Elizabeth Bixler

Introduction: Major Depressive Disorder (depression) is a mood disorder thought to be driven by neurotransmitter imbalance. It is the leading cause of disability worldwide¹, and in any given year, 17.3 million Americans suffer from depression². Many groups have studied the link between elevated proinflammatory cytokines and depression and found that depressed patients have higher levels of proinflammatory cytokines such as IL-6, IL-8, IL-1β, TNF-ɑ, among others^3-6. However, the mechanism by which proinflammatory cytokines become elevated is still unknown. This literature review seeks to describe three peer-reviewed studies testing hypotheses interrogating the mechanism behind elevated proinflammatory cytokine in depressed patients. Methods: In the first study, nucleotide-binding oligomerization domain-like receptor (NOD-like-receptor) containing pyrin (NLRP) inflammasome levels were evaluated via gel electrophoresis and immunohistochemistry⁷. In the second study, toll-like receptor 3 (TLR-3) levels were evaluated via Western blot analysis⁸. And in the third study, RNA isolation of miR-19a-3p and TNF-ɑ gene transcripts was done using the TRIzol® method, and cDNA synthesis and PCR amplification were used to quantify their expression using specialized primer sequences⁵. Results: The first hypothesis tested the possibility that increased expression of NLRP inflammasomes in the central nervous system (CNS) would lead to more IL-1β activation. Indeed, the study found that increased expression of NLRP led to increased detection of IL-1β.⁷. The second hypothesis proposed that increased expression of TLR-3 in the CNS could lead to increased inflammation⁸. Western blot analysis demonstrated that indeed, TLR3 expression was increased in the CNS and correlated with increased inflammation.⁸  The third hypothesis proposed  and demonstrated that increased activity of Human antigen R (HuR) sequesters miR-19a-3p (a microRNA that degrades the TNF-ɑ gene), leads to increased expression of TNF-ɑ⁵. And lastly, a study using cytokine levels as a metric for measuring response to depression treatment found that change in pre- and post-infusion IL-8 was a predictor of treatment response, depending on biological sex.⁹    Conclusion: Exploring the link between pro-inflammatory cytokine levels and depression represents an exciting field of research, as well as an area for the discovery of potentially new biomarkers and metrics for depression diagnosis and treatment, respectively. More research is needed to determine which cytokine or cytokines should be used as biomarkers or metrics, and in defining the mechanism by which cytokines are elevated in patients with depression.

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2. Depression statistics. Depression and Bipolar Support Alliance. https://www.dbsalliance.org/education/depression/statistics/. Published July 12, 2019. Accessed February 1, 2022.
3. Pandey GN, Rizavi HS, Zhang H, Bhaumik R, Ren X. Abnormal protein and mrna expression of inflammatory cytokines in the prefrontal cortex of depressed individuals who died by suicide. Journal of Psychiatry and Neuroscience. 2018;43(6):376-385. doi:10.1503/jpn.170192
4. Zou W, Feng R, Yang Y. Changes in the serum levels of inflammatory cytokines in antidepressant drug-naïve patients with major depression. PLOS ONE. 2018;13(6). doi:10.1371/journal.pone.0197267
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7. Pandey GN, Zhang H, Sharma A, Ren X. Innate immunity receptors in depression and suicide: Upregulated NOD-like receptors containing pyrin (nlrps) and hyperactive inflammasomes in the postmortem brains of people who were depressed and died by suicide. Journal of Psychiatry and Neuroscience. 2021;46(5). doi:10.1503/jpn.210016
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