Faculty Profiles - ALEKSIC Branko

Papers - ALEKSIC Branko

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Genetic evidence for association between NOTCH4 and schizophrenia supported by a GWAS follow-up study in a Japanese population Reviewed

M. Ikeda, B. Aleksic, K. Yamada, Y. Iwayama-Shigeno, K. Matsuo, S. Numata, Y. Watanabe, T. Ohnuma, T. Kaneko, Y. Fukuo, T. Okochi, T. Toyota, E. Hattori, S. Shimodera, M. Itakura, A. Nunokawa, N. Shibata, H. Tanaka, H. Yoneda, H. Arai, T. Someya, T. Ohmori, T. Yoshikawa, N. Ozaki, N. Iwata

MOLECULAR PSYCHIATRY Vol. 18 ( 6 ) page： 636 - 638 2013.6

Analysis of the VAV3 as candidate gene for schizophrenia: evidences from voxel-based morphometry and mutation screening. Reviewed International journal

Branko Aleksic, Itaru Kushima, Ryota Hashimoto, Kazutaka Ohi, Masashi Ikeda, Akira Yoshimi, Yukako Nakamura, Yoshihito Ito, Tomo Okochi, Yasuhisa Fukuo, Yuka Yasuda, Motoyuki Fukumoto, Hidenaga Yamamori, Hiroshi Ujike, Michio Suzuki, Toshiya Inada, Masatoshi Takeda, Kozo Kaibuchi, Nakao Iwata, Norio Ozaki

Schizophrenia bulletin Vol. 39 ( 3 ) page： 720 - 728 2013.5

Language：English Publishing type：Research paper (scientific journal)

In recently completed Japanese genome-wide association studies (GWAS) of schizophrenia (JPN_GWAS) one of the top association signals was detected in the region of VAV3, a gene that maps to the chromosome 1p13.3. In order to complement JPN_GWAS findings, we tested the association of rs1410403 with brain structure in healthy individuals and schizophrenic patients and performed exon resequencing of VAV3. We performed voxel-based morphometry (VBM) and mutation screening of VAV3. Four independent samples were used in the present study: (1) for VBM analysis, we used case-control sample comprising 100 patients with schizophrenia and 264 healthy controls, (2) mutation analysis was performed on a total of 321 patients suffering from schizophrenia, and 2 case-control samples (3) 729 unrelated patients with schizophrenia and 564 healthy comparison subjects, and (4) sample comprising 1511 cases and 1517 healthy comparison subjects and were used for genetic association analysis of novel coding variants with schizophrenia. The VBM analysis suggests that rs1410403 might affect the volume of the left superior and middle temporal gyri (P=.011 and P=.013, respectively), which were reduced in patients with schizophrenia compared with healthy subjects. Moreover, 4 rare novel missense variants were detected. The mutations were followed-up in large independent sample, and one of the novel variants (Glu741Gly) was associated with schizophrenia (P=.02). These findings demonstrate that VAV3 can be seen as novel candidate gene for schizophrenia in which both rare and common variants may be related to increased genetic risk for schizophrenia in Japanese population.

DOI： 10.1093/schbul/sbs038

Effects of repeated dosing with mirtazapine, trazodone, or placebo on driving performance and cognitive function in healthy volunteers

Kazumi Sasada, Kunihiro Iwamoto, Naoko Kawano, Kunihiro Kohmura, Maeri Yamamoto, Branko Aleksic, Kazutoshi Ebe, Yukihiro Noda, Norio Ozaki

HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL Vol. 28 ( 3 ) page： 281 - 286 2013.5

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Objective This study aimed to evaluate the effects of repeated treatments with the sedative antidepressants mirtazapine and trazodone on driving performance and cognitive function. Methods Nineteen healthy men received continuous nocturnal doses of 15-mg mirtazapine , 25-mg trazodone, or placebo for 8days in a double-blinded, three-way crossover trial. Subjects were asked to perform three driving tasks (road tracking, car following, and harsh braking) using a driving simulator and cognitive tasks (the Wisconsin Card Sorting Test, Continuous Performance Test, and N-back Test) at baseline and on Days 2 and 9. Stanford Sleepiness Scale scores were also assessed. Results Mirtazapine significantly increased the standard deviation of lateral position in the road-tracking task as compared with trazodone on Day 2. Mirtazapine significantly increased Stanford Sleepiness Scale scores as compared with trazodone and placebo. For the remaining tasks, no significant effects of treatment were observed. Conclusions Acute treatment of mirtazapine impaired road-tracking performance and increased sleepiness, but sedative effects disappeared under repeated administrations. Trazodone did not affect driving performance or cognitive function under acute or repeated administrations. Both initial sedative effects and pharmacological profiles should be taken into consideration when using sedative antidepressants. Copyright (c) 2013 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.2321

Total palliative care for a patient with multiple cerebral infarctions that occurred repeatedly in association with gastric cancer (Trousseau's syndrome). Reviewed International journal

Katsuyuki Ukai, Akiko Okajima, Aya Yamauchi, Eiji Sasaki, Yohsuke Yamaguchi, Hiroyuki Kimura, Branko Aleksic, Norio Ozaki

Palliative & supportive care Vol. 11 ( 2 ) page： 169 - 172 2013.4

Language：English

OBJECTIVE: Malignancy-related thromboembolism, also referred to as Trousseau's syndrome, can present as acute cerebral infarction, nonbacterial thrombotic endocarditis (NBTE), and migratory thrombophlebitis. Therefore, many physical, neurological, and psychological symptoms associated with Trousseau's syndrome may occur in the clinical course. METHOD: To illustrate this, we report a case of a male patient in his 50s with carcinomatous peritonitis caused by gastric cancer, with multiple cerebral infractions that developed during disease progression. The patient was admitted to our hospital for the treatment of side effects of chemotherapy, although he strongly hoped to go home as soon as possible. In addition to making social supports plans, we were required to perform intensive total palliative care, because of his physical pain, general fatigue, anorexia, abdominal and neck pain, and psychological issues (insomnia, delirium, depression, suicidal thoughts, self-mutilation, panic attacks, agoraphobia, fear of death, and feelings of hopelessness). RESULTS: To the best of our knowledge, based on the literature search, this is the first reported case of Trousseau's syndrome described in the context of total palliative care, especially psychological care. SIGNIFICANCE OF RESULTS: We propose that neurological symptoms of Trousseau's syndrome cause these extensive mental disorders. Furthermore, because of the prognosis of Trousseau's syndrome, we should utilize our expertise fulfill the patient's wishes.

DOI： 10.1017/S1478951512000624

Effects of sedative antidepressants on prefrontal cortex activity during verbal fluency task in healthy subjects: a near-infrared spectroscopy study Reviewed

Kunihiro Kohmura, Kunihiro Iwamoto, Branko Aleksic, Kazumi Sasada, Naoko Kawano, Hiroto Katayama, Yukihiro Noda, Akiko Noda, Tetsuya Iidaka, Norio Ozaki

PSYCHOPHARMACOLOGY Vol. 226 ( 1 ) page： 75 - 81 2013.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Japanese researchers have recently conducted studies using near-infrared spectroscopy (NIRS) to help diagnose psychiatric disorders based on changes in brain activity. However, the influence of psychotropic drugs on NIRS measurements has not been clarified.
To assess the effects of sedative antidepressants on prefrontal cortex activity in healthy subjects using NIRS in a double-blinded, placebo-controlled, crossover trial.
Nineteen healthy males received nocturnal doses of mirtazapine 15 mg, trazodone 25 mg, or placebo for eight consecutive days in rotation, with a washout period of more than 1 week between each rotation. Subjects performed a verbal fluency task during NIRS on a total of seven occasions during the study period: more than a week prior to receiving the first dose of the first medication; and on days 2 and 9 of each rotation. The number of words correctly generated during the task (behavioral performance) was also recorded. Stanford Sleepiness Scale (SSS) scores were determined each day.
Mirtazapine 15 mg significantly increased oxyhemoglobin (oxy-Hb) concentration change in NIRS on day 9, compared to trazodone 25 mg and placebo. Mirtazapine 15 mg significantly increased SSS on day 2, compared to the other conditions. No significant differences in behavioral performance were observed.
Administration of mirtazapine for eight consecutive days affected oxy-Hb changes on NIRS. This result indicates that researchers should consider how certain types of antidepressant could influence brain function when the brain activity of patients with psychiatric disorders is assessed.

DOI： 10.1007/s00213-012-2885-8

The Postpartum Depressive State in Relation to Perceived Rearing: A Prospective Cohort Study Reviewed

Norika Hayakawa, Takayoshi Koide, Takashi Okada, Satomi Murase, Branko Aleksic, Kaori Furumura, Tomoko Shiino, Yukako Nakamura, Ai Tamaji, Naoko Ishikawa, Harue Ohoka, Hinako Usui, Naomi Banno, Tokiko Morita, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Norio Ozaki

PLOS ONE Vol. 7 ( 11 ) page： e50220 2012.11

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background: The relationship between perceived rearing and the postpartum depressive state remains unclear. We aimed to examine whether perceived rearing is a risk factor for postpartum depression as measured by the Edinburgh Postnatal Depression Scale (EPDS), and whether the score of perceived rearing is affected by depressive mood (the state dependency of perceived rearing).
Methods: Pregnant women (n = 448, mean age 31.8+/-4.2 years) completed the EPDS as a measure of depressive state in early pregnancy (T1), late pregnancy (around 36 weeks), and at 1 month postpartum (T2), and the Parental Bonding Instrument (PBI) at T1 as a measure of perceived rearing. Changes in the EPDS and the PBI scores from T1 to T2 were compared between the non depressive (ND) group and the postpartum depressive (PD) group.
Results: There were no significant differences in any PBI category for perceived rearing between the ND and PD groups at T1. EPDS scores did not change significantly from T1 to T2 in the ND group but increased significantly in the PD group. The PBI maternal care score increased significantly in the ND group (p<0.01), while decreasing in the PD group (p<0.05). Additionally, in both the ND and PD groups, significant negative correlation was observed regarding change in the EPDS and PBI maternal care scores from T1 to T2 (r = 20.28, p = 0.013).
Conclusions: The present study suggests that perceived rearing is not a strong risk factor for postpartum depression as measured by the EPDS. Furthermore, the results indicated the state dependency of the PBI maternal care score.

DOI： 10.1371/journal.pone.0050220

Effectiveness of Duloxetine for the Treatment of Chronic Nonorganic Orofacial Pain Reviewed

Wataru Nagashima, Hiroyuki Kimura, Mikiko Ito, Tatsuya Tokura, Munetaka Arao, Branko Aleksic, Keizo Yoshida, Kenichi Kurita, Norio Ozaki

CLINICAL NEUROPHARMACOLOGY Vol. 35 ( 6 ) page： 273 - 277 2012.11

Language：English Publisher：LIPPINCOTT WILLIAMS & WILKINS

Objective: We examined the pain-relieving effect of duloxetine on chronic nonorganic orofacial pain (burning mouth syndrome and atypical odontalgia), considering the influence of baseline depressive symptoms.
Methods: In this study of 12 weeks, duloxetine was administered in a fixed-flexible dose of 20 to 40 mg/d to 41 patients with burning mouth syndrome and/or atypical odontalgia. Pain was evaluated using the visual analog scale (VAS) at baseline and at 2, 4, 6, 8, 10, and 12 weeks of treatment. Depressive symptoms were assessed using the Hamilton Depression Rating Scale at baseline and at 12 weeks of treatment.
Results: We analyzed the data from 29 patients who completed the study. The VAS score at 12 weeks of treatment was significantly lower than that at baseline. The time course of the VAS scores revealed its significant decrease from 2 weeks of treatment compared to the baseline score. To investigate the influence of baseline depressive symptoms on the pain-relieving effect of duloxetine, the subjects were divided into 2 groups based on the Hamilton Depression Rating Scale score on initial consultation: groups with (>= 8) and without (<= 7) depressive symptoms. Two-way repeated-measures analysis of variance revealed no significant interaction between time and initial presence or absence of depression. An additional intent-to-treat last-observation-carried-forward analysis including dropped-out patients revealed a similar result.
Conclusion: Duloxetine significantly relieved chronic nonorganic orofacial pain. Its pain-relieving effect appeared from 2 weeks of treatment. Furthermore, the pain-relieving effects of duloxetine similarly appeared regardless of the presence or absence of baseline depressive symptoms.

DOI： 10.1097/WNF.0b013e31827453fa

An evaluation of polymorphisms in casein kinase 1 delta and epsilon genes in major psychiatric disorders Reviewed

Shinji Matsunaga, Masashi Ikeda, Taro Kishi, Yasuhisa Fukuo, Branko Aleksic, Reiji Yoshimura, Tomo Okochi, Yoshio Yamanouchi, Yoko Kinoshita, Kunihiro Kawashima, Wakako Umene-Nakano, Toshiya Inada, Hiroshi Kunugi, Tadafumi Kato, Takeo Yoshikawa, Hiroshi Ujike, Jun Nakamura, Norio Ozaki, Tsuyoshi Kitajima, Nakao Iwata

NEUROSCIENCE LETTERS Vol. 529 ( 1 ) page： 66 - 69 2012.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Disturbances of the circadian rhythm are involved in the pathophysiology of bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD). Specifically, because clock gene dysfunction is good candidate for enhancing the susceptibility to these psychiatric disorders, we selected two circadian rhythm-related genes (CSNK1D and CSNK1E) and investigated genetic associations of the genes with these three disorders.
None of the SNPs showed a significant association with MDD, but a SNP (rs2075984) in CSNK1E and SNP (rs6502097) in CSNK1D were associated with SCZ (P=0.0091. uncorrected) and BD (P=0.030, uncorrected), respectively. To confirm these findings, we analyzed an independent dataset (maximum N=3815) but found a lack of association (P=0.63 for rs2075984 and P=0.61 for rs6502097). The final meta-analysis showed no association between these SNPs with SCZ (P=0.21) and BD (P=0.53). These results do not support that genetic variation in CSNK1D and CSNK1E is a susceptibility factor for major psychiatric disorders in the Japanese population. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2012.08.070

What is a rational antidepressant treatment for major depression in patients with Parkinson's disease? Reviewed

Minako Hagikura, Kunihiro Iwamoto, Branko Aleksic, Norio Ozaki

PSYCHIATRY AND CLINICAL NEUROSCIENCES Vol. 66 ( 5 ) page： 463 - 463 2012.8

The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with development of autism spectrum disorder: The first case-control study in Asia Reviewed

Yota Uno, Tokio Uchiyama, Michiko Kurosawa, Branko Aleksic, Norio Ozaki

VACCINE Vol. 30 ( 28 ) page： 4292 - 4298 2012.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

Objective: The aim of this study was to investigate the relationship between autism spectrum disorder (ASD) and general vaccinations, including measles-mumps-rubella (MMR) vaccine, in Japanese subjects, a population with high genetic homogeneity.
Patients and methods: A case-control study was performed. Cases (n = 189) were diagnosed with ASD, while controls (n=224) were volunteers from general schools, matched by sex and birth year to cases. Vaccination history and prenatal, perinatal, and neonatal factors from the Maternal and Child Health handbook, which was part of each subject's file, were examined. To determine the relationship between potential risk factors and ASD, crude odds ratios (ORS) and 95% confidence intervals (95% CIs) were calculated, and the differences in mean values of the quantitative variables between cases and controls were analyzed using an unpaired t-test. Moreover, MMR vaccination and the effect of the number of vaccine injections were investigated using a conditional multiple regression model.
Results: For MMR vaccination, the OR was 1.04 (95% CI, 0.65-1.68), and no significant differences were found for the other vaccines. For all of the prenatal, perinatal and neonatal factors, there were no significant differences between cases and controls. Furthermore, regarding the presence of ASD, MMR vaccination and the number of vaccine injections had ORs of 1.10 (95% CI, 0.64-1.90) and 1.10 (95% CI, 0.95-1.26), respectively, in the conditional multiple regression model; no significant differences were found.
Conclusions: In this study, there were not any convincing evidences that MMR vaccination and increasing the number of vaccine injections were associated with an increased risk of ASD in a genetically homogeneous population. Therefore, these findings indicate that there is no basis for avoiding vaccination out of concern for ASD. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.vaccine.2012.01.093

No associations found between the genes situated at 6p22.1, HIST1H2BJ, PRSS16, and PGBD1 in Japanese patients diagnosed with schizophrenia Invited Reviewed

Maiko Kitazawa, Tohru Ohnuma, Yuto Takebayashi, Nobuto Shibata, Hajime Baba, Kazutaka Ohi, Yuka Yasuda, Yukako Nakamura, Branko Aleksic, Akira Yoshimi, Tomo Okochi, Masashi Ikeda, Hiroshi Naitoh, Ryota Hashimoto, Nakao Iwata, Norio Ozaki, Masatoshi Takeda, Heii Arai

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Vol. 159B ( 4 ) page： 456 - 464 2012.6

Language：English Publisher：WILEY-BLACKWELL

Recent GWAS demonstrated an association between candidate genes located at region 6p22.1 and schizophrenia. This region has been reported to house certain candidate SNPs, which may be associated with schizophrenia at HIST1H2BJ, PRSS16, and PGBD1. These genes may presumably be associated with pathophysiology in schizophrenia, namely epigenetics and psychoneuroimmunology. A three-step study was undertaken to focus on these genes with the following aims: (1) whether these genes may be associated in Japanese patients with schizophrenia by performing a 1st stage casecontrol study (514 cases and 706 controls) using Japanese tagging SNPs; (2) if the genetic regions of interest for the disease from the 1st stage of analyses were found, re-sequencing was performed to search for new mutations; (3) finally, a replication study was undertaken to confirm positive findings from the 1st stage were reconfirmed using a larger number of subjects (2,583 cases and 2,903 controls) during a 2nd stage multicenter replication study in Japan. Genotyping was performed using TaqMan PCR method for the selected nine tagging SNPs. Although three SNPs situated at the 3' side of PGBD1; rs3800324, rs3800327, and rs2142730, and two-window haplotypes between rs3800327 and rs2142730 showed positive associations with schizophrenia, these associations did not have enough power to sustain significance during the 2nd stage replication study. In addition, re-sequencing for exons 5 and 6 situated at this region did not express any new mutations for schizophrenia. Taken together these results indicate that the genes HIST1H2BJ, PRSS16, and PGBD1 were not associated with Japanese patients with schizophrenia. (C) 2012 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.b.32049

Slower adaptation to driving simulator and simulator sickness in older adults Reviewed

Naoko Kawano, Kunihiro Iwamoto, Kazutoshi Ebe, Branko Aleksic, Akiko Noda, Hiroyuki Umegaki, Masafumi Kuzuya, Tetsuya Iidaka, Norio Ozaki

AGING CLINICAL AND EXPERIMENTAL RESEARCH Vol. 24 ( 3 ) page： 285 - 289 2012.6

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Background and aims: Methods of assessing driving abilities in the elderly are urgently needed. Although the driving simulator (DS) appears to be a safe and cost-effective method of objectively evaluating driving performance, it may pose adaptation problems for elderly adults. In this study, we examined age-related adaptation deficits on the DS. Methods: Healthy young adults (n=15) and healthy elderly persons (n=17) completed some neuropsychological tests, and then performed a road-tracking task with the DS, which was repeated four times (Trials 1-4). Results: After simulated driving in DS, simulator sickness (SS) was observed in 18.8% of participants. The frequency of SS was 29.4% in elderly adults and 6.7% in young adults, and 17.6% of the elderly participants dropped out of the experiment. Performance on the Necker cube copying task was significantly correlated with the onset of SS. Driving performance also showed a significant interaction between group and trial, for both driving accuracy and vehicle speed. In addition, the performance of elderly adults significantly improved between trials 1 and 4, reaching a plateau in trial 4, whereas that of young adults did not change across trials. Conclusion: This study provides preliminary evidence of slower adaptation to a DS-based driving task by older adults, which was associated with cognitive aging. Age affected driving accuracy and velocity when a road-tracking task was simply repeated. It is concluded that the capacity of elderly people to adapt to DS environments should be taken into consideration when evaluating their performance on DS tasks. (C)2012, Editrice Kurtis

DOI： 10.1007/BF03325260

Common Variants in MAGI2 Gene Are Associated with Increased Risk for Cognitive Impairment in Schizophrenic Patients Reviewed

Takayoshi Koide, Masahiro Banno, Branko Aleksic, Saori Yamashita, Tsutomu Kikuchi, Kunihiro Kohmura, Yasunori Adachi, Naoko Kawano, Itaru Kushima, Yukako Nakamura, Takashi Okada, Masashi Ikeda, Kazutaka Ohi, Yuka Yasuda, Ryota Hashimoto, Toshiya Inada, Hiroshi Ujike, Tetsuya Iidaka, Michio Suzuki, Masatoshi Takeda, Nakao Iwata, Norio Ozaki

PLOS ONE Vol. 7 ( 5 ) page： e36836 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Schizophrenia is a complex psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive impairment. MAGI2, a relatively large gene (similar to 1.5 Mbps) that maps to chromosome 7q21, is involved in recruitment of neurotransmitter receptors such as AMPA- and NMDA-type glutamate receptors. A genetic association study designed to evaluate the association between MAGI2 and cognitive performance or schizophrenia has not been conducted. In this case-control study, we examined the relationship of single nucleotide polymorphism (SNP) variations in MAGI2 and risk for schizophrenia in a large Japanese sample and explored the potential relationships between variations in MAGI2 and aspects of human cognitive function related to glutamate activity. Based on the result of first schizophrenia genome-wide association study in a Japanese population (JGWAS), we selected four independent SNPs and performed an association study using a large independent Japanese sample set (cases 1624, controls 1621). Wisconsin Card Sorting Test (WCST) was used to evaluate executive function in 114 cases and 91 controls. We found suggestive evidence for genetic association of common SNPs within MAGI2 locus and schizophrenia in Japanese population. Furthermore in terms of association between MAGI2 and cognitive performance, we observed that genotype effect of rs2190665 on WCST score was significant (p = 0.034) and rs4729938 trended toward significance (p = 0.08). In conclusion, although we could not detect strong genetic evidence for association of common variants in MAGI2 and increased schizophrenia risk in a Japanese population, these SNPs may increase risk of cognitive impairment in schizophrenic patients.

DOI： 10.1371/journal.pone.0036836

Resequencing and Association Analysis of the KALRN and EPHB1 Genes And Their Contribution to Schizophrenia Susceptibility Reviewed

Itaru Kushima, Yukako Nakamura, Branko Aleksic, Masashi Ikeda, Yoshihito Ito, Tomoko Shiino, Tomo Okochi, Yasuhisa Fukuo, Hiroshi Ujike, Michio Suzuki, Toshiya Inada, Ryota Hashimoto, Masatoshi Takeda, Kozo Kaibuchi, Nakao Iwata, Norio Ozaki

SCHIZOPHRENIA BULLETIN Vol. 38 ( 3 ) page： 552 - 560 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Our genome-wide association study of schizophrenia found association signals at the Kalirin gene (KALRN) and EPH receptor B1 gene (EPHB1) in a Japanese population. The importance of these synaptogenic pathway genes in schizophrenia is gaining independent supports. Although there has been growing interest in rare (< 1%) missense mutations as potential contributors to the unexplained heritability of schizophrenia, there are no population-based studies targeting rare (< 1%) coding mutations with a larger effect size (eg, OR > 1.5) in KALRN or EPHB1.
The present study design consisted of 3 phases. At the discovery phase, we conducted resequencing analyses for all exon regions of KALRN and EPHB1 using a DNA microarray-based method. Seventeen rare (< 1%) missense mutations were discovered in the first sample set (320 schizophrenic patients). After the prioritization phase based on frequencies in the second sample set (729 cases and 562 controls), we performed association analyses for each selected mutation using the third sample set (1511 cases and 1517 controls), along with a combined association analysis across all selected mutations. In KALRN, we detected a significant association between schizophrenia and P2255T (OR = 2.09, corrected P = .048, 1 tailed); this was supported in the combined association analysis (OR = 2.07, corrected P = .006, 1 tailed). We found no evidence of association of EPHB1 with schizophrenia. In silico analysis indicated the functional relevance of these rare missense mutations.
We provide evidence that multiple rare (< 1%) missense mutations in KALRN may be genetic risk factors for schizophrenia.

DOI： 10.1093/schbul/sbq118

Differential effects of diazepam, tandospirone, and paroxetine on plasma brain-derived neurotrophic factor level under mental stress

Ai Tamaji, Kunihiro Iwamoto, Yukiko Kawamura, Masahiro Takahashi, Kazutoshi Ebe, Naoko Kawano, Shohko Kunimoto, Branko Aleksic, Yukihiro Noda, Norio Ozaki

HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL Vol. 27 ( 3 ) page： 329 - 333 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Objectives Serum brain-derived neurotrophic factor (BDNF) levels are reduced in depressed patients, and successful antidepressant treatment leads to increases in BDNF levels. However, little is known about how psychotropic drugs affect the mechanism of the human response to mental stress. We investigated the influence of psychotropic drugs on plasma BDNF levels under mental stress using a driving simulator (DS) task. Methods Fourteen healthy male volunteers received one of four drugs, diazepam (5?mg), tandospirone (20?mg), paroxetine (10?mg), and matched placebo, in a double-blind, crossover manner. Subjects were asked to perform the DS task 4?h post-dosing. Plasma BDNF levels were measured before and after the DS task. Results Plasma BDNF levels under the placebo, diazepam, and tandospirone conditions significantly decreased after the DS task compared with before the task. Conversely, no significant differences in plasma BDNF levels were detected under the paroxetine condition. Conclusion As these three psychotropic drugs have differential effects on plasma BDNF levels under mental stress after 4?h post-dosing, antidepressants, unlike anxiolytics, might have a prompt positive effect on the mental stress response. Copyright (c) 2012 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.2220

Sexual dysfunction and hyperprolactinemia in Japanese schizophrenic patients taking antipsychotics Reviewed

Tsutomu Kikuchi, Kunihiro Iwamoto, Kazumi Sasada, Branko Aleksic, Keizo Yoshida, Norio Ozaki

PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Vol. 37 ( 1 ) page： 26 - 32 2012.4

Language：English Publisher：PERGAMON-ELSEVIER SCIENCE LTD

This study aimed to estimate the prevalence of sexual dysfunction, evaluated by the Nagoya Sexual Function Questionnaire (NSFQ), and hyperprolactinemia in patients with schizophrenia and examine a relationship between sexual dysfunction and serum prolactin levels. This cross-sectional, comparative study was performed using a sample comprising 195 Japanese schizophrenic in- and outpatients treated with antipsychotics (117 males and 78 females). Data were collected from October 2009 to January 2010 using single, cross-sectional ratings of sexual function assessed by the NSFQ and concurrent measurement of serum prolactin levels. The prevalence of sexual dysfunction in patients with schizophrenia was high (males 66.7%; females 79.5%). Hyperprolactinemia (>25 ng/ml) was highly prevalent among schizophrenia patients, affecting 53.8% of females and 51.3% of males. Among female patients, 16.7% had prolactin levels > 100 ng/ml. There was no relationship between sexual dysfunction and serum prolactin levels. The present study demonstrated a higher prevalence of sexual dysfunction and hyperprolactinemia in Japanese schizophrenia patients. Clinicians should keep these problems in mind and discuss potential solutions with patients to improve patients' quality of life and adherence to therapy. (c) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2011.11.016

Prospective Study on the Association between Harm Avoidance and Postpartum Depressive State in a Maternal Cohort of Japanese Women Reviewed

Kaori Furumura, Takayoshi Koide, Takashi Okada, Satomi Murase, Branko Aleksic, Norika Hayakawa, Tomoko Shiino, Yukako Nakamura, Ai Tamaji, Naoko Ishikawa, Harue Ohoka, Hinako Usui, Naomi Banno, Tokiko Morita, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Norio Ozaki

PLOS ONE Vol. 7 ( 4 ) page： e34725 2012.4

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background: Recent studies have displayed increased interest in examining the relationship between personality traits and the onset, treatment response patterns, and relapse of depression. This study aimed to examine whether or not harm avoidance (HA) was a risk factor for postpartum depression measured by the Edinburgh Postnatal Depression Scale (EPDS) and the state dependency of HA.
Methods: Pregnant women (n = 460; mean age 31.9 +/- 4.2 years) who participated in a prenatal program completed the EPDS as a measure of depressive state and the Temperament and Character Inventory (TCI) as a measure of HA during three periods: early pregnancy (T1), late pregnancy (around 36 weeks), and 1 month postpartum (T2). Changes in EPDS and HA scores from T1 to T2 were compared between the non depressive (ND) group and the postpartum depressive (PD) group.
Results: There was no significant difference in the level of HA between the ND and PD groups at T1. In the ND group, EPDS and HA scores did not change significantly from T1 to T2. In the PD group, both scores increased significantly from T1 to T2 (EPDS, p<0.0001; HA, p<0.048). In the ND and PD groups, a significant positive correlation was observed in changes in EPDS and HA scores from T1 to T2 (r = 0.31, p = 0.002).
Conclusions: These results suggest that HA cannot be considered a risk factor for the development of postpartum depression measured by EPDS. Furthermore, HA may be state dependent.

DOI： 10.1371/journal.pone.0034725

Combination use of Beck Depression Inventory and two-question case-finding instrument as a screening tool for depression in the workplace Reviewed

Yasunori Adachi, Branko Aleksic, Ryoko Nobata, Tatsuyo Suzuki, Keizo Yoshida, Yuichiro Ono, Norio Ozaki

BMJ OPEN Vol. 2 ( 3 ) 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ PUBLISHING GROUP

Objectives: The present study aimed to validate screening tools that could be used to identify depression among workers.
Design: Diagnostic test study.
Settings: Workers from three Japanese companies agreed to participate.
Participants: Recruitment for the group 1 occurred between January 2001 and February 2004, and 89 participants (81 men and 8 women with a mean age of 38.4+/-6.6 years) (98.8%) took part in the study. Recruitment for the group 2 occurred between July 2000 and February 2004, and 1500 participants (1408 men and 92 women with a mean age of 40.9+/-7.2 years) (94.2%) took part in the study. Demographic data are shown in supplementary table 1.
Interventions: Primary and secondary outcome measures: the Beck Depression Inventory (BDI) and a two-question case-finding instrument (TQI) were administered to 89 workers and Mini-International Neuropsychiatric Interview was conducted to verify the diagnosis of depression. A second group of 1500 workers completed the BDI and TQI to detect possible sample bias for the distribution of depression. Specificity, sensitivity and positive predictive value were calculated in order to obtain the optimal cut-off scores for BDI and TQI and receiver operating characteristic curves, and Youden Index were applied to further refine the optimal cut-off scores.
Results: When paired together, BDI score >= 10 and TQI score of 2 adequately identified workers who had major depressive disorder and those who had other psychiatric disorders that are frequently comorbid with major depressive disorder.
Conclusions: The combination of BDI score >= 10 and TQI score of 2 can adequately screen for current and potential cases of depression among workers. Furthermore, BDI and TQI offer the advantage of being relatively easy to administer to a large number of workers. Early detection of depression could improve treatment outcomes and decrease economic burden.

DOI： 10.1136/bmjopen-2011-000596

Wisconsin Card Sorting Test scores and clinical and sociodemographic correlates in Schizophrenia: multiple logistic regression analysis Reviewed

Masahiro Banno, Takayoshi Koide, Branko Aleksic, Takashi Okada, Tsutomu Kikuchi, Kunihiro Kohmura, Yasunori Adachi, Naoko Kawano, Tetsuya Iidaka, Norio Ozaki

BMJ OPEN Vol. 2 ( 6 ) 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ PUBLISHING GROUP

Objectives: This study investigated what clinical and sociodemographic factors affected Wisconsin Card Sorting Test (WCST) factor scores of patients with schizophrenia to evaluate parameters or items of the WCST.
Design: Cross-sectional study.
Setting: Patients with schizophrenia from three hospitals participated.
Participants: Participants were recruited from July 2009 to August 2011. 131 Japanese patients with schizophrenia (84 men and 47 women, 43.5 +/- 13.8 years (mean +/- SD)) entered and completed the study. Participants were recruited in the study if they (1) met DSM-IV criteria for schizophrenia; (2) were physically healthy and (3) had no mood disorders, substance abuse, neurodevelopmental disorders, epilepsy or mental retardation. We examined their basic clinical and sociodemographic factors (sex, age, education years, age of onset, duration of illness, chlorpromazine equivalent doses and the positive and negative syndrome scale (PANSS) scores).
Primary and secondary outcome measures: All patients carried out the WCST Keio version. Five indicators were calculated, including categories achieved (CA), perseverative errors in Milner (PEM) and Nelson (PEN), total errors (TE) and difficulties of maintaining set (DMS). From the principal component analysis, we identified two factors (1 and 2). We assessed the relationship between these factor scores and clinical and sociodemographic factors, using multiple logistic regression analysis.
Results: Factor 1 was mainly composed of CA, PEM, PEN and TE. Factor 2 was mainly composed of DMS. The factor 1 score was affected by age, education years and the PANSS negative scale score. The factor 2 score was affected by duration of illness.
Conclusions: Age, education years, PANSS negative scale score and duration of illness affected WCST factor scores in patients with schizophrenia. Using WCST factor scores may reduce the possibility of type I errors due to multiple comparisons.

DOI： 10.1136/bmjopen-2012-001340

Evaluation of factors affecting continuous performance test identical pairs version score of schizophrenic patients in a Japanese clinical sample.

Koide T, Aleksic B, Kikuchi T, Banno M, Kohmura K, Adachi Y, Kawano N, Iidaka T, Ozaki N

Schizophrenia research and treatment Vol. 2012 page： 1 - 5 2012

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