The proposed research aims to compare the onset of action and the efficacy of fludrocortisone, a mineralocorticoid receptor agonist vs. spironolactone, a mineralocorticoid antagonist, vs. placebo as augmentation to a selective serotonin reuptake inhibitor (SSRI) in 65 inpatients with severe depression. The study will also explore the utility of the hypothalamic-pituitary-adrenal (HPA) axis in predicting treatment response. The study will be a 5-week randomized and double-blind trial of fludrocortisone vs. spironolactone vs. placebo during three years.

Inclusion Criteria:

• Depressed male and female inpatients according to DSM-IV
• Age between 18 and 70 years
• Minimum of 17-items Hamilton Depression Score of 18
• Informed consent signed

Exclusion Criteria:

• Relevant medical or neurological disorders
• Pregnancy or unsure contraception
• Relevant psychiatric comorbidity
• Active alcohol or other substance abuse/dependance
• Contraindications to SSRI, fludrocortisone, or spironolactone
• Steroid medication