Cytokines, stress, and depressive illness

Abstract

It has been suggested that immune activation, and particularly increased activity of several cytokines, notably interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor-α as well as their soluble receptors is characteristic of depression. Normalization of cytokine activity does not necessarily occur following successful antidepressant, suggesting that cytokines may be trait markers of depression, or simply represent bystander effects of the illness. The relationship between cytokines and depression is complicated as a variety factors could directly or indirectly influence cytokine activity. While cytokine elevations are most pronounced in severe (melancholic) depression, their activity may also be related to chronicity of illness, neurovegetative features of depression (altered sleep patterns, food intake, weight changes, fatigue or general activity), or the high stress perception characteristic of depression. Although, studies assessing cytokines in depressive populations are basically correlational in nature, patients receiving cytokine immunotherapy frequently show depressive symptoms, which may be attenuated by antidepressant medication, supporting a causal role for cytokines in depressive disorders. The processes underlying such outcomes remain to be established, but the affective changes may stem from the neuroendocrine and central neurochemical changes elicited by cytokines, as these are reminiscent of those associated thought to subserve depression.

Introduction

It has been suggested that stressors instigate hormonal variations, coupled with central neurochemical alterations that favor the development of depressive illness. Indeed, in many respects the effects of stressors are reminiscent of the presumed neurochemical disturbances thought to be associated with depression, including elevated hypothalamic–pituitary–adrenal (HPA) functioning and altered norepinephrine (NE), dopamine (DA), and serotonin (5-HT) activity within hypothalamic and limbic brain regions. Studies in animals have indeed shown that stressors will induce behavioral changes akin to those that characterize depression, and these behavioral disturbances are alleviated by treatments, including antidepressant agents, that attenuate the stressor-provoked amine alterations (Anisman, Zalcman, & Zacharko, 1993).

While it has been assumed that psychological (psychogenic) and physical (neurogenic) stressors are most closely aligned with depression, the suspicion has arisen that systemic stressors, including immune alterations, may also act in such a provocative capacity (Maes, 1999). Communication occurs between the immune, endocrine, autonomic, and central nervous systems (Blalock, 1994; Rothwell & Hopkins, 1995), such that psychological events that affect central neurochemical processes may affect immune activity. Conversely, immune activation may affect hormonal processes and the activity of central neurotransmitters. Thus, by virtue of the neurochemical effects imparted, immune activation may come to affect behavioral outputs and may even be related to behavioral pathology such as depressive illness (Licinio & Wong, 1999; Maes, 1995, Maes, 1999).

The present review will describe the presumed relationship between cytokines and depressive illness in humans, and some of the hypothesized mechanisms that may underlie this relationship. Before discussing the literature concerning depression in humans, a brief overview is presented regarding the neurochemical and hormonal concomitants of cytokine challenge. A more detailed review of this literature is presented in Anisman and Merali (1999) and in the accompanying paper (Anisman, Kokkinidis, & Merali, 2002).