Search

Tanshinone IIA (Tan IIA) is reported to have neuroprotective effects to suppress cell apoptosis of cortical neurons induced by Aβ 25-35 through inhibiting oxidative stress. Nevertheless, few studies have investigated the effects of Tan IIA on depressive disorder. Here, we aimed to measure the effects of Tan IIA on chronic unpredictable mild stress (CUMS) induced mouse model and its underlying mechanism. For 28 days, mice were subjected to CUMS while Tan IIA was administered once daily at doses of 0, 1, 2.5, 5, or 10 mg/kg. CUMS exposure increased depressive-like behaviors, as indicated by increased immobility time in the forced swim and tail suspension tests, decreased sucrose preference in the sucrose preference test, and reduced exploratory behavior in the open field test. All of these behaviors were reversed dose-dependently by Tan IIA treatment. Oxidative stress was determined by measuring malondialdehyde, glutathione peroxidase, and superoxide dismutase activity and total antioxidant capacity. Levels of pro-inflammatory factors IL-1β and IL-18, cAMP response element binding protein and brain derived neurotrophic factor were detected by ELISA and western blot assay, respectively. The results showed that CUMS increased oxidative stress and pro-inflammatory factors and decreased levels of cAMP response element binding protein and brain-derived neurotrophic factor. Tan IIA treatment again reversed these effects. Importantly, RasGRF1 expression increased in CUMS-exposed mice but decreased after Tan IIA administration. Using RasGRF1 -/- mice to determine the role of RasGRF1 in mice exposed to CUMS, we found that knockdown of RasGRF1 reversed the effects of CUMS on mice, just like Tan IIA. These results indicate that Tan IIA may reverse depressive-like behaviors in CUMS-exposed mice by regulating RasGRF1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: No study has investigated the role of inflammation in explaining the association between early exposures to adverse life events and depressive symptoms in adolescence., Method: Using data from the Avon Longitudinal Study of Parents and Children, we tested if inflammatory markers [serum C-reactive protein (CRP) and interleukin 6 (IL-6)] at age 9 years mediate the association between adverse life events, measured separately for the prenatal (since the beginning of pregnancy) and the childhood (ages 0-9 years) periods, and the development of depressive symptoms at ages 10-17 years. Data (n = 4,263) were analyzed using mediation analysis in a latent growth curve modeling framework., Results: Depressive symptoms at the beginning of adolescence (age 10) were associated with the number of prenatal events, the number of events around birth and the increase in events over time in childhood (ages 0-9), even after adjustment for confounders. IL-6 partially mediated the association between increasing exposure to events over time in childhood and depressive symptoms at the beginning of adolescence. IL-6 did not mediate any other association between events and symptoms. There was no evidence for mediation by CRP, which was generally unrelated to exposure to events., Limitations: The small size of the mediation effect and the robust direct effects of events prenatally and around birth suggest there are multiple routes from early stressors to adolescent depression., Conclusions: In the general adolescent population, increasing exposure to psychosocial stressors over time during childhood is associated with the early onset of depressive symptoms, partly via increasing levels of plasma IL-6., (Copyright © 2019. Published by Elsevier B.V.)

Background: Few studies have examined the concurrent effects of physical disease and systemic inflammation on suicide risk in patients with depression. The authors investigated the independent contributions of chronic physical disease and systemic inflammation as indexed by C-reactive protein (CRP), on risk of suicide attempt., Methods: In this case-control study, 1468 cases of suicide attempters and 14 373 controls, both aged 18-65 years with a diagnosis of depression during 2011-2015, were identified from the hospital-wide database. Regression models were implemented to identify separate effects of physical diseases and systemic inflammation indexed by CRP, on risk of suicide attempt., Results: Compared with having no physical disease, having one, two, and three or more physical diseases was associated with a 3.6-, 6.4-, and 14.9-fold increase in odds of making a suicide attempt, respectively, after adjusting for age, sex, and race/ethnicity. In a sub-sample of cases and controls with available CRP values, patients with high CRP (>3 mg/L) had 1.9 times the odds of suicide attempt compared with patients with low CRP (<1 mg/L). This association was no longer significant when controlling for the effect of physical disease., Conclusions: The presence of physical disease is an important risk factor for suicide attempt among patients with depression. Systemic inflammation is likewise associated with increased risk for suicide attempt, however, this association appears to be accounted for by the presence of physical disease among patients receiving care in a medical center setting. Healthcare providers should consider the risk of suicide attempt in depressed patients burdened with multiple comorbidities.

Purpose of Review: Up until the latter part of the previous century, the monoamine theory guided our understanding of psychiatric disorders, notably depressive illness in its various phenotypic manifestations. The purpose of this review is to provide an overview of newer theories that allow a deeper understanding of brain dysfunction and neuropsychiatric disease entities such as depressive illness. One such key theory is the theory of inflammation as a result of stress-induced immune system activation., Recent Findings: Stress activates the hypothalamic-pituitary-adrenal axis and the sympathetic branch of the autonomic nervous system [sympathetic branch (SNS)] with a concomitant reduction in vagal tone. This homeostatic imbalance makes a simultaneous dual contribution to the resulting proinflammatory state of depression. SNS stimulation results in upregulation of proinflammatory signaling, whereas diminution in parasympathetic tone affects the body's immune response. The resulting proinflammatory status has been closely associated with multiple organ dysfunction and comorbid conditions., Summary: The advent of innovative theories about the pathophysiology of psychiatric disorders has ushered in a new era on the basis of the role of the immune system and inflammation in mediating depression in its multifaceted manifestations. Extensive studies have confirmed the proinflammatory status in depression and causal relationships with neurotransmitter dysregulation. Equally importantly the role the autonomic nervous system plays in this complex and multifactorial interplay of body systems is being increasingly elucidated.

Background: Suicide risk assessments are often challenging for clinicians, and therefore, biological markers are warranted as guiding tools in these assessments. Suicidal patients display increased cytokine levels in peripheral blood, although the composite inflammatory profile in the subjects is still unknown. It is also not yet established whether certain inflammatory changes are specific to suicidal subjects. To address this, we measured 45 immunobiological factors in peripheral blood and identified the biological profiles associated with cross-diagnostic suicide risk and depression, respectively., Methods: Sixty-six women with mood and anxiety disorders underwent computerized adaptive testing for mental health, assessing depression and suicide risk. Weighted correlation network analysis was used to uncover system level associations between suicide risk, depression, and the immunobiological factors in plasma. Secondary regression models were used to establish the sensitivity of the results to potential confounders, including age, body mass index (BMI), treatment and symptoms of depression and anxiety., Results: The biological profile of patients assessed to be at increased suicide risk differed from that associated with depression. At the system level, a biological cluster containing increased levels of interleukin-6, lymphocytes, monocytes, white blood cell count and polymorphonuclear leukocyte count significantly impacted suicide risk, with the latter two inferring the strongest influence. The cytokine interleukin-8 was independently and negatively associated with increased suicide risk. The results remained after adjusting for confounders., Limitations: This study is cross-sectional and not designed to prove causality., Discussion: A unique immunobiological profile was linked to increased suicide risk. The profile was different from that observed in patients with depressive symptoms, and indicates that granulocyte mediated biological mechanisms could be activated in patients at risk for suicide., (Copyright © 2019. Published by Elsevier B.V.)

A wealth of evidence has implicated inflammation in the development of depression. Yet, the heterogeneous nature of depression has impeded efforts to understand, prevent, and treat the disease. The purpose of this integrative review is to summarize the connections between inflammation and established core features of depression that exhibit more homogeneity than the syndrome itself: exaggerated reactivity to negative information, altered reward processing, decreased cognitive control, and somatic syndrome. For each core feature, we first provide a brief overview of its relevance to depression and neurobiological underpinnings, and then review evidence investigating a potential role of inflammation. We focus primarily on findings from experimental paradigms of exogenously-induced inflammation. We conclude that inflammation likely plays a role in exaggerated reactivity to negative information, altered reward reactivity, and somatic symptoms. There is less evidence supporting an effect of inflammation on cognitive control as assessed by standard neuropsychological measures. Finally, we discuss implications for future research and recommendationsfor how to test the role of inflammation in the pathogenesis of heterogeneous psychiatric disorders., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Depression is one of the foremost psychological illness which is closely leagued with inflammation. Crocin is a natural product that exhibits both anti-inflammatory and anti-oxidant activities. However, little is known about anti-inflammatory mechanisms of crocin on LPS-induced anxiety and depressive-like behaviors. The objective of this study is emphasized on neuroprotective role of crocin against LPS-induced anxiety and depressive-like behaviors in mice. It is observed that crocin inhibited LPS-induced production of NO, TNF-α, IL-1β and ROS in BV-2 microglial cells. Moreover, crocin significantly declined the expression of iNOS, NF-κB p65 and CD16/32 (M1 marker), as well as elevated the expression of CD206 (M2 marker) in BV-2 cell line with decreased LPS-induced anxiety and depressive-like behaviors by improved locomotor activity, reduced sucrose intake, and decreased immobility time in forced swim and tail suspension test in Kunming mice. Expression of NLRP3, ASC and caspase-1 by i.p administration of LPS found to be neutralized with reduction in level of IL-1β, IL-18 and TNF-α in mouse hippocampus. In conclusion, these results suggested that crocin as a potential therapeutic candidate for neuro-inflammation and depressive-like behaviors induced by LPS. The effect was found to be due to inhibition of NLRP3 inflammasome and NF-κB and its promoted M1 to M2 phenotypic conversion of microglia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Evidence suggests that α7 nicotinic acetylcholine receptor (α7 nAChR) in the central nervous system has a critical role in the regulation of microglial function and neuroinflammation associated with the pathophysiology of major depressive disorder. The objectives of the present study were to determine the effects of PNU 120596, an α7 nAChR positive allosteric modulator (PAM), on depressive-like behavior and expression of ionized calcium binding adaptor molecule 1 (Iba-1), a microglial marker, in male C57BL/6J mice following lipopolysaccharide (LPS) administration, an animal model for depressive-like behavior. Forced swim test (FST), tail suspension test (TST), and sucrose preference test were used to determine the effects of PNU 120596 on depressive-like behavior, measured by increased immobility time or decreased sucrose preference. We also examined the effects of PNU 120596 on Iba-1 expression by using Western blot analysis and immunofluorescence staining in the hippocampus and prefrontal cortex, the brain regions implicated in major depressive disorder. Administration of LPS (1 mg/kg, i.p.) significantly increased immobility time during FST and TST and decreased sucrose preference. The PNU 120596 (1 or 4 mg/kg, i.p.) dose-dependently prevented LPS-induced depressive-like behavior during FST, TST, and sucrose preference test. The PNU 120596 (1 or 4 mg/kg) alone did not show any significant alteration on immobility time and sucrose preference. Pretreatment of methyllycaconitine (3 mg/kg, i.p.), an α7 nAChR antagonist, significantly prevented the antidepressant-like effects of PNU (4 mg/kg). Similarly, the PNU 120596 (4 mg/kg, i.p.) significantly reduced LPS-induced increased expression of Iba-1 in the hippocampus or prefrontal cortex. Overall, these results suggest that PNU 120596 reduces LPS-induced depressive-like behavior and microglial activation in the hippocampus and prefrontal cortex in mice. Therefore, α7 nAChR PAMs could be developed as potential therapeutic utility for the treatment of major depressive disorder in humans., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Increased inflammation is linked to suicide risk. However, it is unclear whether increased inflammation drives suicidal crises or is a trait associated with lifetime suicidal behavior. Limited data exist on the sources of increased inflammation observed in suicidal patients and on its downstream effects., Aims: To examine factors associated with inflammation and with suicidal ideation severity in acutely suicidal depressed patients., Methods: Fifty-two adult depressed patients of both sexes hospitalized for severe suicidal ideation were characterized for suicidality, depression, anxiety, medical comorbidity, psychological and physical pain, impulsivity, verbal fluency, C-reactive protein (CRP) and interleukin (IL) 6. Two generalized linear models were performed with either CRP or suicidal ideation severity as dependent variables., Results: CRP levels were positively associated with age, body mass index (BMI), IL6, current physical pain and number of lifetime suicide attempts. Suicidal ideation severity was not significantly correlated with either CRP or IL6. Suicidal ideation severity was positively associated with female sex, presence of an anxiety disorder, current physical pain, number of lifetime suicide attempts and with delay discounting for medium and large losses., Conclusions: Increased inflammation is not associated with acute suicidal risk, but seems to represent a trait associated with lifetime suicidal behavior.

Background: Observational studies suggest that dietary patterns may impact mental health outcomes, although biologically plausible pathways are yet to be tested. We aimed to elucidate the longitudinal relationship between dietary patterns, adiposity, inflammation and mental health including depressive symptoms in a population-based cohort of adolescents., Methods: Data were provided from 843 adolescents participating in the Western Australian Pregnancy Cohort (Raine) Study at 14 and 17 years (y) of age. Structural equation modelling was applied to test our hypothesised models relating dietary patterns, energy intake and adiposity (body mass index) at 14 y to adiposity and the pro-inflammatory adipokine (leptin) and inflammation (high sensitivity C-reactive protein - hs-CRP) at 17 y, and these inflammatory markers to depressive symptoms (Beck Depression Inventory) and Internalising and Externalising Behavioral Problems (Child Behavior Check List Youth Self- Report) at 17 y. We further tested a reverse hypothesis model, with depression at 14 y as a predictor of dietary patterns at the same time-point., Results: The tested models provided a good fit to the data. A 'Western' dietary pattern (high intake of red meat, takeaway, refined foods, and confectionary) at 14 y was associated with higher energy intake and BMI at 14 y, and with BMI and biomarkers of inflammation at 17 y (all p < .05). A 'Healthy' dietary pattern (high in fruit, vegetables, fish, whole-grains) was inversely associated with BMI and inflammation at 17 y (p < .05). Higher BMI at 14 y was associated with higher BMI (p < .01), leptin (p < .05), hs-CRP (p < .05), depressive symptoms (p < .05) and mental health problems (p < .05), all at 17 y., Conclusion: A 'Western' dietary pattern associates with an increased risk of mental health problems including depressive symptoms in adolescents, through biologically plausible pathways of adiposity and inflammation, whereas a 'Healthy' dietary pattern appears protective in these pathways. Longitudinal modelling into adulthood is indicated to confirm the complex associations of dietary patterns, adiposity, inflammation and mental health problems, including depressive symptoms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Recent studies have suggested that immune function may be dysregulated in persons with depressive and anxiety disorders. Few studies examined the expression of cytokines in response to ex vivo stimulation of blood by lipopolysaccharide (LPS) to study the innate production capacity of cytokines in depression and anxiety. To investigate this, baseline data from the Netherlands Study of Depression and Anxiety (NESDA) were used, including persons (18-65 years; 66% women) with current (that is, past month; N=591) or remitted (N=354) DSM-IV depressive or anxiety disorders and healthy controls (N=297). Depressive and anxiety symptoms were measured by means of the Inventory of Depressive Symptomatology (IDS) and the Beck Anxiety Inventory (BAI). Using Multi-Analyte Profiling technology, plasma levels of 13 cytokines were assayed after whole blood stimulation by addition of LPS. Basal plasma levels of C-reactive protein, interleukin-6 and tumor necrosis factor-α were also available. A basal and a LPS summary index were created. Results show that LPS-stimulated inflammation was associated with increased odds of current depressive/anxiety disorders (odds ratio (OR)=1.28, P=0.009), as was the case for basal inflammation (OR=1.28, P=0.001). These associations were no longer significant after adjustment for lifestyle and health (OR=1.13, P=0.21; OR=1.07, P=0.45, respectively). After adjustment for lifestyle and health, interleukin-8 was associated with both remitted (OR=1.25, P=0.02) and current (OR=1.28, P=0.005) disorders. In addition, LPS-stimulated inflammation was associated with more severe depressive (β=0.129, P<0.001) and anxiety (β=0.165, P<0.001) symptoms, as was basal inflammation. Unlike basal inflammation, LPS-stimulated inflammation was still associated with (anxiety) symptom severity after adjustment for lifestyle and health (IDS: interleukin (IL)-8, MCP-1, MMP2; BAI: LPS index, IL-6, IL-8, IL-10, IL-18, MCP-1, MMP2, TNF-β). To conclude, lifestyle and health factors may partly explain higher levels of basal, as well as LPS-stimulated inflammation in persons with depressive and anxiety disorders. However, production capacity of several cytokines was positively associated with severity of depressive and in particular anxiety symptoms, even while taking lifestyle and health factors into account. Elevated IL-8 production capacity in both previously and currently depressed and anxious persons might indicate a genetic vulnerability for these disorders.

Bipolar I disorder (BD) is associated with increased inflammation, which is believed to be central to disease etiology and progression. However, BD patients also have high rates of obesity, itself an inflammatory condition, and the relative contributions of mood illness and obesity to inflammation are unknown. Moreover, the impact of inflammation on clinical illness course has not been well studied. The objectives of this analysis were therefore: (1) to determine if inflammation in BD is mood illness-related or secondary to elevated body mass index (BMI), and (2) to investigate the impact of inflammation on prospectively-ascertained relapse into depression and mania. We measured the serum levels of 7 inflammatory cytokines (TNF-α, γ-interferon, monocyte chemoattractant protein-1 [MCP-1], IL-1α, IL-2, IL-6, and IL-8) and 2 anti-inflammatory cytokines (IL-4 and IL-10) in 52 early-stage BD patients and 22 healthy subjects. In patients, a multivariate multiple regression model that controlled for psychotropic medications found that higher BMI, but not recent (past-6-month) mood episodes, predicted greater inflammatory cytokines (p=.05). Healthy subjects also had a BMI-related increase in inflammatory cytokines (p<.01), but it was counter-balanced by a compensatory increase in anti-inflammatory cytokines (p=.02), reducing their total inflammatory burden from higher BMI. In patients, linear regression showed that two inflammatory cytokines predicted depressive relapse in the 12 months after cytokine measurement: IL-1α (p<.01) and MCP-1 (p<.01). These results suggest that elevated BMI is a significant contributor to inflammation in BD, more so even than recent mood illness severity. They also point to inflammation as an important predictor of illness course, particularly depressive relapse., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Depression is the most prevalent and among the most debilitating of psychiatric disorders. The precise neurobiology of this illness is unknown. Several lines of evidence suggest that peripheral and central inflammation plays a role in depressive symptoms, and that anti-inflammatory drugs can improve depressive symptoms in patients with inflammation-related depression. Signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomycin receptor kinase B (TrkB) plays a key role in the pathophysiology of depression and in the therapeutic mechanisms of antidepressants. A recent paper showed that lipopolysaccharide (LPS)-induced inflammation gave rise to depression-like phenotype by altering BDNF-TrkB signaling in the prefrontal cortex, hippocampus, and nucleus accumbens, areas thought to be involved in the antidepressant effects of TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist, ANA-12. Here we provide an overview of the tryptophan-kynurenine pathway and BDNF-TrkB signaling in the pathophysiology of inflammation-induced depression, and propose mechanistic actions for potential therapeutic agents. Additionally, the authors discuss the putative role of TrkB agonists and antagonists as novel therapeutic drugs for inflammation-related depression.

Background: Immune system plays an important role in brain development and function. With the discovery of increased circulating inflammatory cytokine levels in depression over two decades ago, evidence implicating immune system alterations in the disease has increasingly accumulated., Objective: To assess the underlying etiology and pathophysiology, a brief overview of the hypothesis free genomic, transcriptomic and proteomic studies in depression is presented here in order to specifically examine if the immune and inflammation hypothesis of depression is supported., Results: It is observed that genes identified in genome-wide association studies, and genes showing differential expression in transcriptomic studies in human depression do separately overrepresent processes related to both development as well as functioning of the immune system, and inflammatory response. These processes are also enriched in differentially expressed genes reported in animal models of antidepressant treatment. It is further noted that some of the genes identified in genome sequencing and proteomic analyses in human depression, and transcriptomic studies in chronic social defeat stress, an established animal model of depression, relate to immune and inflammatory pathways., Conclusion: In conclusion, integrative genomics evidence supports the immune and inflammation hypothesis of depression.

Accumulating evidence supports an association between depression and inflammatory processes, a connection that seems to be bidirectional. Clinical trials have indicated antidepressant treatment effects for anti-inflammatory agents, both as add-on treatment and as monotherapy. In particular, nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine-inhibitors have shown antidepressant treatment effects compared to placebo, but also statins, poly-unsaturated fatty acids, pioglitazone, minocycline, modafinil, and corticosteroids may yield antidepressant treatment effects. However, the complexity of the inflammatory cascade, limited clinical evidence, and the risk for side effects stress cautiousness before clinical application. Thus, despite proof-of-concept studies of anti-inflammatory treatment effects in depression, important challenges remain to be investigated. Within this paper, we review the association between inflammation and depression together with the current evidence on use of anti-inflammatory treatment in depression. Based on this, we address the questions and challenges that seem most important and relevant to future studies, such as timing, most effective treatment lengths and identification of subgroups of patients potentially responding better to different anti-inflammatory treatment regimens.

Depression often has its first onset during adolescence and is associated with obesity. Furthermore, inflammatory processes have been implicated in both depression and obesity, although research amongst adolescents is limited. This review explores associations between depression and obesity, depression and inflammation, and obesity and inflammation from a developmental perspective. The temporal relations between these factors are examined to explore whether obesity and elevated inflammation act as either risk factors for, or outcomes of, adolescent-onset depression. Sex differences in these processes are also summarized. We propose a model whereby increases in sex hormones during puberty increase risk for depression for females, which can lead to obesity, which in turn increases levels of inflammation. Importantly, this model suggests that inflammation and obesity are outcomes of adolescent depression, rather than initial contributing causes. Further research on biological and psychosocial effects of sex hormones is needed, as is longitudinal research with children and adolescents.

Estrogen deficiency is involved in the development of depression. However, the mechanism underlying estrogen modulates depression-like behavior remains largely unknown. Inflammation and indoleamine-2,3-dioxygenase (IDO) have been shown to play pivotal roles in various depression models. The objective of the present study was to investigate whether estrogen deficiency-induced depression-like behavior is associated with inflammation and IDO activation in brain. The results showed that ovariectomy resulted in depression-like behavior in female rats and caused a decrease in 5-HT content and an increase in levels of IDO, IFN-γ, IL-6, toll like receptor (TLR)-4 and phosphorylated NF-κB (p65 subunit) in hippocampus but not in prefrontal cortex (PFC). 17β-Estradiol (E2) treatment ameliorated depression-like behavior and restored above neurochemical alternations in hippocampus in ovariectomized rats. Partial correlation analysis showed that the levels of phosphorylated p65, IFN-γ and IL-6 in hippocampus correlated to serum E2 level. Our study suggests that estrogen inhibits inflammation and activates of IDO and maintains 5-HT level in hippocampus, thereby ameliorating depression-like behavior., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Co-morbid depression and chronic pain are highly prevalent. The purpose of this review is to examine the role of chronic inflammation as a common mediator of these co-morbidities. Dysfunctional bidirectional pathways between the brain and the immune, endocrine and neurotransmitter systems have been extensively described and implicated in pain and psychiatric disorders. This short review therefore accesses the evidence in favour of the psychoneuroendocrine hypothesis of psychiatric disorders under three main headings: (1) by illustrating how different types of stress play a crucial role in initiating chronic inflammation in major depression, (2) by accessing the evidence that pain is frequently an important component of, and an initiator of, depression, and (3) considering the evidence that chronic inflammation provides an important link between chronic pain and depression, and the possible cellular mechanisms involved in this process. By understanding the critical role that chronic inflammation plays in pain and depression, novel approaches to the development of drugs may emerge that offer improvements in treatment., (© 2015 S. Karger AG, Basel.)

Background: Depression is highly prevalent among patients with Chronic Obstructive Pulmonary Disease (COPD). The relationship of depression with systemic inflammation in COPD remains unknown. The objective of this observational study was to compare depression scores at baseline and after 36 months follow-up between COPD patients with persistent systemic inflammation (PSI) and never inflamed patients (NI) in the ECLIPSE cohort., Methods: The ECLIPSE study included 2164 COPD patients. Parameters assessed at baseline and at 36 months follow-up included: demographics, clinical characteristics and symptoms of depression (Center for Epidemiologic Studies of Depression, CES-D). Patients classified as NI had zero and patients with PSI had ≥2 inflammatory biomarkers (white blood cell count, hsCRP, IL-6, and fibrinogen) in the upper quartile, at baseline and 12 months later., Findings: 350 patients (29.1%) were NI and 131 patients (10.9%) had PSI. At baseline, mean CES-D score was higher in patients with PSI than in NI patients (11.7 (8.6) vs. 9.2 (8.9) points, p = 0.01). Differences were not confirmed after adjustment for possible confounders (β (95% CI) = 0.02 (-3.87 to 15.29), adjusted p = 0.98). At 36 months follow-up, CES-D scores were comparable in PSI and NI patients (12.2 (9.3) vs. 10.5 (9.0) points, p = 0.08) as were their temporal changes (0.5 (8.3) vs. 1.3 (7.9) points, p = 0.30)., Conclusion: The ECLIPSE study does not support a strong relationship between PSI and symptoms of depression at baseline and after 36 months follow-up in COPD., Funding: The study was sponsored by GlaxoSmithKline., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Because few studies have examined depression facets or potential moderators of the depression-inflammation relationship, our aims were to determine whether particular depressive symptom clusters are more strongly associated with C-reactive protein (CRP) levels and whether race/ethnicity moderates these relationships. We examined data from 10,149 adults representative of the U.S. population (4858 non-Hispanic White, 1978 non-Hispanic Black, 2260 Mexican American, 1053 Other Hispanic) who participated in the cross-sectional National Health and Nutrition Examination Survey between 2005 and 2010. Depressive symptoms were assessed by the Patient Health Questionnaire-9, and high-sensitivity serum CRP was quantified by latex-enhanced nephelometry. Total (p<.001), somatic (p<.001), and nonsomatic (p=.001) depressive symptoms were each positively related to serum CRP in individual models. However, in the simultaneous model that included both symptom clusters, somatic symptoms (p<.001), but not nonsomatic symptoms (p=.98), remained associated with serum CRP. Evidence of moderation by race/ethnicity was also observed, as six of the nine depressive symptoms×race/ethnicity interactions were significant (ps<.05). Among non-Hispanic Whites, the pattern of results was identical to the full sample; only somatic symptoms (p<.001) remained related to serum CRP in the simultaneous model. No relationships between total, somatic, or nonsomatic symptoms and serum CRP were observed among the non-Hispanic Black, Mexican American, or Other Hispanic groups. Our findings indicate that the link between depressive symptoms and systemic inflammation may be due to the somatic symptoms of sleep disturbance, fatigue, appetite changes, and psychomotor retardation/agitation and may be strongest among non-Hispanic Whites., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Inflammatory and neuroinflammatory processes are increasingly recognized as critical pathophysiologic steps in the development of multiple chronic diseases and in the etiology of persistent pain and depression. Mast cells are immune cells now viewed as cellular sensors in inflammation and immunity. When stimulated, mast cells release an array of mediators to orchestrate an inflammatory response. These mediators can directly initiate tissue responses on resident cells, and may also regulate the activity of other immune cells, including central microglia. New evidence supports the involvement of peripheral and central mast cells in the development of pain processes as well as in the transition from acute, to chronic and neuropathic pain. That behavioral and endocrine states can increase the number and activation of peripheral and brain mast cells suggests that mast cells represent the immune cells that peripherally and centrally coordinate inflammatory processes in neuropsychiatric diseases such as depression and anxiety which are associated with chronic pelvic pain. Given that increasing evidence supports the activated mast cell as a director of common inflammatory pathways/mechanisms contributing to chronic and neuropathic pelvic pain and comorbid neuropsychiatric diseases, mast cells may be considered a viable target for the multifactorial management of both pain and depression.

Background: We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is 'what is the source of this chronic low-grade inflammation?', Discussion: This review explores the role of inflammation and oxidative and nitrosative stress as possible mediators of known environmental risk factors in depression, and discusses potential implications of these findings. A range of factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency., Summary: The identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression. Critically, most of these factors are plastic, and potentially amenable to therapeutic and preventative interventions. Most, but not all, of the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder.

The selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed pharmacological treatment for depression. Since their introduction many have considered the primary mechanism by which the SSRIs produced therapeutic improvement in depression is their effect on monoaminergic signalling. In recent years, however, the credibility of the monoamine theory and the therapeutic efficacy of these compounds in the treatment of depression has been extensively criticized. In the current review the legitimacy of these criticisms is critically examined, in many instances the evidence base used to support these criticisms is found to be weak. Nevertheless, the apparent 'failure' of the monoamine theory has been of benefit in motivating research into alternative mechanisms through which the SSRIs may act. Given research demonstrating that depressive symptoms are intimately linked with disturbances in pro-inflammatory signalling, perhaps the most promising discovery has been the realisation that SSRIs posses significant anti-inflammatory properties. These recent findings are discussed and contextualised with respect to the neurogenic, neurotrophic and gluatamatergic effects that these drugs also possess., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To investigate if there is a higher prevalence of depressive symptoms in older people with metabolic syndrome (MetS) compared with those without and whether dedpressive symptoms are independently associated to MetS and its single components and to the inflammatory markers., Methods: Physical parameters, standard blood analytes, high sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR) were assessed. Fifteen-item Geriatric Depression Scale and mini mental state examination (MMSE) were administered., Results: One hundred thirty-three subjects were enrolled. MetS patients (57) exhibited higher prevalence of depressive symptoms (p < 0.0001), worse cognitive function (p < 0.0001), and higher levels of ESR and hsCRP were higher (p < 0.0001). The univariate analysis showed a linear strong correlation of depressive symptoms (p < 0.0001) with the MMSE score (r = -0.422), body mass index (r = 0.414), MetS (r = 0.582), number of MetS components (r = 0.663), fasting blood glucose (r = 0.565), ESR (r = 0.565), hsCRP (r = 0.745), central obesity (r = 0.269; p = 0.002), and high-density lipoprotein cholesterol (r = -0.241; p = 0.005). However, the multivariate analysis showed that only age (B = -0.093; p = 0.032), MetS (B = 1.446; p = 0.025), fasting blood glucose (B = 0.039; p = 0.005), and hsCRP (B = 7.649; p < 0.0001) were independently associated with depressive symptoms., Conclusions: MetS and inflammation are independently associated with depressive symptoms in older people. Inflammation may explain cognitive decline too. Further investigations are needed to better understand the direction of these associations and to determine whether these can be reversible., (Copyright © 2012 John Wiley & Sons, Ltd.)

Over two-thirds of the 11.4 million cancer survivors in the United States can expect long-term survival, with many others living with cancer as a chronic disease controlled by ongoing therapy. However, behavioral co-morbidities often arise during treatment and persist long-term to complicate survival and reduce quality of life. In this review, the inter-relationships between cancer, depression, and sleep disturbance are described, with a focus on the role of sleep disturbance as a risk factor for depression. Increasing evidence also links alterations in inflammatory biology dynamics to these long-term effects of cancer diagnosis and treatment, and the hypothesis that sleep disturbance drives inflammation, which together contribute to depression, is discussed. Better understanding of the associations between inflammation and behavioral co-morbidities has the potential to refine prediction of risk and development of strategies for the prevention and treatment of sleep disturbance and depression in cancer survivors., (Copyright © 2012 Elsevier Inc. All rights reserved.)

CONTEXT The pathogenesis of depression is not fully understood, but studies suggest that low-grade systemic inflammation contributes to the development of depression. OBJECTIVE To test whether elevated plasma levels of C-reactive protein (CRP) are associated with psychological distress and depression. DESIGN We performed cross-sectional and prospective analyses of CRP levels in 4 clinically relevant categories using data from 2 general population studies. SETTING The Copenhagen General Population and the Copenhagen City Heart studies. PARTICIPANTS We examined 73 131 men and women aged 20 to 100 years. MAIN OUTCOME MEASURES We ascertained psychological distress with 2 single-item self-reports and depression using self-reported antidepressant use, register-based prescription of antidepressants, and register-based hospitalization with depression. RESULTS In cross-sectional analyses, increasing CRP levels were associated with increasing risk for psychological distress and depression (P = 3 × 10-8 to P = 4 × 10-105 for trend). For self-reported use of antidepressants, the odds ratio was 1.38 (95% CI, 1.23-1.55) for CRP levels of 1.01 to 3.00 mg/L, 2.02 (1.77-2.30) for 3.01 to 10.00 mg/L, and 2.70 (2.25-3.25) for greater than 10.00 mg/L compared with 0.01 to 1.00 mg/L. For prescription of antidepressants, the corresponding odds ratios were 1.08 (95% CI, 0.99-1.17), 1.47 (1.33-1.62), and 1.77 (1.52-2.05), respectively; for hospitalization with depression, 1.30 (1.01-1.67), 1.84 (1.39-2.43), and 2.27 (1.54-3.32), respectively. In prospective analyses, increasing CRP levels were also associated with increasing risk for hospitalization with depression (P = 4 × 10-8 for trend). CONCLUSIONS Elevated levels of CRP are associated with increased risk for psychological distress and depression in the general population.

Like all psychiatric conditions, depression is a complex phenomenon that is unlikely to yield to simple monolithic explanatory paradigms. Nonetheless, increasing evidence suggests that the immune system in general and inflammatory processes in particular, may contribute to depressive pathogenesis in a significant proportion of otherwise medically healthy individuals struggling with the disorder. In this chapter, we review the best current evidence suggesting that inflammatory processes contribute to the development of depression, both via direct actions on the brain as well as by effects on secondary pathways that marry brain to body. We review epidemiological evidence linking inflammation to depression before reviewing findings that exposure to inflammatory stimuli produce depressive symptoms in concert with brain-body changes known to be common in depression. Following this review of the role of inflammation in depressive causation, we consider emerging evidence that immunomodulatory interventions may hold promise as antidepressants, especially in individuals with elevations in peripheral inflammatory biomarkers. Interventions discussed include cytokine and cyclo-oxygenase antagonists, as well as agents that impact inflammatory transcription factors/signaling cascades. We conclude with a brief discussion of the potential role of various behavioral strategies in reducing inflammation and thereby enhancing emotional well-being., (Copyright © 2013 S. Karger AG, Basel.)

Growing evidence suggests that immune dysregulation may be involved in depressive disorders, but the exact nature of this association is still unknown and may be restricted to specific subgroups. This study examines the association between depressive disorders, depression characteristics and antidepressant medication with inflammation in a large cohort of controls and depressed persons, taking possible sex differences and important confounding factors into account. Persons (18-65 years) with a current (N = 1132) or remitted (N = 789) depressive disorder according to DSM-IV criteria and healthy controls (N = 494) were selected from the Netherlands Study of Depression and Anxiety. Assessments included clinical characteristics (severity, duration and age of onset), use of antidepressant medication and inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)). After adjustment for sociodemographics, currently depressed men, but not women, had higher levels of CRP (1.33 versus 0.92 mg l(-1), P<0.001, Cohen's d = 0.32) and IL-6 (0.88 versus 0.72 pg ml(-1), P = 0.01, Cohen's d = 0.23) than non-depressed peers. Associations reduced after considering lifestyle and disease indicators--especially body mass index--but remained significant for CRP. After full adjustment, highest inflammation levels were found in depressed men with an older age of depression onset (CRP, TNF-α). Furthermore, inflammation was increased in men using serotonin-norepinephrine reuptake inhibitors (CRP, IL-6) and in men and women using tri- or tetracyclic antidepressants (CRP), but decreased among men using selective serotonin reuptake inhibitors (IL-6). In conclusion, elevated inflammation was confirmed in depressed men, especially those with a late-onset depression. Specific antidepressants may differ in their effects on inflammation.

Currently available antidepressants are effective in less than two thirds of depressed patients, with even lower remission rates in the context of co-morbid medical illness. A rapidly expanding evidence base suggests that maladaptive inflammatory immune responses may be a common pathophysiology underlying depression, particularly in the presence of a general medical condition. The inflammatory hypothesis of depression marks a significant shift away from monoamine-based approaches and is a major step towards developing novel treatments that directly target causal factors of depression. Many antidepressants exert anti-inflammatory effects and there is an emerging literature documenting the efficacy of anti-inflammatory agents as adjunctive treatments for depression. Identification of inflammatory biomarkers in depression will require a re-conceptualization of both the diagnostic phenomenology and the experimental approaches to studying multi-determined psychiatric disorders. In addition to their application in diagnosis, predicting prognosis, and monitoring severity and response to treatment, inflammatory biomarkers may serve as novel therapeutic targets in the treatment of depression.

Elevated plasma cytokines is a common finding in Major Depressive Disorder (MDD), although not consistent. It is currently not known whether the inflammatory changes are confined to any specific subgroup of depressive patients. We here analyzed three inflammatory markers in suicidal and non-suicidal depressed patients, as well as healthy controls. Plasma interleukin (IL)-2, IL-6 and tumor necrosis factor (TNF)-α were measured in 47 suicide attempters, 17 non-suicidal depressed patients and 16 healthy controls. Study participants were evaluated using the Comprehensive Psychopathological Rating Scale (CPRS) with subscales for anxiety and degree of depression, as well as the Suicide Assessment Scale (SUAS). We found increased levels of IL-6 and TNF-α as well as decreased IL-2 concentrations in suicide attempters compared to non-suicidal depressed patients and healthy controls. The results were adjusted for potential confounders of cytokine expression, such as age, sex, body mass index (BMI), degree of depression, anxiety, personality disturbance, abuse and type of medication. These results demonstrate for the first time that suicidal patients display a distinct peripheral blood cytokine profile compared to non-suicidal depressed patients. Thus, our study provides further support for a role of inflammation in the pathophysiology of suicidality., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Both hyper- and hypo-activity of the hypothalamus-pituitary-adrenal (HPA) axis activity are a consistently reported hallmark feature of stress-related disorders, such as major depression and posttraumatic stress disorder (PTSD), respectively. In this manuscript, however, we are summarizing evidence pointing to altered glucocorticoid (GC) sensitivity in relevant target tissues for HPA axis hormones. Specifically, we provide a summary of GC effects on cognitive functions, as an emerging marker for central nervous system GC sensitivity, and of GC effects on peripheral inflammatory responses. With regard to depression and PTSD, evidence thereby points to decreased GC sensitivity of the cognitive and inflammatory systems in depression, and increased GC sensitivity of both systems in PTSD. Taken together, these data support the hypothesis that both psychiatric disorders are characterized by inefficient GC signaling, although through dysregulations at different levels. Potential underlying pathways and implications are discussed.

Much attention has been paid to the potential role of the immune system in the pathophysiology of major depression in humans. While activation of innate immune responses currently dominates the research landscape, early studies in depressed patients demonstrating impairment in acquired immune responses, in particular T cell responses, may warrant further consideration. Intriguing data suggest that activated T cells may play an important neuroprotective role in the context of both stress and inflammation. For example, generation of autoreactive T cells through immunization with central nervous system (CNS) specific antigens has been shown to reverse stress-induced decreases in hippocampal neurogenesis as well as depressive-like behavior in rodents. In addition, trafficking of T cells to the brain following stress, in part related to glucocorticoids, has been found to reduce stress-induced anxiety-like behavior. Data indicate that T regulatory cells may also play a role in depression through downregulation of chronic inflammatory responses. Based on the notion that T cells may subserve neuroprotective and anti-inflammatory functions during stress and inflammation, impaired T cell function may directly contribute to the development of depression. Indeed, increased sensitivity to apoptosis as well as reduced responsiveness to glucocorticoids, may not only decrease the availability of T cells in depressed patients, but also may reduce their capacity to traffic to the brain in response to relevant neuroendocrine or immune stimuli. Further elucidation of T cell pathology may lead to new insights into immune system contributions to depression. Moreover, enhancement of T cell function may represent an alternative strategy to treat depression.

Clinically, pain is a complex phenomenon consisting of both sensory and affective aberrations that can persist indefinitely. Pre-clinically, several animal paradigms have been established that reliably mimic both the acute and chronic aspects of pain pertinent to the human condition; however, the commonly used behavioral models only assess the sensory component of pain elicited by an evoked nociceptive stimulus. Since the affective-motivational component of pain is an important determinant of the overall pain experience in man, we investigated how this aspect may be modeled long-term in rats using novel objects and a modified conditioned place aversion (CPA) paradigm. Findings demonstrate that animals subjected to either neuropathic injury or inflammatory insult display a significant conditioned place aversion to a pain-paired environment that is paralleled by an increased number of hind paw withdrawals and fewer number of novel object interactions during painful conditioning sessions. Moreover, this aversion is maintained for 1 month in the absence of further conditioning. We also determined that a non-analgesic, non-rewarding dose of morphine administered prior to pain-paired conditioning sessions attenuates the pain-induced aversion and its relative persistence in both pain models. Together, these findings underscore the importance of negative affect accompanying painful conditions and its long-term persistence even when the injury or insult has resolved. Lastly, these results suggest how both sensory and affective aberrations associated with neuropathic- and inflammatory-like conditions and the memory of such known to impact quality of life in man may be addressed pre-clinically in rodents.

Objective: Depressive symptoms increase morbidity and mortality from coronary heart disease and systemic inflammation has been proposed as the underlying mechanism. While higher levels of inflammatory mediators have been found in dysphoric individuals, it is not known whether long-term or short-term mood changes are responsible for this phenomenon., Methods: A sample of 65 young women provided weekly web-based self-ratings of depressive mood over a period of 20 weeks using the CES-D, and systemic inflammation was assessed by measuring plasma interleukin-6 (IL-6) and C-reactive protein (CRP) before and after the observation period. CES-D ratings were used to develop state and trait indicators of depressed mood and evaluate their relationship with inflammatory mediators., Results: Hierarchical linear regressions controlling for baseline inflammation, age, and BMI revealed that trait levels of depressive symptoms were not associated with IL-6 (beta=0.09; n.s.) and CRP (beta=0.01; n.s.) concentrations after the observation period. In contrast, state levels of depressive symptoms were associated with changes in IL-6, but not CRP, particularly when they were indexed as the disparity between a person's trait level of symptoms and her CES-D score just prior to IL-6 assessment (beta=0.35; p=0.03)., Conclusion: These results lead us to conclude that in young women, state, rather than trait depressed mood stimulates peripheral inflammation as measured by IL-6. This pattern suggests that in this age group, fast-reacting inflammatory mediators such as IL-6 probably respond to short-term changes, for example, in stress hormones or stress hormone sensitivity, rather than long-term dysregulations of allostatic mechanisms.

Background and Objective: Women with polycystic ovary syndrome (PCOS) present with multiple risk factors for cardiovascular diseases at a young age, including obesity and chronic low-grade inflammation. Since depression is common in PCOS, this study aimed to address whether depression correlates with indices of chronic low-grade inflammation beyond the association with obesity., Methods: Serum concentrations of IL-6, the stimulated production of IFN-gamma, TNF-alpha, IL-2, IL-4, IL-5, and IL-10, leukocyte numbers, and hsCRP were analyzed in 57 PCOS patients and 28 healthy women, together with clinical parameters, including body mass index (BMI), testosterone, and insulin resistance (HOMA-IR), and psychological parameters, including Beck Depression Inventory (BDI) and health-related quality-of-life (SF-36) scores., Results: PCOS patients demonstrated significantly increased hsCRP, IL-6, and leukocyte numbers. Group differences in IL-6 and leukocyte numbers, but not hsCRP, disappeared after controlling for BMI. The stimulated production of IFN-gamma, TNF-alpha, IL-2, IL-4, and IL-5 was significantly decreased, irrespective of BMI. In PCOS, hsCRP, IL-6, and leukocyte numbers were correlated with BMI, HDL, diastolic blood pressure, and with insulin resistance. On the other hand, no correlations were found with depression scores or with PCOS-specific endocrine abnormalities. In regression models, BMI was a significant predictor of the key immune markers, and explained a large amount of variance, whereas BDI was not included in either model., Conclusions: These data confirm that obesity plays a pivotal role in inflammatory processes relevant to cardiovascular risk in women with PCOS. However, even lean PCOS patients may display subtle alterations in specific aspects of immunity. Our findings did not support a correlation of depression with chronic low-grade inflammation in PCOS.

Depressive disorders and cardiovascular disease are inter-connected by a whole range of pathophysiological mechanisms. Three biological mechanisms are fundamental: activation of the hypothalamus-hypohysis-adrenal axis with a subsequent increase in sympathetic-adrenal system activity, decrease in vagal tone with a decrease in heart rate variability, and alterations of thrombogenesis with increased platelet aggregability. Behavioural mechanisms and psycho-social factors are also integral to this common pathophysiology. Recently, research has focused mainly on studying various forms of stress, as well as changes and possibilities of influencing the autonomous vegetative system. Temporal aspects of the incidence and development of depressive episodes in relation to cardiovascular disease and subsequent cardiovascular morbidity and mortality are being studied, as well as general mortality risk factors. These findings are important for clinical practice. It is evident that in patients with untreated depressive disorder, the risk of developing cardiovascular disease is significantly higher than in patients suffering from a depressive disorder being treated with anti-depressants. From the data published so far, it may be surmised that depressive disorders in patients with cardiovascular disease may be reliably and safely treated with anti-depressants that act as inhibitors of serotonin re-uptake.

Major depression is a risk factor, associated with a twofold increase in the incidence of ischemic heart disease (IHD). One of every 6 patients suffers from major depression following acute myocardial infarction (AMI). This connection is of major concern, considering that major depression is an independent risk factor for cardiac morbidity and mortality after AMI, increasing overall mortality fourfold. Activation of the immune system has a significant role in the pathogenesis of IHD and depression. Vast physiological responses, mediated mostly by activation of the immune system, accompany post MI depression and may account for increased prevalence of arrhythmias and high mortality. This includes activation of the hypothalamic-pituitary-adrenocortical axis, endothelial dysfunction, platelets activation and alterations of phospholipid composition in cell membranes. On the other hand, activation of the immune system after AMI includes elevated levels of interleukin-1 and interleukin-6. which induce "sickness behavior", characterized by symptoms similar to those observed in major depression. The key question raised by this data, whether inflammation is the common ground for both AMI and depression, or if it is accompanying one and sets the ground for the other, remains unanswered at this time. The significance of major depression as an independent risk factor for post MI mortality and morbidity raises the practical question, whether treatment of depression can reduce mortality after AMI. Several recent studies that evaluated this presumption, failed to prove it. In this review we present an overview of the cross interaction between depression, AMI and inflammation and its diagnostic and therapeutic implications.

Objective: Depression has been related to a higher risk of developing coronary heart disease, but the mechanism that accounts for this association is unclear. Because atherosclerosis is an inflammatory process, depression could increase the risk of coronary heart disease by inducing or promoting inflammation. The objective of the present study was to investigate the association between history of major depressive episode and presence of low-grade systemic inflammation as measured by serum C-reactive protein (CRP)., Methods: We analyzed data from the Third National Health and Nutrition Examination Survey, a representative sample of the US population from 1988 to 1994. Participants included a total of 6149 individuals aged 17 to 39 years who were free of cardiovascular diseases and chronic inflammatory conditions. The main predictor variable of interest was lifetime history of a major depressive episode as assessed by means of the Diagnostic Interview Schedule. The main outcome variable was the presence or absence of an elevated CRP level (> or =22 mg/dl)., Results: Among men, history of a major depressive episode was associated with elevated CRP, particularly for recent episodes (up to 6 months before assessment). In multivariate analyses, men with a history of major depressive episode had 2.77 times higher odds of elevated CRP compared with never-depressed men (95% confidence interval, 1.43-5.26). The adjusted odds ratio was 3.81, 3.98, 1.51, and 1.52 for men who had their last major depressive episode less than 1 month before, 1 to 6 months before, 7 to 12 months before, and more than 12 months before assessment, respectively (p for trend =.004). In women, a comparable association between depression and CRP was quite weak and not significant., Conclusions: A recent history of major depressive episode is strongly associated with elevated CRP in men aged 17 to 39. In this group, low-grade systemic inflammation could represent a mechanism linking depression to cardiovascular risk.

1. This paper reviews recent findings on cellular and humoral immunity and inflammatory markers in depression. 2. It is shown that major depression may be accompanied by systemic immune activation or an inflammatory response with involvement of phagocytic (monocytes, neutrophils) cells, T cell activation, B cell proliferation, an "acute" phase response with increased plasma levels of positive and decreased levels of negative acute phase proteins, higher autoantibody (antinuclear, antiphospholipid) titers, increased prostaglandin secretion, disorders in exopeptidase enzymes, such as dipeptidyl peptidase IV, and increased production of interleukin (IL)-1 beta and IL-6 by peripheral blood mononuclear cells. 3. It is hypothesized that increased monocytic production of interleukins (Il-1 beta and Il-6) in severe depression may constitute key phenomena underlying the various aspects of the immune and "acute" phase response, while contributing to hypothalamic-pituitary-adrenal-axis hyperactivity, disorders in serotonin metabolism, and to the vegetative symptoms (i.e. the sickness behavior) of severe depression.