内藤 宏

Aims: The purpose of this study was to predict the outcome of cognitive behavior therapy (CBT) by trainees for major depressive disorder (MDD) based on the Parental Bonding Instrument (PBI). The hypothesis was that the higher level of care and/or lower level of overprotection score would predict a favorable outcome of CBT by trainees. Methods: The subjects were all outpatients with MDD treated with CBT as a training case. All the subjects were asked to fill out the Japanese version of the PBI before commencing the course of psychotherapy. The difference between the first and the last Beck Depression Inventory (BDI) score was used to represent the improvement of the intensity of depression by CBT. In order to predict improvement (the difference of the BDI scores) as the objective variable, multiple regression analysis was performed using maternal overprotection score and baseline BDI score as the explanatory variables. Results: The multiple regression model was significant (P=0.0026) and partial regression coefficient for the maternal overprotection score and the baseline BDI was -0.73 (P=0.0046) and 0.88 (P=0.0092), respectively. Therefore, when a patient's maternal overprotection score of the PBI was lower, a better outcome of CBT was expected. Conclusion: The hypothesis was partially supported. This result would be useful in determining indications for CBT by trainees for patients with MDD.

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.

Background: Several investigations have reported that abnormalities in circadian rhythms might be related to the pathophysiology of major depressive disorder (MDD) and the therapeutic response to selective serotonin reuptake inhibitors (SSRIs). Recently, ubiquitin-specific peptidase 46 (USP46), a new molecule related to the circadian clock system, has been described. We conducted a case control study between seven tagging SNPs (rs10517263, rs17675844, rs6554557, rs12646800, rs2244291, rs10034164, rs346005) in the USP46 gene, MDD, and the SSRI therapeutic response in MDD in the Japanese population. Method: We recruited 432 MOD patients (202 males and 230 females) and 792 healthy controls (319 males and 473 females). Two hundred sixty-one of 432 MOD patients were treated with SSRIs (fluvoxamine, sertraline or paroxetine). Result: We detected an association between the USP46 gene and MOD in a haplotype analysis (rs2244291-rs10034164-rs346005 and rs12646800-rs2244291-rs10034164-rs346005). However, we did not find any association between the USP46 gene and SSRI response or remission in MDD in the Japanese population. Limitations: A replication study using larger samples may be required for conclusive results, since our sample size was small. Conclusions: Our results suggest that the USP46 gene might play a role in the pathophysiology of MOD in the Japanese population. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.

Background: Altered serotonergic neural transmission is hypothesized to be a susceptibility factor for psychotic disorders such as schizophrenia. The serotonin 6 (5-HT6) receptor is therapeutically targeted by several second generation antipsychotics, such as clozapine and olanzapine, and D-amphetamine-induced hyperactivity in rats is corrected with the use of a selective 5-HT6 receptor antagonist. In addition, the disrupted prepulse inhibition induced by D-amphetamine or phencyclidine was restored by 5-HT6 receptor antagonist in an animal study using rats. These animal models were considered to reflect the positive symptoms of schizophrenia, and the above evidence suggests that altered 5-HT6 receptors are involved in the pathophysiology of psychotic disorders. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an analysis of the association of the 5-HT6 gene (HTR6) with METH-induced psychosis. Method: Using five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. Results: rs6693503 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this association remained significant after Bonferroni correction. In the haplotype-wise analysis, we detected an association between two markers (rs6693503 and rs1805054) and three markers (rs6693503, rs1805054 and rs4912138) in HTR6 and METH-induced psychosis patients, respectively. Conclusion: HTR6 may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population. Crown Copyright (C) 2010 Published by Elsevier Ireland Ltd. All rights reserved.

Several recent investigations reported that the serotonin 2A receptor gene (HTR2A) was associated with selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder. There have also been two reported association analyses of HTR2A with SSRI response in Japanese MDD patients, but the results were rather inconsistent and both studies had the problem of small sample sizes. Therefore, we conducted a replication association study using a sample larger than those in the two original Japanese studies (265 MDD patients), and found that four SNPs, two functional SNPs (-A1438G: rs6311 and T102C: rs6313) and two SNPs (rs7997012 and rs1928040) in HTR2A, were associated with the therapeutic response to SSRIs. HTR2A was associated with the therapeutic response SSRIs in Japanese MDD patients in a haplotype-wise analysis (P (all markers) = 0.0136), and a significant association between rs1928040 in HTR2A and SSRI response was detected in MDD (P (allele-wise analysis) = 0.0252). However, this significance disappeared after Bonferroni correction (P (allele-wise analysis) = 0.101). In conclusion, we suggest that HTR2A may play an important role in the pathophysiology of the therapeutic response to SSRIs in Japanese MDD patients. However, it will be important to replicate and confirm these findings in other independent studies using large samples.

Objective Several investigations have suggested that alterations in serotonin 6 (5-HT6) receptors might be associated with the pathophysiology of major depressive disorder (MDD), and that 5-HT6 receptors might be a therapeutic target for serotonin selective reuptake inhibitor (SSRI) in MDD. To evaluate the association between HTR6 and the efficacy of SSRI treatment in Japanese MDD patients, we conducted a case-control study in a Japanese population sample. Methods We selected five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997), and performed an association analysis of HTR6 and the efficacy of SSRI treatment in 260 MDD patients. Results We did not detect an association between tagging SNPs in HTR6 and the therapeutic response to SSRI in MDD in allele/genotype or haplotype analysis. Conclusions HTR6 may not play an important role in the pathophysiology of SSRI response in the Japanese population. Because our sample was relatively small, statistical errors were possible in the results of our association analyses. To overcome these limitations, a replication study using a larger sample may be required for conclusive results. Copyright (C) 2010 John Wiley & Sons, Ltd.

Several evidence suggests that alterations in serotonin 6 (5-HT6) receptors might be associated with the pathophysiology of mood disorders. Therefore, to evaluate the association between HTR6 and BP and MDD, we conducted a case-control study of Japanese population samples (1007 BP patients, 447 MDD patients and 1753 controls) with five tagging SNPs, including rs1805054 (C267T), in HTR6. In addition, we conducted a meta-analysis of rs1805054, which has been examined in other studies. We selected five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997). Moreover, three association studies for BP and four association studies for MDD, including this study, met our criteria for the meta-analysis of rs1805054. We did not detect an association between tagging SNPs in HTR6 and BP and MDD in the allele/genotype, haplotype analysis or meta-analysis. In conclusion, we found no association involving polymorphism and mood disorder in the Japanese population. However, because changes in expression level or signal transduction of this receptor may be involved in the pathology of these diseases, it will be necessary to conduct the further study about the relationship between this receptor and mood disorders in the future. Crown Copyright (C) 2010 Published by Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Background: Several investigations have suggested the possible involvement of sigma1 non-opioid intracellular receptor 1 (sigma1 receptor) in the pathophysiology of major depressive disorder (MDD). Sigma1 receptors are also one of the major pharmacological therapeutic targets of selective serotonin reuptake inhibitors (SSRIs). To evaluate the association of sigma1 receptor gene (SIGMAR1) and MDD and SSRIs therapeutic response in MDD, we conducted a case control study of Japanese samples (466 MDD patients, 516 controls and 208 MDD patients treated by fluvoxamine or sertraline). Method: We defined a clinical response as a decrease of more than 50% in baseline the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D) within 8 weeks, and clinical remission as an SIGH-D score of less than 7 at 8 weeks. Therefore, we selected rs1800866 in SIGMAR1 for the following association analysis. Results: In the logistic regression analysis, we detected an association of the phenotypes (MDD or controls) with rs1800866 genotype. However, we did not detect an association between rs1800866 and SSRI therapeutic response in Japanese MDD. In addition, remission with SSRI was not associated with rs1800866. Also, we did not detect a novel polymorphism in SIGMAR1 when we performed a mutation search using MDD treated by SSRIs samples. Conclusion: Our results suggest that rs1800866 in SIGMAR1 may play a role in the pathophysiology of MDD in the Japanese population. Also, SIGMAR1 does not play a role in the therapeutic response to SSRI in Japanese MDD patients. However, because our sample was small, a replication study using another population and larger sample will be required for conclusive results. (C) Crown Copyright 2010 Published by Elsevier Ltd. All rights reserved.

Background: Abnormalities in glutaminergic neural transmission have been suggested to be involved in the pathogenesis of schizophrenia. A recent study reported that alterations in the 5-HT2A-mGluR2 complex may be involved in neural transmission in the schizophrenic cortex. In addition, methamphetamine-induced psychosis is thought to be similar to schizophrenia. Therefore, we conducted a case-control study with Japanese samples (738 schizophrenia patients, 196 methamphetamine-induced psychosis patients, and 802 controls) to evaluate the association and interaction between GRM2, HTR2A and schizophrenia. Methods: We selected three 'tagging SNPs' in GRM2, and two biologically functional SNPs in HTR2A (T102C and A1438G), for the association analysis. Results: We detected a significant association between methamphetamine-induced psychosis and GRM2 in a haplotype-wise analysis, but not HTR2A. We did not detect an association between GRM2 or HTR2A and schizophrenia. In addition, no interactions of GRM2 and HTR2A were found in methamphetamine-induced psychosis or schizophrenia. We did not detect any novel polymorphisms in GRM2 when we performed a mutation search using methamphetamine-induced psychosis samples. Conclusion: Our results suggested that GRM2 may play a role in the pathophysiology of methamphetamine-induced psychosis but not schizophrenia in the Japanese population. A replication study using larger samples or samples of other populations will be required for conclusive results. Crown Copyright (C) 2010 Published by Elsevier Inc. All rights reserved.

Several investigators have reported cognitive dysfunction in chronic schizophrenia that was associated with insight and social skills. Such cognitive dysfunction seriously hinders an immediate return to normal life. Recently. Kaneda et al. reported that the Brief Assessment of Cognition in Schizophrenia. Japanese-language version (BACS-J) was superior in the evaluation of the cognitive function. We investigated which clinical factors (age, sex, duration of illness, level of education, smoking status, the Positive and Negative Syndrome Scale (PANSS) score and medication dosage) affected cognitive dysfunction in 115 Japanese schizophrenic patients, with the use of multiple regression analysis. We detected an association between composite score, verbal memory, working memory and executive function and PANSS total score. Moreover, most cognitive tasks were associated with a negative PANSS score but not a positive PANSS score or general score. We also showed an association between age and verbal fluency and attention in schizophrenia. In addition, anxiolytics/hypnotics (diazepam-equivalent) were associated with composite score, working memory and motor speed. In conclusion, cognitive function was associated with PANSS score, especially negative PANSS score. Because anxiolytics/hypnotics might have a detrimental influence on cognitive function, we strongly suggest that the use of anxiolytics/hypnotics be reduced in schizophrenics as much as possible. Crown Copyright (C) 2009 Published by Elsevier Ireland Ltd on behalf of the Japan Neuroscience Society. All rights reserved.

Studies have also shown that differences in the kind of the antipsychotics influenced disruption of the sensorimotor gating system, including prepulse inhibition (PPI), acoustic startle reflex (ASR), and habituation (HAB). We investigated the influence on startle response in chronic schizophrenia in 20 patients with schizophrenia taking risperidone, 21 patients with schizophrenia taking olanzapine, and 20 patients with schizophrenia taking aripiprazole. The patients who participated in this study were on maintenance therapy with only one antipsychotic drug for 4 months. We performed the test for the association between all PPI measures (ASR, HAB, and PPI at prepulse sound pressure intensities of 82, 86, and 90 dB) and each the risperidene, olanzapine, and aripiprazole groups, with analysis of covariance (ANCOVA; using age, duration of illness, and daily dose of the antipsychotic as covariates). Also, when significant difference was detected in ANCOVA, the differences of PPI measures between every pairs of two drug groups were tested as a post hoc analysis with the use of t test and Bonferroni's correction of multiple tests. We found that PPI90 showed significant differences with ANCOVA among patients with schizophrenia taking each of the antipsychotics. When we performed a post hoc analysis for PPI90, the value was higher in the aripiprazole group than in the olanzapine group and higher in the risperidone group than in the olanzapine group. Aripiprazole and risperidone may improve PPI90. ASR, HAB, PPI82, and PPI86 were no different among the Japanese schizophrenic patient groups with different antipsychotics.

Recent progress in genotyping technology and the development of public databases has enabled large-scale genome-wide association tests with diseases. We performed a two-stage genome-wide association study (GWAS) of bipolar disorder (BD) in Japanese cohorts. First we used Affymetrix 100K GeneChip arrays in the analysis of 107 cases with bipolar I disorder and 107 controls, and selected markers that were nominally significant (P<0.01) in at least one of the three models (1,577 markers in total). In the follow-up stage, we analyzed these markers using an Illumina platform (1,526 markers; 51 markers were not designable for the platform) and an independent sample set, which consisted of 395 cases (bipolar I + II) and 409 controls. We also assessed the population stratification of current samples using principal components analysis. After the two-stage analysis, 89 markers remained nominally significant (allelic P < 0.05) with the same allele being consistently over-represented in both the first and the follow-up stages. However, none of these were significant after correction for multiple-testing by false discovery rates. Sample stratification was virtually negligible. Collectively, this is the first GWAS of BD in the Japanese population. But given the small sample size and the limited genomic coverage, these results should be taken as preliminary. (C) 2009 Wiley-Liss, Inc.