Improved stress response in bipolar affective disorder with adjunctive spironolactone (mineralocorticoid receptor antagonist): case series MF Juruena Section of Neurobiology of Mood Disorders and Stress, Psychiatry and Immunology Lab, Institute of Psychiatry, King’s College/University of London, UK. CS Gama Programa de Pós-Graduação em Medicina: Psiquiatria, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2400 - 2º Andar, 90035-003, Porto Alegre, RS, Brazil; Department of Clinical and Biomedical Sciences, Barwon Health, University of Melbourne, Geelong, VIC, Australia. M Berk Department of Clinical and Biomedical Sciences, Barwon Health, University of Melbourne, Geelong, VIC, Australia. PS Belmonte-de-Abreu Programa de Pós-Graduação em Medicina: Psiquiatria, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2400 - 2º Andar, 90035-003, Porto Alegre, RS, Brazil. 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. Key words bipolar disorder; HPA axis; mineralocorticoid antagonist; serotonin; residual symptoms Introduction Glucocorticoids mediate their actions, including feedback regu- lation of Hypothalamus-Pituary-Adrenal (HPA) axis, through two distinct intracellular corticosteroid receptor subtypes referred to as mineralocorticoid receptors (MR) and glucocorti- coid receptors (GR) (McEwen, 2000). MR type I receptors have a limited distribution and are found in relatively high densities in the hippocampus. Mineralocorticoid receptors bind glucocorti- coids with a 10 fold higher affinity than GR, which are widely distributed in brain and periphery (de Kloet, et al., 2005). The psychopathologies underlying affective disorders are thought to involve persistent changes in the expression and function of both MR and GR in the hippocampus. In addition, exposure to stressful stimuli can precipitate episodes in vulner- able individuals (Juruena, et al., 2003). Stressful life events can also alter hippocampal neurogenesis mediated via glucocorti- coids and cytokines (Cervilla, et al., 2007). The impact of MR on HPA activity in humans is well described. Most studies have demonstrated increased basal plasma cortisol levels after receiving spironolactone, a MR antagonist (Heuser, et al., 2000). Young (Young, et al., 2003) administered spironolac- tone to patients with major depression and matched control subjects and assessed corticotropin and cortisol secretion in response to this acute challenge. This study showed that spiro- nolactone treatment resulted in a significant increase in cortisol secretion levels in both controls and depressed patients, but Short report Journal of Psychopharmacology 00(00) (2008) 1–3 © 2008 British Association for Psychopharmacology ISSN 0269-8811 SAGE Publications Ltd, Los Angeles, London, New Delhi and Singapore 10.1177/0269881108092121 Corresponding author: Clarissa S Gama, Programa de Pós-Graduação em Medicina: Psiquiatria, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2400 - 2º Andar, 90035-003, Porto Alegre, RS, Brazil. Email: csgama@yahoo.com J Psychopharmacol OnlineFirst, published on June 26, 2008 as doi:10.1177/0269881108092121 Copyright 2008 by British Association for Psychopharmacology.