Preclinical and clinical studies have suggested a role of the mineralocorticoid receptor (MR) in the response to antidepressants. We tested in a proof-of-concept study whether adding fludrocortisone (an MR agonist) or spironolactone (an MR antagonist) accelerates onset of action and improves efficacy of escitalopram in patients with major depression. We included 64 in- and outpatients with major depression (Hamilton Depression Scale-17 score>18) in a double-blind, randomized, placebo-controlled trial. Patients were randomized in a 2:2:1 fashion to fludrocortisone (0.2 mg/d, n=24) or spironolactone (100 mg/d, n=27) or placebo (n=13) for the first 3 weeks during a 5-week treatment with escitalopram. No differences in mean HAMD change scores and in time to response emerged between treatments. However, among the responders, patients treated with fludrocortisone responded faster (Breslow test, p=0.05). The mean number of days to response was 16.0+/-2.6 days vs. placebo 22.2+/-2.0 vs. spironolactone 22.6+/-2.3 (F=3.78, p=0.03). In the whole group, plasma cortisol increased during spironolactone and decreased during fludrocortisone treatment (F=2.4, p=0.04). In patients treated with fludrocortisone, non-responders had elevated cortisol values compared to responders throughout the study period (F=5.1, p=0.04). Stimulation of MR with fludrocortisone as adjunct to escitalopram accelerated the response in the group of responders while no effect emerged in the sample as a whole. A larger randomized controlled trial is warranted. Copyright 2009 Elsevier Ltd. All rights reserved.