The effects of antidepressants on endocrine-immune functions
Stress is frequently a trigger factor for depression in vulnerable patients. There is clinical evidence to show that CRF is elevated in the cerebrospinal fluid of untreated depressed patients, which presumably leads to the hypercortisolaemia that usually accompanies the condition. One of the consequences of elevated plasma glucocorticoids is a suppression of some aspects of cellular immunity. It is now established that many cellular (for example, natural killer cell activity, T-cell replication) and non-cellular (for example, raised acute phase proteins) aspects are abnormal in the untreated depressed patient. Such observations could help to explain the susceptibility of depressed patients to physical ill health. A link between CRF, the cytokines which orchestrate many aspects of cellular immunity, and the prostaglandins of the E series has been the subject of considerable research in recent years. There is clinical evidence to show that prostaglandin E2 (PGE2) concentrations are raised in the plasma of untreated depressed patients and are normalized following effective treatment with tricyclic antidepressants. Raised PGE2 concentrations in the brain and periphery reflect increased proinflammatory cytokines (particularly tumour necrosis factor, interleukins 1 and 6) which occur as a consequence of increased macrophage activity in the blood and brain. In the brain the microglia functions as macrophages and produces such cytokines locally. Thus the increased synthesis of PGE2 may contribute to the reduction in amine release in the brain that appears to underlie the pathology of depression. It has recently been postulated that several types of antidepressants (e.g. tricyclics, monoamine oxidase inhibitors) normalize central neurotransmission by reducing brain concentrations of both the cytokines and PGE2 by inhibiting central and peripheral macrophage activity together with cyclooxygenase type 2 activity in the brain. Cyclooxygenase is the key enzyme in the synthesis of the prostaglandins. It is not without interest that the usefulness of tricyclic antidepressants in severe rheumatoid arthritis can now be explained by the inhibitory action of such drugs on cyclooxygenase activity in both the periphery and brain. Such changes, together with those in glucocorticoid receptor function, may therefore incrementally bring about the normalization of defective central neurotransmission as a consequence of antidepressant treatment. Whether the inhibition of cyclooxygenase is a common feature of all classes of antidepressants is presently unknown.
The possible role of prostaglandins and cytokines in depression
1. There is evidence that both cellular and non-cellular immunity are abnormal in the depressed patient.
2. The proinflammatory cytokines (interleukins 1 and 6 and tumour necrosis factor alpha) from macrophages are raised in depression. This leads to increased PGE2 synthesis and release which may lead to a reduction in central monoamine release.
3. Chronic antidepressant treatments reduce both the proinflammatory cytokines and PGE2.
Stress is frequently a trigger factor for depression in vulnerable patients. There is clinical evidence to show that CRF is elevated in the cerebrospinal fluid of untreated depressed patients, which presumably leads to the hypercortisolaemia that usually accompanies the condition. One of the consequences of elevated plasma glucocorticoids is a suppression of some aspects of cellular immunity. It is now established that many cellular (for example, natural killer cell activity, T-cell replication) and non-cellular (for example, raised acute phase proteins) aspects are abnormal in the untreated depressed patient. Such observations could help to explain the susceptibility of depressed patients to physical ill health. A link between CRF, the cytokines which orchestrate many aspects of cellular immunity, and the prostaglandins of the E series has been the subject of considerable research in recent years. There is clinical evidence to show that prostaglandin E2 (PGE2) concentrations are raised in the plasma of untreated depressed patients and are normalized following effective treatment with tricyclic antidepressants. Raised PGE2 concentrations in the brain and periphery reflect increased proinflammatory cytokines (particularly tumour necrosis factor, interleukins 1 and 6) which occur as a consequence of increased macrophage activity in the blood and brain. In the brain the microglia functions as macrophages and produces such cytokines locally. Thus the increased synthesis of PGE2 may contribute to the reduction in amine release in the brain that appears to underlie the pathology of depression. It has recently been postulated that several types of antidepressants (e.g. tricyclics, monoamine oxidase inhibitors) normalize central neurotransmission by reducing brain concentrations of both the cytokines and PGE2 by inhibiting central and peripheral macrophage activity together with cyclooxygenase type 2 activity in the brain. Cyclooxygenase is the key enzyme in the synthesis of the prostaglandins. It is not without interest that the usefulness of tricyclic antidepressants in severe rheumatoid arthritis can now be explained by the inhibitory action of such drugs on cyclooxygenase activity in both the periphery and brain. Such changes, together with those in glucocorticoid receptor function, may therefore incrementally bring about the normalization of defective central neurotransmission as a consequence of antidepressant treatment. Whether the inhibition of cyclooxygenase is a common feature of all classes of antidepressants is presently unknown.
The possible role of prostaglandins and cytokines in depression
1. There is evidence that both cellular and non-cellular immunity are abnormal in the depressed patient.
2. The proinflammatory cytokines (interleukins 1 and 6 and tumour necrosis factor alpha) from macrophages are raised in depression. This leads to increased PGE2 synthesis and release which may lead to a reduction in central monoamine release.
3. Chronic antidepressant treatments reduce both the proinflammatory cytokines and PGE2.
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