Cytokine production capacity in depression and anxiety.

N Vogelzangs,B W Penninx,J H Smit,S Bahn,P De Jonge

doi:10.1038/tp.2016.92

Abstract

Recent studies have suggested that immune function may be dysregulated in persons with depressive and anxiety disorders. Few studies examined the expression of cytokines in response to ex vivo stimulation of blood by lipopolysaccharide (LPS) to study the innate production capacity of cytokines in depression and anxiety. To investigate this, baseline data from the Netherlands Study of Depression and Anxiety (NESDA) were used, including persons (18–65 years; 66% women) with current (that is, past month; N=591) or remitted (N=354) DSM-IV depressive or anxiety disorders and healthy controls (N=297). Depressive and anxiety symptoms were measured by means of the Inventory of Depressive Symptomatology (IDS) and the Beck Anxiety Inventory (BAI). Using Multi-Analyte Profiling technology, plasma levels of 13 cytokines were assayed after whole blood stimulation by addition of LPS. Basal plasma levels of C-reactive protein, interleukin-6 and tumor necrosis factor-α were also available. A basal and a LPS summary index were created. Results show that LPS-stimulated inflammation was associated with increased odds of current depressive/anxiety disorders (odds ratio (OR)=1.28, P=0.009), as was the case for basal inflammation (OR=1.28, P=0.001). These associations were no longer significant after adjustment for lifestyle and health (OR=1.13, P=0.21; OR=1.07, P=0.45, respectively). After adjustment for lifestyle and health, interleukin-8 was associated with both remitted (OR=1.25, P=0.02) and current (OR=1.28, P=0.005) disorders. In addition, LPS-stimulated inflammation was associated with more severe depressive (β=0.129, P<0.001) and anxiety (β=0.165, P<0.001) symptoms, as was basal inflammation. Unlike basal inflammation, LPS-stimulated inflammation was still associated with (anxiety) symptom severity after adjustment for lifestyle and health (IDS: IL-8, MCP-1, MMP2; BAI: LPS index, IL-6, IL-8, IL-10, IL-18, MCP-1, MMP2, TNF-β). To conclude, lifestyle and health factors may partly explain higher levels of basal, as well as LPS-stimulated inflammation in persons with depressive and anxiety disorders. However, production capacity of several cytokines was positively associated with severity of depressive and in particular anxiety symptoms, even while taking lifestyle and health factors into account. Elevated IL-8 production capacity in both previously and currently depressed and anxious persons might indicate a genetic vulnerability for these disorders.

Highlights

As we have previously found basal inflammation to be associated with somatic symptoms than with cognitive symptoms,[25] and more with atypical depression than with melancholic depression,[26] we a priori created several symptom subscales
This study examined innate cytokine production capacity in a large sample of persons with varying levels of depression and anxiety
Lifestyle and health factors may partly explain higher levels of basal, as well as LPS-stimulated inflammation in persons with somatic symptoms and with atypical symptoms, but not with cognitive and melancholic symptoms. This again underlines the differences between the two inflammation measures and suggests that innate cytokine production capacity might be generally involved in depression and anxiety, while basal inflammation is important for depression and anxiety in which somatic with depressive and anxiety disorders

Summary

Introduction

Depression, as well as anxiety disorders are of major importance for public health.[1,2,3] These disorders are associated with a great loss in quality of life,[4] increased (cardiovascular) morbidity and mortality,[5,6,7] and show a high rate of recurrence and chronicity.[8,9,10] Treatment of depression and anxiety disorders, including the prevention of relapse, is only effective in about a third to a half of patients.[11,12] most available antidepressants, which are often prescribed for anxiety disorders, act by increasing monoaminergic transmission, the etiology of depression and anxiety is much more diverse. An increasing number of studies—as summarized in meta-analyses—has indicated that inflammatory marker levels such as C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α are elevated in depressed persons signifying immune dysregulation.[13,14] Depression could bring about disturbances in important stress systems of the human body, that is, the hypothalamus–pituitary–adrenal axis[15,16] and the autonomic nervous system,[17,18] which in turn might stimulate production of cytokines.[19,20] On the other hand, administration of pro-inflammatory cytokines (for instance in cancer or hepatitis C treatment) has consistently been shown to induce depressive symptoms in about a third of patients.[21]

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