Inflammation & Allergy - Drug Targets, 2008, 7, 19-23 19 1871-5281/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Inflammatory Aspects of Depression Ubiratan C. Adler 1 , Andrea H. Marques 2 and Helena M. Calil *,3 1 Doctorate Department of Psychobiology – UNIFESP/EPM, R. Napoleão de Barros, 925, São Paulo, SP. 04024-002, Brazil 2 Institute of Psychiatry, University of São Paulo, Brazil 3 Department of Psychopharmacology, UNIFESP/EPM, Department of Psychobiology - UNIFESP/EPM, R. Napoleão de Barros, 925, São Paulo, SP. 04024-002, Brazil Abstract: A bidirectional relation between depression and natural immunity has been identified: depressive episodes are associated to a relative immunodeficiency, conversely inflammatory activity has been implicated in the development of depressive symptoms and in the pathophysiology of depression. Depression has been associated with a decrease in the number and activity of NK lymphocytes and hence patients with depression may show immunodeficiency towards intra- cellular microorganisms and tumors. Paradoxically, depression is sometimes accompanied by an inflammatory state, de- veloped from the peripheral stimuli (atopy) or central stimuli (chronic stress) and mediated by proinflammatory cytokines (IL-6, TNF and IL-1). These cytokines can play a role in the pathophysiology of depression and of various diseases, sup- porting the hypothesis that many chronic diseases are individual manifestations of a common proinflammatory denomina- tor. Keywords: Depression, pathophysiology, immunology, cytokines, inflammation, natural immunity. INFLAMMATORY ASPECTS OF DEPRESSION “…the more than 100 years of research on etiology without success may be telling us that there is something wrong in our research. For example, the division of illnesses as physical and mental can be a fundamental flaw in our approach” [1]. INTRODUCTION Studies conducted in the 70s suggested an association between depressive states and a higher vulnerability to infec- tious diseases, cancer, and even a higher death rate other than due to suicide [2]. During these 35 years, research has not just confirmed relations among depression, immunodeficiency and somatic disease [3], but also has shown that uncontrolled immunoac- tivation may be a factor associated with the development of depression [4]. As a response to an infection, the immune system is acti- vated, and if this response is systemic, the organism usually shows symptoms common to depressive episodes: increased sleep, anhedonia, malaise, irritability, anorexia, etc. At pre- sent, it is known that these symptoms are due to the endocri- nal action of some cytokines, the “immunotransmitters” of inflammatory and immune responses. *Address correspondence to this author at the Department of Psychophar- macology, UNIFESP/EPM, Department of Psychobiology - UNI- FESP/EPM, R. Napoleão de Barros, 925, São Paulo, SP. 04024-002, Brazil; Tel: 005511 55764550; Fax: 005511 55725092; E-mail: hmcalil@psicobio.epm.br Treatment of patients with oncological, auto-immune and infectious diseases with interferon- has been associated with symptoms similar to those of flu: fatigue, anorexia, anhedonia, lack of social interaction and libido, and cogni- tive impairment - symptoms that are collectively called sick- ness behavior [5, 6]. The similarity between sickness behavior and the symp- toms of a depressive episode have encouraged studies on the role of immunity, especially of cytokines in the pathophysi- ology of depression, which earlier focused on cerebral monoamines and the hypothalamus-pituitary-adrenal (HPA) axis. The result of these studies points to an inflammatory influence on the development of some depressive states, similar to those observed in cardiovascular, rheumatologic and autoimmune diseases [7]. The inflammatory changes which have been associated with depression are the subject of this brief review. CELLULAR CHANGES OF NATURAL IMMUNITY IN INDIVIDUALS WITH DEPRESSION In relation to the cellular components of natural immu- nity, Zorrilla and collaborators [8], in an extensive metanaly- sis, identified the following changes in patients with depres- sion: Leukocytosis due to a relative increase in the number of neutrophils which, nevertheless, show a reduction in their phagocytic activity. Reduction in the absolute number of NK lymphocytes (natural killer) cells and in the cytotoxicity of these cells. According to Irwin, the reduction in the activity of NK cells is one of the most reproducible immunological changes in depression [9]. In patients with depression and whose aver-