Shusuke Numata and Tetsuro Ohmori : 統合失調症, 日経メディカル開発, 2013.
14.
Shusuke Numata and Takeo Tominaga : 統合失調症, 株式会社 中外医学社, Mar. 2011.
15.
Shusuke Numata and Tetsuro Ohmori : 統合失調症, 日経メディカル開発, 2009.
16.
Shusuke Numata : よくわかる精神科治療薬の考え方,使い方 統合失調症，分筆, 株式会社 中外医学社, Tokyo, May 2008.
Academic Paper (Judged Full Paper):
1.
Keita Kiuchi, Hidehiro Umehara, Koushi Irizawa, XIN KANG, Masahito Nakataki, Minoru Yoshida, Shusuke Numata and Kazuyuki Matsumoto : An Exploratory Study of the Potential of Online Counseling for University Students by a Human-Operated Avatar Counselor, Healthcare, Vol.12, No.1287, 2024.
(Summary)
Recently, the use of digital technologies, such as avatars and virtual reality, has been increasingly explored to address university students mental health issues. However, there is limited research on the advantages and disadvantages of counselors using avatars in online video counseling. Herein, 25 university students were enrolled in a pilot online counseling session with a human counselor-controlled avatar, and asked about their emotional experiences and impressions of the avatar and to provide qualitative feedback on their communication experience. Positive emotions during the session were associated with impressions of the avatars intelligence and likeability. The anthropomorphism, animacy, likeability, and intelligent impressions of the avatar were interrelated, indicating that the avatars smile and the counselors expertise in empathy and approval may have contributed to these impressions. However, no associations were observed between participant experiences and their prior communication with avatars, or between participant experiences and their gender or the perceived gender of the avatar. Accordingly, recommendations for future practice and research are provided. Accumulating practical and empirical findings on the effectiveness of human-operated avatar counselors is crucial for addressing university students mental health issues.
(Keyword)
avatar counseling / human-operated avatars / university students / digital mental health / empathy / communication / anthropomorphism / animacy / likeability / perceived intelligence
Tomoya Takeda, Masahito Nakataki, Hidehiro Umehara and Shusuke Numata : Associations between negative and positive automatic thoughts and clinical variables in patients with schizophrenia., Schizophrenia Research. Cognition, Vol.35, 2023.
(Summary)
This study investigated the relationships between negative and positive automatic thoughts and clinical variables in patients with schizophrenia. The participants included 36 patients with schizophrenia (male = 16; female = 20; age = 42.86 ± 9.40) who were outpatients in the Department of Psychiatry at Tokushima University Hospital. We used the Automatic Thoughts Questionnaire-Revised (ATQ-R), Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), and Brief Assessment of Cognition in Schizophrenia (BACS) to assess negative and positive automatic thoughts, positive and negative symptoms, depressive symptoms, and neurocognition, respectively. Spearman rank correlation coefficients were calculated to determine the relationships between negative and positive automatic thoughts and clinical variables. No relationship was observed between negative and positive automatic thoughts. Negative automatic thoughts were related to depressive symptoms. Positive automatic thoughts were related to neurocognition. We therefore surmise that each automatic thought might have different clinical features and outcomes, and should therefore be treated accordingly.
Tzuyao Lo, Itaru Kushima, Hiroki Kimura, Branko Aleksic, Takashi Okada, Hidekazu Kato, Toshiya Inada, Yoshihiro Nawa, Youta Torii, Maeri Yamamoto, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Shusuke Numata, Kiyoto Kasai, Tsukasa Sasaki, Shigeru Yokoyama, Toshio Munesue, Ryota Hashimoto, Yuka Yasuda, Michiko Fujimoto, Masahide Usami, Masanari Itokawa, Makoto Arai, Kazutaka Ohi, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Tsutomu Takahashi, Michio Suzuki, Hidenori Yamasue, Nakao Iwata, Masashi Ikeda and Norio Ozaki : Association between copy number variations in parkin (PRKN) and schizophrenia and autism spectrum disorder: A case-control study., Neuropsychopharmacology Reports, Vol.44, No.1, 42-50, 2023.
(Summary)
The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted.
(Keyword)
Humans / Autism Spectrum Disorder / Case-Control Studies / Comparative Genomic Hybridization / DNA Copy Number Variations / Genome-Wide Association Study / schizophrenia / Ubiquitin-Protein Ligases
Naomi Hasegawa, Yuka Yasuda, Norio Yasui-Furukori, Hisashi Yamada, Hikaru Hori, Kayo Ichihashi, Yoshikazu Takaesu, Hitoshi Iida, Hiroyuki Muraoka, Fumitoshi Kodaka, Junichi Iga, Naoki Hashimoto, Kazuyoshi Ogasawara, Kazutaka Ohi, Kentaro Fukumoto, Shusuke Numata, Takashi Tsuboi, Masahide Usami, Akitoyo Hishimoto, Ryuji Furihata, Taishiro Kishimoto, Toshinori Nakamura, Eiichi Katsumoto, Shinichiro Ochi, Tatsuya Nagasawa, Kiyokazu Atake, Chika Kubota, Hiroshi Komatsu, Hirotaka Yamagata, Kenta Ide, Masahiro Takeshima, Mikio Kido, Saya Kikuchi, Tsuyoshi Okada, Junya Matsumoto, Kenichiro Miura, Taichi Shimazu, Ken Inada, Koichiro Watanabe and Ryota Hashimoto : Effect of education regarding treatment guidelines for schizophrenia and depression on the treatment behavior of psychiatrists: A multicenter study., Psychiatry and Clinical Neurosciences, Vol.77, No.10, 559-568, 2023.
(Summary)
This strategy of providing education regarding the clinical guidelines for psychiatric disorders was effective in improving the treatment-related behavior of psychiatrists. The use of this education-based strategy might contribute to resolving the mental health treatment gap.
Toshiaki Onitsuka, Tsuyoshi Okada, Naomi Hasegawa, Takashi Tsuboi, Junichi Iga, Norio Yasui-Furukori, Naoki Yamada, Hikaru Hori, Hiroyuki Muraoka, Kazutaka Ohi, Kazuyoshi Ogasawara, Shinichiro Ochi, Masahiro Takeshima, Kayo Ichihashi, Kentaro Fukumoto, Hitoshi Iida, Hisashi Yamada, Ryuji Furihata, Manabu Makinodan, Yoshikazu Takaesu, Shusuke Numata, Hiroshi Komatsu, Akitoyo Hishimoto, Mikio Kido, Kiyokazu Atake, Hirotaka Yamagata, Saya Kikuchi, Naoki Hashimoto, Masahide Usami, Eiichi Katsumoto, Takeshi Asami, Chika Kubota, Junya Matsumoto, Kenichiro Miura, Yoji Hirano, Koichiro Watanabe, Ken Inada and Ryota Hashimoto : Combination Psychotropic Use for Schizophrenia With Long-Acting Injectable Antipsychotics and Oral Antipsychotics: A Nationwide Real-World Study in Japan., Journal of Clinical Psychopharmacology, Vol.43, No.4, 365-368, 2023.
(Summary)
Presenting these real-world clinical results, we want to encourage clinicians to keep monotherapy in mind for the treatment of schizophrenia, especially by reducing concomitant use of antipsychotics in the LAI group and reducing hypnotic and/or antianxiety medication in the non-LAI group.
(Keyword)
Humans / Antipsychotic Agents / schizophrenia / Japan / Injections / Administration, Oral / Hypnotics and Sedatives / Delayed-Action Preparations
Hidehiro Umehara, Tomoya Takeda, Leona Yoshida, Kanae Matsuura, Mika Okumura-Fujita, Ryuta Tominaga, Yasuko Abe, Tarishi Masuda, Naoki Yamada and Shusuke Numata : Effects of group therapy on jumping to conclusion bias in adolescents with autism spectrum disorder: An exploratory study., The Journal of Medical Investigation : JMI, Vol.70, No.1.2, 115-122, 2023.
(Summary)
Jumping to conclusion (JTC)-a cognitive bias in thinking processes-leads to drawing conclusions based on little information, and could be related to psychosis and paranoia. While it has recently been pointed out that it could accompany the autism spectrum disorder (ASD), no interventions targeting this bias in adolescents with ASD have been reported. Therefore, this exploratory study investigated the effects of a group social cognition program on JTC bias in adolescents with ASD. Group rehabilitation using social cognition and interaction training (SCIT) was conducted for 12- to 18-year-old adolescents with ASD. An SCIT program comprehensively targets social cognitive functions, including interventions for JTC bias, and examines changes before and after the SCIT intervention, social cognitive functioning tasks, and subjective quality of life (QOL). Thirteen adolescents with ASD participated in this program ; 10 (76.9%) stayed through it. The proportion of participants with JTC bias decreased significantly before and after SCIT (before : 7/10 ; after : 1/10 ; p = 0.041), and subjective QOL increased significantly (p=0.014). The results show that a group social cognition program with a JTC bias approach improves the JTC bias and increases subjective QOL in adolescents with ASD. J. Med. Invest. 70 : 115-122, February, 2023.
(Keyword)
Humans / Adolescent / Child / Quality of Life / Autism Spectrum Disorder / Cognition / Psychotherapy, Group
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.
(Summary)
genes identified in the training set yielded 85% discrimination accuracy for antidepressant responsiveness in the 34 test samples. Pathway analysis of the RNA sequencing data for antidepressant responsiveness identified that hypercytokinemia- and interferon-related genes were increased in non-responders. Disease and biofunction analysis identified changes in genes related to inflammatory and infectious diseases, including coronavirus disease. These results strongly suggest an association between antidepressant responsiveness and inflammation, which may be useful for future treatment strategies for depression.
Yoshitaka Kyou, Norio Yasui-Furukori, Naomi Hasegawa, Kenta Ide, Kayo Ichihashi, Naoki Hashimoto, Hikaru Hori, Yoshihito Shimizu, Yayoi Imamura, Hiroyuki Muraoka, Hitoshi Iida, Kazutaka Ohi, Yuka Yasuda, Kazuyoshi Ogasawara, Shusuke Numata, Junichi Iga, Takashi Tsuboi, Shinichiro Ochi, Fumitoshi Kodaka, Ryuji Furihata, Toshiaki Onitsuka, Manabu Makinodan, Hiroshi Komatsu, Masahiro Takeshima, Chika Kubota, Akitoyo Hishimoto, Kiyokazu Atake, Hirotaka Yamagata, Mikio Kido, Tatsuya Nagasawa, Masahide Usami, Taishiro Kishimoto, Saya Kikuchi, Junya Matsumoto, Kenichiro Miura, Hisashi Yamada, Koichiro Watanabe, Ken Inada and Ryota Hahimoto : The characteristics of discharge prescriptions including pro re nata psychotropic medications for patients with schizophrenia and major depressive disorder from the survey of the "Effectiveness of guidelines for dissemination and education in psychiatric treatment (EGUIDE)" project., Annals of General Psychiatry, Vol.21, No.1, 52, 2022.
(Summary)
Considering PRN psychotropic medications, the monotherapy ratio and no prescription ratio of other psychotropics at discharge decreased in pharmacotherapy for schizophrenia and major depressive disorder. A higher ratio of monotherapy and no prescription of other psychotropics on regular prescriptions may result in less concomitant use of PRN psychotropic medications. Further studies are needed to optimize PRN psychotropic prescriptions.
Hitoshi Iida, Tsuyoshi Okada, Kiyotaka Nemoto, Naomi Hasegawa, Shusuke Numata, Kazuyoshi Ogasawara, Kenichiro Miura, Junya Matsumoto, Hikaru Hori, Junichi Iga, Kayo Ichihashi, Naoki Hashimoto, Hisashi Yamada, Kazutaka Ohi, Norio Yasui-Furukori, Kentaro Fukumoto, Takashi Tsuboi, Masahide Usami, Ryuji Furihata, Yoshikazu Takaesu, Akitoyo Hishimoto, Hiroyuki Muraoka, Eiichi Katsumoto, Tatsuya Nagasawa, Shinichiro Ochi, Hiroshi Komatsu, Saya Kikuchi, Masahiro Takeshima, Toshiaki Onitsuka, Shinichiro Tamai, Chika Kubota, Ken Inada, Koichiro Watanabe, Hiroaki Kawasaki and Ryota Hashimoto : Satisfaction with web-based courses on clinical practice guidelines for psychiatrists: Findings from the "Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)" project., Neuropsychopharmacology Reports, Vol.43, No.1, 23-32, 2022.
(Summary)
To disseminate, educate, and validate psychiatric clinical practice guidelines, the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project was launched in 2016. In this study, we investigated whether the web-based courses offered by this project would be as effective as the face-to-face courses. We analyzed and compared survey answers about overall participant satisfaction with the course and answers regarding clinical knowledge of schizophrenia and major depressive disorder between 170 participants who took the web-based courses in 2020 and 689 participants who took the face-to-face courses from 2016 to 2019. The web-based course participants completed the survey questions about satisfaction with the web-based courses. The web-based courses were conducted using a combination of web services to make it as similar as possible to the face-to-face courses. The degree of satisfaction assessed by the general evaluation of the web-based courses was higher than what was expected from the face-to-face courses. The degree of satisfaction was similar for the courses on schizophrenia and major depressive disorder. In addition, there were no significant differences in overall satisfaction and clinical knowledge between web-based and face-to-face courses. In conclusion, the web-based courses on clinical practice guidelines provided by the EGUIDE project were rated as more satisfying than the face-to-face course that the participants expected to take and no differences in the effectiveness of either course. The results suggest that, after the COVID-19 pandemic, it would be possible to disseminate this educational material more widely by adopting web-based courses additionally face-to-face courses.
(Keyword)
Humans / COVID-19 / Depressive Disorder, Major / internet / Pandemics / Personal Satisfaction / psychiatry / Practice Guidelines as Topic
Shinichiro Ochi, Hiromi Tagata, Naomi Hasegawa, Norio Yasui-Furukori, Junichi Iga, Hiroko Kashiwagi, Fumitoshi Kodaka, Hiroshi Komatsu, Takashi Tsuboi, Akira Tokutani, Shusuke Numata, Kayo Ichihashi, Toshiaki Onitsuka, Hiroyuki Muraoka, Hitoshi Iida, Kazutaka Ohi, Kiyokazu Atake, Taishiro Kishimoto, Hikaru Hori, Yoshikazu Takaesu, Masahiro Takeshima, Masahide Usami, Manabu Makinodan, Naoki Hashimoto, Michiko Fujimoto, Ryuji Furihata, Tatsuya Nagasawa, Hisashi Yamada, Junya Matsumoto, Kenichiro Miura, Mikio Kido, Akitoyo Hishimoto, Shu-ichi Ueno, Koichiro Watanabe, Ken Inada and Ryota Hashimoto : Clozapine Treatment Is Associated With Higher Prescription Rate of Antipsychotic Monotherapy and Lower Prescription Rate of Other Concomitant Psychotropics: A Real-World Nationwide Study., The International Journal of Neuropsychopharmacology, Vol.25, No.10, 818-826, 2022.
(Summary)
Clozapine prescription could be associated with a high rate of antipsychotic monotherapy. Patients will benefit from the correct diagnosis of TRS and thus from proper clozapine prescription.
Ken Inada, Kentaro Fukumoto, Naomi Hasegawa, Yuka Yasuda, Hisashi Yamada, Hikaru Hori, Kayo Ichihashi, Hitoshi Iida, Kazutaka Ohi, Hiroyuki Muraoka, Fumitoshi Kodaka, Kenta Ide, Naoki Hashimoto, Junichi Iga, Kazuyoshi Ogasawara, Kiyokazu Atake, Yoshikazu Takaesu, Tatsuya Nagasawa, Hiroshi Komatsu, Tsuyoshi Okada, Ryuji Furihata, Mikio Kido, Saya Kikuchi, Chika Kubota, Manabu Makinodan, Shinichiro Ochi, Masahiro Takeshima, Hirotaka Yamagata, Junya Matsumoto, Kenichiro Miura, Masahide Usami, Taishiro Kishimoto, Toshiaki Onitsuka, Eiichi Katsumoto, Akitoyo Hishimoto, Shusuke Numata, Norio Yasui-Furukori, Koichiro Watanabe and Ryota Hashimoto : Development of individual fitness score for conformity of prescriptions to the "Guidelines For Pharmacological Therapy of Schizophrenia"., Neuropsychopharmacology Reports, Vol.42, No.4, 502-509, 2022.
(Summary)
We developed an IFS formula, a tool to easily visualize the degree to which current prescriptions conform to the guidelines for the pharmacological treatment of schizophrenia.
Itaru Kushima, Branko Aleksic, Hiroki Kimura, Masahiro Nakatochi, Tzuyao Lo, Masashi Ikeda, Makoto Arai, Ryota Hashimoto, Shusuke Numata, Yasunobu Okamura, Taku Obara, Toshiya Inada and Norio Ozaki : X chromosome aneuploidies and schizophrenia: association analysis and phenotypic characterization., Psychiatry and Clinical Neurosciences, Vol.76, No.12, 667-673, 2022.
(Summary)
These findings indicate that both 47, XXY and 47, XXX are significantly associated with risk for SCZ. Patients with SCZ with 47, XXY may be characterized by treatment-resistance and manic symptoms.
(Keyword)
female / Humans / male / schizophrenia / DNA Copy Number Variations / Comparative Genomic Hybridization / Antipsychotic Agents / Retrospective Studies / Aneuploidy / X Chromosome
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.
(Summary)
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.
(Summary)
Decreased resting-state regional activity of the left DLPFC and decreased plasma kynurenine levels may predict treatment response to escitalopram, suggesting that it may be involved in the pathophysiology of major depressive disorder in response to escitalopram treatment.
(Keyword)
Depressive Disorder, Major / Escitalopram / Humans / Kynurenine / magnetic resonance imaging / Prefrontal Cortex / Transcranial Magnetic Stimulation
In several clinical guidelines for schizophrenia, long-term use of anticholinergic drugs is not recommended. We investigated the characteristics of the use of anticholinergics in patients with schizophrenia by considering psychotropic prescription patterns and differences among hospitals. A cross-sectional, retrospective prescription survey at the time of discharge was conducted on 2027 patients with schizophrenia from 69 Japanese hospitals. We examined the relations among psychotropic drug prescriptions regarding anticholinergic prescription. We divided the hospitals into three groups-low rate group (LG), medium rate group (MG), and high rate group (HG)-according to their anticholinergic prescription rates, and analyzed the relationship between anticholinergic prescription rates and antipsychotic prescription. Anticholinergic drugs were prescribed to 618 patients (30.5%), and the prescription rates were significantly higher for high antipsychotic doses, antipsychotic polypharmacy, and first-generation antipsychotics (FGAs) use. The anticholinergic prescription rate varied considerably among hospitals, ranging from 0 to 66.7%, and it was significantly higher in patients with antipsychotic monotherapy, antipsychotic polypharmacy, and normal and high doses of antipsychotics in HG than in those LG and MG. The anticholinergics prescription rate in patients with second-generation antipsychotic monotherapy in HG was also significantly higher than in those LG and MG; however, the difference was no longer significant in patients with FGA monotherapy. Conclusively, in addition to high antipsychotic doses, antipsychotic polypharmacy, and FGA use, hospital characteristics influence the prescribing of anticholinergic drugs.
BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.
(Keyword)
Autism Spectrum Disorder / Bipolar Disorder / Chromatin / DNA Copy Number Variations / Genetic Predisposition to Disease / Genome-Wide Association Study / Humans / schizophrenia
Hisashi Yamada, Mikuni Motoyama, Naomi Hasegawa, Kenichiro Miura, Junya Matsumoto, Kazutaka Ohi, Norio Yasui-Furukori, Shusuke Numata, Masahiro Takeshima, Nobuhiro Sugiyama, Tatsuya Nagasawa, Chika Kubota, Kiyokazu Atake, Takashi Tsuboi, Kayo Ichihashi, Naoki Hashimoto, Takahiko Inagaki, Yoshikazu Takaesu, Junichi Iga, Hikaru Hori, Toshiaki Onitsuka, Hiroshi Komatsu, Akitoyo Hishimoto, Kentaro Fukumoto, Michiko Fujimoto, Toshinori Nakamura, Kiyotaka Nemoto, Ryuji Furihata, Satoshi Yamamura, Hirotaka Yamagata, Kazuyoshi Ogasawara, Eiichi Katsumoto, Atsunobu Murata, Hitoshi Iida, Shinichiro Ochi, Manabu Makinodan, Mikio Kido, Taishiro Kishimoto, Yuka Yasuda, Masahide Usami, Taro Suwa, Ken Inada, Koichiro Watanabe and Ryota Hashimoto : A dissemination and education programme to improve the clinical behaviours of psychiatrists in accordance with treatment guidelines for schizophrenia and major depressive disorders: the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project., BJPsych Open, Vol.8, No.3, e83, 2022.
(Summary)
All clinical behaviours in accordance with clinical practice guidelines improved after attending the EGUIDE programme, and were maintained for at least 2 years. The EGUIDE project could contribute to improved guideline-based clinical behaviour among psychiatrists.
Kazuyoshi Ogasawara, Shusuke Numata, Naomi Hasegawa, Masahito Nakataki, Manabu Makinodan, Kazutaka Ohi, Masahiro Takeshima, Takashi Tsuboi, Naoki Hashimoto, Toshiaki Onitsuka, Hiroyuki Muraoka, Hikaru Hori, Kayo Ichihashi, Takahiko Inagaki, Norio Yasui-Furukori, Akitoyo Hishimoto, Nobuhiro Sugiyama, Kentaro Fukumoto, Tatsuya Nagasawa, Junya Matsumoto, Yoshikazu Takaesu, Ryuji Furihata, Kiyotaka Nemoto, Toshinori Nakamura, Masahide Usami, Kenichiro Miura, Michiko Fujimoto, Hiromi Tagata, Hisashi Yamada, Hiroshi Komatsu, Shinichiro Ochi, Kiyokazu Atake, Eiichi Katsumoto, Mikio Kido, Taishiro Kishimoto, Taro Suwa, Satoshi Yamamura, Junichi Iga, Hitoshi Iida, Ken Inada, Koichiro Watanabe and Ryota Hashimoto : Subjective assessment of participants in education programs on clinical practice guidelines in the field of psychiatry., Neuropsychopharmacology Reports, Vol.42, No.2, 221-225, 2022.
(Summary)
The Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment (EGUIDE) project, which is a nationwide dissemination and implementation program for clinical practice guidelines (CPGs) in the field of psychiatry, is currently ongoing. In the current study, a subjective assessment of the participants in the EGUIDE programs was assessed using a questionnaire. Then, the relationships between the subjective assessment, the characteristics of the participants, and the clinical knowledge of the CPGs were evaluated. More than 90% of the participants gave a high rating for the components of content, recommendation, knowledge, skill, and adherence, but not for the component of confidence. A positive correlation was found between years of professional experience and the score of confidence. These results suggest that it may be necessary to apply the knowledge and skills of CPGs obtained in the education programs into practice to increase confidence in the proper use of psychiatric therapies based on CPGs.
Hijiri Hasegawa, Ikkei Sasaki, Kaori Tsukakoshi, Yue Ma, Kazuo Nagasawa, Shusuke Numata, Yuuki Inoue, Yeji Kim and Kazunori Ikebukuro : Detection of CpG Methylation in G-Quadruplex Forming Sequences Using G-Quadruplex Ligands., International Journal of Molecular Sciences, Vol.22, No.23, 13159, 2021.
(Summary)
G4-forming sequences were examined by fluorescence-based microtiter plate assay. The differences in fluorescence intensities between methylated and unmethylated G4 DNAs were statistically significant. In addition to fluorescence detection, the binding of G4 ligand to DNA was detected by chemiluminescence. A significant difference was also detected in chemiluminescence intensity between methylated and unmethylated DNA. This is the first study on the detection of CpG methylation in G4 structures, focusing on structural changes using G4 ligands.
(Keyword)
CpG Islands / DNA / DNA Methylation / G-Quadruplexes / Humans / Ligands / Proto-Oncogene Proteins c-bcl-2 / Proto-Oncogene Proteins p21(ras) / Vascular Endothelial Growth Factor A
Norio Yasui-Furukori, Hiroyuki Muraoka, Naomi Hasegawa, Shinichiro Ochi, Shusuke Numata, Hikaru Hori, Akitoyo Hishimoto, Toshiaki Onitsuka, Kazutaka Ohi, Naoki Hashimoto, Tatsuya Nagasawa, Yoshikazu Takaesu, Takahiko Inagaki, Hiromi Tagata, Takashi Tsuboi, Chika Kubota, Ryuji Furihata, Junichi Iga, Hitoshi Iida, Kenichiro Miura, Junya Matsumoto, Hisashi Yamada, Koichiro Watanabe, Ken Inada, Kazutaka Shimoda and Ryota Hashimoto : Association between the examination rate of treatment-resistant schizophrenia and the clozapine prescription rate in a nationwide dissemination and implementation study., Neuropsychopharmacology Reports, Vol.42, No.1, 3-9, 2021.
(Summary)
As a preliminary problem for the use of clozapine, in Japan, the examination rate of TRS varies, and there are many facilities that typically do not consider the possibility of TRS; this trend leads to a low rate of clozapine use. Clearly, further clinician training is needed for the early detection and appropriate management of TRS that includes an explanation of TRS and how to introduce clozapine therapy to patients and their families.
Ryuji Furihata, Rei Otsuki, Naomi Hasegawa, Takashi Tsuboi, Shusuke Numata, Norio Yasui-Furukori, Hiroko Kashiwagi, Hikaru Hori, Shinichiro Ochi, Hiroyuki Muraoka, Toshiaki Onitsuka, Hiroshi Komatsu, Masahiro Takeshima, Akitoyo Hishimoto, Tatsuya Nagasawa, Yoshikazu Takaesu, Toshinori Nakamura, Takeshi Asami, Kenichiro Miura, Junya Matsumoto, Kazutaka Ohi, Yuka Yasuda, Hitoshi Iida, Kazuyoshi Ogasawara, Naoki Hashimoto, Kayo Ichihashi, Hisashi Yamada, Koichiro Watanabe, Ken Inada and Ryota Hashimoto : Hypnotic medication use among inpatients with schizophrenia and major depressive disorder: results of a nationwide study., Sleep Medicine, Vol.89, 23-30, 2021.
(Summary)
Prescription of hypnotic agents was found to be highly frequent among inpatients with psychiatric disorders. Prescription of two or more main antipsychotic agents was commonly associated with the use of hypnotic medication for both schizophrenia and major depressive disorder.
(Keyword)
Antipsychotic Agents / Cross-Sectional Studies / Depressive Disorder, Major / Humans / Hypnotics and Sedatives / Inpatients / schizophrenia
Masataka Kikuchi, Takanobu Nakazawa, Makoto Kinoshita, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Ryota Hashimoto and Shusuke Numata : Methylation Analysis in Monozygotic Twins With Treatment-Resistant Schizophrenia and Discordant Responses to Clozapine., Frontiers in Psychiatry, Vol.12, 734606, 2021.
(Summary)
Schizophrenia is a mental illness that involves both genetic and environmental factors. Clozapine, an atypical antipsychotic, is a well-established therapy for treatment-resistant schizophrenia. In this study, we focused on a set of monozygotic twins with treatment-resistant schizophrenia in which one twin effectively responded to clozapine treatment and the other did not. Our previous study generated neurons from induced pluripotent stem (iPS) cells derived from these patients and compared the transcriptome profiles between mock- and clozapine-treated neurons. In this study, we performed genome-wide DNA methylation profiling to investigate the mechanisms underlying gene expression changes. First, we extracted the differentially methylated sites from each twin based on statistical analysis. Then, we combined the DNA methylation profiling with transcriptome profiling from our previous RNA-seq data. Among the genes with altered methylation and expression, we found the different proportions of the genes related to neuronal and synaptic functions between the clozapine responder and non-responder (35.7 and 6.7%, respectively). This trend was observed even when the basal differences between the responder and non-responder was excluded. These results suggest that effective clozapine action may correct the abnormalities of neuronal and synapse functions in schizophrenia via changes in methylation.
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.
(Summary)
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.
(Keyword)
Blood Chemical Analysis / Blood Preservation / Cryopreservation / DNA / Edetic Acid / Humans / RNA
Naoki Hashimoto, Norio Yasui-Furukori, Naomi Hasegawa, Shuhei Ishikawa, Shusuke Numata, Hikaru Hori, Hitoshi Iida, Kayo Ichihashi, Ryuji Furihata, Atsunobu Murata, Takashi Tsuboi, Masahiro Takeshima, Yoshitaka Kyou, Hiroshi Komatsu, Chika Kubota, Shinichiro Ochi, Yoshikazu Takaesu, Masahide Usami, Tatsuya Nagasawa, Akitoyo Hishimoto, Kenichiro Miura, Junya Matsumoto, Kazutaka Ohi, Hisashi Yamada, Ken Inada, Koichiro Watanabe, Kazutaka Shimoda and Ryota Hashimoto : Characteristics of discharge prescriptions for patients with schizophrenia or major depressive disorder: Real-world evidence from the Effectiveness of Guidelines for Dissemination and Education (EGUIDE) psychiatric treatment project., Asian Journal of Psychiatry, Vol.63, 102744, 2021.
(Summary)
Our results showed the use of high doses of antipsychotics, high percentages of antipsychotic polypharmacy and concurrent use of hypnotics/anxiolytics in patients with schizophrenia. Notably, these data were collected before intensive instruction regarding the guidelines; therefore, we need to assess the change in the prescription pattern post guideline instruction.
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.
(Summary)
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.
Shusuke Numata, Masahito Nakataki, Naomi Hasegawa, Yoshikazu Takaesu, Masahiro Takeshima, Toshiaki Onitsuka, Toshinori Nakamura, Reon Edagawa, Hiroaki Edo, Kenichiro Miura, Junya Matsumoto, Norio Yasui-Furukori, Taishiro Kishimoto, Hikaru Hori, Takashi Tsuboi, Yuka Yasuda, Ryuji Furihata, Hiroyuki Muraoka, Shinichiro Ochi, Tatsuya Nagasawa, Yoshitaka Kyou, Atsunobu Murata, Eiichi Katsumoto, Kazutaka Ohi, Akitoyo Hishimoto, Ken Inada, Koichiro Watanabe and Ryota Hashimoto : Improvements in the degree of understanding the treatment guidelines for schizophrenia and major depressive disorder in a nationwide dissemination and implementation study., Neuropsychopharmacology Reports, Vol.41, No.2, 199-206, 2021.
(Summary)
We reported improvements in clinical knowledge of CPGs after the EGUIDE program in the 2017 group following revision of the lecture materials based on results from the 2016 group. These attempts to improve the degree of understanding of CPGs may facilitate the successful dissemination and implementation of psychiatric guidelines in everyday practice.
(Keyword)
Depressive Disorder, Major / Humans / psychiatry / schizophrenia
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
I Otsuka, M Akiyama, O Shirakawa, S Okazaki, Y Momozawa, Y Kamatani, T Izumi, Shusuke Numata, M Takahashi, S Boku, I Sora, K Yamamoto, Y Ueno, T Toda, M Kubo and A Hishimoto : Genome-wide association studies identify polygenic effects for completed suicide in the Japanese population., Neuropsychopharmacology, Vol.44, No.12, 2119-2124, 2019.
(Summary)
Suicide is a significant public health problem worldwide, and several Asian countries including Japan have relatively high suicide rates on a world scale. Twin, family, and adoption studies have suggested high heritability for suicide, but genetics lags behind due to difficulty in obtaining samples from individuals who died by suicide, especially in non-European populations. In this study, we carried out genome-wide association studies combining two independent datasets totaling 746 suicides and 14,049 non-suicide controls in the Japanese population. Although we identified no genome-wide significant single-nucleotide polymorphisms (SNPs), we demonstrated significant SNP-based heritability (35-48%; P < 0.001) for completed suicide by genomic restricted maximum-likelihood analysis and a shared genetic risk between two datasets (P = 2.7 × 10) by polygenic risk score analysis. This study is the first genome-wide association study for suicidal behavior in an East Asian population, and our results provided the evidence of polygenic architecture underlying completed suicide.
(Keyword)
Age Factors / Asian Continental Ancestry Group / Female / Genome-Wide Association Study / Humans / Japan / Male / Multifactorial Inheritance / Polymorphism, Single Nucleotide / Self-Injurious Behavior / Suicide, Completed
Y Takaesu, K Watanabe, Shusuke Numata, M Iwata, N Kudo, S Oishi, T Takizawa, K Nemoto, Y Yasuda, H Tagata, T Tsuboi, N Tsujino, N Hashimoto, Y Matsui, H Hori, H Yamamori, N Sugiyama, T Suwa, T Kishimoto, A Hishimoto, M Usami, R Furihata, K Iwamoto, H Fujishiro, T Nakamura, K Mizuno, T Inagaki, E Katsumoto, H Tomita, K Ohi, H Muraoka, K Atake, H Iida, T Nagasawa, J Fujita, S Yamamura, T Onitsuka, A Murata, Y Takayanagi, H Noda, Y Matsumura, K Takezawa, Junichi Iga, K Ichihashi, K Ogasawara, H Yamada, K Inada and R Hashimoto : Improvement of psychiatrists' clinical knowledge of the treatment guidelines for schizophrenia and major depressive disorders using the 'Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)' project: A nationwide dissemination, education, and evaluation study., Psychiatry and Clinical Neurosciences, Vol.73, No.10, 642-648, 2019.
(Summary)
Although treatment guidelines for pharmacological therapy for schizophrenia and major depressive disorder have been issued by the Japanese Societies of Neuropsychopharmacology and Mood Disorders, these guidelines have not been well applied by psychiatrists throughout the nation. To address this issue, we developed the 'Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)' integrated education programs for psychiatrists to disseminate the clinical guidelines. Additionally, we conducted a systematic efficacy evaluation of the programs. Four hundred thirteen out of 461 psychiatrists attended two 1-day educational programs based on the treatment guidelines for schizophrenia and major depressive disorder from October 2016 to March 2018. We measured the participants' clinical knowledge of the treatment guidelines using self-completed questionnaires administered before and after the program to assess the effectiveness of the programs for improving knowledge. We also examined the relation between the participants' demographics and their clinical knowledge scores. The clinical knowledge scores for both guidelines were significantly improved after the program. There was no correlation between clinical knowledge and participant demographics for the program on schizophrenia; however, a weak positive correlation was found between clinical knowledge and the years of professional experience for the program on major depressive disorder. Our results provide evidence that educational programs on the clinical practices recommended in guidelines for schizophrenia and major depressive disorder might effectively improve participants' clinical knowledge of the guidelines. These data are encouraging to facilitate the standardization of clinical practices for psychiatric disorders.
(Keyword)
Adult / Depressive Disorder, Major / Education, Medical, Continuing / Health Knowledge, Attitudes, Practice / Humans / Information Dissemination / Practice Guidelines as Topic / Program Evaluation / Psychiatry / Schizophrenia
N Tsujii, I Otsuka, S Okazaki, M Yanagi, Shusuke Numata, N Yamaki, Y Kawakubo, O Shirakawa and A Hishimoto : Mitochondrial DNA Copy Number Raises the Potential of Left Frontopolar Hemodynamic Response as a Diagnostic Marker for Distinguishing Bipolar Disorder From Major Depressive Disorder., Frontiers in Psychiatry, Vol.10, 312, 2019.
(Summary)
Given a lack of markers, diagnoses of bipolar disorder (BD) and major depressive disorder (MDD) rely on clinical assessment of symptoms. However, the depressive mood states of BD and depressive symptoms of MDD are often difficult to distinguish, which leads to misdiagnoses, which in turn leads to inadequate treatment. Previous studies have shown that the hemodynamic responses of the left frontopolar cortex measured by near-infrared spectroscopy (NIRS) differ between BD and MDD; these hemodynamic responses are associated with altered mitochondrial metabolism; and mitochondrial DNA copy number (mtDNAcn), an index of mitochondrial dysfunction, tends to decrease in BD and increase in MDD patients. In this study, we confirmed that mtDNAcn trends in opposite directions in BD and MDD. We then determined whether mtDNAcn could enhance the utility of NIRS as a diagnostic marker to distinguish between BD and MDD. We determined mtDNAcn in peripheral blood samples from 58 healthy controls, 79 patients with BD, and 44 patients with MDD. Regional hemodynamic responses during a verbal fluency task (VFT) in 24 BD patients and 44 MDD patients, matched by age and depression severity, were monitored using NIRS. Measurements of mtDNAcn were lower in BD patients and higher in MDD patients than in controls. The left frontopolar region exhibited the most significant differences in mean VFT-related oxy-Hb changes between the BD and MDD groups. Multivariate logistic regression analysis with variables including age, sex, hemodynamic response of the left frontopolar region, and mtDNAcn showed high accuracy for distinguishing BD from MDD (area under the curve = 0.917; 95% confidence interval = 0.849-0.985). For the BD group, we observed a positive correlation between hemodynamic responses in the left frontopolar region and mtDNAcn, while for the MDD group, we observed a negative correlation. Our findings suggest that the association between hemodynamic response and mitochondrial dysfunction in BD or MDD plays an important role in differentiating the pathophysiological mechanisms of BD from those of MDD.
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.
(Summary)
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.
(Summary)
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.
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Keyword)
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
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.
(Summary)
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.
Here we report de novo non-synonymous single-nucleotide variants (SNVs) by conducting whole exome sequencing of 18 trios consisting of Japanese patients with sporadic schizophrenia and their parents. Among nine SNVs, we explored the functional impact of the de novo mutation in TBL1XR1 [c.30 C > G (p.Phe10Leu)], a gene previously found to be associated with autism spectrum disorder and epilepsy. Protein structural analysis revealed that Phe10Leu mutation may decrease the structural stability of the TBL1XR1 protein. We demonstrate that Phe10Leu mutation alters the interaction of TBL1XR1 with N-CoR and β-catenin, which play critical roles in regulation of Wnt-mediated transcriptional activity. Consistently, TBL1XR1-mediated activation of Wnt signaling was up-regulated by Phe10Leu mutation. These results suggest that a de novo TBL1XR1 point mutation could alter Wnt/β-catenin signaling activity. Further studies are required to clarify the involvement of TBL1XR1 mutations in neuropsychiatric conditions.
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.
(Summary)
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.
(Keyword)
Adult / Antipsychotic Agents / CREB-Binding Protein / Clozapine / CpG Islands / DNA Methylation / Drug Resistance / Female / Humans / Leukocytes / Male / Middle Aged / schizophrenia
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.
(Summary)
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.
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.
(Summary)
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.
(Summary)
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.
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
T Nakazawa, R Hashimoto, K Sakoori, Y Sugaya, A Tanimura, Y Hashimotodani, K Ohi, H Yamamori, Y Yasuda, S Umeda-Yano, Y Kiyama, K Konno, T Inoue, Shuko Yokoyama, T Inoue, Shusuke Numata, T Ohnuma, N Iwata, N Ozaki, H Hashimoto, M Watanabe, T Manabe, T Yamamoto, M Takeda and M Kano : Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders., Nature Communications, Vol.7, 10594, 2016.
(Summary)
Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders.
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Keyword)
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.
(Summary)
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.
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.
(Summary)
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.
(Keyword)
Adult / CpG Islands / DNA Methylation / Depressive Disorder, Major / Female / Genetic Markers / Glycogen Synthase Kinase 3 / Humans / Leukocytes / Male / Middle Aged
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.
(Summary)
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.
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.
(Summary)
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.
Shusuke Numata, T Ye, M Herman and BK Lipska : DNA methylation changes in the postmortem dorsolateral prefrontal cortex of patients with schizophrenia., Frontiers in Genetics, Vol.5, 280, 2014.
(Summary)
Schizophrenia is a complex psychiatric disorder with a lifetime morbidity rate of 0.5-1.0%. The pathophysiology of schizophrenia still remains obscure. Accumulating evidence indicates that DNA methylation, which is the addition of a methyl group to the cytosine in a CpG dinucleotide, might play an important role in the pathogenesis of schizophrenia. To gain further insight into the molecular mechanisms underlying schizophrenia, a genome-wide DNA methylation profiling (27,578 CpG dinucleotides spanning 14,495 genes) of the human dorsolateral prefrontal cortex (DLPFC) was conducted in a large cohort (n = 216) of well characterized specimens from individuals with schizophrenia and non-psychiatric controls, combined with an analysis of genetic variance at ~880,000 SNPs. Aberrant DNA methylation in schizophrenia was identified at 107 CpG sites at 5% Bonferroni correction (p < 1.99 × 10(-6)). Of these significantly altered sites, hyper-DNA methylation was observed at 79 sites (73.8%), mostly in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 31 sites; CGI shore: 35 sites; CGI shelf: 3 sites). Furthermore, a large number of cis-methylation quantitative trait loci (mQTL) were identified, including associations with risk SNPs implicated in schizophrenia. These results suggest that altered DNA methylation might be involved in the pathophysiology and/or treatment of schizophrenia, and that a combination of epigenetic and genetic approaches will be useful to understanding the molecular mechanism of this complex disorder.
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.
(Summary)
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.
(Summary)
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.
(Keyword)
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.
(Summary)
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.
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.
(Summary)
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.
(Summary)
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.
(Keyword)
Adult / Asian Continental Ancestry Group / Case-Control Studies / Genetic Association Studies / Genetic Predisposition to Disease / Hippocampus / Humans / Polymorphism, Single Nucleotide / Schizophrenia
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.
(Summary)
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.
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.
(Summary)
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.
(Keyword)
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.
(Summary)
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.
(Keyword)
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
Shusuke Numata : A commentary on the gender-specific association of TSNAX/DISC1 locus for schizophrenia and bipolar affective disorder in South Indian population., Journal of Human Genetics, Vol.57, No.8, 475-476, 2012.
(Keyword)
Bipolar Disorder / DNA-Binding Proteins / Female / Genetic Association Studies / Humans / Male / Schizophrenia / Sex Characteristics
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.
(Summary)
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.
Shusuke Numata, Tianzhang Ye, Thomas M. Hyde, Xavier Guitart-Navarro, Ran Tao, Michael Wininger, Carlo Colantuoni, Daniel R. Weinberger, Joel E. Kleinman and Barbara K. Lipska : DNA methylation signatures in development and aging of the human prefrontal cortex., American Journal of Human Genetics, Vol.90, No.2, 260-272, 2012.
(Summary)
The human prefrontal cortex (PFC), a mastermind of the brain, is one of the last brain regions to mature. To investigate the role of epigenetics in the development of PFC, we examined DNA methylation in ∼14,500 genes at ∼27,000 CpG loci focused on 5' promoter regions in 108 subjects range in age from fetal to elderly. DNA methylation in the PFC shows unique temporal patterns across life. The fastest changes occur during the prenatal period, slow down markedly after birth and continue to slow further with aging. At the genome level, the transition from fetal to postnatal life is typified by a reversal of direction, from demethylation prenatally to increased methylation postnatally. DNA methylation is strongly associated with genotypic variants and correlates with expression of a subset of genes, including genes involved in brain development and in de novo DNA methylation. Our results indicate that promoter DNA methylation in the human PFC is a highly dynamic process modified by genetic variance and regulating gene transcription. Additional discovery is made possible with a stand-alone application, BrainCloudMethyl.
(Keyword)
Adolescent / Adult / Age Factors / Aged / Aged, 80 and over / aging / children / Child, Preschool / CpG Islands / DNA Methylation / Epigenesis, Genetic / Female / Fetus / Genetic Variation / Humans / infant / Infant, Newborn / Male / Middle Aged / Prefrontal Cortex / Promoter Regions, Genetic / Quantitative Trait Loci / Sex Factors / Young Adult
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.
(Summary)
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.
(Keyword)
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
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.
(Summary)
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.
(Keyword)
Adult / Case-Control Studies / Depressive Disorder, Major / Female / Genetic Association Studies / Humans / Japan / Leukocytes, Mononuclear / Male / Neoplasm Proteins / RNA, Messenger / Receptors, Cell Surface
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.
(Summary)
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.
(Keyword)
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.
(Summary)
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.
(Keyword)
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 / 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.
(Summary)
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.
(Summary)
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.
(Keyword)
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.
(Summary)
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.
(Link to Search Site for Scientific Articles)
● 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.
(Summary)
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.
(Keyword)
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 / 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.
(Summary)
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.
(Keyword)
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.
(Summary)
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.
(Keyword)
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 / 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.
(Summary)
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.
(Keyword)
Adult / Case-Control Studies / Codon / Diabetes Mellitus, Type 2 / Female / Genetic Predisposition to Disease / Genotype / Humans / Japan / Male / Middle Aged / Polymerase Chain Reaction / Polymorphism, Single Nucleotide / Risk Factors / TCF Transcription Factors / Transcription Factor 7-Like 2 Protein
Yasuhiro Kaneda, 住吉 太幹, 中込 和幸, Shusuke Numata, 田中 恒彦, Yoshinori Ueoka, Tetsuro Ohmori and S.E.Keefe Richard : The brief assessment of cognition in schizophrenia Japanese version (BACS-J), Seishin Igaku, Vol.50, No.9, 913-917, 2008.
(Keyword)
Brief Assessment of Cognition in Schizophrenia / BACS / Japanese version / BACS-J / Neuropsychological battery
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.
(Summary)
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.
(Keyword)
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 / quality of life / 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.
(Summary)
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.
(Summary)
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.
(Keyword)
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 / 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.
(Keyword)
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 / 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.
(Summary)
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.
(Summary)
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.
(Keyword)
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
Yasuhiro Kaneda, Tomiki Sumiyoshi, Richard Keefe, Yasuhito Ishimoto, Shusuke Numata and Tetsuro Ohmori : Brief assessment of cognition in schizophrenia: validation of the Japanese version., Psychiatry and Clinical Neurosciences, Vol.61, No.6, 602-609, 2007.
(Summary)
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.
(Keyword)
Adult / Attention / Cognition / Data Interpretation, Statistical / Factor Analysis, Statistical / Female / Humans / Japan / language / Male / memory / Middle Aged / Neuropsychological Tests / Psychomotor Performance / Schizophrenic Psychology / Verbal Behavior
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.
(Summary)
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.
(Keyword)
Adult / Aged / Alleles / Asian Continental Ancestry Group / Female / Genetic Markers / Genetic Predisposition to Disease / Genotype / Haplotypes / Humans / Japan / Linkage Disequilibrium / Male / Middle Aged / Neurotransmitter Agents / Polymorphism, Single Nucleotide / Pyridoxaminephosphate Oxidase / Risk Factors / schizophrenia
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Summary)
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.
(Keyword)
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 / Japan / LIM Domain Proteins / Leukocytes / Male / Middle Aged / Polymorphism, Single Nucleotide / RNA, Messenger / schizophrenia / Up-Regulation
Shusuke Numata, Shu-ichi Ueno, J Iga, K Yamauchi, S Hongwei, S Kinouchi, S Shibuya-Tayoshi, S Tayoshi, H Aki, S Sumitani, M Itakura and T Ohmori : Interaction between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in age at onset and clinical symptoms in schizophrenia, Journal of Neural Transmission, Vol.114, No.2, 255-259, 2007.
(Summary)
Catechol-O-methyltransferase (COMT) gene is one of the candidate genes for schizophrenia because it codes an enzyme that participates in the metabolic inactivation of dopamine and noradrenaline and a limiting factor of dopamine metabolism in the prefrontal cortex. COMT gene lies on chromosome 22q11.2, which has been associated with schizophrenia susceptibility. A single-nucleotide polymorphism of COMT gene at position 108/158 results in an amino acid substitution from valine (val) to methionine (met), which modifies its enzymatic activity and may change the brain morphology and expressional behaviors. On the other hand, brain-derived neurotrophic factor (BDNF) plays a critical role in the development of mesolimbic dopaminergic- related systems. BDNF also contains a functional single-nucleotide polymorphism at codon 66 (Val66Met) of its prodomain and this polymorphism is responsible for schizophrenia susceptibility. In this study, we first investigated the relationship between COMT Val108/158Met polymorphism and age at onset as well as levels of clinical symptoms in 158 of chronic schizophrenia inpatients and then we investigated the gene-by-gene interaction between COMT Val108/158Met polymorphism and BDNF Val66Met polymorphism with age- and sex-matched control subjects (n = 318). We concluded that the COMT Val108/158Met polymorphism was not related to either the onset at age or the levels of clinical symptoms after long-term antipsychotic treatment in schizophrenia.
(Keyword)
Adult / Age of Onset / Brain-Derived Neurotrophic Factor / Catechol O-Methyltransferase / Female / Genetic Predisposition to Disease / Humans / Male / Middle Aged / Polymerase Chain Reaction / Polymorphism, Single Nucleotide / Schizophrenia
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.
(Summary)
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.
(Keyword)
Adaptor Proteins, Signal Transducing / Adult / Biological Markers / Depressive Disorder, Major / Dose-Response Relationship, Drug / female / gene expression / Gene Expression Profiling / Humans / LIM Domain Proteins / Leukocytes / male / Paroxetine / Reproducibility of Results / Risk Assessment / Risk Factors / Sensitivity and Specificity / Statistics as Topic / Treatment Outcome
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.
(Summary)
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.
(Keyword)
Adult / Age of Onset / Aged / Amino Acid Substitution / Antipsychotic Agents / 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 / schizophrenia / Valine
Shusuke Numata, 関 由賀子 and 笠原 敏彦 : 緊迫困惑気分とその関連症状にquetiapineが有効であった初期統合失調症の1例, Japanese Journal of Psychiatric Treatment, Vol.20, No.11, 1165-1170, 2005.
128.
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.
須田 顕, Shusuke Numata, 三澤 仁 and 笠原 敏彦 : Perospirone投与により病的多飲と情動不安定が改善した統合失調症の1例, Japanese Journal of Psychiatric Treatment, Vol.20, No.2, 193-197, 2005.
131.
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.
(Summary)
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.
(Keyword)
antipsychotic drugs / Left atrial thrombosis / schizophrenia
Shusuke Numata : Evaluation of the association between plasma homocysteine concentration and schizophrenia by Mendelian randomization analysis, Vitamins, Vol.88, No.8, 413-418, Aug. 2014.
(Summary)
Previous meta-analyses of studies on the association between blood homocysteine concentration and schizophrenia suggest that elevated blood homocysteine concentration is a risk factor for schizophrenia. However, observational studies on this association have potential problems such as confounding and reverse causation. Mendelian randomization analysis is a method to analyze instrumental variables using genetic variants and can be used for assessing causal relationships. Therefore, we used this Mendelian randomization analysis to investigate the association between blood homocysteine concentration and schizophrenia. As a result, we demonstrated that increased blood homocysteine concentration might be associated with an increased risk of schizophrenia in the Japanese population. This result will offer important insight into the pathophysiology and treatments of schizophrenia.
Hidehiro Umehara, Tomoya Takeda, Matsuura Kanae, Abe Yasuko, Masuda Tarishi, Naoki Yamada and Shusuke Numata : Effectiveness of the group social cognition program on jumping to conclusion bias in adolescents with autism spectrum disorder., The 11th ASCAPAP, Kyoto, May 2023.
2.
S Igarashi, T Tsuboi, N Hasegawa, S Ochi, H Muraoka, K Fukumoto, F Kodaka, J Iga, K Ohi, Y Takaesu, H Kashiwagi, H Tagata, H Iida, H Komatsu, Shusuke Numata, J Matsumoto, K Miura, N Yasui-Furukori, K Inada, K Watanabe and R Hashimoto : Real world survey on psychopharmacology after electroconvulsive therapy in patients with depression: the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project., 34th CINP World Congress of Neuropsychopharmacology, Montreal, May 2023.
3.
S Ochi, H Tagata, H Hasegawa, N Yasui-Furukori, Junichi Iga, H Kashiwagi, F Kodaka, H Komatsu, T Tsuboi, A Tokutani, Shusuke Numata, K Ichihashi, T Onitsuka, H Muraoka, H Iida, K Ohi, K Atake, T Kishimoto, H Hori, Y Takaesu, M Takeshima, M Usami, M Makinodan, N Hashimoto, M Fujimoto, R Furihata, T Nagasawa, H Yamada, J Matsumoto, K Miura, M Kido, A Hishimoto, S Ueno, K Watanabe, K Inada and R Hashimoto : Clozapine treatment is associated with higher prescription rate of antipsychotic monotherapy and lower prescription rate of other concomitant psychotropics: A real-world nationwide study., CINP(33rd Committee of the International College of Neuropsychopharmacology)(2022.6.9-12 ), Virtual & Taipei Hybrid, Jun. 2022.
4.
R Furihata, R Ohtsuki, N Hasegawa, K Miura, J Matsumoto, T Tsuboi, Shusuke Numata, K Watanabe, K Inada and R. Hashimoto : Hypnotic medication use and associated factors among patients with schizophrenia- Findings from the 'Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)' project., 20th WPA(World Psychiatric Assoiation) World Congress of Psychiatry, Online, Mar. 2021.
5.
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.
6.
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.
7.
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.
8.
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.
9.
Shusuke Numata : Elevated glutamate levels in blood in mood disorders, WFSBP Asia Pacific Regional Congress of Biological Psychiatry, Kobe, Sep. 2018.
10.
Shusuke Numata : Blood diagnostic biomarkers for major depressive disorder using multiplex DNA methylation profiles., 13th World Congress of Biological Psychiatry, Copenhagen, Jun. 2017.
11.
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.
12.
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.
13.
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.
14.
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.
15.
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.
16.
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.
17.
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.
18.
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.
19.
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.
20.
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.
21.
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.
22.
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.
23.
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.
24.
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.
25.
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.
26.
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.
27.
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.
28.
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.
29.
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.
30.
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.
31.
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.
32.
Shusuke Numata : DNA Methylation Signatures of Prefrontal Cortex and Peripheral Leukocytes in Schizophrenia., Society of Biological Psychiatry 68th Annual Meeting, San Francisco, May 2013.
33.
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.
34.
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.
35.
Shusuke Numata, Thomas M. Hyde, Tianzheng Ye, Ran Tao, Xavier - Guitart Navarro, Michael Wininger, Daniel R. Weinberger, Joel E. Kleinman and Barbara K. Lipska : Epigenetic modifications in the human prefrontal cortex of patients with schizophrenia, Neuroscinece, Washington, D.C., Nov. 2011.
36.
Shusuke Numata : Epigenetic modifications in development and aging of the human prefrontal coetex., Korean Society of Biological Psychiatry, Seoul, Nov. 2011.
37.
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.
38.
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.
39.
X Guitart, Shusuke Numata, T Ye, TM Hyde, DR Weinberger, BK Lipska and JE Kleinman : DNA methylation analysis of putative schizophrenia susceptibility genes in the human dosolateral prefrontal cortex across the lifespan, The ACNP 49th Annual Meeting, Florida, USA, Dec. 2010.
40.
Shusuke Numata, T Ye, TM Hyde, X Guitart, R Tao, DR Weinberger, JE Kleinma and BK Lipska : DNA methylation signatures of human cortical samples across the life span, The ACNP 49th Annual Meeting, Florida, Dec. 2010.
41.
Shusuke Numata, T Ye, TM Hyde, X Guitart, R Tao, DR Weinberger, JE Kleinma and BK Lipska : Genome-wide DNA methylation analysis of human cortical samples across the lifespan, Neuroscience, SanDiego, USA, Nov. 2010.
42.
X Guitart, Shusuke Numata, T YE, TM Hyde, DR Weinberger, BK Lipska and JE Kleinman : Lifespan DNA methylation changes in schizophrenia susceptibility genes in the human dorsolateral prefrontal coetex, Neoroscience, SanDiego, USA, Nov. 2010.
43.
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.
44.
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.
45.
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.
46.
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.
47.
Shusuke Numata, R. TAO, T. M. HYDE, T. YE, D. R. WEINBERGER, J. E. KLEINMAN and B. K. LIPSKA : Evaluation of variance in genome-wide DNA methylation analysis of human cortical samples, Neuroscience, Chicago, Oct. 2009.
48.
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.
49.
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.
50.
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.
51.
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.
52.
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.
53.
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.
54.
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.
55.
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.
Proceeding of Domestic Conference:
1.
Kotaro Kashihara, Toshiki Takanabe, Keita Kiuchi, Hidehiro Umehara, Koshi Irizawa, Masahito Nakataki, Shusuke Numata, XIN KANG, Minoru Yoshida and Kazuyuki Matsumoto : Constructing multimodal counseling dataset for depression detection and feature analysis, IT healthcare, Vol.19, No.1, 94-99, Aug. 2024.
(Summary)
In recent years, depression caused by stress and anxiety has been on the rise worldwide, and the number of people taking leave due to depression and other mental illnesses has been increasing in Japan as well. However, there is a serious shortage of counselors and psychiatrists, making early detection difficult. In this study, for early detection of depression, 25 Japanese university students were interviewed by a professional counselor for about 30 minutes, and a multimodal dataset consisting of verbal, audio, video, and heart rate data was constructed during the interview. Before and after the interviews, a questionnaire about the subjects' current psychological state was also administered. The constructed dataset was analyzed by extracting features using GiNZA, OpenSMILE, and OpenFace, and comparing them with the results of the questionnaire. In the future, we plan to conduct interviews with mentally ill subjects and collect data from them.
Shusuke Numata : The future prospect on postmortem brain research; from the point of view of similarity and dissimilarity between blood and brain, 第40回日本生物学的精神医学会, Sep. 2018.
50.
Shusuke Numata : Plasma metabolomics of major depressive disorder, 第40回日本生物学的精神医学会, Sep. 2018.
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.
114.
Shusuke Numata, Hyde M. Thomas, Ye Tianzheng, Tao Ran, Weinberger R. Daniel, Kleinman E. Joel and Lipska K. Barbara : 死後脳を用いた統合失調症の網羅的DNAメチル化修飾解析研究, 第7回日本統合失調症学会, Mar. 2012.
Junichi Iga, 菊地 久美子, Masahito Nakataki, Shinya Watanabe, Shusuke Numata and Tetsuro Ohmori : Lithium decreases VEGF mRNA expression in leukocytes of healthy subjects and bipolar patients, 第20回日本臨床精神神経薬理学会, Sep. 2010.
120.
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.
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.
136.
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.
137.
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.
Tetsuro Ohmori, Junichi Iga and Shusuke Numata : Blood-based biomarkers for the diagnosis and drug response for mood disorders, Japanese Journal of Biological Psychiatry, Vol.25, No.2, 79-83, 2014.
(Summary)
Mood disorders are not only central but also systemic disorders involving abnormalities with autonomic nervous, neuroendocrine and neuroimmune systems. Over the past decades a number of investigators have studied to find convenient and reliable blood- based biomarkers. Although changes in peripheral blood are not identical to changes in the CNS, they are known to re ect central changes. Dexamethasone suppression test and brain derived neurotrophic factor (BDNF) levels are the most established biomarkers, but not sensitive enough to be clinically useful diagnostic makers. Recent advances in genomic, genetic, epigenetic and proteomic technologies have opened a new way for biomarker study of psychiatric diseases. These new technologies enable us to measure multiple variables from a small amount of blood sample. Studies with these technologies have revealed that mood disorders show specific changes in the gene and protein expression. It has been shown that mood stabilizers and antidepressants induce multiple gene expressional changes in the peripheral leukocytes or lymphoblastoid cells. The symposium aimed to review the recent progress of blood - based biomarkers for the diagnosis and drug response for mood disorders. The four speakers from USA, Israel and Japan introduced their recent works and then had a general discussion. The symposium provided the audience a cutting edge knowledge and broad perspective in this interesting and promising eld.
A study of the relationship between cerebral quantitative susceptivility mapping and cerebral blood flow in patients with Alzheimer's disease. (Project/Area Number: 24K10735 )
Exploratory study of DNA methylation abnormalities in schizophrenia using a 5th generation sequencerusing a 5th generation sequencer. (Project/Area Number: 24K10680 )
Reserach of depression focusing on D-amino acids (Project/Area Number: 19K08075 )
Establishment of biological marker and pathophysiological study of depression using omics analysis (Project/Area Number: 18H02751 )
Association of DNA methylation with child abuse, suicidal behavior, and stage of illness in major depressive disorder (Project/Area Number: 15K09809 )
An intermediate phenotype study of clinical responses of obsessive-compulsive disorder by using high resolution MRS and NIRS (Project/Area Number: 26461720 )
DNA methylation signatures of peripheral leukocytes in schizophrenia (Project/Area Number: 24791216 )