Mineralocorticoid Receptor, NMDA Receptor and Cognitive Function in Depression

NCT03062150 | Completed DMC

• 2 other identifiers: OT 209/7-12014-005239-15
• Study Type: interventional
• Target: 232
• Locations: 1 country
• Sites: 1

Brief Summary

The steroid hormone cortisol is released in response to stress and acts in the central nervous system upon glucocorticoid (GR) and mineralocorticoid receptors (MR). GR are widely distributed across the brain while MR are predominantly expressed in the hippocampus and prefrontal cortex - two brain areas closely related to memory and executive function. Stimulation of MR leads to an increase of glutamate that act on glutamatergic NMDA receptors in the hippocampus and prefrontal cortex. In previous studies, the investigators have shown that fludrocortisone, a mineralocorticoid receptor (MR) agonist, improves memory and executive function in depressed patients and healthy controls. However, depressed patients not only exhibit cognitive deficits in traditional neuropsychological domains such as memory or executive function. In addition, there are depression-specific alterations such as cognitive bias and deficits in social cognition, two clinically highly relevant areas. Therefore, the specific aims of this renewal proposal are two-fold:

• To examine whether beneficial effects of fludrocortisone in depressed patients can be extended to depression-specific cognitive bias and to social cognition
• To determine whether beneficial effects of fludrocortisone depend on NMDA-receptor function and whether these beneficial effects can be enhanced by NMDA receptor stimulation. The investigators hypothesize that fludrocortisone will improve cognitive bias and social cognition in depressed patients and that its beneficial effects depend on the NMDA receptor. Therefore, the investigators further hypothesize that the effects of fludrocortisone can be enhanced by co-administration of the partial NMDA receptor agonist D-cycloserine. The study not only advances current knowledge by further examining the mechanism of action by which MR stimulation exerts beneficial effects on cognition but extends these effects to depression-specific cognitive bias and alterations in social cognition. Furthermore, a potential interaction between MR and NMDA receptors is highly clinically relevant given the promising results with NMDA receptor antagonists in the treatment of major depression.

Conditions

Major Depression

Outcome Measures

Primary Outcomes (1)

• Emotional dot probe

  In this task, two stimuli (each a photography of a face) are presented quickly on a computer screen (500 ms), and one face stimulus is replaced by a probe (1100 ms). Face pictures can show a sad, happy or neutral expression and are paired as neutralneutral, neutral-sad, or neutral-happy. Participants respond as fast as possible by pressing a key to correspond to the location of the probe. Attentional bias can be derived by the average reaction time when the probe replaces negative stimuli (sad faces), the average reaction time when the probe replaces neutral stimuli (neutral faces), and the average reaction time of positive (happy faces) and neutral stimuli (neutral faces).

  1 hour

Secondary Outcomes (3)

• Facial recognition task

  1 hour

• Multifaceted Empathy Test (MET)

  1 hour

• Virtual Water Maze

  1 hour

Study Arms (4)

Placebo+Placebo

PLACEBO COMPARATOR

Placebo: pill, 8mm, single dose, Lichtenstein, Winthrop Arzneimittel GmbH.

Drug: Placebo

Fludrocortisone+Placebo

ACTIVE COMPARATOR

Fludrocortisone: pill, Astonin H 0,1gm, single dose, Merck Serono GmbH Placebo: pill, 8mm, single dose, Lichtenstein, Winthrop Arzneimittel GmbH.

Drug: Placebo; Drug: Fludrocortisone

Placebo+D-Cycloserine

ACTIVE COMPARATOR

Placebo: pill, 8mm, single dose, Lichtenstein, Winthrop Arzneimittel GmbH. D-Cycloserine: capsule, Cycloserine 250mg, single dose, King Pharmaceuticals Ltd

Drug: Placebo; Drug: D-Cycloserine

Fludrocortison+D-Cycloserine

ACTIVE COMPARATOR

Fludrocortisone: pill, Astonin H 0,1gm, single dose, Merck Serono GmbH D-Cycloserine: capsule, Cycloserine 250mg, single dose, King Pharmaceuticals Ltd

Drug: Fludrocortisone; Drug: D-Cycloserine

Interventions

Placebo DRUG

Placebo

Fludrocortisone+Placebo; Placebo+D-Cycloserine; Placebo+Placebo

Fludrocortisone DRUG

Fludrocortisone

Fludrocortison+D-Cycloserine; Fludrocortisone+Placebo

D-Cycloserine DRUG

D-Cycloserine

Fludrocortison+D-Cycloserine; Placebo+D-Cycloserine

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-65 years
• Depressed male and female patients according to DSM-V \& minimum of 17-items Hamilton Depression Score of 18
• healthy controls
• informed consent signed

You may not qualify if:

• Current use of antidepressants, antipsychotics, or mood stabilizer
• Relevant medical or neurological disorders
• Pregnancy or unsure contraception
• Relevant psychiatric comorbidity (bipolar or psychotic disorders)
• Active alcohol or other substance abuse/dependance

Sponsors & Collaborators

• Charite University, Berlin, Germany: lead
• NeuroCure Clinical Research Center, Charite, Berlin: collaborator

Study Sites (1)

Charité Universitätsmedizin Berlin

Berlin, 12203, Germany

Location

Related Publications (4)

• Otte C, Wingenfeld K, Kuehl LK, Kaczmarczyk M, Richter S, Quante A, Regen F, Bajbouj M, Zimmermann-Viehoff F, Wiedemann K, Hinkelmann K. Mineralocorticoid receptor stimulation improves cognitive function and decreases cortisol secretion in depressed patients and healthy individuals. Neuropsychopharmacology. 2015 Jan;40(2):386-93. doi: 10.1038/npp.2014.181. Epub 2014 Jul 18.

  PMID: 25035081 BACKGROUND

• Hinkelmann K, Wingenfeld K, Kuehl LK, Fleischer J, Heuser I, Wiedemann K, Otte C. Stimulation of the mineralocorticoid receptor improves memory in young and elderly healthy individuals. Neurobiol Aging. 2015 Feb;36(2):919-24. doi: 10.1016/j.neurobiolaging.2014.09.008. Epub 2014 Sep 16.

  PMID: 25442112 BACKGROUND

• Otte C, Wingenfeld K, Kuehl LK, Richter S, Regen F, Piber D, Hinkelmann K. Cognitive function in older adults with major depression: Effects of mineralocorticoid receptor stimulation. J Psychiatr Res. 2015 Oct;69:120-5. doi: 10.1016/j.jpsychires.2015.08.001. Epub 2015 Aug 4.

  PMID: 26343603 BACKGROUND

• Nowacki J, Wingenfeld K, Kaczmarczyk M, Chae WR, Abu-Tir I, Deuter CE, Piber D, Hellmann-Regen J, Otte C. Cognitive and emotional empathy after stimulation of brain mineralocorticoid and NMDA receptors in patients with major depression and healthy controls. Neuropsychopharmacology. 2020 Dec;45(13):2155-2161. doi: 10.1038/s41386-020-0777-x. Epub 2020 Jul 28.

  PMID: 32722659 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

Fludrocortisone; Cycloserine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Hydrocortisone; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oxazolidinones; Oxazoles; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Christian Otte, MD

  Charité University Medical Center Berlin, Dept. of Psychiatry

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Psychiatry

Model Details: randomized double-blind placebo-controlled parallel group design

Study Record Dates

• First Submitted: February 15, 2017
• First Posted: February 23, 2017
• Study Start: September 27, 2016
• Primary Completion: February 11, 2019
• Study Completion: February 11, 2019
• Last Updated: June 23, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)