Table 2.

The relationship between inflammation and depression−The evidence base

Study	Parameter	Result	Conclusion
Wu et al., 2017 [37]	Circulating cytokines	IL-6 levels increased in MDD and BDD.	Depressive episodes are associated with increased levels of proinflammatory cytokines.
Leday et al., 2018 [38]	Examination of the transcriptome of the circulating mononuclear cells.	In MDD subjects proinflammatory genes were stimulated in a replicable manner.	Transcriptomic analysis of the messenger RNA was a more accurate measure as compared to serum cytokines and cell counts. This study showed the use-fulness of transcriptional biomarkers, sub-classifying MDD patients along immunological parameters.
Małyszczak et al., 2019 [39]	Depressive symptoms induced by interferon therapy in Hepatitis C patients	In hepatitis C patients, INF-α treatment for 24 weeks resulted in symptoms of depression. These were more severe in subjects having an underlying biological susceptibility.	Vulnerability that was biologically based and general immune activation, instead of psychological factors (neuroticism) were related to the severity of depression.
Maes et al., 2012 [40]	Serum levels of IgM and IgA against the lipopolysaccharide (LPS) of gram negative enterobacteria	Serum antibodies against LPS of gut commensals were significantly higher in MDD versus controls. IgM levels were statistically higher in patients with chronic depression as compared to those without.	These findings show that increased translocation of gut bacteria along with immunological responses play a part in the development of chronic depression.
Huang et al., 2019 [41]	To assess whether there was a time-based relationship between inflammation (IL-6, hsCRP) and depressive symptoms (BDI), and to evaluate the role of genetic factors on this association.	Eighty-three twin pairs (166 subjects) assessed at baseline and after 7 years. Examination showed a significant positive association from visit 1 IL-6 to visit 2 BDI. But, the opposite trajectory (visit 1 BDI to visit 2 IL-6) was statistically non-significant after correcting for confounding variables.	Elevated IL-6 likely to be a risk factor for depression rather than a consequence, while the opposite may be true for CRP. When taking into account twin factor, significant relationship from IL-6 to depression was only seen in monozygotic twins. This meant that genetic factors played a role in this association.
Vallerand et al., 2019 [42]	The bidirectional association between MDD and alopecia areata (AA) was investigated in a population-based cohort study. The development of incident AA/MDD during follow-up were considered the main outcome measures.	Twenty-six years of follow up showed that MDD increased the risk of subse-quently developing AA by 90%. Anti-depressant use had a protective effect on the risk of AA. Conversely, AA was found to increase the risk of subse-quently developing MDD by 34%.	These results suggested that patients with AA were at increased risk for the later development of MDD. However, having MDD also appeared to be a significant risk factor for AA, with antidepressants moderating this risk.
Li et al., 2018 [43]	Microglia are chief immune mediators in the brain and are implicated in the pathophysiology of MDD. Fifty un-medicated patients with MDD and 30 HC were investigated with positron emission tomography (PET) to examine microglia activation. Cognitive functions were evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).	MDD patients showed microglia activation throughout fronto-limbic regions. The subjects showed impairment on the attention and delayed memory domains of RBANS. In the frontal cortex, increased microglia activation was associated with lower scores on the RBANS attention domain.	In MDD subjects, microglial activation was detected in significant brain regions. Moreover, attentional dysfunction may be associated with microglial pathology in the frontal cortex of untreated MDD subjects.
Suzuki et al., 2019 [44]	Activated microglia may have a causal role in suicide and underline inflammatory processes including the triggering of the kynurenine pathway. Neuropathological studies of the human postmortem brain of suicide victims were reviewed in this study.	Review of original studies showed that there were increased numbers/activation of microglia in crucial areas like dorsolateral prefrontal cortex, anterior cingulate cortex and mediodorsal thalamus.	Firm evidence from post-mortem studies that the chief immune cells of the brain (microglia) were activated in suicide victims. This signified that inflammation played a contributory role in suicide.

BD, bipolar disorder; BDD, bipolar depression; HC, healthy controls; hsCRP, high sensitivity C-reactive protein; LPS, lipopolysaccharide; MDD, major depressive disorder.