In view of all the results presented in this review, it is clear that further research is required to fully elucidate the effect of antidepressant drugs on monocyte function and to specify the role of cytokines in the onset of depression. This line of research would help to extend our understanding of the pathogenesis of depression and may allow the development of new antidepressant drugs. However, different hypotheses can be already suggested with respect to the possible mechanisms underlying the immune effects of antidepressants.
Antidepressants may modify immune reactivity by acting on the neural substrate which is involved in neuroimmunomodulation. Lymphocytes and macrophages are innervated by the sympathetic and parasympathetic nervous systems and this innervation modulates immune reactivity. Furthermore, immune cells are known to have receptors for neurotransmitters and antidepressants may modify the activity of immune cells by acting at the level of these receptors.
Antidepressants may also have direct effects on immune cells. The antidepressant rolipram, a selective type IV phosphodiesterase inhibitor, suppresses the production of TNF and to a lesser extent that of IFNy in human and rat MBP (myelin-basic protein)-specific T cell lines. This suppression may be related to an increase of intacellular cyclic adenosyl monophosphate (Sommer, Loschmann, Northoff, Weller, Steinbrecher, Steinbach, Lichtenfels, Meyerman, Riethmiiller Fontana, Dichgans, & Martin, 1995). Binding sites for imipramine and desmethylimipramine have been documented on lymphocyte membranes as well as on thrombocytes and brain tissues (Audus & Gordon, 1982). Binding of antidepressants was not modified in the presence of 5-HT and NA suggesting that these binding sites are not related to neurotransmitter receptor sites. Bmax of tricyclic receptors was enhanced in depressed patients but Kd values remained normal (Krulik, Sliva, Sikora, Farska, & Fuksova, 1988). The functional significance of these receptors remains unknown. In fact, tricyclics have been shown to depress NK activity (Xiao & Eneroth, 1995), IL-6, IL-ip, and TNFa release in human blood monocytes, and IL-2 and IFNy in T lymphocytes (Xia et al., 1996). However, these effects were observed when using high doses of tricyclics and are not mediated by the specific high affinity binding sites. These immune alterations of immune reactivity may rather result from alterations in lipid or hydrophobic domains of lymphocyte membranes (Audus & Gordon, 1984). Maximal p-2 adrenoreceptor binding (Bmax) on blood mononuclear cells was reduced in unipolar depression but not in bipolar or dysthymic patients. There was a strong inverse correlation between Bmax values and severity of depression in bipolar but also in the whole population of depressed patients (Jeanningros, Mazzola, Azorin, Samuelian-Massa, & Tissot, 1991).
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