北島 剛司

Study Objectives: Patients with circadian rhythm sleep disorders (CRSDs) often have coincidence of orthostatic dysregulation (OD). Both disorders have many common clinical features. However, the prevalence of OD in patients with CRSD has not been examined. Methods: Thirty-eight patients with CRSD with either delayed sleep phase disorder or free-running disorder were tested for OD using the new orthostatic test, which was originally established by Tanaka et al. (< 20 years) and the Schellong test, i.e., the active standing test (>= 20 years). Results: The overall prevalence of OD in patients with CRSD was 57.9% (22/38), and prevalence of OD was 70% in patients under 20 years of age (14/20). These rates exceed the previously reported values in adolescents aged 14-15 years (15%), regarded as the age with highest OD prevalence. Prevalence was not significantly associated with CRSD severity and medications used. Conclusions: We observed a high prevalence of OD in patients with CRSD, suggesting some relationship between CRSD and OD. Large-scale case-control studies are warranted to investigate the underlying mechanisms for this comorbidity.

ICSD-2からICSD-3への改訂において、概日リズム睡眠・覚醒障害(circadian rhythm sleep-wake disorder:CRSWD)は、名称が若干変更されるとともに、病型が7つにまとめられた。注目されるのは、睡眠・覚醒相後退障害(delayed sleep-wake phase disorder:DSWPD)におけるmotivated delayed sleep-wake phase disorderのサブタイプの採用であろう。また全般的に、発達障害や気分障害などの他の精神疾患、あるいは神経発達疾患などとの関連を含めた記載内容が増えている。疾患概念についてはさらに議論が必要であると考えられ、また病態、診断手法、治療においても今後の解明の余地があるが、この分野におけるわが国の研究成果の寄与は大きく、今後の役割がいっそう期待される。(著者抄録)

Objectives: (1) To examine criterion validity of the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) using obstructive sleep apnea (OSA), periodic limb movement disorder (PLMD), rapid eye movement sleep behavior disorder (RBD), and narcolepsy as criterion standard. (2) To summarize the evidence for criterion validity of the ESS for the diagnosis of OSA by a meta-analysis that combines the current and previous studies. (3) To investigate the determinants of the PSQI and ESS scores. Methods: The PSQI and ESS as well as the Hospital Anxiety and Depression Scale (HADS), which measures anxiety and depression levels, were administered to 367 patients consecutively referred to a sleep clinic. They underwent overnight polysomnography (PSG) and the multiple sleep latency test if narcolepsy was suspected. Results: The area under the receiver operating characteristic curves for the ESS and PSQI (and its sub-scale) were <0.9, meaning that these questionnaires were not highly accurate for predicting the four sleep disorders. The meta-analysis found that the ESS had no value in identifying OSA. The variable that most strongly influenced PSQI or ESS scores was the HADS score. Conclusion: The PSQI and ESS should no longer be used as a screening or diagnostic instrument for the four PSG-defined sleep disorders, especially in a low-risk population. (C) 2014 Elsevier B. V. All rights reserved.

A sleep diary is often employed for diagnosing and treating hypersomnia. However, its reliability needs to be evaluated because overlooked chronic sleep insufficiency could be misdiagnosed as narcolepsy. In this study, we compared simultaneous sleep measurements using a sleep diary and by actigraphy in patients visiting our sleep clinic for the first time with complaints of excessive daytime sleepiness. Of the 28 patients enrolled, 24 complied with both these requirements. In this population, the results obtained using a sleep diary tended to estimate a statistically significant earlier sleep onset time and longer total sleep time than those via actigraphy. For total sleep time, this tendency was more prominent in patients with a higher Epworth Sleepiness Scale score. In 5 of the 24 (20.8%) patients, the sleep diary records indicated >6h of total sleep time while the actigraphy records indicated <6h of total sleep time, with a discrepancy of >1h. These results suggested that sleep insufficiency in hypersomnia patients may be overlooked when their sleep time is assessed using only a sleep diary in the initial phase of the diagnostic procedure, and the simultaneous use of actigraphy may be preferable in this assessment.

Background: Tetrahydrobiopterin (BH4) plays an important role in the biosynthesis of serotonin, melatonin and catecholamines, all of which are implicated in the pathophysiology of mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Production of BH4 is regulated by GTP cyclohydrolase transcription and activity. Thus, we considered the GTP cyclohydrolase gene (GCH1) to be a good candidate gene in the pathophysiology of MDs and of the serotonin selective reuptake inhibitors (SSRIs) response in MDD, and conducted a case-control study utilizing three SNPs (rs8007267, rs3783641 and rs841) and moderate sample sizes (405 MDD patients, including 262 patients treated by SSRIs, 1022 BP patients and 1805 controls). Method: A multiple logistic regression analysis was carried out to compare the frequencies of each SNP genotype for the target phenotype across patients and controls in several genetic models, while adjusting for possible confounding factors. A clinical response was defined as a decrease of more than 50% from the baseline score on the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D) within 8 weeks, and clinical remission as a SIGH-D score of less than 7 at 8 weeks. Result: No associations between three SNPs in GCH1 and MDD or BP were observed; however, GCH1 was associated with SSRI therapeutic response in MDD in all the marker's haplotype analysis (Global P value=0.0379). Conclusions: Results suggest that GCH1 may predict response to SSRI in MDD in the Japanese population. Nevertheless, a replication study using larger samples may be required for conclusive results, since our sample size was small. (C) 2012 Elsevier B.V. All rights reserved.

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.

Patients with schizophrenia frequently exhibit behavioral abnormalities associated with its pathological symptoms. Therefore, a quantitative evaluation of behavioral dynamics could contribute to objective diagnoses of schizophrenia. However, such an approach has not been fully established because of the absence of quantitative biobehavioral measures. Recently, we studied the dynamical properties of locomotor activity, specifically how resting and active periods are interwoven in daily life. We discovered universal statistical laws ("behavioral organization") and their alterations in patients with major depressive disorder. In this study, we evaluated behavioral organization of schizophrenic patients (n = 19) and healthy subjects (n = 11) using locomotor activity data, acquired by actigraphy, to investigate whether the laws could provide objective and quantitative measures for a possible diagnosis and assessment of symptoms. Specifically, we evaluated the cumulative distributions of resting and active periods, defined as the periods with physical activity counts successively below and above a predefined threshold, respectively. Here we report alterations in the laws governing resting and active periods; resting periods obeyed a power-law cumulative distribution with significantly lower parameter values (power-law scaling exponents), whereas active periods followed a stretched exponential distribution with significantly lower parameter values (stretching exponents), in patients. Our findings indicate enhanced persistency of both lower and higher locomotor activity periods in patients with schizophrenia, probably reflecting schizophrenic pathophysiology.

Objectives Several lines of evidence suggest that genetic alterations in serotonin 6 (5-HT6) receptors might be associated with the pathophysiology of schizophrenia. We sought to assess the relationship between genotype alterations in 5-HT6 receptors and schizophrenia both in a case-control study and a meta-analysis. Methods We conducted an association study of the 5-HT6 receptor gene (HTR6) in Japanese patients with schizophrenia (n = 836) and controls (n = 857). Five tagging single-nucleotide polymorphisms (SNPs), including rs1805054 (C267T) in HTR6, were selected. In addition, we carried out a meta-analysis between rs1805054, which has been examined in other studies, and schizophrenia, searching PubMed through August 2011. Results There were no significant associations between the tagging SNPs in HTR6 and schizophrenia in any of the genotype models in both the simple and the multiple logistic regression analyses correcting for potential confounds. Similarly, no significant association was found in the all-marker haplotype multiple logistic regression analysis (p = 0.491). Moreover, in the meta-analysis of rs1805054, drawing data from five studies, including our own (schizophrenia patients = 1366, controls = 1376), rs1805054 was also not associated with schizophrenia. Conclusions Our results indicate that tagging SNPs in HTR6 may not play a role in the pathophysiology of schizophrenia. Copyright (C) 2012 John Wiley & Sons, Ltd.

睡眠関連呼吸障害群(sleep related breathing disorders;SRBDs)の代表的病態である閉塞性睡眠時無呼吸症候群(obstructive sleep apnea syndrome;OSAS)は、日中過眠、集中困難、意欲減退、起床時の頭痛などを呈することが知られている。これまでOSASとの関連で注目されている精神疾患はうつ病である。OSASでCPAPのアドヒアランスが良好にもかかわらず、熟眠感の欠如、日中過眠、倦怠感を訴えるケースにはうつ病の合併を考慮する必要がある。うつ病の治療が遷延し、重度の不眠あるいは、日中過眠を訴えるケースにはOSASの合併に留意しPSGを施行する必要がある。もちろん、過眠を主訴とすることの多い双極性うつ病では、肥満体型も多く、OSASの合併頻度が高いことを精神科医は念頭に置いている。うつ病とOSASは相互に関連し、共に患者のQOLを著しく損ない社会活動に支障をきたすため、早期発見・早期治療導入の重要性が示唆される。(著者抄録)

Objectives We previously showed that the sirtuin 1 gene (SIRT1 gene), one of the clock genes, was associated with schizophrenia in a Japanese patient population. Because the symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia and because not every METH user develops psychosis, it is conceivable that METH-induced psychosis and schizophrenia have common susceptibility genes. Therefore, we conducted an analysis of the association of SIRT1 gene with METH-induced psychosis, hypothesizing a significant relationship. Methods This paper presents a case-control study of the SIRT1 gene in 515 Japanese individuals (197 with METH-induced psychosis and 318 age-matched and sex-matched controls) with four tagging single nucleotide polymorphisms (rs12778366, rs2273773, rs4746720, and rs10997875), selected a priori using the HapMap database. Results rs10997875 (located in the 3' flanking region) was associated with METH-induced psychosis (unadjusted p(genotype)=0.0203). However, these results became non-significant after Bonferroni correction (corrected p(genotype)=0.0812). In the all-marker haplotype analysis, the SIRT1 gene was not associated with METH-induced psychosis (p=0.146). Conclusion Our findings suggest that SIRT1 gene does not contribute to the development of METH-induced psychosis in the Japanese population. However, a replication study using larger samples should be conducted to obtain conclusive results. Copyright (C) 2011 John Wiley & Sons, Ltd.

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.

Objectives: Recently, we detected that the prokineticin 2 receptor gene was associated with not only major depressive disorder (MDD) but also methamphetamine dependence. Therefore, it is possible that mood disorders and drug addiction have shared susceptibility genes. The translin-associated factor X gene (TSNAX)/disrupted-in-schizophrenia-1 gene (DISC1) has been associated with psychiatric disorders, including schizophrenia, MDD and bipolar disorder. TSNAX is located immediately upstream of DISC1 and has been shown to undergo intergenic splicing with DISC1. Based on this evidence, we hypothesized that TSNAX might be a good candidate gene for methamphetamine dependence. Methods: We conducted a case-control study of Japanese individuals (215 with methamphetamine dependence and 318 age- and sex-matched controls) with three tagging SNPs (rs1630250, rs766288 and rs6662926) selected by HapMap database. Results: rs1630250 was associated in males with methamphetamine dependence in the allele analysis (P-value: 0.0253). However, these results did not remain significant after Bonferroni correction to adjust for multiple comparisons (corrected P-value: 0.152). Conclusion: Our findings suggest that TSNAX does not play a role in methamphetamine dependence in the Japanese population. A replication study using larger samples needs to be conducted to obtain conclusive results. (C) 2011 Elsevier Inc. All rights reserved.

Several lines of evidence suggest that alterations in circadian rhythms might be associated with the pathophysiology of psychiatric disorders such as schizophrenia and bipolar disorder (BP). A recent study reported that SIRT1 is a molecule that plays an important role in the circadian clock system. Therefore, to evaluate the association among the SIRT1 gene, schizophrenia and BP, we conducted a case-control study of Japanese population samples (1158 schizophrenia patients, 1008 BP patients and 2127 controls) with four tagging SNPs (rs12778366, rs2273773, rs4746720 and rs10997875) in the SIRT1 gene. Marker-trait association analysis was used to evaluate the allele and the genotype association with the chi 2 test, and haplotype association analysis was evaluated with a likelihood ratio test. We showed an association between rs4746720 in the SIRT1 gene and schizophrenia in the allele and the genotype analysis. However, the significance of these associations did not survive after Bonferroni's correction for multiple testing. On the other hand, the SIRT1 gene was associated with Japanese schizophrenia in a haplotype-wise analysis (global P(all markers) = 4.89 x 10-15). Also, four tagging SNPs in the SIRT1 gene were not associated with BP. In conclusion, the SIRT1 gene may play an important role in the pathophysiology of schizophrenia in the Japanese population.

Several investigations suggested abnormalities in circadian rhythms are related to the pathophysiology of psychiatric disorders, including drug addiction. Recently, orphan nuclear receptor rev-erb alpha and glycogen synthase kinase-3 beta (GSK-3 beta) were shown to be important circadian components. In addition, the orphan nuclear receptor rev-erb alpha is a key negative feedback regulator of the circadian clock. These evidences indicate that rev-erb alpha gene (NR1D1) is a good candidate gene for the pathogenesis of methamphetamine dependence. To evaluate the association between NR1D1 and methamphetamine dependence, we conducted a case-control study of Japanese samples (215 methamphetamine dependence and 232 controls) with three tagging SNPs selected by HapMap database. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between NR1D1 and Japanese methamphetamine dependence patients in allele/genotype-wise analysis, or the haplotype analysis. Our findings suggest that NR1D1 does not play a major role in the pathophysiology of methamphetamine dependence in the Japanese population.

Several investigations have reported associations between serotonin 1A (5-HT1A) receptor and major psychiatric disorders, such as schizophrenia and bipolar disorder (BP), making the 5-HT1A receptor gene (HTR1A) a good candidate gene for the pathophysiology of schizophrenia and BP. To evaluate the association between HTR1A and schizophrenia and BP, we conducted a case-control study of Japanese population samples with two single- nucleotide polymorphisms (SNPs), including rs6295 (C-1019G) in HTR1A. In addition, we conducted a meta-analysis of rs6295, which has been examined in other studies. Using one functional single- nucleotide polymorphism (SNP; rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (857 schizophrenic patients, 1028 BP patients and 1810 controls) in the Japanese population. Two association studies for schizophrenia and three association studies for BP, including this study, met our criteria for the meta-analysis of rs6295. We found an association between HTR1A and Japanese BP in a haplotype-wise analysis, the significance of which remained after Bonferroni correction. In addition, we detected an association between rs6295 and BP in the meta-analysis (fixed model: P(Z) = 0.000400). However, we did not detect an association between HTR1A and schizophrenia in the allele/genotype-wise, haplotype-wise or meta-analysis. HTR1A may play an important role in the pathophysiology of BP, but not schizophrenia in the Japanese population. In the meta-analysis, rs6295 in HTR1A was associated with BP patients. Crown Copyright (C) 2010 Published by Elsevier Ireland Ltd. 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.

Disruption of circadian rhythms may be involved in the pathophysiology of psychiatric disorders, including drug addiction. Recently, we detected the significant association between prokineticin 2 receptor gene (PROKR2) and Japanese methamphetamine dependence patients. Also, prokineticin 2 (PK2) gene deficient mice showed reduced physiological and behavioral parameters, including circadian locomotor activity, circulating glucocorticoid, glucose levels and the expression of peripheral clock genes compared with WT mice. These evidences indicate that PK2 gene (PROK2) is a good candidate gene for the pathogenesis of methamphetamine dependence. To evaluate the association between PROK2 and methamphetamine dependence, we conducted a case-control study of Japanese samples (215 methamphetamine dependence and 232 controls) with four tagging SNPs selected by HapMap database. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between PROK2 and Japanese methamphetamine dependence patients in allele/genotype-wise analysis, or the haplotype analysis. Our findings suggest that PROK2 does not play a major role in the pathophysiology of methamphetamine dependence in the Japanese population. ©2011 Bentham Science Publishers Ltd.

Endothelial nitric oxide synthase (NOS3) is one of the enzymes influencing nitric oxide (NO) function in the human brain. NO is a gaseous neurotransmitter that is involved in a variety of mechanisms in the central nervous system, such as N-methyl-D-aspartate receptor activation and oxidative stress. The evidence from animal pharmacological studies and postmortem studies supports an association between NO and psychotic disorders. Methamphetamine (METH) use disorder is a known psychotic disorder, and we therefore conducted a gene-based case-control study between tagging single nucleotide polymorphisms (SNPs) (rs2070744, rs1799983) in NOS3 and METH-induced psychosis in Japanese subjects (183 with METH-induced psychosis and 267 controls). Written informed consent was obtained from each subject. No significant association was found between any tagging SNP in NOS3 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS3 might not contribute to the risk of METH-induced psychosis in the Japanese population. ©2011 Bentham Science Publishers Ltd.

Background: Many studies including our previous ones as to PROKR2 and CLOCK have suggested that circadian genes may be involved in the mechanisms of mood disorders and their treatment responses. Also several recent investigations have reported that SIRT1 plays an important role in the circadian system as conventional circadian clock genes, and also have some relation to dopaminergic metabolism. So we considered the SIRT1 gene to be a good candidate gene for the pathophysiology for MDD and SSRI responses in MDD, and conducted a case-control study using four tagging SNPs (450 MDD patients, including 261 patients treated by SSRIs and 766 controls). Method: The MOD patients in this study had scores of 12 or higher on the 17 items of the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D). We defined a clinical response as a decrease of more than 50% in baseline SIGH-D within 8 weeks, and clinical remission as an SIGH-D score of less than 7 at 8 weeks. Marker-trait association analysis was used to evaluate allele and genotype association with the chi-square test, and haplotype association analysis was evaluated with a likelihood ratio test. Result: We found an association between rs10997875 in SIRT1 gene and MDD in the allele/genotype analysis. In addition, this significance of these associations survived Bonferroni correction. However, we did not find any association between SIRT1 gene and SSRI therapeutic response in MDD in the allele/genotype analysis or haplotype analysis. Limitations: A replication study using larger samples may be required for conclusive results, since our sample size was small. Conclusions: Our results suggest that rs10997875 in SIRT1 gene may play a role in the pathophysiology of MDD in the Japanese population. (C) 2010 Elsevier B.V. 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.

Several investigations have reported that abnormalities in circadian rhythms might be related with the pathophysiology of psychiatric disorders, since many psychiatric patients have insomnia and sleep-awake disturbance. A recent animal study reported that Magel2, which encodes a member of the MAGE/necdin family of proteins, might be associated in the pathophysiology of psychiatric disorders. Magel2 gene knockout mice showed altered concentrations of both dopamine and serotonin in several parts of the brain compared with controls. In addition, the authors of that study detected a bilateral reduction in cortical volume in distinct regions of the Magel2 gene knockout mice brain, including focused regions in the parieto-temporal lobe of the cerebral cortex, the amygdala, the hippocampus, and the nucleus accumbens. These mice were also found to have hypoactivity and abnormalities in circadian rhythms. From this evidence, we considered Magel2 gene (MAGEL2) to be a good candidate gene for the pathophysiology of schizophrenia and mood disorder, and we conducted a case-control study among Japanese (731 schizophrenia patients, 465 MDD patients, 156 BP patients and 758 controls) using three tagging SNPs in MAGEL2 (rs850815, rs8920 and rs4480754), selected using the HapMap database. We did not find any association between MAGEL2 and schizophrenia, BP or MDD in allele/genotype-wise analysis or haplotype-wise analysis. Our results suggest that MAGEL2 may not play a role in the pathophysiology of schizophrenia and mood disorders in the Japanese population. A replication study using larger samples may be required for conclusive results, since our sample size was small and our study analyzed only three SNPs in MAGEL2.

Background: Many patients with drug addiction are reported to have comorbid mood disorders. One of the suggested pathophysiological mechanisms for mood disorders is disruption of circadian rhythms. Several animal studies have shown that methamphetamine altered the expression of circadian clock molecules in the brain. Therefore, it is possible that mood disorders and drug addiction have common susceptibility genes. Recently, we reported that the prokineticin 2 receptor gene (PROKR2) was associated with mood disorders including major depressive disorder and bipolar disorder in the Japanese population. In the present study, therefore, we conducted an association analysis of tagging SNPs in PROKR2 with Japanese methamphetamine dependence patients. Methods: Using five tagging SNPs in PROKR2, we conducted a genetic association analysis of case control samples (199 methamphetamine dependence patients and 337 healthy controls). The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. Results: We detected a significant association between PROKR2 and methamphetamine dependence patients in allele/genotype-wise and haplotype-wise analysis. Conclusion: Our results suggest that PROKR2 may play a role in the pathophysiology of methamphetamine dependence in the Japanese population. However, because we did not perform a mutation scan of PROKR2, a replication study using a larger sample may be required for conclusive results. (C) 2010 Elsevier Inc. All rights reserved.

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.

Gene expression profiling with microarray technology suggests that peripheral blood cells might be a surrogate for postmortem brain tissue in studies of schizophrenia. The development of an accessible peripheral biomarker would substantially help in the diagnosis of this disease. We used a bioinformatics approach to examine whether the gene expression signature in whole blood contains enough information to make a specific diagnosis of schizophrenia. Unpaired t-tests of gene expression datasets from 52 antipsychotics-free schizophrenia patients and 49 normal controls identified 792 differentially expressed probes. Functional profiling with DAVID revealed that eleven of these genes were previously reported to be associated with schizophrenia, and 73 of them were expressed in the brain tissue. We analyzed the datasets with one of the supervised classifiers, artificial neural networks (ANNs). The samples were subdivided into training and testing sets. Quality filtering and stepwise forward selection identified 14 probes as predictors of the diagnosis. ANNs were then trained with the selected probes as the input and the training set for known diagnosis as the output. The constructed model achieved 91.2% diagnostic accuracy in the training set and 87.9% accuracy in the hold-out testing set. On the other hand, hierarchical clustering, a standard but unsupervised classifier, failed to separate patients and controls. These results suggest analysis of a blood-based gene expression signature with the supervised classifier, ANNs, might be a diagnostic tool for schizophrenia. (C) 2009 Elsevier B.V. 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.

Several investigations have reported that the translin-associated factor X gene (TSNAX)/disrupted-inschizophrenia-1 gene (DISC1) was associated with major psychiatric disorders including schizophrenia, bipolar disorder ( BP), and major depressive disorder (MDD). TSNAX is located immediately upstream of DISC1, and has been shown to undergo intergenic splicing with DISC1. It thus may also be influenced by translocation. To our knowledge, there are no reported gene-based association analyses between TSNAX and mood disorders in the Japanese population. We conducted a case-control study of Japanese samples (158 bipolar patients, 314 major depressive disorder patients, and 811 controls) with three tagging SNPs in TSNAX, selected using HapMap database. In addition, we performed an association analysis between TSNAX and the efficacy of fluvoxamine treatment in 120 Japanese patients with MDD. The MDD patients in this study had scores of 12 or higher on the 17 items of the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D). We defined a clinical response as a decrease of more than 50% in baseline SIGH-D within 8 weeks, and clinical remission as an SIGH-D score of less than 7 at 8 weeks. We found an association between rs766288 in TSNAX and female MDD in the allele/genotype analysis. However, we did not find any association between TSNAX and BP or the fluvoxamine therapeutic response in MDD in the allele/genotype analysis or haplotype analysis. Our results suggest that rs766288 in TSNAX may play a role in the pathophysiology of female MDD in the Japanese population. A replication study using larger samples may be required for conclusive results, since our sample size was small.

Background: Copy number variants (CNVs) have been shown to increase the risk to develop schizophrenia. The best supported findings are at 1q21.1, 15q11.2, 15q13.3, and 22q11.2 and deletions at the gene neurexin 1 (NRXN1). Methods: In this study, we used Affymetrix 5.0 arrays to investigate the role of rare CNVs in 575 patients with schizophrenia and 564 control subjects from Japan. Results: There was a nonsignificant trend for excess of rare CNVs in schizophrenia (p = .087); however, we did not confirm the previously implicated association for very large CNVs (>500 kilobase [kb]) in this population. We provide support for three previous findings in schizophrenia, as we identified one deletion in a case at 1q21.1, one deletion within NRXN1, and four duplications in cases and one in a control subject at 16p13.1, a locus first implicated in autism and later in schizophrenia. Conclusions: In this population, we support some of the previous findings in schizophrenia but could not find an increased burden of very large (>500 kb) CNVs, which was proposed recently. However, we provide support for the role of CNVs at 16p13.1, 1q21.1, and NRXN1.

Background: Several investigations have reported associations the serotonin 1A (5-HT1A) receptor to schizophrenia and psychotic disorders, making 5-HT1A receptor gene (HTR1A) an adequate candidate gene for the pathophysiology of schizophrenia and methamphetamine (METH)-induced psychosis. Huang and colleagues reported that rs6295 in HTR1A was associated with schizophrenia. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. It may indicate that METH-induced psychosis and schizophrenia have common susceptibility genes. In support of this hypothesis, we reported that the V-act murine thymoma viral oncogene homologue I (AKT1) gene was associated with METH-induced psychosis and schizophrenia in the Japanese population. Furthermore, we conducted an analysis of the association of HTR1A with METH-induced psychosis. Method: Using one functional SNP (rs6295) and one tagging SNP (rs878567), 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: Rs878567 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this significance remained after Bonferroni correction. In addition, we detected an association between rs6295 and rs878567 in HTR1A and METH-induced psychosis patients in the haplotype-wise analysis. Although we detected an association between rs6295 and METH-induced psychosis patients, this significance disappeared after Bonferroni correction. Conclusion: HTR1A may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population. However, because we did not perform a mutation scan of HTR1A, a replication study using a larger sample may be required for conclusive results. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.

Prepulse inhibition (PPI) deficit. the acoustic startle reflex (ASR) and habituation (HAB) impairment are considered to be endophenotypes for schizophrenia. The recent two studies have reported that a PPI deficit was detected in Japanese schizophrenic patients. We replicated that study using larger samples (115 schizophrenic patients and 111 normal controls) than the original study and a method same as original study. A startle response monitoring system was used to deliver acoustic startle stimuli, and to record and score the electromyographic activity of the orbicularis oculi muscle. We evaluated the startle measures of mean magnitude of ASR, HAB, and PPI at prepulse sound pressure intensities of 82 dB (PPI82),86 dB (PPI86), and 90 dB (PPI90) ASR was significantly different between schizophrenic patients and controls HAB and all PPI session data from schizophrenic patients were significantly lower than in controls. in addition, we detected significant differences for ASR, HAB and each PPI (82, 86 and 90 dB) between schizophrenic patients and controls with the use of multiple regression analysis. The gender and smoking state were not correlated with ASR. HAB or any PPI in multiple regression analysis. In conclusion, we were able to replicate the finding of HAB impairment and PPI deficit in chronic Japanese schizophrenic patients (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved

Several genetic studies have shown an association between the 5-HT1A receptor gene (HTR1A) and major depressive disorder (MDD); however, results have been rather inconsistent. Moreover, to our knowledge, no association study on HTR1A and MDD in the Japanese population has been reported. Therefore, to evaluate the association between HTR1A and MDD, we conducted a case-control study of Japanese population samples with two single-nucleotide polymorphisms (SNPs), including rs6295 (C-1019G) in HTR1A. In addition, we conducted a meta-analysis of rs6295, which has been examined in other papers. Using one functional SNP (rs6295) and one tagging SNP (rs878567) selected with the HapMap database, we conducted a genetic association analysis of case-control samples (331 patients with MDD and 804 controls) in the Japanese population. Seven population-based association studies, including this study, met our criteria for the meta-analysis of rs6295. We found an association between rs878567 and Japanese MDD patients in the allele-wise analysis, but the significance of this association did not remain after Bonferroni's correction. We also did not detect any association between HTR1A and MDD in the allele/genotype-wise or haplotype-wise analysis. On the other hand, we detected an association between rs6295 and MDD in the meta-analysis (P(Z)=0.0327). In an explorative analysis, rs6295 was associated with Asian MDD patients after correction for multiple testing (P(Z)=0.0176), but not with Caucasian MDD patients (P(Z)=0.138). Our results suggest that HTR1A may not have a role in the pathophysiology of Japanese MDD patients. On the other hand, according to the meta-analysis, HTR1A was associated with MDD patients, especially in the Asian population. Journal of Human Genetics (2009) 54, 629-633; doi:10.1038/jhg.2009.84; published online 4 September 2009

Recently the clock genes have been reported to play some roles in neural transmitter systems, including the dopamine system, as well as to regulate circadian rhythms. Abnormalities in both of these mechanisms are thought to be involved in the pathophysiology of major mental illness such as schizophrenia and mood disorders including bipolar disorder (BP) and major depressive disorder (MDD). Recent genetic studies have reported that CLOCK, one of the clock genes, is associated with these psychiatric disorders. Therefore, we investigated the association between the six tagging SNPs in CLOCK and the risk of these psychiatric disorders in Japanese patients diagnosed with schizophrenia (733 patients), BP (149) and MDD (324), plus 795 Japanese controls. Only one association, with schizophrenia in females, was detected in the haplotype analysis (P = 0.0362). However, this significance did not remain after Bonferroni correction (P = 0.0724). No significant association was found with BP and MDD. In conclusion, we suggest that CLOCK may not play a major role in the pathophysiology of Japanese schizophrenia, BP and MDD patients. However, it will be important to replicate and confirm these findings in other independent studies using large samples.

Background: A recent study reported an association between rs2234693, which influences enhancer activity levels in estrogen receptor alpha gene (ESR1), and schizophrenia. This study reported that schizophrenic patients with the CC genotype have significantly lower ESR1 mRNA levels in the prefrontal cortex than patients with other genotypes. The symptoms of methamphetamine induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an association analysis of rs2234693 with Japanese methamphetamine induced psychosis patients. Method: Using rs2234693, we conducted a genetic association analysis of case-control samples (197 methamphetamine induced psychosis patients and 197 healthy controls). The age and sex of the control subjects did not differ from those of the methamphetamine induced psychosis patients. Results: We detected a significant association between ESR1 and methamphetamine induced psychosis patients in allele/genotype-wise analysis. For further interpretation of these associations, we performed single marker analysis of subjects divided by sex. Rs2234693 was associated with male methamphetamine induced psychosis. Discussion: Our results suggest that rs2234693 in ESR1 may play a role in the pathophysiology of Japanese methamphetamine induced psychosis patients. Crown Copyright (C) 2009 Published by Elsevier Inc. All rights reserved.

Background: Several lines of evidence implicate abnormalities in glutamate neural transmission in the pathophysiology of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BP). Preclinical antidepressant effects were also reported for group 11 metabotropic glutamate receptor (Group 11 mGluRs) antagonists show dose-dependent antidepressant-like effects in murine models of depression. Also, it has been suggested that abnormalities in the hypothalamic-pituitary-adrenal axis and serotonergic neural transmission are important mechanisms in the pathophysiology of mood disorders. Group 11 mGluRs play an important role in regulating the function of these mechanisms. From these results, it has been suggested that abnormalities in Group 11 mGluRs might be involved in the pathophysiology of mood disorders, including (MDD) and BP, and may influence the clinical response to treatment with SSRIs in MDD. Therefore, we studied the association between Group 11 mGluR genes (GRM2 and GRM3) and mood disorders and the efficacy of fluvoxamine treatment in Japanese MDD patients. Materials and methods: Using three tagging SNPs in GRM2 and an SNP (rs6465084) reported functional variant in GRM3, we conducted a genetic association analysis of case-control samples (325 MDD patients, 155 BP Patients and 802 controls) in the Japanese population.. In addition, we performed an association analysis of GRM2 and GRM3 and the efficacy of fluvoxamine treatment in 117 Japanese patients with MDD. The MDD patients in this study had scores of 12 or higher on the 17 items of the Structured interview Guide for Hamilton Rating Scale for Depression (SIGH-D). We defined a clinical response as a decrease of more than 50% in baseline SIGH-D within 8 weeks, and clinical remission as an SIGH-D score of less than 7 at 8 weeks, Results: We found an association between rs6465084 in GRM3 and MDD in the allele-wise analysis after Bonferroni's correction (P-value = 0.0371). However, we did not find any association between GRM3 and BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise analysis. We also did not detect any association between GRM2 and MDD, BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise or haplotype-wise analysis. Discussion: We detected an association between only one marker (rs6465084) in GRM3 and Japanese MDD patients. However, because we did not perform an association analysis based on ID and a mutation scan of GRM3, a replication study using a larger sample and based on LD may be required for conclusive results. Crown Copyright (C) 2009 Published by Elsevier Inc. All rights reserved.

The neuregulin 1 gene (NRG1) has been identified as a candidate gene for schizophrenia in a linkage study in the Icelandic population. Recent evidence also suggested that it might be related to the neurodevelopmental hypothesis and glutamate hypothesis for schizophrenia. Because the symptomatology of methamphetamine (METH) use disorder with accompanying psychosis is similar to that of patients with schizophrenia, NRG1 is an appropriate candidate gene for METH-induced psychosis. We conducted a case-control association study between NRG1 and MEM-induced psychosis in a Japanese population (184 subjects with MEM-induced psychosis and 534 controls). Written informed consent was obtained from each subject. We selected four SNPs (SNP8NRG221533, SNP8NRG241930, SNP8NRG243177, and rs3924999) in NRG1 from previous reports. No significant association was found between NRG1 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, NRG1 might not contribute to the risk of METH-induced psychosis in the Japanese population. (C) 2009 Elsevier Inc. All rights reserved.