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.
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
Tomoya Takeda, 福留 広大 and Hidehiro Umehara : COVID-19によって生じた学業への不安が大学生のメンタルヘルスや社会機能に及ぼす影響, Japanese Journal of Child and Adolescent Psychiatry, Vol.63, No.2, 127-136, 2022.
5.
Tomoya Takeda, 福留 広大 and Hidehiro Umehara : COVID-19 により生じた学習不安と経済不安が将来に対する否定的自動思考を介して大学生の抑うつ症状に与える影響, The Journal of Japan Mibyou Association, Vol.28, No.3, 22-28, 2022.
(Keyword)
COVID-19 / Academic anxiety / Economic anxiety / Depressive symptoms / Negative automatic thoughts for the future
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.
武田 知也, Hidehiro Umehara, 梶田 美香 and Tetsuro Ohmori : Metacognitive training for depression to elderly woman with depression : A case report, Japanese Journal of Psychiatric Treatment, Vol.35, No.5, 535-540, 2020.
(Keyword)
depression / metaeogmtive training for depression / elderly woman
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.
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.
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.
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.
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.
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.
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.
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
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
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
Hidehiro Umehara, Junichi Iga and Tetsuro Ohmori : Successful Treatment of Anorexia Nervosa in a 10-year-old Boy with Risperidone Long-acting Injection., Clinical Psychopharmacology and Neuroscience, Vol.12, No.1, 65-66, 2014.
(Summary)
Although the effectiveness of medication in the treatment of anorexia nervosa is uncertain, atypical antipsychotics such as olanzapine and risperidone have been used empirically for decades. we describe the case of a 10-year-old boy with anorexia nervosa in whom remarkable improvement was seen following the administration of risperidone or risperidone long-acting injection and deterioration when these agents were ceased. Because this is, to the best of our knowledge, the first report describing the usefulness of risperidone long-acting injection for adolescent anorexia nervosa.
Hidehiro Umehara, Satsuki Sumitani and Tetsuro Ohmori : Restless legs syndrome with chest and back restlessness as the initial symptom, Psychiatry and Clinical Neurosciences, Vol.64, No.2, 211, 2010.
(Keyword)
Back / Diagnosis, Differential / Humans / Magnetic Resonance Imaging / Male / Middle Aged / Psychomotor Agitation / Restless Legs Syndrome / Thorax
Tomohiko Nakayama, Yukiko Tomioka, Naoki Yamada, Hidehiro Umehara, Makoto Kinoshita, Masahito Nakataki and Shusuke Numata : 臨床現場におけるたとえ話, Japanese Journal of Psychiatric Treatment, Vol.37, No.7, 745-749, 2022.
2.
Hidehiro Umehara : 発達障害概略, めんたるへるす, 67, 2018.
Proceeding of International Conference:
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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, May 2023.
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Shinya Watanabe, Hidehiro Umehara, Yukiko Tomioka, Makoto Kinoshita, Masahito Nakataki, Shusuke Numata and Tetsuro Ohmori : Effects of processing conditions on plasma L-glutamate levels in non-psychiatric healthy subjects., 6th Congress of AsCNP Asian College of Neuropsychopharmacology, Fukuoka, Oct. 2019.
3.
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.
4.
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.
5.
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.
6.
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.
7.
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.
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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.
9.
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.
Proceeding of Domestic Conference:
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Hidehiro Umehara : 社会認知ならびに対人関係のトレーニング(SCIT) の思春期自閉スペクトラム症への適応と工夫, The 8rd annual meeting for Cognitive Enhancement in Psychiatric Disorders, May 2023.
2.
Yukiko Tomioka, Makoto Kinoshita, Tomohiko Nakayama, Hidehiro Umehara, Masahito Nakataki and Shusuke Numata : 統合失調症患者におけるDNMT1と3aの遺伝子発現量の検討, 第16回日本統合失調症学会, Mar. 2022.
Hidehiro Umehara, Shusuke Numata, Shinya Watanabe, Satsuki Sumitani and Tetsuro Ohmori : Altered Serotonin transporter mRNA expression in the peripheral leukocytes of obsessive-compulsive disorder, 第47回日本神経精神薬理学会・第39回日本生物学的精神医学会 合同年会, Sep. 2017.
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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.
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Masatoshi Inoshita, Makoto Kinoshita, Hidehiro Umehara, Masahito Nakataki, Atsushi Tajima, 池田 匡志, 丸山 惣一郎, 山森 英長, 金沢 徹文, 下寺 信次, 橋本 亮太, Issei Imoto, 米田 博, 岩田 仲生, Shusuke Numata and Tetsuro Ohmori : C-reactive protein and schizophrenia; A Mendelian Randomization approach., 第12回日本統合失調症学会, Mar. 2017.
Association study of the polymorphic region and methylation in the serotonin transporter gene promoter in the clinical response to drug treatment in obsessive-compulsive disorder (Project/Area Number: 15K19734 )