Anxiety Inventory-Form JYZ. The results showed that AN patients' Central Coherence Index and accuracy scores in copy, 3-min delayed recall and 30-min delayed recall tasks of the RCFT were significantly lower than those of HC. Moreover, the significant differences in Central Coherence Index score in copy task and accuracy scores in 3-min delayed recall and 30-min delayed recall tasks remained when the effects of depression, anxiety and starvation were eliminated statistically. These findings may explain some characteristics of AN patients such as focusing on local rather than global picture in their perception of body or life.
Kazuo Takiguchi, Akihito Uezato, Michio Itasaka, Hidenori Atsuta, Kenji Narushima, Naoki Yamamoto, Akeo Kurumaji, Makoto Tomita, Kazunari Oshima, Kosaku Shoda, Mai Tamaru, Masahito Nakataki, Mitsutoshi Okazaki, Sayuri Ishiwata, Yasuyoshi Ishiwata, Masato Yasuhara, Kunimasa Arima, Tetsuro Ohmori and Toru Nishikawa : Association of schizophrenia onset age and white matter integrity with treatment effect of D-cycloserine: a randomized placebo-controlled double-blind crossover study., BMC Psychiatry, Vol.17, No.1, 249, 2017.
(要約)
It has been reported that drugs which promote the N-Methyl-D-aspartate-type glutamate receptor function by stimulating the glycine modulatory site in the receptor improve negative symptoms and cognitive dysfunction in schizophrenia patients being treated with antipsychotic drugs. We performed a placebo-controlled double-blind crossover study involving 41 schizophrenia patients in which D-cycloserine 50 mg/day was added-on, and the influence of the onset age and association with white matter integrity on MR diffusion tensor imaging were investigated for the first time. The patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Brief Assessment of Cognition in Schizophrenia (BACS), and other scales. D-cycloserine did not improve positive or negative symptoms or cognitive dysfunction in schizophrenia. The investigation in consideration of the onset age suggests that D-cycloserine may aggravate negative symptoms of early-onset schizophrenia. The better treatment effect of D-cycloserine on BACS was observed when the white matter integrity of the sagittal stratum/ cingulum/fornix stria terminalis/genu of corpus callosum/external capsule was higher, and the better treatment effect on PANSS general psychopathology (PANSS-G) was observed when the white matter integrity of the splenium of corpus callosum was higher. In contrast, the better treatment effect of D-cycloserine on PANSS-G and SANS-IV were observed when the white matter integrity of the posterior thalamic radiation (left) was lower. It was suggested that response to D-cycloserine is influenced by the onset age and white matter integrity. UMIN Clinical Trials Registry (number UMIN000000468 ). Registered 18 August 2006.
(キーワード)
Adult / Age of Onset / Antipsychotic Agents / Cross-Over Studies / Cycloserine / Diffusion Tensor Imaging / Double-Blind Method / Drug Therapy, Combination / Female / Glycine Agents / Humans / Male / Middle Aged / 統合失調症 (schizophrenia) / Schizophrenic Psychology / White Matter
Hidehiro Umehara, Shusuke Numata, Shinya Watanabe, Yutaka Hatakeyama, Makoto Kinoshita, Yukiko Tomioka, Kiyoshi Nakahara, Takeshi Nikawa and Tetsuro Ohmori : Altered KYN/TRP, Gln/Glu, and Met/methionine sulfoxide ratios in the blood plasma of medication-free patients with major depressive disorder., Scientific Reports, Vol.7, No.1, 4855, 2017.
(要約)
Capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS) is a comprehensive, quantitative, and high throughput tool used to analyze metabolite profiles. In the present study, we used CE-TOFMS to profile metabolites found in the blood plasma of 33 medication-free patients with major depressive disorder (MDD) and 33 non-psychiatric control subjects. We then investigated changes which occurred in the metabolite levels during an 8-week treatment period. The medication-free MDD patients and control subjects showed significant differences in their mean levels of 33 metabolites, including kynurenine (KYN), glutamate (Glu), glutamine (Gln), methionine sulfoxide, and methionine (Met). In particular, the ratios of KYN to tryptophan (TRP), Gln to Glu, and Met to methionine sulfoxide were all significantly different between the two groups. Among the 33 metabolites with altered levels in MDD patients, the levels of KYN and Gln, as well as the ratio of Gln to Glu, were significantly normalized after treatment. Our findings suggest that imbalances in specific metabolite levels may be involved in the pathogenesis of MDD, and provide insight into the mechanisms by which antidepressant agents work in MDD patients.
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, H Yamamori, Yuka Yasuda, Michiko Fujimoto, Shinya Watanabe, Hidehiro Umehara, Shinji Shimodera, Takanobu Nakazawa, Masataka Kikuchi, Akihiro Nakaya, Hitoshi Hashimoto, Issei Imoto, Ryota Hashimoto and Tetsuro Ohmori : Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia., International Journal of Molecular Sciences, Vol.18, No.3, E632, 2017.
(要約)
Clozapine is an atypical antipsychotic, that is established as the treatment of choice for treatment-resistant schizophrenia (SCZ). To date, no study investigating comprehensive DNA methylation changes in SCZ patients treated with chronic clozapine has been reported. The purpose of the present study is to reveal the effects of clozapine on DNA methylation in treatment-resistant SCZ. We conducted a genome-wide DNA methylation profiling in peripheral leukocytes (485,764 CpG dinucleotides) from treatment-resistant SCZ patients treated with clozapine (n = 21) in a longitudinal study. Significant changes in DNA methylation were observed at 29,134 sites after one year of treatment with clozapine, and these genes were enriched for "cell substrate adhesion" and "cell matrix adhesion" gene ontology (GO) terms. Furthermore, DNA methylation changes in the CREBBP (CREB binding protein) gene were significantly correlated with the clinical improvements. Our findings provide insights into the action of clozapine in treatment-resistant SCZ.
(キーワード)
Adult / Antipsychotic Agents / CREB-Binding Protein / Clozapine / CpG Islands / DNA Methylation / Drug Resistance / Female / Humans / Leukocytes / Male / Middle Aged / 統合失調症 (schizophrenia)
Tomoya Takeda, Satsuki Sumitani, Sayo Hamatani, Y Yokose, M Shikata and Tetsuro Ohmori : Prefrontal cortex activation during neuropsychological tasks might predict response to pharmacotherapy in patients with obsessive-compulsive disorder., Neuropsychiatric Disease and Treatment, Vol.23, No.13, 577-583, 2017.
(要約)
We investigated oxyhemoglobin change in the prefrontal cortex (PFC) of patients with obsessive-compulsive disorder (OCD) who showed different responses to pharmacotherapy during neuropsychological tasks with near-infrared spectroscopy. A total of 42 patients with OCD (mean age: 35.6±9.6 years, 14 men, 28 women) and healthy control subjects (mean age: 35.4±9.7 years, 13 men, 29 women) were selected. Patients with OCD were divided into three groups (responders to selective serotonin-reuptake inhibitors (SSRIs), responders to SSRIs with antipsychotics, and nonresponders to SSRIs and SSRIs with antipsychotics) based on pharmacological response. We investigated oxyhemoglobin change in the PFC of subjects during Stroop tasks and a verbal fluency test with near-infrared spectroscopy. Responders to SSRIs showed smaller activation compared to control subjects during the Stroop incongruent task and verbal fluency test, but not during the Stroop congruent task. In contrast, responders to SSRIs with antipsychotics showed smaller activation compared to control subjects during all three tasks. Our results suggest that activation of the PFC during Stroop tasks might predict responses to pharmacotherapy of patients with OCD.
Shinya Watanabe, Shusuke Numata, Junichi Iga, Makoto Kinoshita, Hidehiro Umehara, K Ishii and Tetsuro Ohmori : Gene expression-based biological test for major depressive disorder: an advanced study., Neuropsychiatric Disease and Treatment, Vol.13, 535-541, 2017.
(要約)
Recently, we could distinguished patients with major depressive disorder (MDD) from nonpsychiatric controls with high accuracy using a panel of five gene expression markers (ARHGAP24, HDAC5, PDGFC, PRNP, and SLC6A4) in leukocyte. In the present study, we examined whether this biological test is able to discriminate patients with MDD from those without MDD, including those with schizophrenia and bipolar disorder. We measured messenger ribonucleic acid expression levels of the aforementioned five genes in peripheral leukocytes in 17 patients with schizophrenia and 36 patients with bipolar disorder using quantitative real-time polymerase chain reaction (PCR), and we combined these expression data with our previous expression data of 25 patients with MDD and 25 controls. Subsequently, a linear discriminant function was developed for use in discriminating between patients with MDD and without MDD. This expression panel was able to segregate patients with MDD from those without MDD with a sensitivity and specificity of 64% and 67.9%, respectively. Further research to identify MDD-specific markers is needed to improve the performance of this biological test.
Sayo Hamatani, Masahito Tomotake, Tomoya Takeda, Naomi Kameoka, Masashi Kawabata, Hiroko Kubo, Y Tada, Yukiko Tomioka, Shinya Watanabe, Masatoshi Inoshita, Makoto Kinoshita, Masashi Ohta and Tetsuro Ohmori : Influence of cognitive function on quality of life in anorexia nervosa patients, Psychiatry and Clinical Neurosciences, Vol.71, No.5, 328-335, 2017.
(要約)
The purpose of this study was to elucidate determinants of quality of life (QOL) in anorexia nervosa (AN) patients. Twenty-one female patients with AN participated in the study. QOL was assessed with the 36-Item Short Form Health Survey (SF-36), and cognitive function was evaluated using the Wisconsin Card Sorting Test Keio version, the Rey Complex Figure Test, and the Social Cognition Screening Questionnaire. Clinical symptoms were evaluated with the Beck Depression Inventory-II, the State-Trait Anxiety Inventory-Form JYZ (STAI-JYZ), and the Maudsley Obsessive Compulsive Inventory. The Difficulty Maintaining Set score of the Wisconsin Card Sorting Test Keio version was negatively correlated to the SF-36 Physical Component Summary. Scores of the Beck Depression Inventory-II and the STAI-JYZ State and Trait were negatively correlated to the SF-36 Mental Component Summary (MCS), and the Central Coherence Index 30-min Delayed Recall score of the Rey Complex Figure Test was positively correlated with the MCS. Stepwise regression analysis showed that the Difficulty Maintaining Set score was an independent predictor of the Physical Component Summary and scores for Central Coherence Index 30-min Delayed Recall and the STAI-JYZ Trait-predicted MCS. These results suggest that not only trait anxiety but also poor central coherence and impaired ability to maintain new rule worsen AN patients' QOL.
Hiroko Kubo, Masahito Nakataki, Satsuki Sumitani, Junichi Iga, Shusuke Numata, Naomi Kameoka, Shinya Watanabe, Hidehiro Umehara, Makoto Kinoshita, Masatoshi Inoshita, Mai Tamaru, Masashi Ohta, Chiaki Nakayama-Yamauchi, Yasuhiro Funakoshi, Masafumi Harada and Tetsuro Ohmori : 1H-magnetic resonance spectroscopy study of glutamate-related abnormality in bipolar disorder., Journal of Affective Disorders, Vol.208, 139-144, 2017.
(要約)
Previous studies of patients with bipolar disorder (BD) using magnetic resonance spectroscopy (MRS) have shown neurophysiological abnormalities related to the glutamate (Glu)-glutamine (Gln) cycle, membrane turnover, and neuronal integrity, although the results were neither consistent nor conclusive. Recently it has been reported the Gln/Glu ratio is the most useful index, quantifying neuronal-glial interactions and the balance of glutamatergic metabolites In this MRS study, we elucidated the abnormalities of metabolites in a larger sample of patients with BD with a high-field MRI system. Sixty-two subjects (31 patients with BD and 31 healthy controls [HC]) underwent 3T proton MRS (1H-MRS) of the anterior cingulate cortex (ACC) and left basal ganglia (ltBG) using a stimulated echo acquisition mode (STEAM) sequence. After verifying the data quality, 20 patients with BD and 23 age- and gender-matched HCs were compared using repeated-measures analysis of covariance (ANCOVA). Compared to the HC group, the BD group showed increased levels of Gln, creatine (Cr), N-acetyl aspartate (NAA), choline (Cho), and an increased ratio of Gln to Glu in the ACC, and increased Gln and Cho in the ltBG. These findings remained after the participants with BD were limited to only euthymic patients. After removing the influence of lithium (Li) and sodium valproate (VPA), we observed activated glutamatergic neurotransmission in the ACC but not in the ltBG. The present findings are cross-sectional and metabolites were measured in only two regions. Our results support a wide range of metabolite changes in patients with BD involved in glutamatergic neurotransmission, membrane turnover, and neuronal integrity. Moreover, the elevation of Gln/Glu ratio suggested that hyperactivity of glutamatergic neurotransmission in the ACC is a disease marker for BD.
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, Akira Nishi, Sho Muraki, Atsushi Tsuchiya, Hidehiro Umehara, Shinya Watanabe, Issei Imoto and Tetsuro Ohmori : Cumulative effect of the plasma total homocysteine-related genetic variants on schizophrenia risk., Psychiatry Research, Vol.246, 833-837, 2016.
(要約)
Previous studies suggest that elevated total homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which correlates with plasma total homocysteine levels, are risk factors for schizophrenia (SCZ). Recently, a large genome-wide association study (GWAS) of plasma total homocysteine levels in individuals of European ancestry identified many single-nucleotide polymorphisms (SNPs) (n=13,974). The primary purpose of this study was to examine the association between these plasma total homocysteine-related SNPs and SCZ in the Japanese population. First, we investigated associations between six SNPs and plasma total homocysteine levels in non-psychiatric subjects in the Japanese population (n=1030). Then, we evaluated the cumulative effects of three SNPs on SCZ risk by calculating the Genotype Risk Score (GRS) (1120 cases, 2643 controls). Of the six SNPs examined, we replicated similar associations with the European GWAS at four loci (CENPQ, CPS1, MTHFR, and MUT). GRS based on three SNPs (CENPQ, CPS1, and MTHFR) was significantly associated with SCZ. Our findings suggest that common polygenic variations, which are associated with the plasma total homocysteine levels, may contribute to the risk of SCZ.
Sayo Hamatani, Masahito Tomotake, Tomoya Takeda, Naomi Kameoka, Masashi Kawabata, Hiroko Kubo, Yukio Tada, Yukiko Tomioka, Shinya Watanabe and Tetsuro Ohmori : Impaired social cognition in anorexia nervosa patients, Neuropsychiatric Disease and Treatment, Vol.12, 2527-2531, 2016.
(要約)
The purpose of this study was to investigate the characteristics of social cognition in patients with anorexia nervosa (AN). Eighteen female patients with AN (mean age =35.4±8.6 years) and 18 female healthy controls (HC) (mean age =32.8±9.4 years) participated in the study. Their social cognition was assessed with the Social Cognition Screening Questionnaire (SCSQ). The results showed that total score of the SCSQ and scores of theory of mind and metacognition were significantly lower in AN group than those in HC group. Moreover, significant differences in theory of mind, metacognition, and total score of the SCSQ remained when the effects of depression, anxiety, and starvation were eliminated statistically. These results suggest that patients with AN may have difficulty inferring other people's intention and also monitoring and evaluating their own cognitive activities. Therefore, these features may explain some aspects of the pathology of AN.
Y Yoshino, K Kawabe, T Mori, Y Mori, K Yamazaki, Shusuke Numata, S Nakata, T Yoshida, JI Iga, Tetsuro Ohmori and SI Ueno : Low methylation rates of dopamine receptor D2 gene promoter sites in Japanese schizophrenia subjects., The World Journal of Biological Psychiatry, Vol.17, No.6, 449-456, 2016.
(要約)
According to the dopamine hypothesis, several studies on the gene for the dopamine receptor D2 (DRD2) have been conducted. However, no trait biomarkers on DRD2 are available. We examined whether the methylation rates in the upstream region of DRD2 in leukocytes are different in schizophrenia (SCZ) subjects compared to control subjects. We selected seven CpG sites in the upstream region of DRD2 that may theoretically bind major transcription factors. The methylation rates in these regions of 50 medicated and 18 drug-naïve SCZ subjects were compared with those of age-matched control subjects. The methylation rates were significantly lower in medicated (CpG2, P < 0.0001; CpG4, P = 0.013; CpG7, P < 0.0001; and average: 12.9 ± 1.8 vs. 14.1 ± 2.2, P = 0.005) and drug-naïve SCZ subjects (CpG1, P = 0.006; CpG2, P = 0.001; CpG3, P = 0.001; CpG5, P = 0.02; CpG6, P = 0.015; CpG7, P = 0.027; and average: 9.86 ± 0.9 vs. 11.2 ± 1.3, P = 0.002). We confirmed low methylation rates in the upstream region of DRD2 in both medicated and drug-naïve SCZ subjects. Low methylation rates of DRD2 in leukocytes may be a trait biomarker for SCZ.
Hidehiro Umehara, Shusuke Numata, Atsushi Tajima, Akira Nishi, Masahito Nakataki, Issei Imoto, Satsuki Sumitani and Tetsuro Ohmori : Calcium Signaling Pathway Is Associated with the Long-Term Clinical Response to Selective Serotonin Reuptake Inhibitors (SSRI) and SSRI with Antipsychotics in Patients with Obsessive-Compulsive Disorder., PLoS ONE, Vol.11, No.6, e0157232., 2016.
(要約)
Selective serotonin reuptake inhibitors (SSRI) are established first-line pharmacological treatments for obsessive-compulsive disorder (OCD), while antipsychotics are used as an augmentation strategy for SSRI in OCD patients who have either no response or a partial response to SSRI treatment. The goal of the present study was to identify genetic variants and pathways that are associated with the long-term clinical response of OCD patients to SSRI or SSRI with antipsychotics. We first performed a genome-wide association study of 96 OCD patients to examine genetic variants contributing to the response to SSRI or SSRI with antipsychotics. Subsequently, we conducted pathway-based analyses by using Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) to examine the combined effects of genetic variants on the clinical response in OCD. While we failed to detect specific genetic variants associated with clinical responses to SSRI or to SSRI with an atypical antipsychotic at genome-wide levels of significance, we identified 8 enriched pathways for the SSRI treatment response and 5 enriched pathways for the treatment response to SSRI with an antipsychotic medication. Notably, the calcium signaling pathway was identified in both treatment responses. Our results provide novel insight into the molecular mechanisms underlying the variability in clinical response to SSRI and SSRI with antipsychotics in OCD patients.
Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10(-9), 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.Molecular Psychiatry advance online publication, 31 May 2016; doi:10.1038/mp.2016.88.
Yuta Yoshino, Kentaro Kawabe, Kiyohiro Yamazaki, Shinya Watanabe, Shusuke Numata, Yoko Mori, Taku Yoshida, Junichi Iga, Tetsuro Ohmori and Shu-ichi Ueno : Elevated TREM2 mRNA Expression in Leukocytes in Schizophrenia but not Major Depressive Disorder, Journal of Neural Transmission, 2016.
(要約)
The pathological mechanisms of schizophrenia (SCZ) have not been clarified, but the microglia hypothesis has recently been discussed. We previously reported that the mRNA for a protein related to activation of microglia, triggering receptor expressed on myeloid cell 2 (TREM2), is expressed higher in peripheral leukocytes in SCZ than controls. In this study, we analyzed TREM2 mRNA expression in leukocytes from both SCZ and major depressive disorder (MDD) patients. We compared 50 SCZ patients and 42 MDD patients with age-matched controls. Levels of TREM2 mRNA in leukocytes were analyzed with quantitative real-time PCR method using TaqMan probe. TREM2 mRNA expression was significantly higher in leukocytes of SCZ subjects than controls, but the expression level was non-significantly different in MDD subjects. We observed a decrease in TREM2 mRNA expression in leukocytes from one SCZ patient after clozapine treatment. The expression did not change following ECT, but the expression level in this patient was still significantly higher than that in controls. We conclude that the high amount of TREM2 mRNA expression in leukocytes is specific to SCZ but not MDD and that changes in TREM2 mRNA expression may be a trait biomarker for SCZ.
JI Iga, Shinya Watanabe, Shusuke Numata, Hidehiro Umehara, Akira Nishi, Makoto Kinoshita, Masatoshi Inoshita, S Shimodera, H Fujita and Tetsuro Ohmori : Association study of polymorphism in the serotonin transporter gene promoter, methylation profiles, and expression in patients with major depressive disorder., Human Psychopharmacology, Vol.31, No.3, 193-199, 2016.
Hidehiro Umehara, Shusuke Numata, Makoto Kinoshita, Shinya Watanabe, S Nakaaki, Satsuki Sumitani and Tetsuro Ohmori : No association between BDNF Val66Met polymorphism and treatment response in obsessive-compulsive disorder in the Japanese population., Neuropsychiatric Disease and Treatment, Vol.12, 611-615, 2016.
(要約)
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, and it promotes the development and function of dopaminergic and serotonergic neurons. The Met allele of the BDNF Val66Met polymorphism is associated with a decrease in activity-dependent secretion of BDNF compared with the Val allele, and a number of studies have provided evidence for the association between this polymorphism and obsessive-compulsive disorder (OCD). The purpose of this study was to investigate whether this functional variant of the BDNF gene is associated with OCD and treatment response in patients with OCD in the Japanese population. We first performed a case-control association study between the BDNF Val66Met polymorphism and OCD (175 cases and 2,027 controls). Then, we examined an association between this polymorphism and treatment response in 96 patients with OCD. We found no significant association between the Met allele and OCD risk or between the Met allele and treatment responses to selective serotonin reuptake inhibitors or serotonin reuptake inhibitor with an atypical antipsychotic (P>0.05). Our results suggest that the BDNF Val66Met polymorphism may not be associated as a risk factor for developing OCD or with therapeutic response in patients with OCD in the Japanese population.
T Saito, M Ikeda, T Mushiroda, T Ozeki, K Kondo, A Shimasaki, K Kawase, S Hashimoto, H Yamamori, Y Yasuda, M. Fujimoto, K Ohi, M. Takeda, Y Kamatani, Shusuke Numata, Tetsuro Ohmori, SI Ueno, M Makinodan, Y Nishihata, M Kubota, T. Kimura, N Kanahara, N Hashimoto, K. Fujita, K Nemoto, T Fukao, T Suwa, T Noda, Y Yada, M Takaki, N Kida, T Otsuru, M. Murakami, A Takahashi, M Kubo, R Hashimoto and N Iwata : Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population., Biological Psychiatry, 2016.
(要約)
Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine. To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects. We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10(-9), odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10(-8), OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10(-5), OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA. Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated.
Shin-ichi Chiba, Masahito Tomotake, Masatomo Aono, Hidefumi Toshimitsu and Tetsuro Ohmori : Clinical correlates associated with basic ability of social life in schizophrenia inpa-tients, Open Journal of Psychiatry, Vol.6, No.1, 71-75, 2016.
(キーワード)
統合失調症 (schizophrenia) / inpatient / social life functioning / 認知機能 (cognitive function)
Tomoya Takeda, Masahito Tomotake, Yoshinori Ueoka, Tsunehiko Tanaka, Takeo Tominaga, Yasuhiro Kaneda and Tetsuro Ohmori : Relationship between cognitive function and employment in Japanese schizophrenia patients, Open Journal of Psychiatry, Vol.6, 65-70, 2016.
Naomi Kameoka, Junichi Iga, Mai Tamaru, Takeo Tominaga, Hiroko Kubo, Shinya Watanabe, Satsuki Sumitani, Masahito Tomotake and Tetsuro Ohmori : Risk factors for refeeding hypophosphatemia in Japanese inpatients with anorexia nervosa., The International Journal of Eating Disorders, Vol.49, No.4, 402-406, 2016.
(要約)
Refeeding in patients with anorexia nervosa (AN) is associated with a risk of refeeding syndrome, which is a disruption in metabolism with a variety of features including hypophosphatemia. We evaluated the risk factors for refeeding hypophosphatemia (RH) during nutritional replenishment in Japanese patients with AN. We retrospectively examined clinical data for 99 female inpatients (mean age 30.9 ± 10.7 years; range, 9 - 56 years). RH (phosphate < 2.3 mg/dL) occurred within 4.8 ± 3.7 days of hospital admission and was still observed at 28 days after admission in 21 of the 99 cases (21.2%). Oral or intravenous phosphate was given to some patients to treat or prevent RH. Patients with RH had a significantly lower body mass index, were older, and had higher blood urea nitrogen than those without RH. Severe complications associated with RH were recorded in only one patient who showed convulsions and disturbed consciousness at Day 3 when her serum phosphate level was 1.6 mg/dL. The significant risk factors for RH that we identified were lower body mass index, older age, and higher blood urea nitrogen at admission. No significant difference in total energy intake was seen between the RH and no RH groups, suggesting that RH may not be entirely correlated with energy intake. Precisely predicting and preventing RH is difficult, even in patients with AN who are given phosphate for prophylaxis. Thus, serum phosphate levels should be monitored for more than 5 days after admission.
Yoko Mori, Yuta Yoshino, Shinichiro Ochi, Kiyohiro Yamazaki, Kentaro Kawabe, Masao Abe, Tomoji Kitano, Yuki Ozaki, Taku Yoshida, Shusuke Numata, Takaaki Mori, Junichi Iga, Norio Kuroda, Tetsuro Ohmori and Shu-ichi Ueno : TREM2 mRNA Expression in Leukocytes Is Increased in Alzheimer's Disease and Schizophrenia., PLoS ONE, Vol.10, No.9, e0136835, 2015.
(要約)
TREM2 and TYROBP are causal genes for Nasu-Hakola disease (NHD), a rare autosomal recessive disease characterized by bone lesions and early-onset progressive dementia. TREM2 forms a receptor signaling complex with TYROBP, which triggers the activation of immune responses in macrophages and dendritic cells, and the functional polymorphism of TREM2 is reported to be associated with neurodegenerative disorders such as Alzheimer's disease (AD). The objective of this study was to reveal the involvement of TYROBP and TREM2 in the pathophysiology of AD and schizophrenia. We investigated the mRNA expression level of the 2 genes in leukocytes of 26 patients with AD and 24 with schizophrenia in comparison with age-matched controls. Moreover, we performed gene association analysis between these 2 genes and schizophrenia. No differences were found in TYROBP mRNA expression in patients with AD and schizophrenia; however, TREM2 mRNA expression was increased in patients with AD and schizophrenia compared with controls (P < 0.001). There were no genetic associations of either gene with schizophrenia in Japanese patients. TREM2 expression in leukocytes is elevated not only in AD but also in schizophrenia. Inflammatory processes involving TREM2 may occur in schizophrenia, as observed in neurocognitive disorders such as AD. TREM2 expression in leukocytes may be a novel biomarker for neurological and psychiatric disorders.
Shusuke Numata, Makoto Kinoshita, Atsushi Tajima, Akira Nishi, Issei Imoto and Tetsuro Ohmori : Evaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis., BMC Medical Genetics, Vol.16, 54, 2015.
(要約)
The results of meta-analyses conducted by previous association studies between total homocysteine and schizophrenia suggest that an elevated total homocysteine level is a risk factor for schizophrenia. However, observational studies have potential limitations, such as confounding and reverse causation. In the present study, we evaluated a causal relationship between plasma total homocysteine and schizophrenia by conducting a Mendelian randomization analysis. We used the MTHFR C677T polymorphism as an instrumental variable, which affects the plasma total homocysteine levels. To calculate the risk estimate for the association of this single nucleotide polymorphism (SNP) with schizophrenia, we conducted a meta-analysis of case-control studies that comprise a total of 11,042 patients with schizophrenia and 14,557 control subjects. We obtained an estimate for the association of this SNP with the plasma total homocysteine levels from a meta-analysis of genome-wide association studies comprising 44,147 individuals. By combining these two estimates, we demonstrated a significant effect of the plasma total homocysteine on schizophrenia risk, representing an OR of 2.15 (95 % CI = 1.39-3.32; p = 5.3 x 10(-4)) for schizophrenia per 1-SD increase in the natural log-transformed plasma total homocysteine levels. We provided evidence of a causal relationship between the plasma total homocysteine and schizophrenia, and this result will add insight into the pathology and treatment of schizophrenia.
Masatoshi Inoshita, Shusuke Numata, Atsushi Tajima, Makoto Kinoshita, Hidehiro Umehara, Hidenaga Yamamori, Ryota Hashimoto, Issei Imoto and Tetsuro Ohmori : Sex differences of leukocytes DNA methylation adjusted for estimated cellular proportions., Biology of Sex Differences, Vol.6, 11, 2015.
(要約)
DNA methylation, which is most frequently the transference of a methyl group to the 5-carbon position of the cytosine in a CpG dinucleotide, plays an important role in both normal development and diseases. To date, several genome-wide methylome studies have revealed sex-biased DNA methylation, yet no studies have investigated sex differences in DNA methylation by taking into account cellular heterogeneity. The aim of the present study was to investigate sex-biased DNA methylation on the autosomes in human blood by adjusting for estimated cellular proportions because cell-type proportions may vary by sex. We performed a genome-wide DNA methylation profiling of the peripheral leukocytes in two sets of samples, a discovery set (49 males and 44 females) and a replication set (14 males and 10 females) using Infinium HumanMethylation450 BeadChips for 485,764 CpG dinucleotides and then examined the effect of sex on DNA methylation with a multiple linear regression analysis after adjusting for age, the estimated 6 cell-type proportions, and the covariates identified in a surrogate variable analysis. We identified differential DNA methylation between males and females at 292 autosomal CpG site loci in the discovery set (Bonferroni-adjusted p < 0.05). Of these 292 CpG sites, significant sex differences were also observed at 98 sites in the replication set (p < 0.05). These findings provided further evidence that DNA methylation may play a role in the differentiation or maintenance of sexual dimorphisms. Our methylome mapping of the effects of sex may be useful to understanding the molecular mechanism involved in both normal development and diseases.
Hidehiro Umehara, Shusuke Numata, Atsushi Tajima, Makoto Kinoshita, Shutaro Nakaaki, Issei Imoto, Satsuki Sumitani and Tetsuro Ohmori : No association between the COMT Val158Met polymorphism and the long-term clinical response in obsessive-compulsive disorder in the Japanese population., Human Psychopharmacology, Vol.30, No.5, 372-376, 2015.
(要約)
Catechol-O-methyltransferase (COMT) is an enzyme that participates in the metabolic inactivation of dopamine and norepinephrine, and the Met allele of the COMT Val158Met polymorphism is associated with lower enzymatic activity. The purpose of the present study was to investigate whether this functional variant is associated with obsessive-compulsive disorder (OCD) and the clinical responses in OCD. We first performed a case-control association study between the COMT Val158Met polymorphism and OCD (171 cases and 944 controls). Then, we examined the association between this polymorphism and the clinical responses in 91 of the OCD patients. Our study did not find a significant association between the Met allele and OCD risk or between the Met allele and clinical responses (p > 0.05). The present case-control/pharmacogenetic study did not provide clear evidence that the COMT Val158Met polymorphism is a predictor of OCD or of OCD patients' clinical responses.
Shinya Watanabe, Junichi Iga, Shusuke Numata, Hidehiro Umehara, Akira Nishi, Makoto Kinoshita, Masatoshi Inoshita and Tetsuro Ohmori : Polymorphism in the promoter of the gene for the serotonin transporter affects the age of onset of major depressive disorder in the Japanese population., Journal of Affective Disorders, Vol.183, 156-158, 2015.
(要約)
Recent research has suggested that a functional polymorphism in the promoter region of the serotonin transporter gene (serotonin transporter-linked polymorphic region, 5HTTLPR) may be implicated in gene-environment interactions leading to major depressive disorder (MDD). Our study examined the association between 5HTTLPR and clinical variables of MDD in the Japanese population. We genotyped 5HTTLPR in 216 patients with MDD and 213 age- and sex-matched controls. The genotype distributions and allele frequencies were similar in the patients and controls. When the relationships between the polymorphism and several clinical variables (i.e., age of onset, number of episodes, presence of psychotic features, suicidal behavior, and family history) were examined, the dose of the long (l) allele had significant effects on the age of onset. These results suggest that 5HTTLPR may not be entirely related to the development of MDD but may be related to the age of onset of MDD, which may be due to gene-environment interactions in the Japanese population. Because of the low frequencies of psychotic features and suicidal behavior, our results must be treated with caution until they are replicated in larger numbers of Japanese samples. MDD patients did not undergo a structured interview. Clinical information from the medical records may have not been complete.
(キーワード)
Adult / Asian Continental Ancestry Group / Depressive Disorder, Major / Female / Gene Frequency / Gene-Environment Interaction / Genotype / Humans / Male / Middle Aged / Nerve Tissue Proteins / Polymorphism, Genetic / Promoter Regions, Genetic / Serotonin Plasma Membrane Transport Proteins
Shinya Watanabe, Junichi Iga, Kazuo Ishii, Shusuke Numata, Shinji Shimodera, Hirokazu Fujita and Tetsuro Ohmori : Biological tests for major depressive disorder that involve leukocyte gene expression assays., Journal of Psychiatric Research, Vol.66-67C, 1-6, 2015.
(要約)
Development of easy-to-use biological diagnostic tests for major depressive disorder (MDD) may facilitate MDD diagnosis and delivery of optimal treatment. Here, we examined leukocyte gene expression to develop a biological diagnostic test for MDD. 25 drug-naive MDD patients (MDDs) and 25 age- and sex-matched healthy subjects (Controls) participated in a pilot study. A subsequent replication study involved 20 MDDs and 18 Controls. We used custom-made PCR array plates to examine mRNA levels of 40 candidate genes in leukocyte samples to assess whether any combination of these genes could be used to differentiate MDDs from Controls based on expression profiles. Among 40 candidate genes, we identified a set of seven genes (PDGFC, SLC6A4, PDLIM5, ARHGAP24, PRNP, HDAC5, and IL1R2), each of which had expression levels that differed significantly between MDD and Control samples in the pilot study. To identify genes whose expression best differentiated between MDDs and Controls, a linear discriminant function was developed to discriminate between MDDs and Controls based on the standardized values of gene expression after Z-score transformation. Ultimately, five genes (PDGFC, SLC6A4, ARHGAP24, PRNP, and HDAC5) were selected for a multi-assay diagnostic test. In the pilot study, this diagnostic test demonstrated sensitivity and specificity of 80% and 92%, respectively. The replication study yielded nearly identical results, sensitivity of 85% and specificity of 89%. Using leukocyte gene expression profiles, we could differentiate MDDs from Controls with adequate sensitivity and specificity. Additional markers not yet identified might further improve the performance of this test.
Mai Hosokawa, Yoshihiro Nakadoi, Yukina Watanabe, Satsuki Sumitani and Tetsuro Ohmori : Association of autism tendency and hemodynamic changes in the prefrontal cortex during facial expression stimuli measured by multi-channel near-infrared spectroscopy., Psychiatry and Clinical Neurosciences, Vol.69, No.3, 145-152, 2015.
(要約)
The aim of this study is to examine the hemodynamic changes induced by the cognitive process of facial expression by using multi-channel near-infrared spectroscopy in healthy subjects with varying degrees of autism tendency. Subjects were 38 volunteers, 20 men and 18 women. Autism tendency was measured by the Autism Spectrum Quotient. The hemodynamic changes in the prefrontal cortex were measured by 24-channel near-infrared spectroscopy system, while subjects were asked to judge their own emotional response to standardized pictures of eight kinds of facial expressions on a computer screen. There were significant negative correlations between Autism Spectrum Quotient scores and accuracy of fearful expression recognition as well as increases in the concentration of oxygenated hemoglobin in response to four kinds of emotional faces (fear, contempt, sadness and disgust). Our findings suggest that the greater tendency to autism that subjects have, the more difficulty they have in recognizing a fearful expression and the less hemodynamic change in the prefrontal cortex they show in response to negative facial expressions.
Shusuke Numata, K Ishii, Atsushi Tajima, Junichi Iga, Makoto Kinoshita, Shinya Watanabe, Hidehiro Umehara, M Fuchikami, S Okada, S Boku, A Hishimoto, S Shimodera, Issei Imoto, S Morinobu and Tetsuro Ohmori : Blood diagnostic biomarkers for major depressive disorder using multiplex DNA methylation profiles: discovery and validation., Epigenetics, Vol.10, No.2, 135-141, 2015.
(要約)
Aberrant DNA methylation in the blood of patients with major depressive disorder (MDD) has been reported in several previous studies. However, no comprehensive studies using medication-free subjects with MDD have been conducted. Furthermore, the majority of these previous studies has been limited to the analysis of the CpG sites in CpG islands (CGIs) in the gene promoter regions. The main aim of the present study is to identify DNA methylation markers that distinguish patients with MDD from non-psychiatric controls. Genome-wide DNA methylation profiling of peripheral leukocytes was conducted in two set of samples, a discovery set (20 medication-free patients with MDD and 19 controls) and a replication set (12 medication-free patients with MDD and 12 controls), using Infinium HumanMethylation450 BeadChips. Significant diagnostic differences in DNA methylation were observed at 363 CpG sites in the discovery set. All of these loci demonstrated lower DNA methylation in patients with MDD than in the controls, and most of them (85.7%) were located in the CGIs in the gene promoter regions. We were able to distinguish patients with MDD from the control subjects with high accuracy in the discriminant analysis using the top DNA methylation markers. We also validated these selected DNA methylation markers in the replication set. Our results indicate that multiplex DNA methylation markers may be useful for distinguishing patients with MDD from non-psychiatric controls.
(キーワード)
Adult / CpG Islands / DNA Methylation / Depressive Disorder, Major / Female / Genetic Markers / Glycogen Synthase Kinase 3 / Humans / Leukocytes / Male / Middle Aged
Yukina Watanabe, Satsuki Sumitani, M Hosokawa and Tetsuro Ohmori : Prefrontal activation during two Japanese Stroop tasks revealed with multi-channel near-infrared spectroscopy., The Journal of Medical Investigation : JMI, Vol.62, No.1-2, 51-55, 2015.
(要約)
The Stroop task is sometimes used in psychiatric research to elicit prefrontal activity, which presumably reflects cognitive functioning. Although there are two Stroop tasks (Kana script and Kanji script) in Japan, it is unclear whether these tasks elicit the same hemoglobin changes. Moreover, it is unclear whether psychological conditions or characteristics influence hemoglobin changes in the Japanese Stroop task. The aim of this study was to clarify whether hemoglobin changes elicited by the two Japanese Stroop tasks accurately reflected cognitive functioning. Hemoglobin changes were measured with multi-channel near-infrared spectroscopy (NIRS) in 100 healthy Japanese participants performing two Japanese Stroop tasks. The Beck-Depression Inventory (BDI), State-Trait-Anxiety Inventory (STAI), and Maudsley Obsessive Compulsive Inventory (MOCI) were administered to participants to identify psychological conditions or personality characteristics. Compared with the Kanji task, the Kana task produced a greater Stroop effect and a larger increase in oxyhemoglobin (oxy-Hb) concentration. Moreover there were no significant correlations between oxy-Hb concentration and BDI, STAI-trait, STAI-state, or MOCI scores. Therefore we found that a participant's psychological conditions or characteristics did not influence the hemodynamic changes during either task. These data suggest the Kana Stroop task is more useful than the Kanji Stroop task for NIRS studies in psychiatric research.
K Nakamura, Junichi Iga, N Matsumoto and Tetsuro Ohmori : Risk of bipolar disorder and psychotic features in patients initially hospitalised with severe depression., Acta Neuropsychiatrica, Vol.27, No.2, 113-118, 2014.
(要約)
Severe depression may be a risk factor for diagnostic conversion into bipolar disorder (BD), and psychotic depression (PD) has been consistently associated with BD. The aims of the present study were to investigate the stability of the diagnosis of severe depression and the differences between PD and non-psychotic severe depression (non-PD), as well as to assess the effectiveness of electroconvulsive therapy (ECT). Patients who were hospitalised for severe depression (diagnosed according to ICD-10) both with and without psychotic symptoms (n=89; mean age=55.6 years, SD=13.9) from 2001 to 2010 were retrospectively assessed. By the 75th month of follow-up assessments, 11(12.4%) patients had developed BD. Among these 11 converters, nine had developed BD within 1 year after admission. Only sub-threshold hypomanic symptoms were significantly related to developing BD. The number of depressive episodes and history of physical diseases were significantly increased in non-PD compared with PD patients, whereas ECT was significantly increased in PD compared with non-PD patients. There was a significant association between length of stay at the hospital and the number of days between admission and ECT. Sub-threshold hypomanic symptoms may represent a prodrome of BD or an indicator of an already manifest phenotype, especially in older patients, which suggests cautious use of antidepressants. In severe depression, non-PD may often occur secondary to physical diseases and patients may experience increased recurrences compared with PD patients, which may be a more 'primary' disorder and often requires ECT treatments. ECT is effective for severe depression regardless of the presence of any psychotic feature; the earlier ECT is introduced, the better the expected treatment outcome.
H Yamamori, R Hashimoto, Y Fujita, Shusuke Numata, Y Yasuda, M Fujimoto, K Ohi, S Umeda-Yano, A Ito, Tetsuro Ohmori, K Hashimoto and M Takeda : Changes in plasma d-serine, l-serine, and glycine levels in treatment-resistant schizophrenia before and after clozapine treatment., Neuroscience Letters, Vol.582, 93-98, 2014.
(要約)
Hypofunction of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors may be involved in the pathophysiology of schizophrenia. Many studies have investigated peripheral NMDA receptor-related glutamatergic amino acid levels because of their potential as biological markers. Peripheral d-serine levels and the ratio of d-serine to total serine have been reported to be significantly lower in patients with schizophrenia than in controls. Peripheral d-serine levels and the d-/l-serine ratio have also been reported to significantly increase in patients with schizophrenia as their clinical symptoms improve from the time of admission to the time of discharge. In this study, we examined whether peripheral NMDA receptor-related glutamatergic amino acids levels were altered in patients with treatment-resistant schizophrenia compared to controls and whether these peripheral amino acids levels were altered by clozapine treatment. Twenty-two patients with treatment-resistant schizophrenia and 22 age- and gender-matched healthy controls were enrolled. The plasma levels of d-serine, l-serine, glycine, glutamate, and glutamine were measured before and after clozapine treatment. We found that the plasma levels of d-serine and the d-/l-serine ratio were significantly lower in the patients before clozapine treatment than in the controls. The d-/l-serine ratio was significantly increased by clozapine treatment in patients, and no significant difference was observed in the plasma levels of d-serine and the d-/l-serine ratio between the patients after clozapine treatment and the controls. We also found that plasma glycine levels and the glycine/l-serine ratio were significantly increased following clozapine treatment in the patients, and the glycine/l-serine ratio was significantly higher in the patients after clozapine treatment than in the controls. There was no significant difference in the plasma levels of glutamate and glutamine both between the controls and patients and between before and after clozapine treatment. This study firstly demonstrated changes of d-/l-serine and glycine/l-serine ratio between before and after clozapine treatment, suggesting that the plasma d-/l-serine ratio and glycine/l-serine ratio could be markers of therapeutic efficacy or clinical state in treatment-resistant schizophrenia.
M Aono, Junichi Iga, Shu-ichi Ueno, M Agawa, T Tsuda and Tetsuro Ohmori : Neuropsychological and psychiatric assessments following bilateral deep brain stimulation of the subthalamic nucleus in Japanese patients with Parkinson's disease., Journal of Clinical Neuroscience, Vol.21, No.9, 1595-1598, 2014.
(要約)
The physical benefits of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) patients are well documented, but the mental benefits are uncertain, particularly in Japanese patients. This study evaluated the clinical and neuropsychological characteristics before and after STN-DBS surgery in Japanese PD patients. PD patients (n=13, age 67.0 ± 7.8 years) were evaluated pre-surgery (baseline) and at 1 and 6 months post-surgery by two trained psychiatrists. The motor symptoms were assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. The neuropsychological and psychiatric tests performed were the Mini-Mental State Examination, the Wisconsin Card Sorting Test (WCST), the Verbal Fluency Test (VFT), the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale (HAM-A). The UPDRS motor score (p<0.001) and HAM-A score (p=0.004) showed significant improvement at 1 month post-surgery, but a significant decline was observed in the WCST total error (p=0.005) and the semantic VFT score (p<0.001). The phonetic VFT also showed a substantial decline (p=0.015) at 1 month post-surgery. At 6 months post-surgery, the improvement in the UPDRS motor score was maintained, and the scores on the neuropsychological and psychiatric tests had returned to baseline. Although bilateral STN-DBS did not appear to have long-term effects on neuropsychological and psychiatric outcomes, the microlesion effects associated with STN-DBS appear to increase the risk of transient cognitive and psychiatric complications. These complications should be monitored by careful observation of neurological and psychiatric symptoms.
Akira Nishi, Shusuke Numata, Atsushi Tajima, Makoto Kinoshita, K Kikuchi, S Shimodera, Masahito Tomotake, K Ohi, R Hashimoto, Issei Imoto, M Takeda and Tetsuro Ohmori : Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association Studies of the MTHFR C677T Polymorphism in Schizophrenia., Schizophrenia Bulletin, Vol.40, No.5, 1154-1163, 2014.
(要約)
Previous studies suggest that elevated blood homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for schizophrenia. However, the effects of gender and MTHFR C677T genotypes on blood homocysteine levels in schizophrenia have not been consistent. We first investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in controls with stratification by gender and by the MTHFR C677T genotypes in a large cohort (N = 1379). Second, we conducted a meta-analysis of association studies between blood homocysteine levels and schizophrenia separately by gender (N = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia (N = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects (N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization approach. The ANCOVA after adjustment for age demonstrated a significant effect of diagnosis on the plasma total homocysteine levels in all strata, and the subsequent meta-analysis for gender demonstrated elevated blood homocysteine levels in both male and female patients with schizophrenia although antipsychotic medication might influence the outcome. The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization analysis in the Japanese populations yielded an OR of 1.15 for schizophrenia per 1-SD increase in plasma total homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia.
Y Yoshino, Y Mori, S Ochi, Shusuke Numata, T Ishimaru, K Yamazaki, Tetsuro Ohmori and SI Ueno : No abnormal hexanucleotide repeat expansion of C9ORF72 in Japanese schizophrenia patients., Journal of Neural Transmission, Vol.[Epub ahead of print], 2014.
(要約)
Abnormal hexanucleotide repeat expansion of C9ORF72 is known to cause neurodegenerative disorders such as frontotemporal dementia. Additionally, patients with psychotic symptoms are more likely to have abnormal hexanucleotide repeat expansion than are patients without them. We investigated the hexanucleotide repeat sizes of C9ORF72 in 466 Japanese schizophrenia patients. We found no abnormal hexanucleotide repeat expansion. In conclusion, C9ORF72 may not be responsible for schizophrenia susceptibility in the Japanese population.
Y Yoshino, M Abe, Shusuke Numata, S Ochi, Y Mori, T Ishimaru, Makoto Kinoshita, Hidehiro Umehara, K Yamazaki, T Mori, Tetsuro Ohmori and S Ueno : Missense variants of the alanine:glyoxylate aminotransferase 2 gene are not associated with Japanese schizophrenia patients., Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol.53, 137-141, 2014.
(要約)
Alanine:glyoxylate aminotransferase 2 (AGXT2) is the only enzyme that degrades D-3-aminoisobutyrate (D-AIB), which is an intermediate product of thymine, and 30-40% of Japanese lack AGXT2 activity genetically and excrete high amounts of D-AIB in their urine. Recently, AGXT2 is reported to metabolize asymmetric dimethyl arginine (ADMA), a competitive inhibitor of nitric oxide (NO) synthase. Since AGXT2 is expressed in the central nervous system, the loss of AGXT2 activity will be related to the vulnerability for neuropsychiatric disorders related to the NO system. In this study, we recruited 85 Japanese subjects to discover loss variants of the AGXT2 gene with the amount of D-AIB excretion in their urine. From the statistical relevance between them, we found three missense polymorphisms (rs37370, rs37369, and rs180749) independently related to AGXT2 activity (P<0.0001). Then, we performed a case-control association analysis of its missense polymorphisms with 1136 schizophrenia and 1908 control subjects because the NO system may be involved in the vulnerability of schizophrenia processes. We could not find any associations of three functional SNPs with schizophrenia pathogenesis in the analyses of either genotypic or allelic models. We concluded that the AGXT2 gene is not associated with schizophrenia in Japanese subjects.
(キーワード)
Adult / Aminoisobutyric Acids / Asian Continental Ancestry Group / Case-Control Studies / Chi-Square Distribution / Female / Genetic Association Studies / Genetic Predisposition to Disease / Genotype / Humans / Male / Middle Aged / Mutation, Missense / Nitric Oxide / Polymorphism, Single Nucleotide / Schizophrenia / Statistics as Topic / Transaminases
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, Kazutaka Ohi, Ryota Hashimoto, Shinji Shimodera, Issei Imoto, Masatoshi Takeda and Tetsuro Ohmori : Aberrant DNA Methylation of Blood in Schizophrenia by Adjusting for Estimated Cellular Proportions., NeuroMolecular Medicine, Vol.16, No.4, 697-703, 2014.
(要約)
DNA methylation, which is the transference of a methyl group to the 5'-carbon position of the cytosine in a CpG dinucleotide, is one of the major mechanisms of epigenetic modifications. A number of studies have demonstrated altered DNA methylation of peripheral blood cells in schizophrenia (SCZ) in previous studies. However, most of these studies have been limited to the analysis of the CpG sites in CpG islands in gene promoter regions, and cell-type proportions of peripheral leukocytes, which may be one of the potential confounding factors for DNA methylation, have not been adjusted in these studies. In this study, we performed a genome-wide DNA methylation profiling of the peripheral leukocytes from patients with SCZ and from non-psychiatric controls (N = 105; 63 SCZ and 42 control subjects) using a quantitative high-resolution DNA methylation microarray which covered across the whole gene region (485,764 CpG dinucleotides). In the DNA methylation data analysis, we first estimated the cell-type proportions of each sample with a published algorithm. Next, we performed a surrogate variable analysis to identify potential confounding factors in our microarray data. Finally, we conducted a multiple linear regression analysis in consideration of these factors, including estimated cell-type proportions, and identified aberrant DNA methylation in SCZ at 2,552 CpG loci at a 5 % false discovery rate correction. Our results suggest that altered DNA methylation may be involved in the pathophysiology of SCZ, and cell heterogeneity adjustments may be necessary for DNA methylation analysis.
Hidehiro Umehara, Junichi Iga and Tetsuro Ohmori : Successful Treatment of Anorexia Nervosa in a 10-year-old Boy with Risperidone Long-acting Injection., Clinical Psychopharmacology and Neuroscience, Vol.12, No.1, 65-66, 2014.
(要約)
Although the effectiveness of medication in the treatment of anorexia nervosa is uncertain, atypical antipsychotics such as olanzapine and risperidone have been used empirically for decades. we describe the case of a 10-year-old boy with anorexia nervosa in whom remarkable improvement was seen following the administration of risperidone or risperidone long-acting injection and deterioration when these agents were ceased. Because this is, to the best of our knowledge, the first report describing the usefulness of risperidone long-acting injection for adolescent anorexia nervosa.
Yoko Morigaki, Junichi Iga, Naomi Kameoka, Satsuki Sumitani and Tetsuro Ohmori : Psychiatric symptoms in a patient with isolated adrenocorticotropin deficiency: case report and literature review., General Hospital Psychiatry, Vol.36, No.4, 449e3-e5, 2014.
(要約)
We report a 59-year-old man with isolated adrenocorticotropin (ACTH) deficiency. The patient presented with sudden onset of delusions and hallucinations at the age of 54, which resolved gradually without treatment. Subsequently, the patient manifested stereotypy, wandering, hypobulia, and autistic symptoms, and was treated with antipsychotics for 1 year without any improvement. He suffered from neuroleptic malignant syndrome-like symptoms at the age of 59. A thorough endocrine assessment revealed isolated ACTH deficiency. After hydrocortisone supplementation, the physical and psychiatric symptoms improved dramatically. Clinicians should consider this rare disease when diagnosing patients with refractory psychiatric symptoms and unique physical symptoms of isolated ACTH deficiency.
Shinya Watanabe, Junichi Iga, Akira Nishi, Shusuke Numata, Makoto Kinoshita, K Kikuchi, Masahito Nakataki and Tetsuro Ohmori : Microarray analysis of global gene expression in leukocytes following lithium treatment., Human Psychopharmacology, Vol.29, No.2, 190-198, 2014.
(要約)
To elucidate the molecular effects of lithium, we studied global gene expression changes induced by lithium in leukocytes from healthy subjects. Eight healthy male subjects participated in this study. Lithium was prescribed for weeks to reach a therapeutic serum concentration. Leukocyte counts and serum lithium concentrations were determined at baseline (before medication), after 1 and 2 weeks of medication and at 2 weeks after stopping medication. Gene expression profiling was performed at each time point using Agilent G4112F Whole Human Genome arrays (The Agilent Technologies, Santa Clara, CA, USA). Expression of some candidate genes was also assessed by real-time polymerase chain reaction (PCR). Gene ontology analysis revealed that the cellular and immune responses to stimulus and stress indeed played a major role in the cellular response to lithium treatment. Pathway analysis revealed that the interleukin 6 pathway, the inhibitor of differentiation pathway, and the methane metabolism pathway were regulated by lithium. Using real-time PCR, we also confirmed that five candidate genes in these pathways were significantly changed, including suppressor of cytokine signaling 3 and myeloperoxidase. Our investigation suggests that the molecular action of lithium is mediated in part by its effects on the cellular and immune response to stimulus and stress followed by the interleukin 6, inhibitor of differentiation, and methane metabolism pathways.
J Liu, Shusuke Numata, M Ikeda, Y Watanabe, XB Zheng, X Luo, Makoto Kinoshita, A Nunokawa, T Someya, Tetsuro Ohmori, JX Bei, SA Chong, J Lee, Z Li, J Liu, N Iwata, Y Shi, M Li and B Su : An evaluation of association between a novel hippocampal biology related SNP (rs7294919) and schizophrenia., PLoS ONE, Vol.8, No.11, e80696, 2013.
(要約)
Recent genetic analyses have implicated several candidate susceptibility variants for schizophrenia. The single nucleotide polymorphism (SNP) rs7294919 is likely a schizophrenia-susceptibility variant according to its significant association with hippocampal volume, hippocampus function, and cognitive performance as well as the nominal association with schizophrenia. However, all previous analyses were conducted only in Europeans, and whether rs7294919 is associated with schizophrenia in other populations are yet to be tested. Here, we conducted a case-control analysis of rs7294919 with schizophrenia in six independent Chinese (N = 3) and Japanese (N = 3) samples, including a total of 7,352 cases and 10,824 controls. The results of our association analysis were not able to confirm the association of rs7294919 with schizophrenia (p = 0.51 in total samples, odds ratio = 1.02 for allele[C]). The absence of rs7294919's association in Chinese and Japanese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating associations of schizophrenia across different ethnic populations.
(キーワード)
Adult / Asian Continental Ancestry Group / Case-Control Studies / Genetic Association Studies / Genetic Predisposition to Disease / Hippocampus / Humans / Polymorphism, Single Nucleotide / Schizophrenia
J Ishigooka, K Nakagome, Tetsuro Ohmori and N. Iwata : Japan useful medication program for schizophrenia (JUMPs)-long-term study on discontinuation rate, resolution and remission, and improvement in social functioning rate associated with atypical antipsychotic medications in patients with schizophrenia., BMC Psychiatry, Vol.3, No.13, 243, 2013.
(要約)
It is desirable to establish evidence for the selection of antipsychotics from the viewpoint of recovery of social activity in individual patient with schizophrenia receiving medication. From this perspective, awareness of the importance of studies about drug effectiveness on treatment discontinuation rate, remission rate, and improvement in QOL has grown recently. In Western countries, numerous reports are available in effectiveness studies, which are related to olanzapine and risperidone primarily, whereas evidence for other second-generation antipsychotics (SGAs) is poor. In Japan, no effectiveness study has been reported: thus, it is desirable to collect data that will serve as evidence for selection of the 3 SGAs approved after olanzapine. The present study was a long-term effectiveness study under healthcare setting in Japan. It was designed as an open-label, multicenter, randomized, comparative study involving 104-week oral treatment with 1 of the 3 drugs (aripiprazole, blonanserin, and paliperidone) in patients with schizophrenia aged 20 years or over who required antipsychotic medication or switching of the current medication to others for reasons such as lack of efficacy and intolerability. The primary endpoint is treatment discontinuation rate for any causes. The secondary endpoints include remission rate, improvement of social activity, alleviation, aggravation or recurrence of psychiatric symptoms, and safety. The target number of subjects was set at 300. Because this study is expected to yield evidence regarding the selection of antipsychotics for facilitating the recovery of social activity in patients with schizophrenia, it is considered highly valuable to perform this effectiveness study under ordinary healthcare setting in Japan. UMIN Clinical Trials Registry 000007942.
K Kamijima, T Higuchi, J Ishigooka, Tetsuro Ohmori, N Ozaki, S Kanba, T Kinoshita, T Koyama and Group. Study ADMIRE : Aripiprazole augmentation to antidepressant therapy in Japanese patients with major depressive disorder: a randomized, double-blind, placebo-controlled study (ADMIRE study)., Journal of Affective Disorders, Vol.151, No.3, 899-905, 2013.
(要約)
This randomized, placebo-controlled study evaluated the efficacy and safety of a fixed dose (3mg/day) and flexible dose (3-15 mg/day) schedule of aripiprazole as augmentation therapy in Japanese patients with inadequate response to antidepressant therapy (ADT). During an 8-week prospective treatment phase, patients experiencing a major depressive episode received clinicians' choice of ADT. Subjects with inadequate response to ADT were randomized to receive adjunctive treatment with placebo (n=195), fixed dose aripiprazole (n=197) or flexible dose aripiprazole (n=194) for 6 weeks. The primary efficacy endpoint was mean change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from the end of prospective treatment (baseline) to the end of randomized treatment. More than 90% of patients in all treatment groups completed the 6-week double-blind treatment phase. Mean MADRS total score was improved to a significantly greater extent with fixed dose aripiprazole and flexible dose aripiprazole (-10.5 and -9.6, respectively) than with placebo (-7.4). Aripiprazole was well tolerated. The incidence of akathisia observed in the flexible dose group may relate to a higher prevalence of the CYP2D6(*)10 allele in Asian populations. Six weeks of adjunctive treatment is insufficient to draw conclusions about the long-term benefits of aripiprazole. Exclusion of patients with established medical comorbidities does not reflect real-world practice. Aripiprazole augmentation at a fixed or flexible dose was superior to ADT alone and was reasonably well tolerated in Japanese patients with inadequate response to ADT.
(キーワード)
Adult / Akathisia, Drug-Induced / Antidepressive Agents / Asian Continental Ancestry Group / Depressive Disorder, Major / Double-Blind Method / Drug Administration Schedule / Drug Synergism / Drug Therapy, Combination / Female / Humans / Male / Piperazines / Psychiatric Status Rating Scales / Quinolones / Time Factors / Treatment Outcome
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, Shinji Shimodera, Issei Imoto and Tetsuro Ohmori : Plasma total homocysteine is associated with DNA methylation in patients with schizophrenia., Epigenetics, Vol.8, No.6, 584-590, 2013.
(要約)
Schizophrenia (SCZ) is a devastating psychiatric disorder with a median lifetime prevalence rate of 0.7-0.8%. Elevated plasma total homocysteine has been suggested as a risk factor for SCZ, and various biological effects of hyperhomocysteinemia have been proposed to be relevant to the pathophysiology of SCZ. As increased attention is paid to aberrant DNA methylation in SCZ, homocysteine is attracting additional interest as a potential key substance. Homocysteine is formed in the methionine cycle, which is involved in one-carbon methyl group-transfer metabolism, and it acts as a methyl donor when it is converted to S-adenosyl-methionine. To date, no studies have examined the relationship between homocysteine and genome-wide DNA methylation in SCZ. We examined the relationship between plasma total homocysteine and DNA methylation patterns in the peripheral leukocytes of patients with SCZ (n = 42) using a quantitative high-resolution DNA methylation array (485,764 CpG sites). Significant homocysteine-related changes in DNA methylation were observed at 1,338 CpG sites that were located across whole gene regions, including promoters, gene bodies and 3'-untranslated regions. Of the 1,338 sites, 758 sites (56.6%) were located in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 15.8%; CGI shore: 28.2%; CGI shelf: 12.6%), and positive correlations between plasma total homocysteine and DNA methylation were observed predominantly at CpG sites in the CGIs. Our results suggest that homocysteine might play a role in the pathogenesis of SCZ via a molecular mechanism that involves alterations to DNA methylation.
Yasuhiro Kaneda, Tetsuro Ohmori, Yuko Okahisa, Tomiki Sumiyoshi, Shenghong Pu, Yoshinori Ueoka, Manabu Takaki, Kazuyuki Nakagome and Ichiro Sora : Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery: validation of the Japanese version., Psychiatry and Clinical Neurosciences, Vol.67, No.3, 182-188, 2013.
(要約)
This preliminary study was performed to test the reliability and validity of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), developed by the National Institute of Mental Health MATRICS initiative, as an assessment tool in a Japanese-language version (MCCB-J). The subjects for the present study were 37 patients with schizophrenia. Each subject gave written informed consent to participate in the research. In order to examine the validity of the MCCB-J, the correlation between the MCCB-J and the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS) was determined. Cronbach's alpha for the MCCB-J was 0.72. The MCCB-J composite score was significantly correlated with all subtests of the MCCB-J. There was a significant correlation between the MCCB-J and the BACS composite score. This preliminary study indicates that the MCCB-J has good psychometric properties and validity.
(キーワード)
Adult / Antipsychotic Agents / Asian Continental Ancestry Group / Cognition / Data Interpretation, Statistical / Diagnostic and Statistical Manual of Mental Disorders / Emotional Intelligence / Factor Analysis, Statistical / Female / Humans / Male / Memory, Short-Term / Neuropsychological Tests / 問題解決 (problem solving) / Psychiatric Status Rating Scales / Psychomotor Performance / Reproducibility of Results / 統合失調症 (schizophrenia) / Schizophrenic Psychology / Trail Making Test / Verbal Learning
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, S Shimodera, S Ono, A Imamura, Junichi Iga, Shinya Watanabe, Kumiko Kikuchi, Hiroko Kubo, Masahito Nakataki, Satsuki Sumitani, Issei Imoto, Y Okazaki and Tetsuro Ohmori : DNA Methylation Signatures of Peripheral Leukocytes in Schizophrenia., NeuroMolecular Medicine, Vol.Mar;15, No.1, 95-101, 2013.
(要約)
Schizophrenia (SCZ) is a complex psychiatric disease with a lifetime morbidity rate of 0.5-1.0 %. To date, aberrant DNA methylation in SCZ has been reported in several studies. However, no comprehensive studies using medication-free subjects with SCZ have been conducted. In addition, most of these studies have been limited to the analysis of the CpG sites in CpG islands (CGIs) in the gene promoter regions, so little is known about the DNA methylation signatures across the whole genome in SCZ. Genome-wide DNA methylation profiling (485,764 CpG sites) of peripheral leukocytes was conducted in the first set of samples (24 medication-free patients with SCZ and 23 non-psychiatric controls) using Infinium HumanMethylation450 Beadchips. Second, a monozygotic twin study was performed using three pairs of monozygotic twins that were discordant for SCZ. Finally, the data from these two independent cohorts were compared. A total of 234 differentially methylated CpG sites that were common between these two cohorts were identified. Of the 234 CpG sites, 153 sites (65.4 %) were located in the CGIs and in the regions flanking CGIs (CGI: 40.6 %; CGI shore: 13.3 %; CGI shelf: 11.5 %). Of the 95 differently methylated CpG sites in the CGIs, most of them were located in the promoter regions (promoter: 75.8 %; gene body: 14.7 %; 3'-UTR: 2.1 %). Aberrant DNA methylation in SCZ was identified at numerous loci across the whole genome in peripheral leukocytes using two independent sets of samples. These findings support the notion that altered DNA methylation could be involved in the pathophysiology of SCZ.
(キーワード)
3' Untranslated Regions / Adult / Antipsychotic Agents / Cohort Studies / CpG Islands / DNA Methylation / DNA, Intergenic / Diseases in Twins / Female / Humans / Japan / Leukocytes / Male / Promoter Regions, Genetic / Schizophrenia / Twins, Monozygotic / Young Adult
Shinya Watanabe, Junichi Iga, Shusuke Numata, Masahito Nakataki, Toshihito Tanahashi, Mitsuo Itakura and Tetsuro Ohmori : Association Study of Fat-mass and Obesity-associated Gene and Body Mass Index in Japanese Patients with Schizophrenia and Healthy Subjects., Clinical Psychopharmacology and Neuroscience, Vol.10, No.3, 185-189, 2012.
(要約)
Fat-mass and obesity-associated (FTO) gene is known to be involved in the pathophysiology of obesity and a single-nucleotide polymorphism (SNP) rs9939609 of FTO gene is repeatedly confirmed to be associated with body mass index (BMI) and obesity. The aim of this study is to elucidate effects of FTO gene polymorphism on BMI in Japanese patients with schizophrenia and healthy subjects. Three hundred fifty one patients with schizophrenia and 342 age- and sex-matched healthy subjects participated in the study. Information on BMI and antipsychotic medication was also collected from patients and healthy subjects. Genotype of the FTO SNP rs9939609 was determined by TaqMan SNP Genotyping Assays. There was no significant difference in BMI between patients and healthy subjects. No significant difference in BMI was observed among any medications. We observed no significant difference in rs9939609 allele frequencies between patients and healthy subjects. There was a significant difference in BMI between healthy subjects with risk (AA or TA) genotypes and those with TT genotype. We also observed a significant positive correlation between the number of risk allele (A allele) and BMI in healthy subjects. Our study suggested that FTO rs9939609 polymorphism might have some impacts on the BMI in healthy subjects, but might not have same impacts on the BMI of patients with schizophrenia.
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, K Ohi, R Hashimoto, S Shimodera, Issei Imoto, Mitsuo Itakura, M Takeda and Tetsuro Ohmori : Meta-analysis of association studies between DISC1 missense variants and schizophrenia in the Japanese population., Schizophrenia Research, Vol.141, No.2-3, 271-273, 2012.
(キーワード)
Asian Continental Ancestry Group / Case-Control Studies / Female / Gene Frequency / Genetic Association Studies / Genotype / Humans / Male / Mutation, Missense / Nerve Tissue Proteins / Polymorphism, Single Nucleotide / Schizophrenia
W Ye, S Fujikoshi, N Nakahara, M Takahashi, H Ascher-Svanum and Tetsuro Ohmori : One-year outcomes in schizophrenia after switching from typical antipsychotics to olanzapine in Japan: an observational study, Pragmatic and Observational Research, Vol.3, 41-49, 2012.
(要約)
The purpose of this study was to assess the 1-year clinical, functional, and safety-related outcomes following a switch to olanzapine of at least one typical antipsychotic drug in the previous regimen in the treatment of patients of schizophrenia in Japan. Using data from a large 1-year prospective, multicenter, naturalistic study of olanzapine for the treatment of schizophrenia in Japan, patients who were switched from any oral typical antipsychotic to olanzapine were identified. Mixed models for repeated measures, controlling for baseline demographics, were utilized to assess outcomes for clinical and functional measures. Of the 262 patients who switched from typical antipsychotics to olanzapine, 41% were outpatients and 59% were inpatients. Most of these patients were switched due to poor medication efficacy (71.0%) or medication intolerability (25.6%). Most patients (71.4%) completed the 1-year study. Clinically and statistically significant (P < 0.01) improvements were observed in patient illness severity and health-related quality of life, including improvements in global symptom severity and in positive, negative, depressive, and cognitive symptoms. Over half of the patients (58.3%) demonstrated a treatment response to olanzapine and 47.4% achieved symptom remission. Mean weight gain from baseline to endpoint was 2.31 ± 4.72 kg, with 30.4% of patients experiencing clinically significant weight gain (at least 7% of baseline weight). During this 1-year naturalistic treatment of schizophrenia patients in Japan, switching from typical antipsychotics to olanzapine resulted in significant improvements in patients' clinical and functional outcomes. Approximately one-third of patients had clinically significant weight gain. These findings highlight the favorable benefit to risk profile of switching to olanzapine following failure on typical antipsychotics.
W Ye, S Fujikoshi, N Nakahara, M Takahashi, H Ascher-Svanum and Tetsuro Ohmori : Improved outcomes following a switch to olanzapine treatment from risperidone treatment in a 1-year naturalistic study of schizophrenia patients in Japan, Psychiatry and Clinical Neurosciences, Vol.66, No.4, 313-321, 2012.
(要約)
This study assessed clinical and functional outcomes following a switch from risperidone to olanzapine in a 1-year naturalistic study of schizophrenia patients in Japan. We used data from a large 1-year prospective, multicenter, observational non-interventional study of individuals who were initiated on olanzapine for the treatment of schizophrenia in Japan. Current analyses focused on patients who were switched at study entry from risperidone to olanzapine (n = 258). Repeated measures analysis was employed to assess outcomes on validated measures. At study entry, 45% were inpatients and 55% outpatients. Participants were in their early 40s with mean illness duration of 14 years. Approximately half were male. Most were switched from risperidone to olanzapine due to poor medication efficacy (67.8%) rather than medication intolerability (29.1%). Most patients (67.8%) completed the 1-year study. Patients experienced clinically and statistically significant (P < 0.05) improvements in global symptom severity, positive, negative, depressive, and cognitive symptoms, health-related quality of life, and paid work rates. Most patients (59.2%) demonstrated treatment response to olanzapine and 43.4% experienced symptom remission. Mean weight gain was 2.19 kg, with one-third of patients (33.3%) experiencing clinically significant weight gain (≥7%). In this 1-year naturalistic study, inpatients and outpatients who were switched from risperidone to olanzapine experienced clinically and statistically significant improvements in their clinical and functional outcomes. One-third of all patients experienced clinically significant weight gain. Current findings highlight the favorable benefit-to-risk profile of switching to olanzapine therapy following treatment failure on risperidone among patients with schizophrenia in Japan.
(キーワード)
Adult / Antipsychotic Agents / Benzodiazepines / Drug Resistance / Female / Humans / Income / Japan / Male / Prospective Studies / Psychiatric Status Rating Scales / Quality of Life / Retreatment / Risperidone / Schizophrenia / Schizophrenic Psychology / Weight Gain
M Ikeda, B Aleksic, K Yamada, Y Iwayama-Shigeno, K Matsuo, Shusuke Numata, Y Watanabe, T Ohnuma, T Kaneko, Y Fukuo, T Okochi, T Toyota, E Hattori, S Shimodera, M Itakura, A Nunokawa, N Shibata, H Tanaka, H Yoneda, H Arai, T Someya, Tetsuro Ohmori, T Yoshikawa, N Ozaki and N Iwata : Genetic evidence for association between NOTCH4 and schizophrenia supported by a GWAS follow-up study in a Japanese population., Molecular Psychiatry, Vol.18, No.6, 636-638, 2012.
Kazutaka Ohi, Ryota Hashimoto, Yuka Yasuda, Motoyuki Fukumoto, Hidenaga Yamamori, Satomi Umeda-Yano, Takeya Okada, Kouzin Kamino, Takashi Morihara, Masao Iwase, Hiroaki Kazui, Shusuke Numata, Masashi Ikeda, Tohru Ohnuma, Nakao Iwata, Shu-ichi Ueno, Norio Ozaki, Tetsuro Ohmori, Heii Arai and Masatoshi Takeda : Functional genetic variation at the NRGN gene and schizophrenia: evidence from a gene-based case-control study and gene expression analysis., American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, Vol.159B, No.4, 405-413, 2012.
(要約)
Genome-wide association and follow-up studies have reported an association between schizophrenia and rs12807809 of the NRGN gene on chromosome 11q24.2. We investigated the association of five linkage disequilibrium-tagging SNPs and haplotypes that cover the NRGN gene with schizophrenia in a Japanese sample of 2,019 schizophrenia patients and 2,574 controls to determine whether rs12807809 is the most strongly associated variant for schizophrenia in the vicinity of the NRGN gene. We found that the rs12807809-rs12278912 haplotype of the NRGN gene was associated with schizophrenia (global P = 0.0042). The frequencies of the TG and TA haplotypes of rs12807809-rs12278912 in patients were higher (OR = 1.14, P = 0.0019) and lower (OR = 0.85, P = 0.0053), respectively, than in the controls. We did not detect any evidence of association of schizophrenia with any SNPs; however, two nominal associations of rs12278912 (OR = 1.10, P = 0.057) and rs2075713 (OR = 1.10, P = 0.057) were observed. Furthermore, we detected an association between the rs12807809-rs12278912 haplotype and NRGN expression in immortalized lymphoblasts derived from 45 HapMap JPT subjects (z = 2.69, P = 0.007) and confirmed the association in immortalized lymphoblasts derived from 42 patients with schizophrenia and 44 healthy controls (z = 3.09, P = 0.002). The expression of the high-risk TG haplotype was significantly lower than the protective TA haplotype. The expression was lower in patients with schizophrenia than in controls; however, this difference was not statistically significant. This study provides further evidence of the association of the NRGN gene with schizophrenia, and our results suggest that there is a link between the TG haplotype of rs12807809-rs12278912, decreased expression of NRGN and risk of developing schizophrenia.
Yoshihiro Nakadoi, Satsuki Sumitani, Y Watanabe, M Akiyama, Naomi Yamashita and Tetsuro Ohmori : Multi-channel near-infrared spectroscopy reveals reduced activation in the prefrontal cortex during the facial expression processing in patients with pervasive developmental disorders, Psychiatry and Clinical Neurosciences, Vol.66, No.1, 26-33, 2012.
(要約)
The purpose of the present study was to investigate whether individuals with pervasive developmental disorders (PDD) show differential activation during an emotional activation task compared with age- and sex-matched controls, by measuring changes in the concentration of oxygenated (oxyHb) and deoxygenated (deoxyHb) hemoglobin, using near-infrared spectroscopy (NIRS). Fourteen patients with PDD and 14 age- and sex-matched healthy controls participated in the study. The relative changes of concentrations of oxyHb and deoxyHb were measured on NIRS during an implicit processing task of fearful expression using Japanese standard faces. PDD patients had significantly reduced oxyHb changes in the prefrontal cortex (PFC) compared to healthy controls. PFC dysfunction may exist in PDD.
Ryota Hashimoto, Kazutaka Ohi, Yuka Yasuda, Motoyuki Fukumoto, Hidenaga Yamamori, Kouzin Kamino, Takashi Morihara, Masao Iwase, Hiroaki Kazui, Shusuke Numata, Masashi Ikeda, Shu-ichi Ueno, Tetsuro Ohmori, Nakao Iwata, Norio Ozaki and Masatoshi Takeda : No association between the PCM1 gene and schizophrenia: A multi-center case-control study and a meta-analysis., Schizophrenia Research, Vol.129, No.1, 80-84, 2011.
(要約)
Alterations in centrosomal function have been suggested in the pathology of schizophrenia. The molecule pericentriolar material 1 (PCM1) is involved in maintaining centrosome integrity and in the regulation of the microtubule cytoskeleton. PCM1 forms a complex at the centrosome with the disrupted-in-schizophrenia 1 (DISC1) protein, which is a major susceptibility factor for schizophrenia. The association between genetic variants in the PCM1 gene and schizophrenia has been reported by several case-control studies, linkage studies and a meta-analysis. The aims of this study are to replicate the association between four single-nucleotide polymorphisms (SNPs) in the PCM1 gene and schizophrenia in a Japanese population (1496 cases and 1845 controls) and to perform a meta-analysis of the combined sample groups (3289 cases and 3567 controls). We failed to find a significant association between SNPs or haplotypes of the PCM1 gene and schizophrenia in the Japanese population (P>0.28). The meta-analysis did not reveal an association between the four examined SNPs and schizophrenia. Our data did not support genetic variants in the PCM1 gene as a susceptibility locus for schizophrenia.
(キーワード)
Adult / Asian Continental Ancestry Group / Autoantigens / Case-Control Studies / Cell Cycle Proteins / Female / Genetic Predisposition to Disease / Haplotypes / Humans / Japan / Male / Middle Aged / Polymorphism, Single Nucleotide / Schizophrenia
Taisuke Yoshida, Motomu Suga, Kunimasa Arima, Yasuko Muranaka, Tsunehiko Tanaka, Satoshi Eguchi, Crystal Lin, Sumiko Yoshida, Masanori Ishikawa, Yuko Higuchi, Tomonori Seo, Yoshinori Ueoka, Masahito Tomotake, Yasuhiro Kaneda, David Darby, Paul Maruff, Masaomi Iyo, Kiyoto Kasai, Teruhiko Higuchi, Tomiki Sumiyoshi, Tetsuro Ohmori, Kiyohisa Takahashi and Kenji Hashimoto : Criterion and Construct Validity of the Cogstate Schizophrenia Battery in Japanese Patients with Schizophrenia, PLoS ONE, Vol.6, No.5, e20469, 2011.
(要約)
The CogState Schizophrenia Battery (CSB), a computerized cognitive battery, covers all the same cognitive domains as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery but is briefer to conduct. The aim of the present study was to evaluate the criterion and construct validity of the Japanese language version of the CSB (CSB-J) in Japanese patients with schizophrenia. Forty Japanese patients with schizophrenia and 40 Japanese healthy controls with matching age, gender, and premorbid intelligence quotient were enrolled. The CSB-J and the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) were performed once. The structure of the CSB-J was also evaluated by a factor analysis. Similar to the BACS-J, the CSB-J was sensitive to cognitive impairment in Japanese patients with schizophrenia. Furthermore, there was a significant positive correlation between the CSB-J composite score and the BACS-J composite score. A factor analysis showed a three-factor model consisting of memory, speed, and social cognition factors. This study suggests that the CSB-J is a useful and rapid automatically administered computerized battery for assessing broad cognitive domains in Japanese patients with schizophrenia.
(キーワード)
Adult / Aged / Asian Continental Ancestry Group / Case-Control Studies / Cognition / Demography / Female / Humans / Japan / Male / Middle Aged / Neuropsychological Tests / Reproducibility of Results / Schizophrenia / Time Factors / Young Adult
Masahito Nakataki, Junichi Iga, Shusuke Numata, Eriko Yoshimoto, Kanami Kodera, Shinya Watanabe, Hongwei Song, Shu-ichi Ueno and Tetsuro Ohmori : Gene expression and association analysis of the epithelial membrane protein 1 gene in major depressive disorder in the Japanese population., Neuroscience Letters, Vol.489, No.2, 126-130, 2011.
(要約)
The epithelial membrane protein 1 (EMP1) plays a role in neuronal differentiation and neurite outgrowth, which are involved in the pathogenesis of major depressive disorder (MDD). We sought to determine whether the EMP1 gene is implicated in MDD. We determined the mRNA expression levels of the EMP1 gene in peripheral-blood leukocytes of patients and control subjects (n=27 each). Next, we performed case-control association analyses (MDD, n=182; controls, n=350) in the Japanese population. The level of expression of the EMP1 mRNA was significantly lower in medication-free patients compared with control subjects (P<0.001). The association analysis revealed an absence of association between the polymorphisms studied and MDD, whereas a gender-specific association was observed between male controls and male patients for marker rs7315725 (permutation P=0.039). Our results suggest that the EMP1 gene may be implicated in the pathophysiology of MDD in the Japanese population.
Yoshinori Ueoka, Masahito Tomotake, Tsunehiko Tanaka, Yasuhiro Kaneda, Kyoko Taniguchi, Masahito Nakataki, Shusuke Numata, Shinya Tayoshi, Ken Yamauchi, Satsuki Sumitani, Takashi Ohmori, Shu-ichi Ueno and Tetsuro Ohmori : Quality of life and cognitive dysfunction in people with schizophrenia, Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol.35, No.1, 53-59, 2011.
(要約)
The main purpose of the present study was to examine the relationship between quality of life (QOL) and cognitive dysfunction in schizophrenia. Subjects were 61 stabilized outpatients. Quality of life and cognitive function were assessed using the Quality of Life Scale (QLS) and the Brief Assessment of Cognition in Schizophrenia (BACS), respectively. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS). The BACS composite score and the BACS Verbal memory score were positively correlated with the QLS total score and two subscales. The BACS Attention and speed of information processing score had positive correlation with the QLS total and all the subscales scores. The PANSS Positive and Negative syndrome scores also had significant correlations with the QLS total score and all of the subscales. In addition, the CDSS score was negatively correlated with the QLS total score and some of the subscales. Stepwise regression analysis showed that the BACS Attention and speed of information processing score was an independent predictor of the QLS total score but it was less associated with the QLS than the PANSS Negative syndrome score and the CDSS score. The results suggest that negative and depressive symptoms are important factors on patients' QOL and also support the view that cognitive performance provides a determinant of QOL in patients with schizophrenia.
(キーワード)
Adult / Cognition Disorders / Female / Humans / Male / Middle Aged / Neuropsychological Tests / Predictive Value of Tests / Psychiatric Status Rating Scales / Quality of Life / Questionnaires / Retrospective Studies / Schizophrenia / Young Adult
Shinya Tayoshi, Masahito Nakataki, Satsuki Sumitani, Kyoko Taniguchi, Sumiko Tayoshi, Shusuke Numata, Junichi Iga, Shu-ichi Ueno, Masafumi Harada and Tetsuro Ohmori : GABA concentration in schizophrenia patients and the effects of antipsychotic medication: a proton magnetic resonance spectroscopy study., Schizophrenia Research, Vol.117, No.1, 83-91, 2010.
(要約)
Gamma-amino butyric acid (GABA) is thought to play a role in the pathophysiology of schizophrenia. High magnetic field proton magnetic resonance spectroscopy ((1)H-MRS) provides a reliable measurement of GABA in specific regions of the brain. This study measured GABA concentration in the anterior cingulate cortex (ACC) and in the left basal ganglia (ltBG) in 38 patients with chronic schizophrenia and 29 healthy control subjects. There was no significant difference in GABA concentration between the schizophrenia patients and the healthy controls in either the ACC (1.36+/-0.45 mmol/l in schizophrenia patients and 1.52+/-0.54 mmol/l in control subjects) or the ltBG (1.13+/-0.26 mmol/l in schizophrenia patients and 1.18+/-0.20 mmol/l in control subjects). Among the right handed schizophrenia patients, the GABA concentration in the ltBG was significantly higher in patients taking typical antipsychotics (1.25+/-0.24 mmol/l) than in those taking atypical antipsychotics (1.03+/-0.24 mmol/l, p=0.026). In the ACC, the GABA concentration was negatively correlated with the dose of the antipsychotics (rs=-0.347, p=0.035). In the ltBG, the GABA concentration was positively correlated with the dose of the anticholinergics (rs=0.403, p=0.015). To the best of our knowledge, this is the first study to have directly measured GABA concentrations in schizophrenia patients using (1)H-MRS. Our results suggest that there are no differences in GABA concentrations in the ACC or the ltBG of schizophrenia patients compared to healthy controls. Antipsychotic medication may cause changes in GABA concentration, and atypical and typical antipsychotics may have differing effects. It is possible that medication effects conceal inherent differences in GABA concentrations between schizophrenia patients and healthy controls.
The chitinase 3-like 1 (CHI3L1) gene acts as a cellular survival factor in response to several environmental and psychosocial stresses. The expression level of CHI3L1 was increased in the hippocampus and prefrontal cortex regions of patients with schizophrenia. Genetic variants of the CHI3L1 gene have been significantly associated with schizophrenia in two distinct ethnic groups, the Chinese and Irish populations. The aims of this study are to confirm the association between the CHI3L1 gene and schizophrenia in a Japanese population using the largest sample size to date (1463 cases and 1795 controls) and perform a meta-analysis of the combined samples (3005 cases, 3825 controls and 601 trios). We found significant associations between single nucleotide polymorphism (SNP) 4/rs4950928 (p=0.009), which is located in the promoter region of the CHI3L1 gene, and haplotypes including this SNP and schizophrenia (the most significant global p<0.001). As the meta-analysis of the combined samples showed significant heterogeneity among studies of SNP3/rs10399805 (p=0.026) and SNP4 (p<0.001), we performed meta-analyses separately in the Japanese (2033 cases and 2365 controls) and Chinese populations (412 cases, 464 controls and 601 trios), the major groups analyzed in association studies of the CHI3L1 gene. The meta-analysis in Japanese populations showed stronger evidence for the association of schizophrenia with SNP4 (p=0.003), while the meta-analysis in Chinese populations showed an association with a different variant (SNP3) (p=0.003). We conclude that the genetic variants in the CHI3L1 gene have ethnic heterogeneity and confer a susceptibility to schizophrenia in Asian populations.
(キーワード)
Adipokines / Adult / Aged / Asian Continental Ancestry Group / Case-Control Studies / Cross-Cultural Comparison / European Continental Ancestry Group / Female / Gene Frequency / Genetic Predisposition to Disease / Genome-Wide Association Study / Genotype / Glycoproteins / Humans / Lectins / Male / Middle Aged / Polymorphism, Single Nucleotide / Psychiatric Status Rating Scales / 統合失調症 (schizophrenia) / Young Adult
Shusuke Numata, Masahito Nakataki, Junichi Iga, Toshihito Tanahashi, Yoshihiro Nakadoi, Kazutaka Ohi, Ryota Hashimoto, Masatoshi Takeda, Mitsuo Itakura, Shu-ichi Ueno and Tetsuro Ohmori : Association Study Between the Pericentrin (PCNT) Gene and Schizophrenia., NeuroMolecular Medicine, Vol.12, No.3, 243-247, 2009.
(要約)
Disrupted-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia (SZ) and major depressive disorder (MDD), interacts with several proteins and some of them are reported to be genetically associated with SZ. Pericentrin (PCNT) also interacts with DISC1 and recently single-nucleotide polymorphisms (SNPs) within the PCNT gene have been found to show significant associations with SZ and MDD. In this study, case-controlled association analysis was performed to determine if the PCNT gene is implicated in SZ. Nine SNPs were analyzed in 1,477 individuals (726 patients with SZ and 751 healthy controls). No significant difference was observed between the controls and the patients in allelic frequencies or genotypic distributions of eight SNPs. Although allelic distribution of rs11702684 was different between the two groups (P = 0.042), the difference did not reach statistical significance after permutation correction for multiple comparisons. In the haplotypic analysis, we could not find any significant association in our subjects, either. This gene may not play a major role independently in the etiology of SZ in the Japanese population.
Masahito Nakataki, Shusuke Numata, Junichi Iga, Shin'ya Tayoshi, Sumiko Tayoshi-Shibuya, Hongwei Song, Toshihito Tanahashi, Mitsuo Itakura, Shu-ichi Ueno and Tetsuro Ohmori : No association between Rho-associated coiled-coil forming protein serine/threonine kinase1 gene and schizophrenia in the Japanese population., Psychiatric Genetics, Vol.19, No.3, 162, 2009.
Shusuke Numata, Junichi Iga, Masahito Nakataki, Shinya Tayoshi, Kyoko Taniguchi, Satsuki Sumitani, Masahito Tomotake, Toshihito Tanahashi, Mitsuo Itakura, Yoko Kamegaya, Masahiko Tsutsumi, Akira Sano, Takashi Asada, Hiroshi Kunugi, Shu-ichi Ueno and Tetsuro Ohmori : Gene expression and association analyses of the phosphodiesterase 4B (PDE4B) gene in major depressive disorder in the Japanese population., American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, Vol.150B, No.4, 527-534, 2009.
(要約)
The phosphodiesterase 4B (PDE4B) interacts with disrupted-in-schizophrenia 1 (DISC1), which is a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). PDE4B is also important in the regulation of cAMP signaling, a second messenger implicated in learning, memory, and mood. In this study, we determined mRNA expression levels of the PDE4B gene in the peripheral blood leukocytes of patients with MDD and control subjects (n = 33, each). Next we performed two-stage case-controlled association analyses (first set; case = 174, controls = 348; second set; case = 481, controls = 812) in the Japanese population to determine if the PDE4B gene is implicated in MDD. In the leukocytes, a significantly higher expression of the PDE4B mRNA was observed in the drug-naïve MDD patients compared with control subjects (P < 0.0001) and the expression of the MDD patients significantly decreased after antidepressant treatment (P = 0.030). In the association analysis, we observed significant allelic associations of four SNPs (the most significant, rs472952; P = 0.002) and a significant haplotypic association (permutation P = 0.019) between the PDE4B gene and MDD in the first-set samples. However, we could not confirm these significant associations in the following independent second-set of samples. Our results suggest that the PDE4B gene itself does not link to MDD but the elevated mRNA levels of PDE4B might be implicated in the pathophysiology of MDD.
(キーワード)
Adult / Aged / Alleles / Case-Control Studies / Cyclic Nucleotide Phosphodiesterases, Type 4 / Depressive Disorder, Major / Female / Gene Expression / Gene Frequency / Genetic Predisposition to Disease / Genotype / Haplotypes / Humans / Japan / Male / Middle Aged / RNA, Messenger
Shusuke Numata, Junichi Iga, Masahito Nakataki, Shinya Tayoshi, Toshihito Tanahashi, Mitsuo Itakura, Shu-ichi Ueno and Tetsuro Ohmori : Positive association of the pericentrin (PCNT) gene with major depressive disorder in the Japanese population., Journal of Psychiatry & Neuroscience, Vol.34, No.3, 195-198, 2009.
(要約)
BACKGROUND: Pericentrin (PCNT) interacts with disruption-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). We sought to determine whether the PCNT gene is implicated in MDD. METHODS: We performed case-control association analyses in the Japanese population. We analyzed 9 single nucleotide polymorphisms (SNPs) in 173 patients with MDD and 348 healthy controls. RESULTS: We found a significant allelic association between 3 SNPs (rs3788265, rs2073376 and rs2073380) of the PCNT gene and MDD (p = 0.006, 0.005 and 0.021, respectively). After correction for multiple testing, 2 SNPs (rs3788265 and rs2073376) retained significant allelic associations with MDD. In addition, we found a significant association between the 2 marker haplotypes (r3788265 and rs2073376) and MDD (permutation p = 0.011). LIMITATIONS: Our sample was small and comprised only Japanese participants. In addition, owing to the late onset of MDD, it is possible that the disorder will develop in at least some participants in our control group. Finally, we did not show how SNPs of the PCNT gene alter its function. CONCLUSION: Our results suggest that genetic variations in the PCNT gene may play a significant role in the etiology of MDD in the Japanese population.
(文献検索サイトへのリンク)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19448849
Kazutaka Ohi, Ryota Hashimoto, Yuka Yasuda, Tetsuhiko Yoshida, Hidetoshi Takahashi, Naomi Iike, Motoyuki Fukumoto, Hironori Takamura, Masao Iwase, Kouzin Kamino, Ryouhei Ishii, Hiroaki Kazui, Ryuji Sekiyama, Yuri Kitamura, Michiyo Azechi, Koji Ikezawa, Ryu Kurimoto, Eiichiro Kamagata, Hitoshi Tanimukai, Shinji Tagami, Takashi Morihara, Masayuki Ogasawara, Masayasu Okochi, Hiromasa Tokunaga, Shusuke Numata, Masashi Ikeda, Tohru Ohnuma, Shu-ichi Ueno, Tomoko Fukunaga, Toshihisa Tanaka, Takashi Kudo, Heii Arai, Tetsuro Ohmori, Nakao Iwata, Norio Ozaki and Masatoshi Takeda : Association study of the G72 gene with schizophrenia in a Japanese population: a multicenter study., Schizophrenia Research, Vol.109, No.1-3, 80-85, 2009.
(要約)
G72 is one of the most widely tested genes for association with schizophrenia. As G72 activates the D-amino acid oxidase (DAO), G72 is termed D-amino acid oxidase activator (DAOA). The aim of this study is to investigate the association between G72 and schizophrenia in a Japanese population, using the largest sample size to date (1774 patients with schizophrenia and 2092 healthy controls). We examined eight single nucleotide polymorphisms (SNPs), which had been associated with schizophrenia in previous studies. We found nominal evidence for association of alleles, M22/rs778293, M23/rs3918342 and M24/rs1421292, and the genotype of M22/rs778293 with schizophrenia, although there was no association of allele or genotype in the other five SNPs. We also found nominal haplotypic association, including M15/rs2391191 and M19/rs778294 with schizophrenia. However, these associations were no longer positive after correction for multiple testing. We conclude that G72 might not play a major role in the risk for schizophrenia in the Japanese population.
(キーワード)
Asian Continental Ancestry Group / Carrier Proteins / Female / Gene Frequency / Genetic Predisposition to Disease / Genome-Wide Association Study / Genotype / Haplotypes / Humans / Male / Middle Aged / Polymorphism, Single Nucleotide / Receptors, N-Methyl-D-Aspartate / 統合失調症 (schizophrenia)
Toshiyuki Yasui, Masayo Yamada, Hirokazu Uemura, Shu-Ichi Ueno, Shusuke Numata, Tetsuro Ohmori, Naoko Tsuchiya, Masamichi Noguchi, Mitsutoshi Yuzurihara, Yoshio Kase and Minoru Irahara : Changes in circulating cytokine levels in midlife women with psychological symptoms with selective serotonin reuptake inhibitor and Japanese traditional medicine., Maturitas, Vol.62, No.2, 146-152, 2009.
(要約)
OBJECTIVE: The aim of the present study was to compare the effects on serum cytokine concentrations of paroxetine, a selective serotonin re-uptake inhibitor, and kamishoyosan, a Japanese traditional medicine, in midlife women with psychological symptoms. METHODS: Seventy-six women with psychological symptoms such as anxiety and mild depression as menopausal symptoms were enrolled in this study. Thirty-eight women received oral administration of 10mg paroxetine every day, and 38 women received oral administration of kamshoyosan every day for 6 months. Overall climacteric symptoms were assessed using Greene's climacteric scale. Serum levels of cytokines were measured using a multiplexed human cytokine assay. RESULTS: Greene's total scores in both women treated with paroxetine and in women treated with kamishoyosan decreased significantly. Percentage decreases in Greene's total, psychological and vasomotor scores during the 6-month period in the paroxetine group were significantly greater than those in the kamishoyosan group. Serum IL-6 concentration in women treated with paroxetine decreased significantly. Serum concentrations of IL-8, IL-10, macrophage inflammatory protein (MIP)-1beta and monocyte chemoattractant protein-1 in women treated with paroxetine decreased significantly. On the other hand, serum IL-6 concentration in women treated with kamishoyosan decreased significantly, but other serum concentrations did not change significantly. CONCLUSION: Decrease in IL-6 concentration may be involved in the mechanism of the actions of both paroxetine and kamishoyosan in women with psychological symptoms, and IL-6 may therefore be useful as a marker of treatment. The action of paroxetine may also be associated with decreases in IL-8, IL-10, MIP-1beta.
(キーワード)
Administration, Oral / Angiosperms / Climacteric / Cytokines / Depression / Drugs, Chinese Herbal / Hot Flashes / Humans / Medicine, East Asian Traditional / Middle Aged / Paroxetine / Phytotherapy / Plant Extracts / Serotonin Uptake Inhibitors
Shin'Ya Tayoshi, Satsuki Sumitani, Kyoko Taniguchi, Sumiko Shibuya-Tayoshi, Shusuke Numata, Jun-ichi Iga, Masahito Nakataki, Shu-ichi Ueno, Masafumi Harada and Tetsuro Ohmori : Metabolite changes and gender differences in schizophrenia using 3-Tesla proton magnetic resonance spectroscopy (1H-MRS)., Schizophrenia Research, Vol.108, No.1-3, 69-77, 2008.
(要約)
A change in the glutamatergic system is thought to play an important role in the pathophysiology of schizophrenia. The aim of this study was to investigate the changes in metabolites, including glutamate (Glu), in the anterior cingulate cortex (ACC) and the left basal ganglia (ltBG) of patients with chronic schizophrenia using proton magnetic resonance spectroscopy ((1)H-MRS). In addition, since gender differences in this illness were known, we examined the effects of gender on these metabolites. The (1)H-MRS was performed on the ACC and ltBG of 30 patients with schizophrenia and 25 healthy individuals who acted as the control group. The levels of Glu, glutamine (Gln), creatine plus phosphocreatine (Cre), myo-inositol (mI), N-acetylaspartate (NAA), and choline-containing compounds (Cho) were measured. Two-way analysis of variance revealed that the illness significantly affected the levels of Glu and mI in the ACC; both metabolites were lower in the patients with schizophrenia as compared to the control subjects. The results also revealed that gender significantly affected the level of Gln in the ACC and the levels of Cre and NAA in the ltBG; the level of Gln in the ACC were higher in male subjects versus female subjects, whereas Cre and NAA levels in the ltBG were lower in male subjects as compared to female subjects. These results confirmed a change in the glutamatergic system and suggested an involvement of mI in the pathophysiology of schizophrenia.
(キーワード)
Adult / Analysis of Variance / Aspartic Acid / Basal Ganglia / Choline / Creatine / Female / Glutamic Acid / Gyrus Cinguli / Humans / Image Processing, Computer-Assisted / Inositol / Magnetic Resonance Spectroscopy / Male / Middle Aged / Protons / 統合失調症 (schizophrenia) / Sex Characteristics / Young Adult
Kiyoshi Kunika, Toshihito Tanahashi, Shusuke Numata, Shu-ichi Ueno, Tetsuro Ohmori, Naoto Nakamura, Kazue Tsugawa, Katsuyuki Miyawaki, Maki Moritani, Hiroshi Inoue and Mitsuo Itakura : Common coding variant in the TCF7L2 gene and study of the association with type 2 diabetes in Japanese subjects, Journal of Human Genetics, Vol.53, No.11-12, 972-982, 2008.
(要約)
Genetic variants of the transcription factor 7-like 2 (TCF7L2) gene affect the risk of type 2 diabetes in populations with multiple ethnic groups. However, a comprehensive survey of this gene has not been done for a Japanese population. Thus, we conducted this gene-based association study, in which the common genetic variants were analyzed. Using 24 Japanese type 2 diabetic subjects, we first screened a 9.5 kb region, which included the entire coding sequence, to assess potential functional variants of TCF7L2. Sequencing revealed a common coding variant (Pro477Thr) in exon 14 of TCF7L2 that was not enrolled in the public SNP database. Nineteen SNPs and the microsatellite DG10S478 were genotyped across the gene in 2,877 unrelated Japanese subjects. This independent screen identified the previously reported rs7903146 with a strongest association (allele P = 0.0001, odds ratio = 1.59 [95% confidence interval 1.25-2.01]), but there was no significant association between Pro477Thr and type 2 diabetes (allele P = 0.64). Expression of the Pro477Thr variant did not alter TCF7L2 expression in 30 lymphoblast cells. Although a genotypic effect of Pro477Thr on expression of TCF7L2 was not apparent, Pro477Thr was identified as a common variant of TCF7L2 in 2,877 Japanese subjects. Further functional studies are required to determine the possible effect of this coding variant on type 2 diabetes.
Mayumi YAMAMOTO, Masahito Tomotake and Tetsuro Ohmori : Construction and reliability of the Japanese version of the Adolescent Egocentrism-Sociocentrism(AES) scale and its preliminary application in the Japanese university students, The Journal of Medical Investigation : JMI, Vol.55, No.3 4, 254-259, 2008.
(要約)
In recent years, the problem of interpersonal relationships has been reported to be associated with various adolescent psychiatric problems. Egocentrism is one factor related to the problem of interpersonal relationships. The Adolescent Egocentrism-Sociocentrism (AES) scale is used to assess egocentrism in Western countries, but no such scale has been developed in Japan. The purpose of our current study was to develop the Japanese version of the AES scale and investigate the relationship between the egocentrism assessed by the AES scale and the self-consciousness assessed by the Japanese version of the self-consciousness scale. The original version of the AES scale was first translated into Japanese using the forward-backward method and examined for factorial reliability and validity. The results demonstrated that the Japanese version of the AES scale shows adequate factorial reliability and validity, but different from the original version the "egocentrism personal fable" subscale which measures the feeling that oneself is special and unique was not extracted in the Japanese version. We found a moderate correlation between the non-social focuses of the AES scale and the public self-consciousness subscale of the self-consciousness scale. This correlation suggests that a strong attention of others' view on oneself results in the avoidance of others. The Japanese version of the AES scale can examine egocentrism adequately together with sociocentrism and non-social focuses. As this scale is self-reporting and easy to complete, it may have practical utility in a clinical setting.
Ken Yamauchi, Hirofumi Aki, Masahito Tomotake, Junichi Iga, Shusuke Numata, Ikuyo Motoki, Yumiko Izaki, Shinya Tayoshi, Sawako Kinouchi, Satsuki Sumitani, Sumiko Tayoshi, Yumiko Takikawa, Yasuhiro Kaneda, Takahide Taniguchi, Yasuhito Ishimoto, Shu-ichi Ueno and Tetsuro Ohmori : Predictors of subjective and objective quality of life in outpatients with schizophrenia., Psychiatry and Clinical Neurosciences, Vol.62, No.4, 404-411, 2008.
(要約)
AIM: In recent years, greater attention has been given to quality of life (QOL) in schizophrenia and several studies reported that negative and depressive symptoms and cognitive dysfunction are related to patient QOL. But because a variety of QOL measures have been used in the previous studies, there seems to be no unanimous predictors for subjective and objective QOL. The purpose of the present study was to elucidate the relationship between clinical variables and subjective and objective QOL in outpatients with schizophrenia, using schizophrenia disease-specific QOL measures. Particular attention was paid to cognitive function as a predictor of QOL. METHODS: Schizophrenia symptoms of the Positive and Negative Syndrome Scale (PANSS) were divided into five factors: positive factor, negative factor, cognitive factor, emotional discomfort, and hostility. The study sample consisted of 84 schizophrenia outpatients. Subjective and objective QOL were assessed with Schizophrenia Quality of Life Scale (SQLS) and the Quality of Life Scale (QLS), respectively. RESULTS: Subjective QOL correlated significantly with emotional discomfort, positive factor, negative factor, extrapyramidal symptoms and cognitive factor, while objective QOL correlated with negative factor, cognitive factor, emotional discomfort, extrapyramidal symptoms, and dose of antipsychotics. Total score and three of four subscales in the QLS correlated significantly with cognitive factor, while cognitive factor had a significant correlation with only one of three scales of SQLS. Stepwise regression showed that subjective QOL was significantly predicted by emotional discomfort and extrapyramidal symptoms, while negative factor was the most important predictor of objective QOL. CONCLUSION: Cognitive dysfunction had a greater influence on objective QOL than subjective QOL. Treating depressive and negative symptoms and extrapyramidal symptoms might contribute to enhanced subjective and objective QOL.
(キーワード)
Adult / Affective Symptoms / Ambulatory Care / Antipsychotic Agents / Cognition Disorders / Dose-Response Relationship, Drug / Dyskinesia, Drug-Induced / Female / Humans / Male / Middle Aged / Motivation / Psychiatric Status Rating Scales / 生活の質 (quality of life) / 統合失調症 (schizophrenia) / Schizophrenic Psychology / Social Adjustment
Shusuke Numata, Shu-ichi Ueno, Junichi Iga, Ken Yamauchi, Song Hongwei, Ryota Hashimoto, Masatoshi Takeda, Hiroshi Kunugi, Mitsuo Itakura and Tetsuro Ohmori : TGFBR2 gene expression and genetic association with schizophrenia, Journal of Psychiatric Research, Vol.42, No.6, 425-432, 2008.
(要約)
TGFBR2 gene is a tumor suppressor gene located at chromosome 3p22, and the locus is reported to be linked with schizophrenia susceptibility. According to the previous studies, a reduced incidence of cancer is observed in schizophrenic patients compared with the general population and tumor suppressor genes may be associated with schizophrenia. We measured the mRNA expression of TGFBR2 gene in the peripheral leukocytes from 19 medication-free schizophrenics and 25 medication-free major depressive patients compared with age- and sex-matched control subjects using a quantitative real-time PCR method. We also followed up the TGFBR2 mRNA expression levels from 13 schizophrenics after several weeks - antipsychotic treatments. The TGFBR2 mRNA levels of medication free schizophrenics were significantly higher than those of control subjects and decreased to almost the same level as controls after antipsychotic treatment. On the other hand, the TGFBR2 mRNA levels of medication-free major depressive patients were not significantly different from controls. In genetic studies, we failed to find any association between the TGFBR2 gene and schizophrenia with 10 SNPs of TGFBR2 gene in Japanese subjects (279 subjects each) and there was no significant difference with haplotype analysis, either. Our results suggest that the TGFBR2 gene itself does not link to schizophrenia but that the TGFBR2 mRNA levels in the peripheral leukocytes may be a potential state marker for schizophrenia.
Shusuke Numata, Shu-ichi Ueno, Junichi Iga, Hongwei Song, Masahito Nakataki, Shinya Tayoshi, Satsuki Sumitani, Masahito Tomotake, Mitsuo Itakura, Akira Sano and Tetsuro Ohmori : Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population., Journal of Psychiatric Research, Vol.43, No.1, 7-12, 2008.
(要約)
The phosphodiesterase 4B (PDE4B) gene is located at 1p31, a susceptibility region for schizophrenia (SZ). Moreover, PDE4B interacts with DISC1, which is a known genetic risk factor for SZ. Recently, it was reported that the PDE4B gene is associated with SZ in Caucasian and African American populations. In this study, case-controlled association analyses were performed in the Japanese population to determine if the PDE4B gene is implicated in SZ. Thirteen single nucleotide polymorphisms (SNPs) were analyzed in 444 schizophrenic patients and 452 control subjects. Three SNPs (rs2180335, rs910694 and rs472952) were significantly associated with SZ after applying multiple test correction (p=0.039, 0.004 and 0.028). In addition, a significant association was found between specific haplotypes (rs2180335 and rs910694) and SZ (permutation p=0.001). Our result suggests that variations at the PDE4B locus may play a significant role in the etiology of SZ in the Japanese population.
(キーワード)
Asian Continental Ancestry Group / Case-Control Studies / Catechol O-Methyltransferase / Chromosome Mapping / Chromosomes, Human, Pair 1 / Control Groups / Cyclic Nucleotide Phosphodiesterases, Type 4 / Female / Gene Frequency / Genetic Markers / Genetic Predisposition to Disease / Genotype / Haplotypes / Humans / Linkage (Genetics) / Linkage Disequilibrium / Male / Middle Aged / Polymorphism, Single Nucleotide / Risk Factors / 統合失調症 (schizophrenia)
Shusuke Numata, Shu-ichi Ueno, Junichi Iga, Masahito Nakataki, Toshihito Tanahashi, Mitsuo Itakura, Akira Sano, Kazutaka Ohi, Ryota Hashimoto, Masatoshi Takada and Tetsuro Ohmori : No association between the NDE1 gene and schizophrenia in the Japanese population., Schizophrenia Research, Vol.99, No.1-3, 367-369, 2008.
(キーワード)
Adult / Aged / Alleles / Asian Continental Ancestry Group / Female / Gene Frequency / Genetic Predisposition to Disease / Genetics, Population / Genotype / Humans / Male / Microtubule-Associated Proteins / Middle Aged / Polymorphism, Single Nucleotide / 統合失調症 (schizophrenia)
Sawako Kinouchi, Junichi Iga, Shu-ichi Ueno, Ken Yamauchi, Shusuke Numata, Hongwei Song, Satsuki Sumitani, Sumiko Shibuya-Tayoshi, Mari Haku, Toshiyuki Yasui, Minoru Irahara, Kyoko Morita, Kazuhito Rokutan and Tetsuro Ohmori : FKBP5, SERT and COMT mRNA expressions in the peripheral leukocytes during menstruation cycle in healthy reproductive females., Neuroscience Letters, Vol.434, No.1, 124-128, 2008.
(要約)
There have been several evidences that the mRNA expressions in the peripheral leukocytes may indicate not only physical but also psychological states. The purpose of this study is whether the mRNA expressional changes in the leukocytes are related to the mental states across the menstrual cycle in reproductive healthy female subjects. Thirty-eight female subjects (22.4+/-1.4 year-old) were participated in this study at three menstruation cycle periods (menstrual, follicular and luteal phase). The FKBP5 (FK506-binding protein gene), SERT (serotonin transporter gene) and COMT (catechol-o-methyltransferase gene) mRNA expressions in the leukocytes were determined with hormonal data. The psychological changes were assessed with self-rating hospital anxiety and depression scale (HADS). Only one thirds of subjects (n=12) had regular menstrual cycles during the experiment. So we analyzed the data from these 12 subjects. The anxiety score of each subject was changed across the menstrual cycle (Friedman test: P<0.05). The FKBP5 mRNA expression was significantly lower in the follicular phase than in the other phases but no changes were seen in either SERT or COMT mRNA expressions among the phases. In conclusion, there are differences of HADS anxiety score and FKBP5 mRNA expression in the leukocytes across the menstrual cycle but there is no correlation between anxiety scores and FKBP5 mRNA.
Junichi Iga, Shu-ichi Ueno, Ken Yamauchi, Shusuke Numata, Sumiko Tayoshi-Shibuya, Sawako Kinouchi, Masahito Nakataki, Hongwei Song, Kazuhiko Hokoishi, Hirotaka Tanabe, Akira Sano and Tetsuro Ohmori : The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with psychotic feature and suicidal behavior in Japanese major depressive patients, American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, Vol.144, No.8, 1003-1006, 2007.
(要約)
Recent researches have suggested that brain-derived neurotrophic factor (BDNF) may be implicated in the pathophysiology of mood disorder. This study examined the association between the BDNF Val66Met polymorphism and major depressive disorder (MDD) in a Japanese population. We genotyped the BDNF Val66Met polymorphism in 154 major depressive patients and 154 age- and sex-matched control subjects. The genotypic distributions and allele frequencies were similar among the patients and control subjects. When the relationships of the polymorphism with several clinical variables (i.e., age, sex, age of onset, number of episode, presence of psychotic features, suicidal behavior, and family history) were examined, the dose of Met allele had significant effects on psychotic feature and suicidal behavior and family history. These results suggest that the BDNF Val66Met polymorphism is not related to the development of MDD but related to clinical features of MDD in a Japanese population.
(キーワード)
Adult / Age Distribution / Age of Onset / Brain-Derived Neurotrophic Factor / Case-Control Studies / Depressive Disorder, Major / Diagnostic and Statistical Manual of Mental Disorders / Female / Humans / Male / Methionine / Middle Aged / Polymorphism, Genetic / Psychotic Disorders / Sex Distribution / Suicide / Valine
兼田 康宏, Tomiki Sumiyoshi, Richard Keefe, 石元 康仁, 沼田 周助, 大森 哲郎 : Brief assessment of cognition in schizophrenia: validation of the Japanese version., Psychiatry and Clinical Neurosciences, Vol.61, No.6, 602-609, 2007年.
(要約)
This preliminary study was performed to test the reliability and validity of the Brief Assessment of Cognition in Schizophrenia (BACS) as an assessment tool in a Japanese-language version (BACS-J). The subjects for the present study were 30 outpatients with chronic schizophrenia. Each subject gave written informed consent to participate in the research. Cronbach's alpha for the BACS-J was 0.77. The BACS-J composite score was significantly correlated with all primary measures of BACS-J (verbal memory, working memory, motor speed, verbal fluency, attention, and executive function). All BACS-J primary measures and the composite score were significantly correlated between two assessments. The mean score of the Digit Sequencing Task and composite score on the second assessment were significantly larger than those on the first assessment. All BACS-J primary measures except the Symbol Coding Task were significantly correlated with relevant standard neurocognitive tests. Also, the BACS-J composite score was significantly correlated with all standard neurocognitive tests except the Continuous Performance Test. A principal components analysis with varimax rotation resulted in a three-factor solution (executive function and memory; motor speed and general cognitive functions; and working memory). This preliminary study indicates that the BACS-J is a reliable and practical scale to evaluate cognitive function.
Hongwei Song, Shu-ichi Ueno, Shusuke Numata, Junichi Iga, Sumiko Tayoshi, Masahito Nakataki, Shin'Ya Tayoshi, Ken Yamauchi, Satsuki Sumitani, Tomohito Tomotake, Tomohito Tada, Toshihito Tanahashi, Mitsuo Itakura and Tetsuro Ohmori : Association between PNPO and schizophrenia in the Japanese population, Schizophrenia Research, Vol.97, No.1-3, 264-270, 2007.
(要約)
Accumulating evidence suggests that both homocysteine metabolism and monoaminergic neurotransmitter systems are important in schizophrenia pathology. We hypothesized that the gene PNPO (pyridoxine 5'-phosphatase oxidase gene) might be a candidate for susceptibility to schizophrenia because PNPO encodes pyridoxamine 5'-phosphate oxidase (EC 1.4.3.5), a rate-limiting enzyme in pyridoxal 5'-phosphate (PLP, vitamin B(6)) synthesis. PLP is a metabolically-active form of vitamin B(6) and thus, is required as a co-factor for enzymes involved in both homocysteine metabolism and synthesis of neurotransmitters such as catecholamine. We examined 8 single nucleotide polymorphisms (SNPs) in PNPO and its 5'-flanking regions in 359 schizophrenia patients and 582 control subjects. Four marker regions of PNPO showed significant levels of allelic associations with schizophrenia (the highest was rs2325751, P=0.004). In addition, the haplotype case-control study revealed a significant association (permutation P<0.00001) between PNPO and schizophrenia. These findings suggest that variations in PNPO may contribute to overall genetic risk for schizophrenia in the Japanese population.
Junichi Iga, Shu-ichi Ueno, Ken Yamauchi, Shusuke Numata, Sumiko Tayoshi, Sawako Kinouchi, Masahito Nakataki, Song Hongwei, Kazuhiko Hokoishi, Hirotaka Tanabe, Akira Sano and Tetsuro Ohmori : Gene expression and association analysis of vascular endothelial growth factor in major depressive disorder, Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol.31, No.3, 658-663, 2007.
(要約)
Vascular endothelial growth factor (VEGF) has been implicated in neuronal survival, neuroprotection, regeneration, growth, differentiation, and axonal outgrowth, which are known to be involved in the pathophysiology of major depressive disorder (MDD). Recently, the VEGF mRNA expression in the peripheral leukocytes from Alzheimer's disease or cardiovascular disease was reported to be changed. We hypothesized that the expression of the VEGF mRNA in the peripheral leukocytes may be a good candidate for the biological marker for MDD. Thirty two patients with MDD and age- and sex-matched control subjects were included in this expression study. The VEGF mRNA levels in the peripheral leukocytes from drug-naive MDD patients were significantly higher than those from the control subjects and the magnitude of the decrease of VEGF mRNA after 8-week treatment significantly correlated with clinical improvement. Then, we genotyped two single nucleotide polymorphic markers of VEGF gene, which were reported to be associated with amyotrophic lateral sclerosis and Alzheimer's disease, in patients with MDD and control subjects (n=154, each). We did not find any significant association between these markers and MDD or its clinical subtypes. Our investigation indicates that the higher expression levels of VEGF mRNA in the peripheral leukocytes are associated with the depressive state and their recovery after treatment may be associated with the clinical improvement.
Junichi Iga, Shu-ichi Ueno, Ken Yamauchi, Shusuke Numata, Sawako Kinouchi, Sumiko Tayoshi-Shibuya, Hongwei Song and Tetsuro Ohmori : Altered HDAC5 and CREB mRNA expressions in the peripheral leukocytes of major depression, Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol.31, No.3, 628-632, 2007.
(要約)
Gene expressions of the peripheral leukocytes in depressive patients might reflect the systemic dysfunction of major depression. We determined mRNA expression levels of Histone deacetylase 5 (HDAC5) gene and cyclic AMP response element-binding protein 1 (CREB) gene in the leukocyte of depressive patients. HDAC5 and CREB are reported to be important targets of antidepressants, the latter being located in the downstream of the former in lymphocyte calcium signaling. 25 patients with major depression and 25 age- and sex-matched healthy controls were included in this study. Twenty patients were able to be followed up until the 8 week-treatment. The mRNA levels were determined by a quantitative RT-PCR method. Levels of HDAC5 and CREB mRNA were significantly higher in drug-free depressive patients than those of controls and the higher mRNA levels decreased to control levels after 8-week paroxetine treatment. There were positive correlation between levels of HDAC5 and CREB. Our results suggest the alteration of HDAC5 and CREB gene expression in the systemic pathophysiology of major depression.
Toshiyuki Yasui, Masahiko Maegawa, Junko Tomita, Yuka Miyatani, Masayo Yamada, Hirokazu Uemura, Shu-ichi Ueno, Shusuke Numata, Tetsuro Ohmori, Naoko Tsuchiya, Mitsutoshi Yuzurihara, Shuichi Takeda and Minoru Irahara : Association of serum cytokine concentrations with psychological symptoms in midlife women., Journal of Reproductive Immunology, Vol.75, No.1, 56-62, 2007.
(要約)
The purpose of the present study was to clarify the association of serum cytokine concentrations, determined using a multiplexed cytokine assay, with psychological symptoms in midlife women. Fifty-three peri- and post-menopausal women with and without psychological symptoms in Greene's climacteric scale were enrolled in this study. Levels of 17 cytokines in serum samples were measured simultaneously using a multiplexed human cytokine assay. Serum interleukin (IL)-6 concentration in women with psychological symptoms (2.71+/-047 pg/ml) was significantly (p=0.009) higher than that in women without psychological symptoms (0.98+/-0.18 pg/ml). Serum IL-8 concentration in women with psychological symptoms (33.4+/-8.17 pg/ml) was also significantly (p=0.022) higher than that in women without psychological symptoms (7.87+/-1.64 pg/ml). In addition, serum IL-10 concentration in women with psychological symptoms (0.74+/-0.26 pg/ml) was significantly (p=0.048) higher than that in women without psychological symptoms (0.07+/-0.04 pg/ml). Tumor necrosis factor (TNF)-alpha in serum was detected only in women with psychological symptoms. Serum IL-2 concentration in women with psychological symptoms tended (p=0.066) to be higher than that in women without psychological symptoms. No significant differences were found between levels of other cytokines in women with and without psychological symptoms. Psychological stress manifested as climacteric symptoms in midlife women may be associated with increases in serum concentrations of IL-6, IL-8, IL-10, and TNF-alpha.
Shusuke Numata, Shu-ichi Ueno, Junichi Iga, Ken Yamauchi, Song Hongwei, Ryota Hashimoto, Masatoshi Takeda, Hiroshi Kunugi, Mitsuo Itakura and Tetsuro Ohmori : Gene expression in the peripheral leukocytes and association analysis of PDLIM5 gene in schizophrenia, Neuroscience Letters, Vol.415, No.1, 28-33, 2007.
(要約)
PDLIM5 modulates neuronal calcium signaling, co-localizes with synaptic vesicles of neurotransmitters and positive association between its gene and schizophrenia was reported but its relation is still ambiguous. The differential expression of the PDLIM5 gene both in the brain and in the lymphoblasts has been found in schizophrenia compared to control subjects. In this study, we measured the expression level of the PDLIM5 gene transcripts in the peripheral leukocytes from 19 medication-free and 21 chronically medicated schizophrenic patients as well as age- and sex-matched control subjects using a quantitative real-time PCR method. The mRNA levels of the PDLIM5 gene in the leukocytes of medication-free schizophrenic patients were significantly higher than those of control subjects. On the other hand, our group has previously shown that its mRNA expression in the leukocytes of medication-free major depressive patients was significantly lower compared with controls. There was no difference in the PDLIM5 mRNA levels between chronic schizophrenic patients with antipsychotic medication and their controls. Further, we failed to find any genetic association between the PDLIM5 gene and schizophrenia with six single nucleotide polymorphics (SNPs) of the PDLIM5 gene in Japanese subjects (279 subjects each) and there was no significant relation between PDLIM5 gene and schizophrenia with the haplotype analysis (P=0.48), either. We suggest that the higher expression levels of the PDLIM5 mRNA in the peripheral leukocytes may be a candidate marker for medication-free schizophrenic patients.
(キーワード)
Adaptor Proteins, Signal Transducing / Adolescent / Adult / Antipsychotic Agents / Asian Continental Ancestry Group / Case-Control Studies / DNA Mutational Analysis / Female / Gene Expression Regulation / Genetic Markers / Genetic Predisposition to Disease / Genetic Testing / Genotype / Humans / 日本 (Japan) / LIM Domain Proteins / Leukocytes / Male / Middle Aged / Polymorphism, Single Nucleotide / RNA, Messenger / 統合失調症 (schizophrenia) / Up-Regulation
看護職は高い専門性や自律性を求められると同時に,確認や清潔などの徹底も要求される.職場適応障害や燃え尽き症候群など心身医学的治療を要する症状を訴える者も多い.女性看護職に対する質問紙調査では強迫傾向が指摘される.われわれは,心身医学的見地より女性看護職の強迫傾向を検討し,強迫傾向と抑うつ度がQuality of Life (QOL)に与える影響の違いを比較した.自己記入式質問紙MOCI邦訳版(Maudsley Obsessional Compulsive Inventory)による強迫傾向群は16.3%と多かった.心身症患者の心理的特徴とされるアレキシサイミア(失感情症:alexithiymia)傾向は,強迫傾向に有意な相関を示した.アレキシサイミアの中でも「感情の同定困難因子」が,強迫傾向の「確認」「優柔不断」「疑惑」の高さと関係していた.抑うつ度は年齢層やQOL構成項目に限定されず,主観的QOLの低さと相関した.しかし強迫傾向は,若年女性看護職では「身体的領域」「心理的領域」の主観的QOLの低さと相関し,熟年看護職においては「社会的関係」の主観的QOLの高さと相関し,年齢や主観的QOLの領域により異なる影響をもたらす可能性が示唆された.若年看護職は強迫傾向と同時にアレキシサイミア傾向も高く,アレキシサイミアの中でも感情の同定困難と主観的QOLの低さとが関係していた.今後,このような若年看護職に対する心理的サポートをどのようなかたちで,どのような方法で行っていくのかが問われ,心身医学的検討が待たれるところである.
Masahito Tomotake, Yasuhiro Kaneda, Junichi Iga, Sawako Kinouchi, Sumiko Tayoshi, Ikuyo Motoki, Satsuki Sumitani, Ken Yamauchi, Takahide Taniguchi, Yasuhito Ishimoto, Shu-ichi Ueno and Tetsuro Ohmori : Subjective and objective measures of quality of life have different predictors for people with schizophrenia., Psychological Reports, Vol.99, No.2, 477-487, 2006.
(要約)
This study investigated the relationship between subjective and objective quality of life and assessed predictors in people with schizophrenia. The study population consisted of 99 stabilized outpatients with schizophrenia (DSM-IV) who had been regularly receiving outpatient treatment at the Department of Psychiatry, The Tokushima University Hospital. Subjective and objective quality of life were estimated using the Schizophrenia Quality of Life Scale and the Quality of Life Scale, respectively. Psychiatric symptoms were also measured with the Brief Psychiatric Rating Scale and the Calgary Depression Scale for Schizophrenia. Scores on the Schizophrenia Quality of Life Scale Motivation and Energy scales significantly correlated with the Quality of Life Scale total scores -.40 (p <.001), and with the scores on Interpersonal Relations subscale -.42 (p <.001), Instrumental Role subscale -.28 (p = .005), Intrapsychic Foundations subscale -.39 (p<.001), and Common Objects and Activities subscale -.25 (p =.014). The Schizophrenia Quality of Life Scale Psychosocial scale significantly correlated with only the Quality of Life Scale total score -.20 (p =.05), and there was no significant correlation between the scores on the Schizophrenia Quality of Life Scale Symptoms and Side-effects scales and the Quality of Life Scale. Stepwise regression analyses showed that the Calgary Depression Scale for Schizophrenia score was the most important predictor of each scale of the Schizophrenia Quality of Life Scale, and the Brief Psychiatric Rating Scale Negative Symptoms score was the most important predictor of the Quality of Life Scale total score and each subscale. These results suggest that subjective and objective quality of life have different predictors and should be considered as separate and complementary outcome variables.
(キーワード)
Adult / Ambulatory Care / Brief Psychiatric Rating Scale / Cross-Sectional Studies / Depressive Disorder / Female / Humans / Japan / Male / Middle Aged / Quality of Life / Schizophrenia / Schizophrenic Psychology
Junichi Iga, Shu-ichi Ueno, Ken Yamauchi, Shusuke Numata, Ikuyo Motoki, Sumiko Tayoshi, Sawako Kinouchi, Koshi Ohta, Hongwei Song, Kyoko Morita, Kazuhito Rokutan, Hirotaka Tanaba, Akira Sano and Tetsuro Ohmori : Gene expression and association analysis of LIM (PDLIM5) in major depression., Neuroscience Letters, Vol.400, No.3, 203-207, 2006.
(要約)
LIM (PDLIM5) is a small protein that interacts with protein kinase C-epsilon and the N-type calcium channel alpha-1B subunit and modulates neuronal calcium signaling. Recently, the LIM mRNA expression in postmortem brains and immortalized lymphoblastoid cells from mood disorder patients was reported to be changed and seems to be involved in its pathophysiology. We hypothesized that the expression of the LIM mRNA in the native peripheral leukocytes may be a good candidate for the biological marker for mood disorders. Twenty patients with major depression and age- and sex-matched control subjects were included in this expression study. The LIM mRNA levels in the peripheral leukocytes from drug-naive depressive patients were significantly lower than those from control subjects and increased significantly after 4-week paroxetine treatments, to almost the same level as controls'. Hamilton depressive scores (HAM-D) were improved about 50% after 4-week treatment but neither paroxetine concentrations nor the changes of HAM-D scores showed significant correlation with the change of the mRNA levels. Then, we genotyped three single nucleotide polymorphic markers of LIM gene, which were reported to be associated with bipolar disorder in patients with major depression and control subjects (n=130, each), but there were no associations between these SNPs and major depression. Our investigation indicates that the lower expression levels of LIM mRNA in the peripheral leukocytes are associated with the depressive state and that its recovery after treatment may be an adaptive change induced by the antidepressant.
Shusuke Numata, Shu-ichi Ueno, Junichi Iga, Ken Yamauchi, Song Hongwei, Koji Ohta, Sawako Kinouchi, Sumiko Shibuya-Tayoshi, Shin'ya Tayoshi, Michitaka Aono, Naomi Kameoka, Satsuki Sumitani, Masahito Tomotake, Yasuhiro Kaneda, Takahide Taniguchi, Yasuhito Ishimoto and Tetsuro Ohmori : Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in schizophrenia is associated with age at onset and symptoms., Neuroscience Letters, Vol.401, No.1-2, 1-5, 2006.
(要約)
Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that promotes several functions of neurons and modulates neurotransmissions. It has been reported that there are alterations of BDNF levels in schizophrenic brains and that BDNF gene expressional changes would be responsible for the etiology of schizophrenia. Recent studies have shown that a variation of BDNF gene (Val66Met polymorphism) affects the function of neurons, and is associated with several neurological and psychiatrical disorders. We investigated the relationship between BDNF Val66Met polymorphism and the onset age as well as levels of clinical symptoms in 159 of chronic schizophrenia in-patients diagnosed by DSM-IV. The mean onset ages were 27.5+/-9.5 for BDNF Val/Val, 25.5+/-7.4 for BDNF Val/Met and 22.9+/-6.0 for BDNF Met/Met and this polymorphism was significantly associated with age at onset (P=0.023). The mean Brief Psychiatric Rating Scale scores (BPRS) were significantly different among those three groups (P=0.003). No significant differences were demonstrated comparing the BDNF genotype distributions of positive and negative family history (P=0.21). Our investigation indicates that the BDNF gene Val66Met polymorphism is related to the onset age of schizophrenia and the levels of clinical symptoms that remain after long-term antipsychotic treatment.
(キーワード)
Adult / Age of Onset / Aged / Amino Acid Substitution / Antipsychotic Agents / 脳 (brain) / Brain Chemistry / Brain-Derived Neurotrophic Factor / DNA Mutational Analysis / Drug Resistance / Female / Gene Frequency / Genetic Predisposition to Disease / Genetic Testing / Genotype / Humans / Male / Methionine / Middle Aged / Polymorphism, Genetic / 統合失調症 (schizophrenia) / Valine
Satsuki Sumitani, Tsunehiko Tanaka, Shinya Tayoshi, Koshi Ota, naomi Kameoka, Shu-ichi Ueno and Tetsuro Ohmori : Activation of the prefrontal cortex during the Wisconsin Card Sorting Test as measured by multichannel near-infrared spectroscopy., Neuropsychobiology, Vol.53, No.2, 70-76, 2006.
(要約)
The Wisconsin Card Sorting Test (WCST) is a neuropsychological test to evaluate the function of the prefrontal cortex (PFC). However, inconsistent results have been reported concerning whether this task activates the PFC symmetrically or asymmetrically. To investigate the brain activation in the PFC during the WCST, we examined blood oxygenation changes of healthy subjects by using multichannel near-infrared spectroscopy (NIRS). Subjects were 32 healthy volunteers, 18 males and 14 females. The WCST was administered using a computerized version, and the hemodynamic changes of the PFC during the WCST were measured by a 24-channel NIRS system. A bilateral increase in oxygenated hemoglobin (oxyHb) was observed in the PFC in 20 subjects during the WCST. However, 5 subjects showed predominant activation on the left side and 3 subjects one on the right side. No oxyHb change was observed in 4 subjects, although they had good performances in the WCST. These results directly confirmed that the PFC was activated during the WCST in vivo by using the optical technique and suggested that the distribution of the activation in the PFC is different among healthy individuals.
Yasuhiro Kaneda, Ichiro Kawamura and Tetsuro Ohmori : Correlation between the plasma homovanillic acid levels and the response to atypical antipsychotics in male patients with schizophrenia, Clinical Neuropharmacology, Vol.28, No.6, 262-264, 2005.
(要約)
The authors investigated the effects of atypical antipsychotic drugs-olanzapine, perospirone, and quetiapine-on plasma homovanillic acid (pHVA) in male patients with chronic schizophrenia. In this prospective, open-label study, the subjects were 30 inpatients who were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for schizophrenia. The authors switched patients from typical antipsychotic drugs to olanzapine, perospirone, or quetiapine. Each patient gave informed consent for the research. pHVA was assessed before and after switching medications. After the switch, the authors found a significant improvement in psychotic symptoms, nonsignificant improvement in extrapyramidal symptoms, and a nonsignificant reduction in pHVA. In addition, the baseline pHVA correlated positively with the score changes from baseline in the Brief Psychiatric Rating Scale (BPRS) total, positive, and negative symptoms in the group with a whole sample and in the olanzapine-treated group, and with the score changes in the BPRS total and positive symptoms in the quetiapine-treated group. Our findings indicated that the preswitching pHVA levels could be used to predict changes in the psychotic symptoms of male patients with chronic schizophrenia when switching to atypical antipsychotic drugs.
Junichi Iga, Shu-ichi Ueno, K Yamauchi, I Motoki, S Tayoshi, K Ohta, H Song, Kyoko Morita, Kazuhito Rokutan and Tetsuro Ohmori : Serotonin transporter mRNA expression in peripheral leukocytes of patients with major depression before and after treatment with paroxetine., Neuroscience Letters, Vol.389, No.1, 12-16, 2005.
(要約)
Serotonin transporter (5HTT) is thought to be involved in the pathophysiology of major depression and the target of antidepressants. We hypothesized that 5HTT mRNA levels in peripheral leukocytes may be associated with depressive states and the therapeutic response to antidepressant treatments. Fifteen patients with major depression and age-, sex-matched control subjects were studied. 5HTT mRNA levels were determined with quantitative real-time PCR method. 5HTT mRNA levels in leukocytes were significantly higher in depressive patients at baseline (before medication) than in control subjects. 5HTT mRNA levels were decreased significantly after 8 weeks of paroxetine medication compared with those at baseline. Our investigation suggested that the increased expression of 5HTT mRNA in peripheral leukocytes may be related with the pathophysiology of depression and its reduction after treatment may reflect the adaptive change induced by the antidepressant.
Satsuki Sumitani, Tsunehiko Tanaka, Shin'Ya Tayoshi, Koshi Ota, Naomi Kameoka, Mizuki Morimune, Sumiko Shibuya-Tayoshi, Sawako Kinouchi, Shu-ichi Ueno and Tetsuro Ohmori : Hemodynamic changes in the prefrontal cortex during mental works as measured by multi channel near-infrared spectroscopy (NIRS), The Journal of Medical Investigation : JMI, Vol.52, No.Supplement, 302-303, 2005.
(要約)
To investigate the brain activation in the prefrontal cortex (PFC) during mental works, we examined blood oxygenation changes of healthy subjects by using multi channel near infrared spectropcopy (NIRS). It was directly confirmed that the PFC was activated during mental tasks in vivo and it was suggested that distribution of the activation in the PFC is different among healthy individuals.
(キーワード)
near infrared spectropcopy (NIRS) / prefrontal cortex (PFC) / the wisconsin card sorting test (WCST) / the verbal fluency test (VFT) / the uchida-kraepelin test (UKT)
Nobuyasu Bando, Kumi Watanabe, Masahito Tomotake, Takahide Taniguchi and Tetsuro Ohmori : Central pontine myelinolysis associated with a hypoglycemic coma in anorexia nervosa, General Hospital Psychiatry, Vol.27, No.5, 372-374, 2005.
(キーワード)
Adult / Anorexia Nervosa / Coma / Female / Humans / Hypoglycemia / Myelinolysis, Central Pontine
In this study, we have developed a microarray including 1467 cDNAs that were selected to specifically measure stress response in peripheral blood leukocytes. Venous blood was collected from 10 graduate students 2 h before and 2 or 24 h after an open presentation for their Ph.D. The mRNA levels in leukocytes were compared with those prepared 4 weeks before the presentation. Hierarchical cluster showed that distinct groups of genes uniformly changed their expression values in response to the stress. Bayesian t test identified significantly up-regulated 49 genes and down-regulated 21 genes. Most of them are categorized into cytokines, cytokine receptors, growth- or apoptosis-related molecules, and heat shock proteins, suggesting that stressful life events trigger acute responses in leukocytes. Our results suggest that gene expression profile in peripheral blood leukocytes may be a potentially useful method for the assessment of complex stress responses.
Shusuke Numata, Song Hongwei, Shu-ichi Ueno and Tetsuro Ohmori : The effect of milnacipran (serotonin noradrenaline reuptake inhibitor) on memory in Korsakoff's syndrome after encephalitis, General Hospital Psychiatry, Vol.27, No.3, 224-226, 2005.
Yasuhiro Kaneda and Tetsuro Ohmori : Relation between estradiol and negative symptoms in men with schizophrenia, The Journal of Neuropsychiatry and Clinical Neurosciences, Vol.17, No.2, 239-242, 2005.
(要約)
The authors tested the hypothesis that estradiol would be associated with negative symptoms in 30 male schizophrenia inpatients. Medications were switched from typical to atypical antipsychotics. Estradiol concentrations were inversely correlated with negative symptoms significantly before the switch and at a trend level of significance after the switch. Changes in negative symptoms were positively correlated with those in estradiol concentrations at a trend level of significance. Estradiol could be a biological marker for negative symptoms even in male schizophrenia patients.
Shusuke Numata, On Kato, Hitoshi Misawa, Hiroshi Tokuda, Toshihiko Kasahara and Tetsuro Ohmori : Left atrial thrombosis associated with antipsychotic drugs, Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol.29, No.1, 153-155, 2005.
(要約)
The authors report a case of a 36-year-old shizophrenic patient with left atrial thrombosis. There have been small number of case reports of antipsychotic drugs-associated thromboembolic events. All of them are venous ones. This paper describes the first case of atrial thrombosis associated with antipsychotic drugs.
(キーワード)
抗精神病薬 (antipsychotic drugs) / Left atrial thrombosis / 統合失調症 (schizophrenia)
Jun-ichi Iga, Takahide Taniguchi and Tetsuro Ohmori : Acute abdominal distension secondary to urinary retention in a patient after alcohol withdrawal., Alcohol and Alcoholism, Vol.40, No.1, 86-87, 2004.
(要約)
Several cases of alcohol-induced bladder dysfunction have been reported previously, but the mechanism of its development is varied and unclear. We report a case of symptomatic abdominal distension due to urinary retention after alcohol withdrawal. The timing of the onset suggests that it was induced by alcohol withdrawal.
Eiji Takeda, Junji Terao, Yutaka Nakaya, Ken-ichi Miyamoto, Yoshinobu Baba, Hiroshi Chuman, Ryuji Kaji, Tetsuro Ohmori and Kazuhito Rokutan : Stress control and human nutrition, The Journal of Medical Investigation : JMI, Vol.51, No.3-4, 139-145, 2004.
(要約)
Stress is a pervasive factor in everyday life that critically affects development and functioning. Severe and prolonged stress exposure impairs homeostatic mechanisms, particularly associated with the onset of depressive illness. Brain food is aimed at preventing as well as treating a growing number of stress-related mental disorders. Some topics on the association of stress and nutrition is reviewed. (1) An increased activity of serotonergic neurons in the brain is an established consequence of stress. An increase in brain tryptophan levels on the order of that produced by eating a carbohydrate-rich/protein-poor meal causes parallel increases in the amounts of serotonin released into synapses. (2) Eating is thought to be suppressed during stress, due to anorectic effects of corticotrophin releasing hormone, and increased during recovery from stress, due to appetite stimulating effects of residual cortisol. (3) A strong inverse association between coffee intake and risk of suicide. (4) Night eating syndrome has been found to occur during periods of stress and is associated with poor results at attempts to lose weight and disturbances in the hypothalamic-pituitary-adrenal axis. (5) Dietary antioxidants present in fruits and vegetables may improve cognitive function. Therefore, it is concluded that the establishment of functional foods that correctly regulate stress response must be firmly based upon scientific knowledge and legal regulation.
Ken Yamauchi, Koushi Ohta, Takahide Taniguchi and Tetsuro Ohmori : A case of social phobia with obsessive-compulsive symptoms improved by paroxetine in combination with risperidone, General Hospital Psychiatry, Vol.26, No.3, 242-243, 2004.
Yasuhiro Kaneda, Ichiro Kawamura, Akira Fujii and Tetsuro Ohmori : Impact of a switch from typical to atypical antipsychotic drugs on quality of life and gonadal hormones in male patients with schizophrenia, Neuroendocrinology Letters, Vol.25, No.1-2, 135-140, 2004.
(要約)
We investigated the effects of a switch from typical to atypical antipsychotic drugs (olanzapine, n=8; perospirone, n=9; or quetiapine, n=13) on quality of life and hypothalamo-pituitary-gonadal axis hormones. The subjects were 30 male chronic schizophrenia inpatients. The assessment was done before and after the switch. After the switch, (i) scores of the Brief Psychiatric Rating Scale total and three factors (anxiety-depression, anergia, and thought disturbance) decreased, (ii) the overall severity score of the Drug Induced Extra-Pyramidal Symptoms Scale tended to decrease, (iii) prolactin decreased but gonadal hormones remained unchanged, and (iv) scores on all three subscales (psychosocial, motivation/energy, and symptoms/side effects) in the Japanese version of the Schizophrenia Quality of Life Scale (JSQLS) decreased. However, there were no significant group effects, or time-by-group interactions. In addition, score changes from baseline in psychosocial and motivation/energy subscales in the JSQLS were correlated with those in psychotic symptoms, particularly in the anxiety-depression factor. Moreover, responders had been taking lower doses of typical antipsychotic drugs, and had higher serum estradiol concentrations than non-responders before the switch. The study indicated that the switch to atypical antipsychotic drugs was effective in reducing elevated prolactin without affecting the gonadal hormones and in improving quality of life patients who had been treated with typical antipsychotic drugs.
(キーワード)
Adult / Analysis of Variance / Antipsychotic Agents / Benzodiazepines / Dibenzothiazepines / Gonadal Steroid Hormones / Humans / Hypothalamo-Hypophyseal System / Indoles / Isoindoles / Male / Pituitary-Adrenal System / Prolactin / Prospective Studies / Psychiatric Status Rating Scales / Quality of Life / Schizophrenia / Schizophrenic Psychology / Sickness Impact Profile / Statistics as Topic / Thiazoles
(文献検索サイトへのリンク)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15159697
Yasuhiro Kaneda and Tetsuro Ohmori : Impact of risperidone medication on quality of life and gonadal axis hormones in schizophrenia male patients with acute exacerbation, The International Journal of Neuropsychopharmacology, Vol.6, No.3, 247-252, 2003.
(要約)
We investigated the effects of risperidone on quality of life (QoL) and hypothalamo-pituitary-gonadal (HPG) axis hormones. In this prospective, open-label study, the subjects were 10 male schizophrenia patients with acute exacerbation. After a mean period of 44.6 d treatment, patients were taking a mean dose of 7.0 mg risperidone daily. After treatment, we found that (i) the total BPRS score decreased, (ii) the scores on psychosocial and motivation/energy subscales in the Japanese version of the Schizophrenia Quality of Life Scale decreased, but the scores on symptoms/side-effects subscale did not, (iii) prolactin increased, but the HPG axis hormones did not change, and (iv) the mean plasma homovanillic acid concentration decreased. Eight patients needed anticholinergic medications, one patient reported impotence, and one patient reported ejaculatory dysfunction during treatment. Our findings suggested that risperidone might improve psychosocial and motivation/energy QoL subscales, and increase prolactin without affecting the HPG axis hormones.
Yasuhiro Kaneda and Tetsuro Ohmori : Effects of quetiapine on gonadal axis hormones in male patients with schizophrenia: a preliminary, open study, Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol.27, No.5, 875-878, 2003.
(要約)
The authors investigated the effects of a novel antipsychotic agent, quetiapine administration on hypothalamo-pituitary-gonadal (HPG) axis hormones in patients with chronic schizophrenia. In this prospective, open-label study, the subjects were nine male inpatients. We tried to switch the patients from typical antipsychotics to quetiapine. The patients took a mean dose of 636.1 mg quetiapine daily for a mean period of 104.7 days. (i) Although the total Brief Psychiatric Rating Scale score did not show significant changes, no patients needed anticholinergic medications after the switch. (ii) Before the switch, only the prolactin concentration showed a significant difference between the patients and normal subjects. After the switch, neither prolactin nor HPG axis hormone concentrations showed significant differences between the groups. Our preliminary results indicated that quetiapine might not affect prolactin and HPG axis hormones at least in chronic schizophrenia patients with normal levels of HPG axis hormones.
Yasuhiro Kaneda, Ichiro Kawamura, Akira Fujii and Tetsuro Ohmori : Repetitive behaviors in chronic schizophrenia: using the Japanese version of the Elgin Behavior Rating Scale (JEBRS), International Journal of Neuroscience, Vol.113, No.6, 879-890, 2003.
(要約)
The main aim of this study was to test the reliability and value of the Japanese Elgin Behavior Rating Scale (JEBRS) with 92 schizophrenia patients. Cronbach's alpha for the JEBRS was 0.61. All inter-rater reliability coefficients were in the satisfactory range. The JEBRS had a high stability over time. Almost all of the correlations among the nine item scores and total score in the JEBRS were significant. The total score for nine repetitive behaviors in the JEBRS was positively correlated with positive and negative symptoms. This study showed that the JEBRS is a useful and reliable scale.
Yasuhiro Kaneda, Akira Imakura, Akira Fujii and Tetsuro Ohmori : Schizophrenia Quality of Life Scale: validation of the Japanese version, Psychiatry Research, Vol.113, No.1-2, 107-113, 2002.
(要約)
This study was performed to test the validity and value of the Schizophrenia Quality of Life Scale as an assessment tool in a Japanese-language version (JSQLS). The subjects for the present study were 55 inpatients with a diagnosis of schizophrenia as defined by DSM-IV. The JSQLS was administered together with two other self-report measures, the Medical Outcomes Study 36-item short-form health survey questionnaire (SF-36) and the WHO QOL-26, to assess validity. Psychotic symptoms and extrapyramidal symptoms were assessed using the BPRS and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), respectively. All the scales (psychosocial, motivation/energy and symptoms/side effects) showed good internal consistency reliability (Cronbach's alpha=0.93, 0.73 and 0.80, respectively). The correlations of items with their scale total revealed that almost all items were significantly correlated with their own scale score. There were associations with relevant SF-36, WHO QOL-26, and DIEPSS scores. From the results of the testing of the reliability and validity of the JSQLS, it is concluded that the JSQLS is a simple and reliable scale.
(キーワード)
Adult / Factor Analysis, Statistical / Female / Humans / Language / Male / Middle Aged / Quality of Life / Questionnaires / Reproducibility of Results / Schizophrenia / Schizophrenic Psychology / Translating
Masahito Tomotake and Tetsuro Ohmori : Personality profiles in patients with eating disorders, The Journal of Medical Investigation : JMI, Vol.49, No.3-4, 87-96, 2002.
(要約)
The present review focused on the personality profiles of patients with eating disorders. Studies using the Structured Clinical Interview for DSM-III-R Personality Disorder showed high rates of diagnostic co-occurrence between eating disorders and personality disorders. The most commonly observed were histrionic, obsessive-compulsive, avoidant, dependent and borderline personality disorders. Studies using the Cloninger's personality theory suggested that high Harm Avoidance might be relevant to the pathology of anorexia nervosa and high Novelty Seeking and Harm Avoidance to bulimia nervosa. Moreover, high Self-Directedness was suggested to be associated with favorable outcome in bulimia nervosa. The assessment of personality in a cross-sectional study, however, might be influenced by the various states of the illness. Therefore, a sophisticated longitudinal study will be required to advance this area of research.
Yasuhiro Kaneda, Akira Fujii and Tetsuro Ohmori : The hypothalamic-pituitary-adrenal axis in chronic schizophrenic patients long-term treated with neuroleptics, Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol.26, No.5, 935-938, 2002.
(要約)
The authors investigated the hypothalamic-pituitary-adrenal (HPA) axis of regularly medicated schizophrenic patients. The subjects were 53 patients who were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders--Fourth Edition (DSM-IV) criteria for schizophrenia. Each patients gave informed consent for the research. Psychiatric symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Based on the dosages of neuroleptics (NLPs), the subjects were classified into two groups: those with lower dosages (LD) and those with higher dosages (HD). (a) The medicated schizophrenic patients had significantly higher plasma corticotropin (ACTH) levels than the normals. (b) There was no significant difference in plasma cortisol levels between the schizophrenic patients and normals. (c) There was a significant difference in plasma ACTH levels between the HD and normal groups, but not between the LD and normal groups. (d) There was no significant difference in administration periods of NLPs, positive (POS) or negative symptoms (NES) between the HD and LD groups. (e) There was a positive correlation between the plasma ACTH and plasma cortisol levels in patients. Our results showed that, in chronic schizophrenic patients long-term treated with NLPs, ACTH secretion was elevated.
Yasuhiro Kaneda, Yasuhito Ishimoto and Tetsuro Ohmori : Evaluation of quazepam treatment of anxiety with insomnia, Brain Pharmacology, Vol.1, 209-213, 2002.
193.
Yasuhiro Kaneda, Tetsuro Ohmori and Akira Fujii : The serotonin syndrome: investigation using the Japanese version of the Serotonin Syndrome Scale, Psychiatry Research, Vol.105, No.1-2, 135-142, 2001.
(要約)
This preliminary study was performed to investigate the prevalence of the serotonin syndrome in a group of Japanese patients in a clinical setting and to test the reliability and value of the Serotonin Syndrome Scale (SSS) as an assessment tool in a Japanese-language version (JSSS). Twenty-three patients, all being treated with serotonin agonists, gave informed consent to participate. Only one patient fulfilled strict diagnostic criteria of the serotonin syndrome and none of the JSSS scores reached the cutoff point of the SSS. Cronbach's alpha coefficient for the JSSS was 0.56. All inter-rater reliability coefficients were in the excellent range, and the JSSS had a high stability over time. The mean dose of fluvoxamine in the subgroup with high scores on the JSSS was significantly larger than that in the subgroup with low scores and there was a positive but non-significant correlation between total JSSS scores and doses of fluvoxamine. This preliminary study indicates that (1) a full serotonin syndrome was a rare phenomenon in a group of Japanese patients in a clinical setting and (2) the JSSS is a simple and reliable scale for evaluating the serotonin syndrome.
(キーワード)
Adult / Aged / Cross-Cultural Comparison / Female / Humans / Japan / Male / Middle Aged / Neurologic Examination / Reproducibility of Results / Serotonin Syndrome
Jun-Ichi Iga, Makoto Araki, Yasuhito Ishimoto and Tetsuro Ohmori : A case of Korsakoff's syndrome improved by high doses of donepezil., Alcohol and Alcoholism, Vol.36, No.6, 553-555, 2001.
(要約)
We present a case of Korsakoff's syndrome that was successfully treated with high doses of donepezil, an inhibitor of acetylcholine esterase, known to retard the progress of symptoms in Alzheimer's disease. The patient was a 46-year-old married Japanese woman who began to drink alcohol after she married. After several years of drinking she developed typical symptoms of the Korsakoff syndrome. Donepezil was started after treatment with thiamine or thiamine plus fluvoxamine had failed. Her amnestic symptoms as well as her quality of life improved markedly during donepezil treatment. Inhibition of acetylcholine esterase may be an effective treatment for Korsakoff's syndrome.
Yasuhiro Kaneda, Yasuhito Ishimoto and Tetsuro Ohmori : Mild serotonin syndrome on fluvoxamine, International Journal of Neuroscience, Vol.109, No.3-4, 165-172, 2001.
(要約)
This preliminary study was performed to investigate the prevalence and severity of the serotonin-related symptoms for a group of patients in a clinical setting during fluvoxamine (FLU) using the Japanese version of the Serotonin Syndrome Scale (JSSS). The subjects for the present study were 37 patients (20 and 17 patients with mood and anxiety disorders, respectively), meeting a diagnosis of DSM-IV. Each subject gave informed consent for the research involved in this study. Presence and severity of the serotonin-related symptoms were determined by Sternbach's criteria and the JSSS, respectively. (1) At the time of assessment, none of the patients fulfilled the diagnostic criteria of SS proposed by Sternbach, or none of the total JSSS scores of the patients was sufficient to reach the cutoff point of 7. (2) Sixteen of the 37 patients (43.2%) showed at least one symptom in the JSSS. (3) Spearman's rank correlations showed that there was a positive but nonsignificant correlation between the total JSSS scores and dosages of FLU. This preliminary study suggested that milder forms of the serotonin syndrome may exist for a group of patients in a clinical setting during FLU therapy.
(キーワード)
Adult / Dose-Response Relationship, Drug / Female / Fluvoxamine / Humans / Male / Middle Aged / Mood Disorders / Prevalence / Psychiatric Status Rating Scales / Serotonin Syndrome / Serotonin Uptake Inhibitors / Severity of Illness Index
(文献検索サイトへのリンク)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11699328
Yasuhiro Kaneda, Akira Fujii and Tetsuro Ohmori : Stereotyped behaviors in chronic schizophrenia in a Japanese mental hospital, International Medical Journal, Vol.8, No.1, 35-39, 2001.
Tetsuro Ohmori, Tomohiro Abekawa and Tsukasa Koyama : Context determines the type of sensitized behaviour:a brief review and a hypothesis on the role of environment in behavioural sensitization., Behavioural Pharmacology, Vol.11, No.3·4, 211-221, 2000.
201.
Yasuhiro Kaneda, Akira Fujii and Tetsuro Ohmori : Psychometric properties of the Japanese version of the Calgary Depression Scale for Schizophrenics, The Journal of Nervous and Mental Disease, Vol.188, No.4, 237-239, 2000.
Tetsuro Ohmori, Kouichi Ito, Tomohiro Abekawa and Tsukasa Koyama : Psychotic relapse and maintenance therapy in paranoid schizophrenia:a 15 year follow up, European Archives of Psychiatry and Clinical Neuroscience, Vol.249, 73-78, 1999.
学術レター:
1.
Ryoma Morigaki, Masahito Nakataki, Toshitaka Kawarai, Lillian V. Lee, Rosalia A. Teleg, Ma Daisy P. Tabuena, Hideo Mure, Wataru Sako, Paul Matthew D. Pasco, Shinji Nagahiro, Junichi Iga, Tetsuro Ohmori, Satoshi Goto and Ryuji Kaji : Depression in X-linked dystonia-parkinsonism:A case-control study, Parkinsonism & Related Disorders, Vol.19, No.9, 844-846, 2013.
Hidehiro Umehara, Satsuki Sumitani and Tetsuro Ohmori : Restless legs syndrome with chest and back restlessness as the initial symptom, Psychiatry and Clinical Neurosciences, Vol.64, No.2, 211, 2010.
(キーワード)
Back / Diagnosis, Differential / Humans / Magnetic Resonance Imaging / Male / Middle Aged / Psychomotor Agitation / Restless Legs Syndrome / Thorax
Yasuhiro Kaneda and Tetsuro Ohmori : Quetiapine Impact on Quality of Life in Patients with Schizophrenia, The Annals of Pharmacotherapy, Vol.37, No.6, 917-918, 2003.
(キーワード)
Adult / Dibenzothiazepines / Humans / Middle Aged / Quality of Life / Schizophrenia
Yasuhiro Kaneda, Ichiro Kawamura, Akira Fujii and Tetsuro Ohmori : Serotonin syndrome - 'potential' role of the CYP2D6 genetic polymorphism in Asians, The International Journal of Neuropsychopharmacology, Vol.5, No.1, 105-106, 2002.
Yasuhiro Kaneda, Tetsuro Ohmori and Hiromichi Okabe : Possible mild serotonin syndrome related to co-prescription of tandospirone and trazodone, General Hospital Psychiatry, Vol.23, No.2, 98-101, 2001.
Typical antipsychotic drugs were introduced in 1950's. Atypical antipsychotics developed in 1990's and 2000's have been reported to show superiority over typical antipsychotics. However, when comparison was made with a low dose of a typical drug, the superiority disappeared in some studies. Both types of antipsychotics have in common a pharmacological property to decrease dopamine D2 receptor neurotransmission. Polypharmacy once prevailed in Japan and a high dose therapy once dominated in western countries should not be used anymore. The proper dose of typical antipsychotics is much lower than the dose used previously. Typical as well as atypical antipsychotics should be used as monotherapy with a proper dosage. It is of clinical significance for treatment staffs to become to pay more attention to quality of life and rehabilitation of patients.
Tomohiko Nakayama, Hiroaki Edo, Yoshida Tomohiro, Matsumoto Yui, Shinya Watanabe, Masahito Nakataki, Shusuke Numata and Tetsuro Ohmori : Nortriptyline Therapy of Treatment-Resistant Depression: two case reports, The CINP 2021 Virtual World Congress, Online, Feb. 2021.
2.
Shinya Watanabe, Hidehiro Umehara, Yukiko Tomioka, Makoto Kinoshita, Masahito Nakataki, Shusuke Numata and Tetsuro Ohmori : Effects of processing conditions on plasma L-glutamate levels in non-psychiatric healthy subjects., 6th Congress of AsCNP Asian College of Neuropsychopharmacology, Fukuoka, Oct. 2019.
3.
Masashi Ohta, Masahito Nakataki, Tomoya Takeda, Shusuke Numata, Takeo Tominaga, Naomi Kameoka, Hiroko Kubo, Makoto Kinoshita, Matsuura Kanae, Maki Ohtomo, Takeichi Naoya, Masafumi Harada and Tetsuro Ohmori : Causal relationship between salience network dysfunction, depressed mood, and subjective quality of life in schizophrenia., 6th Congress of AsCNP Asian College of Neuropsychopharmacology, Fukuoka, Oct. 2019.
4.
Yukiko Tomioka, Hidehiro Umehara, Shinya Watanabe, Masahito Nakataki, Masuda Rumiko, Kazuaki Mawatari, Takeshi Nikawa, Akira Takahashi, Shusuke Numata and Tetsuro Ohmori : Altered plasma metabolites related to one-carbon metabolism in schizophrenia., WFSBP Asia Pacific Regional Congress of Biological Psychiatry, Kobe, Sep. 2018.
5.
Tomoya Takeda, Masahito Nakataki, Masashi Ohta, Hamatani Sayo, Matsuura Kanae, Yoshida Reona and Tetsuro Ohmori : Relationship clinical variables and positive self-thought in patients with schizophrenia., The 46th BABCP Annual Workshops and Conference, Glasgow, Scotland., Jul. 2018.
6.
Tetsuro Ohmori : Partnership with patients and their family in an psychiatric meeting; taking an example in the 13th Annual Meeting of the Japanese Society of Schizophrenia Research in Tokushima., The Royal Australian and New Zealand College of Psychiatrists (RANZCP), Auckland, New Zealand, May 2018.
7.
Tomoya Takeda, Masahito Nakataki, Masashi Ohta, Hamatani Sayo, Matsuura Kanae and Tetsuro Ohmori : The effect of negative thoughts on QOL in patients with schizophrenia., The 45th BABCP Annual Workshops and Conference, Manchester, Jul. 2017.
8.
Hidehiro Umehara, Shinya Watanabe, Makoto Kinoshita, Shusuke Numata and Tetsuro Ohmori : Pharmacometabolomic changes following antidepressants in patients with major depressive disorder., 5th Congress of Asian College of Neuropsychopharmacology, Indonesia, Apr. 2017.
9.
Shinya Watanabe, Hidehiro Umehara, Makoto Kinoshita, Kazuo Ishii, Shusuke Numata and Tetsuro Ohmori : Gene expression-based diagnostic marker for bipolar disorder., 5th Congress of Asian College of Neuropsychopharmacology, Indonesia, Apr. 2017.
10.
Hamatani Sayo, Masahito Tomotake, Tomoya Takeda, Naomi Kameoka, Masashi Kawabata, Hiroko Kubo, Yukio Tada, Yukiko Tomioka, Shinya Watanabe and Tetsuro Ohmori : Characteristics of social cognition in women with anorexia nervosa., London Eating Disorders Confirence., London, Mar. 2017.
11.
Sayo Hamatani, Masahito Tomotake, Tomoya Takeda, Naomi Kameoka, Masashi Kawabata, Hiroko Kubo, Yukio Tada, Yukiko Tomioka, Shinya Watanabe and Tetsuro Ohmori : Impaired social cognition in anorexia nervosa patients, 13th London International Eating Disorders Conference, Vol.12, 2527-2531, London, Mar. 2017.
(要約)
The purpose of this study was to investigate the characteristics of social cognition in patients with anorexia nervosa (AN). Eighteen female patients with AN (mean age =35.4±8.6 years) and 18 female healthy controls (HC) (mean age =32.8±9.4 years) participated in the study. Their social cognition was assessed with the Social Cognition Screening Questionnaire (SCSQ). The results showed that total score of the SCSQ and scores of theory of mind and metacognition were significantly lower in AN group than those in HC group. Moreover, significant differences in theory of mind, metacognition, and total score of the SCSQ remained when the effects of depression, anxiety, and starvation were eliminated statistically. These results suggest that patients with AN may have difficulty inferring other people's intention and also monitoring and evaluating their own cognitive activities. Therefore, these features may explain some aspects of the pathology of AN.
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Issei Imoto, Ryota Hashimoto and Tetsuro Ohmori : DNA methylation changes in leukocytes by clozapine treatment in patients with treatment-resistant schizophrenia., Society for Neuroscience 2016 annual Meeting, San Diego, Nov. 2016.
13.
Hidehiro Umehara, Shusuke Numata, Shinya Watanabe, Satsuki Sumitani and Tetsuro Ohmori : Altered Serotonin transporter mRNA expression in the peripheral leukocytes of obsessive-compulsive disorder., 30th CINP World Congress of Neuropsychopharmacology, Seoul, Jul. 2016.
14.
Masashi Ohta, Y Funakoshi, Masafumi Harada, Junichi Iga, Hiroko Kubo, Masahito Nakataki, C Nakayama, T Nishikawa, Shusuke Numata, Tetsuro Ohmori, Satsuki Sumitani, M Tamaru and A. Uezato : Structural and functional brain alterations in schizophrenia patients treated with D-cycloserine:a combination of VBM and resting-state functional connectivity study., 30th CINP World Congress of Neuropsychopharmacology, Seoul, Jul. 2016.
15.
Tomoya Takeda, Satsuki Sumitani, Masahito Nakataki, Sayo Hamatani, Y Yokose, M Shikata and Tetsuro Ohmori : Relationship between WAIS- and AQ in Japanese ASD patients with average intelligence quotient., 31st International Congress of Psychology, Tokyo, Jul. 2016.
16.
Sayo Hamatani, Masahito Tomotake, Tomoya Takeda, Chikako Kane and Tetsuro Ohmori : Social cognition in women with eating disorder, 31st International Congress of Psychology, Jul. 2016.
17.
Sayo Hamatani, Masahito Tomotake, Tomoya Takeda, Chikako Kane and Tetsuro Ohmori : Set Shifting and Centarl Coherence in Eating Disorders, 31st International Congress of Psychology, Tokyo, Jul. 2016.
18.
Tomoya Takeda, Sayo Hamatani, M Tamaru, Masahito Tomotake, Motohiro Sakai and Tetsuro Ohmori : Successful cognitive behavioral intervention in a case of psychogenic hearing loss, 8th World Congress of Behavioral and Cognitive Therapies, Jun. 2016.
19.
Tomoya Takeda, Masahito Tomotake, Yoshinori Ueoka, T Tanaka, Takeo Tominaga, Yasuhiro Kaneda and Tetsuro Ohmori : Relationship between cognitive function and employment in Japanese schizophrenia patients, 8th World Congress of Behavioral and Cognitive Therapies, Jun. 2016.
20.
Hidehiro Umehara, Shusuke Numata, Atsushi Tajima, A NISHI, Issei Imoto, Satsuki Sumitani and Tetsuro Ohmori : A genome-wide association study of the long-term clinical response to SSRI or SSRI with antipsychotics in obsessive-compulsive disorder in the Japanese population, Neuroscience, Chicago, Oct. 2015.
21.
Shusuke Numata, Makoto Kinoshita, Atsushi Tajima, K OHI, R HASHIMOTO, S SHIMODERA, Issei Imoto, M TAKEDA and Tetsuro Ohmori : The effect of blood cellular heterogeneity on DNA methylation in schizophrenia, Neuroscience, Chicago, Oct. 2015.
22.
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, A NISHI, Issei Imoto and Tetsuro Ohmori : Genome-wide association study of plasma total homocysisteine in schizophrenia, Neuroscience, Chicago, Oct. 2015.
23.
A NISHI, Shusuke Numata, Atsushi Tajima, Makoto Kinoshita, S SHIMODERA, S ONO, S OCHI, N KUROTAKI, A IMAMURA, Shu-ichi Ueno, Issei Imoto and Tetsuro Ohmori : Trio-based exome sequencing identified de novo non-synonymous missense mutations in schizophrenia., Neuroscience, Chicago, Oct. 2015.
24.
Tetsuro Ohmori : The mental health support to the great east Japan earthquake stricken areas - Contribution of Tokushima University, 20th National Conference on Medical and Health Sciences, Kota Bharu, Kelantan, Sep. 2015.
25.
Tetsuro Ohmori : Diagnosis and treatment of depression and stress related disorders., 20th National Conference on Medical and Health Sciences, Kota Bharu, Kelantan, Sep. 2015.
26.
Shusuke Numata, Ishii Kazuo, Atsushi Tajima, Junichi Iga, Makoto Kinoshita, Shinya Watanabe, Hidehiro Umehara, Fuchikami Manabu, Okada Satoshi, Shimodera Shinji, Issei Imoto, Morinobu Shigeru and Tetsuro Ohmori : Blood diagnostic biomarkers for major depressive disorder using DNA methylation profiles., Neuroscience, Washington DC, Nov. 2014.
27.
Masatoshi Inoshita, Shusuke Numata, Atsushi Tajima, Makoto Kinoshita, Issei Imoto and Tetsuro Ohmori : Sex differences of blood in DNA methylation., Neuroscience, Washington DC, Nov. 2014.
28.
Hidehiro Umehara, Shusuke Numata, Atsushi Tajima, Makoto Kinoshita, Nakaaki Shutaro, Issei Imoto, Satsuki Sumitani and Tetsuro Ohmori : Association between the COMT Val158Met polymorphism and the clinical response to SSRI or SSRI with antipsychotics in obsessive-compulsive disorder., Neuroscience, Washington DC, Nov. 2014.
29.
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, Nishi Akira, Issei Imoto and Tetsuro Ohmori : Blood homocysteine and schizophrenia evaluated by a Mendelian randomization analysis., Neuroscience, Washington DC, Nov. 2014.
30.
Shinya Watanabe, Junichi Iga, Shusuke Numata, S Shimodera, H Fujita, K Ishii and Tetsuro Ohmori : Leukocyte gene expression-based diagnostic test for major depressive disorder: A pilot and replication study., 29th CINP World Congress of Neuropsychopharmacology, Canada, Jun. 2014.
31.
Junichi Iga, K Nakamura, N Matsumoto and Tetsuro Ohmori : Risk for bipolar disorder and physical comorbidity in patients initially hospitalized with severe depression:Results of a retrospective chart review., 29th CINP World Congress of Neuropsychopharmacology, Canada, Jun. 2014.
32.
Tetsuro Ohmori : Diagnosis and treatment of antidepressant-resistant depression., 台湾生物学的精神医学会, Taipei, Mar. 2014.
33.
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, Kazutaka Ohi, Ryota Hashimoto, Shinji Shimodera, Issei Imoto, Masatoshi Takeda and Tetsuro Ohmori : The effect of MTHFR C677T on DNA methylation of peripheral leukocytes in schizophrenia., Neuroscience, San Diego, Nov. 2013.
34.
Akira Nishi, Shusuke Numata, Atsushi Tajima, Kumiko Kikuchi, Makoto Kinoshita, Shinji Shimodera, Masahito Tomotake, Issei Imoto and Tetsuro Ohmori : Total plasma homocysteine and schizophrenia: gender and MTHFR C677T genotypes., Neuroscience, San Diego, Nov. 2013.
35.
Masahito Nakataki, M Harada and Tetsuro Ohmori : Glutamate and GABA concentrations in schizophrenia patients and the effects of antipsychotic medication: results from proton magnetic resonance spectroscopy studies., The 3rd Congress of Asian College of Neuropsychopharmacology, China, Sep. 2013.
36.
Satsuki Sumitani and Tetsuro Ohmori : Clinical features and response to pharmacotherapy in patients with obsessive-compulsive disorder., 11th World Congress of Biological Psychiatry, Kyoto, Jun. 2013.
37.
Masahito Nakataki, Satsuki Sumitani, Hiroko Kubo, Shusuke Numata, Junichi Iga, Shinya Watanabe, Makoto Kinoshita, Masafumi Harada and Tetsuro Ohmori : Structural brain asymmetry in obsessive-compulsive disorder., 11th world congress of biological psychiatry, Kyoto, Jun. 2013.
38.
Shinya Watanabe, Junichi Iga, Shusuke Numata, Makoto Kinoshita and Tetsuro Ohmori : Biological diagnostic test for major depressive disorder based on the leukocytes gene expression: Preliminary study., 11th world congress of biological psychiatry, Kyoto, Jun. 2013.
39.
Shusuke Numata, Makoto Kinoshita, Atsushi Tajima, Shinji Shimodera, Junichi Iga, Shinya Watanabe, Issei Imoto and Tetsuro Ohmori : Genome-wide methylation status of human leukocytes in mood disorders., 11th world congress of biological psychiatry, Kyoto, Jun. 2013.
40.
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, Shinji Shimodera, Issei Imoto and Tetsuro Ohmori : Genome-wide association study of plasma homocysteine and DNA methylation in patients with schizophrenia., 11th world congress of biological psychiatry, Kyoto, Jun. 2013.
41.
Shusuke Numata, Kumiko Kikuchi, Atsushi Tajima, Makoto Kinoshita, Shinji Shimodera, Masahito Tomotake, Issei Imoto and Tetsuro Ohmori : Plasma homocysteine and schizophrenia: A gender-specific meta-analysis., 11th world congress of biological psychiatry, Kyoto, Jun. 2013.
42.
Tetsuro Ohmori : An experience of clozapine in Japan Expert meeting, The 3rd Asian Congress on Schizophrenia Research, Bali Indonesia, Feb. 2013.
43.
Tetsuro Ohmori : Cognitive dysfunction associates with some clinical symptoms. Symposium:On improving functioning in schizophrenia, The 3rd Asian Congress on Schizophrenia Research, Bali Indonesia, Feb. 2013.
44.
Shusuke Numata, Makoto Kinoshita, Atsushi Tajima, Shinji Shimodera, Junichi Iga, Shinya Watanabe, Issei Imoto and Tetsuro Ohmori : Blood-based DNA methylation biomarkers for schizophrenia., Neuroscience, New Orleans, Oct. 2012.
45.
Yoshihiro Nakadoi, Naomi Kameoka, Masahito Tomotake and Tetsuro Ohmori : The characteristics of eating disorder inpatients in a Japanese university hospital, IACAPAP 20th World Congress, Paris, Jul. 2012.
46.
Yoshihiro Nakadoi, Naomi Kameoka, Masahito Tomotake and Tetsuro Ohmori : The characteristics of eating disorder inpatients in a Japanese university hospital, IACAPAP 20th World Congress, Paris, Jul. 2012.
47.
Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, Shinya Watanabe, Junichi Iga, S Shinji, Issei Imoto and Tetsuro Ohmori : Genome-wide DNA methylation analysis using peripheral blood samples derived from unmedicated patients with schizophrenia., 28th CINP Congress, Stockholm, Jun. 2012.
48.
Masahito Nakataki, Satsuki Sumitani, Hiroko Kubo, Masafumi Harada and Tetsuro Ohmori : Caudate asymmetry in obesessive compulsive disorder: A voxel based morphometry study, 28th CINP World Congress of Neuropsychopharmacology, Stockholm, Jun. 2012.
49.
Hiroko Kubo, Sumiko Tayoshi, Satsuki Sumitani and Tetsuro Ohmori : Effects of Lithium on the Cognitive Function in healthy Volunteers, 2nd Congress of Asian College of Neuropsychopharmacology, Seoul, Sep. 2011.
50.
Takeo Tominaga, 井下 真利, Shinya Tayoshi and Tetsuro Ohmori : Seven year-acute and maintenance modified electroconvulsive therapy for an elderly patient with catatonia, 2nd Congress of Asian College of Neuropsychopharmacology, Sep. 2011.
51.
Masahito Nakataki, Shinya Tayoshi, Hiroko Kubo, Junichi Iga, Shinya Watanabe, Satsuki Sumitani, Masafumi Harada and Tetsuro Ohmori : Amino acid neurotransmission in schizophrenia patients and the effects of antipsychotic medication: A proton magnetic resonance spectroscopy study, 10th World Conbress of Biological Psychiatry, Prague, Czech Republic, Jun. 2011.
52.
Satsuki Sumitani, 渡部 幸奈, 秋山 麻衣 and Tetsuro Ohmori : Relationship between he level of difficulty of task and hemodynamic change measured by NIRS, 10th World Conbress of Biological Psychiatry, Prague, Czech Republic, Jun. 2011.
53.
Shinya Watanabe, Junichi Iga, Masahito Nakataki, Shusuke Numata, 菊地 久美子 and Tetsuro Ohmori : Association study of fat-mass and obesity-associated(FTO) gene and body mass index in a Japanese schizophrenia and healthy Japanese population, 10th World Conbress of Biological Psychiatry, Prague, Czech Republic, May 2011.
54.
Junichi Iga, 菊地 久美子, Shinya Tayoshi, Masahito Nakataki, Shinya Watanabe, Shusuke Numata and Tetsuro Ohmori : SOCS3, a candidate gene for the molecular effects of lithium and pathophysiology of MDD, 10th World Conbress of Biological Psychiatry, Prague, Czech Republic, May 2011.
55.
Masahito Tomotake, 上岡 義典, 田中 恒彦, Yasuhiro Kaneda and Tetsuro Ohmori : Effect of cognitive dysfunction on subjective quality of life in people with schizophrenia, British Association for Behavioural & Cognitive Psychotherapies: 38th BABCP Annual Conference & Workshops, Manchester, Jul. 2010.
56.
Satsuki Sumitani and Tetsuro Ohmori : Clinical features in patients with obsessive-compulsive disorder with different pharmacological response, XXVII CINP CONGRESS 2010 WORLD CONGRESS, Hong Kong, Jun. 2010.
57.
菊地 久美子, Junichi Iga, Shinya Tayoshi, Masahito Nakataki, Shinya Watanabe, Shusuke Numata and Tetsuro Ohmori : Lithium decreases VEGF mRNA expression in leukocytes of healthy subjects., XXVII CINP CONGRESS 2010 WORLD CONGRESS, Hong Kong, Jun. 2010.
58.
Junichi Iga, 菊地 久美子, Sumiko Tayoshi, Masahito Nakataki, Shinya Watanabe, Shusuke Numata and Tetsuro Ohmori : Effect of lithium on gene expression in leukocytes of healthy subjects., XXVII CINP CONGRESS 2010 WORLD CONGRESS, Hong Kong, Jun. 2010.
59.
Masahito Nakataki, Junichi Iga, Shusuke Numata, E Yoshimoto, K Kodera, Shinya Watanabe, H Song, S Ueno and Tetsuro Ohmori : Gene expression and association analysis of the epithelial membrane protein 1 gene in major depressive disorder in the Japanese population, XXVII CINP CONGRESS 2010 WORLD CONGRESS, Hong Kong, Jun. 2010.
60.
Shinya Watanabe, Junichi Iga, Masahito Nakataki, Shusuke Numata, Kumiko Kikuchi and Tetsuro Ohmori : Association study of cannabinoid receptor 1 gene and schizophrenia and body mass index in a Japanese population, XXVII CINP CONGRESS 2010 WORLD CONGRESS, Hong Kong, Jun. 2010.
61.
Kirino Yasushi, Kazuhiko Teraoka, Kujime Toshihide, Kazuyoshi Kawazoe, Tetsuro Ohmori and Kazuo Minakuchi : Analysis of body weight gain in patients treated with the second-generation antipsychotic drugs in Tokushima University Hospital, 15th Anniversary Congress of EAHP, Niece, Mar. 2010.
62.
Masahito Tomotake, Yoshinori Ueoka, Tsunehiko Tanaka, Yasuhiro Kaneda and Tetsuro Ohmori : Effect of cognitive dysfunction on subjective quality of life in people with schizophrenia, British Association for Behavioural & Cognitive Psycho-Therapies 38th Annual Conference & Workshop, 2010.
63.
Yoshinori Ueoka, Masahito Tomotake, Tsunehiko Tanaka, Yasuhiro Kaneda, Masahito Nakataki, Satsuki Sumitani, Shu-ichi Ueno and Tetsuro Ohmori : Quality of Life and Cognitive Dysfunction in People with Schizophrenia, The 1st Meeting of the Asian College of Neuropsychopharmacology, Nov. 2009.
64.
Tsunehiko Tanaka, Yoshinori Ueoka, Masahito Tomotake, Yasuhiro Kaneda and Tetsuro Ohmori : Relationship between Cognitive Function and Clinical Symptoms in People with Schizophrenia, The 1st Meeting of the Asian College of Neuropsychopharmacology, Nov. 2009.
65.
Yoshinori Ueoka, Masahito Tomotake, Tsunehiko Tanaka, Yasuhiro Kaneda, Kazusa Kawahara, Hatsumi Iwasaki, Ai Okamoto, Ayumi Hase, Mai Ikebuchi, Natsuki Mori, Keiko Momo and Tetsuro Ohmori : Clinical factors related to cognitive function in people with schizophrenia, XIV World Congress of Psychiatry, Sep. 2008.
66.
Masahito Tomotake, Yoshinori Ueoka, Tsunehiko Tanaka, Yasuhiro Kaneda, Ken Yamauchi, Kyoko Taniguchi, Yumiko Takikawa, Masahito Nakataki, Shusuke Numata, Shinya Tayoshi, Satsuki Sumitani, Yumiko Izaki, Takashi Ohmori, Shu-ichi Ueno and Tetsuro Ohmori : Subjective quality of life and cognitive function in people with schizophrenia, XIV World Congress of Psychiatry, Sep. 2008.
67.
Yoshinori Ueoka, Masahito Tomotake, Tsunehiko Tanaka, Yasuhiro Kaneda, Ken Yamauchi, Kyoko Taniguchi, Yumiko Takikawa, Masahito Nakataki, Shusuke Numata, Shinya Tayoshi, Satsuki Sumitani, Yumiko Izaki, Takashi Ohmori, Shu-ichi Ueno and Tetsuro Ohmori : Predictors of objective quality of life in people with schizophrenia, XIV World Congress of Psychiatry, Sep. 2008.
68.
Masahito Nakataki, Junichi Iga, Shu-ichi Ueno, K Yamauchi, Shusuke Numata, S Tayoshi-Shibuya, S Kinouhci, H Song, K Hokoishi, H Tanabe, A Sano and Tetsuro Ohmori : Gene expression and association analysis of vascular endothelial growth factor in major depressive disorder., Neuroscience, SanDiego, USA, Nov. 2007.
69.
Shusuke Numata, Shu-ichi Ueno, Junichi Iga, Song Hongwei, Masahito Nakataki, Mitsuo Itakura, Akira Sano and Tetsuro Ohmori : Positive Association of The PDE4B (Phosphodiesterase 4B) gene with Schizophrenia in the Japanese Population, Neuroscience, San Diego, USA, Nov. 2007.
70.
Shinya Tayoshi, Sumiko Tayoshi, Satsuki Sumitani, Masafumi Harada, Shu-ichi Ueno and Tetsuro Ohmori : Maintenance modified electroconvulsive therapy for an elderly patient with recurrent catatonia, Higashihiroshima, Oct. 2006.
71.
Shinya Tayoshi, Sumiko Tayoshi, Satsuki Sumitani, Masafumi Harada, Shu-ichi Ueno and Tetsuro Ohmori : Six cases of elderly patients with psychotic feature refractory to drug therapy but response to ECT, Higashihiroshima, Oct. 2006.
72.
Junichi Iga, Shu-ichi Ueno, Ken Yamauchi, Shusuke Numata, I Motoki, Shinya Tayoshi, S Kinouchi, K Ohta, H Song, Kyoko Morita, Kazuhito Rokutan, H Tanabe, A Dano and Tetsuro Ohmori : Gene expression and association analysis of LIM (PDLIM5) in major depression, Neuroscience, Atlanta, Oct. 2006.
73.
Shusuke Numata, Shu-ichi Ueno, Junichi Iga, Ken Yamauchi, Song Hongwei, Ryota Hashimoto, Masatoshi Takeda, Hiroshi Kunugi, Mitsuo Itakura and Tetsuro Ohmori : Gene expression and association analysis of LIM (PDLIM5) in schizophrenia, Neuroscience, Atlanta, Oct. 2006.
74.
Shinya Tayoshi, Satsuki Sumitani, Sumiko Tayoshi, Shu-ichi Ueno, Masafumi Harada and Tetsuro Ohmori : Acute administration of benzodiazepine did not change the level of GABA in 3T 1H-Magnetic resonance spectroscopy, Chicago, Jul. 2006.
75.
Shusuke Numata, Song Hongwei, Junichi Iga, Ken Yamauchi, Takahide Taniguchi, Shu-ichi Ueno and Tetsuro Ohmori : The effect of milnacipran ( serotonin noradrenaline reuptake inhibitor ) on memory in Korsakoffs syndrome after encephalitis., 8th World Congress of Biological Congress, Wien, Jun. 2005.
76.
Yasuhiro Kaneda and Tetsuro Ohmori : Relation between estradiol and negative symptoms in men with schizophrenia, 12th Symposium of the Association of European Psychiatrists, Mannheim, Jun. 2004.
77.
Satsuki Sumitani, Mami Matsushita, Kayoko Wada, Masahito Tomotake, Shu-ichi Ueno, Taketoshi Yamashita, Shinichi Matsumoto, Ryuji Kaji and Tetsuro Ohmori : Comparison of the temperament between obsessive-compulsive disorder and idiopathic dystonia, CINP, Paris, Jun. 2004.
78.
Yasuhiro Kaneda, Takashi Harada and Tetsuro Ohmori : Impact of risperidone on QOL in schizophrenia, World Congress of Psychiatry, Yokohama, Aug. 2002.
79.
Shusuke Numata, Masahito Tomotake, K Taniguchi, T Harada and Tetsuro Ohmori : Short-term lithium therapy induced silent thyroiditis, 12 th World Congress of Psychiatry, Yokohama, Aug. 2002.
80.
Yasuhiro Kaneda, Akira Imakura, Akira Fujii and Tetsuro Ohmori : The Effects of quetiapine on quality of life in schizophrenia, Collegium Internationale Neuro-Psychopharmacologicum Congress, Montreal, Jun. 2002.
81.
Yasuhiro Kaneda, Akira Imakura, Akira Fujii and Tetsuro Ohmori : Impact of atypical antipsychotic medication on quality of life in patients with schizophrenia: a preliminary report, Collegium Internationale Neuro-Psychopharmacologicum) Regional Meeting, Hiroshima, Oct. 2001.
82.
Yasuhiro Kaneda, Akira Fujii and Tetsuro Ohmori : Depressive symptoms in schizophrenia, World Congress of Biological Psychiatry, Berlin, Jul. 2001.
83.
Yasuhiro Kaneda, Akira Imakura, Akira Fujii and Tetsuro Ohmori : The Japanese version of the Schizophrenia Quality of Life Scale (JSQLS), Pan-Pacific Conference of the International Society for Quality of Life Research, Tokyo, Apr. 2001.
84.
Yasuhiro Kaneda, Akira Fujii and Tetsuro Ohmori : Plasma homovanillic acid in chronically medicated schizophrenic patients; a marker for symptoms?, International Catecholamine Symposium, Kyoto, Apr. 2001.
Shusuke Numata, Hidehiro Umehara and Tetsuro Ohmori : DNA methylation of the serotonin transporter gene in obsessive-compulsive disorder., 第39回日本生物学的精神医学会, Sep. 2017.
K Ohi, R Hashimoto, Y Yasuda, M Fukumoto, H Yamamori, S Umeda-Yano, T Okada, K Kamino, T Morihara, M Iwase, H Kazui, Shusuke Numata, M Ikeda, T Ohnuma, N Iwata, Shu-ichi Ueno, N Ozaki, Tetsuro Ohmori, H Arai and M Takeda : Functional genetic variation at the NRGN gene and schizophrenia: evidence from a gene-based case-control study and gene expression analysis, The 7th Annual Meeting of Japanese Society of Schizophrenia Research, Mar. 2012.
Tetsuro Ohmori : Molecular assessment of depression from mRNAs in the peripheral leukocytes, Memorial symposium for academic cooperation between the Faculty of Medicine ,the University of Tokushima and Seoul National University College of Medicine, Jan. 2011.
Yoshinori Ueoka, Masahito Tomotake, Tsunehiko Tanaka, Yasuhiro Kaneda, Masahito Nakataki, Shusuke Numata, Shinya Tayoshi, Satsuki Sumitani, Takashi Ohmori, Shu-ichi Ueno and Tetsuro Ohmori : Subjective Quality of Life and Cognitive Function in Outpatients with Schizophrenia, 第5回日本統合失調症学会, Mar. 2010.
Yoshinori Ueoka, Masahito Tomotake, Tsunehiko Tanaka, Yasuhiro Kaneda, Masahito Nakataki, Satsuki Sumitani, Shu-ichi Ueno and Tetsuro Ohmori : Quality of Life and Cognitive Dysfunction in People with Schizophrenia, 第19回日本臨床精神神経薬理学会・第39回日本神経精神薬理学会合同年会, Nov. 2009.
204.
Tsunehiko Tanaka, Yoshinori Ueoka, Masahito Tomotake, Yasuhiro Kaneda and Tetsuro Ohmori : Relationship between Cognitive Function and Clinical Symptoms in People with Schizophrenia, 第19回日本臨床精神神経薬理学会・第39回日本神経精神薬理学会合同年会, Nov. 2009.
Shusuke Numata, Shu-ichi Ueno, Junichi Iga, Ken Yamauchi, Hongwei Song, Ryota Hashimoto, Masatoshi Takeda, Hiroshi Kunugi, Mitsuo Itakura and Tetsuro Ohmori : TGFBR2 gene expression and genetic association with schizophrenia, The 29th Annual Meeting of Japanese Society of Biological Psychiatry, Jul. 2007.
Shusuke Numata, Junichi Iga, Shu-ichi Ueno, Ken Yamauchi, Hongwei Song, Sumiko Tayoshi, Shinya Tayoshi, Masahito Nakataki, Ryota Hashimoto, Masatoshi Takeda, Hiroshi Kunugi and Tetsuro Ohmori : Differential expression of Disrupted-In-Schizophrenia-1 (DISC1) in the peripheral leukocytes from schizophrenia and major depressive disorder, The 2nd Annual Meeting of Japanse Society of Schizophrenia Research, Mar. 2007.
230.
Shusuke Numata, Shu-ichi Ueno, Junichi Iga, Ken Yamauchi, Hongwei Song, Koji Ohta, Sawako Kinouchi, Sumiko Tayoshi, Shinya Tayoshi, Michitaka Aono, Naomi Kameoka, Satsuki Sumitani, Masahito Tomotake, Yasuhiro Kaneda, Takahide Taniguchi, Yasuhito Ishimoto and Tetsuro Ohmori : Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in schizophrenia is associated with age of onset, The 2nd Annual Meeting of Japanse Society of Schizophrenia Research, Mar. 2007.
Shusuke Numata, Shu-ichi Ueno, Junichi Iga, Ken Yamauchi, Hongwei Song, Sawako Kinouchi, Sumiko Tayoshi, Shinya Tayoshi, Satsuki Sumitani and Tetsuro Ohmori : BDNFVal66Met polymorphism in schizophrenia is associated with age of onset and symptoms., The 28th Annual Meeting of Japanese Society of Biological Psychiatry, Sep. 2006.