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.

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