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Masataka Otake,1 Shin Ono,1 Yuichiro Watanabe,1 Koichiro Kumagai,1 Koji Matsuzawa,1 Hiroyuki Kasahara,1 Masaya Ootake,1 Takuro Sugai,1,2 Toshiyuki Someya1 1Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Japan; 2Murakami Hamanasu Hospital, Murakami, Niigata, JapanCorrespondence: Yuichiro Watanabe, Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-ichibancho, Chuo-ku, Niigata, 951-8510, Japan, Tel +81-25-227-2213, Fax +81-25-227-0777, Email yuichiro@med.niigata-u.ac.jpPurpose: There is little evidence regarding the effects of dental status on body mass index (BMI) in inpatients with schizophrenia. Thus, we performed a cross-sectional study to explore the associations between the number of remaining teeth and BMI in Japanese inpatients with schizophrenia.Patients and Methods: We performed multiple regression analysis to assess the effects of potential predictors (age, sex, number of remaining teeth, number of antipsychotics prescribed, chlorpromazine equivalent dose, and antipsychotic type) on BMI in 212 inpatients with schizophrenia. We then compared the number of remaining teeth between inpatients with schizophrenia and the Japanese general population (3283 individuals) from the Japan Dental Diseases Survey 2016, using an analysis of covariance with age and sex as covariates.Results: Multiple regression analysis showed that the number of remaining teeth and the number of antipsychotics prescribed were significantly correlated with BMI (standardized regression coefficient = 0.201 and 0.235, respectively). In the analysis of covariance, inpatients with schizophrenia had significantly fewer remaining teeth compared with the Japanese general population (mean 14.8 [standard deviation: 10.9] vs mean 23.0 [standard deviation: 8.1]).Conclusion: These results suggested that tooth loss and antipsychotic polypharmacy affect BMI in inpatients with schizophrenia, and that inpatients with schizophrenia lose more teeth compared with the general population.Keywords: antipsychotic polypharmacy, body mass index, oral health, tooth loss

Koyo Hashijiri,1 Yuichiro Watanabe,1 Naoki Fukui,1 Takaharu Motegi,1 Maki Ogawa,1 Jun Egawa,1 Takayuki Enomoto,2 Toshiyuki Someya1 1Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 2Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, JapanCorrespondence: Yuichiro Watanabe Email yuichiro@med.niigata-u.ac.jpPurpose: Identification of pregnant women with bonding difficulties is important to provide early intervention. However, few studies have examined the utility of self-report questionnaires that assess mother–infant bonding as screening tools for bonding difficulties. This longitudinal study aimed to identify pregnant women with bonding difficulties using the Japanese version of the Mother-to-Infant Bonding Scale (MIBS-J) and to estimate its optimal cutoff points in the peripartum period.Patients and Methods: A total of 1301 pregnant women completed the MIBS-J and Hospital Anxiety and Depression Scale (HADS) at three time points: first trimester (T1; approximately 12– 15 weeks gestation), third trimester (T2; approximately 30– 34 weeks gestation), and postpartum (T3; approximately 4 weeks postpartum). A two-step cluster analysis was conducted to classify pregnant women based on their MIBS-J subscale scores at the three time points. Based on the cluster analysis results, receiver operating characteristic curve analysis was performed to estimate the optimal cutoff scores for the MIBS-J total score at each time point.Results: The two-step cluster analysis produced two clusters: Cluster 1 (n = 824) and Cluster 2 (n = 477). Both the MIBS-J and HADS scores were significantly higher in Cluster 2 than in Cluster 1 at all time points. The MIBS-J tentative cutoff points were 3/4, 3/4, and 2/3 at T1, T2, and T3, respectively.Conclusion: We identified two distinct groups across the perinatal period: pregnant women with bonding difficulties and pregnant women with normal bonding. Our findings suggest the usefulness of the MIBS-J as a screening tool to identify bonding difficulties during pregnancy.Keywords: bonding difficulties, cluster analysis, HADS, MIBS-J, ROC analysis

Maki Ogawa,1 Yuichiro Watanabe,1 Takaharu Motegi,1 Naoki Fukui,1 Koyo Hashijiri,1 Ryusuke Tsuboya,1 Takuro Sugai,1 Jun Egawa,1 Rie Araki,2 Kazufumi Haino,3 Masayuki Yamaguchi,3 Koji Nishijima,4 Takayuki Enomoto,3 Toshiyuki Someya1 1Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 2Nursing, Niigata University Medical and Dental Hospital, Niigata, Japan; 3Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 4General Center for Perinatal, Maternal and Neonatal Medicine, Niigata University Medical and Dental Hospital, Niigata, JapanCorrespondence: Yuichiro WatanabeDepartment of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, JapanTel +81-25-227-2213Fax +81-25-227-0777Email yuichiro@med.niigata-u.ac.jpPurpose: The Hospital Anxiety and Depression Scale (HADS) is a self-report questionnaire widely used to assess anxiety and depression. To the best of our knowledge, only four studies have examined the factor structure of the HADS for assessing pregnant women, with conflicting results. This study aimed to assess the factor structure and measurement invariance of the HADS for use with pregnant Japanese women.Participants and Methods: A total of 936 pregnant Japanese women completed the HADS questionnaire at three time points: the first and third trimester of pregnancy, and postpartum. We examined the factor structure of the HADS in Group 1 (n = 466) using exploratory factor analysis (EFA). We then compared the models identified in Group 1 with those from previous studies using confirmatory factor analysis (CFA) in Group 2 (n = 470). We performed multiple-group CFA for Group 2 to test the measurement invariance of the best-fit model across the three time points.Results: The EFA for the Group 1 data at the three time points revealed a two-factor model. In the CFA, the two-factor model from Group 1 showed the best fit with the data at the three time points. In the multiple-group CFA for Group 2, we confirmed the configural and metric invariance of the two-factor model across the three time points.Conclusion: Our findings provide evidence for a two-factor structure and weak measurement invariance of the HADS in pregnant Japanese women during the peripartum period.Keywords: confirmatory factor analysis, exploratory factor analysis, Hospital Anxiety and Depression Scale

Takaharu Motegi,1 Yuichiro Watanabe,1 Naoki Fukui,1 Maki Ogawa,1 Koyo Hashijiri,1 Ryusuke Tsuboya,1 Takuro Sugai,1 Jun Egawa,1 Rie Araki,2 Kazufumi Haino,3 Masayuki Yamaguchi,3 Koji Nishijima,4 Takayuki Enomoto,3 Toshiyuki Someya1 1Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 2Nursing, Niigata University Medical and Dental Hospital, Niigata, Japan; 3Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 4General Center for Perinatal, Maternal and Neonatal Medicine, Niigata University Medical and Dental Hospital, Niigata, JapanCorrespondence: Yuichiro WatanabeDepartment of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-Ku, Niigata 951-8510, JapanTel +81-25-227-2213Fax +81-25-227-0777Email yuichiro@med.niigata-u.ac.jpPurpose: Postpartum depression is a well-known risk factor, and postpartum anxiety and parity are potential risk factors, for mother–infant bonding disorder. However, few studies have focused on the relationships among these factors and mother–infant bonding. This cross-sectional study explored the associations between depression, anxiety and parity, and mother–infant bonding.Materials and Methods: Japanese mothers, both primiparas and multiparas, completed the Mother-to-Infant Bonding Scale (MIBS) and the Hospital Anxiety and Depression Scale (HADS) one month after childbirth. We performed a stepwise multiple regression analysis with the forward selection method to assess the effects of HADS anxiety and depression scores and parity as independent variables on mother–infant bonding as the dependent variable.Results: A total of 2379 Japanese mothers (1116 primiparas and 1263 multiparas) took part in the study. MIBS score (2.89 ± 2.68 vs 1.60 ± 2.11; p < 0.0001) was significantly higher in primiparas than in multiparas. HADS anxiety (6.55 ± 4.06 vs 4.63 ± 3.41; p < 0.0001) and depression (6.56 ± 3.43 vs 5.98 ± 3.20; p < 0.0001) scores were also significantly higher in primiparas than in multiparas. A stepwise multiple regression analysis with the forward selection method revealed that HADS depression and anxiety scores and parity were significantly associated with MIBS score (p = 0.003, 0.015 and 0.023).Conclusion: Depression, anxiety and primiparity were negatively associated with mother–infant bonding one month after childbirth.Keywords: HADS, Japanese, MIBS, parity, postpartum

Norio Sugawara,1,2 Norio Yasui-Furukori,1,2 Manabu Yamazaki,3 Kazutaka Shimoda,1,2 Takao Mori,3 Takuro Sugai,2,4 Hiroshi Matsuda,3 Yutaro Suzuki,2,4 Yuji Ozeki,2,5 Kurefu Okamoto,3 Toyoaki Sagae,3,6 Toshiyuki Someya2,4 1Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi 321-0293, Japan; 2Japanese Society of Clinical Neuropsychopharmacology, Chiyoda-ku, Tokyo 101-0003, Japan; 3Japan Psychiatric Hospital Association, Minato-ku, Tokyo 108-8554, Japan; 4Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan; 5Department of Psychiatry, Shiga University of Medical Science, Otsu, Shiga 520-2134, Japan; 6Department of Health and Nutrition, Yamagata Prefectural Yonezawa University of Nutrition Sciences, Yonezawa, Yamagata 992-0025, JapanCorrespondence: Norio SugawaraDepartment of Psychiatry, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, JapanTel +81-28-287-2153 (extension: 7141)Fax +81-28-286-5187Email nsuga3@dokkyomed.ac.jpBackground: Reliable and easy screening for metabolic syndrome (MetS) is important for patients with schizophrenia. The aim of this study was to assess the predictive utility of body mass index (BMI) for MetS among patients with schizophrenia in Japan.Methods: In total, 8468 patients (4705 males, 3763 females) with schizophrenia or schizoaffective disorders based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), or the International Classification of Diseases, tenth revision (ICD-10), were assessed for MetS using the criteria of the National Cholesterol Education Program Adult Treatment Panel III (ATP III-A). We applied a stratum-specific likelihood ratio (SSLR) analysis, which is independent of the prevalence of the target disease.Results: The mean (± standard deviation) age of these patients was 57.4 ± 13.5 years. The prevalence of MetS was 20.4%. Among males, the SSLRs predicting MetS were 0.03 (95% CI 0.02– 0.06), 0.54 (95% CI 0.48– 0.60), 2.77 (95% CI 2.44– 3.14) and 8.75 (95% CI 7.40– 10.36) for BMI < 20 kg/m2, 20 kg/m2 ≤ BMI < 25 kg/m2, 25 kg/m2≤ BMI < 28 kg/m2, and 28 kg/m2≤BMI, respectively. For females, the SSLRs predicting MetS were 0.08 (95% CI 0.05– 0.12), 0.73 (95% CI 0.66– 0.82), 2.50 (95% CI 2.16– 2.90) and 4.83 (95% CI 4.12– 5.67) for the same BMI categories, respectively.Conclusion: The predictive utility of BMI is confirmed, and BMI has more predictive value in males than in females. Patients with a BMI of 28 kg/m2 or greater had a significantly higher SSLR than those with a BMI less than 28 kg/m2.Keywords: body mass index, metabolic syndrome, schizoaffective disorder, schizophrenia

Hirofumi Igeta,1 Yuichiro Watanabe,1 Ryo Morikawa,1 Masashi Ikeda,2 Ikuo Otsuka,3 Satoshi Hoya,1 Masataka Koizumi,1 Jun Egawa,1 Akitoyo Hishimoto,3 Nakao Iwata,2 Toshiyuki Someya11Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 2Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan; 3Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Hyogo, JapanCorrespondence: Yuichiro WatanabeDepartment of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-ichibancho, Chuo-ku, Niigata 951-8510, JapanTel +81 25 227 2213Fax +81 25 227 0777Email yuichiro@med.niigata-u.ac.jpPurpose: Whole-exome sequencing (WES) of multiplex families is a promising strategy for identifying causative variations for common diseases. To identify rare recessive risk variations for schizophrenia, we performed a WES study in a consanguineous family with affected siblings. We then performed follow-up sequencing of SPATA7 in schizophrenia-affected families. In addition, we performed a case-control study to investigate association between SPATA7 variations and schizophrenia.Patients and methods: WES was performed on two affected siblings and their unaffected parents, who were second cousins, of a multiplex schizophrenia family. Subsequently, we sequenced the coding region of SPATA7, a potential risk gene identified by the WES analysis, in 142 affected offspring from 137 families for whom parental DNA samples were available. We further tested rare recessive SPATA7 variations, identified by WES and sequencing, for associations with schizophrenia in 2,756 patients and 2,646 controls.Results: Our WES analysis identified rare compound heterozygous missense SPATA7 variations, p.Asp134Gly and p.Ile332Thr, in both affected siblings. Sequencing SPATA7 coding regions from 137 families identified no rare recessive variations in affected offspring. In the case-control study, we did not detect the rare compound heterozygous SPATA7 missense variations in patients or controls.Conclusion: Our data does not support the role of the rare compound heterozygous SPATA7 missense variations p.Asp134Gly and p.Ile332Thr in conferring a substantial risk of schizophrenia.Keywords: Japanese, multiplex schizophrenia family, next-generation sequencing, recessive variations

Norio Sugawara,1–3 Norio Yasui-Furukori,2,3 Manabu Yamazaki,4 Kazutaka Shimoda,3,5 Takao Mori,4 Takuro Sugai,3,6 Hiroshi Matsuda,4 Yutaro Suzuki,3,6 Yoshitake Minami,4 Yuji Ozeki,3,5 Kurefu Okamoto,4 Toyoaki Sagae,7 Toshiyuki Someya3,6 1Aomori Prefectural Center for Mental Health and Welfare, Aomori, 2Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, 3Japanese Society of Clinical Neuropsychopharmacology, 4Japan Psychiatric Hospital Association, Tokyo, 5Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, 6Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 7Department of Health and Nutrition, Yamagata Prefectural Yonezawa University of Nutrition Sciences, Yonezawa, Japan Background: Metabolic syndrome is a growing concern among patients with schizophrenia because metabolic abnormalities are widely regarded as a major risk factor for cardiovascular disease and premature death. The current study assessed attitudes toward metabolic adverse events among patients with schizophrenia. Methods: A brief questionnaire was constructed to investigate patient recognition of the following broad areas: dietary habits, lifestyle, self-monitoring, knowledge, and medical practice. Between January 2012 and June 2013, questionnaires were sent to patients associated with 520 outpatient facilities and 247 inpatient facilities belonging to the Japan Psychiatric Hospital Association. All of the participants (n=22,072; inpatients =15,170, outpatients =6,902) were diagnosed with schizophrenia based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, or the International Classification of Diseases, tenth revision. Results: Approximately 55.0% (8,069/14,669) of inpatients and 44.8% of outpatients (2,978/6,649) reported that they did not exercise at all. Although 60.9% (4,116/6,760) of outpatients reported that they felt obese, only 35.6% (5,261/14,794) of inpatients felt obese. More than half of the inpatients (51.2%; 7,514/14,690) and outpatients (60.8%; 4,086/6,721) hoped to receive regular blood tests to prevent weight gain and diseases such as diabetes. Conclusion: Although more than half of patients hoped to prevent weight gain and diabetes, only a minority of patients were mindful of eating balanced meals and having physical exercise. Educational efforts and the promotion of the best pharmacotherapy and monitoring practices are needed for patients with schizophrenia. Keywords: metabolic syndrome, schizophrenia, attitude, Japan

Ikuo Otsuka,1 Yuichiro Watanabe,2 Akitoyo Hishimoto,1 Shuken Boku,1 Kentaro Mouri,1 Kyoichi Shiroiwa,1 Satoshi Okazaki,1 Ayako Nunokawa,2 Osamu Shirakawa,3 Toshiyuki Someya,2 Ichiro Sora1 1Department of Psychiatry, Graduate School of Medicine, Kobe University, Kobe, 2Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, 3Department of Neuropsychiatry, School of Medicine, Kinki University, Osaka, Japan Background: Cadherin13 (CDH13) is a glycosylphosphatidylinositol-anchored cell adhesion molecule that plays a crucial role in morphogenesis and the maintenance of neuronal circuitry. CDH13 has been implicated in the susceptibility to a variety of psychiatric diseases. A recent genome-wide association study using Danish samples showed, for the first time, the involvement of a single nucleotide polymorphism (SNP) of CDH13 (intronic SNP rs8057927) in schizophrenia. Here, we investigated the association between other SNPs of CDH13 and schizophrenia and tried to replicate the association for the SNP of rs8057927, in the Japanese population.Methods: Using TaqMan® SNP genotyping assays, five tag SNPs (rs12925602, rs7193788, rs736719, rs6565051, and rs7204454) in the promoter region of CDH13 were examined for their association with schizophrenia in two independent samples. The first sample comprised 665 patients and 760 controls, and the second sample comprised 677 patients and 667 controls. One tag SNP for rs8057927 was also examined for the association with schizophrenia in the first sample set.Results: A GACAG haplotype of the five SNPs in the promoter region of CDH13 was significantly associated with schizophrenia in the first sample set (P=0.016 and corrected P=0.098). A combined analysis of the GACAG haplotype with the second sample set enhanced the significance (P=0.0026 and corrected P=0.021). We found no association between rs8057927 and schizophrenia in the first sample set.Conclusion: Our results suggest that CDH13 may contribute to the genetic risk of schizophrenia. Further replication on the association of CDH13 with schizophrenia and functional studies are required to confirm the current findings. Keywords: CDH13, promoter region, haplotype, SNP