Enoxolone in Major Depression – Biomarker-outcome Relationship

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Diagnostic
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: March 2025

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: 1. The effects of enoxolone on salivary and plasma hormones, to establish molecular target engagement, in particular a reduction of aldosterone concentration. 2. The relationship between changes in hormone concentrations and markers of CNS activation of MR, i.e. functional target engagement. These are: 1. Heart rate variability and heart rate 2. Nocturnal blood pressure 3. Total sleep- and slow wave sleep duration 4. Salt taste sensitivity and -preference 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 3. 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. 4. 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.

Interventions

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

Arms, Groups and Cohorts

  • Experimental: enoxolone
    • 100 mg enoxolone in a capsule
  • Placebo Comparator: placebo
    • Placebo in a capsule

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

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

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Philipps University Marburg Medical Center
  • Collaborator
    • Slovak Academy of Sciences
  • Provider of Information About this Clinical Study
    • Principal Investigator: Harald Murck, Apl. Professor – Philipps University Marburg Medical Center
  • Overall Official(s)
    • Harald Murck, MD PhD, Study Director, Philipps University Marburg Medical Center
  • Overall Contact(s)
    • Ulrich Schu, MD, +49 6421 5865200, schu@uni-marburg.de

References

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, Műller 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 Jan 25:1-12. doi: 10.1080/15622975.2021.2020334. [Epub ahead of print]

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.

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. Epub 2007 Nov 20.

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.