If cytokines cause depression then their antagonists acting in the brain should have antidepressant activity. Besides the previously mentioned studies on the ability of IL-1 antagonists to block learned helplessness in certain conditions (see point 1), this possibility has received little attention so far. There is obviously room for investigating the effects of cytokine antagonists in animal models of depression and anxiety, especially since these antagonists have little or no effect on their own, besides their capacity to interfere with the production and action of proinflammatory cytokines. In such a quest, cytokine antagonists with a relatively wide spectrum of action, such as IL-10 and IL-4 which inhibit the synthesis of several proinflammatory cytokines by activated monocytes, are better suited than more specific cytokine antagonists, such as IL-lra, which interferes only with the ability of IL-la and IL-lp to bind to their receptors.
At the clinical level, clinical trials on the possible effects of centrally acting anti-inflammatory compounds on depression should be undertaken, as the results of these trials are likely to play an important role in shaping the future of the field. In the meantime, it is important to note that in a pilot study designed to objectively evaluate the effects of a single dose of endotoxin on depression, administration of a low dose of LPS significantly improved mood in seven drug-free severely depressed patients on the next day following the treatment, at a time when the expression of anti-inflammatory cytokines should be expected to be maximal (Bauer, Hohagen, Gimmel, Bruns, Lis, Krieger, Ambach, Guthmann, Grunze, & Fritsch-Montero, 1995). However, these changes in mood were transient and dissipated during the next days.
These observations support the notion that depression is far too complex a disorder to be corrected by a "golden bullet" (i.e., a drug targeting a single molecule).
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