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Background: Childhood parental bonding and cognitive complaints (CCs) affect a worker's mental health (MH), and CCs affect presenteeism. However, the impact of childhood parental bonding on presenteeism and the mediating effect of CCs with respect to the association among childhood parental bonding and presenteeism remain poorly understood., Aim: We aimed to investigate the mediating role of CCs on the relationship between childhood parental bonding and presenteeism to better understand the influence of childhood parental bonding on adulthood presenteeism., Setting: A total of 440 Japanese adult workers recruited using convenience sampling were evaluated., Methods: The Parental Bonding Instrument, Cognitive Complaints in Bipolar Disorder Rating Assessment and Work Limitations Questionnaire 8 were used to assess childhood parental bonding, CCs, and presenteeism, respectively. We performed Spearman's correlation analysis and path analysis to investigate the relationship among the variables., Results: Path analysis revealed that childhood parental bonding and CCs significantly affected presenteeism. More specifically, CCs fully and partially mediated the effect of paternal and maternal care on presenteeism, respectively. Moreover, CCs partially mediated the effects of both paternal and maternal overprotection on presenteeism., Conclusion: The mediating role of CCs on the relationship between childhood parental bonding and presenteeism was shown in this study. In occupational MH, evaluating the mediating effect of CCs may be useful for addressing adulthood presenteeism associated with childhood parental bonding., Competing Interests: JM has received personal compensation from Otsuka Pharmaceutical, Eli Lilly, Astellas, and Meiji Yasuda Mental Health Foundation, as well as grants from Pfizer. IK has received honoraria from Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Lundbeck, Meiji Seika Pharma, Mochida Pharmaceutical, MSD, Mylan, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Shionogi, Shire, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, Tsumura, and Yoshitomiyakuhin, and has received research/grant support from Asahi Kasei Pharma, Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Mochida Pharmaceutical, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, Takeda Pharmaceutical and Tanabe Mitsubishi Pharma. TI is a member of the advisory boards of Pfizer, Novartis Pharma, and Mitsubishi Tanabe Pharma and has received personal fees from Mochida Pharmaceutical, Takeda Pharmaceutical, Eli Lilly, Janssen Pharmaceutical, MSD, Taisho Toyama Pharmaceutical, Yoshitomiyakuhin, and Daiichi Sankyo; he has received grants from Shionogi, Astellas, Tsumura, and Eisai and grants and personal fees from Otsuka Pharmaceutical, Dainippon Sumitomo Pharma, Mitsubishi Tanabe Pharma, Kyowa Pharmaceutical Industry, Pfizer, Novartis Pharma, and Meiji Seika Pharma. YF received research and grant support from Novartis Pharma, Otsuka Pharmaceutical, Astellas, Dainippon Sumitomo Pharma, and Shionogi. SH has received honoraria from Dainippon Sumitomo Pharma and Novartis Pharma. Akiyoshi Shimura reports personal fees from Eisai, Dainippon Sumitomo Pharma, MSD, Yoshitomi Yakuhin, and Meiji Seika Pharma, outside the submitted work. KT does not have any actual or potential conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Social anxiety disorder (SAD) develops in the early teens and is a common disorder among university students. Understanding the predictive factors of SAD comorbid with major depressive episode (MDE) is important for student mental health care. The aim of this study was to identify the personality traits that predict SAD with MDE by analyzing longitudinal data of Japanese university students., Methods: In this retrospective study, Japanese university students who visited the health care center of Hokkaido University for the first time were divided into the following four groups: "Control" (n = 43), "MDE" (n = 16), "SAD" (n = 28), and "SAD with MDE" (n = 61) based on the Patient Health Questionnaire-9 (PHQ-9), the Liebowitz Social Anxiety Scale, and core anxiety symptoms for SAD in the Mini International Neuropsychiatric Interview during screening. Predictors for SAD with MDE were identified by a four-group comparison of the Temperament and Character Inventory and PHQ-9 data previously obtained at the enrollment using analysis of variance and post-hoc tests., Results: Upon comparing the four groups using analysis of variance, there were significant differences in the baseline PHQ-9 summary score, Harm-Avoidance (HA), and Self-Directedness (SD). According to results of the post-hoc test, all three showed a significant difference between the "Control" and "SAD with MDE." Furthermore, there was a significant difference in HA scores between "SAD" and "Control." In all the groups, the mean time from enrollment to the first visit to the center was >2 years., Conclusion: A higher HA score at baseline is a predictor of SAD with or without MDE. Higher PHQ-9 summary and lower SD scores at baseline are predictive factors of SAD with MDE., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Nobuyuki Mitsui received lecture fees from Mochida Pharmaceutical. Satoshi Asakura has received honoraria from Mochida Pharmaceutica and Yoshitomiyakuhin. Keisuke Takanobu received personal fees from Tsumura & Co. and Otsuka Pharmaceutical. Yutaka Fujii received personal fees from Yoshitomiyakuhin, Otsuka Pharmaceutical, Dainippon Sumitomo Pharma, Eisai and Meiji Seika Pharma. Yuki Kako has received honoraria from Dainippon Sumitomo Pharma, Eli Lilly, Otsuka Pharmaceutical, Tanabe Mitsubishi Pharma, and Yoshitomiyakuhin. Ichiro Kusumi has received honoraria from Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Lundbeck, Meiji Seika Pharma, MSD, Mylan, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Shionogi, Shire, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Tsumura, and Yoshitomiyakuhin, and has received research/grant support from Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Kyowa Hakko Kirin, Mochida Pharmaceutical, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, and Takeda Pharmaceutical. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors do not have any potential competing interests.

Aim: To enable early identification of university students at high risk for suicide, we examined personality as a predictive factor for major depressive episodes and suicide-related ideation., Methods: From 2011 to 2013, we administered the Patient Health Questionnaire-9 (PHQ-9) and the Temperament and Character Inventory (TCI) to 1,997 university students at enrollment (T1). We previously conducted a study using the same data set; this is a re-analysis of the dataset. To prevent contamination of data, participants diagnosed with a depressive episode were excluded at T1. Three years after enrollment (T2), we re-administered the PHQ-9 to the same students. We statistically compared TCI scores at T1 among depressive episode groups and suicide-related ideation groups. Two-way ANOVA and Cochran-Armitage trend tests were used to analyze the relationships between personality traits, depressive episodes, and suicide-related ideation., Results: The PHQ-9 summary scores at baseline (T1) were 3.0 (±2.7), with female students scoring 4.6 (±2.9) and male students 2.9 (±2.6, p = 0.025). The major depressive episode group at T2 had lower self-directedness (SD) scores at T1 than the non-depressive episode control group. The suicide-related ideation (SI) group at T2 also had higher harm avoidance (HA), lower SD, and lower cooperativeness (C) scores than the non-SI group at T1. The Cochran-Armitage trend tests revealed significant associations between character configurations composed of SD and C, and both depressive episodes at T2 and SI at T2., Conclusion: The temperament feature of high HA at baseline and character configurations of low SD and low C at baseline are the most contributory predictors for the novel development of depressive episodes and SI among Japanese university students., Competing Interests: KT has received personal fees from Tsumura & Co. and Otsuka Pharmaceutical. NM received lecture fees from Mochida Pharmaceutical. YF has received personal fees from Yoshitomiyakuhin, Otsuka Pharmaceutical, Dainippon Sumitomo Pharma, Eisai and Meiji Seika Pharma. YK has received honoraria from Dainippon Sumitomo Pharma, Eli Lilly, Otsuka Pharmaceutical, Tanabe Mitsubishi Pharma, and Yoshitomiyakuhin. SA has received honoraria from Mochida Pharmaceutica and Yoshitomiyakuhin. IK has received honoraria from Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Lundbeck, Meiji Seika Pharma, MSD, Mylan, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Shionogi, Shire, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Tsumura, and Yoshitomiyakuhin, and has received research/grant support from Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Kyowa Hakko Kirin, Mochida Pharmaceutical, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, and Takeda Pharmaceutical. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors do not have any potential competing interests.

Background: Childhood maltreatment affects social functioning in the general adult population. However, how child abuse affects functional disability in adulthood remains unknown. Thus, we investigated the correlation between child abuse, depressive symptoms, cognitive complaints, and functional disability in adult community volunteers., Methods: Participants (N = 556) completed the Child Abuse and Trauma Scale, Patient Health Questionnaire-9, Cognitive Complaints in Bipolar Disorder Rating Assessment, and Sheehan Disability Scale. Multiple regression analyses and structural equation modeling were performed to evaluate scale correlations., Results: Structural equation modeling showed that the direct effect of childhood maltreatment on depressive symptoms, the indirect effect of childhood maltreatment on cognitive function via depressive symptoms, and the indirect effects of childhood maltreatment on functional disability via depressive symptoms and via cognitive function were all significant. The direct effects of childhood maltreatment on cognitive function and functional disability were not significant. There was no significant association between variables., Limitations: Cross-sectional designs cannot identify causal relationships between parameters. Participants were adult volunteers from the community; therefore, results may not be generalizable to individuals with psychiatric disorders. Sociodemographic variability was a limitation because we used self-reported childhood maltreatment., Conclusions: Childhood maltreatment indirectly affects functional disability via depressive symptoms and via cognitive function through depressive symptoms. We suggest that depressive symptoms and cognitive function play crucial roles in the influence of childhood maltreatment on functional disability in adult community volunteers., Competing Interests: Jiro Masuya has received personal compensation from Otsuka Pharmaceutical, Eli Lilly, Astellas, and Meiji Yasuda Mental Health Foundation, as well as grants from Pfizer. Ichiro Kusumi has received honoraria from Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Lundbeck, Meiji Seika Pharma, MSD, Mylan, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Shionogi, Shire, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Tsumura, and Yoshitomiyakuhin, and has received research/grant support from Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Kyowa Hakko Kirin, Mochida Pharmaceutical, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, and Takeda Pharmaceutical, and is a member of the advisory board of Dainippon Sumitomo Pharma. Takeshi Inoue is a member of the advisory boards of Pfizer, Novartis Pharma, and Mitsubishi Tanabe Pharma and has received personal fees from Mochida Pharmaceutical, Takeda Pharmaceutical, Eli Lilly, Janssen Pharmaceutical, MSD, Taisho Toyama Pharmaceutical, Yoshitomiyakuhin, and Daiichi Sankyo; grants from Shionogi, Astellas, Tsumura, and Eisai; and grants and personal fees from Otsuka Pharmaceutical, Dainippon Sumitomo Pharma, Mitsubishi Tanabe Pharma, Kyowa Pharmaceutical Industry, Pfizer, Novartis Pharma, and Meiji Seika Pharma. Yota Fujimura received research and grant support from Novartis Pharma, Otsuka Pharmaceutical, Astellas, Dainippon Sumitomo Pharma, and Shionogi. Shinji Higashi received honoraria from Dainippon Sumitomo Pharma and Novartis Pharma. The others do not have any actual or potential conflict of interest. This does not alter our adherence to the PLOS ONE policies on sharing data and materials.

Background: The association between temperament characteristics and mood disorders has gained much attention in recent years. The Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A) is a self-rating scale measuring 5 affective temperament dimensions. In this study, we aimed to clarify whether each affective temperament of TEMPS-A is a differentiating factor between major depressive disorder (MDD), bipolar I disorder (BD-I), and bipolar II disorder (BD-II), and analyzed the utility of TEMPS-A in their differential diagnosis in a clinical setting., Methods: A total of 346 patients (MDD, n = 176; BD-II, n = 112; BD-I, n = 58) filled out TEMPS-A. To assess the patients' mood state at the time of temperament assessment, Patient Health Questionnaire-9 (PHQ-9) and Young Mania Rating Scale (YMRS) were also conducted., Results: Multivariate logistic regression analysis demonstrated that cyclothymic and anxious temperament scores were significant factors differentiating the diagnosis of BD-I and BD-II from the diagnosis of MDD, and hyperthymic temperament score was a specific factor for the differential diagnosis of BD-I versus the diagnosis of BD-II., Limitations: All of the patients included in our study received treatment in large general hospitals. Because the nature of the present study was cross-sectional, some MDD subjects in this study might have unrecognized BD-I/BD-II., Conclusions: Cyclothymic and anxious temperament scores assessed by TEMPS-A might enable differentiation between MDD and BD, and hyperthymic temperament score on TEMPS-A might be useful in distinguishing between BD-I and BD-II., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Jiro Masuya has received personal compensation from Otsuka Pharmaceutical, Eli Lilly, Astellas, and Meiji Yasuda Mental Health Foundation, and grants from Pfizer. Masahiko Ichiki has received personal compensation from Otsuka Pharmaceutical, Pfizer, Eli Lilly, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Meiji Seika Pharma, Janssen Pharmaceutical, Takeda Pharmaceutical, MSD, Dainippon Sumitomo Pharma, and Eisai; grants from Otsuka Pharmaceutical, Eli Lilly, Eisai, Shionogi, Takeda Pharmaceutical, MSD, and Pfizer; and is a member of the advisory board of Meiji Seika Pharma. Ichiro Kusumi has received personal compensation from Astellas, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Nippon Chemiphar, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Mitsubishi Tanabe Pharma, Shionogi, and Yoshitomiyakuhin; has received research/grant support from AbbVie GK, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Shionogi, and Yoshitomiyakuhin; and is a member of the advisory board of Dainippon Sumitomo Pharma and Tanabe Mitsubishi Pharma. Takeshi Inoue has received personal compensation from Mochida Pharmaceutical, Takeda Pharmaceutical, Eli Lilly, Janssen Pharmaceutical, MSD, Taisho Toyama Pharmaceutical, Yoshitomiyakuhin, and Daiichi Sankyo; grants from Shionogi, Astellas, Tsumura, and Eisai; grants and personal fees from Otsuka Pharmaceutical, Dainippon Sumitomo Pharma, Mitsubishi Tanabe Pharma, Kyowa Pharmaceutical Industry, Pfizer, Novartis Pharma, and Meiji Seika Pharma; and is a member of the advisory boards of Pfizer, Novartis Pharma, and Mitsubishi Tanabe Pharma. All other authors declare that they have no actual or potential conflicts of interest associated with this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Suicide has been a leading cause of death among young adult populations in Japan. The aim of this study was to predict major depressive episodes (MDEs) and suicide-related ideation among university students using the Patient Health Questionnaire-9 (PHQ-9) and the Temperament and Character Inventory (TCI)., Methods: The subjects were 2194 university students who completed the PHQ-9 and TCI in the 1st year (T1) and the PHQ-9 in the 4th year (T2) of university. Multiple logistic regression analysis was performed to predict MDEs and suicide-related ideation at T2. Moreover, recursive partitioning analyses were conducted to reveal the future risk of MDEs and suicide-related ideation., Results: The multiple logistic regression analyses of MDEs and suicide-related ideation at T2 revealed that depressive episodes, suicide-related ideation, and low self-directedness(SD) scores at T1 were significant predictors. The area under the curve of the model for MDEs was 0.858 and that for suicide-related ideation was 0.741. The recursive partitioning analyses revealed that a PHQ-9 summary score ≥15 at T1 predicted a high risk of MDEs at T2 and that both a PHQ-9 summary score ≥5 and a PHQ-9 #9 score ≥1 predicted a high risk of suicide-related ideation at T2., Conclusions: MDEs, suicide-related ideation, and low SD scores are significant predictors of future MDEs and suicide-related ideation., Competing Interests: The authors have declared that no competing interests exist.

Although the Japanese diet is believed to be balanced and healthy, its benefits have been poorly investigated, especially in terms of effects on mental health. We investigated dietary patterns and physical and mental health in the Japanese population using an epidemiological survey to determine the health benefits of the traditional Japanese diet. Questionnaires to assess dietary habits, quality of life, sleep quality, impulsivity, and depression severity were distributed to 550 randomly selected middle-aged and elderly individuals. Participants with any physical or mental disease were excluded. Two-hundred and seventy-eight participants were selected for the final statistical analysis. We determined rice to be one of the most traditional foods in Japanese cuisine. Scores for each questionnaire were computed, and the correlations between rice intake and health indices were assessed. When analyzing the direct correlations between rice intake and health indices, we found only two correlations, namely those with quality of life (vitality) and sleep quality. Path analysis using structural equation modeling was performed to investigate the association between rice intake and health, with indirect effects included in the model. Additional associations between rice intake and health were explained using this model when compared to those using direct correlation analysis. Path analysis was used to identify mediators of the rice-health association. These mediators were miso (soybean paste) soup, green tea, and natto (fermented soybean) intake. Interestingly, these mediators have been major components of the Japanese diet since 1975, which has been considered one of the healthiest diets since the 1960s. Our results indicate that the combination of rice with other healthy foods, which is representative of the traditional Japanese diet, may contribute to improvements in physical and mental health.

Several studies of self-monitoring dysfunction in schizophrenia have focused on the sense of agency to motor action using behavioral and psychophysiological techniques. So far, no study has ever tried to investigate whether the sense of agency or causal attribution for external events produced by self-generated decision-making is abnormal in schizophrenia. The purpose of this study was to investigate neural responses to feedback information produced by self-generated or other-generated decision-making in a multiplayer gambling task using even-related potentials and electroencephalogram synchronization. We found that the late positive component and theta/alpha synchronization were increased in response to feedback information in the self-decision condition in normal controls, but that these responses were significantly decreased in patients with schizophrenia. These neural activities thus reflect the self-reference effect that affects the cognitive appraisal of external events following decision-making and their impairment in schizophrenia.

Several studies indicate that dietary habits are associated with mental health. We are interested in identifying not a specific single nutrient/food group but the population preferring specific food combinations that can be related to mental health. Very few studies have examined relationships between dietary patterns and multifaceted mental states using cluster analysis. The purpose of this study was to investigate population-level dietary patterns associated with mental state using cluster analysis. We focused on depressive state, sleep quality, subjective well-being, and impulsive behaviors using rating scales. Two hundred and seventy-nine Japanese middle-aged people participated in the present study. Dietary pattern was estimated using a brief self-administered diet-history questionnaire (the BDHQ). We conducted K-means cluster analysis using thirteen BDHQ food groups: milk, meat, fish, egg, pulses, potatoes, green and yellow vegetables, other vegetables, mushrooms, seaweed, sweets, fruits, and grain. We identified three clusters characterized as "vegetable and fruit dominant," "grain dominant," and "low grain tendency" subgroups. The vegetable and fruit dominant group showed increases in several aspects of subjective well-being demonstrated by the SF-8. Differences in mean subject characteristics across clusters were tested using ANOVA. The low frequency intake of grain group showed higher impulsive behavior, demonstrated by BIS-11 deliberation and sum scores. The present study demonstrated that traditional Japanese dietary patterns, such as eating rice, can help with beneficial changes in mental health.

Background: Suicide rates are vastly higher in Japan than in many other countries, although the associations between affective temperaments and suicide-related ideations in the general adult population remain unclear. Therefore, we aimed to elucidate these associations in the present study., Methods: We analyzed data from 638 Japanese volunteers who completed both the Patient Health Questionnaire (PHQ-9) and the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A). Participants were then divided into three groups based on PHQ-9 summary scores and responses to the suicide-related ideation item: non-depressive control group (NC; N = 469), depressive symptoms without suicide-related ideations group (non-SI; N = 135), and depressive symptoms with suicide-related ideations group (SI; N = 34). The depressive symptoms were defined for PHQ-9 summary scores ≥5, and the suicide-related ideations were defined for PHQ-9 #9 score ≥1. We then compared TEMPS-A scores among the groups using Kruskal-Wallis tests. Then the 95% confidence intervals of differences in TEMPS-A subscale scores between the NC and non-SI groups, or between NC and SI groups, were calculated., Results: Participants of the SI group exhibited significantly higher scores on the depressive, irritable, and anxious temperament subscales than those of the non-SI group. Similarly, women of the SI group exhibited significantly higher scores of the depressive and irritable temperament subscales than women of the non-SI group, while men of the SI group exhibited significantly higher depressive temperament scores than those of the non-SI group. Among all participants and only men, cyclothymic subscale scores were higher in those of the SI group than the non-SI group (not significant), although the 95% confidence intervals did not overlap., Limitations: The cross-sectional study design was the main limitation., Conclusions: Depressive, irritable, and anxious temperaments are significant risk factors for suicide-related ideations in the Japanese general adult population. Furthermore, irritable temperament in women and depressive temperament in men are associated with suicide-related ideations.

Objective: Surgical intervention can result in complete seizure remission rates of up to 80% in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). However, certain patients cannot be treated surgically for various reasons. We analyzed the very long-term clinical outcomes of patients with TLE-HS who could not be treated surgically., Methods: Subjects were selected from among patients with TLE-HS who were actively followed up for >10 years and treated with medication without surgical treatment. Patient medical records were used to retrospectively study seizure frequency, various clinical factors, and social adjustment. Patients who were seizure-free or had only aura were classified into Group 1; the others were classified into Group 2. Clinical factors including both patient and disease-specific factors were compared between the two groups. Current social adjustment, including the education, work, and economic status of each patient, was also investigated., Results: Forty-one (41) subjects met the criteria for analysis, of which 12 (29%) were classified into Group 1. The average age of patients in Group 1 was higher than that of Group 2 (p = 0.0468). Group 2 included a significantly higher rate of patients who had more than one seizure per week at the onset (p = 0.0328), as well as a greater mean number of anti-epileptic drugs taken (p = 0.0024). Regarding social adjustment, Group 2 contained significantly fewer current jobholders than Group 1 (p = 0.0288)., Conclusions: After very long-term follow-up periods, 29% of patients with TLE-HS had a good outcome through treatment with anticonvulsant medications. Older patients tended to have fewer seizures, and seizure frequency at the onset was the only factor that predicted outcome.

The serotonergic pathway has been implicated in the pathogenesis of impulsivity, and sensitivity to aversive outcomes may be linked to serotonin (5-HT) levels. Polymorphisms in the gene that encodes the serotonin transporter (5-HTT), which have differential effects on the level of serotonin transmission, display alternate responses to aversive stimuli. However, recent studies have shown that 5-HT does not affect motor function, which suggests that the functioning of the serotonin-transporter-linked polymorphic region (5-HTTLPR) does not directly affect the behavioral regulatory process itself, but instead exerts an effect via the evaluation of the potential risk associated with particular behavioral outputs. The aim of the present study was to examine the effect of specific 5-HTTLPR genotypes on the motor regulatory process, as observed during a Go/Nogo punishment feedback task. 5-HTT gene-linked promoter polymorphisms were analyzed by polymerase chain reaction, using lymphocytes from 61 healthy Japanese volunteers. Impulsivity was defined as the number of commission errors (responding when one should not) made during a Go/Nogo task. We found that the s/s genotype group made fewer impulsive responses, specifically under aversive conditions for committing such errors, compared to those in the s/l group, without affecting overall motor inhibition. These results suggest that 5-HTTLPRs do not directly affect the behavioral regulatory process itself, but may instead exert an effect on the evaluation of potential risk. The results also indicate that under such aversive conditions, decreased expression of 5-HTT may promote motor inhibitory control.

Stress during postnatal development is associated with an increased risk for depression, anxiety disorders, and substance abuse later in life, almost as if mental illness is able to be programed by early life stressors. Recent studies suggest that such "programmed" effects can be caused by epigenetic regulation. With respect to conditioned fear, previous studies have indicated that early life stress influences its development in adulthood, whereas no potential role of epigenetic regulation has been reported. Neurotensin (NTS) is an endogenous neuropeptide that has receptors densely located in the amygdala and hippocampus. Recently, NTS systems have constituted an emerging target for the treatment of anxiety. The aim of the present work is to clarify whether the NTS system is involved in the disturbance of conditioned fear in rats stressed by maternal separation (MS). The results showed that MS enhanced freezing behaviors in fear-conditioned stress and reduced the gene expression of NTS receptor (NTSR) 1 but not of NTS or NTSR2 in the amygdalas of adult rats. The microinjection of a NTSR1 antagonist into the amygdala increased the percentage of freezing in conditioned fear, whereas the microinjection of NTSR1 agonist decreased freezing. These results suggest that NTSR1 in the amygdala may play a role in the effects of MS on conditioned fear stress in adult rats. Moreover, MS increased DNA methylation in the promoter region of NTSR1 in the amygdala. Taken together, MS may leave epigenetic marks in the NTSR1 gene in the amygdala, which may enhance conditioned fear in adulthood. The MS-induced alternations of DNA methylation in the promoter region of NTSR1 in the amygdala may be associated with vulnerability to the development of anxiety disorders and depression in adulthood.

Antidepressants increase the proliferation of neural precursors in adult dentate gyrus (DG), which is considered to be involved in the therapeutic action of antidepressants. However, the mechanism underlying it remains unclear. By using cultured adult rat DG-derived neural precursors (ADP), we have already shown that antidepressants have no direct effects on ADP. Therefore, antidepressants may increase the proliferation of neural precursors in adult DG via unknown indirect mechanism. We have also shown that amitriptyline (AMI), a tricyclic antidepressant, induces the expressions of GDNF, BDNF, FGF2 and VEGF, common neurogenic factors, in primary cultured astrocytes (PCA). These suggest that AMI-induced factors in astrocytes may increase the proliferation of neural precursors in adult DG. To test this hypothesis, we examined the effects of AMI-induced factors and conditioned medium (CM) from PCA treated with AMI on ADP proliferation. The effects of CM and factors on ADP proliferation were examined with BrdU immunocytochemistry. AMI had no effect on ADP proliferation, but AMI-treated CM increased it. The receptors of GDNF, BDNF and FGF2, but not VEGF, were expressed in ADP. FGF2 significantly increased ADP proliferation, but not BDNF and GDNF. In addition, both of a specific inhibitor of FGF receptors and anti-FGF2 antibody significantly counteracted the increasing effect of CM on ADP proliferation. In addition, FGF2 in brain is mainly derived from astrocytes that are key components of the neurogenic niches in adult DG. These suggest that AMI may increase ADP proliferation indirectly via PCA and that FGF2 may a potential candidate to mediate such an indirect effect of AMI on ADP proliferation via astrocytes.

Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study., Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling., Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders)., Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Major depression, because of its recurring and life-threatening nature, is one of the top 10 diseases for global disease burden. Major depression is still diagnosed on the basis of clinical symptoms in patients. The search for specific biological markers is of great importance to advance the method of diagnosis for depression. We examined the methylation profile of 2 CpG islands (I and IV) at the promoters of the brain-derived neurotrophic factor (BDNF) gene, which is well known to be involved in the pathophysiology of depression. We analyzed genomic DNA from peripheral blood of 20 Japanese patients with major depression and 18 healthy controls to identify an appropriate epigenetic biomarker to aid in the establishment of an objective system for the diagnosis of depression. Methylation rates at each CpG unit was measured using a MassArray® system (SEQUENOM), and 2-dimensional hierarchical clustering analyses were undertaken to determine the validity of these methylation profiles as a diagnostic biomarker. Analyses of the dendrogram from methylation profiles of CpG I, but not IV, demonstrated that classification of healthy controls and patients at the first branch completely matched the clinical diagnosis. Despite the small number of subjects, our results indicate that classification based on the DNA methylation profiles of CpG I of the BDNF gene may be a valuable diagnostic biomarker for major depression.