A chicken and egg scenario in psychoneuroimmunology: Bidirectional mechanisms linking cytokines and depression.

Background: Cytokines are an important part of the immune system. Certain cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), have well-described associations with depression. Various mechanisms exist that may explain bidirectional effects of cytokines on depression and vice versa. No recent reviews to our knowledge have comprehensively characterized both these mechanisms and the interaction of these mechanisms using evidence from the molecular level to the clinical level. The goal of this review is to both evaluate the present knowledge base and identify knowledge gaps to help guide future research. Methods: We conducted an extensive bibliographic search across multiple databases, using both general (e.g. "cytokine") and topic-specific (e.g. "kynurenine") keywords. Results: We describe the most recent evidence outlining these mechanisms, including the role of the hypothalamic pituitary axis, the kynurenine pathway, and neural circuitry. For relevant topics, we outline the pathways by which cytokine activation may lead to depressive symptoms, and how depressive symptomology may lead to elevations in cytokines. We also identify key areas for future research, including the need for longitudinal clinical studies to examine causality in pertinent mechanisms and modulating factors in the cytokine-depression interaction. Limitations: Given the numerous potential mechanisms associating cytokines and depressions, this review paper solely focuses on the most commonly described mechanisms at a basic level. Conclusions: Bidirectional evidence exists for several mechanisms in the relationship between cytokines and depression. However, more work is required to further elucidate the role of these mechanisms in specific clinical populations.