DISEÑO DEL MODELO

The hypothalamic-pituitary-adrenal axis controls the release o f cortisol, a steroid hormone that is crucial in the stress response, but also is involved in the homeostasis of many physiological systems. The pathway starts in the limbic system o f the brain, which stimulates the paraventricular nucleus in the hypothalamus to release corticotrophin- releasing hormone (CRH) into the hypophyseal portal system, which then stimulates the anterior pituitary gland to release adrenocorticotrophic hormone (ACTH) into the blood stream. This, in turn, stimulates cortisol release from the zona fasciculata of the adrenal cortex. Cortisol is a stress hormone. It promotes the breakdown o f fat and muscle to release glucose and inhibits glucose uptake into cells, opposing the action o f insulin. It increases appetite and leads to fat deposition in the trunk. In excess, it increases blood pressure. It suppresses the immune response and excess can lead to serious infections.

The metabolic syndrome (MS)) is a cluster o f adverse risk factors, comprising increased blood pressure; central obesity; high plasma triglyceride; low HDL cholesterol; and insulin resistance*^"*’ *^^. It is a recognised risk factor for CHD and the metabolic disturbances in the MS are implicated in atherogenesis, so that it is likely to be acting early in the pathogenesis of CHD.

Bjomtorp and others argue that HPA activation and an increase in cortisol production are central to the development of the Research to examine this has focused on the link between central obesity and exaggerated cortisol responses to either mental stressors or CRH stimulation'^^. This has been interpreted as evidence that stressors are involved in MS development via HPA activation. Other studies have found associations between central obesity, blood pressure and the sympathetic nervous system, indicating sympathetic influence on the MS, but have suggested that insulin resistance may lead to sympathetic activation rather be produced by it'^^’ Recent debate has concentrated on whether the association between the HPA axis and the MS reflects a defeat reaction rather than a defence reaction. The initial defence reaction to stress is to activate the pathways, but after prolonged stress the system becomes exhausted, resulting in a so-called defeat reaction, with an inadequate HPA response resulting in hypocortisolism and increases in inflammatory processes''^*’ This would be compatible with current ideas concerning and mirrors some of Chrousos’ models of HPA activation and suppression in relation to stress^"'.

An increase in cortisol levels in some depressed patients is one o f the most consistent findings in biological psychiatry and hence HPA activation has always been considered as a likely mediator between depressive illness/symptoms and CHD. Most of the available data focuses on depressive symptoms rather than anxiety.

Evidence linking depression to the HPA axis has been extensively reviewed ’ . The dexamethasone suppression test (DST) may be the closest available to a biological test for depression^""'. This test shows that the usual negative feedback o f ACTH-cortisol production in response to a glucocorticoid load (dexamethasone) is diminished in some cases o f depressive illness. Studies into neurotransmitters and CNS pathways are beyond the scope o f this thesis, but in summary HPA activation in depressive illness is thought to be in three parts: increase in central drive (via either CRH or arginine vasopressin); decreased negative feedback by glucocorticoids at the pituitary and hypothalamus; and adrenal hypertrophy^"^. The conventional view has been that monoaminergic disturbances, involving noradrenaline or serotonin in the CNS, resulting from depressive illness, lead to these changes in the HPA axis. More recently it has been argued that the causation may

changes in the CNS, including inflammatory cytokines, which then cause depressive illness'"*-

Much o f the research on depressive illness and HPA axis is unrelated to the hypothesis that the HPA axis mediates the association between distress and CHD. Several important points remain unresolved before this can be proven as a mechanism, including demonstrating HPA abnormalities in wider populations and linking such HPA activation to an accepted CHD risk factor. One postulated pathway to CHD requires that links from distress symptoms to HPA activation and then to features o f the MS be demonstrated.

Depressive svmptoms: HPA activation

Studies o f HPA activation, as assessed by the DST, in depression were initially restricted to a subgroup o f clinically depressed patients, often with what is described as the melancholic or endogenous form of the illness. Major depression has also been shown to be associated with the sequelae o f HPA activation, such as reduced bone density^^^’ and with increased adrenal gland size^®*. However, an increase in cortisol production has not been demonstrated in all patients with depressive illness, and certainly not across the range o f depressive symptoms that have been shown to predict CHD. Studies examining the HPA axis in broader populations have methodological problems due to the complexity o f the measures involved. Some investigators have assessed cortisol reactivity using salivary cortisol, since delayed recovery o f cortisol after stress may be a marker o f allostatic load^^®. Findings have been contradictory with persistent cortisol responses associated with a range o f psychological measures, including depressive symptoms^^^’^*^ and anxiety

Depression: MS

Evidence for associations between depressive symptoms and the components o f the MS is also contradictory. Depressive symptoms may be associated with central obesity^^^’ and have been linked to both high and low blood pressure, although the longitudinal studies give more support to an association between depressive symptoms and future hypertension^ ^

Research on the association between depressive symptoms and cholesterol has focused on the association between low cholesterol levels and depression, with regard to the possible

hazards o f cholesterol lowering therapy. The direction o f causation has been debated, but the association has been found consistently^’ Some work has indicated that there is a greater reduction in HDL than in LDL cholesterol associated with depression^’ which is consistent with the MS pathway mediating in the increased CHD risk.

Other psychological characteristics have been linked to the MS, including hostility and social class^^’ which suggests that it may be a potential mediator between stress and CHD.

Whole pathway

There has been little work to include depressive symptoms in the analysis o f associations between HPA activation and the MS. Katz et al found that the relationship between CRH response and central obesity in men was independent o f depressive symptoms^^^. Rosmond and Bjomtop identified a subgroup o f obese men in which a blunted dexamethasone response was linked to symptoms o f anxiety and depression^^^. In one small cross- sectional study in men, vital exhaustion was linked to both HPA activation and MS variables^^'’. More research examining the whole pathway is required, ideally with longitudinal assessment o f the development o f risk factors and future CHD events.

In summary, the pathway from psychological distress, including depressive symptoms, to HPA activation or suppression and then to features o f the MS has not been established. Other psychological variables may impact on this pathway and there is no support for a specific effect o f distress. Current studies have been mainly cross-sectional and small, due to the nature o f tests involved. Larger studies using HPA axis measures are impractical but large longitudinal studies examining the clustering o f MS variables and distress symptoms would make a contribution to the debate. Within the Whitehall II study, data were available, at Phase 3, on components o f the MS, including waist-hip ratio, body mass index, glucose tolerance tests, triglyceride and HDL cholesterol.