研究活動情報

• Preliminary development of a risk predictor for severe complication in patients with anorexia nervosa.

  Toshiyuki Shirai, Takaki Tanifuji, Ikuo Otsuka, Satoshi Okazaki, Tadasu Horai, Naruhisa Yamaki, Haruka Minami, Masao Miyachi, Shohei Okada, Akitoyo Hishimoto

  Anorexia nervosa (AN) is life-threatening because of many physical complications, hence a quantitative indicator for early therapeutic intervention through hospitalization is needed. Here, we compared the demographics of 21 patients with AN who required intensive treatment in the internal medicine ward and those of 61 patients with AN who directly admitted to the psychiatric ward. We developed a risk score for severe physical complications in patients with AN, by using six items with significant differences between two groups; body mass index, blood urea nitrogen, corrected calcium, albumin, aspartate transaminase, and C-reactive protein (area under the curve = 0.824).

  2024年09月, Psychiatry research, 342, 116151 - 116151, 英語, 国際誌

  研究論文（学術雑誌）


• Comprehensive analysis including in-game spending and violent game playing in patients with internet gaming disorder.

  Haruka Minami, Toshiyuki Shirai, Shohei Okada, Masao Miyachi, Takaki Tanifuji, Satoshi Okazaki, Tadasu Horai, Kentaro Mouri, Ikuo Otsuka, Akitoyo Hishimoto

  AIM: Internet gaming disorder (IGD) is receiving increasing attention. In particular, violent gameplay or in-game spending affects the psychiatric conditions and economic difficulties of patients. We conducted regression analysis and path analysis to investigate the associations between a comprehensive list of factors in patients with IGD, including the degree of internet or gaming dependence, developmental problems, family background, severity of depression, sleeping habits, in-game spending, and first-person shooter (FPS) and third-person shooter (TPS) game playing. METHODS: The participants were 47 Japanese individuals (39 males and 8 females) aged ≤20 years diagnosed with IGD with complete data from the internet addiction test, autism spectrum quotient, Quick Inventory of Depressive Symptomatology, and Pittsburgh Sleep Quality Index. All participants were asked whether their parents have divorce history, whether they have siblings, whether they play FPS or TPS games, and whether they engage in in-game spending. Firstly, we compared these factors between males and females; secondly, we conducted regression analysis and path analysis in male patients. RESULTS: As for simple comparison between sex, female patients showed greater severity of IGD and depressive score. In regression analysis of male patients, significant associations were found between FPS or TPS game playing and in-game spending. We also created path diagrams. CONCLUSION: The results of the comprehensive analyses suggest the possibility that bidirectional synergistic effects could be achieved by gradually reducing both violent game playing and in-game spending. The concept of internet dependence has a wide range of meanings, and for each subtype, it is important to consider the background that led to the dependence to make individualized environmental adjustments and provide psychotherapy.

  2024年07月, Neuropsychopharmacology reports, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Accelerated epigenetic aging in alcohol dependence.

  Toshiyuki Shirai, Satoshi Okazaki, Ikuo Otsuka, Masao Miyachi, Takaki Tanifuji, Ryota Shindo, Shohei Okada, Haruka Minami, Tadasu Horai, Kentaro Mouri, Akitoyo Hishimoto

  Alcohol dependence poses a global health threat associated with aging and reduced life expectancy. Recently, aging research through deoxyribonucleic acid (DNA) methylation has gained attention. New epigenetic clocks have been developed; however, no study has investigated GrimAge components, GrimAge2 components and DunedinPACE in patients with alcohol dependence. In this study, we aimed to perform epigenetic clock analysis to evaluate epigenetic age acceleration and DNA methylation-based age-predictive components in patients with alcohol dependence and controls. We utilized publicly available DNA methylation data (GSE98876) for our analysis. Additionally, we compared the values of the same items before and after the patients underwent a treatment program. The dataset comprised 23 controls and 24 patients. We observed that DunedinPACE accelerated more in patients with alcohol dependence. AgeAccelGrim and AgeAccelGrim2 decelerated more after the treatment program than before, and beta-2-microglobulin and Cystatin C decreased after the treatment program than before. These findings are crucial as they affect the cranial nerve area, potentially contributing to cognitive dysfunction and psychiatric symptoms in patients with alcohol dependence.

  2024年05月, Journal of psychiatric research, 173, 175 - 182, 英語, 国際誌

  研究論文（学術雑誌）


• Association study of a single nucleotide polymorphism in the hypoxia response element of the macrophage migration inhibitory factor gene promoter with suicide completers in the Japanese population.

  Toshiyuki Shirai, Satoshi Okazaki, Takaki Tanifuji, Ikuo Otsuka, Masao Miyachi, Shohei Okada, Ryota Shindo, Tadasu Horai, Kentaro Mouri, Motonori Takahashi, Takeshi Kondo, Yasuhiro Ueno, Akitoyo Hishimoto

  BACKGROUND: More than 800 000 people die by suicide annually. The heritability of suicide is 30%-50%. We focused on the hypoxia response element (HRE), which promotes the expression of macrophage migration inhibitory factor (MIF) via the hypoxia-inducible factor (HIF) pathway, important in neurogenesis and neuroprotection. We examined a genetic polymorphism of rs17004038, a single-nucleotide polymorphism (SNP), in suicide completers and controls. METHODS: The study population included 1336 suicide completers and 814 unrelated healthy controls. All participants were Japanese. We obtained peripheral blood, extracted DNA, and genotyped the patients for SNP rs17004038 (C > A). RESULTS: No significant differences were observed between the two groups in either the allele or genotype analyses. Subgroup analyses by sex, age (<40 or ≥40), and suicide method (violent or nonviolent suicide) were performed with similar results. CONCLUSION: No association was observed between SNP rs17004038 and suicide completion. Although it is challenging to collect a large number of samples from suicide completers, further MIF-related genetic studies, including those of rs17004038, are necessary with larger sample sizes.

  2024年03月, Neuropsychopharmacology reports, 44(1) (1), 262 - 266, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Epigenome-wide association study on methamphetamine dependence.

  Toshiyuki Shirai, Satoshi Okazaki, Takaki Tanifuji, Ikuo Otsuka, Tadasu Horai, Kentaro Mouri, Yukihiro Takemura, Katsuro Aso, Noriya Yamamoto, Akitoyo Hishimoto

  Repeated abuse of methamphetamine (METH) can cause dependence, repeated relapse of psychotic symptoms, compulsive drug-seeking behaviour, and various neurological symptoms. These long-term biological changes may be associated with epigenetic mechanisms; however, the association between METH use and epigenetic mechanisms has been poorly investigated. Thus, we performed an epigenome-wide association study of METH dependence using genomic DNA extracted from the blood samples of 24 patients with METH dependence and 24 normal controls. All participants were of Japanese descent. We tested the association between METH dependence and DNA methylation using linear regression analysis. We found epigenome-wide significant associations at four CpG sites, one of which occurred in the CNOT1 gene and another in the PUM1 gene. We especially noted the CNOT1 and PUM1 genes as well as several other genes that indicated some degree of association with METH dependence. Among the relatively enriched Gene Ontology terms, we were interested in terms of mRNA metabolism, respirasome, and excitatory extracellular ligand-gated ion channel activity. Among the relatively enriched Kyoto Encyclopedia of Genes and Genome pathways, we noted pathways of several neurological diseases. Our results indicate that genetic changes akin to those in other psychiatric or neurodegenerative disorders may also occur via epigenetic mechanisms in patients with METH dependence.

  2024年03月, Addiction biology, 29(3) (3), e13383, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Accelerated epigenetic aging and decreased natural killer cells based on DNA methylation in patients with untreated major depressive disorder.

  Ryota Shindo, Takaki Tanifuji, Satoshi Okazaki, Ikuo Otsuka, Toshiyuki Shirai, Kentaro Mouri, Tadasu Horai, Akitoyo Hishimoto

  Major depressive disorder (MDD) is known to cause significant disability. Genome-wide DNA methylation (DNAm) profiles can be used to estimate biological aging and as epigenetic clocks. However, information on epigenetic clocks reported in MDD patients is inconsistent. Since antidepressants are likely confounders, we evaluated biological aging using various DNAm-based predictors in patients with MDD who had never received depression medication. A publicly available dataset consisting of whole blood samples from untreated MDD patients (n = 40) and controls (n = 40) was used. We analyzed five epigenetic clocks (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge), DNAm-based telomere length (DNAmTL), and DNAm-based age-related plasma proteins (GrimAge components), as well as DNAm-based white blood cell composition. The results indicate that patients with untreated MDD were significantly associated with epigenetic aging acceleration in HannumAge and GrimAge. Furthermore, a decrease in natural killer cells, based on DNAm, was observed in patients with untreated MDD.

  2023年09月, npj aging, 9(1) (1), 19 - 19, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Epigenetic clock解析により明らかとなった大うつ病性障害におけるDNAメチル化に基づくcystatin C値の上昇(Epigenetic clock analysis reveals increased cystatin C levels based on DNA methylation in major depressive disorder)

  谷藤 貴紀, 岡崎 賢志, 大塚 郁夫, 毛利 健太郎, 蓬莱 政, 新藤 良太, 白井 寿行, 菱本 明豊

  (一社)日本抗加齢医学会, 2023年06月, 日本抗加齢医学会総会プログラム・抄録集, 23回, 252 - 252, 英語


• 胎児性アルコールスペクトラム障害児におけるEpigenetic Clock解析(Epigenetic Clock Analysis in Children with Fetal Alcohol Spectrum Disorder)

  岡崎 賢志, 谷藤 貴紀, 大塚 郁夫, 蓬莱 政, 山木 愛久, 菱本 明豊

  (一社)日本抗加齢医学会, 2023年06月, 日本抗加齢医学会総会プログラム・抄録集, 23回, 264 - 264, 英語


• Association of two variable number of tandem repeats in the monoamine oxidase A gene promoter with suicide completion: The present study and meta-analysis.

  Masashi Hasegawa, Takaki Tanifuji, Satoshi Okazaki, Ikuo Otsuka, Toshiyuki Shirai, Ryota Shindo, Tadasu Horai, Kentaro Mouri, Motonori Takahashi, Takeshi Kondo, Yasuhiro Ueno, Akitoyo Hishimoto

  BACKGROUND: One potential cause of suicide is serotonergic dysfunction. Sex differences have been reported to modulate the effects of serotonergic polymorphisms. Monoamine oxidase A (MAOA) is an enzyme that degrades serotonin and is located on the X chromosome. A previous study indicated that the upstream (u) variable number of tandem repeat (VNTR) in the MAOA gene promoter may be associated with suicide. However, a meta-analysis showed that this polymorphism may not be related to suicide. According to a recent study, compared with the uVNTR, the distal (d)VNTR and the haplotypes of the two VNTRs modulate MAOA expression. METHODS: We examined the two VNTRs in the MAOA gene promoter in 1007 subjects who committed suicide and 844 healthy controls. We analyzed the two VNTRs using fluorescence-based polymerase chain reaction assays. We conducted a meta-analysis for the two VNTRs to update it. RESULTS: Our results demonstrated that neither the genotype-based associations nor allele/haplotype frequencies of the two VNTRs were significantly associated with suicide. In the meta-analysis, we did not indicate relationships between uVNTR and suicide nor did we identify articles analyzing dVNTR in suicide. CONCLUSION: Overall, we did not find a relationship between the two VNTRs in the MAOA promoter and suicide completion; thus, warranting further studies are required.

  2023年05月, Neuropsychopharmacology reports, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Epigenetic clock analysis reveals increased plasma cystatin C levels based on DNA methylation in major depressive disorder.

  Takaki Tanifuji, Satoshi Okazaki, Ikuo Otsuka, Kentaro Mouri, Tadasu Horai, Ryota Shindo, Toshiyuki Shirai, Akitoyo Hishimoto

  Major depressive disorder (MDD) is a common mental illness and a major public health concern worldwide. Depression is associated with epigenetic changes that regulate gene expression, and analyzing these changes may help elucidate the pathophysiology of MDD. Genome-wide DNA methylation (DNAm) profiles can function as 'epigenetic clocks' that can help estimate biological aging. Here, we assessed biological aging in patients with MDD using various DNAm-based indicators of epigenetic aging. We used a publicly available dataset containing data obtained from the whole blood samples of MDD patients (n = 489) and controls (n = 210). We analyzed five epigenetic clocks (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge) and DNAm-based telomere length (DNAmTL). We also investigated seven DNAm-based age-predictive plasma proteins (including cystatin C) and smoking status, which are components of GrimAge. Following adjustment for confounding factors such as age and sex, patients with MDD showed no significant difference in epigenetic clocks and DNAmTL. However, DNAm-based plasma cystatin C levels were significantly higher in patients with MDD than controls. Our findings revealed specific DNAm changes predicting plasma cystatin C levels in MDD. These findings may help elucidate the pathophysiology of MDD, leading to the development of new biomarkers and medications.

  2023年04月, Psychiatry research, 322, 115103 - 115103, 英語, 国際誌

  研究論文（学術雑誌）


• Effective use of memantine for catatonia in major depressive disorder after failure of electroconvulsive therapy: A case report

  Takaki Tanifuji, Ikuo Otsuka, Toshio Atarashiya, Atsushi Kimura, Tadasu Horai, Satoshi Okazaki, Akitoyo Hishimoto

  Wiley, 2023年03月, Psychiatry and Clinical Neurosciences Reports, 2(1) (1)

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Ribosomal DNA gene copies are increased in blood and brain of Japanese schizophrenia patients.

  Sen Li, Ikuo Otsuka, Takaki Tanifuji, Satoshi Okazaki, Tadasu Horai, Motonori Takahashi, Takeshi Kondo, Yasuhiro Ueno, Akitoyo Hishimoto

  Past evidence has indicated increased ribosomal DNA (rDNA) content in the blood of patients with schizophrenia (SCZ) among European populations. Here, for the first time, we investigated the rDNA copy number (rDNAcn) of SCZ in East Asian populations as well as in blood and brain tissues. In this study, we measured 18S/28S rDNAcn in the peripheral blood of live participants (81 patients with SCZ and 98 healthy controls) and the dorsolateral prefrontal cortices (DLPFCs) of postmortem individuals (10 patients with SCZ and 23 non-psychiatric controls) in the Japanese population. Patients with SCZ had significantly increased 18S/28S rDNAcn in the blood compared to controls (p < 0.05). 18S rDNAcn was significantly increased in the brain of patients with SCZ compared to controls (p < 0.05). In conclusion, regarding the increased rDNAcn in the blood of patients with SCZ that was previously reported in Europeans, we successfully replicated this by using a different, ethnically East Asian, cohort. Additionally, we provide the first evidence of increased rDNAcn in the brain of patients with SCZ. These findings may help to elucidate the molecular underpinnings of SCZ pathophysiology related to ribosomal DNA abnormalities.

  2023年, PloS one, 18(1) (1), e0280694, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Development of an individual fitness score (IFS) based on the depression treatment guidelines of in the Japanese Society of Mood Disorders.

  Kentaro Fukumoto, Fumitoshi Kodaka, Naomi Hasegawa, Hiroyuki Muraoka, Hikaru Hori, Kayo Ichihashi, Yuka Yasuda, Hitoshi Iida, Kazutaka Ohi, Shinichiro Ochi, Kenta Ide, Naoki Hashimoto, Masahide Usami, Toshinori Nakamura, Hiroshi Komatsu, Tsuyoshi Okada, Tatsuya Nagasawa, Ryuji Furihata, Kiyokazu Atake, Mikio Kido, Saya Kikuchi, Hirotaka Yamagata, Taishiro Kishimoto, Manabu Makinodan, Tadasu Horai, Masahiro Takeshima, Chika Kubota, Takeshi Asami, Eiichi Katsumoto, Akitoyo Hishimoto, Toshiaki Onitsuka, Junya Matsumoto, Kenichiro Miura, Hisashi Yamada, Norio Yasui-Furukori, Koichiro Watanabe, Ken Inada, Kotaro Otsuka, Ryota Hashimoto

  AIM: Treatment guidelines are designed to assist patients and health care providers and are used as tools for making treatment decisions in clinical situations. The treatment guidelines of the Japanese Society of Mood Disorders establish treatment recommendations for each severity of depression. The individual fitness score (IFS) was developed as a simple and objective indicator to assess whether individual patients are practicing treatment by the recommendations of the depression treatment guidelines of the Japanese Society of Mood Disorders. METHODS: The EGUIDE project members determined the IFS through the modified Delphi method. In this article, the IFS was calculated based on the treatment of depressed patients treated and discharged between 2016 and 2020 at facilities participating in the EGUIDE project. In addition, we compared scores at admission and discharge. RESULTS: The study included 428 depressed patients (mild n = 22, moderate/severe n = 331, psychotic n = 75) at 57 facilities. The mean IFS scores by severity were statistically significantly higher at discharge than at admission with moderate/severe depression (mild 36.1 ± 34.2 vs. 41.6 ± 36.9, p = 0.49; moderate/severe 50.2 ± 33.6 vs. 55.7 ± 32.6, p = 2.1 × 10-3; psychotic 47.4 ± 32.9 versus 52.9 ± 36.0, p = 0.23). CONCLUSION: We developed the IFS based on the depression treatment guideline, which enables us to objectively determine how close the treatment is to the guideline at the time of evaluation in individual cases. Therefore, the IFS may influence guideline-oriented treatment behavior and lead to the equalization of depression treatment in Japan, including pharmacotherapy.

  2022年11月, Neuropsychopharmacology reports, 43(1) (1), 33 - 39, 英語, 国際誌

  研究論文（学術雑誌）


• Successful electroconvulsive therapy for 22q11.2 deletion syndrome with Schizophrenia and Parkinson's disease.

  Takaki Tanifuji, Ikuo Otsuka, Atsushi Kimura, Tadasu Horai, Satoshi Okazaki, Wataru Satake, Akitoyo Hishimoto

  2022年11月, Psychiatry and clinical neurosciences, 76(11) (11), 603 - 604, 英語, 国際誌


• Epigenetic clock analysis in methamphetamine dependence.

  Yukihiro Takemura, Takaki Tanifuji, Satoshi Okazaki, Yutaka Shinko, Ikuo Otsuka, Tadasu Horai, Toshiyuki Shirai, Katsuro Aso, Noriya Yamamoto, Akitoyo Hishimoto

  Methamphetamine (MA) is used worldwide and causes serious public health and social problems. MA affects the central nervous, cardiac, and immune systems, which causes neuropsychiatric and cardiovascular diseases and infection. Epigenetic changes, including DNA methylation (DNAm), are associated with various clinical phenotypes of MA abuse. DNAm is related to biological aging and health risks; hence, we aimed to assess the changes in biological aging in MA dependence using the DNAm age and DNA methylation-based telomere length (DNAmTL). We used five measures of DNAm age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge), DNAmTL, and DNAm-based age-predictive factors (plasma proteins and blood cell composition). We compared patients with MA dependence and healthy controls (n = 24 each) using the DNAm profiles obtained from whole-blood samples. Patients with MA dependence showed significant acceleration in PhenoAge and GrimAge, as well as a trend for significant acceleration in DNAmTL. Following adjustment for confounding factors, MA dependence was significantly associated with accelerations in PhenoAge, GrimAge, and DNAmTL, as well as alterations in DNAm-based age-predictive factors (beta-2-microglobulin, granulocytes, and naive cluster of differentiation 4+ T cells). Our results suggested an acceleration of biological aging and specific changes in the DNAm of age- predictive factors in MA dependence.

  2022年11月, Psychiatry research, 317, 114901 - 114901, 英語, 国際誌

  研究論文（学術雑誌）


• Effects of electroconvulsive therapy on the use of anxiolytics and sleep medications: a propensity score-matched analysis.

  Takashi Tsuboi, Yoshikazu Takaesu, Naomi Hasegawa, Shinichiro Ochi, Kentaro Fukumoto, Kazutaka Ohi, Hiroyuki Muraoka, Tsuyoshi Okada, Funitoshi Kodaka, Shun Igarashi, Hitoshi Iida, Hiroko Kashiwagi, Hikaru Hori, Kayo Ichihashi, Kazuyoshi Ogasawara, Naoki Hashimoto, Jun-Ichi Iga, Toshinori Nakamura, Masahide Usami, Tatsuya Nagasawa, Mikio Kido, Hiroshi Komatsu, Hirotaka Yamagata, Kiyokazu Atake, Ryuji Furihata, Saya Kikuchi, Tadasu Horai, Masahiro Takeshima, Yoji Hirano, Manabu Makinodan, Junya Matsumoto, Kenichiro Miura, Akitoyo Hishimoto, Shusuke Numata, Hisashi Yamada, Norio Yasui-Furukori, Ken Inada, Koichiro Watanabe, Ryota Hashimoto

  AIM: We investigated the association of electroconvulsive therapy (ECT) with anxiolytic and sleep medication use in patients with major depressive disorder (MDD) and schizophrenia (SZ). METHODS: This nationwide observational study analyzed data from 3483 MDD inpatients and 6663 SZ inpatients. Patients with MDD and SZ were classified into those who underwent ECT during hospitalization and those who did not. A propensity score-matching method was performed to adjust for preadmission characteristics and clinical information, which were expected bias between the two groups. Rates of anxiolytic and sleep medication use at discharge were compared in the matched sample. RESULTS: 500 MDD patients were assigned to both groups. In the matched MDD sample, the rate of anxiolytic and sleep medication use at discharge was significantly lower in the ECT group than in the non-ECT group (64.9% vs. 75.8%, P = 1.7 × 10-4 ). In the ECT group, the rate of anxiolytic and sleep medication use at discharge was significantly lower than that prior to admission (64.9% vs. 73.2%, P = 1.2 × 10-14 ). 390 SZ patients were allocated. In the matched SZ sample, the ECT group was not significantly different from the non-ECT group in the rate of anxiolytics and sleep medications use at discharge (61.3% vs. 68.2%, P = 4.3 × 10-2 ). In the ECT group, the rate of anxiolytics and sleep medications use at discharge was significantly lower than that before admission (61.3% vs. 70.5%, P = 4.4 × 10-4 ), although this was not the primary outcome. CONCLUSION: Reduction of anxiolytic and sleep medication use may be considered positively when ECT is indicated for treatment of MDD.

  2022年10月, Psychiatry and clinical neurosciences, 77(1) (1), 30 - 37, 英語, 国際誌

  研究論文（学術雑誌）


• Preventive effects of preoperative ramelteon on postoperative delirium in Asian elderly population: A randomized, double-blind, placebo-controlled trial, and a systematic review and meta-analysis.

  Takaki Tanifuji, Ikuo Otsuka, Satoshi Okazaki, Tadasu Horai, Ryuhei So, Kyoichi Shiroiwa, Kentaro Mouri, Motofumi Tanaka, Nobuko Ohmoto, Ichiro Sora, Midori Hirai, Takumi Fukumoto, Yonson Ku, Akitoyo Hishimoto

  2022年10月, Asian journal of psychiatry, 78, 103282 - 103282, 英語, 国際誌


• Searching for biomarkers in schizophrenia and psychosis: Case-control study using capillary electrophoresis and liquid chromatography time-of-flight mass spectrometry and systematic review for biofluid metabolites.

  Saehyeon Kim, Satoshi Okazaki, Ikuo Otsuka, Yutaka Shinko, Tadasu Horai, Naofumi Shimmyo, Takashi Hirata, Naruhisa Yamaki, Takaki Tanifuji, Shuken Boku, Ichiro Sora, Akitoyo Hishimoto

  Metabolomics has been attracting attention in recent years as an objective method for diagnosing schizophrenia. In this study, we analyzed 378 metabolites in the serum of schizophrenia patients using capillary electrophoresis- and liquid chromatography-time-of-flight mass spectrometry. Using multivariate analysis with the orthogonal partial least squares method, we observed significantly higher levels of alanine, glutamate, lactic acid, ornithine, and serine and significantly lower levels of urea, in patients with chronic schizophrenia compared to healthy controls. Additionally, levels of fatty acids (15:0), (17:0), and (19:1), cis-11-eicosenoic acid, and thyroxine were significantly higher in patients with acute psychosis than in those in remission. Moreover, we conducted a systematic review of comprehensive metabolomics studies on schizophrenia over the last 20 years and observed consistent trends of increase in some metabolites such as glutamate and glucose, and decrease in citrate in schizophrenia patients across several studies. Hence, we provide substantial evidence for metabolic biomarkers in schizophrenia patients through our metabolomics study.

  2022年03月, Neuropsychopharmacology reports, 42(1) (1), 42 - 51, 英語, 国際誌

  研究論文（学術雑誌）


• Accelerated epigenetic age and shortened telomere length based on DNA methylation in Nicolaides-Baraitser syndrome.

  Yutaka Shinko, Satoshi Okazaki, Ikuo Otsuka, Tadasu Horai, Saehyeon Kim, Takaki Tanifuji, Akitoyo Hishimoto

  BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a rare disorder characterized by neurodevelopmental delays, seizures, and diverse physical characteristics. The DNA methylation (DNAm) profile in NCBRS is significantly different. DNAm is linked to the biological aging of cells and the health risks associated with biological aging. In this study, we examined changes in biological ages in NCBRS to provide insights into the prognosis and health risks of NCBRS. METHODS: We used a publicly available dataset to examine biological aging in NCBRS using DNAm-based epigenetic ages, such as PhenoAge and GrimAge, as well as DNAm-based estimator of telomere length (DNAmTL). We investigated 12 cases, clinically diagnosed as NCBRS, and 27 controls. RESULTS: Compared to controls, NCBRS cases exhibited significantly accelerated PhenoAge and GrimAge as well as significantly shortened DNAmTL. CONCLUSION: These results suggest an acceleration of biological aging in NCBRS and provide insights into the prognosis and health risks of NCBRS.

  2022年03月, Molecular genetics & genomic medicine, 10(3) (3), e1876, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• The characteristics of patients receiving psychotropic pro re nata medication at discharge for the treatment of schizophrenia and major depressive disorder: A nationwide survey from the EGUIDE project.

  Kayo Ichihashi, Yoshitaka Kyou, Naomi Hasegawa, Norio Yasui-Furukori, Yoshihito Shimizu, Hikaru Hori, Naoki Hashimoto, Kenta Ide, Yayoi Imamura, Hisashi Yamada, Shinichiro Ochi, Jun-Ichi Iga, Yoshikazu Takaesu, Kazutaka Ohi, Takashi Tsuboi, Hitoshi Iida, Hirotaka Yamagata, Akitoyo Hishimoto, Tadasu Horai, Masahide Usami, Manabu Makinodan, Tatsuya Nagasawa, Hiroshi Komatsu, Mikio Kido, Hiroyuki Muraoka, Kiyokazu Atake, Masahiro Takeshima, Chika Kubota, Takahiko Inagaki, Shinichiro Tamai, Taishiro Kishimoto, Ryuji Furihata, Junya Matsumoto, Kenichiro Miura, Ken Inada, Koichiro Watanabe, Kiyoto Kasai, Ryota Hashimoto

  BACKGROUND: Although several guidelines indicate that daily pharmacotherapy is an important part of the treatment of schizophrenia and major depressive disorder, there are few reports regarding pro re nata (PRN) prescriptions. The purpose of this study is to clarify the characteristics of patients receiving psychotropic PRN prescription for the treatment of schizophrenia and major depressive disorder. METHOD: We used data from 'the effectiveness of guideline for dissemination and education in psychiatric treatment' (EGUIDE) project to evaluate the presence or absence of psychotropic PRN prescription at the time of discharge, the age and sex of patients receiving PRN prescription for each diagnosis, and the association between PRN prescription and regular daily psychotropics. RESULTS: The psychotropic PRN prescription ratio was 29.9% among 2617 patients with schizophrenia and 31.1% among 1248 patients with major depressive disorder at discharge. In schizophrenia, the psychotropic PRN prescription ratio was 21.6% for patients aged 65 years or older, which was lower than that of all other age groups. In major depressive disorder, the psychotropic PRN prescription ratio was 34.2% for female patients, which was significantly higher than that for male patients (25.5%). In schizophrenia, there was an association between psychotropic PRN prescription and regular use of multiple psychotropic medications. CONCLUSIONS: Psychotropic PRN prescription was less common in elderly patients with schizophrenia and more common in female patients with major depressive disorder. In schizophrenia, psychotropic PRN prescription led to polypharmacy of psychotropics. Further studies are needed to accumulate evidence and to provide education on appropriate PRN prescriptions.

  2022年03月, Asian journal of psychiatry, 69, 103007 - 103007, 英語, 国際誌

  研究論文（学術雑誌）


• Polymorphisms in the hypoxia inducible factor binding site of the macrophage migration inhibitory factor gene promoter in schizophrenia.

  Satoshi Okazaki, Shuken Boku, Yuichiro Watanabe, Ikuo Otsuka, Tadasu Horai, Ryo Morikawa, Atsushi Kimura, Naofumi Shimmyo, Takaki Tanifuji, Toshiyuki Someya, Akitoyo Hishimoto

  BACKGROUND: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that promotes neurogenesis and neuroprotection. MIF is predominantly expressed in astrocytes in the brain. The serum MIF level and microsatellites/single nucleotide polymorphisms (SNPs) in the MIF gene promoter region are known to be associated with schizophrenia (SCZ). Interestingly, previous studies reported that hypoxia, an environmental risk factor for SCZ, induced MIF expression through binding of the hypoxia inducible factor (HIF)-1 to the hypoxia response element (HRE) in the MIF promoter. METHODS: We investigated the involvement of MIF in SCZ while focusing on the HIF pathway. First, we conducted an association study of the SNP rs17004038 (C>A) in the HRE of the MIF promoter between 1758 patients with SCZ and 1507 controls. Next, we investigated the effect of hypoxia on MIF expression in primary cultured astrocytes derived from neonatal mice forebrain. RESULTS: SNP rs17004038 was significantly associated with SCZ (p = 0.0424, odds ratio = 1.445), indicating that this SNP in the HRE of the MIF promoter was a genetic risk factor for SCZ. Hypoxia induced MIF mRNA expression and MIF protein production and increased HIF-1 binding to the MIF promoter, while the activity of the MIF promoter was suppressed by mutations in the HRE and by deletion of the HRE in astrocytes. CONCLUSION: These results suggest that SNP rs17004038 in the HRE of the MIF promoter was significantly associated with SCZ and may be involved in the pathophysiology of SCZ via suppression of hypoxia and HIF pathway-induced MIF expression.

  2022年, PloS one, 17(3) (3), e0265738, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• 精神病性障害に対するブレクスピプラゾールの使用経験

  蓬莱 政, 青山 慎介, 木村 敦, 新名 尚史, 平田 尚士, 岡崎 賢志, 江口 典臣, 山木 愛久, 新光 穣, 曽良 一郎

  (公社)日本精神神経学会, 2021年09月, 精神神経学雑誌, (2021特別号) (2021特別号), S572 - S572, 日本語


• Serum levels of glial cell line-derived neurotrophic factor as a biomarker for mood disorders and lithium response

  Keita Idemoto, Tomihisa Niitsu, Tatsuki Hata, Tamaki Ishima, Sumiko Yoshida, Kotaro Hattori, Tadasu Horai, Ikuo Otsuka, Hidenaga Yamamori, Shigenobu Toda, Yosuke Kameno, Kiyomitsu Ota, Yasunori Oda, Atsushi Kimura, Tasuku Hashimoto, Norio Mori, Mitsuru Kikuchi, Yoshio Minabe, Ryota Hashimoto, Akitoyo Hishimoto, Kazuyuki Nakagome, Kenji Hashimoto, Masaomi Iyo

  Elsevier BV, 2021年07月, Psychiatry Research, 301, 113967 - 113967

  研究論文（学術雑誌）


• Clozapine increases macrophage migration inhibitory factor (MIF) expression via increasing histone acetylation of MIF promoter in astrocytes.

  Satoshi Okazaki, Shuken Boku, Ikuo Otsuka, Tadasu Horai, Atsushi Kimura, Naofumi Shimmyo, Naruhisa Yamaki, Akitoyo Hishimoto

  Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and promotes neurogenesis and neuroprotection in brains. In addition, MIF has been identified as a potential marker of schizophrenia (SCZ). Our recent study also showed that serum MIF level is higher in SCZ and positively correlated with antipsychotic doses, and that MIF promoter polymorphisms are associated with SCZ. Here, we investigated the effects of antipsychotics such as clozapine on MIF expression in primary cultured astrocytes derived from neonatal mouse forebrain. MIF mRNA expression was estimated with quantitative reverse-transcription polymerase chain reaction. MIF protein concentration was measured with enzyme-linked immunosorbent assay. The histone acetylation of MIF promoter was examined with chromatin immunoprecipitation assay. As a result, common antipsychotics, especially clozapine, increased MIF mRNA expression in a dose-dependent manner. Clozapine increased MIF mRNA expression and protein concentration in a time-dependent manner. Moreover, clozapine increased the acetylation of histone H3 at lysine 27 residues (H3K27) in MIF promoter. In conclusion, we provide novel evidence that antipsychotics such as clozapine increases MIF expression via the acetylation of H3K27 in astrocytes, and that MIF may have a potential role for astrocytes in the action mechanisms of antipsychotics.

  2021年03月, Journal of psychiatric research, 135, 237 - 242, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Epigenetic Clock Analysis in Children With Fetal Alcohol Spectrum Disorder.

  Satoshi Okazaki, Ikuo Otsuka, Yutaka Shinko, Tadasu Horai, Takashi Hirata, Naruhisa Yamaki, Ichiro Sora, Akitoyo Hishimoto

  BACKGROUND: Fetal alcohol spectrum disorder (FASD) is characterized by severe clinical impairment, considerable social burden, and high mortality and morbidity, which are due to various malformations, sepsis, and cancer. As >50% of deaths from FASD occur during the first year of life, we hypothesized that there is the acceleration of biological aging in FASD. Several recent studies have established genome-wide DNA methylation (DNAm) profiles as "epigenetic clocks" that can estimate biological aging, and FASD has been associated with differential DNAm patterns. Therefore, we tested this hypothesis using epigenetic clocks. METHODS: We investigated 5 DNAm-based measures of epigenetic age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge) and telomere length (DNAmTL) using 4 independent publicly available DNAm datasets; 2 datasets were derived from buccal epithelium, and the other 2 datasets were derived from peripheral blood. RESULTS: Compared with controls, children with FASD exhibited an acceleration of GrimAge in 1 buccal and 2 blood datasets. No significant difference was found in other DNAm ages and DNAmTL. Meta-analyses showed a significant acceleration of GrimAge in the blood samples but not in the buccal samples. CONCLUSIONS: This study provides novel evidence regarding accelerated epigenetic aging in children with FASD.

  2021年02月, Alcoholism, clinical and experimental research, 45(2) (2), 329 - 337, 英語, 国際誌

  研究論文（学術雑誌）


• Platelet-derived growth factor BB: A potential diagnostic blood biomarker for differentiating bipolar disorder from major depressive disorder.

  Keita Idemoto, Tamaki Ishima, Tomihisa Niitsu, Tatsuki Hata, Sumiko Yoshida, Kotaro Hattori, Tadasu Horai, Ikuo Otsuka, Hidenaga Yamamori, Shigenobu Toda, Yosuke Kameno, Kiyomitsu Ota, Yasunori Oda, Atsushi Kimura, Tasuku Hashimoto, Norio Mori, Mitsuru Kikuchi, Yoshio Minabe, Ryota Hashimoto, Akitoyo Hishimoto, Kazuyuki Nakagome, Masaomi Iyo, Kenji Hashimoto

  Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping depressive symptoms. This study investigated whether serum platelet-derived growth factor BB (PDGF-BB) is a differential diagnostic biomarker for BD and MDD. An initial SOMAscan proteomics assay of 1311 proteins in small samples from patients with BD and MDD and healthy controls (HCs) suggested that serum levels of PDGF-BB differed between BD and MDD. We then conducted a two-step, exploratory, cross-sectional, case-control study at our institute and five sites that included a total of 549 participants (157 with BD, 144 with MDD, and 248 HCs). Clinical symptoms were assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. In the initial analysis at our institute, serum PDGF-BB levels in the MDD group (n = 36) were significantly lower than those in the BD (n = 39) and HC groups (n = 36). In the multicenter study, serum PDGF-BB levels in the MDD group were again significantly lower than those in the BD and HC groups, with no significant difference between the BD and HC groups. Treatment with sodium valproate was associated with significantly lower serum PDGF-BB levels in patients with BD. After controlling for confounding factors (sex, age, body mass index, clinical severity, and valproate medication), serum PDGF-BB levels were lower in the MDD group than in the BD group regardless of mood state. Our findings suggest that serum PDGF-BB may be a potential biomarker to differentiate BD and MDD.

  2021年02月, Journal of psychiatric research, 134, 48 - 56, 英語, 国際誌

  研究論文（学術雑誌）


• Association of Two Variable Number of Tandem Repeats in the Monoamine Oxidase A Gene Promoter with Schizophrenia.

  Takaki Tanifuji, Satoshi Okazaki, Ikuo Otsuka, Tadasu Horai, Yutaka Shinko, Saehyeon Kim, Ichiro Sora, Akitoyo Hishimoto

  Background: Monoamine oxidase-A (MAO-A) decomposes dopamine and serotonin, and decreased MAO-A expression increases monoamine levels and is related to the pathophysiology of schizophrenia. Previous studies have reported that variable number of tandem repeats (VNTR), namely, upstream (u)VNTR, and some single nucleotide polymorphisms (SNPs) in the MAOA gene are associated with schizophrenia. Methods: We investigated the two VNTRs and their related SNPs (rs6323 and rs1137070) in the MAOA gene promoter in 859 patients with schizophrenia and 826 healthy controls. Distal (d)VNTR and uVNTR were genotyped with fluorescence-based fragment polymerase chain reaction assays, and rs6323 and rs1137070 with TaqMan SNP genotyping assays. Results: Neither the genotype nor allelic frequency of the VNTRs or SNPs showed significant differences between the schizophrenia and control groups. On the other hand, analysis of the dVNTR-uVNTR-rs6323-rs1137070 haplotype showed significant association for nine repeats (9R)-3R-T-C in female patients (corrected p = 0.0006, odds ratio [confidence interval] = 2.17 [1.446-3.257]). Conclusion: Our findings provide novel evidence that MAOA gene polymorphisms are associated with an increased risk of developing schizophrenia in females.

  2021年, Neuropsychiatric disease and treatment, 17, 3315 - 3323, 英語, 国際誌

  研究論文（学術雑誌）


• Unmet needs of patients with major depressive disorder - Findings from the 'Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)' project: A nationwide dissemination, education, and evaluation study.

  Hitoshi Iida, Junichi Iga, Naomi Hasegawa, Yuka Yasuda, Tomoya Yamamoto, Kenichiro Miura, Junya Matsumoto, Atsunobu Murata, Kazuyoshi Ogasawara, Hisashi Yamada, Hikaru Hori, Kayo Ichihashi, Naoki Hashimoto, Kazutaka Ohi, Norio Yasui-Furukori, Takashi Tsuboi, Toshinori Nakamura, Masahide Usami, Ryuji Furihata, Yoshikazu Takaesu, Kunihiro Iwamoto, Nobuhiro Sugiyama, Taishiro Kishimoto, Naohisa Tsujino, Hiroki Yamada, Akitoyo Hishimoto, Kiyotaka Nemoto, Kiyokazu Atake, Hiroyuki Muraoka, Eiichi Katsumoto, Satoru Oishi, Takahiko Inagaki, Fumiaki Ito, Yayoi Imamura, Mikio Kido, Tatsuya Nagasawa, Shusuke Numata, Shinichiro Ochi, Masaaki Iwata, Hidenaga Yamamori, Junichi Fujita, Toshiaki Onitsuka, Satoshi Yamamura, Manabu Makinodan, Michiko Fujimoto, Yoichiro Takayanagi, Kenji Takezawa, Hiroshi Komatsu, Kentaro Fukumoto, Shinichiro Tamai, Hirotaka Yamagata, Chika Kubota, Tadasu Horai, Ken Inada, Koichiro Watanabe, Hiroaki Kawasaki, Ryota Hashimoto

  2020年12月, Psychiatry and clinical neurosciences, 74(12) (12), 667 - 669, 英語, 国際誌


• miR-19b is elevated in peripheral blood of schizophrenic patients and attenuates proliferation of hippocampal neural progenitor cells.

  Tadasu Horai, Shuken Boku, Satoshi Okazaki, Ikuo Otsuka, Woraphat Ratta-Apha, Kentaro Mouri, Naruhisa Yamaki, Takashi Hirata, Akitoyo Hishimoto

  MicroRNAs (miRNAs) have been investigated in neurodevelopmental and psychiatric disorders including schizophrenia (SZ). Previous studies showed miRNAs dysregulation in postmortem brain tissues and peripheral blood of SZ patients. These suggest that miRNAs may play a role in the pathophysiology of SZ and be a potential biomarker of SZ. Previous studies also showed that miRNAs regulated neurogenesis and that neurogenesis was involved in the pathophysiology of SZ. In addition, a recent study showed that miR-19a and 19b, enriched in neural progenitor cells (NPC) in adult hippocampus, were increased in human NPC derived from induced pluripotent stem cell derived from SZ patients. However, it remains unclear whether the levels of miR-19a and 19b are altered in peripheral blood of SZ patients and how miR-19a and 19b affects neurogenesis. To elucidate them, first we examined the levels of miR-19a and 19b in peripheral blood of SZ patients with quantitative RT-PCR and showed that the level of miR-19b, but not miR-19a, was significantly higher (miR-19a: p = 0.5733, miR-19b: p = 0.0038) in peripheral blood of SZ patients (N = 22) than that of healthy controls (N = 19). Next, we examined the involvement of miR-19b in proliferation and survival of mouse neonatal mice hippocampus-derived NPC with BrdU assay and TUNEL assay. The silencing of miR-19b significantly increased proliferation (N = 5, p = 0.0139), but not survival (N = 5, p = 0.9571), of neonatal mice hippocampus-derived NPC. These results suggest that the level of miR-19b in peripheral blood is a potential biomarker of schizophrenia and that the higher level of miR-19b may increase the vulnerability of SZ via attenuating proliferation of hippocampal NPC.

  2020年12月, Journal of psychiatric research, 131, 102 - 107, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Prescription patterns in patients with schizophrenia in Japan: First-quality indicator data from the survey of "Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment (EGUIDE)" project.

  Kayo Ichihashi, Hikaru Hori, Naomi Hasegawa, Yuka Yasuda, Tomoya Yamamoto, Takashi Tsuboi, Kunihiro Iwamoto, Taishiro Kishimoto, Tadasu Horai, Hiroki Yamada, Nobuhiro Sugiyama, Toshinori Nakamura, Naohisa Tsujino, Kiyotaka Nemoto, Satoru Oishi, Masahide Usami, Eiichi Katsumoto, Hidenaga Yamamori, Hiroaki Tomita, Taro Suwa, Ryuji Furihata, Takahiko Inagaki, Junichi Fujita, Toshiaki Onitsuka, Kenichiro Miura, Junya Matsumoto, Kazutaka Ohi, Yuki Matsui, Yoshikazu Takaesu, Naoki Hashimoto, Junichi Iga, Kazuyoshi Ogasawara, Hisashi Yamada, Koichiro Watanabe, Ken Inada, Ryota Hashimoto

  BACKGROUND: Guideline for Pharmacological Therapy for Schizophrenia was published by the Japanese Society of Neuropsychopharmacology in 2015. "Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment (EGUIDE)" project aimed to standardize medical practice using quality indicators (QIs) as indices to evaluate the quality of medical practice. In this study, we have reported the quality indicator values of prescription before the beginning of the guideline lectures in the EGUIDE project to ascertain the baseline status of treating patients with schizophrenia. METHODS: A cross-sectional, retrospective case record survey was conducted, involving 1164 patients with schizophrenia at the time of discharge. We checked all types and dosage of psychotropic drugs. RESULTS: Forty-three percent of patients had antipsychotic polypharmacy, and substantial concomitant medication was observed (antidepressants; 8%, mood stabilizers: 37%, anxiolytics or hypnotics: 68%). CONCLUSIONS: In the results obtained in this study, we plant to report changes in the effectiveness of education in the EGUIDE project near the future.

  2020年09月, Neuropsychopharmacology reports, 40(3) (3), 281 - 286, 英語, 国際誌

  研究論文（学術雑誌）


• メタボローム解析による統合失調症血液バイオマーカーの探究

  金 世賢, 岡崎 賢志, 大塚 郁夫, 新光 穣, 木村 敦, 蓬莱 政, 新名 尚史, 平田 尚士, 谷藤 貴紀, 山木 愛久, 青山 慎介, 菱本 明豊, 曽良 一郎

  日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会, 2020年08月, 日本神経精神薬理学会年会・日本生物学的精神医学会年会・日本精神薬学会総会・学術集会合同年会プログラム・抄録集, 50回・42回・4回, 190 - 190, 日本語


• 気分障害のバイオマーカーとしての血清中血小板由来増殖因子(PDGF-BB)に関する多施設共同研究

  井手本 啓太, 石間 環, 新津 富央, 畑 達記, 小田 靖典, 木村 敦史, 亀野 陽亮, 蓬莱 政, 山森 英長, 戸田 重誠, 菱本 明豊, 橋本 亮太, 中込 和幸, 伊豫 雅臣, 橋本 謙二

  日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会, 2020年08月, 日本神経精神薬理学会年会・日本生物学的精神医学会年会・日本精神薬学会総会・学術集会合同年会プログラム・抄録集, 50回・42回・4回, 197 - 197, 日本語


• 自殺完遂者の死後脳におけるケモカインの変化

  新光 穣, 大塚 郁夫, 岡崎 賢志, 蓬莱 政, 朴 秀賢, 高橋 玄倫, 上野 易弘, 曽良 一郎, 菱本 明豊

  日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会, 2020年08月, 日本神経精神薬理学会年会・日本生物学的精神医学会年会・日本精神薬学会総会・学術集会合同年会プログラム・抄録集, 50回・42回・4回, 197 - 197, 日本語


• Decelerated epigenetic aging associated with mood stabilizers in the blood of patients with bipolar disorder.

  Satoshi Okazaki, Shusuke Numata, Ikuo Otsuka, Tadasu Horai, Makoto Kinoshita, Ichiro Sora, Tetsuro Ohmori, Akitoyo Hishimoto

  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.

  2020年05月, Translational psychiatry, 10(1) (1), 129 - 129, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Accelerated extrinsic epigenetic aging and increased natural killer cells in blood of suicide completers.

  Satoshi Okazaki, Ikuo Otsuka, Tadasu Horai, Takashi Hirata, Motonori Takahashi, Yasuhiro Ueno, Shuken Boku, Ichiro Sora, Akitoyo Hishimoto

  BACKGROUND: Studies suggest aberrant DNA methylation in victims of suicide. Recently, DNA methylation profiles have been developed for determining "epigenetic age," which is the most accurate estimate of biological age. Subsequently, two refined measures of epigenetic age acceleration have been expanded for blood samples as intrinsic and extrinsic epigenetic age acceleration (IEAA and EEAA, respectively). IEAA involves pure epigenetic aging independent of blood cell composition, whereas EEAA involves immunosenescence in association with blood cell composition. METHODS: We investigated epigenetic age acceleration using two independent DNA methylation datasets: a brain dataset from 16 suicide completers and 15 non-psychiatric controls and a blood dataset compiled using economical DNA pooling technique from 56 suicide completers and 60 living healthy controls. In the blood dataset, we considered IEAA and EEAA, as well as DNA methylation-based blood cell composition. RESULTS: There was no significant difference in universal epigenetic age acceleration between suicide completers and controls in both brain and blood datasets. Blood of suicide completers exhibited an increase in EEAA, but not in IEAA. We additionally found that suicide completers had more natural killer cells but fewer granulocytes compared to controls. CONCLUSION: This study provides novel evidence for accelerated extrinsic epigenetic aging in suicide completers and for the potential application of natural killer cells as a biomarker for suicidal behavior.

  2020年03月, Progress in neuro-psychopharmacology & biological psychiatry, 98, 109805 - 109805, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• 摂食障害との鑑別が必要な体重減少を伴った嘔吐恐怖症の症例

  内藤 敦海, 谷藤 貴紀, 蓬莱 政, 木村 敦, 曽良 一郎

  (公社)日本精神神経学会, 2020年01月, 精神神経学雑誌, 122(1) (1), 58 - 59, 日本語


• Chemokine alterations in the postmortem brains of suicide completers.

  Yutaka Shinko, Ikuo Otsuka, Satoshi Okazaki, Tadasu Horai, Shuken Boku, Motonori Takahashi, Yasuhiro Ueno, Ichiro Sora, Akitoyo Hishimoto

  Suicide is a major health problem in the modern world. However, its physiological mechanisms have not been well elucidated yet. Immunological disturbances have been reported in psychiatric disorders such as major depressive disorder (MDD), bipolar disorder (BP), and schizophrenia. Some studies have also suggested an association between immunological alterations especially neuroinflammation, and suicide. Chemokines play important roles in inflammation, and studies investigating chemokines in psychiatric diseases such as schizophrenia, MDD, and BP have reported chemokine dysregulations. However, there have been very few studies on the association between chemokines and suicide. We studied chemokine alterations in the postmortem brains of suicide completers and compared them to those of controls. We obtained brain tissue samples of the dorsolateral prefrontal cortex from 16 suicide completers and 23 controls. We examined the concentrations of chemokines and related substances in the brain tissue from these two groups using the Bio-Plex Pro™ Human Chemokine Panel 40-Plex. We performed multiple regression analysis with covariates. The levels of CCL1, CCL8, CCL13, CCL15, CCL17, CCL19, CCL20, CXCL11, and IL-10 were significantly decreased, whereas the IL-16 levels were significantly increased in the suicide completers after adjustment with the Benjamini-Hochberg method to control for type Ⅰ errors (Q < 0.05). The observed chemokine alterations might suggest the presence of suicide-specific immunological mechanisms.

  2020年01月, Journal of psychiatric research, 120, 29 - 33, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Major depressive disorder-associated SIRT1 locus affects the risk for suicide in women after middle age.

  Takashi Hirata, Ikuo Otsuka, Satoshi Okazaki, Kentaro Mouri, Tadasu Horai, Shuken Boku, Motonori Takahashi, Yasuhiro Ueno, Ichiro Sora, Osamu Shirakawa, Akitoyo Hishimoto

  A recent genome-wide association study (GWAS) for major depressive disorder (MDD) in Chinese women identified a single-nucleotide polymorphism (SNP), rs12415800, near the Sirtuin1 (SIRT1) gene as one of the top candidate loci. However, no study has shown a genetic association between SIRT1 and completed suicide, which is one of the most serious outcomes of MDD. In this study, 778 suicide completers and 760 controls in a Japanese population were genotyped for two SNPs in strong linkage disequilibrium (rs12415800 and rs4746720 in 3'UTR). We found significant associations between both SNPs and completed suicide among women aged ≥50 years. Additional analysis using postmortem brain tissues (10 suicide brains and 13 non-suicide brains) revealed the following: while SIRT1 gene expression in the prefrontal cortex did not differ between suicide and non-suicide brains, DNAJC12 gene expression, potentially implicated by the SNPs genotyped here, was significantly decreased in suicide brains (p = 0.003). In conclusion, regarding the genetic association of SIRT1 with MDD that was previously identified in women by the Chinese GWAS, we successfully validated our results using a female suicidal cohort in the same Asian population with the same direction of allelic effect.

  2019年08月, Psychiatry research, 278, 141 - 145, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• 統合失調症患者におけるBrexpiprazoleの使用経験

  菱本 明豊, 青山 慎介, 大塚 郁夫, 朴 秀賢, 蓬莱 政, 木村 敦, 新名 尚史, 山木 愛久, 曽良 一郎

  (公社)日本精神神経学会, 2019年06月, 精神神経学雑誌, (2019特別号) (2019特別号), S409 - S409, 日本語


• 鑑別と診断に苦慮した遷延するアルコール離脱せん妄の一例

  長妻 渉, 新名 尚史, 塚本 亮, 木村 敦, 蓬莱 政, 大塚 郁夫, 青山 慎介, 菱本 明豊, 曽良 一郎

  (公社)日本精神神経学会, 2019年06月, 精神神経学雑誌, (2019特別号) (2019特別号), S484 - S484, 日本語


• 妊娠経過中に躁症状や精神病症状を呈し、内分泌疾患が判明するまで診断に苦慮した1症例

  蓬莱 政, 青山 慎介, 大塚 郁夫, 新名 尚史, 森脇 光信, 倉持 裕子, 曽良 一郎

  (公社)日本精神神経学会, 2019年06月, 精神神経学雑誌, (2019特別号) (2019特別号), S623 - S623, 日本語


• 統合失調症におけるマクロファージ遊走阻止因子(MIF)の血清濃度増加と遺伝子多型関連解析

  岡崎 賢志, 大塚 郁夫, 渡部 雄一郎, 朴 秀賢, 新名 尚史, 平田 尚士, 蓬莱 政, 染矢 俊幸, 曽良 一郎, 菱本 明豊

  (公社)日本精神神経学会, 2019年06月, 精神神経学雑誌, (2019特別号) (2019特別号), S441 - S441, 日本語

  [査読有り]


• 統合失調症におけるY染色体モザイク欠損の検討

  平田 尚士, 菱本 明豊, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 木村 敦, 蓬莱 政, 曽良 一郎

  (公社)日本精神神経学会, 2019年06月, 精神神経学雑誌, (2019特別号) (2019特別号), S473 - S473, 日本語

  [査読有り]


• 男性アルコール依存症患者の骨密度低下に関する横断的研究

  蓬莱 政, 菱本 明豊, 大塚 郁夫, 新名 尚史, 岡崎 賢志, 毛利 健太朗, 朴 秀賢, 曽良 一郎

  (公社)日本精神神経学会, 2019年06月, 精神神経学雑誌, (2019特別号) (2019特別号), S749 - S749, 日本語

  [査読有り]


• 自殺既遂者の血液・脳組織におけるY染色体喪失の解析

  木村 敦, 菱本 明豊, 平田 尚士, 山本 愛久, 蓬莱 政, 新名 尚史, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 曽良 一郎

  (公社)日本精神神経学会, 2019年06月, 精神神経学雑誌, (2019特別号) (2019特別号), S759 - S759, 日本語

  [査読有り]


• うつ病の診断で加療中に、著しい嚥下機能障害と非典型的な亜昏迷様症状を呈し診断に苦慮した1例

  塚本 亮, 木村 敦, 新名 尚史, 蓬莱 政, 大塚 郁夫, 田宮 裕子, 青山 慎介, 朴 秀賢, 菱本 明豊, 曽良 一郎

  (公社)日本精神神経学会, 2019年03月, 精神神経学雑誌, 121(3) (3), 233 - 233, 日本語


• Epigenetic clock analysis of blood samples from Japanese schizophrenia patients.

  Satoshi Okazaki, Ikuo Otsuka, Shusuke Numata, Tadasu Horai, Kentaro Mouri, Shuken Boku, Tetsuro Ohmori, Ichiro Sora, Akitoyo Hishimoto

  The accelerated aging hypothesis of schizophrenia (SCZ) has been proposed. DNA methylation profiles were developed for determining "epigenetic age." Here, we assessed intrinsic and extrinsic epigenetic age acceleration (IEAA and EEAA, respectively) in SCZ. We examined two independent cohorts of Japanese ancestry. The first cohort consisted of 80 patients with SCZ under long-term or repeated hospitalization and 40 controls, with the economical DNA pooling technique. The second cohort consisted of 24 medication-free patients with SCZ and 23 controls. Blood of SCZ subjects exhibited decreased EEAA in the first cohort (p = 0.0162), but not in the second cohort. IEAA did not differ in either cohort. We performed replication analyses using publicly available datasets from European ancestry (three blood and one brain datasets). One blood dataset showed increased EEAA in SCZ (p = 0.0228). Overall, our results provide evidence for decreased EEAA in SCZ associated with hospitalization in the Japanese population.

  2019年02月, NPJ schizophrenia, 5(1) (1), 4 - 4, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• アルコール依存症にアルコール性心筋症が合併し、断酒により心機能が改善した症例

  塚本 亮, 菱本 明豊, 青山 慎介, 朴 秀賢, 田宮 裕子, 大塚 郁夫, 松山 賢一, 木村 敦, 蓬莱 政, 曽良 一郎

  (公社)日本精神神経学会, 2019年01月, 精神神経学雑誌, 121(1) (1), 68 - 68, 日本語


• Mitochondrial DNA copy number of peripheral blood in bipolar disorder: The present study and a meta-analysis.

  Naruhisa Yamaki, Ikuo Otsuka, Shusuke Numata, Masaya Yanagi, Kentaro Mouri, Satoshi Okazaki, Shuken Boku, Tadasu Horai, Tetsuro Ohmori, Osamu Shirakawa, Ichiro Sora, Akitoyo Hishimoto

  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.

  2018年11月, Psychiatry research, 269, 115 - 117, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Longer telomeres in elderly schizophrenia are associated with long-term hospitalization in the Japanese population.

  Yuan Zhang, Akitoyo Hishimoto, Ikuo Otsuka, Yuichiro Watanabe, Shusuke Numata, Hidenaga Yamamori, Shuken Boku, Tadasu Horai, Toshiyuki Someya, Tetsuro Ohmori, Ryota Hashimoto, Ichiro Sora

  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.

  2018年08月, Journal of psychiatric research, 103, 161 - 166, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Quetiapine-related Acute Kidney Injury Requiring Transient Continuous Hemodiafiltration.

  Haruhi Yamada, Yukiko Katsumori, Miki Kawano, Shumpei Mori, Ryo Takeshige, Jun Mukai, Hiroshi Imada, Hiroyuki Shimoura, Hachidai Takahashi, Tadasu Horai, Yutaka Okita, Ken-Ichi Hirata

  A 73-year-old man, with congestive heart failure due to combined valvar disease, underwent curative surgery. Although the surgery was successful, his clinical course was eventful because of pulmonary complications, and he began to deteriorate mentally. Quetiapine was prescribed, which appeared to effectively settle his mental status. Following the administration of quetiapine, however, he developed acute kidney injury (AKI) that required continuous hemodiafiltration. Subsequent to discontinuation of quetiapine, his renal function gradually improved. Atypical antipsychotic drugs, including quetiapine, are frequently used to treat delirium in elderly patients in the intensive-care setting. This case highlights a potential risk of quetiapine-related AKI.

  2018年06月, Internal medicine (Tokyo, Japan), 57(12) (12), 1763 - 1767, 英語, 国内誌

  研究論文（学術雑誌）


• Loss of chromosome Y in blood, but not in brain, of suicide completers.

  Atsushi Kimura, Akitoyo Hishimoto, Ikuo Otsuka, Satoshi Okazaki, Shuken Boku, Tadasu Horai, Takeshi Izumi, Motonori Takahashi, Yasuhiro Ueno, Osamu Shirakawa, Ichiro Sora

  Men have a higher rate of completed suicide than women, which suggests that sex chromosome abnormalities may be related to the pathophysiology of suicide. Recent studies have found an aberrant loss of chromosome Y (LOY) in various diseases; however, no study has investigated whether there is an association between LOY and suicide. The purpose of this study was to determine whether LOY occurs in men who completed suicide. Our study consisted of 286 male Japanese subjects comprised of 140 suicide completers without severe physical illness (130 post-mortem samples of peripheral blood and 10 brains) and 146 age-matched control subjects (130 peripheral blood samples from healthy individuals and 16 post-mortem brains). LOY was measured as the chromosome Y/chromosome X ratio of the fluorescent signal of co-amplified short sequences from the Y-X homologous amelogenin genes (AMELY and AMELX). Regression analyses showed that LOY in the blood of suicide completers was significantly more frequent than that found in controls (odds ratio = 3.50, 95% confidence interval = 1.21-10.10), but not in the dorsolateral prefrontal cortex (DLPFC) region of brain. Normal age-dependent LOY in blood was found in healthy controls (r = -0.353, p < 0.001), which was not seen in suicide completers (r = -0.119, p = 0.177). DLPFC tissue had age-dependent LOY (B = -0.002, p = 0.015), which was independent of phenotype. To our knowledge, this is the first study demonstrating that LOY in blood is associated with suicide completion. In addition, our findings are the first to also indicate that age-dependent LOY may occur not only in blood, but also in specific brain regions.

  2018年, PloS one, 13(1) (1), e0190667, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• A cross-sectional study exploring useful indicators for low bone mineral density in male alcoholic patients.

  Tadasu Horai, Akitoyo Hishimoto, Ikuo Otsuka, Tatsuhiro So, Kentaro Mouri, Naofumi Shimmyo, Shuken Boku, Noriaki Okishio, Ichiro Sora

  Background: Alcohol dependence induces low bone mineral density (BMD), predicting osteoporosis, while low and moderate alcohol consumption may even increase BMD. In recent years, undercarboxylated osteocalcin (ucOC) and tartrate-resistant acid phosphatase-5b (TRACP-5b), bone turnover markers, have gained special interest as useful indicators of low BMD. However, it remains unclear whether other alcohol-related variables (eg, duration of abstinence and continuous drinking) are linked to aberrant BMD. In addition, no previous study has investigated whether ucOC or TRACP-5b is clinically useful to predict low BMD not only in the general population, but also in alcohol-dependent subjects. Patients and methods: We recruited 275 male alcohol-dependent subjects and collected information about their drinking habits, comorbid diseases, smoking history and walking exercise behavior. BMD in each subject was determined by ultrasonography. Serum liver enzymes (AST, ALT, ALP, ChE, γ-GTP and LDH), ucOC and TRACP-5b were measured in all subjects. T-scores were calculated according to BMD for all subjects. Results: The mean T-scores of our subjects were negatively shifted compared to the general population (-0.75±1.36 SD). We divided our subjects into a normal BMD group (n=137) and a low BMD group (n=138) according to their T-scores (T-score ≥-1 SD, normal BMD; T-score <-1 SD, low BMD). Multivariate logistic regression analysis showed that body mass index (BMI) was negatively associated with low BMD (95% CI: 0.75-0.90). By contrast, long abstinence period (95% CI: 1.40-4.21), smoking (95% CI: 1.30-5.56), hypertension (95% CI: 1.04-3.76), lactate dehydrogenase (LDH) (95% CI: 1.00-1.01) and ucOC (95% CI: 1.04-1.22) were positively associated with low BMD. Conclusion: In alcohol-dependent males, smoking habits and higher ucOC are associated with low BMD. Our study suggests that smoking cessation may prevent lower BMD, and ucOC may predict lower BMD in alcohol-dependent individuals.

  2018年, Neuropsychiatric disease and treatment, 14, 663 - 669, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Investigation of chromosome Y loss in men with schizophrenia.

  Takashi Hirata, Akitoyo Hishimoto, Ikuo Otsuka, Satoshi Okazaki, Shuken Boku, Atsushi Kimura, Tadasu Horai, Ichiro Sora

  Background: Life expectancy is 10-20 years lower in patients with schizophrenia than in the general population. In addition, men with schizophrenia have an earlier age at onset, more pronounced deficit symptoms, poorer course, and poorer response to antipsychotic medications than women. Recent studies have indicated that loss of chromosome Y (LOY) in peripheral blood is associated with an increased risk of all-cause mortality. In order to elucidate the pathophysiology of male-specific features, we investigated the association between LOY and schizophrenia. Materials and methods: The present study included 360 Japanese men (146 patients with schizophrenia vs 214 controls). The relative amount of Y chromosome was defined as the ratio of chromosome Y to chromosome X (Y/X ratio) based on the fluorescent signal of co-amplified short sequences from the Y-X homologous amelogenin genes (AMELY and AMELX). Results: There was no significant difference in the frequency of LOY between the schizophrenia and control groups. However, longer duration of illness was associated with LOY after controlling for age and smoking status in the schizophrenia group (P=0.007, OR =1.11 [95% CI =1.03-1.19]). Conclusion: According to our results, schizophrenia may not have a remarkable effect on blood LOY; however, LOY may be associated with disease course in patients with schizophrenia.

  2018年, Neuropsychiatric disease and treatment, 14, 2115 - 2122, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• 日本人自殺既遂者におけるMIF遺伝子プロモーター領域機能的多型の関連解析

  新名 尚史, 菱本 明豊, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 毛利 健太朗, 蓬莱 政, 江口 典臣, 木村 敦, 山木 愛久, 平田 尚士, 高橋 玄倫, 上野 易弘, 白川 治, 曽良 一郎

  日本生物学的精神医学会・日本神経精神薬理学会, 2017年09月, 日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集 39回・47回, 39回・47回, 190 - 190, 英語

  研究論文（その他学術会議資料等）


• 脳機能からみたベンゾジアゼピン系薬剤のリスクとベネフィット 依存・耐性および認知機能への影響

  曽良 一郎, 蓬莱 政, 木村 敦, 松山 賢一

  (株)先端医学社, 2017年03月, Depression Strategy, 7(1) (1), 7 - 9, 日本語


• Association study of MIF promoter polymorphisms with suicide completers in the Japanese population.

  Naofumi Shimmyo, Akitoyo Hishimoto, Ikuo Otsuka, Satoshi Okazaki, Shuken Boku, Kentaro Mouri, Tadasu Horai, Motonori Takahashi, Yasuhiro Ueno, Osamu Shirakawa, Ichiro Sora

  BACKGROUND: Numerous studies suggest that inflammation plays a key role in suicidal behavior. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has received increasing attention in depression research. However, no study has investigated whether MIF has genetic involvement in completed suicide. In this study, we sought to explore the relationship between two functional polymorphisms on the MIF gene promoter (MIF-794CATT5-8 microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) and completed suicide by using one of the largest samples of suicide completers ever reported. METHODS: The subjects comprised 602 suicide completers and 728 healthy controls. We genotyped MIF-794CATT5-8 microsatellite by polymerase chain reaction-based size discrimination assay and MIF-173G/C SNP by TaqMan® SNP genotyping assay. The allele-, genotype-, or haplotype-based association analyses between the suicide completers and the controls were carried out with the χ2 test, the Cochran-Armitage trend test, or Fisher's exact test. RESULTS: Analyses of allele or genotype frequency distributions of the polymorphisms studied here did not reveal any significant differences between the suicide completers and the controls. Haplotype analysis also revealed no association with completed suicide. CONCLUSION: To our knowledge, this is the first study that has examined the genetic association between MIF and completed suicide. Our results suggest that the effects of MIF-794CATT5-8 microsatellite and MIF-173G/C SNP on the MIF gene promoter might not contribute to the genetic risk of completed suicide in the Japanese population.

  2017年, Neuropsychiatric disease and treatment, 13, 899 - 908, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• 男性アルコール依存症患者における骨密度減少のリスクファクターに関する横断研究(The risk factors of low bone mineral density in male alcoholic patients: cross-sectional study)(英語)

  蓬莱政, 菱本明豊, 毛利健太朗, 朴秀賢, 江口典臣, 新名尚史, 木村敦, 曽良一郎

  2016年07月, 日本神経精神薬理学会年会プログラム・抄録集 46回, 223, 日本語

  [査読有り]

  研究論文（学術雑誌）

• アルコール依存症でのエピゲノム年齢加速

  白井寿行, 岡崎賢志, 大塚郁夫, 南陽香, 岡田将平, 宮地真生, 蓬莱政, 毛利健太朗, 菱本明豊

  2024年, 日本精神科診断学会プログラム・抄録集, 43rd


• 未治療のうつ病患者におけるエピジェネティック年齢の加速とDNAメチル化に基づくナチュラルキラー細胞の減少

  岡崎賢志, 新藤良太, 谷藤貴紀, 大塚郁夫, 白井寿行, 毛利健太朗, 蓬莱政, 菱本明豊

  2024年, 日本精神科診断学会プログラム・抄録集, 43rd


• 日本人の自殺既遂者における,マクロファージ遊走阻害因子(MIF)の低酸素応答因子における遺伝子研究

  宮地真生, 白井寿行, 岡崎賢志, 谷藤貴紀, 大塚郁夫, 岡田将平, 新藤良太, 蓬莱政, 毛利健太郎, 高橋玄倫, 近藤武史, 上野易弘, 菱本明豊

  2024年, 日本生物学的精神医学会(Web), 46th


• メタンフェタミン依存症におけるエピゲノムワイド関連研究

  白井寿行, 岡崎賢志, 谷藤貴紀, 大塚郁夫, 蓬莱政, 毛利健太朗, 麻生克郎, 山本訓也, 菱本明豊

  2024年, 日本生物学的精神医学会(Web), 46th


• DNAメチル化に代表される後天的遺伝子修飾と精神疾患の解明

  白井寿行, 岡崎賢志, 大塚郁夫, 谷藤貴紀, 宮地真生, 岡田将平, 蓬莱政, 毛利健太朗, 菱本明豊

  2024年, 統合失調症研究(CD-ROM), 13(1) (1)


• 統合失調症におけるマクロファージ遊走阻止因子(MIF)の血清濃度増加と遺伝子多型関連解析

  岡崎 賢志, 大塚 郁夫, 渡部 雄一郎, 朴 秀賢, 新名 尚史, 平田 尚士, 蓬莱 政, 染矢 俊幸, 曽良 一郎, 菱本 明豊

  (公社)日本精神神経学会, 2019年06月, 精神神経学雑誌, (2019特別号) (2019特別号), S441 - S441, 日本語


• 全身性エリテマトーデス加療中に急性精神病状態を呈し診断に難渋した症例

  塚本亮, 松山賢一, 菱本明豊, 青山慎介, 朴秀賢, 田宮裕子, 大塚郁夫, 木村敦, 蓬莱政, 曽良一郎

  2018年03月, 精神神経学雑誌, 120(3号) (3号), 232, 日本語

  [査読有り]

  会議報告等


• The risk factors of low bone mineral density in male alcoholic patients: cross-sectional study

  Tadasu Horai, Shunken Boku, Noriomi Eguchi, Akitoyo Hishimoto, Atsushi Kimura, Kentaro Mori, Naofumi Shinmyo, Ichiro Sora

  2016年06月, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 19, 164 - 164, 英語

  研究発表ペーパー・要旨（国際会議）

• ベンゾジアゼピン系薬と修正型電気けいれん療法（ｍECT）が奏功せずメマンチンが有効であった遅発性緊張病の１例

  新谷 敏夫, 菱本 明豊, 谷藤 貴紀, 木村 敦, 新名 尚史, 蓬莱 政, 大塚 郁夫, 青山 慎介, 曽良 一郎

  第124回 近畿精神神経学会, 2019年02月, 日本語, 近畿精神神経学会, 和歌山, 国内会議

  口頭発表（一般）


• 妊娠・出産と精神医療

  蓬莱 政

  21ｔｈ有床フォーラム2018KOBE, 2018年09月, 日本語, 兵庫県総合病院精神医学会, 神戸, 国内会議

  シンポジウム・ワークショップパネル（公募）


• Mosaic loss of chromosome Y in peripheral blood and its risk variants in men with schizophrenia

  平田 尚士, 岡﨑 賢志, 大塚 郁夫, 朴 秀賢, 青山 慎介, 江口 典臣, 木村 敦, 蓬莱 政, 曽良 一郎, 菱本 明豊

  WFSBP Asia Pacific Regional Congress of Biological Psychiatry 2018 KOBE, 2018年09月, 英語, Kobe, 国際会議

  ポスター発表


• Loss of chromosome Y in blood, but not in brain, of suicide completers

  大塚 郁夫, 岡﨑 賢志, 木村 敦, 蓬莱 政, 泉 剛, Motonori Takahashi, Yasuhiro Ueno, 白川 治, 曽良 一郎, 菱本 明豊

  WFSBP Asia Pacific Regional Congress of Biological Psychiatry 2018 KOBE, 2018年09月, 英語, Kobe, 国際会議

  ポスター発表


• うつ病の診断で加療中に、著しい嚥下機能障害と非定型的な亜昏迷様症状を呈し診断に苦慮した１例

  塚本 亮, 木村 敦, 新名 尚史, 蓬莱 政, 大塚 郁夫, 田宮 裕子, 青山 慎介, 朴 秀賢, 菱本 明豊, 曽良 一郎

  第123回近畿精神神経学会, 2018年08月, 日本語, 近畿精神神経学会, 大阪, 国内会議

  口頭発表（一般）


• アルコール依存症にアルコール性心筋症が合併し、断酒により心機能が改善した症例

  塚本 亮, 菱本 明豊, 青山 慎介, 朴 秀賢, 田宮 裕子, 大塚 郁夫, 松山 賢一, 木村 敦, 蓬莱 政, 曽良 一郎

  第122回近畿精神神経学会, 2018年02月, 日本語, 近畿精神神経学会, 京都, 国内会議

  口頭発表（一般）


• SIRT1 遺伝子と自殺

  平田 尚士, 大塚 郁夫, 岡崎 賢志, 蓬莱 政, 木村 敦, 山木 愛久, 朴 秀賢, 菱本 明豊

  第36回躁うつ病の薬理・生物学的研究懇話会, 2017年10月, 日本語, 東京, 国内会議

  口頭発表（一般）


• 日本人自殺既遂者におけるMIF遺伝子プロモーター領域機能的多型の関連解析

  新名 尚史, 菱本 明豊, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 毛利 健太朗, 蓬莱 政, 江口 典臣, 木村 敦, 山木 愛久, 平田 尚士, 高橋 玄倫, 上野 易弘, 白川 治, 曽良 一郎

  第39回日本生物学的精神医学会・第47回日本神経精神薬理学会 合同年会, 2017年09月, 日本語, 日本生物学的精神医学会・日本神経精神薬理学会, 札幌, 国内会議

  ポスター発表


• 全身性エリテマトーデス加療中に急性精神病状態を呈し診断に難渋した症例

  塚本 亮, 松山 賢一, 菱本 明豊, 青山 慎介, 朴 秀賢, 田宮 裕子, 大塚 郁夫, 木村 敦, 蓬莱 政, 曽良 一郎

  第121回近畿精神神経学会, 2017年08月, 日本語, 近畿精神神経学会, 滋賀, 国内会議

  口頭発表（一般）

• MIFに着目した低酸素暴露と統合失調症を結ぶ分子メカニズムの解明

  岡崎 賢志, 江口 典臣, 蓬莱 政

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2021年04月01日 - 2024年03月31日

  統合失調症は世界的に有病率約1%のありふれた疾患であるが、その生物学的基盤は明らかでなく、診断や治療は症状と経過に依存している。本研究の目的は、統合失調症の病態機序において、低酸素―低酸素誘導因子（HIF）―マクロファージ遊走阻止因子（MIF）経路の役割を明らかにし、治療標的やバイオマーカーとして臨床応用へ展開するための研究基盤を確立することである。 R3年度の実験としては、統合失調症患者と健常対照者の末梢血由来DNAを用いて、MIF遺伝子プロモーター領域に存在する、HIF結合部位である低酸素応答領域（HRE）に存在するSNPの多型解析を行った。その結果、このSNPのマイナーアレルが統合失調症患者群では有意に多く、リスクアレルであることを見出した。性別によるサブグループ解析を行ったところ、これらの結果は女性において男性よりも顕著であった。さらに新生仔C57BL/6マウス皮質由来アストロサイトの初代培養系を用いて、低酸素によるアストロサイトのMIF発現機構の解析を進めた。HIF活性化因子であるML228によるMIF mRNAの有意な増加を見出した。さらに低酸素処置による実験を行い、MIF mRNAとMIF蛋白が低酸素条件で有意に増加することを見出した。マウスMIF遺伝子プロモーター領域においても、ヒトMIF遺伝子と相同するHRE領域が存在する。低酸素応答におけるMIF遺伝子発現機構について、ルシフェラーゼアッセイ法を用いて、プロモーター活性に変化の解析を進めている。新生仔マウス海馬由来神経幹細胞の初代培養系も維持継続している。また患者および健常者由来iPS細胞の樹立と長期培養維持継代も継続して行っている。


• 腸内細菌へ介入するうつ病の予防法開発のための研究

  蓬莱 政

  科学研究費補助金／若手研究, 2018年04月 - 2021年03月, 研究代表者

  競争的資金