A systematic review and meta-analysis of the evidence on inflammation in depressive illness and symptoms in chronic and end-stage kidney disease.

BACKGROUND: Depression affects approximately 27% of adults with chronic kidney disease (CKD) and end-stage kidney failure (ESKF). Depression in this population is associated with impaired quality of life and increased mortality. The extent of inflammation and the impact on depression in CKD/ESKF is yet to be established. Through a systematic literature review and meta-analysis, we aim to understand the relationship between depression and inflammation in CKD/ESKF patients. METHODS: We searched nine electronic databases for published studies until January 2022. Titles and abstracts were screened against inclusion and exclusion criteria. Data extraction and study quality assessment was carried out independently by two reviewers. A meta-analysis was carried out where appropriate; otherwise a narrative review of studies was completed. RESULTS: Sixty studies met our inclusion criteria and entered the review (9481 patients included in meta-analysis). Meta-analysis of cross-sectional associations revealed significantly higher levels of pro-inflammatory biomarkers; C-reactive protein; Interleukin 6 (IL-6) and tumour necrosis factor-alpha in patients with depressive symptoms (DS) compared to patients without DS. Significantly lower levels of anti-inflammatory cytokine IL-10 were found in patients with DS compared to patients without DS. Considerable heterogeneity was detected in the analysis for most inflammatory markers. CONCLUSION: We found evidence for an association of higher levels of pro-inflammatory and lower anti-inflammatory cytokines and DS in patients with CKD/ESKF. Clinical trials are needed to investigate whether anti-inflammatory therapies will be effective in the prevention and treatment of DS in these patients with multiple comorbidities.

Combined influence of depressive symptoms and systemic inflammation on all-cause and cardiovascular mortality: evidence for differential effects by gender in the English Longitudinal Study of Ageing.

BACKGROUND: Depressive symptoms and inflammation are risk factors for cardiovascular disease (CVD) and mortality. We investigated the combined association of these factors with the prediction of CVD and all-cause mortality in a representative cohort of older men and women. METHODS: We measured C-reactive protein (CRP) and depressive symptoms in 5328 men and women aged 52-89 years in the English Longitudinal Study of Ageing. Depressive symptoms were measured using the eight-item Centre for Epidemiological Studies Depression Scale. CRP was analysed from peripheral blood. Mortality was ascertained from national registers and associations with depressive symptoms and inflammation were estimated using Cox proportional hazard models. RESULTS: We identified 112 CVD related deaths out of 420 all-cause deaths in men and 109 CVD related deaths out of 334 all-cause deaths in women over a mean follow-up of 7.7 years. Men with both depressive symptoms and high CRP (3-20 mg/L) had an increased risk of CVD mortality (hazard ratio; 95% confidence interval: 3.89; 2.04-7.44) and all-cause mortality (2.40; 1.65-3.48) after adjusting for age, socioeconomic variables and health behaviours. This considerably exceeds the risks associated with high CRP alone (CVD 2.43; 1.59-3.71, all-cause 1.49; 1.20-1.84). There was no significant increase in mortality risk associated with depressive symptoms alone in men. In women, neither depressive symptoms or inflammation alone or the combination of both significantly predicted CVD or all-cause mortality. CONCLUSIONS: The combination of depressive symptoms and increased inflammation confers a considerable increase in CVD mortality risk for men. These effects appear to be independent, suggesting an additive role.

Inflammation associated with coronary heart disease predicts onset of depression in a three-year prospective follow-up: A preliminary study.

Depression frequently co-occurs with coronary heart disease (CHD), worsening clinical outcomes of both, and inflammation has been proposed as a biological link between these two disorders. The aim of the present study was to investigate the role of inflammation in the development of depression in CHD patients during a 3-year follow-up. We examined the inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), measured at baseline, as a potential predictor of later onset of depression. We recruited 89 CHD patients, who were assessed at baseline and then every 6 months, for three years. The sample included, at baseline, 25 depressed and 64 non-depressed CHD patients, as confirmed by Clinical Interview Schedule Revised (CIS-R). Depressive symptoms were assessed at baseline and all follow-up points by the Patient Health Questionnaire-9 (PHQ-9). In all CHD patients (n = 89), we found a significant positive correlation between hsCRP levels and the severity of depressive symptoms at baseline (PHQ-9, r = 0.23, p = 0.032). During follow-up, n = 21 patients (of the 64 non-depressed at baseline) developed depression, defined as being PHQ-9 positive (a score ≥ 10) in at least one follow-up assessment. Of these, n = 9 subjects were defined as developing clinically-significant depression, that is, having a positive PHQ-9 in at least 3 of the 6 follow-up assessments, implying a duration of symptoms of at least one year. We found that increased hsCRP values at baseline predicted future onset of depression. Specifically, baseline hsCRP values were higher in patients who later developed clinically-significant depression (mean ±â€¯SD; 6.76 ±â€¯6.52 mg/L) compared with never-depressed (2.77 ±â€¯3.13 mg/L; F(1,48) = 7.29, p = 0.010), even after controlling for baseline PHQ-9 scores. In conclusion, inflammation in CHD patients is associated with future development of clinically-significant depression. HsCRP, a reliable and ready-to-use biological marker of inflammation, may help to identify depression high-risk phenotypes even among CHD patients, who already have high baseline inflammation. Our study conveys important preliminary findings that will require further replication but that have the potential to affect the mental and physical health of a vulnerable group of individuals.

Depressive symptoms, pain and disability for adolescent patients with juvenile idiopathic arthritis: results from the Childhood Arthritis Prospective Study.

Objectives: To determine if depressive symptoms assessed near diagnosis associate with future measures of pain, disability and disease for adolescent patients diagnosed with JIA. Methods: Data were analysed from JIA patients aged 11-16 years recruited to the Childhood Arthritis Prospective Study, a UK-based inception cohort of childhood-onset arthritis. Depressive symptoms (using the Mood and Feelings Questionnaire; MFQ), active and limited joint count, disability score (Childhood Health Assessment Questionnaire), pain visual analogue scale and patient's general evaluation visual analogue scale were collected. Associations between baseline measures (first visit to paediatric rheumatologist) were analysed using multiple linear regression. Linear mixed-effect models for change in the clinical measures of disease over 48 months were estimated including MFQ as an explanatory variable. Results: Data from 102 patients were analysed. At baseline, median (IQR) age was 13.2 years (11.9-14.2 years) and 14.7% scored over the MFQ cut-off for major depressive disorder. At baseline, depressive symptoms significantly associated with all clinical measures of disease (P ⩽ 0.01). High baseline depressive symptoms scores predicted worse pain (P ⩽ 0.005) and disability (P ⩽ 0.001) 12 months later but not active and limited joint counts. Conclusions: Adolescent patients with JIA and depressive symptoms had more active joints, pain and disability at the time of their first specialist appointment. The associations between baseline depression and both pain and disability continued for at least one year, however, this was not the case for active joint count.

The effect of beta-adrenergic blockade on inflammatory and cardiovascular responses to acute mental stress.

Acute mental stress elicits increases in plasma cytokine concentrations in humans, but the underlying mechanisms remain poorly understood. We assessed the impact of beta-adrenergic blockade on plasma interleukin 6 (IL-6) and IL-1 receptor antagonist (IL-1Ra) responses in a parallel group, double-blind randomised placebo-controlled trial involving 64 healthy young adult volunteers. Participants were administered 80 mg slow-release propranolol or placebo daily for 7 days before the stress testing session in which responses to 3 behavioural challenges (public speaking, mirror tracing, mental arithmetic) were evaluated. Propranolol administration was associated with reduced baseline levels of heart rate and IL-1Ra, and systolic blood pressure (BP) in men. Tasks stimulated increased plasma IL-6 concentrations sampled 45 min and 75 min after challenge, but these responses were blocked by propranolol in men (p < 0.001). Propranolol did not influence IL-6 responses in women, or IL-1Ra in either sex. Blood pressure and heart rate increased markedly during the tasks, but there was no differential stress reactivity in propranolol and placebo conditions. The results of the study support a role of sympathetic nervous system activation in stimulating acute IL-6 responses to stress, but only in men. The reasons for the differences between men and women remain to be resolved.

Disruption of multisystem responses to stress in type 2 diabetes: investigating the dynamics of allostatic load.

Psychological stress-related processes are thought to contribute to the development and progression of type 2 diabetes, but the biological mechanisms involved are poorly understood. Here, we tested the notion that people with type 2 diabetes experience chronic allostatic load, manifest as dynamic disturbances in reactivity to and recovery from stress across multiple (cardiovascular, neuroendocrine, inflammatory, metabolic) biological systems, coupled with heightened experience of chronic life stress. We carried out an experimental comparison of 140 men and women aged 50-75 y with type 2 diabetes and 280 nondiabetic individuals matched on age, sex, and income. We monitored blood pressure (BP) and heart rate, salivary cortisol, plasma interleukin (IL)-6, and total cholesterol in response to standardized mental stress, and assessed salivary cortisol over the day. People with type 2 diabetes showed impaired poststress recovery in systolic and diastolic BP, heart rate and cholesterol, and blunted stress reactivity in systolic BP, cortisol, cholesterol, and IL-6. Cortisol and IL-6 concentrations were elevated, and cortisol measured over the day was higher in the type 2 diabetes group. Diabetic persons reported greater depressive and hostile symptoms and greater stress experience than did healthy controls. Type 2 diabetes is characterized by disruption of stress-related processes across multiple biological systems and increased exposure to life stress. Chronic allostatic load provides a unifying perspective with implications for etiology and patient management.

Shorter telomeres with high telomerase activity are associated with raised allostatic load and impoverished psychosocial resources.

Recent work has linked psychological stress with premature cellular aging as indexed by reduced leukocyte telomere length. The combination of shorter telomeres with high telomerase activity (TA) may be indicative of active cell stress. We hypothesized that older individuals characterized by shorter telomeres with high TA in unstimulated leukocytes would show signs of high allostatic load and low levels of protective psychosocial resources. We studied 333 healthy men and women aged 54-76 y who underwent laboratory testing in which we measured cardiovascular, neuroendocrine, and inflammatory responses to standardized mental stress tasks. The tasks elicited prompt increases in blood pressure (BP), heart rate, cortisol, and mediators of inflammation and reductions in heart rate variability, returning toward baseline levels following stress. However, men having shorter telomeres with high TA showed blunted poststress recovery in systolic BP, heart rate variability, and monocyte chemoattractant protein-1, together with reduced responsivity in diastolic BP, heart rate, and cortisol, in comparison to men with longer telomeres or men with shorter telomeres and low TA. Shorter telomeres with high TA were also associated with reduced social support, lower optimism, higher hostility, and greater early life adversity. These effects were independent of age, socioeconomic status, and body mass index. We did not observe differences among older women. Our findings suggest that active cell stress is associated with impaired physiological stress responses and impoverished psychosocial resources, reflecting an integration of cellular, systemic, and psychological stress processes potentially relevant to health in older men.

Hearing impairment and incident disability and all-cause mortality in older British community-dwelling men.

BACKGROUND AND OBJECTIVE: hearing impairment is common in older adults and has been implicated in the risk of disability and mortality. We examined the association between hearing impairment and risk of incident disability and all-cause mortality. DESIGN AND SETTING: prospective cohort of community-dwelling older men aged 63-85 followed up for disability over 2 years and for all-cause mortality for 10 years in the British Regional Heart Study. METHODS: data were collected on self-reported hearing impairment including hearing aid use, and disability assessed as mobility limitations (problems walking/taking stairs), difficulties with activities of daily living (ADL) and instrumental ADL (IADL). Mortality data were obtained from the National Health Service register. RESULTS: among 3,981 men, 1,074 (27%) reported hearing impairment. Compared with men with no hearing impairment, men who could hear and used a hearing aid, and men who could not hear despite a hearing aid had increased risks of IADL difficulties (age-adjusted OR 1.86, 95% CI 1.29-2.70; OR 2.74, 95% CI 1.53-4.93, respectively). The associations remained after further adjustment for covariates including social class, lifestyle factors, co-morbidities and social engagement. Associations of hearing impairment with incident mobility limitations, incident ADL difficulties and all-cause mortality were attenuated on adjustment for covariates. CONCLUSION: this study suggests that hearing problems in later life could increase the risk of having difficulties performing IADLs, which include more complex everyday tasks such as shopping and light housework. However, further studies are needed to determine the associations observed including the underlying pathways.

Hostility and physiological responses to acute stress in people with type 2 diabetes.

OBJECTIVE: Hostility is associated with cardiovascular mortality and morbidity, and one of the mechanisms may involve heightened reactivity to mental stress. However, little research has been conducted in populations at high risk for cardiovascular disease. The aim of the present study was to assess the relationship between hostility and acute stress responsivity in individuals with Type 2 diabetes. METHODS: A total of 140 individuals (median age [standard deviation] 63.71 [7.00] years) with Type 2 diabetes took part in laboratory-based experimental stress testing. Systolic blood pressure, diastolic blood pressure, heart rate, plasma interleukin-6 (IL-6), and salivary cortisol were assessed at baseline, during two stress tasks, and 45 and 75 minutes later. Cynical hostility was assessed using the Cook Medley Cynical Hostility Scale. RESULTS: Participants with greater hostility scores had heightened increases in IL-6 induced by the acute stress tasks (B = 0.082, p = .002), independent of age, sex, body mass index, smoking, household income, time of testing, medication, and baseline IL-6. Hostility was inversely associated with cortisol output poststress (B = -0.017, p = .002), independent of covariates. No associations between hostility and blood pressure or heart rate responses were observed. CONCLUSIONS: Hostile individuals with Type 2 diabetes may be susceptible to stress-induced increases in inflammation. Further research is needed to understand if such changes increase the risk of cardiovascular disease in this population.

Clinical characteristics of inflammation-associated depression: Monocyte gene expression is age-related in major depressive disorder.

Increased inflammatory activation might only be present in a subgroup of depressed individuals in which immune processes are especially relevant to disease development. We aimed to analyze demographic, depression, and trauma characteristics of major depressive disorder (MDD) patients with regard to inflammatory monocyte gene expression. Fifty-six naturalistically treated MDD patients (32 ± 12 years) and 57 healthy controls (HC; 31 ± 11 years) were analyzed by the Inventory of Depressive Symptomatology (IDS) and by the Childhood Trauma Questionnaire (CTQ). We determined the expression of 38 inflammatory and immune activation genes including the glucocorticoid receptor (GR)α and GRß genes in purified CD14(+) monocytes using quantitative-polymerase chain reaction (RT-qPCR). Monocyte gene expression was age-dependent, particularly in MDD patients. Increased monocyte gene expression and decreased GRα/ß ratio were only present in MDD patients aged ⩾ 28 years. Post hoc analyses of monocyte immune activation in patients <28 years showed two subgroups: a subgroup with a severe course of depression (recurrent type, onset <15 years) - additionally characterized by panic/arousal symptoms and childhood trauma - that had a monocyte gene expression similar to HC, and a second subgroup with a milder course of the disorder (73% first episode depression, onset ⩾15 years) - additionally characterized by the absence of panic symptoms - that exhibited a strongly reduced inflammatory monocyte activation compared to HC. In conclusion, monocyte immune activation was not uniformly raised in MDD patients but was increased only in patients of 28 years and older.

Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression.

Coronary heart disease (CHD) and depression are very common and often co-existing disorders. In addition to psychological and social morbidity, depression exacerbates adverse cardiac outcomes in CHD patients. Inflammation has been proposed as one of the mechanisms involved in the association between these two debilitating diseases. Therefore, the present study aimed to evaluate inflammatory responses as well as to investigate the pathophysiological mechanisms underlying the putative inflammatory activation in CHD patients with and without depression, by assessing the function of two important biological factors regulating inflammation, the hypothalamus-pituitary-adrenal (HPA) axis and the glucocorticoid receptor (GR). Eighty-three CHD patients with (n=28) and without (n=55) comorbid depression were recruited from primary care services in South London. Depression status was assessed by means of Clinical Interview Schedule Revised for diagnosis of depression, and Beck Depression Inventory for the presence of depressive symptoms. Serum C-reactive protein (CRP), plasma vascular endothelial growth factor (VEGF), and plasma and salivary cortisol were measured using commercially available ELISA kits. Gene expression of GR and interleukin-6 (IL-6) were conducted via qPCR. GR sensitivity was evaluated in vitro in isolated peripheral blood mononuclear cells using the dexamethasone inhibition of lipopolysaccharide-stimulated IL-6 levels. Serum levels of kynurenine pathway metabolites were measured using high performance liquid chromatography. Our results show that CHD patients with depression had higher levels of CRP, IL-6 gene expression, and VEGF compared with CHD non-depressed, as well as lower plasma and saliva cortisol levels. The CHD depressed group also exhibited a reduction in GR expression and sensitivity. Finally, tryptophan levels were significantly lower in patients with depression, who also showed an increased kynurenine/tryptophan ratio. In conclusion, CHD patients with depression had elevated levels of inflammation in the context of HPA axis hypoactivity, GR resistance, and increased activation of the kynurenine pathway. Reduced cortisol bioavailability and attenuated glucocorticoid responsiveness due to decreased expression and sensitivity of GR may lead to insufficient glucocorticoid signaling and thus elevation of inflammation in these patients.

Effect of short-term weight loss on mental stress-induced cardiovascular and pro-inflammatory responses in women.

Epidemiologic evidence links psychosocial stress with obesity but experimental studies examining the mechanisms that mediates the effect of stress on adiposity are scarce. The aim of this study was to investigate whether changes in adiposity following minimal weight loss affect heightened stress responses in women, and examine the role of the adipokine leptin in driving inflammatory responses. Twenty-three overweight or obese, but otherwise healthy, women (M age = 30.41 ± 8.0 years; BMI = 31.9 ± 4.1 kg/m(2)) completed standardized acute mental stress before and after a 9-week calorie restriction program designed to modify adiposity levels. Cardiovascular (blood pressure and heart rate) and inflammatory cytokines (leptin and interleukin-6; IL-6) responses to mental stress were assessed several times between baseline and a 45-min post-stress recovery period. There were modest changes in adiposity measures while the adipokine leptin was markedly reduced (-27%) after the intervention. Blood pressure reactivity was attenuated (-3.38 ± 1.39 mmHg) and heart rate recovery was improved (2.07 ± 0.96 Bpm) after weight loss. Blood pressure responses were inversely associated with changes in waist to hip ratio post intervention. Decreased levels of circulating leptin following weight loss were inversely associated with the IL-6 inflammatory response to stress (r = -0.47). We offered preliminary evidence suggesting that modest changes in adiposity following a brief caloric restriction program may yield beneficial effect on cardiovascular stress responses. In addition, reductions in basal leptin activity might be important in blunting pro-inflammatory responses. Large randomized trials of the effect of adiposity on autonomic responses are thus warranted.

Investigating inflammation in depression in the chronically ill: Theoretical model and perspectives.

BACKGROUND: Inflammation is a risk factor for chronic physical illnesses. Evidence is building that inflammation is also a risk factor for mental illnesses making inflammation a common mechanism which could explain the high comorbidity between mental and physical illnesses. METHODS: Based on a systematic search, a review on factors associated with inflammation in the depressed chronically ill has been conducted. Relevant articles have been selected according to the methodological considerations (scope, sample size, type of analysis and bias). RESULTS: Five categories of factors mediate the association between chronic physical and mental illnesses: (1) social-demographic factors, (2) social-economic background, (3) adverse health behaviours, (4) psychological stress and (5) genetics. Psychological therapies and medication also moderate this association. A theoretical model of the interplay between inflammation, depression and chronic physical illness is then presented. DISCUSSION: Inflammation contribute to both chronic physical and mental illnesses. These conclusions support future advances in clinical and research practice, as well as training and education.

TREM-1 and DAP12 expression in monocytes of patients with severe psychiatric disorders. EGR3, ATF3 and PU.1 as important transcription factors.

INTRODUCTION: Immune activation is a characteristic of schizophrenia (SCZ), bipolar disorder (BD) and unipolar major depressive disorder (MDD). The triggering receptor expressed on myeloid cells 1 (TREM-1), its' adaptor molecule DAP12 and their transcription factor (TF) PU.1 are important key genes in inflammation and expressed in activated monocytes and microglia. AIM: To test: (1) if the expressions of TREM-1, DAP12 and PU.1 are increased in monocytes of patients with severe psychiatric disorders and (2) if PU.1 and the TFs ATF3 and EGR3 (which have been found as prominent increased monocyte genes in previous studies) are involved in the regulation of TREM-1 and DAP12 expression. METHODS: Using Q-PCR, we studied the gene expression of TREM-1, DAP12, PU.1, ATF3 and EGR3 in the monocytes of 73 patients with severe psychiatric disorders (27 recent onset SCZ patients, 22 BD patients and 24 MDD patients) and of 79 healthy controls (HC). Using in silico TF binding site prediction and in vivo chromatin immunoprecipitation (ChIP), we studied the actual binding of EGR3, ATF3 and PU.1 to the promoter regions of TREM-1 and DAP12. RESULTS: 1. TREM-1 gene expression was increased in the monocytes of SCZ and BD patients and tended to be increased in the monocytes of MDD patients. 2. DAP12 gene levels were neither increased in the monocytes of SCZ, BD, nor MDD patients. 3. PU.1 expression levels were increased in the monocytes of MDD patients, but not in those of SCZ and BD patients. 4. TREM-1 expression levels correlated in particular to ATF3 and EGR3 expression levels, DAP12 expression levels correlated in particular to PU.1 expression levels. 5. We found using binding site prediction and ChIP assays that the TFs EGR3 and ATF3 indeed bound to the TREM-1 promoter, PU.1 bound to both the TREM-1 and DAP12 promoter. CONCLUSION: In this study, we provide evidence that TREM-1 gene expression is significantly increased in monocytes of SCZ and BD patients and that the TREM-1 gene is a target gene of the TFs ATF3 and EGR3. In MDD patients, PU.1 gene expression was increased with a tendency for TREM-1 gene over expression. Our observations support the concept that monocytes are in a pro-inflammatory state in severe psychiatric conditions and suggest differences in monocyte inflammatory set points between SCZ, BD and MDD.

Association of Anxiety With Pain and Disability but Not With Increased Measures of Inflammation in Adolescent Patients With Juvenile Idiopathic Arthritis.

OBJECTIVE: To explore whether anxiety and depression are associated with clinical measures of disease for adolescent patients with juvenile idiopathic arthritis (JIA) and whether anxiety and depression are associated with increased peripheral proinflammatory cytokine levels in adolescent patients with JIA and in healthy adolescent controls. METHODS: A total of 136 patients with JIA and 88 healthy controls ages 13-18 years completed questionnaires on anxiety and depressive symptoms. For patients with JIA, pain, disability, physician global assessment (using a visual analog scale [VAS]), and number of joints with active inflammation (active joint count) were recorded. In a subsample, we assessed lipopolysaccharide-stimulated interleukin 6 (IL-6) production from peripheral blood mononuclear cells, serum IL-6, cortisol, and C-reactive protein levels. Data were analyzed by linear regression analysis. RESULTS: Levels of anxiety and depressive symptoms in patients with JIA were not significantly different than those in healthy controls. For patients with JIA, anxiety was significantly associated with disability (ß = 0.009, P = 0.002), pain (ß = 0.029, P = 0.011), and physician global assessment VAS (ß = 0.019, P = 0.012), but not with active joint count (ß = 0.014, P = 0.120). Anxiety was not associated with any laboratory measures of inflammation for JIA patients. These relationships were also true for depressive symptoms. For healthy controls, there was a trend toward an association of anxiety (but not depressive symptoms) with stimulated IL-6 (ß = 0.004, P = 0.052). CONCLUSION: Adolescent patients with JIA experience equivalent levels of anxiety and depressive symptoms as healthy adolescents. For adolescent patients with JIA, anxiety and depressive symptoms are associated with pain, disability, and physician global assessment VAS, but not with inflammation.

Self-Reported Sensory Impairments and Changes in Cognitive Performance: A Longitudinal 6-Year Follow-Up Study of English Community-Dwelling Adults Aged ⩾50 Years.

Objective: To investigate the influence of single and dual sensory impairments prospectively on cognition in adults aged ⩾50 years. Method: Community-dwelling English adults (n = 4,621) were followed up from 2008 to 2014. Self-reported hearing and vision were collected in 2008. Change in cognitive performance on working memory and executive function between 2008 and 2014 was evaluated. Results: Compared with good hearing and good vision, respectively, poor hearing and poor vision were associated with worse cognitive function (hearing: unstandardized coefficient B = 0.83, 95% Confidence Interval [CI] = [0.29, 1.37]; vision: B = 1.61, 95% CI = [0.92, 2.29] adjusted for age, sex, baseline cognition). Compared with no sensory impairment, dual sensory impairment was associated with worse cognition (B = 2.30, 95% CI = [1.21, 3.39] adjusted for age, sex, baseline cognition). All associations remained after further adjustment for sociodemographic characteristics, lifestyle factors, chronic conditions, falls, mobility, depression, and lack of companionship. Discussion: The findings are important as age-related sensory impairments are often preventable or modifiable, which may prevent or delay cognitive impairment.

Effect of antidepressants on melatonin metabolite in depressed patients.

Antidepressants increase melatonin levels, but it is still unclear whether this effect is related to the improvement of depressive symptoms or to unrelated pharmacological action of antidepressants. To answer this question, the effect of antidepressants on 6-sulphatoxymelatonin (aMT6s), the main melatonin urinary metabolite, was examined in drug-free depressed patients - most of them antidepressant-naive. aMT6s was evaluated in 34 depressed patients, before and after 8 weeks of placebo (n = 12) or antidepressant (n = 22; fluoxetine, duloxetine or Hypericum perforatum). Both groups showed an improvement of depressive symptoms after treatment compared to baseline (Hamilton Depression scores): 17.0 +/- 1.4 vs. 9.0 +/- 2.8, P = 0.007 for placebo, and 18.6 +/- 1.1 vs. 11.8 +/- 1.6, P < 0.001 for antidepressants). After treatment, aMT6s levels increased after antidepressants (P < 0.01), but not after placebo (P > 0.05). As depressive symptoms improved both in patients taking antidepressant and in those taking placebo, but an effect of antidepressants could only be seen in those taking antidepressants, we suggest that melatonin changes after antidepressants are more likely due to a pharmacological action of these drugs on melatonin secretion.

Long work hours, weekend working and depressive symptoms in men and women: findings from a UK population-based study.

BACKGROUND: Globalised and 24/7 business operations have fuelled demands for people to work long hours and weekends. Research on the mental health effects of these intensive temporal work patterns is sparse, contradictory or has not considered gender differences. Our objective was to examine the relationship between these work patterns and depressive symptoms in a large nationally representative sample of working men and women in the UK. METHOD: The current study analysed data from Understanding Society, the UK Household Longitudinal Study, of 11 215 men and 12 188 women in employment or self-employment at the time of the study. Ordinary least squares regression models, adjusted for potential confounders and psychosocial work factors, were used to estimate depressive symptoms across categories of work hours and weekend work patterns. RESULTS: Relative to a standard 35-40 hours/week, working 55 hours/week or more related to more depressive symptoms among women (ß=0.75, 95% CI 0.12 to 1.39), but not for men (ß=0.24, 95% CI -0.10 to 0.58). Compared with not working weekends, working most or all weekends related to more depressive symptoms for both men (ß=0.34, 95% CI 0.08 to 0.61) and women (ß=0.50, 95% CI 0.20 to 0.79); however, working some weekends only related to more depressive symptoms for men (ß=0.33, 95% CI 0.11 to 0.55), not women (ß=0.17, 95% CI -0.09 to 0.42). CONCLUSION: Increased depressive symptoms were independently linked to working extra-long hours for women, whereas increased depressive symptoms were associated with working weekends for both genders, suggesting these work patterns may contribute to worse mental health.

In vitro modulation of the glucocorticoid receptor by antidepressants.

Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamus-pituitary-adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Accordingly, reduced GR function has also been demonstrated in vitro, in peripheral tissues of depressed patients, as shown by reduced sensitivity to the effects of glucocorticoids on immune and metabolic functions. We and others have shown that antidepressants in vitro are able to modulate GR mRNA expression, GR protein level and GR function. This paper reviews the in vitro studies that have examined the effect of antidepressants on GR expression, number and function in human and animal cell lines, and the possible molecular mechanisms underlying these effects. Antidepressants are shown to both increase and decrease GR function in vitro, based on different experimental conditions. Specifically, increased GR function is likely to be mediated by an increased intracellular concentration of glucocorticoids, while decreased GR function seems to be the consequence of GR downregulation. We suggest that the study of the effects of antidepressants on glucocorticoid function might help clarify the therapeutic action of these drugs.

The effects of six-day SSRI administration on diurnal cortisol secretion in healthy volunteers.

RATIONALE: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been widely reported in depression, and evidence suggests that selective serotonin reuptake inhibitors (SSRIs) might exert their therapeutic effects through altering cortisol secretion. OBJECTIVE: This study assessed the effects of SSRI administration on diurnal cortisol secretion in healthy volunteers. METHODS: Sixty-four healthy men and women were randomised to receive either 10 mg escitalopram or placebo for six days in a double-blind fashion. On day six of medication, saliva samples were obtained at home for measurement of diurnal cortisol parameters (cortisol slope, cortisol awakening response, total daily cortisol output). RESULTS: Women receiving escitalopram had significantly steeper cortisol slopes across the day compared with those receiving placebo (F(1, 36) = 7.54, p = 0.009). This alteration in cortisol slope was driven by increases in waking cortisol levels (F(1, 35) = 9.21, p = 0.005). Escitalopram did not have any significant effect on the cortisol awakening response or the total daily cortisol output. CONCLUSIONS: Flattened cortisol slopes have been seen in depression. The results of this study suggest that escitalopram might exert its therapeutic effect in women in part through correction of a flattened diurnal cortisol rhythm.