Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research

Abstract

Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g. C-reactive protein, and pro-inflammatory cytokines, e.g. interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways.Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g. activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, activation of the Toll-like Receptor and neuroprogressive pathways. Thirdly, antiinflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e. path and drug discovery processes, omics-based techniques and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics and microbiomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular 4 networks, pathways and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.

Adult neurogenesis in the mammalian dentate gyrus

“…Neuroinflammation also contributes to neuronal loss in general and impaired hippocampal neurogenesis specifically (Wu et al, ). These recent studies have led to formulation of the “inflammatory hypothesis” of depression (Huang & Lin, ; Maes et al, ). This pro‐inflammatory state of the adult hippocampus appears to be related to increased glucocorticoid expression (Horowitz & Zunszain, ).…”

International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets

“…It has been hypothesized that both high cortisol levels and the activation of immune system in MDD can be explained with the development of the so called "glucocorticoid receptor resistance" found in depressed patients. According to this idea, GR dysfunction may lead to an impaired function of the negative feedback, resulting in HPA axis hyperactivity and elevated cortisol levels (de Kloet et al, 2005;Maes et al, 2016;Pariante, 2017). GR resistance is particularly evident in patients with TRD (Bauer et al, 2003).…”

“…Over the last two decades several studies have demonstrated that inflammation and dysfunction of the immune system play a key role in the pathophysiology of major depression and may therefore contribute to treatment resistance (Caraci et al, 2010;Capuron and Miller, 2011;Maes et al, 2016;Remus and Dantzer, 2016;Bhattacharya and Drevets, 2017;Pariante, 2017). An altered activation of the immune system and the ensuing state of "peripheral and central inflammation" seem to be strictly correlated to HPA axis dysfunction observed in depressed patients (Remus and Dantzer, 2016; Pariante, 2017).…”

“…Depressed patients show higher levels of proinflammatory cytokines, such as interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), interferon-g and tumor necrosis factor-a (TNF-a) (Dowlati et al, 2010;Capuron and Miller, 2011), as well as increased acute phase proteins, chemokines, and cellular adhesion molecules (Maes et al, 2016). In particular, recent meta-analyses found the most relevant longitudinal association between two inflammatory markers, namely C-reactive protein and IL-6, and depressive disorders, suggesting that indeed inflammation may contribute to the development of the disease (Valkanova et al, 2013;Smith et al, 2018).…”

Neuroimmune Interface in the Comorbidity between Alcohol Use Disorder and Major Depression

“…Thus, it is high time that the theoretically embraced entity of “inflammatory cytokine-associated depression” (87) be phenotype based on relevant biological and clinical characteristics. Omics-based approaches highlighting systems biomedicine could be beneficial (88). Only such progress would lead to an enhanced understanding of comorbid conditions of MD.…”