Cytokine Research in Depression: Principles, Challenges, and Open Questions

Abstract

Cytokines have been implicated in the pathology of depression. Currently, the evidence is based on cross-sectional studies and meta-analytic research comparing blood concentrations of T helper type 1 (TH1), T helper type 2 (TH2), pro-inflammatory or anti-inflammatory cytokines of patients with a depressive disorder to those of healthy controls. Additionally, multiple longitudinal studies have investigated cytokine levels during antidepressant treatment. According to the current literature, it seems that peripheral levels of interleukin (IL)-6, IL-10, IL-12, IL-13, and tumor necrosis factor (TNF)-α are elevated and that interferon (IFN)-γ levels are lower in patients with depression compared to healthy controls. However, the overlap of cytokine values between acutely depressed patients, remitted and recovered patients and healthy controls is considerable. Thus, the discriminative power of cytokine concentrations between depressed and non-depressed people is likely weak. Treatment with certain antidepressants appears to decrease peripheral levels of IL-6, IL-10, and TNF-α. However, weight gain-inducing psychopharmacological substances, such as the antidepressant mirtazapine, have been reported to potentially increase the production of pro-inflammatory cytokines. Even though cytokines are often discussed as biomarkers for depression, they have also been shown to be altered in other psychiatric disorders. Moreover, many environmental, social, psychological, biological, and medical factors are also associated with cytokine changes. Thus, cytokine alterations seem extremely unspecific. The interpretation of the results of these studies remains a challenge because it is unknown which type of cells are most responsible for cytokine changes measured in the blood nor have the main target cells or target tissues been identified. The same cytokine can be produced by multiple cell types, and the same cell can produce various cytokines. Additionally, redundancy, synergy, antagonism, and signaling cascades of cytokine signaling must be considered. Cytokines might not be associated with the diagnosis of depression according to the currently used diagnostic manuals, but rather with specific subtypes of depression, or with depressive symptoms across different psychiatric diagnoses. Therefore, the currently available diagnostic systems may not be the ideal starting point for psychiatric cytokine research.

Personalized Psychiatry and Depression: The Role of Sociodemographic and Clinical Variables

“…As discussed throughout the paper, the lack of reliable conclusions may be partly explained by limitations that this body of studies suffered from, including heterogeneity in design, duration, setting, features of the sample, statistical power, criteria and/or tools used to assess clinical symptoms or profiles, and the limited number of comparative studies testing the differential efficacy of specific antidepressants. In addition, it should be noted that our review focused only on a limited set of variables, while other individual/clinical factors, relatively easy to assess in clinical practice, may play a role, such as childhood maltreatment/adversities, [124][125][126] inflammatory markers, 127,128 other symptom profiles or individual features. Among the latter, alexithymia, reflecting difficulty with identifying and expressing emotions, seems to be associated with higher severity of depression, increased suicide risk, and pro-inflammatory imbalance; [129][130][131][132][133] thus its potential contribute to selection of specific antidepressant class/compound may be worth investigating.…”

Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression

“…Along these lines, chronic stress and low-grade inflammation are believed to contribute to the pathophysiology of MDD 8 – 10 . In fact, patients with MDD express increased levels of proinflammatory cytokines like interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α in peripheral blood, which can access the central nervous system (CNS) and activate tissue-resident macrophages like microglia, impair HPA axis function, modulate monoaminergic neurotransmission, and reduce neural plasticity 11 – 13 . The tryptophan-kynurenine pathway links depression and inflammation, and under stressful and inflammatory conditions, microglial indoleamine 2,3-dioxygenase (IDO) activity reduces serotonin availability and results in the production of excitotoxic metabolites such as quinolinic acid 8 , 9 .…”

Porcine liver decomposition product-derived lysophospholipids promote microglial activation in vitro

“…In BV-2 microglia cells, IL-4, but not IL-10, re-directed LPS (lipopolysaccharide)-activated microglia towards an M2 phenotype 68 . These cytokines which are influenced by regulatory T cells and prevent inflammatory processes 69 . Our results showed that the LPS-mediated inflammatory response, including the observed increase in microglial cytokine production, was suppressed by LPC exposure.…”