Until now, very few investigations have been carried out to assess the effects of antidepressant medications on the immune alterations associated with depression and more specifically to assess whether antidepressants normalize immunity and/or abrogate the production and release of proinflammatory cytokines. In order to answer these questions, it is first necessary to depict the immune status that is usually observed during depression. The immune parameters studied in depressed patients usually include mitogen-induced lymphoproliferation, natural killer cell activity, peripheral blood leukocyte counts and cytokine plasma levels.
Lymphoproliferation induced by phytohemagglutinin (PHA), concanavalin A (ConA) or pockweed mitogen (PWM) has been usually found to be decreased in depressed patients. For example, Kronfol, Silva, Greden, Dembinski, Gardner, & Carroll (1983) found that this lymphoproliferation was reduced in depressed in-patients compared to healthy out-patient controls, although this reduction was not correlated with severity of depression as reflected by Hamilton scores. Despite the well known inhibitory action of glucocorticoids on immune activity, the decrease in lymphoprolif-eration was not related to the HPA axis hyperactivity (Cosyns, Maes, Vandewoude, Stevens, De Clerk, & Schottel, 1989; Kronfol & House 1985), as assessed by the dexamethasone suppression test (DST). Indeed, depression of lymphoproliferation was equally found in both DST positive and DST negative patients (Albrecht, Helderman, Schlesser, & Rush, 1985). However, others authors (Maes, Bosmans, Suy, Minner, & Raus, 1989; Maes, Bosmans, Suy, Vandervorst, Dejonckheere, Minner, & Raus, 1991) did find an inverse correlation between lymphocyte proliferation and Cortisol levels. The decrease of mitogenesis has also been found to be inversely correlated to the turn-over of norepinephrine and the age of the patients (Maes et al., 1989). Likely, Schleifer, Keller, Bond, Cohen, & Stein (1989) described a reduced mitogenesis in old but not in young patients. In fact, an increase in lymphoproliferation induced by optimal doses of PHA has been even reported in young patients (Altshuler, Plaeger-Marshall, Richeimer, Daniels, & Baxter, 1989). A small decrease of mitogenesis induced by a low dose of ConA was observed in a group of depressed patients, whereas lymphoproliferation and IL-2 production induced by PHA remained unchanged, eventhough, there was no change in plasma levels of Cortisol, ACTH, growth hormone, and prolactin (Darko, Lucas, Gillin, Risch, Golshan, Hamburger, Silverman, & Janowsky, 1988). Finally, other studies showed normal mitogenesis induced by ConA, PHA, or PWM irrespective of the severity of the disease (Albrecht et al., 1985).
Classically, natural killer cell (NK) activity is found to be reduced in major depression (Irwin et al., 1987; 1990). Nerozzi, Santoni, Bersani, Magnani, Bressan, Pasini, Antonozzi, & Frajese (1989) found that the slightly reduced NK activity measured in depressed patients was not inversely correlated with plasma Cortisol. It has also been shown that NK activity was unchanged in male depressed patients but enhanced in depressed women. This increase was not correlated with Cortisol levels nor the severity of depression (Miller, Asnis, Lackner, Halbreich, & Norin (1991). As pointed out by Schleifer et al. (1989), such a variability of results could be related to age, severity of depression, and hospitalization.
In depressed patients, the percentage of neutrophils was increased and the percentage of lymphocytes was decreased, and these modifications were correlated with plasma levels of Cortisol (Kronfol & House, 1989). Furthermore, these authors observed a decrease of CD3 and CD4 positive cells. Another longitudinal study showed that the number of leukocytes, granulocytes, eosinophils, basophils, and thrombocytes was elevated over the 6 week-period study (Seidel, Arolt, Hunstiger, Rink, Behnisch, & Kirchner, 1996). Sub-classes of lymphocytes were similar to those of controls, but macrophage counts, high at the onset, slightly decreased with time. Schleifer, Keller, Bartlett, Eckholdt, & Delaney (1996) reported that in young adults with major depression, there was an increase in granulocytes, a decrease in NK cells, but no modification in the percentage of monocytes, and T, CD4+, CD8+, and B lymphocytes. In this study no correlation was found between immune alterations and the gravity of depression. In aged depressed women, the number of T lymphocytes and helper T cells was decreased compared to aged controls, whereas the percentage of B cells and suppressor T cells was unaffected (Targum, Marshall, Ficshman, & Martin, 1989). Interestingly, these alterations were more pronounced in DST resistant patients, and may be related to modifications in cell distribution induced by high level of circulating Cortisol. By contrast, no difference in lymphocyte subsets, including CD3+, CD4+, CD8+ was found.
whereas an increased CD4/CD8 ratio was observed in patients with endogenous depression. Interestingly, this ratio increase was correlated with the score of anxiety but not with the plasma level of Cortisol (Charles, Machowski, Brohee, Wilmotte, & Kennes, 1992). On the contrary, Darko et al. (1988) only found an increase of CD4+ cells in depressed patients, with no modification in the percentage of T, B, CD8+ cells, and NK cell activity. Finally, other authors, measuring the percentage of lymphocyte subsets in blood, concluded that depression is associated with an immune activation instead of a suppression (Maes, Lambrechts, Bosmans, Jacobs, Suy, Vandervorst, De Jonckheere, Minner, & Raus, 1992; Perini, Zara, Carraro, Tosin, Gava, Santucci, Valverde, & De Franchis, 1995). In fact, the signs of immune activation were reported to be more pronounced in patients with melancholic-type depression than in patients with other types of major depression or with minor depression.
More recently it has been proposed, in the light of the monocyte-T-lymphocyte hypothesis of major depression, that activation of the HPA axis and brain metabolic alterations may result from an hyperproduction of cytokines (for a review, see the chapter by Maes in this volume). Monocyte phagocytosis was enhanced during the acute phase of depression and returned to normal values with recovery. These changes in phagocytosis were not due to hypercortisolemia or to the direct effects of antidepressant drugs. Neutrophil phagocytosis was depressed during the acute phase of depression and returned to normal values with recovery (McAdams & Leonard, 1993). There are some data in favor of an increase of plasma levels of inflammatory cytokines in depressed patients. High levels of acute phase proteins (Maes, Bosmans, Meltzer, Scharpe, & Suy, 1993a) were observed, together with increased number of IL-2 receptor-bearing cells and levels of soluble IL-2 receptors (Maes et al., 1991). These studies also revealed, in patients with major depression, a positive correlation between mitogen-stimulated production of IL-lp by peripheral blood mononuclear cells and post-DST Cortisol values. Moreover, the Cortisol non-suppressor patients showed higher IL-ip production than the Cortisol suppressor ones. However, the correlation between IL-1 (3 production and post-DST Cortisol levels was also found in normal controls (Maes et al., 1993a). In a controlled longitudinal study, induced levels of several cytokines (IL-lp, IL-2, IL-10,and IFNy) were measured in whole blood of unmedicated depressed in-patients. On admission, the patients had higher levels of cytokines in the super-natants of mononuclear blood cells stimulated by PHA, but the levels decreased over a 6-week period (Seidel, Arolt, Hunstiger, Rink, Behnisch, & Kirchner, 1995). However, the differences were not very large and substantial interindividual differences were observed. IL-ip and IL-6 levels were higher than in controls, but not significantly, and decreased thereafter. Similarly, the non-significant increase of IL-2, IFNy, and IL-2R dissipated with time. Likewise, the level of IL-10 was lower at day 43 as compared to day 1. These results clearly show that the production of both proinflammatory and anti-inflammatory cytokines may be enhanced during the onset of a depressive episode (Seidel et al., 1995). Even though this enhanced IL-6 production was observed in DST-suppressor patients, there was a correlation between IL-6 production and plasma levels of post-DST Cortisol (Maes, Scharpe, Meltzer, Bosmans, Suy, Calabrese, & Cosyns, 1993b). Likewise, plasma levels of IL-6 were higher in the acute state of depression and similar to those of controls after remission (Frommberger, Bauer, Haselbauer, Fraiilin, Riemann, & Berger, 1997). By contrast, IL-lp, IL-2, and IL-3 were found to be lowered in major depression (Weizman, Laor, Podliszewski, Notti, Djaldetti, & Bessler, 1994). In another report, plasma levels of IFNy and in vitro production of TNF were studied in DST-responder patients with unipolar depression and long-lasting disease.
The values measured before or after a DST were similar to those observed in controls (Landmann, Schaub, Link, & Wacker, 1997). In accordance with the findings of increased production of cytokines during depression, plasma levels of acute phase proteins, including C reactive protein, haptoglobin, a2 macroglobulin, al-antitrypsine, and ceruloplasmin were higher in depression, and this increase was related to the disease severity (Maes et al., 1992; Seidel et al., 1995). In another study, some acute phase proteins like haptoglobin and ocl-antichimotrypsin were also found to be increased, whereas others like transferrin, al-antitrypsin, ceruloplasmin, C reactive protein or al-acid glycoprotein remained unchanged (Joyce, Hawes, Mulder, Sellman, Wilson, & Boswell, 1992). Plasma levels of haptoglobin were increased in major depression, associated or not with melancholia, but not in minor depression, whereas levels of transferrin were decreased in all types of depression. These variations were correlated with the production of IL-6 (Maes et al., 1993b). However, the increased plasma levels of IL-6 observed in acute depression was not correlated with age, severity of the disease, and concentrations of C reactive protein (Frommberger et al., 1997). The discrepancies observed in the enhanced production of cytokines during the acute phase of depression may result from the fact that this increase is not observed in all patients. An increase of plasma level of IL-6, associated with an increase of acute phase proteins and monocyte counts was observed only in 6 out of 22 patients. These increases were not correlated with the severity of the disease (Sluzewska, Rybakowski, Sobieska, Bosmans, Pollet, & Wiktorowicz, 1995b). The increase of plasma IL-6 associated with increase in plasma levels of a-l-acid glycoprotein and C reactive protein was observed in patients resistant but not in patients sensitive to antidepressant treatment. Furthermore, the increase of a-l-acid glycoprotein was higher in DST non-suppressor patients (Sluzewska et al., 1995b).
The increase of cytokines during depression may have an adaptive value as suggested by the data of Bauer, Hohagen, Gimmel, Bruns, Lis, Krieger, Ambach, Guthmann, Grunze, Fritsch-Montero, Weissbach, Ganter, Frommberger, Riemann, & Berger (1995). In patients with major depression, administration of endotoxin induced an increase of TNF and IL-6 plasma levels, as well as a higher expression of IL-l[i mRNA in LPS-stimulated mononuclear blood cells. Interestingly, these cytokine changes were associated with an increase in body temperature, a transient suppression of REM sleep, and an improvement of depression, even though this improvement was only transient and usually followed by a relapse. Moreover, a correlation was observed between maximal plasma concentrations of IL-6 reached after endotoxin adminstra-tion and the decrease of Hamilton scores.
From the results summarized above, it appears that no clear conclusion can be drawn on the immunological profile of depressed patients. As already pointed out, this reflects some methodological problems in the psychoimmunological research on depression. The investigation of the immune system in depression has been primarily embedded in the conceptual framework of the role of immune function in the maintenance of health and the development of physical disease. The functional measures of the immune system used in the studies of depressive disorders have been based on in vitro correlates of immune system activity. It has not been established, however, that mitogen-induced lymphocyte proliferation is related to in vivo immune responses as might be expected in response to infections or tumors. There is some evidence suggesting a relationship between NK activity and in vivo viral infections. However, no study has demonstrated concomitantly, i.e. in the same individuals, depression-related alterations in NK activity, mitogenic responses, cytokine production or any immune measures for that matter, and changes in health and illness, thereby limiting any causal inferences. Finally, the observations that depression is associated with an immune suppression or an immune stimulation appear to be contradictory. This results is due, in part, to a misuse of the terms of suppression and stimulation concerning the immune system as a whole. Indeed, any single immune measure cannot be used as a marker for immune responsiveness, since different immune parameters may change in opposite directions during an immune response. In depression, an enhanced production of cytokines appears to be associated with a decrease in mitogen-induced lymphoproliferation and NK cell activity. Studies with experimental animals favor this hypothesis. For example, an intraperitoneal injection of LPS induces both an increase of cytokine production in the periphery and in the brain (Layé, Parnet, Goujon, & Dantzer, 1994) and an inhibition of mitogen-induced lymphoproliferation (Delrue et al., 1994). Likely, IL-1 injected intracerebroventricularly decreases NK cell activity (Sundar, Cierpial, Kilts, Ritchie, & Weiss, 1990). These effects of cytokines appear to result from the activation of the HPA axis.
On the clinical side, the diagnosis of major depression possibly includes different pathophysiological subtypes of depressive illness that show different immune alterations, which may be epiphenomena or contribute to pathophysiological processes. It has been proposed that an immune suppression may occur in psychogenic types of depression and an immune activation in endogenous types (Muller, 1995). Furthermore, differences are mainly marked in studies of older patients and those hospitalized for more severe disorders, suggesting that age and/or severity of depression are independent determinants of impaired immunity, or that a higher-order central nervous system disturbance is a cause of both the endogenous subtype and immune dysfunctions (Hickie, 1990). Future studies concerned with psychological influences, such as depression, on immunocompetence should use more clinically relevant and specific immune measures and/or the actual disease end points (Stein et al., 1991).
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