I had persuaded myself that depression was related to abnormal sadness, hence my book, Malignant Sadness. But I now realise that I might have missed a very important aspect of depression, its relationship to the immune system. Friends did try to persuade me to take it seriously, but to no avail. Then I read an article in a leading medical journal that described the treatment of hepatitis with alpha interferon. I was struck by the fact that they gave such patients an antidepressant at the same time, for otherwise there was a high incidence of depression. I contacted the authors in the USA and they told me that their patients' depression was not related to sadness, but more to fatigue. They also sent me a review which has persuaded me how important the immune system may be in depression.
That there is a relationship between physical and psychological health goes back to the ancient Greeks, but it is only quite recently that it has been recognised that the immune system can have profound effects on thinking and emotion. One link is via stress. The stress response is adaptive in many situations, such as danger, and helps the individual to deal with the threat. The physiological response involves both hormones and the nervous system, and makes more energy available. However, this becomes a danger to health when it remains chronically overactive, and this condition is frequently found in patients with severe depression.
Stress and depression can affect the immune system, which is complex, with many interactions between cells such as lymphocytes and macrophages, those white cells that are at the core of the immune system, and numerous cytokines, the chemical signals between these and other cells. Chronic stress can affect the function of lymphocytes and cytokine production, and a longer time is needed to recover from an infectious disease. Surprisingly, the same stressors can also activate the immune system.
There is now evidence that depression can both activate and suppress immune-system function. With immune-system activation, there can be induction of a state that is called sickness behaviour, which resembles depression. It is this that underlies the depression caused by giving interferon, which is itself a cytokine controlling aspects of the immune system. The similarity of depression with sickness behaviour predicts that those with illnesses should have higher rates of depression. This is the case.
Increased cytokine levels after birth could account for postnatal depression. How the cytokines act on the brain to cause depression is not clear, but they can enter the brain. Stress hormones such as cortisol are very likely key players, as depression in many is associated with an increase in the activity of the interactions between the hypothalamus, pituitary and adrenal glands, which are activated by stress. Increase in cytokines can stimulate this system, and the normal negative feedback that returns it after a short while to normal function may be prevented from operating.
There is a further fascinating connection with the placebo effect. In his new book, Placebo, Dylan Evans argues that the acute phase response is involved. This response is a result of some injury and the immune system is activated, moreover only those illnesses that involve this response are capable of being relieved by the placebo effect, and they include depression. The complexity of all these interacting factors is disturbing, but will eventually lead to new drugs for depression, perhaps acting on the immune system.
Lewis Wolpert is Professor of Biology as Applied to Medicine at UCL
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