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

Abstract

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.

Target-based biomarker selection – Mineralocorticoid receptor-related biomarkers and treatment outcome in major depression

“…An interesting aspect is that the sensitivity of the MR appears to be a trait rather than a state marker, as acutely depressed and recovered patients are not different (Juruena et al, 2010), which is also reflected in a reduced hippocampal MR expression in depressed patients post mortem independent of depressive state at time of death (Klok et al, 2011). These findings are in line with the suggestion that reduced peripheral MR sensitivity may lead to a counter-regulatory increase in aldosterone (Murck et al, , 2014, which affects brain function in a deleterious way. The action of aldosterone in influencing central MR-function is complex.…”

“…More recently a closer characterization identified the nucleus of the solitary tract (NTS), the amygdala and the paraventricular nucleus (PVN) of the hypothalamus as relevant targets (Geerling et al, 2006;Geerling and Loewy, 2009). Directly and through their connections these areas are involved in neuroendocrine regulation, salt appetite, sleep and, blood pressure regulation ( (Murck et al, 2014) for review). From a syndromal perspective these regions are involved in anxiety and depression as well as emotions, and body perception.…”

Does mineralocorticoid receptor play a vital role in the development of depressive disorder?

“…A lot of studies have confirmed that the MR controls the neuroendocrine activation of the HPA axis not only in basal condition but also under stress context (Berardelli et al, 2013;Murck et al, 2014). In animal studies, transgenic mice lacking the MR in the forebrain displayed an altered basal and stress-induced corticosterone secretion, with especially enhanced corticosterone levels in response to restraint stress.…”

On the Pleotropic Actions of Mineralocorticoids

“…Mineralocorticoids further enhance salt appetite [2,4 ]and thus foster salt intake, as amplified in separate reviews of this special issue [20,21]. Enhanced salt intake and renal salt retention lead to extracellular volume expansion with increase of blood pressure [7,8,22].…”

“…Mineralocorticoids affect neuronal function and survival [3,64,65,66,67] as amplified in a separate review of this special issue [21]. …”