Fludrocortisone and Information Processing in Healthy Volunteers

February 23, 2014 updated by: Willem Van der Does, Leiden University Medical Center

The Effects of Fludrocortisone on Information Processing in Healthy Female Volunteers

Stimulating the mineralocorticoid receptor (MR) may restore a disturbed balance as seen in depression. In this double-blind, randomized, placebo-controlled trial the investigators will test the effects of a single dose (500mg) fludrocortisone, an MR-agonist, on the information processing in healthy female volunteers (N = 2x20).

The investigators want to investigate whether the acute administration of fludrocortisone (FC) in healthy females enhances the appraisal of emotional information related to depression, hypothesizing that:

  • FC relative to placebo selectively improves the recognition of happy and fearful faces: resulting in more correct responses and faster RTs.
  • FC induces a bias towards more positive self-description and an improved memory for positive information.

Female participants were selected because the haplotype MRI180V is related to depression vulnerability in women, not in men. If the effects of fludrocortisone are comparable to the effects of antidepressants on the same tests and the same population, it might be a first indication that fludrocortisone may function as an antidepressant.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

We found in depressed individuals, compared with non-depressed controls, that MRs had a decreased (approximately -30%) expression in hippocampus, inferior frontal gyrus and cingulate gyrus. It is proposed that decreased expression of MRs is part of the underlying pathological process in depression.

Recent studies have revealed considerable interpersonal differences with regard to the functioning of the MRs. Firstly, common MR gene polymorphisms influence the cortisol awakening response (CAR). Secondly, clinical populations differ in observed depressive symptoms as a function of MRI180V genotype. This MR I180V gene variant showed less activity in vitro, which suggests that functionality in vivo is decreased. Finally, MR haplotype 2, which is prevalent in 35% of the Caucasian population, enhances the transcription, translation and transactivation of the MR. This haplotype is associated with higher dispositional optimism, fewer thoughts of hopelessness and lower risk of major depression. These effects are restricted to pre-menopausal women. This suggests that female sex steroids may interact with the MR gene, thereby modulating resilience. Indeed, it has been shown that progesterone and oestrogen modulate MR-expression in rats. Taken together, mineralocorticoid receptors in the brain are considered to be a new target for the treatment of stress related disorders like depression.

Fludrocortisone (9α fluoro-hydrocortisone) (FC) is a specific MR-agonist currently used to treat diseases of the adrenal cortex, septic shock (Russel, 2008) and occasionally orthostatic hypotension. It is shown that FC significantly inhibits nocturnal HPA axis activity without first depleting MR receptors with an MR-antagonist. This suggests FC have interesting implications in disorders of HPA axis excess, such as depression. Consistent with the idea that the stimulation of the MR might be useful in the treatment of depression, fludrocortisone accelerated the antidepressant effects of the SSRI escitalopram, at least in those patients who responded to escitalopram. This is in line with a previous observation that spironolactone, a MR antagonist, decreased the efficacy of the antidepressant amitriptyline in depressed patients. These studies show that stimulation of the MR might be a useful addition to the treatment of depression. Though, the explanatory mechanism behind these observations remains unclear.

This project is a first step in investigating the potential antidepressant effects of MR stimulation by fludrocortisone. We will test the effects of FC on indices of emotional information processing in healthy volunteers, which is a recently validated model of antidepressant drug action. It has been demonstrated repeatedly that a single dose of an antidepressant changes the processing of emotionally relevant information in healthy volunteers, within a few hours after administration. For instance, one dose of citalopram improved the recognition of facial expressions of fear and happiness relative to placebo in healthy female volunteers. This finding has been replicated with different antidepressants and different populations.

Study Type

Interventional

Enrollment (Actual)

40

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Zuid-Holland
      • Leiden, Zuid-Holland, Netherlands, 2333 AK
        • Leiden University - Institute of Psychology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 33 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Fluent in Dutch
  • Age 18-35 yrs
  • BMI 18 to 30 kg/m2
  • Northwestern European ancestry

Exclusion Criteria:

  • Known contra-indications for fludrocortisone use:

    • Allergy to fludrocortisone.
    • Ulcus ventriculi et duodeni.
    • Acute infectious processes; viral infections
    • Tropical worm infections.
    • Vaccination with living virus
  • Major physical illness, such as diabetes, thyroid disease, epilepsy, multiple sclerosis, pituitary disease, or any other serious medical condition.
  • Hypertension or history of stroke. Increased blood clot formation.
  • Major infections.
  • Any current or past psychiatric disorder
  • Use of medication likely to interfere with the study (e.g., benzodiazepines, St John's Wort).
  • Pregnancy or breastfeeding.
  • History of regular (more than once per month during three or more months) use of hard drugs (including XTC) or any use during past month.
  • Alcohol use of more than 14 units per week or more than 4 units on any day during the week prior to the study or during the study period.
  • Regular smoker during past year or use of nicotine product during past week
  • Participants will be tested outside their menstrual period (two days before until five days after start of period).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Fludrocortisone
Fludrocortisone 500 mg in capsule
Drug: Fludrocortisone
single dose 500 mg, capsule
Other Names:
  • Florinef
Placebo Comparator: Placebo
Placebo capsule, single dose, main ingredient lactose
Drug: Placebo
Other Names:
  • Placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Accuracy to recognize emotions in facial expressions
Time Frame: 2 hrs after intake fludrocortisone or placebo
This primary outcome is measured by performing the Facial Expression Recognition Task (FERT).
2 hrs after intake fludrocortisone or placebo
Explicit memory for positive and negative information
Time Frame: 2 hrs after intake of fludrocortisone or placebo
This primary outcome is measured by the Emotional categorization and Memory(EMT)task. This task consists of two parts, the encoding and recall.
2 hrs after intake of fludrocortisone or placebo

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Subjective mood states
Time Frame: 2 hrs after intake fludrocortisone or placebo
This is measured by administration of the 'Positive Affect Negative Affect Schedule'(PANAS). It measures positive and negative mood states (tension, vigor, anxiety, fatigue, boredom, alertness...) (20 items adding to two subscales, positive and negative affect).
2 hrs after intake fludrocortisone or placebo

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Leiden University Medical Center

Investigators

  • Principal Investigator: Willem van der Does, Professor, Leiden University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2012

Primary Completion (Actual)

June 1, 2013

Study Completion (Actual)

December 1, 2013

Study Registration Dates

First Submitted

May 23, 2012

First Submitted That Met QC Criteria

July 20, 2012

First Posted (Estimate)

July 25, 2012

Study Record Updates

Last Update Posted (Estimate)

February 25, 2014

Last Update Submitted That Met QC Criteria

February 23, 2014

Last Verified

February 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P12-12

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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