The association between cancer, autoimmune diseases, myocardial infarction, stroke and dementia with depression and the activation of the immune system, particularly involving the proinflammatory cytokines, has been the subject of considerable discussion in recent years. The initial studies indicating that patients suffering from major depression had decreased cellular immune response compared to healthy controls (Kronfol and House, 1985; Schleifer, Keller, Siris, Davis, and Stein, 1985) helped to lay the scientific basis whereby psychosocial factors could profoundly affect the development of physical and psychiatric disease. However, in well over 30 studies in the last 15 years, the consistency of the immune changes in depression is uncertain, with some investigators findings impaired immunocompetence while others do not. This situation led Miller, Spencer, McEwen, and Stein (1993) to review all the published studies regarding the changes in differential white blood cell counts, mitogen induced proliferation of T cells and changes in NK cell activity in depression. The results of their survey failed to find significant differences between depressives and their controls in the majority of the 30 studies assessed. For example, with regard to mitogen-induced lymphocyte proliferation, approximately half the studies demonstrated a significant decrease in lymphocyte proliferation whereas half the studies found no differences. Finally, of the 10 studies of changes in NK cell activity in depressed patients, 6 reported decreased activity and 4 found no difference. Thus of the 3 parameters of immune function that are frequently evaluated in studies of depression and stress, it does not appear that alterations in the immune system are specific or reproducible correlates of the psychological state, but may be associated with other variables that characterize the patients, such as the age, gender, severity, and duration of the stress or depressive episode.
The following factors appear to contribute to the equivocal outcome of the reported changes in cellular immunity in depression.
i. The heterogeneity of the patients used and the controls selected for comparison. In many of the studies cited, the patients were older than their controls and had been hospitalized for several weeks. It is well established that age, gender, and hospitalization status can profoundly affect the immune status that is frequently not taken into account (Evans, Folds, and Pettito, 1991; Miller, Asmis, and Lackner, 1991, Schleifer, Keller, Bond, Cohen, and Stein, 1989).
ii. The variability of the immune assays used. This applies particularly to the mitogen-induced lymphocyte proliferation assay where it has been shown that up to a 50% variability in the results can be obtained in the same laboratory using the same method (Schleifer et al. 1989).
iii. The relevance of the assays used. The relationship between the number of immune cells, or NKC activity in the peripheral blood, and the competence of the immune system in otherwise healthy individuals is unclear. Given that the immune system is a complex network of multiple cell types with various specialized functions, the number and location of these cells in any one immune compartment of the immune system may not reflect their activity in other compartment (Keller, Weiss, Schleifer, Miller, and Stein, 1981). Furthermore, the endocrine and peripheral sympathetic system can vary in their effects on the different immune compartments. For example, while the inhibitory effects of stress on mitogen induced proliferation, in the spleen is mediated by catecholamines in the blood it is mediated by glucocorticoids (Rabin, Cunnick, and Lysle, 1990).
iv. The variation in an immune parameter may be statistically significant between the patients and their controls but still lie within the normal range for immune function. Thus patients may not be immunocompromised from the clinical viewpoint. This could be relevant to the interpretation of the data showing that there is a greater risk of cancer for individuals with high depressive scores (Persky, Kempthone-Rawson, and Shekelle, 1991). However, further examination of the increased mortality rate in patients with affective disorders indicates that this is due to suicide and accidents rather than to causes related to a disorganized immune system (Martin, Cloninger, Guze, and Clayton, 1985).
v. It is evident that both stressful and non stressful environmental events can profoundly affect the immune systems. The degree to which stressor can cause suppression of the immune system can be influenced by the perception of the stressful event. Thus there is evidence that the immune system can be classically conditioned (Ader and Cohen, 1991). Animals can learn to immunosuppress, or more dramatically immunoenhance, their T-cell, B-cell, NKC, and most immune cell functions (Dark, Peeke, Ellman, and Salfi, 1987; Solvason, Ghanta, and Hiramoto, 1988). Such factors are frequently ignored in both clinical and experimental studies that seek to explore the relationships between the effects of different types of stress on the immune system.
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