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.
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