Modulation of the mineralocorticoid receptor as add-on treatment in depression: A randomized, double-blind, placebo-controlled proof-of-concept study

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.