Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] 34S reduced in the hippocampi of subjects who committed suicide. 41 Vice versa, the levels of expression of MR mRNA increased in the hippocampi of rats a fter chronic (8-weeks) treatment with antidepressant drugs. An increase was observed as early as two weeks. 42 Taken together, these data suggest that the MR is linked to depression. The role of aldosterone, which is its physiological ligand, has for a long time not been taken into account based on the belief that MRs within the brain are mostly occupied by corticosterone. However, when comparing the levels of nocturnal HPA and RAAS hormones in depressed patients versus healthy controls, a significant elevations of aldosterone over the eight-hour course of the night was observed, with no such differences in renin and ACTH. 43 There was also a non-significant trend (p<0.10) for elevations in cortisol among depressed patients over the same period. This observation was independently replicated 44 and refined: 45 It appears that MDD patients with hypertension had elevated levels of aldosterone compared to both non-depressed hypertensive subjects as well as normotensive depressed subjects, which may point to a specificity of the overlap of both conditions as a correlate of hyperaldosteronism. In light of the above observations, the question arises as to whether high aldosterone is a biomarker (as an epiphenomenon), or potentially causally involved in some forms of depression. Indirect evidence for a causal relationship comes from genetic studies: In a study of 273 patients with MDD, AT1- and ACE-polymorphisms predict outcome in antidepressant response. 46 In fact the genotypes, which are linked to a higher ACE and a higher AT1 activity and therefore a higher aldosterone level showed more therapy refractoriness. Unfortunately aldosterone itself was not determined in this study. Animal data support the role of aldosterone: subchronic administration of aldosterone with a minipump over a period of 3 weeks leads to depression- and anxiety like behavior, 47 which is accompanied with changed in hippocampal gene expression related to inflammation and glutamatergic transmission. All of these pathways have been recognized f or their link to therapy refractory depression. The physiologic consequences of aldosterone excess have been reviewed by Gomez-Sanchez. 48 Central effects include increased salt appetite, increased vasopressin release, decreased baroreceptor sensitivity, increased sympathetic drive and increases in the concentrations of pro- inflammatory cytokines. In the kidney one sees an increase in sodium and water reabsorption. Effects on the cardiovascular system include increased vascular tone and increased inflammation, which may similarly result in hypertrophy, necrosis and fibrosis. With this in mind aldosterone is a good candidate to explain the overlap between the risk of depression and that of cardiovascular disease. In the current context it is important to state that there are known biomarkers for peripheral and central MR activity, based on the observation of their physiological effect: the MR agonist 11- deoxycorticosterone (DOC), a precursor of aldosterone, suppresses nocturnal cortisol secretion in healthy volunteers. 49 This is well in line with the known activity of the MR to suppress the HPA axis. Therefore the ratio of aldosterone and cortisol emerged as a reasonable marker for peripheral MR activity (this action is probably mediated at the level of the pituitary). Further, MR-antagonism with the CNS active compound canrenoate reduces slow wave sleep (SWS) in healthy controls 50 pointing to an increased SWS as a marker of high central MR activity. Further central markers for MR activity are heart rate variability and salt-liking, whereas blood pressure and electrolyte levels are additional peripheral markers. These markers were utilized in an observational study in patients with depression. 51 Measures were taken at Baseline, 2 weeks and 6 weeks. Parameters evaluated included 1) HAMD-6, HAMD-21, Quick Inventory of Depressive Symptomatology-self rated (QIDS-SR), and Beck's Depression Inventory (BDI); 2) salivary aldosterone and salivary c ortisol; 3) slow wave sleep; 4) heart rate, heart rate variability, and blood pressure; and 5) salt taste test. Aldosterone and cortisol were determined by means of saliva collection after awakening. In the pooled total dataset, which include data from all visits, salivary aldosterone correlated with depression severity as measured by HAMD-21. Furthermore, the aldosterone/cortisol ratio at baseline was found to predict the improvement in depression during the treatment period. Furthermore, cortisol reduction at Week 2 was found to be predictive for depression severity at outcome. Some of the findings were limited to male gender: improvement in HAMD-21 score at the final visit was inversely correlated with heart rate variability at baseline. Clinical improvement also correlated inversely with slow wave sleep at baseline as well as with plasma Na + concentrations at baseline. The data are in line with a peripheral MR resistance in therapy refractory patients, which was recently confirmed by a neuroendocrine challenge. 5 2 The peripheral MR desensitization appears to correlate with a reactive peripheral aldosterone increase and as a consequence a central MR overactivity. This mechanism suggests that some patients may benefit from treatment with centrally active MR antagonists and potentially peripheral agonists. 39 Preliminary data indeed suggest that MR antagonists have beneficial effects on affective symptoms. In a crossover- design study, 53 spironolactone decreased irritability, depression, food craving, and pain in patients with premenstrual syndrome. Additionally, drospirenone, a MR antagonist, is approved for the treatment of premenstrual dysphoric syndrome and has been shown to decrease depressive mood 54 in the population with this disease. From the data discussed above, one may conclude that several inexpensive and easy to handle markers exist for

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