The objective of the study is 1. to confirm patient characteristics, which are related to lesser responsivity to antidepressant treatment and 2. to explore the utility of the 11 beta hydroxysteroid-dehydrogenase type 2 (11betaHSD2) inhibitor enoxolone to reverse these markers of refractoriness and, potentially, improve clinical outcome. A broad spectrum of patients is recruited in order to provide the opportunity to compare those with relevant markers of refractoriness vs. those without.~The identified markers are related to the activity of aldosterone, which appears to affect specific CNS areas, which are involved in mood and autonomic regulation. One area of particular relevance is the pontine nucleus of the solitary tract (NTS). Potential primary triggers for an increased aldosterone release under stressful conditions are related to low blood pressure, electrolyte alterations and a dysfunction of the peripheral mineralocorticoid receptor (MR).~Enoxolone leads to an activation of the peripheral MR by reducing the activity of the 11betaHSD2, therefore allowing cortisol access to the MR and, as a consequence, suppress the release of renin, angiotensin and aldosterone. In addition, it can increase blood pressure slightly.~A set of markers is studied, which follow this mechanistic pathway, in detail:~The effects of enoxolone on salivary and plasma hormones, to establish molecular target engagement, in particular a reduction of aldosterone concentration.~The relationship between changes in hormone concentrations and markers of CNS activation of MR, i.e. functional target engagement. These are:~Heart rate variability and heart rate~Nocturnal blood pressure~Total sleep- and slow wave sleep duration~Salt taste sensitivity and -preference~Inflammatory markers~Optional: volumes of lateral ventricles, corpus callosum and choroid plexi.~Optional: white matter integrity, as measured by diffusion tensor imaging~The correlation between the baseline levels of these markers of molecular and functional target engagement and clinical outcome are studied, as determined by the relative change of the Hamilton-Depression Rating Scale (HAMD-17) and other scales.~Exploration will be performed whether markers, which define an increased activity of brain MR activation at baseline, characterize a group of subjects with preferential differentiation between enoxolone vs. placebo treatment. This allows to further establish the subgroup of subjects, who may benefit from the administration of enoxolone best.
Many different forms of depression exist. It is difficult to predict to what treatment a given patient with depression responds. Studies demonstrate that biomarkers can help to distinguish different forms of depression. Simple markers, like aldosterone from the saliva, blood pressure and inflammation markers from the blood, have been identified as predictors of a more difficult to treat depression. Enoxolone is a molecule derived from the licorice plant and has demonstrated an effect on these biomarkers, which may indicate a better response. In a randomized placebo controlled trial this study is assessing whether the administration of enoxolone vs. placebo can change these markers and if patients benefit from these biomarker changes clinically. In addition, this study records the volume and structure of certain brain areas, which could be involved in this action.