Development Of Stress-related Disorders Research Articles

The impact of physical fitness on resilience to modern life stress and the mediating role of general self-efficacy

Substantial evidence shows that physical activity and fitness play a protective role in the development of stress related disorders. However, the beneficial effects of fitness for resilience to modern life stress are not fully understood. Potentially protective effects may be attributed to enhanced resilience via underlying psychosocial mechanisms such as self-efficacy expectations. This study investigated whether physical activity and fitness contribute to prospectively measured resilience and examined the mediating effect of general self-efficacy. 431 initially healthy adults participated in fitness assessments as part of a longitudinal-prospective study, designed to identify mechanisms of resilience. Self-efficacy and habitual activity were assessed in parallel to cardiorespiratory and muscular fitness, which were determined by a submaximal step-test, hand strength and standing long jump test. Resilience was indexed by stressor reactivity: mental health problems in relation to reported life events and daily hassles, monitored quarterly for nine months. Hierarchical linear regression models and bootstrapped mediation analyses were applied. We could show that muscular and self-perceived fitness were positively associated with stress resilience. Extending this finding, the muscular fitness–resilience relationship was partly mediated by self-efficacy expectations. In this context, self-efficacy expectations may act as one underlying psychological mechanism, with complementary benefits for the promotion of mental health. While physical activity and cardiorespiratory fitness did not predict resilience prospectively, we found muscular and self-perceived fitness to be significant prognostic parameters for stress resilience. Although there is still more need to identify specific fitness parameters in light of stress resilience, our study underscores the general relevance of fitness for stress-related disorders prevention.

Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders.

Stress is defined as a state of threatened or perceived as threatened homeostasis. The well-tuned coordination of the stress response system is necessary for an organism to respond to external or internal stressors and re-establish homeostasis. Glucocorticoid hormones are the main effectors of stress response and aberrant glucocorticoid signaling has been associated with an increased risk for psychiatric and mood disorders, including schizophrenia, post-traumatic stress disorder and depression. Emerging evidence suggests that life-stress experiences can alter the epigenetic landscape and impact the function of genes involved in the regulation of stress response. More importantly, epigenetic changes induced by stressors persist over time, leading to increased susceptibility for a number of stress-related disorders. In this review, we discuss the role of glucocorticoids in the regulation of stress response, the mechanism through which stressful experiences can become biologically embedded through epigenetic alterations, and we underline potential associations between epigenetic changes and the development of stress-related disorders.

The role of the microbiota in acute stress-induced myeloid immune cell trafficking

There has been a growing recognition of the involvement of the gastrointestinal microbiota in the development of stress-related disorders. Acute stress leads to activation of neuroendocrine systems, which in turn orchestrate a large-scale redistribution of innate immune cells. Both these response systems are independently known to be primed by the microbiota, even though much is still unclear about the role of the gastrointestinal microbiota in acute stress-induced immune activation. In this study, we investigated whether the microbiota influences acute stress-induced changes in innate immunity using conventionally colonised mice, mice devoid of any microbiota (i.e. germ-free, GF), and colonised GF mice (CGF). We also explored the kinetics of stress-induced immune cell mobilisation in the blood, the spleen and mesenteric lymph nodes (MLNs). Mice were either euthanised prior to stress or underwent restraint stress and were then euthanised at various time points (i.e. 0, 45- and 240-minutes) post-stress. Plasma adrenaline and noradrenaline levels were analysed using ELISA and immune cell levels were quantified using flow cytometry. GF mice had increased baseline levels of adrenaline and noradrenaline, of which adrenaline was normalised in CGF mice. In tandem, GF mice had decreased circulating levels of LY6Chi and LY6Cmid, CCR2+ monocytes, and granulocytes, but not LY6C−, CX3CR1+ monocytes. These deficits were normalised in CGF mice. Acute stress decreased blood LY6Chi and LY6Cmid, CCR2+ monocytes while increasing granulocyte levels in all groups 45 min post-stress. However, only GF mice showed stress-induced changes in LY6Chi monocytes and granulocytes 240 min post-stress, indicating impairments in the recovery from acute stress-induced changes in levels of specific innate immune cell types. LY6C−, CX3CR1+ monocytes remained unaffected by stress, indicating that acute stress impacts systemic innate immunity in a cell-type-specific manner. Overall, these data reveal novel cell-type-specific changes in the innate immune system in response to acute stress, which in turn are impacted by the microbiota. In conclusion, the microbiota influences the priming and recovery of the innate immune system to an acute stressor and may inform future microbiota-targeted therapeutics aimed at modulating stress-induced immune activation in stress-related disorders.

Cortisol response to stress: The role of expectancy and anticipatory stress regulation

An exacerbated physiological response to stress is associated with the development of stress-related disorders (e.g., depression and anxiety disorders). Recently, it has been proposed that individuals with high expectancies of being able to deal with stressful situations will activate regulatory mechanisms during the anticipation of the stressful event that would improve stress regulation. To test this hypothesis, 52 women in young adulthood (M = 21.06; SD = 2.58) anticipated and performed a laboratory-based stress task after receiving positive or negative bogus feedback on their abilities to deal with stressful events. Heart rate variability and salivary cortisol were assessed throughout the experimental protocol. Participants receiving positive bogus feedback (i.e., High Expectancy group) showed a more positive anticipatory cognitive stress appraisal (i.e., they anticipated the stress task as less threatening/challenging, and they perceived that they were more able to deal with it), and they showed a lower cortisol response to stress. Moreover, a more positive anticipatory cognitive stress appraisal was associated with better anticipatory stress regulation (indexed as less decrease in heart rate variability), leading to a lower cortisol response. Our results indicate that people with positive expectancy initiate mechanisms of anticipatory stress regulation that enhance the regulation of the physiological stress response. Expectancy and anticipatory stress regulation may be key mechanisms in the development and treatment of stress-related disorders.

The Role of the Intestinal Microbiome in Chronic Psychosocial Stress-Induced Pathologies in Male Mice.

Chronic psychosocial stress is a risk factor for the development of physical and mental disorders accompanied or driven by an activated immune system. Given that chronic stress-induced systemic immune activation is lacking in germ-free and antibiotics-treated mice, a causal role of the gut microbiome in the development of stress-related disorders is likely. To address this hypothesis in the current study we employed the chronic subordinate colony housing (CSC, 19 days) paradigm, a pre-clinically validated mouse model for chronic psychosocial stress, known to alter the gut microbial signature and to induce systemic low-grade inflammation, as well as physical and mental abnormalities. In detail, we investigated if (i) CSC-induced alterations can be prevented by repeated transplantation of feces (FT) from non-stressed single-housed control (SHC) mice during CSC exposure, and (ii) if the transplantation of a “stressed” CSC microbiome is able to induce CSC effects in SHC mice. Therefore, we repeatedly infused SHC and CSC recipient mice rectally with SHC donor feces at days 4 and 11 of the CSC paradigm and assessed anxiety-related behavior on day 19 as well as physiological, immunological, and bone parameters on day 20. Furthermore, SHC and CSC recipient mice were infused with CSC donor feces at respective days. To exclude effects of rectal infusions per se, another set of SHC and CSC mice was infused with saline, respectively. Our results showed that transplantation of SHC feces had mild stress-protective effects, indicated by an amelioration of CSC-induced thymus atrophy, anxiety, systemic low-grade inflammation, and alterations in bone homeostasis. Moreover, transplantation of CSC feces slightly aggravated CSC-induced systemic low-grade inflammation and alterations in bone homeostasis in SHC and/or CSC animals. In conclusion, our data provide evidence for a role of the host’s microbiome in many, but not all, adverse consequences of chronic psychosocial stress. Moreover, our data are consistent with the hypothesis that transplantation of healthy feces might be a useful tool to prevent/treat different adverse outcomes of chronic stress. Finally, our data suggests that stress effects can be transferred to a certain extend via FT, proposing therapeutic approaches using FT to carefully screen fecal donors for their stress/trauma history.

Exhaustion mediates the relationship between stress and long-term health status in outpatients

ObjectiveStress is considered to impair health and to be a burden for the individual and the health system. Here, we compared the influence of psychosocial stress and perceived exhaustion as predictors for the development of stress related disorders. MethodsOutpatients took part in a clinical trial with Neuropattern, a diagnostic tool to detect stress pathology (Hellhammer, D. H., Hero, T., Gerhards, F., & Hellhammer, J., 2012). The patients answered questions about perceived exhaustion, mental health, psychosocial stress, and demographic variables at their first visit. Further, they answered questions about their health status at five different time points (baseline and 3, 6, 9, and 12 months later). Associations between psychosocial stress, perceived exhaustion, and health status were analyzed at these five time points with mixed models. Furthermore, we explored the potential role of perceived exhaustion as a mediator for the association between psychosocial stress and health status. ResultsBoth perceived exhaustion and psychosocial stress predicted the development of a poorer health status. Statistical analyses showed the association between psychosocial stress and health status to be mediated by perceived exhaustion. ConclusionOur findings highlight the importance of perceived exhaustion as a relevant and easy measure to predict the development of impaired health in stress-related disorders.

The association of childhood maltreatment with depression and anxiety is not moderated by the oxytocin receptor gene

BackgroundThe oxytocin receptor (OXTR) gene may be involved in resilience or vulnerability towards stress, and hence in the development of stress-related disorders. There are indications that OXTR single nucleotide polymorphisms (SNPs) interact with early life stressors in predicting levels of depression and anxiety. To replicate and extend these findings, we examined whether three literature-based OXTR SNPs (rs2254298, rs53576, rs2268498) interact with childhood maltreatment in the development of clinically diagnosed depression and anxiety disorders.MethodsWe included 2567 individuals from the Netherlands Study of Depression and Anxiety. This sample consisted of 387 healthy controls, 428 people with a current or past depressive disorder, 243 people with a current or past anxiety disorder, and 1509 people with both lifetime depression and anxiety diagnoses. Childhood maltreatment was measured with both an interview and via self-report. Additional questionnaires measured depression and anxiety sensitivity.ResultsChildhood maltreatment was strongly associated with both lifetime depression and anxiety diagnoses, as well as with depression and anxiety sensitivity. However, the OXTR SNPs did not moderate these associations nor had main effects on outcomes.ConclusionsThe three OXTR gene SNPs did not interact with childhood maltreatment in predicting lifetime depression and anxiety diagnoses or sensitivity. This stresses the importance of replication studies with regard to OXTR gene variants in general populations as well as in clearly established clinical samples.

Functional connectivity of resting-state, working memory and inhibition networks in perceived stress

Experimental imaging studies on the effects of acute stress have revealed functional changes in the amygdalae, hippocampi and medial frontal cortices. However, much less is known about the association between perceived stress and neurological function which may have implications for the development of stress related disorders. Participants completed a working-memory task and an inhibition task whilst undergoing a functional magnetic resonance imaging (fMRI) scan. Task related and resting-state fMRI data from 22 women and 24 men were analysed to investigate changes in task activations and functional connectivity associated with perceived stress over the past month. Analyses were stratified by gender due to gender differences in the stress response. Stress was associated with faster working memory response time in women, but not men. Stress was not associated with any differences in task activations in either gender. There were many significant associations between stress and connectivity: findings in women were consistent with increased emotional regulation; men exhibited decreases in connectivity between affective processing areas during the tasks and showed no relation between perceived stress and resting-state connectivity; very few of the within gender differences were significantly different between gender. Dysregulated connectivity between areas involved in the neural stress response and self-referential thoughts (e.g. the default mode network) suggests that perceived stress may have a subtle impact on cognitive processing and neural correlates.

Serotonin 2A receptor (5-HT2A) gene promoter variant interacts with chronic perceived stress to modulate resting parasympathetic activity in humans

Decreased resting vagal (parasympathetic) tone is implicated in the development of stress-related disorders, including anxiety and depression. Chronic stress elevates the expression of serotonin 2A receptors (5-HT2A), while activation of 5-HT2A leads to inhibition of parasympathetic synaptic transmission. The T allele of the promoter variant, rs6311 (C>T), of the 5-HT2A gene has been shown to increase the 5-HT2A expression in vitro and to be associated with anxiety and depressive disorders. We thus hypothesized that the 5-HT2A functional polymorphism may influence resting vagal activity among persons with chronically high levels of perceived stress. A total of 1138 well-defined healthy, medication-free Han Chinese were included for 5-HT2A genotyping. The Perceived Stress Scale (PSS) was used to measure the level of perceived stress during the last month and participants were divided into low and high PSS groups. Resting-state heart rate variability (HRV) was used to assess autonomic function. No significant between-genotype difference was found in any HRV variable in the low PSS group (n=610). However, in the high PSS group (n=528), high frequency power and root mean square of successive heartbeat interval differences (both HRV indices of parasympathetic activity) were significantly reduced in T/T genotype carriers compared to C/C homozygotes. Our findings are the first to show that individuals homozygous for the high-expressing 5-HT2A (T) allele exhibit diminished resting vagal tone—an index of stress vulnerability—when experiencing chronically elevated levels of perceived stress. The present results may advance our understanding of the genetic mechanism underlying individual differences in susceptibility to stress.

Carbohydrate-enriched diet predispose to anxiety and depression-like behavior after stress in mice

Objectives: Obesity is a chronic disease frequently associated with serious co-morbidities, such as diabetes type II, metabolic syndrome, and psychiatric disorders. Little is known, however, regarding the behavioral consequences of modified diet constituents and the propensity to development of stress related disorders. Thus, the aim of this study was to verify whether chronic exposure to a normocaloric/high-carbohydrate diet will modify the animal's behavior after different stressful stimuli.Methods: BALB/c mice were fed for 12 weeks with a standard chow diet or high refined carbohydrate-containing diet (HC). Following this period, independent groups of animals were exposed to different stress paradigms: 1 – two hours of restraint stress followed by exposure to the Elevated Plus Maze test (EPM) 24 hours later; 2 – The contextual fear conditioning (CFC) test and 3 – the tail suspension test (TST).Results: Despite no change on total body weight, animals fed with HC diet showed increase in serum leptin levels and higher adiposity compared to diet control group. In behavioral tests, animals from HC diet group displayed reduction in the percentage of entries into the open arms of the EPM, evaluated 24 hours after restraint stress, suggesting an anxiogenic-like effect. It is also observed increase in aversive memory in the CFC test and depressive-like behavior in TST.Discussion: Our results suggest that a moderate obesity, induced by high refined carbohydrate diet, may facilitate the development of anxiety and depressive-like behaviors after the stress. The mechanisms responsible for such effects remain to be elucidated.

Potential pleiotropic beneficial effects of adjuvant melatonergic treatment in posttraumatic stress disorder

Loss of circadian rhythmicity fundamentally affects the neuroendocrine, immune, and autonomic system, similar to chronic stress and may play a central role in the development of stress-related disorders. Recent articles have focused on the role of sleep and circadian disruption in the pathophysiology of posttraumatic stress disorder (PTSD), suggesting that chronodisruption plays a causal role in PTSD development. Direct and indirect human and animal PTSD research suggests circadian system-linked neuroendocrine, immune, metabolic and autonomic dysregulation, linking circadian misalignment to PTSD pathophysiology. Recent experimental findings also support a specific role of the fundamental synchronizing pineal hormone melatonin in mechanisms of sleep, cognition and memory, metabolism, pain, neuroimmunomodulation, stress endocrinology and physiology, circadian gene expression, oxidative stress and epigenetics, all processes affected in PTSD. In the current paper, we review available literature underpinning a potentially beneficiary role of an add-on melatonergic treatment in PTSD pathophysiology and PTSD-related symptoms. The literature is presented as a narrative review, providing an overview on the most important and clinically relevant publications. We conclude that adjuvant melatonergic treatment could provide a potentially promising treatment strategy in the management of PTSD and especially PTSD-related syndromes and comorbidities. Rigorous preclinical and clinical studies are needed to validate this hypothesis.

When time stands still: an integrative review on the role of chronodisruption in posttraumatic stress disorder.

The human circadian system creates and maintains cellular and systemic rhythmicity essential to homeostasis. Loss of circadian rhythmicity fundamentally affects the neuroendocrine, immune and autonomic system, similar to chronic stress and, thus, may play a central role in the development of stress-related disorders. This article focuses on the role of circadian misalignment in the pathophysiology of posttraumatic stress disorder (PTSD). Sleep disruption is a core feature of PTSD supporting the important supraordinate pathophysiological role of circadian system in PTSD. Furthermore, direct and indirect human and animal PTSD research suggests circadian system linked neuroendocrine, immune, metabolic and autonomic dysregulation with blunted diurnal rhythms, specific sleep pattern pathologies and cognitive deficits, as well as endocannabinoid and neuropeptide Y system alterations and altered circadian gene expression, linking circadian misalignment to PTSD pathophysiology. PTSD development is associated with chronodisruption findings. Evaluation and treatment of sleep and circadian disruption should be the first steps in PTSD management. State-of-the-art methods of circadian rhythm assessment should be applied to bridge the gap between clinical significance and limited understanding of the relationship between traumatic stress, sleep and circadian system.

The endocannabinoid system and the regulation of memory for emotionally arousing experiences

Event Abstract Back to Event The endocannabinoid system and the regulation of memory for emotionally arousing experiences Patrizia Campolongo1* 1 Università degli Studi di Roma La Sapienza, Physiology and Pharmacology, Italy The activation of neuromodulatory systems affecting the amygdala and its projections to other brain regions, plays a key role in enabling emotionally significant experiences to be well remembered. Although it is vital for a human being to be able to remember emotionally arousing experiences, the efficient encoding of emotional memories can, in certain conditions, become maladaptive. Indeed, severe stress often turns emotional memories into a source of chronic anxiety, which may lead to the development of stress related disorders. In this talk I will present the results of studies that addressed the effects induced by the manipulation of the endocannabinoid system in the modulation of memory for emotional experiences. I will focus on the role of the endocannabinoid system in the modulation of memory consolidation for emotionally arousing experiences, showing how this system interacts with other neuromodulatory systems in the regulation of such processes. Keywords: endocannabinoid system, learning and memory, emotional arousal, Rats, Glucocorticoids Conference: 4th Conference of the Mediterrarnean Neuroscience Society, Istanbul, Turkey, 30 Sep - 3 Oct, 2012. Presentation Type: Symposium Topic: Abstracts Citation: Campolongo P (2013). The endocannabinoid system and the regulation of memory for emotionally arousing experiences. Conference Abstract: 4th Conference of the Mediterrarnean Neuroscience Society. doi: 10.3389/conf.fnhum.2013.210.00012 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 26 Jan 2013; Published Online: 11 Apr 2013. * Correspondence: Dr. Patrizia Campolongo, Università degli Studi di Roma La Sapienza, Physiology and Pharmacology, Rome, 00159, Italy, Patrizia.Campolongo@uniroma1.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Patrizia Campolongo Google Patrizia Campolongo Google Scholar Patrizia Campolongo PubMed Patrizia Campolongo Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The biochemical complexity of the endocannabinoid system with some remarks on stress and related disorders: a minireview

Nowadays, the endocannabinoid-regulated processes are in the focus of interest, among others, for the treatment of stress-related disorders. In this minireview, we attempt to give some possible explanations for the conflicting results of the cannabinoidergic regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis and related disorders, drawing attention to the complexity of the endocannabinoid system. The endocannabinoid system is a part of an intricate network of lipid pathways and consists of the cannabinoid receptors, their endogenous ligands, and the enzymes catalyzing their formation and degradation. The stress research is focused almost exclusively on the anandamide and 2-arachidonyl glycerol, and the cannabinoid 1 receptor. However, physiological, pathological, and pharmacological perturbations of the interconnected lipid pathways have a profound effect on the regulation of the endocannabinoid signaling system. For example, diet may substantially influence the lipid composition of the body. Recent studies have indicated that beside cannabinoid 1 receptor, the endocannabinoids may act on the cannabinoid 2, peroxisome proliferator-activated, and transient receptor potential of vanilloid type-1 receptors, too. All of these receptors are implicated in the development of stress-related disorders. However, it has to be mentioned that degradation of the endocannabinoids may result in the production of active compounds as well. Since endocannabinoids have a widespread distribution in the body, they may influence a phenomenon at several points. Different effects (stimulatory or inhibitory) at different levels of endocannabinoids (e.g. hypothalamus, hypophysis, adrenal gland in the case of HPA axis) may explain some of their unequivocal results.

Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance

Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis has been associated with the etiology of major depression. One of the factors underlying altered glucocorticoid signaling might be variability of the glucocorticoid receptor gene (GR, NR3C1). GR polymorphisms have been associated with variability in glucocorticoid sensitivity and endocrine responses to psychosocial stress. Furthermore, a common GR SNP (rs10482605), located in the promoter region, has been associated with major depression. We performed functional characterization of this SNP in vitro using a reporter gene assay under different stimulation conditions. Furthermore, we genotyped 219 subjects previously genotyped for four common GR SNPs to further characterize GR haplotype structure. The minor C allele of the rs10482605 SNP showed reduced transcriptional activity under unstimulated conditions and under different stimulation conditions in two brain derived cell lines. Linkage analyses revealed that the rs10482605 SNP is in high linkage disequilibrium with a A/G SNP in exon 9beta (rs6198), associated with relative glucocorticoid resistance and increased GRbeta mRNA stability. We provide evidence that two functional GR SNPs in linkage disequilibrium are responsible for both regulation of GR expression and mRNA stability. This newly characterized haplotype could increase the risk for the development of stress related disorders, including major depression.

Growth hormone response to different consecutive stress stimuli in healthy men: Is there any difference?

The contribution of growth hormone (GH), released during acute and repeated stressful situations, to the development of stress-related disorders is often neglected. We have hypothesized that the modulation of the GH response to sequential stress exposure in humans depends mainly on the nature of the stressor. To test this hypothesis, we compared GH responses to different stressful situations, namely aerobic exercise, hypoglycemia and hyperthermia, which were applied in two sequential sessions separated by 80–150 min. In addition, administration of the dopaminergic drug apomorphine was used as a pharmacological stimulus. GH responses to submaximal exercise (bicycle ergometer, increasing work loads of 1.5, 2.0 and 2.5 W/kg, total duration 20 min) and hyperthermia in a sauna (80°C, 30 min) were prevented when preceded by the same stress stimulus. Hypoglycemia induced by insulin (0.1 IU/kg intravenously) resulted in a significant GH response also during the second of the two consecutive insulin tests, though the response was reduced. Administration of apomorphine (0.75 mg subcutaneously) or insulin prevented the increase in GH release in response to a sequential bolus of apomorphine, while hypoglycemia induced a significant elevation in GH levels even if applied after a previous treatment with apomorphine. In conclusion, the feedback inhibition of the GH response to a sequential stress stimulus depends on the stimulus used. Unlike in the case of exercise and hyperthermia, mechanisms involved in the stress response to hypoglycemia appear to overcome the usual feedback mechanisms and to re-induce the GH response when applied after another stimulus.

Type 2 diabetes does not increase risk of depression

Although diabetes mellitus has a strong association with the presence of depression, it is unclear whether diabetes itself increases the risk of developing depression. The objective of our study was to evaluate whether people with diabetes have a greater incidence of depression than those without diabetes. We conducted a population-based retrospective cohort study using the administrative databases of Saskatchewan Health from 1989 to 2001. People older than 20 years with newly identified type 2 diabetes were identified by means of diagnostic codes and prescription records and compared with a nondiabetic cohort. Depression was ascertained via diagnostic codes and prescriptions for antidepressants. Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for age, sex, frequency of visits to physicians and presence of comorbidities. We identified 31 635 people with diabetes and 57 141 without. Those with diabetes were older (61.4 v. 46.8 yr; p < 0.001), were more likely to be male (55.4% v. 49.8%; p < 0.001) and had more physician visits during the year after their index date (mean 14.5 v. 5.9; p < 0.001). The incidence of new-onset depression was similar in both groups (6.5 v. 6.6 per 1000 person-years among people with and without diabetes, respectively). Similarity of risk persisted after controlling for age, sex, number of physician visits and presence of prespecified comorbidities (adjusted HR 1.04, 95% CI 0.94- 1.15). Other chronic conditions such as arthritis (HR 1.18) and stroke (HR 1.73) were associated with the onset of depression. Using a large, population-based administrative cohort, we found little evidence that type 2 diabetes increases the risk of depression once comorbid diseases and the burden of diabetes complications were accounted for.