Glucocorticoids, cytokines and brain abnormalities in depression

Abstract

Major depression (MD) is a common psychiatric disorder with a complex and multifactor aetiology. Potential mechanisms associated with the pathogenesis of this disorder include monoamine deficits, hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, inflammatory and/or neurodegenerative alterations. An increased secretion and reactivity of cortisol together with an altered feedback inhibition are the most widely observed HPA abnormalities in MD patients. Glucocorticoids, such as cortisol, are vital hormones that are released in response to stress, and regulate metabolism and immunity but also neuronal survival and neurogenesis. Interestingly depression is highly prevalent in infectious, autoimmune and neurodegenerative diseases and at the same time, depressed patients show higher levels of pro-inflammatory cytokines. Since communication occurs between the endocrine, immune and central nervous system, an activation of the inflammatory responses can affect neuroendocrine processes, and vice versa. Therefore, HPA axis hyperactivity and inflammation might be part of the same pathophysiological process: HPA axis hyperactivity is a marker of glucocorticoid resistance, implying ineffective action of glucocorticoid hormones on target tissues, which could lead to immune activation; and, equally, inflammation could stimulate HPA axis activity via both a direct action of cytokines on the brain and by inducing glucocorticoid resistance. In addition, increased levels of pro-inflammatory cytokines also induce the production of neurotoxic end products of the tryptophan–kynurenine pathway. Although the evidence for neurodegeneration in MD is controversial, depression is co-morbid with many other conditions where neurodegeneration is present. Since several systems seem to be involved interacting with each other, we cannot unequivocally accept the simple model that glucocorticoids induce neurodegeneration, but rather that elevated cytokines, in the context of glucocorticoid resistance, are probably the offenders. Chronic inflammatory changes in the presence of glucocorticoid resistance may represent a common feature that could be responsible for the enhanced vulnerability of depressed patients to develop neurodegenerative changes later in life. However, further studies are needed to clarify the relative contribution of glucocorticoids and inflammatory signals to MD and other disorders.

Introduction

Major depression (MD) is one of the most common psychiatric disorders in the Western World, and according to the World Health Organization it is predicted to be the leading cause of burden of disease by 2030 (WHO report 2004). Only a third of patients receive adequate treatment and up to half of them relapse despite the increasing number of antidepressant drugs currently available (Thase, 2006). This reflects the heterogeneity of the disorder, which has a complex and multifactorial aetiology originating from the interaction between environmental and genetic factors and presents frequent co-morbidity. Several theories have been proposed to explain its pathogenesis, including the monoamine hypothesis, based on deficiency of the biogenic amine system (particularly serotonin and norepinephrine) (Charney, 1998, Hirschfeld, 2000), the hypothalamic-pituitary-adrenal (HPA) axis dysfunction theory, based on hyperactivity of this system usually reflected in high levels of glucocorticoids (Dinan, 1994, Pariante and Lightman, 2008), cognitive and behavioural theories (Beck et al., 1979, Harmer et al., 2009), the neurogenesis hypothesis (Jacobs et al., 2005, Duman, 2004, Kempermann and Kronenberg, 2003, Sahay and Hen, 2007, Kempermann et al., 2008, Zhao et al., 2008), the inflammatory theory, also known as the malaise or cytokine theory (Smith, 1991, Ur et al., 1992, Maes et al., 2009, Miller et al., 2009), and the neurodegenerative hypothesis (Myint and Kim, 2003, Maes et al., 2009). With the aim to better understand the pathophysiology of depression, these hypotheses, which indeed have some biological features in common, are being drawn together. Specifically, the last two models, reviewed in this special issue on ‘Neuro-inflammatory and Neuro-degenerative Pathways in Major Depression’, are gaining more relevance. Most interesting is the role of glucocorticoids not only in the HPA axis dysfunction model but also in the two models stated above. Are glucocorticoids a potential link between inflammation and degeneration? The answer to this question is not clear.

Glucocorticoids, released by the adrenal gland in response to stress, are among the most potent anti-inflammatory hormones in the body (Vinson, 2009). Some studies have suggested that they contribute to the hippocampal atrophy found in depressed patients (Sapolsky, 2000, McEwen, 2005). The involvement of stress in the development of depressive symptomatology may involve several systems, including the neuroendocrine, the neurotransmitter and the immune systems, that interact with the HPA axis in complex ways (Baune, 2009). However, to date, the role of the above-mentioned systems in the pathogenesis of depression is contradictory and subject to differing interpretations. In this review we will focus the attention on glucocorticoids and inflammation processes, trying to summarize and clarify as best as we can their involvement in MD, and to understand whether they have a direct cause in the abnormalities observed in the brain of depressed patients.