Fludrocortisone and Information Processing in Healthy Volunteers
Condition: Depression
MeSH terms: Depression
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

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.
    

Intervention name(s): Fludrocortisone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): single dose 500 mg, capsule
Other intervention name(s): Florinef; Placebo comparator
Intervention MeSH terms: Fludrocortisone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Mineralocorticoid receptor; Fludrocortisone; Information Processing; Cognition; Depression