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Sonoko Harada,1,2 Hitoshi Sasano,1 Shoko Ueda,1 Yuuki Sandhu,1 Sumiko Abe,1 Yuki Tanabe,1 Kyoko Shima,3 Tetsuya Kuwano,3 Yuya Uehara,3 Takayoshi Inoue,3 Ko Okumura,2 Kazuhisa Takahashi,1,4 Norihiro Harada1,2,4 1Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan; 2Atopy (Allergy) Research Center, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan; 3Biological Science Research, Kao Corporation, Tochigi, Japan; 4Research Institute for Diseases of Old Ages, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, JapanCorrespondence: Norihiro Harada, Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3 hongo, Bunkyo-ku, Tokyo, 113-8431, Japan, Tel +81-3-5802-1063, Fax +81-3-5802-1617, Email nor@juntendo.ac.jpBackground: Examining human coding and non-coding RNAs present in skin surface lipids (SSL-RNAs) offers a promising approach to understanding the physiological state of the skin. Benralizumab treatment can reduce exacerbations and improve symptom control and quality of life in patients with severe eosinophilic asthma. Although this treatment effectively depletes peripheral blood eosinophils, the impact of benralizumab on SSL-RNA remains completely unknown.Objective: To investigate the effects of benralizumab treatment on SSL-RNA profiles in patients with severe asthma.Methods: Skin samples were non-invasively collected from patients before and after one year of benralizumab treatment. Sixteen patients were enrolled, but the SSL-RNA analysis was only feasible for five patients due to collection challenges, mainly in female participants.Results: Following benralizumab treatment, asthma symptoms, exacerbation rates, and lung function parameters improved. Peripheral blood eosinophils were completely depleted and serum eotaxin-1 levels increased. SSL-RNA analysis revealed differential expression of 134 genes, with significant downregulation of immune-related pathways and genes associated with neutrophilic inflammation.Conclusion: These findings suggest a suppression of both type 2 and non-type 2 inflammation in response to benralizumab treatment, with potential implications for asthma management. However, the limitations of the study include a small sample size and challenges in sebum collection, particularly among female participants. Although the noninvasive nature of this sampling method makes it attractive for both research and clinical applications, additional studies are needed to fully investigate the potential of SSL-RNA analysis as a noninvasive biomarker to assess treatment response in asthma.Keywords: asthma, benralizumab, skin surface lipid, sebum, type 2 inflammation

Yunosuke Usui,1 Miki Ono,1 Rintaro Nibuya,1 Masayuki Kikkawa,1 Shunichiro Ito,1 Chihiro Morishita,1 Mina Honyashiki,1 Yu Tamada,1,2 Takeshi Inoue,1 Jiro Masuya1 1Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan; 2Department of Psychiatry, Tokyo Medical University Hachioji Medical Center, Hachioji-shi, Tokyo, JapanCorrespondence: Jiro Masuya, Department of Psychiatry, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan, Tel +81-(0)3-3342-6111, Email j-masuya@tokyo-med.ac.jpBackground: Prior research has shown that inappropriate childhood nurturing experiences (low care and high overprotection), trait anxiety, and depressive rumination are risk factors for depression. However, no studies to date have analyzed the overall association between these factors and depressive symptoms. In the present study, we hypothesized that depressive rumination mediates the impacts of inappropriate childhood nurturing experiences on depressive symptoms, and that these mediating effects are moderated by trait anxiety, and tested these hypotheses in adult volunteers.Methods: The subjects were adult volunteers who were investigated between April 2017 and April 2018. A self-report questionnaire on demographic data, childhood nurturing experiences, trait anxiety, depressive rumination, and depressive symptoms was distributed to conduct the survey, and written informed consent and valid responses were obtained from 585 subjects. Mediation and moderated-mediation analyses were performed by SPSS 28 and macro PROCESS 4.0 software. This study was approved by the Ethics Committee of Tokyo Medical University.Results: Parental care showed a significant negative indirect effect on depressive symptoms via its effect on depressive rumination (p < 0.01), whereas parental overprotection showed the opposite effect (p < 0.01). Furthermore, the mediation effect of depressive rumination on depressive symptoms was increased by trait anxiety (p < 0.05).Conclusion: Our present study demonstrated that the main factor affecting depressive symptoms is inappropriate childhood nurturing experiences, which indirectly enhance depression by intensifying depressive rumination, and that depressive rumination and trait anxiety mutually reinforce each other to enhance depressive symptoms. These findings may be useful for the prevention of depressive symptoms. Large-scale prospective studies are needed to confirm the causal associations among these factors in the future.Keywords: childhood parenting experiences, depressive rumination, trait anxiety, depressive symptoms, moderated-mediation analysis

Ai Kozaki,&ast; Rishu Inoue,&ast; Naoko Yaji,&ast; Koichi Nishiyama,&ast; Toshu Inoue&ast; Olympia Eye Hospital, Tokyo, Japan&ast;These authors contributed equally to this workCorrespondence: Ai Kozaki, Olympia Eye Hospital, 2-18-12 Jingumae, Shibuya-ku, Tokyo, 150-0001, Japan, Tel +81-3-3746-8981, Fax +81-3-3746-8830, Email kouzaki@olympia.netPurpose: To evaluate the efficacy of subcutaneous injection of triamcinolone acetonide (SCTA) in treating upper eyelid retraction and swelling in patients with thyroid eye disease (TED).Patients and Methods: This case series included consecutive patients (aged 16– 69 years, monitored from June 2012 to December 2015) with TED-related eyelid symptom and without an enlarged extraocular muscle on magnetic resonance imaging (MRI). SCTA (0.5 mL, 40 mg/mL) was administered to target the orbital fat around the levator palpebrae superioris (LPS) muscle. Patients who did not exhibit improvement after the first trial received an additional injection. Follow-up was conducted for 12 months with 3-month intervals. Eyelid retraction, eyelid swelling, and eyelid lag were evaluated at each follow-up visit.Results: In total, 116 eyelids of 102 patients were analyzed. SCTA led to significant improvement in 93% of eyes (108/116), disappearance of eyelid symptoms (74%, 87%, and 73% in retraction, swelling, and lag, respectively), and improvement of scores (from 1.64 to 0.12, 1.32 to 0.26, and 1.72 to 0.30, respectively). Improvement in eyelid symptoms was observed in eight eyes; however, additional steroid therapy was required in these cases due to the emergence of other extraocular muscle inflammation. Additional injection was required in 39.8% of patients. The clinical activity score was lower in the single SCTA group than in the multiple SCTA group (1.5 vs 0.9; p < 0.01). However, the levels of thyroid-stimulating hormone receptor antibody and MRI findings were not significantly different between the two groups. No elevation in intraocular pressure was observed. Eight female patients experienced menstrual disorder.Conclusion: SCTA effectively reduced LPS muscle enlargement and fat tissue swelling in patients with TED. A single SCTA was sufficient in almost 60% of the patients; nevertheless, follow-up is necessary to detect early signs of orbital inflammation even in eyelid-symptom-improved patients.Keywords: Graves’ disease, triamcinolone injection, magnetic resonance imaging, levator palpebrae superioris muscle, inflammation

Yoshio Iwata,1 Miki Ono,1 Yoshitaka Ishii,1 Shunichiro Ito,1 Masayuki Kikkawa,1 Chihiro Morishita,1 Yu Tamada,1,2 Mina Honyashiki,1 Takeshi Inoue,1 Jiro Masuya1 1Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 2Department of Psychiatry, Tokyo Medical University Hachioji Medical Center, Tokyo, JapanCorrespondence: Jiro Masuya, Department of Psychiatry, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan, Tel +81-3-3342-6111, Email j-masuya@tokyo-med.ac.jpBackground: The experience of peer victimization in childhood increases the risk of developing anxiety disorders and depression, risk of suicide, as well as sensitivity to stress, in adulthood. Various personality traits are known to be associated with these effects. However, the influence of trait anxiety on job stress has not yet been reported. In the present study, we tested the hypothesis that the experience of peer victimization in childhood and trait anxiety influence job stress in adulthood.Methods: A questionnaire survey, including State-Trait Anxiety Inventory, Childhood Victimization Rating Scale, and Brief Job Stress Questionnaire, was administered to 566 adult workers. The interrelationship between multiple variables was analyzed by multiple regression analysis and path analysis.Results: In the path model, childhood peer victimization had a positive direct effect on trait anxiety and the psychological and physical stress response (PPSR). Trait anxiety had a positive direct effect on job stressors and PPSR, and job stressors had a positive direct effect on PPSR. Regarding indirect effects, childhood peer victimization had a significant adverse effect on job stressors and PPSR via trait anxiety.Conclusion: Our results showed that childhood peer victimization has a negative impact on job stress in adulthood, which is influenced by trait anxiety. Interventions to address peer victimization in childhood and trait anxiety may reduce job stress in adulthood, and thus contribute to improved occupational mental health and productivity in the workplace.Keywords: job stress, peer victimization, trait anxiety, path analysis, mediation effect

Misaki Endo,1,2 Miki Ono,1 Ayaka Deguchi,1 Yoshio Iwata,1 Yu Tamada,1,3 Jiro Masuya,1 Hajime Tanabe,4 Naoki Hashimoto,5 Takeshi Inoue,1 Mina Honyashiki1 1Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 2Department of Psychiatry, Saitama Prefectural Psychiatric Hospital, Saitama, Japan; 3Department of Psychiatry, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan; 4Faculty of Humanities and Social Sciences, Shizuoka University, Shizuoka, Japan; 5Department of Psychiatry, Hokkaido University, Sapporo, JapanCorrespondence: Miki Ono, Department of Psychiatry, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan, Tel +81-3-3342-6111, Email mikky@tokyo-med.ac.jpBackground: Subjective social status influences anxiety, but at present, the mechanism is not fully understood. It has been reported that negative childhood experiences, such as abuse, can influence depressive symptoms through subjective social status and personality traits, such as self-esteem. A similar mechanism is presumed to underlie anxiety symptoms in adulthood. Therefore, we hypothesized that subjective social status and self-esteem are intermediate factors in the indirect effects of childhood abuse on state anxiety in adulthood, and analyzed the indirect effects via these factors using a path analysis.Subjects and Methods: Child Abuse and Trauma Scale, Subjective Social Status, Rosenberg Self-Esteem Scale, and State-Trait Anxiety Inventory Form Y questionnaires were administered in a self-report format to 404 adult volunteers from January 2014 to August 2014. In addition, a path analysis was conducted to determine whether subjective social status and self-esteem are associated with the indirect effects of childhood abuse on anxiety symptoms in adulthood.Results: Childhood abuse did not directly affect state anxiety in adulthood, but affected state anxiety via subjective social status and self-esteem. Subjective social status affected state anxiety via self-esteem. This model explained 25.2% of the variation in state anxiety in adult volunteers.Conclusion: The present study demonstrated that childhood abuse affects anxiety in adulthood through subjective social status and self-esteem. Therefore, interventions that enhance subjective social status and self-esteem for adults who experienced childhood abuse may help reduce their anxiety.Keywords: childhood abuse, subjective social status, self-esteem, anxiety

Motoki Sonohata,1,2,&ast; Atsushi Doi,3,&ast; Kazuyoshi Uchihashi,4 Akira Hashimoto,2 Sakumo Kii,1 Takao Inoue,5 Masaaki Mawatari1 1Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan; 2Department of Orthopaedic Surgery, Saga Central Hospital, Saga, Japan; 3Department of Rehabilitation, Kumamoto Health Science University, Kumamoto, Japan; 4Department of Surgical Pathology, National Hospital Organization Saga Hospital, Saga, Japan; 5Organization of Research Initiatives, Yamaguchi University, Yamaguchi, Japan&ast;These authors contributed equally to this workCorrespondence: Atsushi Doi, Department of Rehabilitation, Kumamoto Health Science University, 324, Izumi, Kumamoto-kitaku, Kumamoto, 861-5598, Japan, Tel +81-96-275-2111, Email atsushidoi01@gmail.comPurpose: This study used a sciatic nerve injury rat model to investigate the short-term effects of a polyglycolic acid (PGA)-collagen tube for nerve injury in continuity.Materials and Methods: Sixteen female Wistar rats (6– 8 weeks) were used, and the left sciatic nerve was crushed with a Sugita aneurysm clip. Sciatic nerve model rats were randomly categorized into two groups (n = 8; control group, n = 8; nerve wrapping group). Then, we measured four sensory thresholds, magnetically stimulated the lumbar region to induce motor-evoked potentials (MEPs), and evaluated the sciatic nerve histopathologically.Results: In the sensory thresholds, there were significant differences for the main effect in 250 and 2000 Hz stimulation (p = 0.048 and 0.006, respectively). Further, a significant difference was observed with 2000 Hz stimulation at 1 week (p = 0.003). In the heat stimulation, there were significant differences for the main effect in both weeks and groups (p = 0.0002 and 0.0185, respectively). The post-hoc test showed a significant difference between groups only in 2W (p = 0.0283). Three weeks after the surgery, both 2nd and 3rd MEPs waves-related latencies in the nerve wrapping group were significantly shorter than those in the control group (p = 0.0207 and 0.0271, respectively). Histological evaluation of the sciatic nerve revealed considerable differences in the number of axons between the two groups (p = 0.0352).Conclusion: The short-term PGA-collagen tube nerve wrapping facilitated motor and sensory recovery from nerve degeneration in the sciatic nerve injury rat model.Keywords: polyglycolic acid-collagen tube, nerve wrapping, sciatic nerve injury, sensory threshold, motor and sensory recovery

Shunichiro Ito,1 Chihiro Morishita,1 Jiro Masuya,1 Miki Ono,1 Mina Honyashiki,1 Shinji Higashi,1,2 Yu Tamada,1,3 Yota Fujimura,1,3 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Tokyo, 160-0023, Japan; 2Department of Psychiatry, Ibaraki Medical Center, Tokyo Medical University, Ibaraki, 300-0395, Japan; 3Department of Psychiatry, Tokyo Medical University Hachioji Medical Center, Tokyo, 193-0998, JapanCorrespondence: Chihiro Morishita, Department of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan, Tel +81 3 3342 6111, Fax +81 3 3340 4499, Email mchihiro@tokyo-med.ac.jpBackground: Parenting quality experienced in childhood affects depressive symptoms in adulthood, and neuroticism and resilience are attracting attention as personality traits that mediate the effects of parental rearing quality experienced in childhood on adulthood depressive symptoms. However, the interaction between neuroticism and resilience remains unclear. In this study, we hypothesized that resilience and neuroticism are mediators between parental rearing quality experienced in childhood and depressive symptoms in adulthood, and furthermore, that resilience and neuroticism interact with each other in their effects on depressive symptoms. To test these hypotheses, we conducted structural equation modeling and hierarchical multiple regression analysis including interactions in adult volunteers.Methods: A self-administered questionnaire survey was conducted on 528 adult volunteers recruited at Tokyo Medical University for 1 year from April 2017 to April 2018. The Parental Bonding Instrument (PBI), Eysenck Personality Questionnaire-revised short version, Connor-Davidson Resilience Scale, and Patient Health Questionnaire-9 were used as questionnaires, and their scores were analyzed using structure equation modeling. The interaction between resilience and neuroticism was analyzed using hierarchical multiple regression analysis.Results: Structural equation modeling showed that parenting quality (care and overprotection) experienced in childhood had a significant indirect effect on the severity of depressive symptoms in adulthood, mediated by both neuroticism and resilience. Among the subscores of the PBI, “care” showed opposite effects to “overprotection”. Structural equation modeling of “care” and “overprotection” explained 36.9% and 36.6% of the variability in depressive symptoms in adulthood, respectively. Hierarchical multiple regression analysis showed that the negative interaction between neuroticism and resilience had a significant effect on depressive symptom severity in adulthood.Conclusion: The results of this study show that resilience and neuroticism are mediators of the effects from parental child-rearing to depressive symptoms in adulthood. Furthermore, resilience antagonizes the effect of neuroticism on adulthood depressive symptoms.Keywords: parenting, resilience, neuroticism, depressive symptoms, structure equation modeling, hierarchical multiple regression analysis

Itsuki Terao,1 Jiro Masuya,1 Chihiro Morishita,1 Motoki Higashiyama,1 Akiyoshi Shimura,1 Yu Tamada,1,2 Takeshi Inoue,1 Yota Fujimura1 1Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 2Department of Psychiatry, Toranomon Hospital Kajigaya, Kawasaki, Kanagawa, JapanCorrespondence: Chihiro Morishita, Department of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan, Tel +81 3 3342 6111, Fax +81 3 3340 4499, Email mchihiro@tokyo-med.ac.jpPurpose: Depression poses a substantial burden worldwide. Therefore, elucidating the pathophysiological mechanism of depression is important. Sleep disturbance and sleep reactivity are symptoms of depression and are also known to exacerbate depressive symptoms. On the other hand, it is well known that resilience ameliorates depressive symptoms. To our knowledge, there have been no reports to date regarding the interaction effects among sleep disturbance, sleep reactivity, and resilience on depressive symptoms. We hypothesized that resilience buffers the aggravating effects of sleep disturbance and sleep reactivity on depressive symptoms. To test this hypothesis, we conducted hierarchical multiple regression analyses.Subjects and Methods: A total of 584 Japanese adult volunteers were recruited between April 2017 and April 2018 by convenience sampling. Their demographic characteristics, sleep disturbance, sleep reactivity, resilience, and depressive symptoms were investigated using self-administered questionnaires. The data were analyzed using hierarchical multiple regression analyses.Results: Sleep disturbance and sleep reactivity were significantly positively associated with depressive symptoms, whereas resilience was significantly negatively associated with depressive symptoms. Moreover, there was a significant interaction between sleep disturbance or sleep reactivity and resilience on depressive symptoms. Resilience significantly alleviated the aggravating effect of sleep disturbance and sleep reactivity on depressive symptoms.Conclusion: Our results indicate that people with lower resilience have more severe depressive symptoms that are associated with sleep disturbance and sleep reactivity. Therefore, there is a possibility that the enhancement of resilience will buffer the aggravating effects of sleep disturbance and sleep reactivity on depressive symptoms, and that improving sleep quality might alleviate the negative effect of low resilience on depressive symptoms.Keywords: depression, resilience, sleep disturbance, sleep reactivity, CD-RISC

Jiro Masuya,1,&ast; Masahiko Ichiki,1,&ast; Chihiro Morishita,1 Motoki Higashiyama,1 Miki Ono,1 Mina Honyashiki,1 Yoshio Iwata,1 Hajime Tanabe,2 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo, 160-0023, Japan; 2Faculty of Humanities and Social Sciences, Shizuoka University, Suruga-ku, Shizuoka, 422-8529, Japan&ast;These authors contributed equally to this workCorrespondence: Jiro Masuya, Department of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan, Tel +81-3-3342-6111, ext. 5754, Fax +81-3-3340-4499, Email j-masuya@tokyo-med.ac.jpBackground: When assessing patients with depressive and anxiety disorders in psychiatric clinical practice, it is common to encounter children and adolescents who have experienced abuse and victimization. To date, it has been clarified that experiences of “childhood abuse” and “childhood victimization” lead to “neuroticism”, and that neuroticism leads to “adult depressive symptoms”. In this study, we analyzed how these four factors are interrelated.Subjects and Methods: The following self-administered questionnaire surveys were conducted in 576 adult volunteers: Patient Health Questionnaire-9, Eysenck Personality Questionnaire-revised shortened version, Child Abuse and Trauma Scale, and Childhood Victimization Rating Scale. For statistical analysis, Pearson correlation coefficient analysis, t-test, multiple regression analysis, and covariance structure analysis (path analysis) were performed.Results: Path analysis showed that the indirect effects of childhood abuse and childhood victimization on depressive symptoms through neuroticism were statistically significant. In addition, the indirect effects of childhood abuse on neuroticism through childhood victimization were statistically significant. Finally, the indirect effects of childhood abuse on depressive symptoms through the combined paths of childhood victimization and neuroticism were statistically significant.Conclusion: Our results suggest that “childhood abuse (A)” induces changes in the personality trait of “neuroticism (C)” with “childhood victimization (B)” as a mediator, and that these adversities affect the expression of “depressive symptoms in adulthood (D)” through “neuroticism (C)” as a mediator. In other words, to our knowledge, this is the first study to clarify that these four factors are not only individually associated with each other but also cause a chain reaction of A to B to C to D.Keywords: childhood abuse, childhood victimization, neuroticism, depressive symptoms, path analysis

Shogo Hashimoto,1,&ast; Masahiko Ichiki,2,&ast; Yoshitaka Ishii,2,3 Chihiro Morishita,2 Akiyoshi Shimura,2 Ichiro Kusumi,1 Takeshi Inoue,2 Jiro Masuya2 1Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan; 2Department of Psychiatry, Tokyo Medical University, Tokyo, 160-0023, Japan; 3Fuji Psychosomatic Rehabilitation Institute Hospital, Fujinomiya, Shizuoka, 418-0035, Japan&ast;These authors contributed equally to this workCorrespondence: Takeshi Inoue, Tel +81 3 3342 6111, Fax +81 3 3340 4499, Email tinoue@Tokyo-med.ac.jpBackground: Victimization in childhood profoundly influences the mental health of individuals in adulthood, causing depression, anxiety disorder, suicidality, and self-harm, which leads to productivity loss in the workplace, ie, presenteeism. However, the specific effects of victimization on presenteeism remain unclear. We hypothesized that victimization affects the presenteeism of workers through neuroticism and perceived job stressors and analyzed the association among these factors by path analysis.Methods: A questionnaire survey, including demographic and clinical data, Japanese versions of victimization scale in childhood, Brief Job Stress Questionnaire, and Work Limitations Questionnaire (WLQ), was administered to 443 adult volunteers between April 2017 and April 2018 in Tokyo, Japan. Multiple variables were analyzed by multiple regression analysis and path analysis. The Institutional Review Board of Tokyo Medical University approved this study.Results: Path analysis demonstrated that neuroticism and perceived job stressors had direct effects on presenteeism in the WLQ. Victimization indirectly increased presenteeism via neuroticism and its subsequent effects on perceived job stressors. This model accounted for 18% of the variability of presenteeism (R2 = 0.180).Limitations: There may be possible recall bias owing to the self-administration of the questionnaire. In addition, this study had a cross-sectional design, and hence the causal associations among variables should be validated in a prospective study.Conclusion: The present study indicates that the experience of victimization in childhood is a risk factor of adulthood presenteeism, and this effect is mediated by neuroticism and adverse effects on job stressors. These results suggest that multiple factors, including childhood victimization, neuroticism, and job stressors, should be considered when assessing and preventing presenteeism.Keywords: victimization, neuroticism, job stressor, presenteeism, childhood

Makito Miyake,1 Nobutaka Nishimura,1,2 Takuto Shimizu,1,3 Mikiko Ohnishi,4 Masaomi Kuwada,4 Yoshitaka Itami,5 Takeshi Inoue,5 Kenta Ohnishi,6 Yoshihiro Matsumoto,6 Takanori Yoshida,7 Yoshihiro Tatsumi,8 Masatake Shinohara,9 Shunta Hori,1 Yosuke Morizawa,1 Daisuke Gotoh,1 Yasushi Nakai,1 Satoshi Anai,1 Kazumasa Torimoto,1 Katsuya Aoki,1 Tomomi Fujii,10 Nobumichi Tanaka,1,11 Kiyohide Fujimoto1 1Department of Urology, Nara Medical University, Kashihara, Nara, 634-8522, Japan; 2Department of Urology, Okanami General Hospital, Iga, Mie, Japan; 3Department of Urology, Saiseikai Chuwa Hospital, Nara, Japan; 4Department of Urology, Matsusaka Chuo General Hospital, Matsusaka, Mie, Japan; 5Department of Urology, Nara Prefecture General Medical Center, Nara, Japan; 6Department of Urology, Hoshigaoka Medical Center, Hirakata, Osaka, Japan; 7Department of Urology, Tane General Hospital, Osaka, Japan; 8Department of Urology, JCHO Yamato Koriyama Hospital, Koriyama, Nara, Japan; 9Department of Urology, Osaka Gyoumeikan Hospital, Osaka, Japan; 10Department of Diagnostic Pathology, Nara Medical University, Kashihara, Nara, 634-8522, Japan; 11Department of Prostate Brachytherapy, Nara Medical University, Kashihara, Nara, 634-8522, JapanCorrespondence: Makito Miyake, Department of Urology, Nara Medical University, 840 Shijo-cho, Nara, 634-8522, Japan, Tel +81-744-22-3051 (ext 2338), Fax +81-744-22-9282, Email makitomiyake@yahoo.co.jpPurpose: The treatment landscape for advanced, unresectable, or metastatic urothelial carcinoma (aUC) has shifted substantially since the advent of immune checkpoint inhibitors (ICIs). We investigated the extent to which pembrolizumab therapy is superior to conventional chemotherapy as a second-line treatment.Patients and Methods: A multicenter-derived database registered 454 patients diagnosed with aUC between 2008 and 2020. Of these, 94 patients (21%) who received second-line pembrolizumab and 75 (17%) who received second-line chemotherapy but never received third-line or later ICI therapy were included. We compared overall survival (OS) from the initial date of first-line chemotherapy between two groups by adjusting for prognostic factors through propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). The IPTW-adjusted hazard ratio and 95% confidence interval were estimated using a multivariate Cox regression analysis. To identify patients who were more likely to benefit from second-line pembrolizumab than from chemotherapy, we performed a subgroup analysis for OS with an IPTW-adjusted model.Results: The PSM-adjusted comparison showed a significant improvement in the prognosis with second-line pembrolizumab use (P = 0.01). The OS benefit with the advent of pembrolizumab was 8 months (18 months vs 26 months). Multivariable analyses using IPTW adjustment demonstrated that lymph node metastasis (P = 0.001), lung metastasis (P = 0.013), and bone metastasis (P = 0.003) were poor independent prognostic factors, and pembrolizumab use (P = 0.021) was a favorable independent prognostic factor. Subgroup analyses revealed that pembrolizumab was associated with survival benefits over chemotherapy in all subgroups, including young patients (age < 70 years), those who received radical surgery, and those without visceral metastasis.Conclusion: We demonstrated a significant improvement in prognosis after the advent of pembrolizumab for patients with aUC. ICIs should not be restricted based on patient characteristics.Keywords: urinary bladder neoplasms, immunotherapy, chemotherapy, survival, propensity score

Koichiro Watanabe,1 Shinji Fujimoto,2 Tatsuro Marumoto,2 Tadayuki Kitagawa,3 Kazuyuki Ishida,3 Tadashi Nakajima,2 Yoshiya Moriguchi,4 Keita Fujikawa,2 Takeshi Inoue5 1Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, Japan; 2Japan Medical Office, Takeda Pharmaceutical Co., Ltd, Tokyo, Japan; 3Takeda Development Center – Japan, Takeda Pharmaceutical Co., Ltd, Osaka, Japan; 4Medical Affairs, Lundbeck Japan K.K., Tokyo, Japan; 5Department of Psychiatry, Tokyo Medical University, Tokyo, JapanCorrespondence: Koichiro Watanabe, Department of Neuropsychiatry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan, Tel +81-422-47-5511, Fax +81-422-45-4697, Email koichiro@tke.att.ne.jpAim: Anhedonia in major depressive disorder may be resistant to first-line antidepressants. We examined the effect of vortioxetine, a multimodal antidepressant, on anhedonia-like symptoms in Japanese patients with major depressive disorder.Methods: This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20– 75 years with recurrent major depressive disorder and a Montgomery–Åsberg Depression Rating Scale (MADRS) total score of at least 26. The primary outcome was the mean change from baseline to week 8 in anhedonia-like symptoms as measured by MADRS anhedonia factor score, composed of: Q1, apparent sadness; Q2, reported sadness; Q6, concentration; Q7, lassitude; and Q8, inability to feel. Mean change in MADRS total score and anhedonia factor score were compared among treatment groups, with data categorized by median baseline anhedonia factor score (0– 17 or ≥ 18).Results: Data were available for 489 patients. The least-squares mean difference in MADRS anhedonia factor score change from baseline to week 8 versus placebo was − 1.34 for vortioxetine 10 mg (P = 0.0300) and − 1.77 for vortioxetine 20 mg (P = 0.0044). The least-squares mean difference between vortioxetine and placebo in MADRS total score change from baseline to week 8 was − 3.11 (10 mg dose) and − 3.37 (20 mg dose) for patients with a higher baseline anhedonia factor score (≥ 18), and − 2.08 (10 mg) and − 2.61 (20 mg) for patients with a lower baseline score (0– 17).Conclusion: This post hoc analysis suggests that vortioxetine may have therapeutic potential in patients with anhedonia-like symptoms of major depressive disorder. ClinicalTrials.gov identifier for primary study: NCT02389816.Keywords: anhedonia, antidepressant, Japanese, major depressive disorder, vortioxetine

Takeshi Inoue,1 Shinji Fujimoto,2 Tatsuro Marumoto,2 Tadayuki Kitagawa,3 Kazuyuki Ishida,3 Tadashi Nakajima,2 Yoshiya Moriguchi,4 Keita Fujikawa,2 Koichiro Watanabe5 1Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 2Japan Medical Office, Takeda Pharmaceutical Co., Ltd, Tokyo, Japan; 3Takeda Development Center – Japan, Takeda Pharmaceutical Co., Ltd, Osaka, Japan; 4Medical Affairs, Lundbeck Japan K.K., Tokyo, Japan; 5Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, JapanCorrespondence: Takeshi InoueDepartment of Psychiatry, Tokyo Medical University, 6‐7‐1 Nishishinjuku, Shinjuku‐ku, Tokyo, 160‐0023, JapanTel +81-3-3342-6111 (ext. 5754)Fax +81-3-3340-4499Email tinoue@tokyo-med.ac.jpAim: Several weeks of treatment with an antidepressive agent may be required before efficacy is demonstrated in patients with major depressive disorder. This study investigated the predictive value of early partial improvement with vortioxetine for treatment response and remission.Methods: This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, Phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20– 75 years with recurrent major depressive disorder and a Montgomery–Åsberg Depression Rating Scale (MADRS) score of at least 26. The key outcomes were the predictive value of early partial improvement (reduction in MADRS total score of ≥ 20% from baseline to week 2) with vortioxetine for MADRS response (≥ 50% decrease in score from baseline) and remission (decrease in score to ≤ 10) at week 8.Results: Relevant data were available for 478 patients; 62/158 patients receiving placebo, 71/162 receiving vortioxetine 10 mg, and 66/158 receiving vortioxetine 20 mg were early improvers. Early improvers receiving vortioxetine (10 mg or 20 mg) were more likely than non-early improvers to achieve a week 8 response (71.2– 73.2% vs 29.7– 38.0%) or remission (50.7– 51.5% vs 17.4– 18.7%). Positive predictive values for response and remission with vortioxetine were ∼ 70% and ∼ 50%, respectively; negative predictive values were ∼ 70% and ∼ 80%, respectively.Conclusion: Improvement with vortioxetine may be predicted by early partial improvement in MADRS score. Some patients may benefit from longer-term treatment even without early improvement, another finding that may aid clinical decision-making. ClinicalTrials.gov registration for primary study: NCT02389816.Keywords: antidepressant, Japanese, major depressive disorder, vortioxetine

Takeshi Inoue,1 Shinji Fujimoto,2 Tatsuro Marumoto,2 Tadayuki Kitagawa,3 Kazuyuki Ishida,3 Tadashi Nakajima,2 Yoshiya Moriguchi,4 Keita Fujikawa,2 Koichiro Watanabe5 1Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 2Japan Medical Office, Takeda Pharmaceutical Co., Ltd, Tokyo, Japan; 3Takeda Development Center – Japan, Takeda Pharmaceutical Co., Ltd, Osaka, Japan; 4Medical Affairs, Lundbeck Japan K.K., Tokyo, Japan; 5Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, JapanCorrespondence: Takeshi InoueDepartment of Psychiatry, Tokyo Medical University, 6‐7‐1 Nishishinjuku, Shinjuku‐ku, Tokyo, 160‐0023, JapanTel +81-3-3342-6111 (ext. 5754)Fax +81-3-3340-4499Email tinoue@tokyo-med.ac.jpAim: Antidepressants, including selective serotonin reuptake inhibitors, often elicit a poor response in patients with major depressive disorder (MDD) with significant anxiety symptoms. This study investigated the effects of the multimodal antidepressant vortioxetine in patients with MDD and associated anxiety.Methods: This was a post hoc analysis of data from an 8-week, randomized, double-blind, placebo-controlled, Phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20– 75 years with recurrent MDD and a Montgomery–Åsberg Depression Rating Scale (MADRS) score of at least 26. Changes from baseline to week 8 in MADRS total score and Hamilton Depression Rating Scale (HAM-D) anxiety/somatization factor score were assessed in patients with anxious depression (HAM-D anxiety/somatization factor score ≥ 7) and without anxious depression.Results: Data were available for 489 patients. In patients with anxious depression, the least-squares (LS) mean difference (95% confidence interval [CI]) versus placebo in change in MADRS total score was − 3.44 (− 6.10, − 0.77) for vortioxetine 10 mg and − 4.51 (− 7.15, − 1.87) for vortioxetine 20 mg. In patients with non-anxious depression, the LS mean difference (95% CI) versus placebo was − 1.81 (− 4.71, 1.09) and − 1.05 (− 4.00, 1.90) for vortioxetine 10 mg and 20 mg, respectively. Changes from baseline in HAM-D anxiety/somatization factor score were greater in patients treated with vortioxetine 10 mg or 20 mg than in those treated with placebo.Conclusion: Vortioxetine may be effective for patients with anxiety symptoms in MDD. Further research is warranted to investigate these effects in a real-world clinical setting.Clinical Trials Registration: ClinicalTrials.gov identifier for primary study: NCT02389816.Keywords: antidepressant, anxiety, major depressive disorder, serotonin reuptake inhibitor and modulator (S-RIM), vortioxetine

Ayaka Deguchi,1– 3 Jiro Masuya,1 Mayu Naruse,4 Chihiro Morishita,1 Motoki Higashiyama,1 Hajime Tanabe,5 Takeshi Inoue,1 Masahiko Ichiki1 1Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo, 160-0023, Japan; 2Department of Psychiatry, Maruyamasou Hospital, Ishioka, Ibaraki, 315-0116, Japan; 3Department of Psychiatry, Deguchi Hospital, Nagasaki, Nagasaki, 851-1134, Japan; 4Department of Welfare Psychology, Tokyo International University, Kawagoe, Saitama, 350-1198, Japan; 5Faculty of Humanities and Social Sciences, Shizuoka University, Suruga-ku, Shizuoka, 422-8529, JapanCorrespondence: Takeshi InoueDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, JapanTel +81 3 3342 6111Fax +81 3 3340 4499Email tinoue@Tokyo-med.ac.jpBackground: Several psychological studies have shown that depressive rumination is associated with the onset and severity of depression. However, it is unclear how rumination interacts with other predisposing factors to cause depression. In this study, we hypothesized that rumination mediates the association between depression and two predisposing factors of depression, ie, childhood maltreatment and trait anxiety.Subjects and Methods: Between 2017 and 2018, 473 adult volunteers were surveyed using self-report questionnaires regarding the following: demographic information, rumination (Ruminative Responses Scale), trait anxiety (State-Trait Anxiety Inventory-Y), and the experience of childhood maltreatment (Child Abuse and Trauma Scale). The effects of these factors on depression (Patient Health Questionnaire-9) were analyzed by multiple regression and path analysis to analyze the mediating effects of rumination. This study was conducted with approval from the relevant ethics committee.Results: Multiple regression analysis using depression as a dependent variable demonstrated that trait anxiety, rumination, childhood maltreatment, and living alone were significantly associated with depression. Path analysis showed that childhood maltreatment had a positive effect on trait anxiety, rumination, and depression; trait anxiety had a positive effect on rumination and depression; and rumination had a positive effect on depression. Regarding indirect effects, the experience of childhood maltreatment increased rumination and depression indirectly via trait anxiety. Furthermore, the experience of childhood maltreatment increased depression indirectly via rumination, and trait anxiety significantly increased depression via rumination. In other words, rumination mediated the indirect effects of abusive experiences and trait anxiety on depression. This model accounted for 50% of the variance in depression in adult volunteers.Conclusion: Our results suggest that rumination mediates the association between childhood maltreatment, trait anxiety, and depression in adulthood.Keywords: rumination, trait anxiety, childhood maltreatment, depression, path analysis

Yoshitaka Ishii,1,2 Jiro Masuya,1 Chihiro Morishita,1 Motoki Higashiyama,1 Takeshi Inoue,1 Masahiko Ichiki1 1Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo, 160-0023, Japan; 2Fuji Psychosomatic Rehabilitation Institute Hospital, Fujinomiya, Shizuoka, 418-0035, JapanCorrespondence: Takeshi InoueDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, JapanTel +81 3 3342 6111Fax +81 3 3340 4499Email tinoue@tokyo-med.ac.jpBackground: Various stressors during childhood and adulthood, such as experiencing poor parenting, abuse, and harassment, have long-lasting effects on depression. The long-term effects of childhood stressors, such as childhood abuse and inappropriate parenting experiences, on adult depression are mediated by personality traits. In the present study, we hypothesized that parental bonding in childhood influences adulthood depression, and that this association is mediated by childhood victimization experiences and negative life event evaluations in adulthood. To test this hypothesis, multiple regression analysis and structural equation modeling were performed.Methods: A questionnaire survey, including Patient Health Questionnaire-9, victimization scale in childhood, Parental Bonding Instrument (PBI), and Life Experiences Survey was administered to 449 general adult volunteers (age: 41.1 ± 11.7 years; 196 men and 253 women). Multiple variables were analyzed by multiple regression analysis and structural equation modeling.Results: Multiple regression analysis demonstrated that victimization experiences in childhood affect adulthood depression independently of several other factors. Structural equation modeling showed that the “parental care” subscale of the PBI decreased adulthood depression directly, as well as indirectly through its effects on victimization experiences in childhood and negative life events. On the other hand, the “parental overprotection” subscale of the PBI increased adulthood depression directly, as well as indirectly through its effects on the experience of victimization in childhood and negative life events.Conclusion: The present study indicates that the experience of victimization in childhood is a risk factor of adulthood depression. Furthermore, we found that parenting quality experienced in childhood influences adulthood depression, and that these effects are mediated by the experiences of victimization in childhood and negative life events in adulthood.Keywords: victimization, parental bonding, negative life event appraisal, depression, structural equation modeling

Hiroshi Nakazawa,1 Jiro Masuya,1 Hajime Tanabe,2 Ichiro Kusumi,3 Takeshi Inoue,1 Masahiko Ichiki1 1Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo, 160-0023, Japan; 2Faculty of Humanities and Social Sciences, Shizuoka University, Suruga-ku, Shizuoka, 422-8529, Japan; 3Department of Psychiatry, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, 060-8638, JapanCorrespondence: Takeshi InoueDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, JapanTel +81 3 3342 6111Fax +81 3 3340 4499Email tinoue@tokyo-med.ac.jpBackground: Childhood maltreatment has long-lasting psychological effects, which often manifest in adulthood. Previous studies have suggested that the effects of childhood maltreatment are not only direct but also indirect, being mediated by other factors. In this study, we hypothesized that the effects of childhood maltreatment on state anxiety in adulthood are mediated by interpersonal sensitivity and the evaluation of life events, and investigated this possibility by covariance structure analysis.Subjects and Methods: Self-administered questionnaires (Child Abuse and Trauma Scale, State-Trait Anxiety Inventory Form Y, Life Experiences Survey, and Interpersonal Sensitivity Measure) were distributed to adult community volunteers in Japan, and 404 eligible responses were collected. A structural equation model was constructed to analyze the direct and indirect effects of childhood maltreatment on state anxiety, with interpersonal sensitivity and the evaluation of life events as potential mediators.Results: Our model showed that childhood maltreatment increases state anxiety in adulthood both directly and indirectly via interpersonal sensitivity. In addition, interpersonal sensitivity mediated the effects of childhood maltreatment on the negative evaluation of life events, and the negative evaluation of life events mediated the effects of interpersonal sensitivity on anxiety symptoms.Limitations: There may be possible recall bias owing to the self-administration of the questionnaire. In addition, this study had a cross-sectional design, and hence the results should be validated by a prospective study.Conclusion: The effects of childhood maltreatment on the state anxiety of adult volunteers are not only direct but are also mediated by interpersonal sensitivity. Our results suggest that assessing interpersonal sensitivity may help to determine optimal treatments for patients with anxiety who experienced maltreatment in childhood.Keywords: covariance structure analysis, child abuse and trauma scale, state-trait anxiety inventory form Y, interpersonal sensitivity measure, life experiences survey

Yu Tamada,1– 3 Takeshi Inoue,2 Atsushi Sekine,4 Hiroyuki Toda,5 Minoru Takeshima,2,6 Masaaki Sasaki,3 Keisuke Shindome,5 Wataru Morita,5 Nagisa Kuyama,3 Susumu Ohmae3 1Department of Psychiatry, Toranomon Hospital Kajigaya, Kawasaki, Kanagawa, Japan; 2Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 3Department of Psychiatry, Toranomon Hospital, Tokyo, Japan; 4The Medical Foundation of Keishin-Kai, Kei Mental Clinic, Daisen, Akita, Japan; 5Department of Psychiatry, National Defense Medical College, Tokorozawa, Saitama, Japan; 6Shibata Hospital, Takaoka, Toyama, JapanCorrespondence: Yu TamadaDepartment of Psychiatry, Toranomon Hospital Kajigaya, 1-3-1 Kajigaya, Takatsu-ku, Kawasaki, Kanagawa, 213-8587, JapanTel +81 44 877 5111Fax +81 44 877 5333Email y-tmd@umin.ac.jpPurpose: Melancholia has recently been re-evaluated, because patients with major depressive disorder (MDD) were found to be heterogeneous. However, the DSM-5 criteria for melancholia (DSM-MEL) have been criticized, because of the difficulty in clearly distinguishing between melancholic and non-melancholic depression using DSM-MEL. Psychomotor disturbance (PMD) is one of the most important, as well as one of the only measurable symptoms of melancholia. Parker et al developed the CORE measure, which assesses PMD as a behavioral characteristic. The aim of our study was to objectively identify the subjective symptoms of melancholia by analyzing the symptoms associated with PMD.Patients and Methods: A total of 106 participants with MDD were examined by psychiatrists. Multiple regression analysis was performed in which the total CORE score was the dependent variable, and items of the DSM-MEL and historically suggested melancholic features were independent variables.Results: The following five independent variables were able to predict the total CORE score: 1) feelings of having lost feeling, 2) depressive delusions, 3) perplexity, 4) indecisiveness, and 5) no aggression against others. These five variables were more strongly associated with the total CORE score than the DSM-MEL.Limitation: The major limitation of this study was that when choosing non-DSM melancholic signs and symptoms, we did not comprehensively evaluate and select the symptoms but chose items that are clinically important.Conclusion: We identified five subjective symptoms that were associated with PMD. These five symptoms may be clinically useful as diagnostic criteria for melancholia.Keywords: major depressive disorder, melancholic features, CORE measure, endogenous depression, diagnosis, psychomotor retardation

Kuniyoshi Toyoshima,1,* Masahiko Ichiki,2,* Takeshi Inoue,2 Jiro Masuya,2 Yota Fujimura,2,3 Shinji Higashi,3,4 Ichiro Kusumi1 1Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan; 2Department of Psychiatry, Tokyo Medical University, Tokyo, 160-0023, Japan; 3Department of Psychiatry, Tokyo Medical University Hachioji Medical Center, Tokyo, 193-0998, Japan; 4Department of Psychiatry, Ibaraki Medical Center, Tokyo Medical University, Ibaraki, 300-0395, Japan*These authors contributed equally to this workCorrespondence: Kuniyoshi ToyoshimaDepartment of Psychiatry, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Sapporo, 060-8638, JapanTel +81 011 716 1161Fax +81 011 706 5081Email toyoshima@med.hokudai.ac.jpPurpose: Trait anxiety, depressive symptoms, and cognitive complaints affect mental health. The mediating role of cognitive complaints has been reported recently. However, the mediating effects of cognitive complaints in the relationships between trait anxiety, depressive symptoms, and subjective well-being (SWB) and ill-being (SIB) remain unknown. Therefore, we used path analyses to investigate these mediating effects.Materials and Methods: A total of 554 adult community volunteers in Japan were studied using the State-Trait Anxiety Inventory (Form Y), Patient Health Questionnaire-9, Cognitive Complaints in Bipolar Disorder Rating Assessment, and Subjective Well-Being Inventory. These assessment tools evaluated trait anxiety, depressive symptoms, cognitive complaints, SWB, and SIB. Path analyses were performed in this study.Results: Path analyses revealed that there were significant indirect effects, via cognitive complaints, of trait anxiety and depressive symptoms on SIB. However, there were no significant indirect effects of trait anxiety and depressive symptoms on SWB. There were significant indirect effects, via depressive symptoms, of trait anxiety on cognitive complaints, SWB, and SIB.Conclusion: The role of cognitive complaints may be different between SWB and SIB associated with trait anxiety and depressive symptoms. Evaluating the mediating effect of cognitive complaints may be more useful on SIB than SWB associated with trait anxiety and depressive symptoms. These findings may be useful when considering intervention targets in mental health.Keywords: trait anxiety, depressive symptoms, cognitive complaints, well-being, ill-being, mediator

Takeshi Inoue,1 Hiromi Sano,2 Yoshitsugu Kojima,3 Sakiko Yamada,3 Osamu Shirakawa4 1Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 2Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan; 3Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan; 4Department of Neuropsychiatry, Kindai University Faculty of Medicine, Osaka, JapanCorrespondence: Sakiko YamadaMedical Affairs, Otsuka Pharmaceutical Co., Ltd., Shinagawa Grand Central Tower, 2-16-4 Konan, Minato-Ku, Tokyo, 108-8242, JapanTel +81 3 6717 1400Fax +81 3 6716 1398Email yamadasa@otsuka.jpPurpose: This study aimed to describe real-world treatment patterns and medication adherence among patients with bipolar disorder (BD) in Japan.Patients and Methods: Adult patients with a BD diagnosis were identified between July 2013 and February 2018, using an employment-based health insurance claims database from the JMDC Inc. Treatment patterns of target drugs (mood stabilizers, antipsychotics) and adherence (measured by the proportion of days covered [PDC]) were assessed during the first- through third-year follow-up. Adherence was also assessed for patient subgroups.Results: The analyzed population included 13,788 patients with BD. They were mostly prescribed sodium valproate, lithium, or aripiprazole (range: 21.1– 27.4%) across 3 years of follow-up, whereas lamotrigine was prescribed to 11.2– 12.8% of patients. Benzodiazepines (70– 87%) and antidepressants (52– 71%) were commonly prescribed during all three follow-up periods. The mean PDC among all patients with BD was 0.51 during the first and increased to 0.61 during the third year. The mean PDC was 0.42 (first year) in patients aged < 30 years and 0.49 in those aged 30– 40 years. The PDC was 0.44– 0.61 (depending on the drug class) in those who were prescribed a single-class target drug and 0.68– 0.83 in those prescribed two drug classes concomitantly.Conclusion: This study documented generally low medication adherence among patients with BD, and those at young age. These patients may require more attention.Keywords: bipolar disorders, treatment patterns, medication adherence, oral antipsychotics, mood stabilizers, claims database

Taito Hayashida,1,2 Akiyoshi Shimura,2 Motoki Higashiyama,2 Yota Fujimura,1 Kotaro Ono,2 Takeshi Inoue2 1Department of Psychiatry, Tokyo Medical University Hachioji Medical Center, Hachioji-shi, Tokyo, 193-0998, Japan; 2Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo,160-0023, JapanCorrespondence: Akiyoshi ShimuraDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, JapanTel +81-3-3342-6111Fax +81-3-3340-4499Email sim@tokyo-med.ac.jpBackground: Presenteeism is the loss of work productivity of workers owing to physical and mental problems, and its socioeconomic effects are greater than those of absenteeism. Presenteeism is caused by psychological and physical dysfunctions. On the other hand, the regularity of mealtimes is an important factor associated with physical and mental health conditions. We hence assessed the association among the irregularity of mealtimes, presenteeism, psychological and physical stress responses, and sleep disturbance in office workers in companies.Methods: From May to December 2017, the data of 2905 participants who had given their consent to use their information for academic purposes, and answered a questionnaire about the survey and their lifestyle were collected. Path analysis was performed to analyze the association between the irregularity of mealtimes, psychosomatic symptoms (Brief Job Stress Questionnaire), sleep disturbance (Pittsburgh Sleep Questionnaire), and presenteeism (Work Limitations Questionnaire).Results: The direct effect of the irregularity of mealtimes on presenteeism was significant but weak. However, the irregularity of mealtimes had a strong effect on presenteeism indirectly through psychological and physical stress responses and sleep disturbance.Conclusion: Psychological and physical stress responses and sleep disturbance were identified as mediating factors of the effects of irregularity of mealtimes on presenteeism.Keywords: presenteeism, Work Limitations Questionnaire, WLQ, mealtimes, sleep disturbance, stress reaction, mediating effect

Manami Watahiki,1 Shigeo Horinaka,1 Toshihiko Ishimitsu,2 Shigeru Toyoda,1 Teruo Inoue1 1Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan; 2Department of Kidney and Hypertension, Dokkyo Medical University, Mibu, JapanCorrespondence: Shigeo HorinakaDepartment of Cardiovascular Medicine, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, JapanEmail horinaka@dokkyomed.ac.jpPurpose: The cardio-ankle vascular index, applying the stiffness parameter β theory, was calculated using the pulse-wave velocity and blood pressure from the aortic orifice to the ankle. Accordingly, the impact of the stiffness of the aorta [heart–thigh β (htBETA)] and medium-sized muscular artery [thigh–ankle β (taBETA)] on the stiffness of the heart–ankle β (haBETA) was investigated; further, whether the htBETA (haBETA − taBETA) improved the power of diagnosis of coronary artery disease (CAD) was examined.Materials and Methods: Segmental βs were calculated using VaSela with an additional thigh cuff and compared using the receiver operating characteristic (ROC) curve analysis to evaluate CAD.Results: Overall, 90 healthy subjects and 41 patients with CAD were included. In both groups, haBETA and htBETA, but not taBETA, correlated with age, and taBETA was three times higher than htBETA (p < 0.01). Multiple regression analysis revealed that haBETA can be estimated using htBETA and taBETA in healthy subjects and patients with CAD (r = 0.86, r = 0.67, respectively, p < 0.01), and two-thirds of the haBETA components can be estimated by htBETA using the component analysis. The area under the ROC curve (AUC) for CAD in taBETA (0.493, p = n.s.) was smaller than that in haBETA (0.731, p < 0.01) or htBETA (0.757, p < 0.01); no difference was observed in AUC between haBETA and htBETA.Conclusion: The stiffness of medium-sized muscular arteries of the age-independent thigh–ankle segment (taBETA) was constant, which was three times greater than that of the elastic artery of the heart–thigh artery (htBETA). Two-thirds of the haBETA components could be estimated using htBETA. The ROC curve analysis revealed that the AUC of haBETA could be replaced by that of htBETA, prolonging the measurement segment without affecting the diagnostic power for CAD.Keywords: arterial stiffness, stiffness parameter, cardio-ankle vascular index, coronary artery disease

Tomoteru Seki,1,2 Akiyoshi Shimura,1 Hitoshi Miyama,1 Wataru Furuichi,1 Kotaro Ono,1 Jiro Masuya,1 Yuko Odagiri,3 Shigeru Inoue,3 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo 160-0023, Japan; 2Fuji Psychosomatic Rehabilitation Institute Hospital, Fujinomiya, Shizuoka 418-0035, Japan; 3Department of Preventive Medicine and Public Health, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, JapanCorrespondence: Akiyoshi ShimuraDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, JapanTel +81-3-3342-6111Fax +81-3-3340-4499Email sim@tokyo-med.ac.jpBackground: The complex interaction between parenting styles, job stressors, and the stress response has not been clarified to date. We hypothesized that neuroticism acts as a mediator in the effects of parenting quality on perceived job stressors and the psychological and physical stress response (PPSR), and tested this hypothesis using covariance structure analysis.Subjects and Methods: We conducted research between April 2017 and April 2018 on 597 adult from the community, and 69 subjects were excluded owing to missing data or nonworkers. Finally, a total of 528 participants were analyzed using the following self-administered questionnaires: the Parental Bonding Instrument, the shortened Eysenck Personality Questionnaire-Revised, and the Brief Job Stress Questionnaire (BJSQ). The data were analyzed by single regression analyses and covariance structure analyses. Job stress was assessed by the BJSQ and 2 subscales, ie, perceived job stressors and the PPSR. This study was approved by the Ethics Committee of Tokyo Medical University.Results: On covariance structure analysis, high parental overprotection was associated with high neuroticism and high PPSR directly, but had no significant effect on perceived job stressors. High parental overprotection was associated with high-perceived job stressors and the high PPSR indirectly through enhanced neuroticism. High parental overprotection was also associated with the high PPSR indirectly through 2 combined paths of neuroticism and perceived job stressors. This model accounted for 40% of the variability of the PPSR. On the other hand, parental care had opposite effects to parental overprotection, and this model of parental care accounted for 39% of the variability of PPSR. The model fits of the 2 models were good.Conclusion: Our results suggest that the quality of parenting in childhood is associated with perceived job stressors and the PPSR indirectly through neuroticism.Keywords: parental care, parental overprotection, neuroticism, job stress, covariance structure analysis, structural equation model

Hitoshi Miyama,1,2 Akiyoshi Shimura,1 Wataru Furuichi,1 Tomoteru Seki,1 Kotaro Ono,1 Jiro Masuya,1 Yuko Odagiri,3 Shigeru Inoue,3 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Tokyo 160-0023, Japan; 2Department of Psychiatry, Maruyamasou Hospital, Ishioka, Ibaraki 315-0116, Japan; 3Department of Preventive Medicine and Public Health, Tokyo Medical University, Tokyo 160-8402, JapanCorrespondence: Akiyoshi ShimuraDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-Ku, Tokyo 160-0023, JapanTel +81-3-3342-6111Fax +81-3-3340-4499Email sim@tokyo-med.ac.jpBackground: Chronotype, which is a person’s circadian characteristics throughout a day, greatly influences a person’s lifestyle, health, and sleep pattern; however, the association between job stress and chronotype remains unknown to date. Therefore, in this study, we analyzed the effects of chronotype on the job stress response, and the mediating effects of sleep disturbance using path analysis.Methods: A cross-sectional survey was conducted on 535 adult volunteers (239 men and 296 women; average age, 41.2 ± 11.9 years) from the community. Participants were evaluated using the Diurnal Type Scale for chronotype, Pittsburg Sleep Quality Index for sleep disturbance, Brief Job Stress Questionnaire for job stressors, and the psychological and physical stress response (PPSR). To investigate the association between chronotype, sleep disturbance, perceived job stressors, and PPSR, a covariance structure analysis was performed.Results: The eveningness chronotype had a significant weak direct effect on sleep disturbance, perceived job stressors, and PPSR, and had a significant indirect effect through sleep disturbance. The perceived job stressors indirectly increased PPSR through sleep disturbance. Sleep disturbance mediated the effects of the eveningness chronotype and perceived job stressors on PPSR. This model accounted for 37.3% of the variability in PPSR of adult workers.Conclusion: Chronotype affected PPSR through sleep disturbance. Therefore, improving the sleep disturbance of workers with the eveningness chronotype may reduce their stress response.Keywords: eveningness chronotype, sleep disturbance, job stress, Diurnal Type Scale

Wataru Furuichi,1,2 Akiyoshi Shimura,1 Hitoshi Miyama,1 Terutomo Seki,1 Kotaro Ono,1 Jiro Masuya,1 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Tokyo 160-0023, Japan; 2Department of Psychiatry, Seiwakai Nakayama Hospital, Ichikawa, Chiba, 272-0813, JapanCorrespondence: Akiyoshi Shimura Tel +81-3-3342-6111Fax +81-3-3340-4499Email sim@tokyo-med.ac.jpBackground: Occupational mental health, work environment, sleep health, presenteeism, and loss of work productivity caused by health problems are all public health concerns. Although sleep affects mental health and presenteeism, the associations between sleep disturbance, job stressors, stress responses, and presenteeism have remained unclear. We hypothesized that job stressors affect the presenteeism of office workers through sleep disturbance and analyzed the association among these factors.Subjects and Methods: In 2017, a cross-sectional survey of adult office workers was performed. A total of 2899 subjects who provided written consent were included in the analysis. The survey collected demographic information, as well as the Work Limitation Questionnaire (WLQ), Pittsburgh Sleep Quality Index (PSQI), and Brief Job Stress Questionnaire (BJSQ). Associations between each of the variables were analyzed by path analysis (covariance structure analysis). This study was approved by the Ethics Committee of Tokyo Medical University.Results: The path analysis demonstrated that job stressors, psychological and physical stress response (PPSR) in the BJSQ, and sleep disturbance in the PSQI had direct effects on presenteeism in the WLQ. Both job stressors and social support in the BJSQ indirectly affected presenteeism through effects on sleep disturbance and PPSR. Sleep disturbance indirectly affected presenteeism via PPSR. This model accounted for the variation of presenteeism (R2 = 0.322).Conclusion: In the workplace, job stressors and low social support increase presenteeism through psychological and physical stress responses, as well as sleep disturbance. Evaluating and resolving work problems and sleep disturbance would hence be beneficial from the aspects of public health and socioeconomics.Keywords: job stress, occupational stress, sleep disturbance, presenteeism, work limitation questionnaire, WLQ

Takeshi Inoue,1 Toshifumi Kimura,2 Yoshifumi Inagaki,2 Osamu Shirakawa3 1Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 2Medical Affairs Department, Medical Division, GlaxoSmithKline K.K., Tokyo, Japan; 3Department of Neuropsychiatry, Kindai University Faculty of Medicine, Osaka, JapanCorrespondence: Takeshi InoueDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-Ku, Tokyo 160-0023, JapanTel +81 3 3342 6111Fax +81 3 3345 1437Email tinoue@tokyo-med.ac.jpObjective: Comorbid anxiety disorders in patients with mood disorders have a negative impact on outcomes, such as persistence of depressive symptoms, deterioration of quality of life (QoL), increased suicide risk, mood instability with antidepressant treatment, but often go underrecognized in clinical practice. To identify features useful for supporting the confirmation of comorbid anxiety disorders, we investigated the prevalence of comorbid anxiety disorders and their associated factors in Japanese patients with mood disorders using data from our previously reported JET-LMBP study.Patients and Methods: Patients with bipolar disorder (BD; n=114) and patients with major depressive disorder (MDD; n=334), all with major depressive episodes (DSM-IV-TR) were analyzed. Comorbid anxiety disorders were confirmed using the Mini-International Neuropsychiatric Interview. Demographic and clinical features were assessed using patient background forms, including the Quick Inventory of Depressive Symptomatology–Self Report Japanese version, 36-Item Short-Form Health Survey (SF-36), and Child Abuse and Trauma Scale (CATS). Multivariate logistic regression analysis adjusted for age, sex, and severity of depressive symptoms was used to identify factors associated with comorbid anxiety disorders (post hoc analysis).Results: The prevalence of comorbid anxiety disorders was significantly higher in patients with BD (53.2%) than in patients with MDD (37.2%). Factors associated with comorbid anxiety disorders in BD included no spouse, interpersonal rejection sensitivity, higher CATS sexual abuse scores, and lower SF-36 mental component summary scores. In MDD, factors included hypersomnia, pathological guilt feelings, higher CATS neglect scores, and lower SF-36 physical component summary scores.Conclusion: Comorbid anxiety disorders were commonly seen in Japanese patients with mood disorders. Childhood abuse, atypical depression symptoms, and deterioration of health-related QoL were commonly associated with comorbid anxiety disorders in BD and MDD, suggesting that the presence of these features may be useful to support the confirmation of comorbid anxiety disorders in these patients.Keywords: anxiety disorders, bipolar disorder, comorbidity, major depressive disorder, prevalence

Kuniyoshi Toyoshima,1 Takeshi Inoue,2 Jiro Masuya,2 Yota Fujimura,2 Shinji Higashi,2,3 Ichiro Kusumi1 1Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 3Department of Psychiatry, Ibaraki Medical Center, Tokyo Medical University, Ibaraki, JapanCorrespondence: Kuniyoshi ToyoshimaDepartment of Psychiatry, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Sapporo 060-8638, JapanTel +81 11 716 1161Fax +81 11 706 5081Email toyoshima@med.hokudai.ac.jpPurpose: Functional disability is affected by subjective cognitive function, depressive symptoms, and affective temperaments in adults. However, the role of subjective cognitive function as a mediator of affective temperaments in functional disability remains unknown. Therefore, we aimed to determine how subjective cognitive function mediates the effect of affective temperaments on functional disability in adults.Materials and Methods: A total of 544 participants completed the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Auto questionnaire version (TEMPS-A), the Patient Health Questionnaire-9 (PHQ-9), the cognitive complaints in bipolar disorder rating assessment (COBRA), and the Sheehan Disability Scale (SDS). The association among these instruments was evaluated by multiple regression and covariance structure analyses.Results: The structural equation model showed that the COBRA scores could be predicted directly by the four affective temperaments of the TEMPS-A (cyclothymic, depressive, irritable, and anxious) and indirectly by the PHQ-9. Moreover, the SDS score was predicted directly by these four affective temperaments and indirectly by the COBRA and PHQ-9.Conclusion: Subjective cognitive function mediates the effect of affective temperaments on functional disability in Japanese adults. However, the cross-sectional design may limit the identification of causal associations between the parameters. In the present study, the participants were from a specific community population; therefore, the results may not be generalizable to other communities.Keywords: cognition, depression, adult, Sheehan Disability Scale, TEMPS-A, subjective cognitive dysfunction

Yumi Wakatsuki,1 Takeshi Inoue,2 Naoki Hashimoto,1 Yota Fujimura,2 Jiro Masuya,2 Masahiko Ichiki,2 Hajime Tanabe,3 Ichiro Kusumi1 1Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; 2Department of Psychiatry, Tokyo Medical University, Tokyo 160-0023, Japan; 3Department of Clinical Human Sciences, Graduate School of Humanities and Social Sciences, Shizuoka University, Shizuoka 422-8529, JapanCorrespondence: Takeshi InoueDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, JapanTel +81-3-3342-6111Fax +81-3-3340-4499Email tinoue@tokyo-med.ac.jpBackground: Previous studies have shown that childhood maltreatment is associated with premenstrual dysphoric disorder (PMDD). In this study we analyzed how multiple factors, such as childhood maltreatment, affective temperaments, and adult life events influence the severity of premenstrual mental (PMM) symptoms in nonclinical adult volunteers from the community.Methods: A total of 204 participants were recruited and administered the following self-administered questionnaire surveys: PMDD scale, visual analogue scale, Patient Health Questionnaire-9, Life Experience Survey, Temperament Evaluation of Memphis, Pisa, Paris, and San Diego autoquestionnaire version, and the Child Abuse and Trauma scale. In addition to single and multiple regression analyses, structural equation modeling was used for the statistical analyses.Results: A history of neglect indirectly predicted PMM symptoms through affective temperaments in nonclinical adult volunteers. Three affective temperaments (irritable, cyclothymic, and anxious) directly predicted PMM symptoms.Conclusion: This study is the first to report that childhood maltreatment, particularly neglect, indirectly predicted PMM symptoms through affective temperaments. The results of our study suggest that affective temperament is a mediator of the influence of childhood maltreatment on PMM symptoms.Keywords: premenstrual mental symptoms, neglect, childhood maltreatment, affective temperament, TEMPS-A, structural equation modeling

Shuichiro Tachi,1,2 Miki Asamizu,2 Yoshihiro Uchida,1–3 Shigemasa Katayama,1,2 Mayu Naruse,1 Jiro Masuya,1,3 Masahiko Ichiki,1 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Tokyo 160-0023, Japan; 2Seijin Hospital, Tokyo 121-0815, Japan; 3Department of Psychiatry, Ibaraki Medical Center, Tokyo Medical University, Ibaraki 300-0395, JapanCorrespondence: Takeshi InoueDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, JapanTel +81 3 3342 6111 (Ext. 5754)Fax +81 3 3340 4499Email tinoue@tokyo-med.ac.jpBackground: Adverse experiences, such as low care, overprotection, or abuse in childhood increase the likelihood of depression via their effects on personality traits. Similarly, being victimized in childhood may affect the likelihood of depression via personality traits. In this case-control study, we hypothesized that being victimized in childhood is associated with depression in adulthood via its effect on neuroticism, and verified this hypothesis using path analysis.Subjects and methods: Eighty-two major depressive disorder (MDD) patients and 350 age-and-sex matched healthy controls completed self-administered questionnaires of demographic data, Patient Health Questionnaire-9, neuroticism, and victimization. The association between victimization, neuroticism, and depressive symptoms or having major depression was investigated by path analysis.Results: Multiple group path analysis, in which depressive symptoms were considered as dependent variables, showed that the direct effect of victimization in childhood on depressive symptoms was not statistically significant in either healthy controls or MDD patients (standardized path coefficient: 0.079 and 0.084, respectively), but their indirect effects via neuroticism were statistically significant (standardized path coefficient: 0.059 and 0.141, respectively). Path analysis, in which the distinction between healthy controls and MDD patients was a dependent variable, showed that both direct effects and indirect effects of victimization in childhood via neuroticism on the distinction between healthy controls and MDD patients were statistically significant (standardized path coefficient: 0.186 and 0.164, respectively).Limitations: Recall bias and the relatively small number of MDD patients are limitations of this study. Because it was a case-control survey, this study could not make any conclusions regarding causal associations.Conclusion: This study suggests the possibility of causal associations between victimization in childhood and depressive symptoms or MDD in adulthood, and the mediation of this association by neuroticism.Keywords: victimization, neuroticism, depression, major depressive disorder, path analysis

Kuniyoshi Toyoshima,1 Takeshi Inoue,2 Jiro Masuya,2 Masahiko Ichiki,2 Yota Fujimura,2 Ichiro Kusumi1 1Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Department of Psychiatry, Tokyo Medical University, Tokyo, JapanCorrespondence: Kuniyoshi ToyoshimaDepartment of Psychiatry, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Sapporo 060-8638, JapanTel +81-11-716-1161Fax +81-11-706-5081Email toyoshima@med.hokudai.ac.jpPurpose: To examine the relationship between depressive symptoms, subjective cognitive function, and quality of life in Japanese adults using the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA).Patients and methods: We evaluated 585 adult community volunteers using the Patient Health Questionnaire-9 (PHQ-9) for evaluation of depressive symptoms and the COBRA for evaluation of subjective cognitive function. We additionally used the 8-item Short-Form Health Survey and the Sheehan Disability Scale to evaluate the quality of life (QoL).Results: Measures of subjective cognitive function were significantly correlated with depressive symptoms and QoL. Structural equation modeling demonstrated that depressive symptoms directly and indirectly decreased QoL via their effects on subjective cognitive dysfunction. Measures of depressive symptoms were more closely related to QoL than were measures of subjective cognitive function.Limitations: Study participants were general adult population community volunteers and included healthy people; thus, these results may not be generalizable to patients with depression or bipolar disorder. In addition, the cross-sectional design of this study prevented the identification of causal relationships among the parameters.Conclusion: Changes in subjective cognitive function may affect QoL via depressive symptoms. Evaluations of subjective cognitive function may help identify factors that reduce QoL.Keywords: 8-item Short-Form Health Survey, Sheehan Disability Scale, Patient Health Questionnaire-9, QoL, subjective cognitive dysfunction

Motoki Higashiyama,1 Taito Hayashida,1 Keisuke Sakuta,1 Yota Fujimura,2 Jiro Masuya,3 Masahiko Ichiki,1 Hajime Tanabe,4 Ichiro Kusumi,5 Takeshi Inoue11Department of Psychiatry, Tokyo Medical University, Tokyo 160-0023, Japan; 2Department of Psychiatry, Tokyo Medical University Hachioji Medical Center, Tokyo 193-0998, Japan; 3Department of Psychiatry, Tokyo Medical University Ibaraki Medical Center, Ibaraki 300-0395, Japan; 4Department of Clinical Human Sciences, Graduate School of Humanities and Social Sciences, Shizuoka University, Shizuoka 422-8529, Japan; 5Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, JapanCorrespondence: Takeshi InoueDepartment of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, JapanTel +81 33 342 6111Fax +81 33 340 4499Email tinoue@tokyo-med.ac.jpBackground: How subjective social status is associated with childhood abuse and affective temperament in the mechanism of depressive symptom exacerbation remains unknown. In this study, we investigated how the complex effects of subjective social status, childhood abuse, and affective temperament influence depressive symptoms in adulthood.Methods: Self-report questionnaires were distributed to 853 adult volunteers between January and August 2014. Of them, 404 people gave full consent and returned complete anonymous responses. The following five questionnaires were analyzed: demographic information, Patient Health Questionnaire-9, subjective social status, Child Abuse and Trauma Scale, and Temperament Evaluation of Memphis, Pisa, Paris and San Diego autoquestionnaire. The associations between the scores were analyzed by structural equation modeling. This study was conducted with approval from the ethics committees of Tokyo Medical University and Hokkaido University Hospital.Results: Covariance structure analysis demonstrated that childhood abuse and subjective social status did not have a direct effect on adulthood depressive symptoms. Childhood abuse had direct effects on subjective social status and affective temperament and childhood abuse indirectly affected adulthood depressive symptoms through subjective social status and affective temperament. Subjective social status also affected depressive symptoms through an effect on affective temperament. This model explained 43% of the variability in depressive symptoms and the fitness of this model was good.Conclusion: Regarding childhood abuse and adulthood depressive symptoms, subjective social status as well as affective temperament may be mediators. The results of this study are expected to contribute to the elucidation of the mechanism of depression.Keywords: childhood abuse, subjective social status, affective temperament, depression, covariance structure analysis

Yoshihiro Uchida,1–3 Toshinao Takahashi,1,3 Shigemasa Katayama,1,3 Jiro Masuya,1,2 Masahiko Ichiki,1 Hajime Tanabe,4 Ichiro Kusumi,5 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo 160-0023, Japan; 2Department of Psychiatry, Ibaraki Medical Center, Tokyo Medical University, Ami-machi, Inashiki-gun, Ibaraki 300-0395, Japan; 3Department of Psychiatry, Seijin Hopital, Adachi-ku, Tokyo 121-0815, Japan; 4Department of Clinical Human Sciences, Graduate School of Humanities and Social Sciences, Shizuoka University, Suruga-ku, Shizuoka 422-8529, Japan; 5Department of Psychiatry, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan Background: Various personality traits mediate the association between childhood stress and depressive symptoms in adulthood. The aim of this study was to clarify the indirect effects of the experience of child maltreatment on depressive symptoms and appraisal of life events in adulthood through trait anxiety. Subjects and methods: A total of 404 participants who were volunteer subjects from the community were studied using the following self-administered questionnaire surveys: Patient Health Questionnaire-9, which measures depressive symptoms; State-Trait Anxiety Inventory Form Y, which measures trait anxiety; the Child Abuse and Trauma Scale, which measures child maltreatment; and Life Experiences Survey, which measures negative and positive appraisal of adulthood life events. Results: Structural equation modeling demonstrated that the experience of child maltreatment increased depressive symptoms in adulthood as well as the negative appraisal of life events in adulthood through an increase in trait anxiety. Furthermore, trait anxiety affected depressive symptoms in adulthood through its influence on the negative appraisal of adulthood life events. The following indirect effect was also significant: the experience of child maltreatment increased the negative appraisal of adulthood life events via trait anxiety and subsequently influenced adult depressive symptoms. Limitations: The subjects of this study are volunteer subjects from the community including healthy people, and hence the results may not be generalizable to major depressive patients. Recall bias should be considered when interpreting the results. Because this study is a cross-sectional study, the causality between the experience of child maltreatment and depression is not clear. Conclusion: This study suggests that trait anxiety may play a mediating role in the influence of the experience of child maltreatment on depressive symptoms in adulthood and negative appraisal of adulthood life events. Keywords: child maltreatment, covariance structure analysis, depression, STAI-Y, trait anxiety, life events

Ai Kozaki,1 Hiroshi Nakamura,2 Toshu Inoue1 1Olympia Eye Hospital, Tokyo, Japan; 2Ooimachi Nakamura Eye Clinic, Tokyo, Japan Aim: To evaluate the efficacy of transcutaneous triamcinolone acetonide (TA) injection for the treatment of upper eyelid retraction and swelling in thyroid eye disease (TED) patients.Patients and methods: This is a case series. Three euthyroid TED patients with features of both upper eyelid retraction and swelling were recruited. TED signs appeared within 6 months prior to treatment. Next, 0.5 mL of TA (40 mg/mL) was transcutaneously injected targeting the orbital fat around the levator palpebrae superioris (LPS) muscle. At each visit, eyelid retraction was evaluated by palpebral fissure height and the presence of scleral show above the superior corneoscleral limbus. Eyelid swelling was judged by the appearance of upper eyelid bulging and the lack of an eyelid sulcus. In addition, the LPS muscle, orbital and retro-orbicularis oculi fat were observed using MRI before and after treatment.Results: Two patients had resolution of their upper lid retraction and swelling within 12 months. In the other patient who had proptosis, eyelid retraction resolved, while eyelid swelling remained mild. In all cases, MRI revealed that treatment resulted in thinner LPS muscle and reduced fat swelling. In addition, both high-intensity signals on T2 images and prolonged T2 relaxation time were normalized. No adverse signs were observed.Conclusion: Transcutaneous TA injection was effective as a treatment for upper eyelid retraction and swelling in euthyroid TED patients who had signs within 6 months prior to treatment. Transcutaneous TA injection induced reduction of LPS muscle enlargement and fat tissue swelling. These reductions by transcutaneous TA injection were verified using MRI. Keywords: thyroid eye disease, transcutaneous triamcinolone injection, upper eyelid retraction, eyelid swelling, MRI, ROOF, LPS muscle

Nobuhiro Kanaji,1 Hitoshi Mizoguchi,1 Takuya Inoue,1 Akira Tadokoro,2 Naoki Watanabe,1 Tomoya Ishii,1 Yasunori Tojo,2 Masahiro Yamaguchi,3 Norimitsu Kadowaki1 1Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, 2Department of Respiratory Medicine, National Hospital Organization Takamatsu Medical Center, 3Department of Internal Medicine, Shodoshima Central Hospital, Kagawa, Japan Purpose: Thromboembolism (TE) and disseminated intravascular coagulation (DIC) are often present concomitantly. This study aimed to investigate the clinical features of patients with lung cancer and TE and/or DIC. Patients and methods: Data on 716 patients with pathologically confirmed diagnoses of lung cancer were retrospectively analyzed for TE/DIC. Results: TE was identified in 16 patients (2.2%) and DIC was identified in 5 (0.7%) during the diagnosis of cancer. TE was more often observed in adenocarcinoma (4.0%). Both TE and DIC were more often observed in stage IV (4.7% and 1.5%, respectively). In patients with stage IV adenocarcinoma who received some systemic treatment, overall survival (OS) was significantly shorter in patients with TE (median 280 days) and with DIC (72 days) than in non-TE/DIC patients (538 days). Multivariate analysis showed that older age, poor performance status, greater number of metastatic organs, no EGFR mutation/ALK fusion, presence of interstitial lung disease, and DIC were poor prognostic factors for OS. In 339 patients in stage IV, 25 (7.4%) and 21 (6.2%) patients had TE and DIC, respectively, during the course. Six patients exhibited both TE and DIC. TE was more often observed in adenocarcinoma (20 of 196 patients; 10.2%). Patients with DIC had extremely shorter survival (median 13 days) after onset. Cancer control by systemic therapy, such as chemotherapy and molecular-targeted therapy, contributed to long survival. Conclusion: Patients with TE/DIC had shorter OS than patients without TE/DIC. Control of lung cancer by systemic therapy was important for longer survival after the onset of events. Keywords: deep vein thrombosis, pulmonary embolism, survival, Trousseau’s syndrome, venous thrombotic event, prognosis

Keiko Azuma,1 Ryo Asaoka,1 Aya Matsuda,2 Jihee Lee,3 Kimiko Shimizu,1 Hiroko Inui,1 Hiroshi Murata,1 Asako Ogawa,1 Motoshi Yamamoto,1 Tatsuya Inoue,1 Ryo Obata1 1Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; 2Department of Ophthalmology, Toranomon Byoin, Tokyo, Japan; 3Department of Ophthalmology, Miyata Eye Hospital, Miyakonojo, Japan Background: The purpose of the study was to evaluate the 2-year outcome and predictive factors of treat-and-extend aflibercept in patients with eyes affected by typical neovascular age-related macula degenelation (t-AMD) or polypoidal choroidal vasculopathy (PCV), who were switched from ranibizumab. Patients and methods: The patients underwent three monthly aflibercept injections and subsequent administration following the treat-and-extend protocol. Sixty-two eyes of 62 patients were reviewed retrospectively. R statistical software was used for statistical analysis. Results: Twenty-two eyes were t-AMD and the remaining 40 eyes were PCV. There was no significant difference in the logarithm of the minimal angle of resolution visual acuity (VA) between baseline and 2 years after switching to aflibercept (0.40 vs 0.40; P=0.99). Multivariate analyses suggested that the following factors were significantly correlated with better VA at 2 years after switching to aflibercept: patients with PCV, the absence of intraretinal fluid at baseline, and better VA at baseline. Conclusion: In conclusion, VA was maintained and there was an anatomical improvement at 2 years in patients with t-AMD and PCV who were switched from ranibizumab to treat-and-extend aflibercept. PCV patients showed more favorable visual outcomes and less injections at 2 years compared to t-AMD patients. Intraretinal fluid and VA at baseline were predictors of VA at 2 years. Keywords: typical neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, persistent exudative changes with ranibizumab, aflibercept, 2-year outcome

Rintaro Onoe,1 Tsuneo Yamashiro,2,3 Hiroshi Handa,1 Shinya Azagami,1 Shin Matsuoka,2 Takeo Inoue,1 Teruomi Miyazawa,1 Masamichi Mineshita1 1Division of Respiratory Medicine, Department of Internal Medicine, St Marianna University School of Medicine, Kawasaki, Japan; 2Department of Radiology, St Marianna University School of Medicine, Kawasaki, Japan; 3Department of Radiology, Graduate School of Medical Science, University of the Ryukyus, Nishihara, Japan Purpose: To assess tracheobronchial angles and their changes on combined inspiratory and expiratory thoracic computed tomography (CT) scans and to determine correlations between tracheobronchial angles and several indices of chronic obstructive pulmonary disease (COPD). Materials and methods: A total of 80 smokers underwent combined inspiratory and expiratory CT scans. Of these, 65 subjects also performed spirometry and 55 patients were diagnosed with COPD. On CT scans, 3-dimensinal tracheobronchial angles (trachea–right main bronchus [RMB], trachea–left main bronchus [LMB], and RMB–LMB) were automatically measured by software. Lung volumes at inspiration and expiration were also automatically calculated. Changes in tracheobronchial angles between inspiration and expiration were assessed by the Mann–Whitney test. Correlations of the angles with lung volume, airflow limitation, and CT-based emphysema index were evaluated by Spearman rank correlation. Results: The trachea–LMB angle was significantly smaller and the RMB–LMB angle was significantly larger at expiration than inspiration (P

Nami Suzuki,1 Jaeduk Yoshimura Noh,1 Toshiaki Kameda,1 Ai Yoshihara,1 Hidemi Ohye,1 Miho Suzuki,1 Masako Matsumoto,1 Yo Kunii,1 Kenji Iwaku,1 Natsuko Watanabe,1 Koji Mukasa,1 Ai Kozaki,2 Toshu Inoue,2 Kiminori Sugino,1 Koichi Ito1 1Department of Internal Medicine, Ito Hospital, Tokyo, Japan; 2Department of Ophthalmology, Olympia Eye Hospital, Tokyo, Japan Background: Euthyroid Graves’ disease (EGD) is a rare condition defined as the presence of thyroid-associated ophthalmopathy (TAO) in patients with normal thyroid function. Due to the rarity of this disease, only a limited number of studies and case reports are available for further evaluation of the characteristics of the disease. The aim of this study was to examine the changes in the thyroid function, thyrotropin receptor antibodies (TRAb) and eye symptoms, and then determine whether TRAb is related to TAO in EGD patients. TRAb in this study was defined as including both thyrotropin-binding inhibitory immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSAb). Patients and methods: Medical records of patients diagnosed with EGD were reviewed. Ophthalmologists specializing in TAO examined the eyes of all subjects. Results: Of the 58 patients diagnosed with EGD, 24.1% developed hyperthyroidism, while 3.4% developed hypothyroidism. A total of 72.4% of the 58 patients remained euthyroid throughout the entire follow-up period. At the initial presentation, TBII and TSAb were positive in 74.5% and 70.5%, respectively. Ophthalmic treatments were administered to 30 (51.7%) out of the 58 patients. A significant spontaneous improvement of the eye symptoms was found in 28 of the EGD patients who did not require eye treatments. EGD patients exhibited positive rates for both TBII and TSAb, with the number of the TRAb-positive patients gradually decreasing while the eye symptoms spontaneously improved over time. There were no correlations found between TRAb at initial presentation and the eye symptoms. Conclusion: TBII and TSAb were positive in about 70% of EGD patients at their initial visit. Thyroid functions of EGD patients who have been euthyroid for more than 6.7 years may continue to remain euthyroid in the future. Keywords: euthyroid Graves’ orbitopathy, euthyroid Graves’ ophthalmopathy, thyroid-associated ophthalmopathy, TSH receptor antibody, thyroid-stimulating immunoglobulin

Toshihiko Inoue,1 Yoshishige Okuno,1 Iku Nishiguchi,1 Koji Ikenaga,1 Osamu Mimura2 1Department of Radiation Oncology, Ashiya Radiotherapy Clinic Nozomi, Ashiya, Japan; 2Department of Neuro-Ophthalmological Therapeutics, Hyogo College of Medicine, Nishinomiya, Japan Purpose: To report the outcomes of early intervention with fractionated stereotactic radiotherapy (FSRT) in a patient with primary optic nerve sheath meningioma (ONSM).Patient and methods: A male patient in his early 40s underwent 5-beam FSRT at a prescribed dose of 50 Gy in 25 fractions over 35 days. The patient had an 11-month history of progressive visual impairment at the time of FSRT.Results: On day 14 of treatment, the patient reported early improvement in his vision. Two weeks after the completion of FSRT, his left eye visual acuity and field recovered completely. However, the tumor regressed only slightly in the 2 years of follow-up.Conclusion: Early intervention with FSRT for optic nerve sheath meningioma resulted in a rapid response and complete improvement of visual impairment. Keywords: fractionated stereotactic radiotherapy, optic nerve sheath meningioma, early intervention, rapid recovery of visual impairment

Ayano Otsuka,1 Yoshikazu Takaesu,1 Mitsuhiko Sato,1 Jiro Masuya,1 Masahiko Ichiki,1 Ichiro Kusumi,2 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Tokyo, 2Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan Background: Recent studies have suggested that multiple factors interact with the onset and prognosis of major depressive disorders. In this study, we investigated how child abuse, affective temperaments, and interpersonal sensitivity are interrelated, and how they affect depressive symptoms in the general adult population. Subjects and methods: A total of 415 volunteers from the general adult population completed the Patient Health Questionnaire-9, the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire version, the Child Abuse and Trauma Scale, and the Interpersonal Sensitivity Measure, which are all self-administered questionnaires. Data were subjected to structural equation modeling (Mplus), and single and multiple regression analyses. Results: The effect of child abuse on depressive symptoms was mediated by interpersonal sensitivity and 4 affective temperaments, including depressive, cyclothymic, anxious, and irritable temperaments. In addition, the effect of these temperaments on depressive symptoms was mediated by interpersonal sensitivity, indicating the indirect enhancement of depressive symptoms. In contrast to these 4 temperaments, the hyperthymic temperament did not mediate the effect of child abuse on depressive symptoms; its effect was not mediated by interpersonal sensitivity. However, a greater hyperthymic temperament predicted decreased depressive symptoms and interpersonal sensitivity, independent of any mediation effect. Limitations: Because this is a cross-sectional study, long-term prospective studies are necessary to confirm its findings. Therefore, recall bias should be considered when interpreting the results. As the subjects were adults from the general population, the results may not be generalizable towards all patients with major depression. Conclusion: This study suggests that child abuse and affective temperaments affect depressive symptoms partly through interpersonal sensitivity. Interpersonal sensitivity may have a major role in forming the link between abuse, affective temperament, and depression. Keywords: child abuse, affective temperament, TEMPS-A, interpersonal sensitivity, depression, structural equation modeling

Kentaro Matsui,1,2 Yoshikazu Takaesu,2,3 Takeshi Inoue,3 Ken Inada,1 Katsuji Nishimura1 1Department of Psychiatry, Tokyo Women’s Medical University, 2Japan Somnology Center, Neuropsychiatric Research Institute, 3Department of Psychiatry, Tokyo Medical University, Tokyo, Japan Background: Patients with non-24-hour sleep–wake rhythm disorder (N24SWD) exhibit a sleep pattern that is asynchronous with the external light–dark cycle, typically involving a cycling, relapsing–remitting pattern of sleep disturbances, including nighttime insomnia and daytime sleepiness. Here, we report the case of a patient with N24SWD comorbid with major depressive disorder, who was successfully treated with a low dose of aripiprazole.Case presentation: A 47-year-old female presented with an 8-year complaint of difficulty falling asleep and waking up in the morning. The patient was diagnosed with major depressive disorder at the age of 35 years and was treated with various antidepressants since that time. At the age of 40 years, the patient’s sleep–wake cycle began to extend without exacerbation of depressive symptoms. The patient was diagnosed with N24SWD at the age of 43 years. Ramelteon 8 mg/d and then melatonin 1 mg/d were administered, but these did not provide effective treatment. In January 2016, after treatment with aripiprazole 3 mg/d in the morning for 4 weeks, the patient’s sleep–wake cycle became markedly synchronized to the environmental light–dark cycle. Her sleep–wake cycle remained synchronized when the same dose of aripiprazole was administered for at least 6 months.Conclusion: Treatment-refractory asynchrony of the sleep–wake cycle in an N24SWD patient with depression was successfully treated with aripiprazole. Although the detailed mechanism of action is unclear, aripiprazole may be an appropriate treatment for patients with circadian rhythm sleep–wake disorders. Keywords: circadian rhythm sleep–wake disorder, non-24-hour sleep–wake rhythm disorder, melatonin, long sleep duration, antipsychotic

Kotaro Ono,1 Yoshikazu Takaesu,1 Yukiei Nakai,2 Akiyoshi Shimura,1 Yasuyuki Ono,1 Akiko Murakoshi,1 Yasunori Matsumoto,1 Hajime Tanabe,3 Ichiro Kusumi,2 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, Tokyo, 2Department of Psychiatry, Hokkaido University Graduate School of Medicine, Hokkaido, 3Department of Clinical Human Sciences, Graduate school of Humanities and Social Sciences, Shizuoka University, Shizuoka, Japan Background: Recent studies have suggested that the interactions among several factors affect the onset, progression, and prognosis of major depressive disorder. This study investigated how childhood abuse, neuroticism, and adult stressful life events interact with one another and affect depressive symptoms in the general adult population. Subjects and methods: A total of 413 participants from the nonclinical general adult population completed the Patient Health Questionnaire-9, the Child Abuse and Trauma Scale, the neuroticism subscale of the shortened Eysenck Personality Questionnaire – Revised, and the Life Experiences Survey, which are self-report scales. Structural equation modeling (Mplus version 7.3) and single and multiple regressions were used to analyze the data. Results: Childhood abuse, neuroticism, and negative evaluation of life events increased the severity of the depressive symptoms directly. Childhood abuse also indirectly increased the negative appraisal of life events and the severity of the depressive symptoms through enhanced neuroticism in the structural equation modeling. Limitations: There was recall bias in this study. The causal relationship was not clear because this study was conducted using a cross-sectional design. Conclusion: This study suggested that neuroticism is the mediating factor for the two effects of childhood abuse on adulthood depressive symptoms and negative evaluation of life events. Childhood abuse directly and indirectly predicted the severity of depressive symptoms. Keywords: childhood abuse, depression, neuroticism, stressful life events, structural equation modeling

Yukika Takita,1 Yoshikazu Takaesu,1 Kotaro Ono,1 Kunihiro Futenma,1 Akiyoshi Shimura,1 Akiko Murakoshi,1 Yoko Komada,2 Yuichi Inoue,1,2 Takeshi Inoue1 1Department of Psychiatry, 2Department of Somnology, Tokyo Medical University, Tokyo, Japan Background: High-dose use of benzodiazepines (BZPs) reportedly causes adverse effects on cognitive function and quality of life in patients with schizophrenia. However, effects of BZPs on the clinical course of schizophrenia have not been clarified. This study was set out to investigate the association between BZPs and rehospitalization of patients with schizophrenia.Methods: In this retrospective study, patients with schizophrenia who were discharged from Tokyo Medical University Hospital between January 2009 and February 2012 were eligible as subjects. One hundred and eight patients who continued treatment for >2 years after hospital discharge were included in this study. Clinical characteristics, doses of prescribed medication such as BZPs and antipsychotics, and Global Assessment of Functioning scores at discharge were investigated. The primary outcome was rehospitalization of patients for any reason.Results: In a total of 108 subjects with schizophrenia, 44 subjects (40.7%) experienced rehospitalization during the 2-year study period. A multivariate analysis by the Cox proportional hazards model revealed that low educational history (hazard ratio =2.43, P=0.032), younger onset age of schizophrenia (hazard ratio =2.10, P=0.021), and higher diazepam-equivalent dose (hazard ratio =6.53, P=0.011) were significantly associated with the time to rehospitalization after hospital discharge.Conclusion: The results of this study suggest that high-dose use of BZPs at discharge in patients with schizophrenia might be associated with a shorter time to rehospitalization. Keywords: schizophrenia, rehospitalization, risk factor, high-dose benzodiazepine, Cox proportional hazards model

Koichiro Watanabe,1 Eiji Harada,2 Takeshi Inoue,3 Yuka Tanji,2 Toshiaki Kikuchi1 1Department of Neuropsychiatry, Kyorin University, School of Medicine, Tokyo, 2Medical Science, Medicines Development Unit-Japan, Eli Lilly Japan KK, Hyogo, 3Department of Psychiatry, Tokyo Medical University, Tokyo, Japan Abstract: Bipolar disorder is a recurrent and episodic illness. This survey study assessed experiences and identified clinical insights of individuals with bipolar disorder. An Internet-based monitor system database was screened for patients with bipolar disorder in Japan (February and March 2013). Of 1,050 patients, 457 completed surveys, and results were analyzed with descriptive statistics. Approximately one-fourth of respondents were diagnosed with bipolar disorder on their first visit to medical institutions, although the most common initial diagnosis was depression/depressive state (65%). Mean time lag between first-time visit to a medical institution and receipt of correct diagnosis of bipolar disorder was 4 years; one-third of patients experienced more than 5 years of lag time. Three perceived reasons for lapsed time before correct diagnosis were “(patients) Did not consider manic symptoms as illness, and did not tell the doctor about them,” “I (patient) did not know of bipolar disorder,” and “Lack of communication between my doctor and myself (patient).” Among participants who believed that they were initially incorrectly diagnosed and improperly treated, most experienced socioeconomic problems, such as having long-term inability to work or to study (65%). Sources of encouragement for participants included “To have someone to consult with” (41%) followed by having “People around me treat me the same as before” (40%). Individuals with bipolar disorder reported a time lag of many years before accurate diagnosis, and substantial burden imposed by the illness. Encouragement should be provided for individuals to live positively with bipolar disorder. Keywords: bipolar disorder, mania, depression, perception, diagnosis, cost of illness

Yasuya Nakato,1 Takeshi Inoue,1,2 Shin Nakagawa,1 Yuji Kitaichi,1 Rie Kameyama,1 Yumi Wakatsuki,1 Kan Kitagawa,1 Yuki Omiya,1 Ichiro Kusumi1 1Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, 2Department of Psychiatry, Tokyo Medical University, Tokyo, Japan Background: The Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A) is a 110-item questionnaire that assesses five affective temperaments. However, a valid shortened version is desired for large-scale investigations to enhance the compliance of respondents. Methods: A confirmatory factor analysis was conducted among 320 psychiatric patients and 61 general adults. The participants completed the Japanese 39-item short version of the TEMPS-A, and a portion of the participants completed the 110-item version. An exploratory factor analysis with the principal factor method and varimax rotation was conducted to identify a more suitable model of the short version of the TEMPS-A. Results: The confirmatory factor analysis revealed that the 39-item version exhibited a poor model fit. However, we found that the 18-item version exhibited a firm five-factor structure based on the exploratory factor analysis, and this model exhibited an acceptable model fit. It had good or acceptable internal consistency (Cronbach’s αs: 0.672–0.819). Limitations: The majority of the subjects in the present study were patients, and the temperament data may have been affected by psychiatric symptoms. Conclusion: A firm five-factor structure was not found in the 39-item short version of the Japanese TEMPS-A. Therefore, an 18-item version was proposed. This new 18-item version of the TEMPS-A might be useful for clinical applications and large-scale investigations. Keywords: TEMPS-A, affective temperament, depression, validation, confirmatory factor analysis

Yoshiaki Kanai,1,2 Yoshikazu Takaesu,1 Yukiei Nakai,3 Masahiko Ichiki,1 Mitsuhiko Sato,1 Yasunori Matsumoto,1 Jun Ishikawa,1 Yasuyuki Ono,1 Akiko Murakoshi,1 Hajime Tanabe,4 Ichiro Kusumi,3 Takeshi Inoue1 1Department of Psychiatry, Tokyo Medical University, 2Department of Palliative Medicine, The University of Tokyo Hospital, Tokyo, 3Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, 4Department of Clinical Human Sciences, Graduate School of Humanities and Social Sciences, Shizuoka University, Shizuoka, Japan Background: Previous studies have shown the effects of childhood abuse, life events, and temperaments on well-being (positive affect) and ill-being (negative affect). We hypothesized that childhood abuse, affective temperaments, and adult life events interact with one another and influence positive and negative affects in the general adult population and tested this hypothesis using structural equation modeling. Methods: A total of 415 participants from the general, nonclinical adult population were studied using the following self-administered questionnaires: the Subjective Well-Being Inventory (SUBI); Life Experiences Survey (LES); Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A); and the Child Abuse and Trauma Scale (CATS). The data were analyzed with single and multiple regression analyses and structural equation modeling (Mplus). Results: Childhood abuse indirectly predicted the worsening of positive and negative affects through cyclothymic, anxious, and irritable temperaments as measured by the TEMPS-A in the structural equation model. The cyclothymic, anxious, and irritable temperaments directly worsened the positive and negative affects and the negative appraisal of life events that occurred during the past year, while the hyperthymic temperament had the opposite effects. Limitations: The subjects of this study were nonclinical volunteers. The findings might not be generalizable to psychiatric patients. Conclusion: This study demonstrated that childhood abuse, particularly neglect, indirectly worsened the well-being of individuals through cyclothymic, anxious, and irritable affective temperaments. An important “mediator” role of affective temperaments in the effect of childhood abuse on well-being was suggested. Keywords: childhood abuse, well-being, affective temperament, TEMPS-A, adult life events, structural equation model

Hiroyuki Toda,1 Takeshi Inoue,2,3 Tomoya Tsunoda,1 Yukiei Nakai,2 Masaaki Tanichi,1 Teppei Tanaka,1 Naoki Hashimoto,2 Yasuya Nakato,2 Shin Nakagawa,2 Yuji Kitaichi,2 Nobuyuki Mitsui,2 Shuken Boku,4 Hajime Tanabe,5 Masashi Nibuya,1 Aihide Yoshino,1 Ichiro Kusumi2 1Department of Psychiatry, National Defense Medical College, Tokorozawa, Saitama, Japan; 2Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan; 3Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 4Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan; 5Department of Clinical Human Sciences, Graduate School of Humanities and Social Sciences, Shizuoka University, Shizuoka, Japan Background: Previous studies have shown the interaction between heredity and childhood stress or life events on the pathogenesis of a major depressive disorder (MDD). In this study, we tested our hypothesis that childhood abuse, affective temperaments, and adult stressful life events interact and influence the diagnosis of MDD. Patients and methods: A total of 170 healthy controls and 98 MDD patients were studied using the following self-administered questionnaire surveys: the Patient Health Questionnaire-9 (PHQ-9), the Life Experiences Survey, the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire, and the Child Abuse and Trauma Scale (CATS). The data were analyzed with univariate analysis, multivariable analysis, and structural equation modeling. Results: The neglect scores of the CATS indirectly predicted the diagnosis of MDD through cyclothymic and anxious temperament scores of the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire in the structural equation modeling. Two temperaments – cyclothymic and anxious – directly predicted the diagnosis of MDD. The validity of this result was supported by the results of the stepwise multivariate logistic regression analysis as follows: three factors – neglect, cyclothymic, and anxious temperaments – were significant predictors of MDD. Neglect and the total CATS scores were also predictors of remission vs treatment-resistance in MDD patients independently of depressive symptoms. Limitations: The sample size was small for the comparison between the remission and treatment-resistant groups in MDD patients in multivariable analysis. Conclusion: This study suggests that childhood abuse, especially neglect, indirectly predicted the diagnosis of MDD through increased affective temperaments. The important role as a mediator of affective temperaments in the effect of childhood abuse on MDD was suggested. Keywords: neglect, major depressive disorder, affective temperament, mediator

Utako Kuroda, Toshihiro Inoue, Nanako Awai-Kasaoka, Kohei Shobayashi, Sachi Kojima, Hidenobu TaniharaDepartment of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanPurpose: To compare the surgical outcomes of limbal-based and fornix-based trabeculectomy in eyes with a history of ocular incisional surgery.Methods: Twenty-six eyes underwent limbal-based trabeculectomy (group LB), and were condition matched with 26 eyes that received fornix-based trabeculectomy (group FB). Surgical failure was recorded retrospectively if the intraocular pressure value was either ≥21, ≥18, and ≥15 mmHg (conditions A, B, and C, respectively) or

Sachi Kojima, Toshihiro Inoue, Takahiro Kawaji, Hidenobu TaniharaDepartment of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto, JapanPurpose: To determine the clinical features of tear fluid signs associated with filtration blebs via three-dimensional anterior segment optical coherence tomography (3D AS-OCT).Methods: In total, 152 eyes (130 patients) with glaucoma that underwent trabeculectomy with mitomycin C were evaluated retrospectively. We investigated tear fluid signs associated with filtration blebs, using 3D AS-OCT with custom software, and compared the findings of lower tear meniscus. We also analyzed postoperative intraocular pressure and the bleb parameters of filtration blebs between eyes with and without tear fluid signs.Results: We found tear fluid signs associated with filtration blebs in 45 (30%) of 152 eyes. The mean postoperative intraocular pressure of the eyes with the tear fluid sign in a filtration bleb was significantly lower than that in eyes without the tear fluid sign (P

Yuji Kitaichi,1 Takeshi Inoue,1 Nobuyuki Mitsui,1 Shin Nakagawa,1 Rie Kameyama,1 Yoshiyuki Hayashishita,1 Tohru Shiga,2 Ichiro Kusumi,1 Tsukasa Koyama1 1Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan Abstract: We report a case in which selegiline, an irreversible monoamine oxidase B (MAO-B) inhibitor, greatly improved depressive symptoms in an adult with stage 5 treatment-resistant major depressive disorder. Four antidepressants and four augmentation therapies had previously been ineffective or intolerable, and electroconvulsive therapy had only a temporary effect. After 20 weeks of treatment with selegiline (10 mg/day), the patient's score on the 17-item Hamilton Depression Rating Scale (HDRS) had decreased from 19 to 4 points. [18F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) showed increased glucose metabolism in the bilateral basal ganglia after initiating selegiline treatment; blood dopamine levels were also increased after selegiline treatment. These results raise the possibility that selegiline enhances dopaminergic neural transmission in treatment-resistant depression, thus leading to an improvement in depressive symptoms. Keywords: treatment-resistant depression, FDG-PET, glucose metabolism, basal ganglia

Akira Haga,1 Masaru Inatani,1,2 Kohei Shobayashi,1 Sachi Kojima,1 Toshihiro Inoue,1 Hidenobu Tanihara11Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, JapanPurpose: To evaluate the risk factors for choroidal detachment after trabeculectomy with mitomycin C (MMC).Materials and methods: We retrospectively evaluated 420 patients (420 eyes) with glaucoma who underwent trabeculectomy with MMC between June 1, 2005 and December 31, 2010 at Kumamoto University Hospital, Japan. Choroidal detachment after trabeculectomy was defined as a solid-appearing elevation of the retina and choroid. Logistic multivariable analysis was applied to determine the risk factors for choroidal detachment. The following factors were assessed: gender, age, subtypes of glaucoma, eye laterality, history of previous cataract surgery, preoperative intraocular pressure (IOP; mean of three Goldmann applanation readings recorded on different days), postoperative IOP (mean of seven Goldmann applanation readings recorded on 7 consecutive days after trabeculectomy), and postoperative laser suture lysis.Results: Of the 420 patients, 79 (18.8%) revealed choroidal detachments. The mean period between trabeculectomy and choroidal detachment was 6.1 ± 3.6 days. The mean IOP at the time of the choroidal detachment was 5.5 ± 3.6 mmHg. Age (odds ratio [OR] = 1.028/year, P = 0.0068) and postoperative IOP (OR = 0.887/mmHg, P < 0.0001) were risk factors for choroidal detachment after trabeculectomy. The subgroup analysis for eyes with open angle glaucoma (201 patients) revealed that age (OR = 1.060/year, P = 0.0040) and postoperative IOP (OR = 0.898/mmHg, P = 0.0110) were significant risk factors for choroidal detachment after trabeculectomy with MMC.Conclusion: Among glaucoma patients, older age and lower postoperative IOP are risk factors for choroidal detachment after trabeculectomy with MMC. In eyes with open angle glaucoma, older age and lower postoperative IOP are risk factors for choroidal detachment after trabeculectomy with MMC.Keywords: choroidal detachment, intraocular pressure, mitomycin C, trabeculectomy