title: The role of mineralocorticoid receptor function in treatment-resistant depression.
abstract: BACKGROUND
  Treatment-resistant depression patients show both reduced glucocorticoid receptor function and a hyperactive hypothalamic-pituitary-adrenal axis. However, few studies have examined the role of the mineralocorticoid receptor. This study aimed to evaluate the functional activity of the mineralocorticoid receptor system in regulating the hypothalamic-pituitary-adrenal axis in well-defined treatment-resistant depression patients.
  
  
  METHODS
  We recruited 24 subjects divided into: (a) treatment-resistant depression; (b) healthy controls. We evaluated: (a) the effect of combined glucocorticoid receptor/mineralocorticoid receptor stimulation with prednisolone; (b) the effect of prednisolone with the mineralocorticoid receptor antagonist spironolactone; and (c) the effect of spironolactone alone. The response of the hypothalamic-pituitary-adrenal axis was measured using salivary cortisol and plasma levels of drugs were also measured.
  
  
  RESULTS
  Treatment-resistant depression patients had higher cortisol compared with controls after all challenges. In controls, spironolactone increased cortisol compared to placebo. The co-administration of spironolactone with prednisolone in controls decreases the suppressive effects of prednisolone. In contrast, in treatment-resistant depression, spironolactone did not increase cortisol compared to placebo and spironolactone with prednisolone had no effect on the suppressive effects of prednisolone. Patients with treatment-resistant depression had a reduction in the conversation of spironolactone to the active metabolite canrenone.
  
  
  CONCLUSIONS
  Our data confirmed that treatment-resistant depression is associated with hypercortisolism and these patients no longer show an hypothalamic-pituitary-adrenal response to the administration of a mineralocorticoid receptor antagonist, suggesting that there is a mineralocorticoid receptor malfunctioning, such as a down regulation, however, pharmacokinetics and pharmacodynamics in these subjects could also have had an effect on the lack of mineralocorticoid receptor response.
authors.affiliation: 1King's College London, Institute of Psychiatry, Section of Neurobiology of Mood Disorders, London, UK.
authors.forename: Mario F
authors.initials: MF
authors.lastname: Juruena
authors.forename: Carmine M
authors.initials: CM
authors.lastname: Pariante
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Papadopoulos
authors.forename: Lucia
authors.initials: L
authors.lastname: Poon
authors.forename: Stafford
authors.initials: S
authors.lastname: Lightman
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Cleare
mesh_terms: D002192:Canrenone / Q000378:metabolism; D016022:Case-Control Studies; D061218:Depressive Disorder, Treatment-Resistant / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011239:Prednisolone / Q000008:administration & dosage / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism*; D012463:Saliva / Q000737:chemistry; D016037:Single-Blind Method; D013148:Spironolactone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D002192:Canrenone; D011239:Prednisolone; D006854:Hydrocortisone
keywords: Cortisol; hypothalamic-pituitary-adrenal axis; mineralocorticoid receptor; mineralocorticoid receptor antagonist; prednisolone; treatment resistant depression