The fiery landscape of depression: A review of the inflammatory hypothesis

The purpose of this article is to review the evidence linking depression with inflammation, to examine the bi-directional relationship between the neuro-humeral circuitry of depression and the inflammatory response, and point out new treatment implications of these ideas. The evidence available is in areas of genetic links, association of depression with raised inflammatory markers such as Tumour Necrosis Factor (TNF)-alpha, Interleukin (IL)-1, IL-6, co-morbidity of depression with inflammatory medical illnesses, administration of cytokines leading to depression, and the recognition that anti-depressants have antiinflammatory and neuro-protective properties. Inflammatory response and mood regulation constitute a system of bi-directional communication such that inflammatory cytokines can penetrate the CNS and influence behavior. Activation of the CNS cytokine network leads to a cascade of effects such as disturbed metabolism of amino acids, neurotoxicity, diminished neurotrophic support, decreased neurogenesis, impaired negative feedback regulation of HPA axis function and glucocorticoid resistance. Treatment implications include strategies to screen for patients with increased inflammatory activity, possible treatment with anti-inflammatory agents, and the recognition of new target areas for antidepressant medications. Methods: A literature search for articles published during the last ten years was conducted using various combinations of key words (‘depression’, ‘inflammation’, ‘cytokines’, ‘immune system’, ‘interleukins’) utilizing the databases Google Scholar and PubMed. An outline of the most relevant aspects of the role of inflammatory processes in depression was created. Major papers, including other review articles, were identified in accordance with our outline. These articles were subsequently hand searched and reviewed individually for further references of significance. Conclusion: The inflammatory response leading to formation of inflammatory cytokines plays a significant role in the pathophysiology of depression, and this has important implications with regards to new and personalized treatment of depression.