Clinical trial NCT03062150: Mineralocorticoid Receptor, NMDA Receptor and Cognitive Function in Depression
Official title: Effects of Mineralocorticoid Receptor Stimulation on Cognitive Bias and Social Cognition in Patients With Major Depression and Healthy Controls: What's the Role of NMDA Receptors?
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Major Depression
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
Collaborators: name: NeuroCure Clinical Research Center, Charite, Berlin
First posted: 2017-02-23
Enrollment: 232
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized double-blind placebo-controlled parallel group design
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Emotional dot probe
timeFrame: 1 hour
Secondary outcomes:
measure: Facial recognition task
timeFrame: 1 hour
measure: Multifaceted Empathy Test (MET)
timeFrame: 1 hour
measure: Virtual Water Maze
timeFrame: 1 hour
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
Study officials:
affiliation: Charité University Medical Center Berlin, Dept. of Psychiatry
name: Christian Otte, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.