Chronic stress causes maladaptative changes in the neurotransmitter, immune and endocrine systems which, as a result, play a major role in causing physical ill-health and depression.

In recent years, there has been a paradigm shift in our understanding of the inter-relationship between the hypothalamic-pituitary-adrenal axis (hpa-axis) and the immune axes. Thus activation, rather than suppression, of important aspects of the immune system occur following chronic stress and depression. A primary cause of this is ascribed to the glucocorticoid-induced apoptosis of hippocampal neurons together with a desensitisation of cortical and peripheral glucocorticoid receptors. This chronic, low grade inflammation results in the further activation of the hypothalamic-pituitary-adrenal axis (primarily through the activity of interleukin-6) and the subsequent rise in cortisol. The combination of the increase in inflammatory mediators (pro-inflammatory cytokines and prostaglandin E2) and cortisol (that causes insulin resistance and deposition of fat in the coronary circulation etc) is now considered to be central to the pathogenesis of depression and top diabetes, cancer, asthma, arthritis and cardiovascular disease that are often co-morbid with depression.

Evidence in support of the macrophage hypothesis postulating that the symptoms of depression arise from a stress/genetically programmed activation of peripheral and central macrophages, is provided by the elevation of pro-inflammatory cytokines in the plasma and to some extent in the cerebrospinal fluid (csf). Acute phase proteins are also elevated in the plasma of untreated depressed patients. In short, in depression there is an imbalance between the pro-inflammatory and anti-inflammatory arm of the immune system. Effective antidepressant treatment largely restores the balance within the immune system.

Thus in chronic depression the inflammatory changes, coupled with hypercortisolaemia that blocks the synthesis of neurotrophic factors that normally repair damaged dendrites, a situation arises whereby the neurodegenerative pathways predominate over the neuroprotective pathways. As there is increasing clinical and epidemiological evidence linking chronic depression with the likelihood of dementia, there is increasing evidence how this may occur. Indeed, all of the changes that occur in depression are even more prominent in dementia.

Thus depression and dementia are part of a continuum in which chronic stress is a common factor.