Epidemiological evidence for the inflammatory hypothesis of depression is largely cross-sectional; people with depression have elevated levels of circulating pro-inflammatory markers compared to people without depression. The limitation of cross sectional research is the potential for extraneous factors to influence observed effects. The purpose of this meta-analysis of cross-sectional studies of interleukin(IL)-6 and IL-10 in people with and without depression is to provide a targeted analysis of potential moderator factors relating to the diagnosis of depression and to physical and psychiatric comorbidity. Electronic searches of Embase and Medline databases were conducted using subject headings "interleukin-6" or "interleukin-10" and those relating to depression. Studies were included if they measured circulating marker levels in serum or plasma in a group of people with and without depressive symptoms (99 studies for IL-6, 19 studies for IL-10). IL-6 was elevated in depressed compared to non-depressed groups (d=0.46, 99% CI 0.34 to 0.58, I(2)=85.9%). This effect was larger in subgroups where depressive disorders were diagnosed compared to those with only depressive symptoms via standardized inventory, and subgroups where participants were recruited from inpatient or outpatient settings compared to the general community. The effect was also larger in those who were not selected for a particular comorbidity compared to those selected for cardiovascular disease. IL-10 effect size was not significant (d=-0.31, 99% CI -0.95 to 0.32, I(2)=94.1%) which was not accounted for in subgroup analyses or meta-regression, indicating there is not a global elevation in cytokines. These data highlight that comorbidity and behavioral aspects of depression need to be measured and controlled in future prospective and experimental research testing the inflammatory hypothesis of depression.
"including the key interleukins (particularly IL-6, IL-2, IL-1β), tumor necrosis factor (TNF-α) and its receptors, and interferon gamma (IFN-γ) in schizophrenia (Gaughran, 2002; Drzyzga et al., 2006), bipolar disorder (O'Brien et al., 2006; Hope et al., 2009) and depression (Hiles et al., 2012; Liu et al., 2012; Dahl et al., 2014). However there is also increasing evidence of inflammatory cytokines and activation of microglia in the brains of affective disorder subjects. "
[Show abstract][Hide abstract] ABSTRACT: Pathophysiology associated with several psychiatric disorders has been linked to inflammatory biomarkers. This has generated a theory of major depressive disorders as an inflammatory disease. The idea of pro-inflammatory cytokines altering behavior is now well accepted however many questions remain. Microglia can produce a plethora of inflammatory cytokines and these cells appear to be critical in the link between inflammatory changes and depressive disorders. Microglia play a known role in sickness behavior which has many components of depressive-like behavior such as social withdrawal, sleep alterations, and anorexia. Numerous candidate genes have been identified for psychiatric disorders in the last decade. Single nucleotide polymorphisms (SNPs) in the human P2X7 gene have been linked to bipolar disorder, depression, and to the severity of depressive symptoms. P2X7 is a ligand-gated cation channel expressed on microglia with lower levels found on astrocytes and on some neuronal populations. In microglia P2X7 is a major regulator of pro-inflammatory cytokines of the interleukin-1 family. Genetic deletion of P2X7 in mice is protective for depressive behavior in addition to inflammatory responses. P2X7(-/-) mice have been shown to demonstrate anti-depressive-like behavior in forced swim and tail suspension behavioral tests and stressor-induced behavioral responses were blunted. Both neurochemical (norepinephrine, serotonin, and dopamine) and inflammatory changes have been observed in the brains of P2X7(-/-) mice. This review will discuss the recent evidence for involvement of P2X7 in the pathophysiology of depressive disorders and propose mechanisms by which altered signaling through this ion channel may affect the inflammatory state of the brain.
"The meta-analysis conducted by Hiles et al. (2012b) found that the association between IL-6 and depression did not significantly differ between smokers and non-smokers and samples analysed by different processing techniques. However, in agreement with our cumulative meta-analysis and previous standard meta-analyses, inclusion of patients using psychotropic medication and the lack of adjustment for overweight/obesity resulted in slightly larger effect size estimates between the levels of CRP, IL-6 and depression (Hiles et al., 2012b; Howren et al., 2009). The observed heterogeneity between study-specific effect estimates was either high (TNF-a and IL-1b) or moderate (IL-6 and CRP). "
[Show abstract][Hide abstract] ABSTRACT: Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and PsychInfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d = 0.54, p < 0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d = 0.47, p < 0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-α levels and major depression (d = 0.40, p = 0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1β levels and major depression (d = −0.05, p = 0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-α, interleukin-1β and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression.
"Interleukin-6 (IL-6) is an important biomarker in metabolic syndrome , and is also reported to play a mechanistic role in the development of many disorders, including chronic fatigue syndrome  and clinical depression . The discovery that IL-6 is released directly from exercising muscle  has led to an increase in the volume of research investigating the impact of exercise on plasma concentrations of IL-6. "
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