The effect of fludrocortisone on emotional information processing in healthy volunteers

The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the
regulation of the stress response while the reactivity of the HPA-axis shows
large individual differences (DeRijk, 2009). Cortisol, a main stress hormone
produced and secreted by the adrenals, exerts effects on almost all nucleated
cells in the body. However, chronic stress dysregulates the HPA-axis, which
leads to an increased vulnerability for disease (Sapolsky et al., 1996, 2000;
Lupien et al., 2007, 2009). More specifically, it is hypothesezed that chronic
stress and impaired HPA-axis regulation are involved in the pathophysiology and
course of depression (Holsboer, 2000, 1999).

The mineralocorticoid receptor seems to be involved in the appraisal processes
of psychological stressors. These processes including higher mental functions
like emotion, cognition, and behaviour determine the release of corticotrophin
releasing hormone (CRH) from the hypothalamic paraventricular nucleus (PNV)
(Holsboer & Ising, 2010). Next, CRH stimulates the release of
adrenocorticotropic hormone (ACTH) from the pituitary gland. Additionally,
arginine vasopressin (AVP) stimulates synergistically with CRH the release of
ACTH (Swaab et al, 2005). Subsequently, ACTH is binding to specialized
receptors at the adrenal gland to cause glucocorticoid production and secretion
from the adrenal cortex in a pulsatile fashion: amplitude and frequency of
these secretory bursts are heightened under stressful conditions (Holsboer &
Ising, 2010). Once the perceived stressor has disappeared, the glucocorticoids
act in a negative feedback loop on the hypothalamus and the pituitary gland in
order to suppress the production of CRH and ACTH, enabling return to
homeostasis (De Kloet et al, 2005, 2007; Lupien et al., 2007, 2009).

Cortisol, which is the most important human glucocorticoid, exerts its effects
through two corticosteroid receptors: the glucocorticoid receptor (GR) and
mineralocorticoid receptor (MR). MRs bind cortisol with a ten-fold higher
affinity than GRs, which implicates that MRs are sensitive to low levels of
glucocorticoids. In the brain MRs are involved in the determination of the
onset of the stress response by appraising psychosocial stressors and
modulating behavioral flexibility (Brinks et al., 2009; Klok et al., 2011),
whereas GRs terminate stress responses and contribute to recovery and memory
storage for coping with future events (De Kloet et al., 2005, 2007; Otte et
al., 2007). Furthermore, MRs seem to be important for cognitive processes like
selective attention and emotions like fear (Otte et al., 2007; Brinks et al.,
2007). This is consistent with other findings that MRs are located especially
in the hippocampus, septum and amygdala: these limbic regions of the brain are
crucial for memory formation and emotional response, whereas GRs are
distributed ubiquitously in the brain (De Kloet, 2005). An imbalance in
mediated actions by these receptors results in cortisol responses of less
optimal magnitude and duration, which might increase vulnerability to mental
disorders like depression (De Kloet et al., 2005, 2007; Holsboer, 2000, 1999).
Another indication for the relation between depression and the
mineralocorticoid receptor is discovered in post-mortem brain tissue of
patients diagnosed with major depressive disorder (MDD). 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 (Klok et al., 2011).

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; Klok et al., 2011; Pruessner et al.,
1997). Secondly, clinical populations differ in observed depressive symptoms as
a function of MRI180V genotype (Kunningas et al., 2006). This MR I180V gene
variant showed less activity in vitro, which suggests that functionality in
vivo is decreased (DeRijk et al., 2006). Finally, MR haplotype 2, which is
prevalent in 35% of the Caucasian population, enhances the transcription,
translation and transactivation of the MR (Klok et al., 2009, 2011). 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 (Klok et al., 2011). This suggests that female sex
steroids may interact with the MR gene, thereby modulating resilience (Klok et
al., 2009, 2011). Indeed, it has been shown that progesterone and oestrogen
modulate MR-expression in rats (Castrén et al., 1995). 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) is a specific MR-agonist currently
used to treat diseases of the adrenal cortex (Coursin & Wood, 2002), septic
shock (Russel, 2008) and occasionally orthostatic hypotension (Schatz, 2001).
Consistent with the idea that the stimulation of the MR might be useful in the
treatment of depression, fludrocortison accelerated the antidepressant effects
of the SSRI escitalopram, at least in those patients who responded to
escitalopram (Otte et al., 2010). This is in line with a previous observation
that spironolactone, a MR antagonist, decreased the efficacy of the
antidepressant amitriptyline in depressed patients (Holsboer et al., 1999).
Both 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.

In the present experiment we will investigate the effects of acute
administration of 500 µg fludrocortisone (FC) in healthy, female, unmedicated
volunteers. This project is a first step in investigating the potential
antidepressant effects of MR stimulation by fludrocortison. 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
(Harmer et al., 2009). 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 (Harmer et al.,
2003). This finding has been replicated with different antidepressants and
different populations (see Harmer et al., 2009).

To investigate the effects of a single dose of fludrocortisone, a
mineralocorticoid receptor agonist, on emotional information processing in
healthy female participants.

Randomized double-blind, placebo-controlled trial.
Stratification on current use of oral contraceptives (yes/no).

Fludrocortisone 500 µg, single dose, oral.

Fludrocortisone may decrease plasma ACTH and cortisol and slightly increase
blood pressure and transiently enlarge sodium and water retention. Other
side-effects are not expected since these have only been described over longer
periods of intake.