Plasma metabolome analysis of patients with major depressive disorder.

AIM: This study sought to characterize the plasma metabolite profiling of patients with major depressive disorder (MDD). METHODS: Psychiatric assessments were made with the Structured Clinical Interview for DSM-IV Axis I Disorders. In the exploratory cohort, plasma metabolite profiles of 34 MDD patients and 31 mentally healthy controls were compared using capillary electrophoresis-mass spectrometry. Among the candidate metabolites, we focused on a metabolite showing the largest difference. The absolute concentrations were measured in two cohorts from a psychiatric primary care clinic to characterize the accuracy of the metabolite biomarker. RESULTS: Among 23 metabolites significantly lower in the MDD group than in healthy controls, we focused on phosphoethanolamine (PEA) as a candidate. The reduction of PEA levels in MDD was checked in independent clinical sample sets. An ion-chromatography-fluorescence detection method was developed to measure plasma PEA levels. In the preliminary cohort, we examined 34 MDD and 43 non-MDD subjects. The area under the receiver-operator curve (AUC) was 0.92, with sensitivity/specificity greater than 88%, at a cut-off of 1.46 µM. In the checking cohort, with 10 MDD and 13 non-MDD subjects, AUC was 0.89, with sensitivity/specificity of 86% and 100%, respectively, at a cut-off of 1.48 µM. Plasma PEA inversely correlated with MDD severity, depressed mood, loss of interest, and psychomotor retardation. CONCLUSION: These results suggest that plasma PEA level could be a candidate biomarker of MDD in the clinical setting. Further studies comparing MDD and mentally healthy controls are needed to confirm the utility of PEA as a biomarker for depression.

Coping strategies and risk of cardiovascular disease incidence and mortality: the Japan Public Health Center-based prospective Study.

AIMS: Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. METHODS AND RESULTS: The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000-04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50-79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality.The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73-1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55-0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64-0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01-4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07-11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03-1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40-0.99), respectively. CONCLUSION: An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort.

The association between complete and partial non-response to psychosocial questions and suicide: the JPHC Study.

BACKGROUND: Non-participants to psychosocial studies have been shown to have higher mortality, and mortality differs between partial and complete responders to psychosocial questionnaires. Yet, there is very little information available directly linking survey response status with completing suicide. METHODS: The study population consisted of the participants of the Japanese Public Health Center-based prospective study. Ninety-nine thousand four hundred thirty-nine subjects who returned the 10-year follow-up questionnaire and 31 754 individuals who did not return the questionnaire were included in our analyses. The risk of dying by suicide according to response status was estimated by Cox regression models. RESULTS: There were 358 suicides during 1 128 831 person-years of follow-up (mean follow-up time: 8.6 years). Of those who returned the questionnaire, 53.9% were full responders, 42.8% were partial non-responders, and 3.3% were complete non-responders. The risk of suicide was increased for both complete non-responders [hazard ratio (HR) = 1.84, 95% confidence interval (CI), 0.51, 6.64] and partial non-responders (HR = 1.36, 95% CI, 0.999, 1.84) to the questionnaire as a whole. The adjusting variables explained around 40% of the risk for complete non-responders whereas they did not explain the increased risk of suicide for partial non-responders. The risk of dying by suicide was significantly increased for partial non-responders to the subscale on coping (HR = 1.36, 95% CI, 1.01, 1.85) and for complete non-responders to questions on sleep (HR = 2.07, 95% CI, 1.03, 4.16). CONCLUSIONS: Partial and complete non-responders have increased suicide risk compared with full responders. More than one non-responder category should therefore be considered when interpreting data pertaining to psychosocial questionnaires in longitudinal studies.

Persistent distress after psychological exposure to the Nagasaki atomic bomb explosion.

BACKGROUND: Although there is speculation that individuals living in the vicinity of nuclear disasters have persistent mental health deterioration due to psychological stress, few attempts have been made to examine this issue. AIMS: To determine whether having been in the vicinity of the Nagasaki atomic bomb explosion in the absence of substantial exposure to radiation affected the mental health of local inhabitants more than half a century later. METHOD: Participants were randomly recruited from individuals who lived in the vicinity of the atomic bomb explosion in uncontaminated suburbs of Nagasaki. This sample (n = 347) was stratified by gender, age, perception of the explosion and current district of residence. Controls (n = 288) were recruited from among individuals who had moved into the area from outside Nagasaki 5-15 years after the bombing, matched for gender, age and district of residence. The primary outcome measure was the proportion of those at high risk of mental disorder based on the 28-item version of the General Health Questionnaire, with a cut-off point of 5/6. Other parameters related to individual perception of the explosion, health status, life events and habits were also assessed. RESULTS: Having been in the vicinity of the explosion was the most significant factor (OR = 5.26, 95% CI 2.56-11.11) contributing to poorer mental health; erroneous knowledge of radiological hazard showed a mild association. In the sample group, anxiety after learning of the potential radiological hazard was significantly correlated with poor mental health (P<0.05), whereas anxiety about the explosion, or the degree of perception of it, was not; 74.5% of the sample group believed erroneously that the flash of the explosion was synonymous with radiation. CONCLUSIONS: Having been in the vicinity of the atomic bomb explosion without radiological exposure continued to be associated with poorer mental health more than half a century after the event. Fear on learning about the potential radiological hazard and lack of knowledge about radiological risk are responsible for this association.

The relationship between past traumatic experience and sickness absence.

BACKGROUND: Past traumatic experiences have been reported to lower stress tolerance, thereby increasing job strain. However, the relationship between past traumatic experiences and employee sickness absence is poorly understood. AIMS: This study explores the relationship between sickness absence and past traumatic experience with regard to the amount of time lapsed after the experience, job strain and other mental health states such as depression and anxiety. METHODS: A total of 3238 workers were assessed for levels of traumatic stress, depressive status, anxiety and job stress. RESULTS: Odds ratios of the presence of traumatic experiences to sickness absence, adjusted for sex, age and depressive and anxiety states, were presented according to the length of time that had passed since the traumatic events. The odds ratio in the 0-1 Years Group was 1.75 (p < 0.05), and the odds ratio for the 19+ Years Group was 1.46 (p < 0.1). CONCLUSIONS: Past traumatic events are related to sickness absence. Sickness absence resulting from a past traumatic experience is important with respect to industrial health.

Coping strategies and cancer incidence and mortality: The Japan Public Health Center-based prospective study.

BACKGROUND: Psychological stress is a modifiable risk factor for health outcomes and can be managed through coping mechanisms. Biological and behavioral hypotheses have been proposed to explain the association between stress coping strategies and cancer outcomes. METHODS: The Japan Public Health Center-based study asked questions on coping behaviors in its 10-year follow-up survey. 55,130 subjects aged 50-79 without a history of cancer diagnosis and who provided complete answers on coping were included in analyses on cancer incidence and mortality. Hazard Ratios (HR) according to coping style were determined using Cox regression models adjusted for known confounders for cancer. RESULTS: Mean follow-up time was 9.5 years for cancer incidence and 9.8 years for cancer mortality. The utilization of the approach-oriented coping strategy (HR=0.85, 95% CI: 0.72-0.99) and a behavior of positive reappraisal (HR=0.84, 95% CI: 0.72-0.97) was associated with a reduced risk of cancer mortality. The approach-oriented coping strategy was further associated with localized cancer incidence (HR=1.13, 95% CI: 1.01-1.27) and screening-detected cancers (HR=1.35, 95% CI: 1.15-1.58). The avoidance oriented coping strategy was inversely associated with cancer incidence (HR=0.69, 95% CI: 0.50-0.94) only after excluding events occurring in the first three years of follow-up. CONCLUSION: The results of this study may favor the behavioral hypothesis to explain associations between premorbid coping styles and cancer outcomes.

The immunophilin ligand FK506 protects against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum.

Repeated use of methamphetamine (MAP) is known to cause neurotoxicity in the dopaminergic neurons of the striatum. Recently, we reported that FK506, a calcineurin inhibitor and immunosuppressive agent, could attenuate acute behavioral changes and the development of sensitization after administration of MAP. In this study, we investigated the effects of FK506 on the neurotoxicity in the dopaminergic neurons induced by repeated administration of MAP. BALB/c mice were injected subcutaneously (s.c.) with vehicle (10 ml/kg) or MAP (4 mg/kg) four times every 2h. Vehicle (10 ml/kg) or FK506 (0.1, 0.3, 1 or 3 mg/kg i.p.) was administered 15 min before the first MAP administration. Three days later, we assessed the contents of dopamine (DA) and its major metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the mouse striatum using high-performance liquid chromatography (HPLC). We also examined the immunohistochemistry of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the mouse brain. Repeated administration of MAP decreased significantly the contents of DA and DOPAC in the mouse striatum, and pretreatment with FK506 inhibited significantly the reduction of DA and DOPAC in the mouse brain by repeated administration of MAP. Furthermore, repeated administration of MAP decreased significantly the immunoreactivity of DAT and TH in the striatum as compared to controls. Pretreatment with FK506 (3 mg/kg) attenuated significantly the reduction of DAT and TH immunoreactivity after repeated administration of MAP. These results suggest that FK506 shows protective effects on the MAP-induced neurotoxicity in the dopaminergic neurons of the mouse striatum.

Association between perceived social support and Th1 dominance.

Social support is supposed to have a positive health effect via alteration of immunity. In this study, associations between perceived social support and immune systems were examined. Immunological assessments, e.g. T cell count, Natural Killer cell count, Interferon-gamma, Interleukin-4, and psychological assessments, e.g. Generic Job Stress Questionnaire were conducted on male employees. Two-way (social support x job stressor) analyses of covariance controlling for age, smoking, alcohol consumption, and exercise revealed that there were main effects of perceived social support on NK cell counts, IL-4, and Th1/Th2 balance. On the other hand, interaction effects were observed on T cell counts and INF-gamma production in vitro. Social support affects immune function in a way that is consistent with both the direct and buffering hypotheses depending on the sources of support and the immune parameter.

Long-term influence of working abroad on returnees' mental health.

Although international business travel is increasing, there is a lack of research on its repercussions for mental health. This study analysed the long-term influence of international business travel on the mental health status by comparing depression, anxiety and job stress between workers with and without international assignment experience. The subjects were divided into an 'experienced group' composed of 70 male workers who had experienced an overseas assignment of at least six months, and a 'non-experienced group' consisting of 2,163 male workers who had not. To assess the mental health status, Zung's Self-Rating Depression Scale (SDS) and Sheehan's Patient Rated Anxiety Scale (Sheehan) were employed. The Job Content Questionnaire (JCQ) was used to examine job stress. In addition, information about the characteristics of the overseas assignments was collected. The experienced group had significantly higher scores for job control, supervisor support and co-worker support in the JCQ, while no differences were observed for the SDS and Sheehan. Whether or not the subjects travelled abroad with their families, whether or not they went against their will, and whether or not they enjoyed their stay had no effects on their mental health. Job demand had a significantly positive correlation with the duration of the assignment.

Association of lymphocyte sub-populations with clustered features of metabolic syndrome in middle-aged Japanese men.

To examine the relationship between altered cellular immune status and clustered features of the metabolic syndrome, we measured body mass index (BMI), serum concentrations of high-density lipoprotein-cholesterol, triglycerides, fasting plasma glucose, and blood pressure levels as well as differential leukocyte counts and lymphocyte sub-populations among 439 apparently healthy Japanese men aged 35-60 years. The components of the metabolic syndrome were defined based on the following criteria: BMI >/=25.0 kg/m(2), fasting plasma glucose >/=6.11 mmol/l, systolic blood pressure >/=130 mmHg and/or diastolic blood pressure >/=85 mmHg, high-density lipoprotein (HDL)-cholesterol <1.03 mmol/l, and fasting triglyceride >/=1.69 mmol/l. Counts of total leukocyte, total lymphocyte, CD3 + T cell, CD4 + T cell, and CD4 + CD45RO + T cell significantly correlated with the number of components of the metabolic syndrome (0, 1, 2, and 3+) after adjustment for age and smoking status. These findings were more evident among smokers than among non-smokers. The counts of total leukocytes, total lymphocytes and more specifically memory (CD4 + CD45RO + T) cells were elevated with clustered features of the metabolic syndrome in middle-aged men, which suggest the involvement of altered cellular immune status in the pathogenesis of atherosclerosis.

Relevance of neuropeptide Y for the neuroimmune crosstalk.

Both cellular and humoral functions of the immune system are modulated by the sympathetic nervous system (SNS). This interaction is mainly mediated by the release of catecholamines (CA) and their receptor-specific action on immune cells. However, neuropeptide Y (NPY), also present in sympathetic nerve terminals, is released upon SNS-stimulation. NPY modulates potent immunological effects in vitro and in vivo, such as differentiation of T helper cells, monocyte mediator release, NK cell activation, and immune cell redistribution. In addition to this direct action within the neuroimmune crosstalk, NPY is also able to modulate the immunomodulatory effects of other neurotransmitters, thereby acting as a neuroimmune co-transmitter. This review will discuss key findings from recent studies, provide implications for the clinical situation, and integrate the pleiotropic functions of NPY in the context of neuroimmune interactions.

Uncoupling protein-2/uncoupling protein-3 gene polymorphism is not associated with anorexia nervosa.

Energy expenditure abnormalities have been observed in anorexia nervosa (AN). The uncoupling proteins (UCPs) have been implicated as having a role in energy metabolism and thermogenesis, and an association between a marker flanking the UCP-2/UCP-3 gene cluster and AN has been reported. Also known are insertion/deletion and -866G/A polymorphisms in the UCP-2 gene, and the -55C/T polymorphism in the UCP-3 gene. Differences in these alleles are reportedly related to changes in energy expenditure, body mass index, fat tissue accumulation and obesity. Therefore, this case-control association analysis was done to determine whether any of these UCP-2/3 gene polymorphisms are related to a predisposition to AN. In analysis of a cohort of 106 female Japanese AN sufferers and 126 normal female controls, we found no between-group differences in the polymorphism frequencies of these groups. The hypothesis that differences in the UCP-2/3 gene influence the susceptibility to AN was not supported.

Development of the overt-covert aggression inventory.

The expression of anger in Japanese people is different from that of other races. We developed a new brief inventory, the Overt-Covert Aggression Inventory, to assess aggressive behavior ofJapanese people by focusing on their uniqueness and examined its reliability and validity. This inventory, the Center for Epidemiological Studies Depression scale, the Japanese version of the Buss-Perry Aggression Questionnaire, and the Picture-Frustration Study were administered to 3,104 men and 316 women in a factory. Internal consistency, test-retest reliability, concurrent validity, and construct validity of the scale were examined. We confirmed that the Overt-Covert Aggression Inventory has adequate reliability and sufficient concurrent validity, however, further studies of the construct validity and discriminant validity are required.

Coping behaviors and suicide in the middle-aged and older Japanese general population: the Japan Public Health Center-based Prospective Study.

PURPOSE: Cross-sectional studies have shown an association between different coping styles and suicidal behavior. It is unknown whether there is any prospective association between coping behaviors and suicide in the general population. METHODS: The study population consisted of participants of the Japanese Public Health Center-based Prospective Study. In the 10-year follow-up questionnaire, subjects aged 50-79 years were asked how they handle daily problems. Coping behaviors were used to determine two coping strategies (approach coping and avoidance coping). Of 99,439 subjects that returned the 10-year follow-up questionnaire, 70,213 subjects provided complete answers on coping and were included in our analyses. Cox regression models, adjusted for confounders, were used to determine the risk of committing suicide according to coping style. Mean follow-up time was 8.8 years. RESULTS: Two coping behaviors were significantly associated with suicide over time: planning (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.41-0.98) and self-blame (HR, 2.20; 95% CI, 1.29-3.76). Of the coping strategies, only the avoidance coping strategy was significantly associated with suicide (HR, 2.45; 95% CI, 1.24-4.85). CONCLUSIONS: For the first time, two coping behaviors and one coping strategy have been shown to have a significant prospective association with suicide in a general population.

Depressive symptoms and life satisfaction in elderly women are associated with natural killer cell number and cytotoxicity.

Well-preserved natural killer (NK) cell cytotoxicity (NKCC) is associated with healthy aging. The objective of the survey was to investigate psychological factors related to NKCC and NK cell populations in elderly women. A cross-sectional study involving 181 participants was conducted using the Japanese version of the 28-item General Health Questionnaire (GHQ) and additional questions assessing psychological status and lifestyle. Spearman's rank test revealed a significant negative correlation between NKCC and the GHQ depression subscale (GHQ-D) scores. Significantly reduced NKCC was found in participants presenting high GHQ-D scores (12 < or = GHQ-D, n = 58) compared with those showing middle (8 < or = GHQ-D < or = 11, n = 55) or low (GHQ-D = 7, n = 68) scores. Adjusting for covariates regarding lifestyle, multiple logistic regression analysis was applied; consequently, significant associations were found between reduced NKCC and high depressive symptoms and between increased NK cell numbers and life satisfaction. These results indicated a clue to longitudinal studies in the future.

Psychological stress increases human T cell apoptosis in vitro.

OBJECTIVES: Recent studies have shown that apoptosis is involved in stress responses. The present study examined if stressors increase in vitro apoptosis of peripheral blood T lymphocytes in a dose-dependent manner. METHODS: Daily subjective stress was quantitatively analyzed in 40 nonsmoking men with a daily hassles questionnaire. Apoptosis of T lymphocytes was measured by flowcytometry using Annexin V/PI double staining method after 0, 12, and 24 h of culture in the presence or absence of dexamethasone (DEX). Using a cross-sectional design, the current study examined the relationship between stress and in vitro apoptosis of T cells. RESULTS: Results showed that apoptosis of T lymphocytes in vitro has a significant correlation with stress and age. Stress was positively correlated with percentage of apoptosis in T cells after 12 h of culture, irrespective of DEX treatment. Age was positively correlated with the percentage of T cell apoptosis after 0 and 12 h of coculture with DEX. CONCLUSIONS: These results indicate that age-related apoptosis and stress-related apoptosis of T cells are modulated through different mechanisms. This is the first study to show that in vitro lymphocyte apoptosis is influenced by daily stress in a dose-dependent manner.

Positive coping up- and down-regulates in vitro cytokine productions from T cells dependent on stress levels.

BACKGROUND: Specific coping styles have been shown to modulate stress-induced immune alterations and influence actual health outcomes. This study examined the effects of stressors and coping styles on human T-cell subpopulations and in vitro cytokine production using a cross-sectional design. METHODS: Seventy-one men (18-60 years old) were asked to complete a self-administered questionnaire that evaluates quantitative workload, mental demand and coping styles. The numbers of T-cell subpopulations and concentrations of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) after stimulation with phytohemaglutinin were measured. RESULTS: Positive and negative coping were negatively related to IL-4 and the number of CD4+ cells, respectively. Interactions between positive coping and mental demand significantly affected the number of CD8+ cells, IFN-gamma, IL-4 and the IFN-gamma/IL-4 ratio. Among men reporting high mental demand, positive coping was related to increased IFN-gamma and IFN-gamma/IL-4. Among men reporting low mental demand, positive coping was related to a decreased number of CD8+ cells and lower concentrations of IFN-gamma and IL-4. Analyses adjusting for the numbers of CD3+ and CD8+ cells revealed that the interactive effects of positive coping and mental demand on cytokine levels were attributable to the changes in T-cell function rather than the number of T cells. No modulating effect of anxiety on the associations of stressors and coping with immune function was observed. Depressive symptoms slightly, though not significantly, modulated the association of negative coping and the number of CD4+ cells. CONCLUSIONS: From the perspective of immunology, optimal stress characteristics were determined by an individual's coping styles, with positive coping being associated with stress-induced changes in the number of CD8+ cells and in vitro cytokine production from T cells. Our findings suggest that it is important to consider the interactive effects of the complexity of work and the individual coping style in stress management.

Coemergence of insomnia and a shift in the Th1/Th2 balance toward Th2 dominance.

OBJECTIVES: Insomnia is associated with physical and mental disorders. We examined the effect of insomnia on immune functions, focusing on the T helper 1 (Th1)/ T helper 2 (Th2) balance, by a cross-sectional design. METHODS: We provided a self-administered questionnaire to evaluate sleep habits, smoking and medical disorders to 578 men without any toxic exposure (20-64 years old), and measured natural killer (NK) cell activity in 324 men and production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) after stimulation with phytohemagglutinin in 254 men. According to the criteria of DSM-IV, in which insomnia is classified into primary and secondary insomnia, we assessed the effect of insomnia on immune functions, controlling for age and smoking in groups with and without medical disorders. RESULTS: The prevalence of insomnia in the present study was 9.2%. In the absence of medical disorders, insomniac men had a significantly lower IFN-gamma and ratio of IFN-gamma to IL-4 than noninsomniac men. Men with insufficient sleep or difficulty initiating sleep (DIS) had a significantly lower IFN-gamma to IL-4 ratio than those not suffering from insufficient sleep or DIS. In the presence of medical disorders, insomniac men had significantly higher IL-4 than noninsomniac men. Men with difficulty maintaining sleep (DMS) had a significantly lower IFN-gamma to IL-4 ratio than men without DMS. NK cell activity was independent of insomnia. CONCLUSIONS: The present results showed a link between insomnia unrelated to medical disorders and a shift in the Th1/Th2 balance toward Th2 dominance, indicating that the relationship between sleep quality and the etiology of immune-related diseases should be reconsidered.

Reliability and validity of the Japanese-language version of the impact of event scale-revised (IES-R-J): four studies of different traumatic events.

The authors developed the Japanese-language version of the Impact of Event Scale-Revised (IES-R-J) and investigated its reliability and validity in four different groups: workers with lifetime mixed traumatic events, survivors of an arsenic poisoning case, survivors of the Hanshin-Awaji earthquake, and survivors of the Tokyo Metro sarin attack. Evidence includes retest reliability and internal consistency of the IES-R-J. Posttraumatic stress disorder (PTSD) and partial PTSD cases indicated significantly higher scores than non-PTSD cases. The IES-R-J can be a useful self-rating diagnostic instrument particularly for survivors with PTSD symptoms as a clinical concern (PTSD + partial PTSD) by using a 24/25 cutoff in total score. In analysis of scale structure, the majority of intrusion and hyperarousal items were subsumed under the same cluster, whereas avoidance items made up a separate cluster. Female patients indicated higher scores than male patients. A negative weak correlation between age and the score was found only among female earthquake survivors. The IES-R-J can be used as a validated instrument in future international comparative research.