Defective Inflammatory Pathways in Never-Treated Depressed Patients Are Associated with Poor Treatment Response

Abstract

Inflammation has been involved in the pathophysiology and treatment response of major depressive disorder (MDD). Plasma cytokine profiles of 171 treatment-naive MDD patients (none of the MDD patients received an adequate trial of antidepressants or evidence-based psychotherapy) and 64 healthy controls (HCs) were obtained. MDD patients exhibited elevated concentrations of 18 anti- and proinflammatory markers and decreased concentrations of 6 cytokines. Increased inflammasome protein expression was observed in MDD patients, indicative of an activated inflammatory response. The plasma of MDD patients was immunosuppressive on healthy donor peripheral blood mononuclear cells, inducing reduced activation of monocytes/dendritic cells and B cells and reduced T cell memory. Comparison between 33 non-responders and 71 responders at baseline and 12 weeks revealed that after treatment, anti-inflammatory cytokine levels increase in both groups, whereas 5 proinflammatory cytokine levels were stabilized in responders, but continued to increase in non-responders. MDD patients exhibit remodeling of their inflammatory landscape.

Neuro-transcriptomic signatures for mood disorder morbidity and suicide mortality

“…Together, our current findings are consistent with data on the role of immune dysfunctions in CNS diseases (Oquendo et al 2014;Wohleb et al 2016;Pantazatos et al 2017;Butovsky et al 2018), and inflammasome functional prediction of major depressive disorder treatment outcomes (Syed et al 2018). The results further lend credence to the hypothesis that neurodevelopmental and transcription-factor genes are critical mediators of complex adaptive At the systems level, the toll-like receptor (TLR) pathway genes found to be underexpressed here are documented to recognize conserved motifs in microorganisms (Akira 2003) and stimulation of TLRs are shown to mediate acute-immune defense and cytokine production/release (Perkins 2007).…”

“…Third, the identified under-expressed chemokine-signaling pathways govern critical spatiotemporal cell-positioning during developmental coordination and translational guidance of cell-locomotion and migration(Turner et al 2014). Fourth, the identified under-expressed cytokines are implicated in cell-specific innate and adaptive inflammatory host defenses, cellular-development, cell-death, angiogenesis, and maintenance of cellular homeostasis(Syed et al 2018). Conversely, the Wnt-β-catenin signaling pathway found to be over-expressed in major depressive disorder suicides is an evolutionarily conserved intercellular communication system that mediates stem cell renewal, cell-proliferation and differentiation during embryogenesis and adulthood(Meffert et al 2003).…”

Analyzing the genes and pathways related to major depressive disorder via a systems biology approach

“…Such results suggest that the immune system plays important roles in the onset of MDD. Both stress and inflammatory cytokine activation have been reported to have adverse effect on the neurogenesis and neural plasticity (Syed et al, 2018). By comparing our results with that of a meta-analysis on genes implicated in MDD (Gatt et al, 2015;Manoharan et al, 2016;Yin et al, 2016), we found that most of the pathways reported earlier were also identified in the current study.…”

“…Interleukin-17 in the IL-17 signaling pathway plays a crucial role in acute and chronic inflammatory responses (Zhao, Li, Li, Wang, Manthari, & Wang, 2018). Both stress and inflammatory cytokine activation have been reported to have adverse effect on the neurogenesis and neural plasticity (Syed et al, 2018). Such results suggest that the immune system plays important roles in the onset of MDD.…”

Neuroimmune nexus of depression and dementia: Shared mechanisms and therapeutic targets

“…Cytokines generated in these responses regulate cell-mediated immunity and phagocytic-dependent inflammation in response to intracellular parasites and can promote autoimmunity (Calcagni & Elenkov, 2006). While the variance in the magnitude and types of overexpressed cytokines can be significant between trials and results can conflict (Orlovska-Waast et al, 2018), a set of cytokines including IL-1β, TNF-α, IL-6, IL-18, IL-17A, and IL-10 do exhibit consistent up regulation in the plasma of untreated MDD patients (Hodes, Kana, Menard, Merad, & Russo, 2015;Syed et al, 2018). Similar alterations in the concentration of these cytokines are noted in their CSF (Young, Bruno, & Pomara, 2014).…”