Effects of SSRIs on peripheral inflammatory markers in patients with major depressive disorder: A systematic review and meta-analysis

Introduction: Peripheral levels of inflammatory markers are elevated in major depressive disorder (MDD). Selective serotonin reuptake inhibitors (SSRIs) affect levels of inflammatory markers in patients with MDD, but studies have reported inconsistent findings. This systematic review and meta-analysis aims to investigate the effects of SSRI treatment on peripheral levels of a range of inflammatory markers in MDD patients. Methods: Systematic literature search (Pubmed, Web of Science, Embase, Cochrane) for studies published before November 2018. Studies were included if they used SSRI monotherapy and peripheral levels of interleukin (IL)-1 beta, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were measured before and after treatment in patients with MDD. Meta-analysis was conducted using Comprehensive Meta-analysis (version 2). Effect sizes were calculated using bias-corrected standardized mean difference (Hedges' g) between pre- and post-treatment. Sub-group analyses, meta-regression and publication bias estimates were undertaken; sensitivity analyses were performed using different estimated pre- and post-treatment correlations and after removing poor quality studies. Results: Twenty two eligible studies including 827 MDD patients were included in the meta-analysis: fifteen studies for IL-6; eleven for TNF-alpha; eight for IL-10; seven for IL-1 beta; six for IL-4; five for IL-2; and four for IFN-gamma. The pooled effect estimate indicates SSRI treatment decreased levels of pro-inflammatory markers IL-6 (Hedges' g, - 0.418; 95%CI, - 0.663 to - 0.174; I-2 = 89.412), TNF-alpha (Hedges' g, - 0.554; 95%CI, - 0.990 to - 0.118; I-2 = 95.438) and IL-1 beta (Hedges' g = -0.574; 95%CI, -1.014 to - 0.135; I-2 = 91.622), and anti-inflammatory marker IL-10 (Hedges' g = - 0.615; 95%CI, - 0.989 to - 0.242; I-2 = 90.406). There were no significant treatment effects on levels of IL-2, IL-4, or IFN-gamma. There was a high level of heterogeneity between studies. Sensitivity analyses indicated the robustness of the primary analyses. Conclusions: The current review and meta-analysis indicates moderate immunomodulating effects of SSRI treatment for MDD, which suggests SSRIs may owe some of their therapeutic effect to their anti-inflammatory properties. High heterogeneity across studies may limit interpretation of the findings and larger randomized clinical trials are warranted.