Enoxolone in Major Depression - Biomarker-outcome Relationship

Unipolar Depression Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05570110
• Other study ID #: MNS_02.1
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: September 23, 2022
• Est. completion date: March 2025

Study information

• Verified date: April 2024
• Source: Philipps University Marburg Medical Center
• Contact: Ulrich Schu, MD
• Phone: +49 6421 5865200
• Email: schu[@]uni-marburg.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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/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.

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). 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: March 2025
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Unipolar Depression

Intervention

Drug:
• Enoxolone
one capsule of active or placebo in the evening

Locations

Country	Name	City	State
Germany	Clinic for Psychiatry and Psychotherapy	Marburg	Hessen

Sponsors (2)

Lead Sponsor	Collaborator
Philipps University Marburg Medical Center	Slovak Academy of Sciences

Country where clinical trial is conducted

Germany, 

References & Publications (5)

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. — View Citation

Kubo Y, Kazui H, Yoshida T, Kito Y, Kimura N, Tokunaga H, Ogino A, Miyake H, Ishikawa M, Takeda M. Validation of grading scale for evaluating symptoms of idiopathic normal-pressure hydrocephalus. Dement Geriatr Cogn Disord. 2008;25(1):37-45. doi: 10.1159/000111149. Epub 2007 Nov 20. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Lateral cerebral ventricular volume	Volume of lateral ventricles (sum) (mL), measured by MRI with freesurfer program	change from baseline to 4 weeks
Other	Corpus callosum volume	Volume of corpus callosum (mL) segments, measured by MRI with freesurfer program	change from baseline to 4 weeks
Other	Choroid Plexus Volume	Volume of Choroid Plexi (sum) (mL), measured by MRI with freesurfer program	change from baseline to 4 weeks
Other	Saliva aldosterone/cortisol ratio	Ratio of saliva aldosterone concentration/saliva cortisol concentration	change from baseline to 4 weeks
Primary	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
Primary	Urine aldosterone/cortisol ratio	Ratio of nocturnal urine aldosterone concentration/urine cortisol concentration	Baseline, as predictor for differentiation of treatment groups clinical resposne
Primary	Depression rating	Hamilton depression rating scale (HAMD) - 17 items; higher is worse	change from baseline to week 4, with systolic blood pressure as covariate
Primary	Depression self rating	Patient health questionnaire for depression (PHQ-9), higher is worse	change from baseline to week 4, with systolic blood pressure as covariate
Secondary	Systolic blood pressure	Systolic blood pressure at rest	change from baseline to week 4
Secondary	Urine aldosterone/cortisol ratio	Ratio of nocturnal urine aldosterone concentration/urine cortisol concentration	change from baseline to week 4
Secondary	Plasma ratio of sodium/potassium	Ratio of the plasma concentration of sodium/ plasma concentration of potassium	change from baseline to week 4
Secondary	Nocturnal heart rate variability	Average nocturnal heart rate variability, expressed as stress level (Garmin, arbitrary unit)	change from baseline to week 4
Secondary	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
Secondary	Total sleep duration	Total sleep duration, as determined by wearable device (Garmin) (minutes)	change from baseline to week 4
Secondary	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
Secondary	Inflammation: C-reactive protein	Plasma C-reactive protein concentration (mg/L)	change from baseline to week 4
Secondary	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