Current and past depression as risk factors for incident type 2 diabetes mellitus and pre-diabetes in men and women: evidence from a longitudinal community cohort.

BACKGROUND: Depression is associated with an increased risk for type 2 diabetes mellitus. However, depression may take different courses, and it is not fully understood how these affect the development of diabetes. It is further to be determined whether sex modifies the association between depression and type 2 diabetes. METHODS: We analyzed data from the Gutenberg Health Study, a longitudinal and population-based cohort study (N = 15,010) in Germany. Depressive symptoms (measured by PHQ-9), history of depression, diabetes mellitus, and relevant covariates were assessed at baseline, and the outcomes of prediabetes and type 2 diabetes mellitus were evaluated 5 years later. Logistic regression was used to estimate odds ratios of incident prediabetes and type 2 diabetes mellitus, adjusting for potential confounders as identified in a Directed Acyclic Graph. RESULTS: In the confounder adjusted model, current depression (PHQ-9 ≥ 10 at baseline; OR = 1.79, 95% CI = 1.11 to 2.74, p = 0.011), and persistent depression had a statistically significant (OR = 2.44, 95% CI = 1.62 to 3.54, p = 0.005) effect on incident type 2 diabetes mellitus. A history of depression without current depression had no statistically significant effect on type 2 diabetes (OR = 1.00, 95% CI = 0.68 to 1.43, p = 0.999). The effect of depression on incident diabetes did not differ significantly between women (OR = 2.02; 95% CI = 1.32 to 3.09) and men (OR = 2.16; 95% CI = 1.41 to 3.31; p-value for interaction on the multiplicative scale p = 0.832 and on the additive scale p = 0.149). Depression did not have a significant effect on incident prediabetes. CONCLUSION: This study shows how the history and trajectory of depression shape the risk for diabetes. This raises interesting questions on the cumulative effects of depression trajectories on diabetes and body metabolism in general. Depression can negatively affect physical health, contributing to increased morbidity and mortality in people with mental disorders.

Autoantibodies against the chemokine receptor 3 predict cardiovascular risk.

BACKGROUND AND AIMS: Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. METHODS: Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation. RESULTS: The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. CONCLUSIONS: In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.

Optimism and pessimism are antithetically associated with post-operative knee function in patients' undergoing total knee arthroplasty.

PURPOSE: Personality traits, such as dispositional optimism and pessimism, have impact on a variety of health-related problems. Influence on outcome in total knee arthroplasty (TKA) could only be shown for other personality trait concepts, but not for dispositional optimism/pessimism. This study aims to examine the association of dispositional optimism/pessimism with pre-operative joint function and post-operative outcome in TKA. METHODS: Data were acquired in a multicentre, cross-sectoral, prospective study (the PROMISE Trial). Patients were followed for 12 months post-operatively. Dispositional optimism/pessimism was measured pre-operatively via the revised Life Orientation Test (LOT-R), pre- and post-operative function was measured via the 12 Item Knee-osteoarthritis outcome Scores (KOOS-12). Log-linear regression models considering known confounders and t-test were carried out to show the association of LOT-R scores with pre- and post-operative KOOS-12 scores. RESULTS: 740 patients were analyzed. Optimistic LOT-R was significantly positively associated to the mean scores of KOOS-12 pre- and post-operative, while pessimistic LOT-R was significantly associated negatively (pre-operative: optimistic p = 0.001, pessimistic p = 0.001; post-operative optimistic: 3M p = 0.001, 6M p = 0.001, 12M p = 0.001; post-operative pessimistic: 3M p = 0.01, 6M p = 0.004, 12M p = 0.001). CONCLUSION: Optimism was positively associated with pre-operative joint function and, more importantly, post-operative functional outcome in TKA, while pessimism was associated with the opposite. Assessing patients' general personality traits prior to surgery to identify pessimistic patients, hence being at risk for poor outcome in TKA, should be considered to react to the patients' special needs and possible pessimistic expectations, i.e., through a cognitive-behavioral intervention, to potentially increase optimism and hereby post-operative outcome in TKA. LEVEL OF EVIDENCE: Prognostic Level III.

The fear-defense system, emotions, and oxidative stress.

Psychosocial stress has a profound impact on well-being and health. The response to stress is associated mainly with the amygdala, a crucial structure of the fear-defense system, essential for social cognition and emotion regulation. Recent neuroimaging-studies demonstrated how an increased metabolic activity of the amygdala enhances inflammation, and leads to cardiometabolic disease. The development of therapeutic strategies depends on our understanding of both which factors activate the fear-defense system and the subsequent molecular mechanisms that translate emotional stress into cell damage. Fear of emotions as an aftermath of attachment trauma is the most important trigger of the maladaptive activation of the fear-defense system. The central molecular pathways are enhanced myelopoiesis and upregulated proinflammatory gene expression, glucocorticoid and insulin resistance, and oxidative stress. Therapeutic strategies may benefit from holistic approaches. Psychotherapy can reduce the maladaptively increased activation of the fear-defense system. Biological interventions can buffer the detrimental effects of oxidative stress in the organism.

Symptoms of depersonalization/derealization are independent risk factors for the development or persistence of psychological distress in the general population: Results from the Gutenberg health study.

BACKGROUND: Symptoms of depersonalization (DP) and derealization (DR) have a high prevalence in patient and community samples. Previous studies suggested that DP/DR symptoms might represent a marker of disease severity and poor prognosis. However, population-based studies investigating the impact of DP/DR symptoms on the course of depression and anxiety are sparse. Therefore, we aimed to analyze whether symptoms of DP/DR are longitudinally associated with the persistence or incidence of elevated symptoms of depression/anxiety. METHODS: We analyzed observational data from a sample of 13.182 participants of the Gutenberg Health Study. The outcomes were elevated symptoms of depression/anxiety at the 2.5 years follow-up as determined by the 2-item depression scale (PHQ-2), the 2-item anxiety scale (GAD-2), and the compound measure PHQ-4 respectively. The predictor was the 2-item Cambridge Depersonalization Scale (CDS-2). RESULTS: 8.7% of the sample were bothered by symptoms of DP/DR at baseline. They had an increased risk for elevated symptoms of depression/anxiety at the 2.5-year follow-up beyond baseline depression/anxiety and other factors. Each point increment in the CDS-2 scale, ranging from 0-6, was associated with a 21% increase of risk for PHQ-4 ≥ 3 at the follow-up (odds ratio 1.21, 95% confidence interval 1.11-1.32). LIMITATIONS: The study was mostly questionnaire-based. CONCLUSION: Symptoms of DP/DR are independent risk factors for the persistence or incidence of elevated symptoms of depression/anxiety. Symptoms of DP/DR represent an easily assessable risk factor for the course of mental disorders. Treatment and prevention of mental disorders might benefit from the broader recognition of these phenomena.

Course of depressive symptoms in men and women: differential effects of social, psychological, behavioral and somatic predictors.

In this study, we aimed to identify the most important and sex-specific social, psychological, behavioral and somatic predictors of recurrent depressive symptoms. Data was obtained at two measurement points within five years by the Gutenberg Health Study (GHS). Out of N = 12,061 individuals, a sample of 877 (age 52.3 ± 9.9) who reported clinically relevant depressive symptoms at baseline was analyzed. Univariate analyses and multiple logistic regression analyses were conducted. Almost half of participants depressed at baseline also reported depressive symptoms five years later. Sex-stratified multivariate analyses revealed that solely social support remained a significant protective predictor against recurrence of depression in men (OR = 0.93; CI95% = 0.87-0.99), whereas in women smoking (OR = 1.97; CI95% = 1.23-3.22), and Type D personality (OR = 1.65; CI95% = 1.10-2.49) were significant risk factors. However, when analyzing the entire sample, no interaction effect between sex and each predictor turned out to be significant. Only social support was retained as an overall predictive factor. As depressive symptoms recur, depressive vulnerability is established involving personality, health behavior and social factors. Although no significant sex-specific interactions were observed, sex-stratified analyses point out different patterns for relevant predictors of recurrent depressive symptoms in men and women.

Association between medicated obstructive pulmonary disease, depression and subjective health: results from the population-based Gutenberg Health Study.

Medicated obstructive pulmonary disease (asthma or COPD) has been associated with depression. Yet, there is little knowledge of the interplay of contributing social, biological, behavioral and psychological factors in the community. The study was conducted: (1) To determine the prevalence of depression in participants with medicated COPD or asthma from the general population, (2) to identify underlying social, biological, behavioral and psychological factors and (3) to determine the contribution of obstructive pulmonary disease and depression to subjective health. The population-based sample of 15.010 study participants (35-74 years) from the Gutenberg Health Study (GHS) was queried according to a medical diagnosis of obstructive pulmonary disease, defined as medicated COPD or asthma, and comorbid disorders. Demographic, behavioral and psychological factors were assessed by self-report; lung function (FEV1; FCV) was measured by spirometry. 307 men (4.3%) and 396 women (5.6%) reported a medical diagnosis of COPD or asthma. The prevalence of depression (PHQ-9 > = 10) was twice as high (16.2% vs. 7.5%) compared to participants without obstructive pulmonary disease. Participants with obstructive pulmonary disease were older, had a lower SES, more comorbid diseases and cardiovascular risk factors, higher distress and took more psychotropic medication. In multivariable logistic regression analyses, obstructive pulmonary disease was associated with a 71% increase of depression (OR = 1.71; 95% CI = 1.30 to 2.24). Additional contributors were FEV1 (1.18; 95% CI = 1.05 to 1.32) and dyspnea (NYHA > = 1) (2.19; 1.82 to 2.64), sex (women) (OR = 1.73; 95% CI 1.41 to 2.12), lower SES (OR = 0.98; 95%CI = 0.96 to 0.99). Lack of active sports OR = 0.79; 95% CI 0.68 to 0.92), obesity (OR 1.27; 95% CI 1.07 to 1.50), smoking (OR = 1.26; 95% CI 1.06 to 1.49) and dyslipidemia (OR = 1.35; 95% CI 1.15 to 1.57) also increased the risk of depression. Additional psychological risks were social phobia, type D, low social support, loneliness and life events in the past 12 months. In multivariable linear regression analyses, obstructive pulmonary disease and depression independently contributed to reduced subjective health in addition to sedentary behavior, smoking and comorbid somatic and mental disorders. These findings provide evidence that COPD and asthma are associated with depression in the community. Complex underlying demographic, medical and psychosocial variables have been identified which may justify an integrative treatment approach. Promoting health behavior (smoking cessation, exercising, weight reduction) and social integration may not only improve the somatic course of the disease, but also mental health. Mental health treatment may also improve health behavior and subjective health.

Somatic symptom load in men and women from middle to high age in the Gutenberg Health Study - association with psychosocial and somatic factors.

The purpose of the study was (1) to determine the prevalence of somatic symptoms in men and women in the general population and (2) to identify the contributions of psychosocial factors and somatic disease on symptom reporting. A total of 7,925 participants aged 40 to 80 years underwent medical and psychological assessments, based on the PHQ-15 (Patient Health Questionnaire). We excluded 3 items in order to avoid confounding findings: 2 items overlapping with the depression measure (PHQ-9) and the menstruation complaints item which biases sex comparisons. Pain complaints (arms, legs, joints, back pain) affected the majority of men and women, and somatic symptom reporting increased with age. When confounding has been reduced, psychosocial factors (lack of social support, adverse life events, loneliness, depression, generalized anxiety, panic, social phobia) have remained the strongest predictors of somatic symptoms. As shown by the interaction between sex and depression, depression plays a smaller role for somatic symptom reporting in women vs. men. Findings highlight the complex psychosocial and somatic contributions to somatic symptom reporting.

Effects of telmisartan or amlodipine monotherapy versus telmisartan/amlodipine combination therapy on vascular dysfunction and oxidative stress in diabetic rats.

Our previous studies identified potent antioxidant effects and improvement of vascular function by telmisartan therapy in experimental diabetes and nitrate tolerance. The present study compared the beneficial effects of single telmisartan or amlodipine versus telmisartan/amlodipine combination therapy (T+A) in streptozotocin (STZ)-induced type 1 diabetic rats. Male Wistar rats were injected once with STZ (60 mg/kg, i.v.) and 1 week later the drugs (telmisartan, amlodipine, or T+A) were administrated orally by a special diet (2.5-5 mg kg(-1) day(-1)) for another 7 weeks. We only observed a marginal beneficial on-top effect of T+A therapy over the single drug regimen that was most evident in the improvement of endothelial function (acetylcholine response) and less pronounced in the reduction of whole blood, vascular and cardiac oxidative stress (blood leukocyte oxidative burst, aortic dihydroethidine and 3-nitrotyrosine staining, as well as cardiac NADPH oxidase activity and uncoupling of endothelial nitric oxide synthase) in diabetic rats. These effects on oxidative stress parameters were paralleled by those on the expression pattern of NADPH oxidase and nitric oxide synthase isoforms. In addition, development of mild hypotension in the T+A-treated rats was observed. Reasons for this moderate synergistic effect of T+A therapy may be related to the potent beneficial effects of telmisartan alone and the fact that amlodipine and telmisartan share similar pathways to improve endothelial function. Moreover, hypotension in the T+A-treated rats could partially antagonize the beneficial additive effects by counter-regulatory mechanisms (e.g., activation of the renin-angiotensin-aldosterone system).