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Background Although structural correlation network (SCN) analysis is an approach to evaluate brain networks, the neurobiological interpretation of SCNs is still problematic. Brain-derived neurotrophic factor (BDNF) is well-established as a representative protein related to neuronal differentiation, maturation, and survival. Since a valine-to-methionine substitution at codon 66 of the BDNF gene (BDNF Val66Met single nucleotide polymorphism (SNP)) is well-known to have effects on brain structure and function, we hypothesized that SCNs are affected by the BDNF Val66Met SNP. To gain insight into SCN analysis, we investigated potential differences between BDNF valine (Val) homozygotes and methionine (Met) carriers in the organization of their SCNs derived from inter-regional cortical thickness correlations. / Methods Forty-nine healthy adult subjects (mean age = 41.1 years old) were divided into two groups according to their genotype (n: Val homozygotes = 16, Met carriers = 33). We obtained regional cortical thickness from their brain T1 weighted images. Based on the inter-regional cortical thickness correlations, we generated SCNs and used graph theoretical measures to assess differences between the two groups in terms of network integration, segregation, and modularity. / Results The average local efficiency, a measure of network segregation, of BDNF Met carriers’ network was significantly higher than that of the Val homozygotes’ (permutation p-value = 0.002). Average shortest path lengths (a measure of integration), average local clustering coefficient (another measure of network segregation), small-worldness (a balance between integration and segregation), and modularity (a representative measure for modular architecture) were not significantly different between group (permutation p-values ≧ 0.01). / Discussion and Conclusion Our results suggest that the BDNF Val66Met polymorphism may potentially influence the pattern of brain regional morphometric (cortical thicknes

type:Journal Article, Understanding the neural correlates of the neurotic brain is important because neuroticism is a risk factor for the development of psychopathology. We examined the correlation between brain structural networks and neuroticism based on NEO Five-Factor Inventory (NEO-FFI) scores. Fifty-one healthy participants (female, n = 18; male, n = 33; mean age, 38.5 ± 11.7 years) underwent the NEO-FFI test and magnetic resonance imaging (MRI), including diffusion tensor imaging and 3D T1WI. Using MRI data, for each participant, we constructed whole-brain interregional connectivity matrices by deterministic tractography and calculated the graph theoretical network measures, including the characteristic path length, global clustering coefficient, small-worldness, and betweenness centrality (BET) in 83 brain regions from the Desikan-Killiany atlas with subcortical segmentation using FreeSurfer. In relation to the BET, neuroticism score had a negative correlation in the left isthmus cingulate cortex, left superior parietal, left superior temporal, right caudal middle frontal, and right entorhinal cortices, and a positive correlation in the bilateral frontal pole, left caudal anterior cingulate cortex, and left fusiform gyrus. No other measurements showed significant correlations. Our results imply that the brain regions related to neuroticism exist in various regions, and that the neuroticism trait is likely formed as a result of interactions among these regions. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Science, Sports and Culture of Japan., source:https://doi.org/10.1038/s41598-018-34846-1

Shingo Kakeda,1 Keita Watanabe,1 Asuka Katsuki,2 Koichiro Sugimoto,1 Issei Ueda,1 Natsuki Igata,1 Taro Kishi,3 Nakao Iwata,3 Osamu Abe,4 Reiji Yoshimura,2 Yukunori Korogi1 1Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan; 2Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Japan; 3Department of Psychiatry, Fujita Health University, School of Medicine, Toyoake, Japan; 4Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Background: A genome-wide association study using megadata identified 17 single-nucleotide polymorphisms (SNPs) in candidate genes for major depressive disorder (MDD). These MDD susceptibility polymorphisms may affect white matter (WM) integrity. This study aimed to investigate the relationship between WM alterations and 17 SNPs in candidate genes for MDD in the first depressive episode of drug-naive MDD patients using a tract-based spatial statistics (TBSS) method. Methods: Thirty-five drug-naive MDD patients with a first depressive episode and 47 age- and sex-matched healthy subjects underwent diffusion tensor imaging scans and genotyping. The genotype–diagnosis interactions related to WM integrity were evaluated using TBSS for the 17 SNPs. Results: For the anterior thalamic radiation, cingulum, corticospinal tract, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, uncinate fasciculus, forceps major, and forceps minor, the genotype effect significantly differed between diagnosis groups (P<0.05, family-wise error corrected) in only one SNP, rs301806, in the arginine–glutamic acid dipeptide (RE) repeats (RERE) gene. Conclusion: The RERE polymorphism was associated with WM alterations in first-episode and drug-naive MDD patients, which may be at least partially related to the manifestation of MDD. Future studies are needed to explore the gene&am

Reiji Yoshimura, Asuka Katsuki, Kiyokazu Atake, Hikaru Hori, Ryohei Igata, Yuki KonishiDepartment of Psychiatry, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Fukuoka, Japan Objectives: The etiology of depression remains unknown. There is, however, a growing body of evidence that cytokines are involved in the pathophysiology of depression. The aim of this study is to investigate the effects of fluvoxamine on plasma interleukin-6 (IL-6) levels and on clinical improvement of the depressive state.Subjects and methods: Thirty patients who met the DSM-IV criteria for major depressive disorder (MDD) were enrolled in the study. Thirteen were male and 17 were female, and their ages ranged from 26 to 70 years (mean ± standard deviation 45.0±14.2). The patients were treated with fluvoxamine for 8 weeks. The dosages of fluvoxamine varied among the patients and, based on ethical considerations, were not fixed.Results: The fluvoxamine doses were positively related to plasma fluvoxamine levels (r=0.8798, P<0.001). A significant correlation was observed between the patients’ plasma IL-6 levels and their 17-item Hamilton Rating Scale for Depression (HAMD17) scores (r=0.4555, P=0.0010). A positive correlation was found between the delta plasma IL-6 (week 0–week 8) and the delta HAMD17 (week 0–week 8) (r=0.5226, P=0.002).Conclusion: Effect of fluvoxamine on IL-6 is partially associated with its clinical efficacy for MDD. Keywords: fluvoxamine, interleukin, Hamilton Rating Scale for Depression, major depressive disorder

Ryohei Igata, Hikaru Hori, Kiyokazu Atake, Asuka Katsuki, Jun Nakamura Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Japan Abstract: A 54-year-old Japanese woman was diagnosed with major depressive disorder and prescribed paroxetine 20 mg/day. In around May 2013, the patient experienced gastric discomfort, so metoclopramide was prescribed. Beginning on June 4, 2013, the patient was given metoclopramide, 10 mg intravenously, twice per week. On the seventh day after beginning metoclopramide, facial hot flushes, increased sweating, muscle rigidity, and galactorrhea were noted. Extrapyramidal symptoms (EPS) rapidly subsided in response to an intramuscular injection of biperiden. Blood biochemical tests revealed an elevated serum prolactin level of 44 ng/mL. After stopping metoclopramide, EPS disappeared. Serum prolactin level decreased to 15 ng/mL after 4 weeks. In our case, although no adverse reactions had previously occurred following the administration of metoclopramide, the patient developed EPS and hyperprolactinemia following the administration of this antiemetic in combination with paroxetine. Paroxetine and metoclopramide are mainly metabolized by CYP2D6, and they are inhibitors for CYP2D6. We report a case with EPS and hyperprolactinemia whose plasma paroxetine and metoclopramide level rapidly increased after the addition of metoclopramide. Our experience warrants the issuing of a precaution that adverse reactions may arise following the coadministration of metoclopramide and paroxetine even at their respective standard dose levels. Keywords: metoclopramide, paroxetine, extrapyramidal symptoms, SSRI, hyperprolactinemia, depression

Kiyokazu Atake, Reiji Yoshimura, Hikaru Hori, Asuka Katsuki, Jun Nakamura Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan Purpose: This study investigated the relationships among the plasma levels of catecholamine metabolites, the clinical response to duloxetine treatment, and Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene. Subjects and methods: Sixty-four patients and 30 healthy control subjects were recruited. Major depressive episodes were diagnosed using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. The severity of depression was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD17). Patients whose HAMD17 scores were 15 or greater were enrolled in the study. Blood sampling and clinical evaluation were performed at week 0 and week 8. The levels of plasma catecholamine metabolites were measured using high-performance liquid chromatography with electrochemical detection. Genotyping was performed using direct sequencing. Results: Thirty of 45 patients (67%) responded to duloxetine treatment during the 8 weeks of treatment. The baseline plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), but not homovanillic acid (HVA), were lower in patients with major depressive disorder (MDD) who had the Val/Val genotype than in patients who were Met-carriers. Patients with MDD and the Val/Val genotype, but not Met carriers, had increased plasma levels of MHPG after 8 weeks of duloxetine treatment. The baseline plasma MHPG levels in healthy control subjects with the Val/Val genotype were significantly higher than those in patients with MDD. Among the subjects in the MDD group with the Val/Val genotype, the plasma MHPG levels increased to the same degree as in the healthy control subjects with the Val/Val genotype after 8 weeks of duloxetine treatment. Conclusion: The relationship among

Hikaru Hori, Kenji Yamada, Dan Kamada, Yuka Shibata, Asuka Katsuki, Reiji Yoshimura, Jun NakamuraDepartment of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, JapanBackground: This study aims to determine the effectiveness of blonanserin (BNS) on the cognitive and social functions of patients with schizophrenia compared with risperidone (RIS) during acute-phase (8-week) treatment.Methods: A total of 39 schizophrenia inpatients were included in this study. The subjects received either BNS (N=20) or RIS (N=19), and the clinical responses were evaluated periodically. The concomitant use of mood stabilizers was not allowed. Efficacy was assessed with the Positive and Negative Syndrome Scale for schizophrenia. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia, Japanese-language version. Social function was assessed using the Life Assessment Scale for the Mentally Ill.Results: For both groups, each assessment exhibited a decrease in the mean change from baseline on the Positive and Negative Syndrome Scale. The depression subscale was significantly improved in the BNS group compared with the RIS group at 8 weeks after administration. BNS improved verbal fluency and executive function (cognitive function) and daily living and work skills (social function). Compared with the RIS group, BNS was observed to improve daily living.Conclusion: BNS may improve psychotic symptoms, cognitive function, and daily living in patients with acute-phase schizophrenia. BNS may be superior to RIS in the improvement of daily living.Keywords: risperidone, blonanserin, schizophrenia, cognitive function, social function, acute-phase

Kenji Hayashi,1 Reiji Yoshimura,1 Shingo Kakeda,2 Taro Kishi,3 Osamu Abe,4 Wakako Umene-Nakano,1 Asuka Katsuki,1 Hikaru Hori,1 Atsuko Ikenouchi-Sugita,1 Keita Watanabe,2 Satoru Ide,2 Issei Ueda,2 Junji Moriya,2 Nakao Iwata,3 Yukunori Korogi,2 Marek Kubicki,5 Jun Nakamura1 1Department of Psychiatry, 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan; 3Department of Psychiatry, Fujita Health University, Toyoake, Japan; 4Department of Radiology, Nihon University School of Medicine, Tokyo, Japan; 5Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Abstract: We investigated the association between the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene, and white matter changes in patients with major depressive disorder (MDD) and healthy subjects using diffusion tensor imaging (DTI). We studied 30 patients with MDD (17 males and 13 females, with mean age ± standard deviation [SD] =44±12 years) and 30 sex- and age-matched healthy controls (17 males and 13 females, aged 44±13 years). Using DTI analysis with a tract-based spatial statistics (TBSS) approach, we investigated the differences in fractional anisotropy, radial diffusivity, and axial diffusivity distribution among the three groups (patients with the COMT gene Val158Met, those with the BDNF gene Val66Met, and the healthy subjects). In a voxel-wise-based group comparison, we found significant decreases in fractional anisotropy and axial diffusivity within the temporal lobe white matter in the Met-carriers with MDD compared with the controls (P<0.05). No correlations in fractional anisotropy, axial diffusivity, or radial diffusivity were observed between the MDD patients and the controls, either among those with the BDNF Val/Val genotype or among the BDNF Met-carriers. Thes

Naoki Goto1, Reiji Yoshimura1, Shingo Kakeda2, Joji Nishimura2, Junji Moriya2, Kenji Hayashi1, Asuka Katsuki1, Hikaru Hori1, Wakako Umene-Nakano1, Atsuko Ikenouchi-Sugita1, Yukunori Korogi2, Jun Nakamura11Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan; 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, JapanObjective: To study the effects of treatment with atypical antipsychotic drugs on brain levels of glutamate plus glutamine in early-stage first-episode schizophrenia.Participants: Sixteen patients (eight males, eight females; aged 30 ± 11 years) completed the study.Methods: We used administered 6 months of atypical antipsychotic drugs and used proton magnetic resonance spectroscopy to evaluate the results.Results: We found that the administration of atypical antipsychotic drugs for 6 months decreased the glutamate plus glutamine/creatine ratio in the frontal lobe. These results suggest that the administration of atypical antipsychotic drugs for at least 6 months decreased glutamatergic neurotransmissions in the frontal lobe in early-stage first-episode schizophrenia, but there was no difference in frontal-lobe levels between patients and control subjects before administration.Conclusion: Taking these findings into account, the glutamatergic and GABAergic neurons are implicated in early-stage first-episode schizophrenia, but in complex ways.Keywords: Proton magnetic resonance spectroscopy, creatine, frontal lobe, parieto-occipital node, left basal gangliaA Letter to the Editor has been received and published for this article.