CRP, IL-6 and depression: A systematic review and meta-analysis of longitudinal studies

Inflammatory markers are raised in cross-sectional studies of depressed patients and may represent an important mediating factor for behaviour, neural plasticity and brain structure. We undertook a systematic review of longitudinal studies, investigating whether raised inflammatory markers indicate an increased risk of subsequent depressive symptoms. We searched three databases (1970–2012) for longitudinal studies with repeat data on CRP or IL-6 levels and subsequent depressive symptoms. We calculated effect sizes using a mixed-effects model, with separate meta-analyses for inflammatory markers and age groups. We identified eight papers for CRP (14,832 participants) and three for IL-6 (3695 participants). There was a significant association between increased CRP and depressive symptoms (weighted-mean effect size ‘unadjusted r’=0.069, p<0.0005; ‘adjusted r’=0.046, p<0.0005), with moderate heterogeneity between studies (Q=11.21, p=0.08, I2=46.5). For IL-6 the weighted-mean effect size was smaller (‘unadjusted r’=0.045, p-value=0.007; ‘adjusted r’=0.097, p-value=0.06). The meta-analysis was based on a relatively small number of studies (particularly for IL-6) and only two inflammatory markers. There was moderate heterogeneity between studies and some evidence of publication bias. Raised inflammatory markers have a small but significant association with the subsequent development of depressive symptoms. This is a robust effect which remains significant after adjustment for age and a wide range of factors associated with risk for depression. Our results support the hypothesis that there is a causal pathway from inflammation to depression.