Enoxolone in Major Depression - Biomarker-outcome Relationship

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Double-blind Randomized Placebo Controlled Study on the Effect of Enoxolone ( 11-beta Hydroxysteroid-dehydrogenase Type 2 Inhibitor) on the RAAS, Autonomic and Imaging Biomarkers and the Outcome of Depression

Conditions
-----------------
Unipolar Depression

Intervention / Treatment
-----------------
* Drug: Enoxolone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Unipolar Depression in women: Contraceptive means Exclusion Criteria: Schizophrenic and delusional disorders Neurological diseases in which central nervous system involvement is known, such as epilepsies, storage diseases; severe mental retardation Internistic diseases of moderate or higher severity, which may make participation in the study risky from a clinical point of view. In particular, multiple systolic blood pressure (measured after at least 5 min supine position) of > 145 mm Hg as well as hypokalemia (< 3.5 mmol/l) and clinically relevant ECG changes Poorly controlled diabetes mellitus (HbA1c > 10) Pregnancy or active desire for pregnancy for the duration of the study Non-consent or inability to consent to the study Treatment with the following substances: spironolactone or eplerenone; systemic glucocorticoids Treatment with ketamine or electroconvulsive therapy in the last 3 months before randomization Acute suicidality Intolerance to licorice preparations or licorice contents.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized parallel group design, first two subjects open label.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: enoxolone<br>100 mg enoxolone in a capsule | Drug: Enoxolone<br>* one capsule of active or placebo in the evening<br>* Other names: glycyrrhetinic acid;|
| Placebo Comparator: placebo<br>Placebo in a capsule | Drug: Enoxolone<br>* one capsule of active or placebo in the evening<br>* Other names: glycyrrhetinic acid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saliva aldosterone/cortisol ratio | Ratio of saliva aldosterone concentration/saliva cortisol concentration | week 2 (baseline as covariate) | 
| Urine aldosterone/cortisol ratio | Ratio of nocturnal urine aldosterone concentration/urine cortisol concentration | week 2 (baseline as covariate) | 
| Nocturnal heart rate variability | Average nocturnal heart rate variability, expressed as stress level (Garmin, arbitrary unit) | week 2 (baseline as covariate) | 
| Nocturnal blood pressure minimum | Minimum of continuously monitored systolic blood pressure (mmHg) | week 2 (baseline as covariate) | 
| Total sleep duration | Total sleep duration, as determined by wearable device (Garmin) (minutes) | week 2 (baseline as covariate) | 
| Salt taste preference | salt taste preference, as determined by tasting a 0.9% NaCl solution, 11 item Likert scale (Murck et al., 2018) | week 2 (baseline as covariate) | 
| Inflammation: C-reactive protein | Plasma C-reactive protein concentration (mg/L) | week 2 (baseline as covariate) | 
| Depression rating | Hamilton depression rating scale (HAMD) - 17 items; higher is worse | week 2 (baseline as covariate) | 
| Depression self rating | Patient health questionnaire for depression (PHQ-9), higher is worse | week 2 (baseline as covariate) | 
| Rating for symptoms of normal pressure hydrocephalus | Idiopathic normal pressure hydrocephalus grading scale (iNPHGS) (Kubo et al., 2008), higher is worse | week 2 (baseline as covariate) | 
| Cerebral ventricular volume | Volume of lateral ventricles (sum) (mL) | change from baseline to 4 weeks | 
| Corpus callosum volume | Volume of corpus callosum (mL) | change from baseline to 4 weeks | 
| Choroid Plexus Volume | Volume of Choroid Plexi (sum) (mL) | change from baseline to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saliva aldosterone/cortisol ratio | Ratio of saliva aldosterone concentration/saliva cortisol concentration | week 4 (baseline as covariate) | 
| Urine aldosterone/cortisol ratio | Ratio of nocturnal urine aldosterone concentration/urine cortisol concentration | week 4 (baseline as covariate) | 
| Nocturnal heart rate variability | Average nocturnal heart rate variability, expressed as stress level (Garmin, arbitrary unit) | week 4 (baseline as covariate) | 
| Nocturnal blood pressure minimum | Minimum of continuously monitored systolic blood pressure (mmHg) | week 4 (baseline as covariate) | 
| Total sleep duration | Total sleep duration, as determined by wearable device (Garmin) (minutes) | week 4 (baseline as covariate) | 
| Salt taste preference | salt taste preference, as determined by tasting a 0.9% NaCl solution, 11 item Likert scale (Murck et al., 2018) | week 4 (baseline as covariate) | 
| Inflammation: C-reactive protein | Plasma C-reactive protein concentration (mg/L) | week 4 (baseline as covariate) | 
| Depression rating | Hamilton depression rating scale (HAMD) - 17 items; higher is worse | week 4 (baseline as covariate) | 
| Depression self rating | Patient health questionnaire for depression (PHQ-9), higher is worse | week 4 (baseline as covariate) | 
| Rating for symptoms of normal pressure hydrocephalus | Idiopathic normal pressure hydrocephalus grading scale (iNPHGS) (Kubo et al., 2008), higher is worse | week 4 (baseline as covariate) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Atypical depression;