Enoxolone in Major Depression - Biomarker-outcome Relationship

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

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/cortisol in body fluids, blood pressure and inflammation markers , have been identified as predictors of therapy resistance in depression. Enoxolone is a molecule derived from the licorice plant and has demonstrated an effect on these biomarkers, which may imply an improved response. The current randomized placebo controlled study is assessing whether the presence of markers of therapy resistance can predict a preferential effect of enoxolone vs. placebo on clinical outcome. Secondarily, it is tested whether these markers change differentially in the treatment groups. Finally, the relationship between the change of the markers and clinical change will be assessed.

Study Overview

• Status: Recruiting
• Conditions: Unipolar Depression
• Intervention / Treatment: Drug: Enoxolone

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) and toll-like receptor (TLR)-4 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). The resultant aldosterone release evokes activity at the NTS, which may lead to depression and anxiety.

Enoxolone leads to an activation primarily 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.

1. A set of potentially predictive markers for therapy response of enoxolone vs. placebo will be studied, based on this mechanistic pathway, in detail:

   For the primary analysis subjects are grouped into those with higher vs. lower systolic blood pressure values, as determined by the median systolic blood pressure value at baseline.

   For the secondary analysis the ratio of urine aldosterone/cortisol, as collected over night will be used as a differentiating parameter. Split at the median defines the groups.

   Exploratory parameters for a split are the following:

   1. sleep duration
   2. heart rate variability
   3. salt taste sensitivity and salt preference
   4. inflammation markers, in particular C-reactive protein in plasma.
   5. Optional: volumes of lateral ventricles, corpus callosum and choroid plexi.
   6. Optional: white matter integrity, as measured by diffusion tensor imaging

2. Markers of target engagement:

   1. Effect of enoxolone vs. placebo on systolic blood pressure.
   2. Effect of enoxolone vs. placebo on urine aldosterone/cortisol concentration.
   3. Effect of enoxolone vs. placebo on plasma sodium/potassium concentration ratio.
   4. Effect of enoxolone on C-reactive protein and other inflammation markers.

3. The relationship between changes in hormone concentrations and markers of CNS activation of MR, i.e. functional CNS target engagement. These are:

   1. Heart rate variability and heart rate
   2. Systolic blood pressure at rest and nocturnal blood pressure dip
   3. Total sleep time
   4. Salt taste preference and sensitivity
   5. Inflammatory markers
   6. Optional: volumes of lateral ventricles, corpus callosum and choroid plexi.
   7. Optional: white matter integrity, as measured by diffusion tensor imaging

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Ulrich Schu, MD; Phone Number: +49 6421 5865200; Email: schu@uni-marburg.de

Study Locations

• Germany
  • Hesse
    • Marburg, Hesse, Germany, 35039
      • Recruiting
      • Clinic for Psychiatry and Psychotherapy
      • Contact: Ulrich Schu, MD; Phone Number: +49 6421 5865200; Email: schu@uni-marburg.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: enoxolone; 100 mg enoxolone in a capsule	Drug: Enoxolone; one capsule of active or placebo in the evening; Other Names: glycyrrhetinic acid
Placebo Comparator: placebo; Placebo in a capsule	Drug: Enoxolone; one capsule of active or placebo in the evening; Other Names: glycyrrhetinic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic blood pressure	Systolic blood pressure at rest at baseline as a predictor for treatment differentiation	Baseline, as predictor for differentiation of treatment groups clinical response
Depression rating	Hamilton depression rating scale (HAMD) - 17 items; higher is worse	change from baseline to week 4, with systolic blood pressure as covariate
Plasma and urine aldosterone/cortisol ratio	ratio of plasma aldosterone/cortisol at awakening; ratio of nocturnal urine aldosterone concentration/urine cortisol concentration	Baseline, as predictor for differentiation of treatment groups clinical response
C-reactive protein	C-reactive protein in plasma	Baseline, as predictor for differentiation of treatment groups clinical response and change from baseline (4 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine aldosterone/cortisol ratio	Ratio of nocturnal urine aldosterone concentration/urine cortisol concentration	change from baseline to week 4
Plasma ratio of sodium/potassium	Ratio of the plasma concentration of sodium/ plasma concentration of potassium	change from baseline to week 4
Nocturnal heart rate variability	Average nocturnal heart rate variability, expressed as stress level (Garmin, arbitrary unit)	change from baseline to week 4
Nocturnal blood pressure dip (difference between pre-sleep and minimal nocturnal blood pressure	Minimum of continuously monitored systolic blood pressure (mmHg)	change from baseline to week 4
Total sleep duration	Total sleep duration, as determined by wearable device (Garmin) (minutes)	change from baseline to week 4
Salt taste preference and sensitivity	salt taste preference, as determined by tasting a 0.9% NaCl solution, 11 item Likert scale (Murck et al., 2018)	change from baseline to week 4
Rating for symptoms of normal pressure hydrocephalus	Idiopathic normal pressure hydrocephalus grading scale (iNPHGS) (Kubo et al., 2008), higher is worse	change from baseline to week 4
Depression self rating	Patient health questionnaire-9 (PHQ-9), higher is worse	change from baseline to week 4

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lateral cerebral ventricular volume	Volume of lateral ventricles (sum) (mL), measured by MRI with freesurfer program	change from baseline to 4 weeks
Corpus callosum volume	Volume of corpus callosum (mL) segments, measured by MRI with freesurfer program	change from baseline to 4 weeks
Choroid Plexus Volume	Volume of Choroid Plexi (sum) (mL), measured by MRI with freesurfer program	change from baseline to 4 weeks
Saliva cortisol ratio	Ratio of saliva cortisol concentration	change from baseline to 4 weeks

Collaborators and Investigators

• Sponsor: Philipps University Marburg
• Collaborators: Slovak Academy of Sciences
• Investigators: Study Director: Harald Murck, MD PhD, Philipps University Marburg

Publications and helpful links

General Publications

• Murck H, Luerweg B, Hahn J, Braunisch M, Jezova D, Zavorotnyy M, Konrad C, Jansen A, Kircher T. Ventricular volume, white matter alterations and outcome of major depression and their relationship to endocrine parameters - A pilot study. World J Biol Psychiatry. 2021 Feb;22(2):104-118. doi: 10.1080/15622975.2020.1757754. Epub 2020 May 15.
• Murck H, Lehr L, Hahn J, Braunisch MC, Jezova D, Zavorotnyy M. Adjunct Therapy With Glycyrrhiza Glabra Rapidly Improves Outcome in Depression-A Pilot Study to Support 11-Beta-Hydroxysteroid Dehydrogenase Type 2 Inhibition as a New Target. Front Psychiatry. 2020 Dec 10;11:605949. doi: 10.3389/fpsyt.2020.605949. eCollection 2020.
• Engelmann J, Murck H, Wagner S, Zillich L, Streit F, Herzog DP, Braus DF, Tadic A, Lieb K, Muller MB. Routinely accessible parameters of mineralocorticoid receptor function, depression subtypes and response prediction: a post-hoc analysis from the early medication change trial in major depressive disorder. World J Biol Psychiatry. 2022 Oct;23(8):631-642. doi: 10.1080/15622975.2021.2020334. Epub 2022 Jan 25.
• Murck H, Braunisch MC, Konrad C, Jezova D, Kircher T. Markers of mineralocorticoid receptor function: changes over time and relationship to response in patients with major depression. Int Clin Psychopharmacol. 2019 Jan;34(1):18-26. doi: 10.1097/YIC.0000000000000239.
• Murck H. Discovery of Personalized Treatment for Immuno-Metabolic Depression-Focus on 11beta Hydroxysteroid Dehydrogenase Type 2 (11betaHSD2) and Toll-like Receptor 4 (TLR4) Inhibition with Enoxolone. Pharmaceuticals (Basel). 2025 Oct 10;18(10):1517. doi: 10.3390/ph18101517.

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2022
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: September 28, 2022
• First Submitted That Met QC Criteria: October 3, 2022
• First Posted (Actual): October 6, 2022

Study Record Updates

• Last Update Posted (Actual): December 8, 2025
• Last Update Submitted That Met QC Criteria: December 1, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Atypical depression
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Organic Chemicals; Hydrocarbons; Terpenes; Pentacyclic Triterpenes; Triterpenes; Glycyrrhetinic Acid
• Other Study ID Numbers: MNS_02.1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Plan to share study data in concordance with local regulations
• IPD Sharing Time Frame: available after study completion
• IPD Sharing Access Criteria: CDA or other agreements
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No