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BackgroundWe 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?’DiscussionThis 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.SummaryThe 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.

Objective To conduct a systematic review and meta‐analysis of studies that measured cytokine and chemokine levels in individuals with major depressive disorder (MDD) compared to healthy controls (HCs). Method The PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched up until May 30, 2016. Effect sizes were estimated with random‐effects models. Result Eighty‐two studies comprising 3212 participants with MDD and 2798 HCs met inclusion criteria. Peripheral levels of interleukin‐6 (IL‐6), tumor necrosis factor (TNF)‐alpha, IL‐10, the soluble IL‐2 receptor, C‐C chemokine ligand 2, IL‐13, IL‐18, IL‐12, the IL‐1 receptor antagonist, and the soluble TNF receptor 2 were elevated in patients with MDD compared to HCs, whereas interferon‐gamma levels were lower in MDD (Hedge's g = −0.477, P = 0.043). Levels of IL‐1β, IL‐2, IL‐4, IL‐8, the soluble IL‐6 receptor (sIL‐6R), IL‐5, CCL‐3, IL‐17, and transforming growth factor‐beta 1 were not significantly altered in individuals with MDD compared to HCs. Heterogeneity was large (I2: 51.6–97.7%), and sources of heterogeneity were explored (e.g., age, smoking status, and body mass index). Conclusion Our results further characterize a cytokine/chemokine profile associated with MDD. Future studies are warranted to further elucidate sources of heterogeneity, as well as biosignature cytokines secreted by other immune cells.