Improved stress response in bipolar affective disorder with adjunctive spironolactone (mineralocorticoid receptor antagonist): case series

Abstract

The psychopathologies underlying affective disorders are thought to involve persistent changes in the expression and function of both mineralocorticoid receptors and glucocorticoid receptors in the hippocampus. In addition, exposure to stressful stimuli can precipitate episodes in vulnerable individuals. The aim of this study is to determine if spironolactone as an adjunctive therapy is effective in improving residual symptoms in bipolar disorder. Four cases of euthymic bipolar disorder (BD) patients were treated with spironolactone as an adjunctive therapy in a private treatment sector. All patients met the DSM-IV diagnosis criteria for bipolar disorder. Clinical response was assessed retrospectively using the Clinical Global Impression Scale for Improvement. Spironolactone was effective in all patients. The four cases illustrate a clinical response to residual symptoms and improvement in stress response after use of spironolactone as an adjunctive therapy in BD. This pilot case series suggests reducing in residual symptoms, with spironolactone as an adjunctive therapy in these DSM-IV BD patients. Mineralocorticoid receptors antagonists’ role in reducing stress-induced symptoms deserves further investigation through placebo-controlled trials.

Keywords

bipolar disorder HPA axis mineralocorticoid antagonist serotonin residual symptoms

Get full access to this article

View all access options for this article.

References

Bendtzen, K. , Hansen, PR , Rieneck, K. ; The Spironolactone/Arthritis Study Group ( 2003) Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis. Clin Exp Immunol 134: 151-158.

Cervilla, JA , Molina, E. , Rivera, M. , Torres-González, F. , Bellón, JA , Moreno, B. , et al. (2007) The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort. Mol Psychiatry 12: 748-755.

Deakin, JFW , Graeff, FG ( 1991) 5-HT and mechanisms of defence. J Psychopharmacol 5: 305-315.

de Kloet, ER , Joels, M. , Holsboer, F. ( 2005) Stress and the brain: from adaptation to disease . Nat Rev Neurosci 6: 463-475.

de Kloet, ER , Vreugdenhil, E. , Oitzl, MS , Joels, M. ( 1998) Brain corticosteroid receptor balance in health and disease . Endocr Rev 19: 269-301.

Heuser, I. , Deuschle, M. , Weber, B. , Stalla, GK , Holsboer, F. ( 2000) Increased activity of the hypothalamus-pituitary-adrenal system after treatment with the mineralocorticoid receptor antagonist spironolactone . Psychoneuroendocrinology 25: 513-518.

Juruena, MF , Cleare, AJ , Bauer, ME , Pariante, CM ( 2003) Molecular mechanism of GR sensitivity and relevance for affective disorders, for special issue. Acta Neuropsychiatrica 15: 354-367.

Juruena, MF , Cleare, AJ , Papadopoulos, AS , Poon, L. , Lightman, S. , Pariante, CM ( 2006) Different responses to dexamethasone and prednisolone in the same depressed patients. Psychopharmacology ( Berl) 189: 225-235.

Lopez, JF, Chalmers, DT, Little, KY, Watson, SJ ; A.E. Bennett Research Award (1998) Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 43: 547-573.

10.

McEwen, BS ( 2000) Allostasis and allostatic load: implications for neuropsychopharmaco-logy . Neuropsychopharmacology 22: 108- 124.

11.

Myin-Germeys, I. , Peeters, F. , Havermans, R. , Nicolson, NA , deVries, MW , Delespaul, P. , et al. (2003) Emotional reactivity to daily life stress in psychosis and affective disorder: an experience sampling study. Acta Psychiatr Scand 107: 124-131.

12.

Pariante, CM ( 2008) The role of multi-drug resistance p-glycoprotein in glucocorticoid function: Studies in animals and relevance in humans. Eur J Pharmacol, in press.

13.

Reul, JM , de Kloet, ER ( 1985) Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117: 2505-2511.

14.

Semont, A. , Fache, M. , Ouafik, L. , Hery, M. , Faudon, M. , Hery, F. ( 1999) Effect of serotonin inhibition on glucocorticoid and mineralocorticoid expression in various brain structure. Neuroendocrinology 69: 121-128.

15.

Storey, JD , Balfour, DJK ( 2002) The influence of repetitive stress on hippocampal 5-HT overflow and plus maze activity in the rat. Br J Pharmacol 137: 143.

16.

Webster, MJ , Knable, MB , O’Grady, J. , Orthmann, J. , Weickert, CS ( 2002) Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders. Mol Psychiatry 7: 985-94, 924.

17.

Young, EA , Lopez, JF , Murphy-Weinberg, V. , Watson, SJ , Akil, H. ( 2003) Mineralocorticoid receptor function in major depresión . Arch Gen Psychiatry 60: 24-28.