Dysregulated relationship of inflammation and oxidative stress in major depression

Abstract

Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after 8 weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p<0.05) and were negatively correlated with IL-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD.

Fig. 1

Correlations between F2-IsoPs and IL-6, IL-10 and the IL-6/IL-10 ratio among the control group at baseline (1a, d and g, respectively), and among the MDD group at baseline (1b, e and h, respectively) and after 8 weeks treatment with sertraline (1c, f and i, respectively). Figures portray raw data; correlation coefficients and p values are determined by partial correlation tests, adjusted for covariates BMI and tobacco when significantly correlated.

Fig. 2

Two-way interaction plot illustrating the differential relationship between F2-IsoPs and IL-6, as a function of high versus low depression scores on the IDS. High and low are defined as 1 SD above or below the mean value for both F2-IsoPs and the IDS, based on the approach described by Hayes and Matthes (2009) and the corresponding modprobe macro in SPSS. In subjects with low depression scores, F2- IsoP and IL-6 concentrations are not significantly related. But in subjects with high depression ratings, progressively higher F2-IsoP concentrations are associated with higher IL-6 concentrations.

Fig. 3

Complex interactions between the oxidative and inflammatory pathways contain mechanisms for both mutual amplification (positive feedback or a “vicious cycle”) and for negative feedback homeostasis. In this Figure, some of the specific mediators of positive feedback are portrayed. For example, reactive oxygen species (ROS) activate inflammasomes such as NLRP3, which increase pro-inflammatory cytokines such as IL-1β. ROS also increase inflammation by activating certain stress-activated kinases such as ERK, JNK, and p38. Also, ROS can stimulate transcription factors, e.g. NF-κB and activator protein-1 (AP-1), to stimulate pro-inflammatory cytokine expression. Conversely, pro-inflammatory cytokines can indirectly provoke oxidative stress by activating microglia and macrophages, which release ROS; activating indoleamine 2,3-dioxygenase (IDO), which produces byproducts, 3-hydroxy-kynurenine and quinolonic acid; and stimulating nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase), which generates free radicals. Just as negative acute phase reactants (APRs) can have antioxidant effects, some positive APRs, such as C-reactive protein (CRP), have been linked to increased oxidative stress (Il’yasova et al., 2008).