The immune system, depression and the action of antidepressants

1. It is well established that the hypothalamic-pituitary-adrenal axis (HPA ) is activated by both external and internal stressors which result in the hypersecretion of adrenal glucocorticoids. In major depression the prolonge d elevation of the glucocorticoid concentration leads to a desensitisation of the central glucocorticoid receptors and probably those receptors locate d on macrophages. These changes may account for the observation that many a spects of cellular immunity are activated in depression (for example, the i ncreased release of pro-inflammatory cytokines from activated macrophages i n the periphery and brain, and the increased release of acute phase protein s from the liver) even though other aspects of immunity (for example, natur al killer cell activity and T-cell replication) are depressed. It is also k nown that some of the pro-inflammatory cytokines are potent activators of t he HPA axis. 2. Evidence is provided that the consequences of the hypersecretion of gluc ocorticoids and proinflammatory cytokines result in the malfunctioning of n oradrenergic and serotonergic neurotransmission in the brain, changes which are reflected in the major symptoms of depression.Support for this view is provided by observations of the effects of some of these cytokines in non- depressed individuals being treated with pro-inflammatory and related cytok ines for cancer. This has led to the hypothesis that depression is a form o f sickness behaviour which forms the basis of the macrophage theory of depr ession. 3. The review concludes with a discussion of the role of antidepressants in attenuating the adverse effects of glucocorticoids and pro-inflammatory cy tokines on central neurotransmission. Although the precise mechanisms where by antidepressants these changes is uncertain, there is evidence that they reduce the release of pro-inflammatory cytokines from activated macrophages and thereby facilitate the feedback inhibition of the HPA axis; this resul ts in a reduction in the release of glucocorticoids from the adrenal glands . In addition, many antidepressants have been shown to increase the release of endogenous cytokine antagonists such as interleukin -1 receptor antagon ist and interleukin-10. Evidence is also presented to show that different c lasses of antidepressants act as cyclooxygenase inhibitors which, by loweri ng the concentration of inflammatory prostaglandins in the brain, reduce th e detrimental impact of the inflammatory changes on neurotransmitter functi on. 4. An advantage of the macrophage hypothesis is that it extends the biogeni c amine hypothesis of depression to take account of changes in the endocrin e and immune systems which also play a crucial role in the aetiology of dep ression. In addition, the macrophage hypothesis may broaden the basis of un derstanding the mechanism of action of antidepressants.