Genetic, Molecular and Clinical Determinants for the Involvement of Aldosterone and Its Receptors in Major Depression

Major depression (MDE) has metabolic and neuroendocrine correlates, which point to a biological overlap between MDE and cardiovascular diseases. Whereas the hypothalamic-pituitary-adrenocortical axis has long been recognized for its involvement in depression, the focus was mostly on cortisol/corticosterone, whereas aldosterone appears to be the ‘forgotten' stress hormone. Part of the reason for this is that the receptors for aldosterone, the mineralocorticoid receptors (MR), were thought to be occupied by glucocorticoids in most parts of the brain. However, recently it turned out that aldosterone acts selectively in relevant mood-regulating brain areas, without competing with cortisol/corticosterone. These areas include the nucleus of the solitary tract (NTS), the amygdala and the paraventricular nucleus of the hypothalamus. These regions are intimately involved in the close relationship between emotional and vegetative symptoms. Genetic analysis supports the role of aldosterone and of MR-related pathways in the pathophysiology of depression. Functional markers for these pathways in animal models as well as in humans are available and allow an indirect assessment of NTS function. They include heart rate variability, baroreceptor reflex sensitivity, blood pressure, salt taste sensitivity and slow-wave sleep. MR activation in the periphery is related to electrolyte regulation. MR overactivity is a risk factor for diabetes mellitus and a trigger of inflammatory processes. These markers can be used not only to assist the development of new treatment compounds, but also for a personalized approach to treat patients with depression and related disorders by individual dose titration with an active medication, which targets this system.