Depression an allostatic disorder with premature mortality

Human depression is a clear example of the allostatic link between chronic stress and reduced longevity. The importance of psychosocial stress for provocation of depressive episodes, for vulnerability to, and for risk of depression has been reviewed by Checkley (1996). Depression is an established outcome of stress, and the ongoing depressive episode itself constitutes a chronic stress. In large, prospective studies of adverse medical outcomes in depression, the customary psychiatric distinction between depressive symptoms and a depressive syndrome appears not to be important. Stress is a risk factor for both major depression (syndrome) and minor depression (symptoms). Minor depression is both a prodrome of major depression and an outcome of major depression; and major depression is a major outcome of minor depression.

The neuroendocrinology of human depression closely resembles that of chronic stress models in the laboratory (Checkley 1996, Lopez et al 1998). One sees increased central HPA activity, reduced feedback, and adrenocortical hypertrophy. Mean 24 h plasma cortisol concentrations are normal to slightly elevated, as are urinary free cortisol excretion, plasma and cerebrospinal fluid free cortisol concentrations, and salivary cortisol. Nocturnal plasma cortisol concentrations are significantly raised, whereas daytime plasma cortisol concentrations usually are not. Moreover, body temperatures, both nocturnal and diurnal, are significantly elevated in depression by 0.4-0.6 °C (Szuba et al 1997, Rausch et al 2000). These are classical allostatic changes.

Recent studies suggest a linear relationship between the number of depressive symptoms and premature mortality. Koenig et al (1999) found in a nine-year prospective study of 1001 male general medical inpatients that the adjusted mortality hazard increased 10% for each one-point increase in baseline depression score. In a prospective study of 7518 elderly community-resident women followed for six years, Whooley & Browner (1998) found 7% mortality in those with no depressive symptoms, 17% in those with three to five symptoms, and 24% in those with six or more depressive symptoms. The excess mortality was associated with both cardiovascular and non-cardiovascular deaths, but not with cancer. Depression is associated with many cardiovascular risk factors. These include hypertension, elevated plasma noradrenaline concentrations, decreased heart rate variability (an index of cardiac vagal tone), increased platelet reactivity, increased plasma fibrinogen, myocardial ischaemia and myocardial infarction. Non-cardiac morbidity associated with depression includes Type II diabetes mellitus, osteoporosis, increased risk of falls (a correlate of decreased muscle mass), increased intra-abdominal fat (a corticosteroid-related risk factor for cardiovascular disease), impaired wound healing and immune system suppression with increased incidence of influenza in the elderly (see Whooley & Browner 1998).

Several of these depression-associated pathologies can be related to abnormal GR occupancy (for example, osteoporosis, increased intra-abdominal fat, immune system impairment and impaired glucose tolerance). Others may reflect accelerated ageing through the interaction of allostatic nocturnal hyperthermia with general cellular degenerative mechanisms, as was discussed above in relation to chronic stress. Thus, this human disorder well illustrates the connections among ageing, stress and the brain. Human depression provides an excellent model for refining the concept of allostasis and for advancing our understanding of the long-term effects of stress on lifespan.

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