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Several lines of evidence suggest that stress induces the neurovascular dysfunction associated with increased blood–brain barrier (BBB) permeability, which could be an important pathology linking stress and psychiatric disorders, including major depressive disorder (MDD). However, the detailed mechanism resulting in BBB dysfunction associated in the pathophysiology of MDD still remains unclear. Herein, we demonstrate the role of vascular endothelial growth factor (VEGF), a key mediator of vascular angiogenesis and BBB permeability, in stress-induced BBB dysfunction and depressive-like behavior development. We implemented an animal model of depression, chronic restraint stress (RS) in BALB/c mice, and found that the BBB permeability was significantly increased in chronically stressed mice. Immunohistochemical and electron microscopic observations revealed that increased BBB permeability was associated with both paracellular and transcellular barrier alterations in the brain endothelial cells. Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction.

There is no scientific consensus that a relationship exists between the ABO blood group and personality traits. However, a recent study hypothesized that the dopamine beta-hydroxylase (DBH) gene is in linkage with the ABO gene. The sample population consisted of 1,427 healthy Japanese subjects who completed the Temperament and Character Inventory (TCI). Each subject's ABO blood type was determined by genotyping the rs8176719 and rs8176746 ABO gene single-nucleotide polymorphisms (SNPs) using a TaqMan genotyping assay. The relationships between the six ABO genotypes or four ABO phenotypes and personality traits were examined using a multivariate analysis of covariance (MANCOVA), controlling for age and sex. The MANCOVA data showed a significant difference in TCI scores among the ABO genotype groups (F [7, 1393] = 3.354, p = 0.001). A subsequent univariate analysis showed a significant difference in the mean scores for Persistence among the genotype groups (F = 2.680, partial η2 = 0.010, p = 0.020). Similarly, dividing the ABO blood type into four phenotypes revealed a significant difference among the phenotype groups (F [7, 1397] = 2.529, p = 0.014). A subsequent univariate analysis showed a significant difference among the phenotype groups in the mean scores for Persistence (F = 2.952, partial η2= 0.006, p = 0.032). We observed a significant association between ABO blood group genotypes and personality traits in a large number of healthy Japanese subjects. However, these results should be regarded as preliminary and should be interpreted with caution because it is possible that the association between ABO blood group genotype and the Persistence trait is relatively weak.

Dorsal stream, which has a neuronal connection with dorsolateral prefrontal cortex (DLPFC), is known to be responsible for detection of motion including optic flow perception. Using magnetoencephalography (MEG), this study aimed to examine neural responses to optic flow stimuli with looming motion in the DLPFC in patients with mild cognitive impairment due to Alzheimer’s disease (AD-MCI) compared with cognitively unimpaired participants (CU). We analyzed the neural responses by evaluating maximum source-localized power for the AD-MCI group (n = 11) and CU (n = 20), focusing on six regions of interest (ROIs) that form the DLPFC: right and left dorsal Brodmann area 9/46 (A9/46d), Brodmann area 46 (A46) and ventral Brodmann area 9/46 (A9/46v). We found significant differences in the maximum power between the groups in the left A46 and A9/46v. Moreover, in the left A9/46v, the maximum power significantly correlated with the Wechsler Memory Scale-Revised general memory score and delayed recall score. The maximum power in the left A9/46v also revealed high performance in AD-MCI versus CU classification with the area under the ROC curve of 0.90. This study demonstrated that MEG during the optic flow task can be useful in discriminating AD-MCI from CU.

Background: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a pivotal role in regulating neuronal function throughout life, and this factor is regarded as a potential biomarker of mental disorders. However, previous studies have suggested that plasma BDNF levels are more variable than serum BDNF levels. Methods: We determined the influence of time and temperature on the measurement of peripheral blood BDNF levels. Blood samples were aliquoted into four types of tubes, including tubes containing heparin, ethylenediaminetetraacetic acid (EDTA), and citrate for plasma, and anticoagulant-free tubes for serum. The samples were stored at 4 or 25°C for 0, 1, 2, 4, 6, 24 or 48 h, and the plasma and serum BDNF levels were measured using enzyme-linked immunosorbent assay. Results: There were interindividual and interanticoagulant compound variability in the plasma BDNF levels. The measured plasma BDNF levels increased over time, whereas the serum BDNF levels remained unchanged. Furthermore, the BDNF levels detected in plasma stored in heparin tubes at 4°C and those for samples stored in EDTA tubes at 25°C were much higher than those of the other samples. Conclusion: This study indicates that measurements of plasma BDNF levels are dependent not only on the anticoagulant compounds but also on the storage time and temperature conditions used after blood sampling.

The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene has been associated with differences in prefrontal cognitive functions in patients with schizophrenia and healthy individuals. Several studies have indicated that the Met allele is associated with better performance on measures of cognitive function. We investigated whether the COMT Val158Met genotype was associated with cognitive function in 149 healthy controls and 118 patients with schizophrenia. Cognitive function, including verbal memory, working memory, motor speed, attention, executive function and verbal fluency, was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS-J). We employed a one-way analysis of variance (ANOVA) and a multiple regression analysis to determine the associations between the COMT Val158Met genotype and the BACS-J measurements. The one-way ANOVA revealed a significant difference in the scores on the Tower of London, a measure of executive function, between the different Val158Met genotypes in the healthy controls (p = 0.023), and a post-hoc analysis showed significant differences between the scores on the Tower of London in the val/val genotype group (18.6 ± 2.4) compared to the other two groups (17.6 ± 2.7 for val/met and 17.1 ± 3.2 for met/met; p = 0.027 and p = 0.024, respectively). Multiple regression analyses revealed that executive function was significantly correlated with the Val158Met genotype (p = 0.003). However, no evidence was found for an effect of the COMT on any cognitive domains of the BACS-J in the patients with schizophrenia. These data support the hypothesis that the COMT Val158Met genotype maintains an optimal level of dopamine activity. Further studies should be performed that include a larger sample size and include patients on and off medication, as these patients would help to confirm our findings.

The efficacy of treatment with selective serotonin reuptake inhibitors in patients with major depressive disorder (MDD) can differ depending on the patient's serotonin transporter-linked polymorphic region (5-HTTLPR) genotype, and the effects of varying plasma concentrations of drugs can also vary. We investigated the association between the paroxetine plasma concentration and clinical response in patients with different 5-HTTLPR genotypes. Fifty-one patients were enrolled in this study. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate patients at 0, 1, 2, 4, and 6 weeks. The patients' paroxetine plasma concentrations at week 6 were measured using high-performance liquid chromatography. Additionally, their 5-HTTLPR polymorphisms (alleles S and L) were analyzed using a polymerase chain reaction with specific primers. We divided the participants into two groups based on their L haplotype: the SS group and the SL and LL group. We performed single and multiple regression analyses to investigate the associations between MADRS improvement and paroxetine plasma concentrations or other covariates for each group. There were no significant differences between the two groups with regard to demographic or clinical data. In the SS group, the paroxetine plasma concentration was significantly negatively correlated with improvement in MADRS at week 6. In the SL and LL group, the paroxetine plasma concentration was significantly positively correlated with improvement in MADRS at week 6 according to the results of the single regression analysis; however, it was not significantly correlated with improvement in MADRS at week 6 according to the results of the multiple regression analysis. Among patients with MDD who do not respond to paroxetine, a lower plasma concentration or a lower oral dose of paroxetine might be more effective in those with the SS genotype, and a higher plasma concentration might be more effective in those with the SL or LL genotype.

Although the use of placebo in clinical trials of schizophrenia patients is controversial because of medical and ethical concerns, placebo-controlled clinical trials are commonly used in the licensing of new drugs. The objective of this study was to assess the attitudes toward placebo-controlled clinical trials among patients with schizophrenia in Japan. Using a cross-sectional design, we recruited patients (n = 251) aged 47.7±13.2 (mean±SD) with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder who were admitted to six psychiatric hospitals from December 2013 to March 2014. We employed a 14-item questionnaire specifically developed to survey patients' attitudes toward placebo-controlled clinical trials. The results indicated that 33% of the patients would be willing to participate in a placebo-controlled clinical trial. Expectations for improvement of disease, a guarantee of hospital treatment continuation, and encouragement by family or friends were associated with the willingness to participate in such trials, whereas a belief of additional time required for medical examinations was associated with non-participation. Fewer than half of the respondents stated that they would be willing to participate in placebo-controlled clinical trials. Therefore, interpreting the results from placebo-controlled clinical trials could be negatively affected by selection bias.

We studied the differences between groups that were divided according to personality characteristics with respect to the relationship between drug concentration and symptom improvement. A total of 120 patients with major depressive disorder were treated with paroxetine for 6 weeks, and 89 patients completed the protocol. The Montgomery-Åsberg Depression Rating Scale (MADRS) was used to evaluate the patients. Patients' paroxetine plasma concentrations at week 6 were measured. Their personalities were evaluated by the Temperament and Character Inventory (TCI) at the first visit. We divided the patients into two groups according to the median of each TCI dimension. We compared the responder rate between \"high\" and \"low\" groups in each TCI dimension and analyzed Pearson's correlation coefficients of paroxetine plasma concentration and MADRS-improvement rate. A total of 62 patients completed the TCI. Low-novelty-seeking, high-harm-avoidance, low-reward-dependence, and low-self-directedness groups exhibited significant negative correlations between paroxetine plasma concentration and MADRS improvement. Among the groups with combined personality traits, the high-harm-avoidance and low-self-directedness groups showed a markedly significant negative correlation. Patients with depression exhibiting specific personality traits, especially those with high harm-avoidance and low self-directedness scores, exhibited a significant negative association between paroxetine plasma concentration and MADRS-improvement rate. Therefore, a lower dose might be suitable for patients with specific personality traits.

Background Studies of the associations between diet and depression have primarily focused on single nutrients or foods. Recently, dietary patterns representing a combination of foods have attracted more interest than individual nutrient. The objective of this study was to examine the association between dietary patterns and depressive symptoms among a community-dwelling population in Japan. Methods We examined the association between dietary patterns and the risk of depression among 791 Japanese community-dwelling individuals. Diet was assessed with a validated brief-type self-administered diet history questionnaire (BDHQ). Dietary patterns from 52 predefined food groups [energy-adjusted food (g/d)] were extracted by principal component analysis. The Center for Epidemiologic Studies Depression Scale (CES-D) with a cut-off point of 16 was used to assess the prevalence of depression. Results A total of 97 subjects (12.3%) were classified as having depression. Four dietary patterns were identified: “Healthy”, “Western”, “Bread and confectionery”, and “Alcohol and accompanying” dietary patterns. After adjusting for potential confounders, the dietary patterns were not related to the risk of depression. Conclusions The present study failed to find associations between dietary patterns and the risk of depression. However, the interpretation of our results was hampered by the lack of certain data, including employment physical activity and longitudinal observations. Potential associations between dietary patterns and depressive symptoms were not completely ruled out. Future research exploring dietary patterns and depressive symptoms is warranted.

Background and Aim: Personality traits and vascular endothelial growth factor (VEGF) levels are both independently correlated with major depressive disorder and depressive mood. However, no studies have reported associations between personality traits and VEGF levels. Thus, we hypothesized that there is a correlation between the results of the Temperament and Character Inventory (TCI) and VEGF levels. Methods: We investigated 179 healthy participants who completed the TCI. We collected a serum sample from each subject and measured each participant's VEGF level by an enzyme-linked immunosorbent assay (ELISA). Simple and multiple regression analyses were performed to examine the correlations between the scores on the seven TCI dimensions and several other factors, including gender, age and VEGF level. Results: A total of 150 subjects completed the examination. Among the dimensions of the TCI, the harm avoidance (HA) scores were negatively correlated with VEGF levels, but there were no significant correlations between the scores for any other dimensions and VEGF levels. The HA score was significantly correlated with sex, age and VEGF level, and single and multiple regression analyses yielded the same results. Conclusion: VEGF may be associated with certain personality factors. This study is the first to demonstrate a direct association between VEGF levels and a dimension of the TCI in healthy subjects.