Depression is a complex disease which is likely to involve several pathophysiological pathways. There is clear evidence that depression is associated with neurochemical and neuroendocrine alterations. Reduced activity of the serotoninergic (5-HT) and noradrenergic (NA) central systems are observed in a majority of patients with major depression (Garver & Davis, 1979). Depressed patients usually also exhibit an alteration of the hypothalamus-pituitary-adrenal (HPA) axis activity characterized by an hyperproduction of corticotropin-releasing hormone (CRH), which stimulates adrenocorticotropic hormone (ACTH) and Cortisol release (Holsboer, Bardeleben, Gerken, Stalla, & Muller, 1984). Therefore, the biochemical activity of most antidepressants, including selective 5-HT reuptake inhibitors, monoamine oxidase inhibitors, and tricyclic antidepressants, has been assessed on the basis of their ability to reverse the alterations of monoamine and/or HPA axis activities (Hollister, 1986). However, the metabolic activity of these drugs is not necessarily related directly to their clinical efficacy (Barden, Reul, & Holsboer, 1995; Blier & de Montigny, 1994). Despite repeated attempts, the neuro-hormonal abnormalities observed in depression have never been shown to predict therapeutic response, nor can they account for the symptomatic profile of the patients. Furthermore, depletion of 5-HT or NA in healthy individuals does not induce clinically significant depressive symptomatology (Young, Smith, Pihl, & Erwin, 1985). In addition, there are also some atypical antidepressants with known experimental and clinical therapeutic effects, but devoid of the classic antidepressant actions on central monoamine activity (Guelfi, 1992; Van Riezen & Leonard, 1990).
Because of the growing interest for brain-immune interactions, many authors
Cytokines, Stress, and Depression, edited by Dantzer et at. Kluwer Academic / Plenum Publishers, New York, 1999.
have also looked for a possible defect of immune responsiveness in depression (Anderson, 1996; Stein, Miller, & Trestman, 1991), and considerable attention is now paid to the possible role of immunological dysregulation in the pathogenesis of this disease. For decades, the neuro-hormonal changes observed in depression were believed to be exclusively associated with an immunosuppression, especially because of the well known inhibitory influence of glucocorticoids on the immune system (Munck, Guyre, & Meltzer, 1984), as well as the regulatory role of central monoamines on immune activity (see for review Deleplanque & Neveu, 1995). As detailed below, there is both clinical and experimental evidence that various aspects of the immune system, including mitogen-induced cell proliferation, natural killer cell activity, and variations of lymphocyte subsets, are severely compromised in depression (Irwin, Daniels, Bloom, Smith, & Weiner, 1987; Irwin, Patterson, Smith, Caldwell, Brown, Gillin, & Grant, 1990). However, recent studies have provided some evidence that major depression may be also accompanied by an immune activation in the form of an acute phase reaction mediated by the synthesis and release of proinflammatory cytokines (mainly interleukin-1: IL-1, interleukin-6: IL-6, tumor necrosis factor: TNF) by activated macrophages (Connor & Leonard, 1998; Maes, 1995; Maes, Smith, & Scharpe, 1995; Smith 1991; Ur, White, & Grossman, 1992). Interestingly, these results were proposed by some authors to provide a possible explanation for the neuroendocrine abnormalities observed in depressed patients, since cytokines, i.e. the key factors for immune activation, exert important changes in the HPA axis activity (Besedovsky & Del Rey, 1996). By extension, it has also been suggested that the immune system, and more specifically cytokines, may play a role in the onset of depressive symptoms.
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