Peripheral blood cellular immunophenotype in depression: a systematic review and meta-analysis

Introduction: Meta-analyses implicate immune dysfunction in depression confirming increased levels of circulating immune proteins (e.g., cytokines) in depression cases compared to controls. White blood cells (WBC) both produce and are influenced by cytokines, and play key roles in orchestrating innate and adaptive immune responses, but their role in depression remains unclear. Therefore, a systematic review of studies of various WBC subsets in depression is required for a greater understanding of the nature of immune dysfunction in this illness. Methods: We searched PubMed and PsycINFO databases (inception to 5^thApril 2022) and conducted a systematic review and meta-analysis of identified studies comparing absolute count and/or relative percentage of flow cytometry-derived WBC subsets between depression cases and controls. Selected studies were quality assessed. Random-effect meta-analysis was performed. Results: Thirty-three studies were included and 27 studies (n= 2277) were meta-analysed. We report an increase in mean absolute counts of WBC (seven studies; standardised mean difference [SMD] = 1.07; 95% CI, 0.61–1.53; P< 0.01; I²= 64%), granulocytes (two studies; SMD = 2.07; 95% CI, 1.45–2.68; P< 0.01; I²= 0%), neutrophils (four studies; SMD = 0.91; 95% CI, 0.23–1.58; P< 0.01; I²= 82%), monocytes (seven studies; SMD = 0.60; 95% CI, 0.19–1.01; P< 0.01; I²= 66%), CD4⁺helper T cells (11 studies; SMD = 0.30; 95% CI, 0.15–0.45; P< 0.01; I²= 0%), natural killer cells (11 studies; SMD = 1.23; 95% CI, 0.38–2.08; P< 0.01; I²= 95%), B cells (10 studies; SMD = 0.30; 95% CI, 0.03–0.57; P= 0.03; I²= 56%), and activated T cells (eight studies; SMD = 0.45; 95% CI, 0.24–0.66; P< 0.01; I²= 0%) in depression, compared to controls. Fewer studies reported relative percentage, indicating increased neutrophils and decreased total lymphocytes, Th1, and Th2 cells in depression. Conclusions: Depression is characterised by widespread alterations in circulating myeloid and lymphoid cells, consistent with dysfunction in both innate and adaptive immunity. Immune cells could be useful biomarkers for illness subtyping and patient stratification in future immunotherapy trials of depression, along with cytokines, other biomarkers, and clinical measures.