Journal of Psychiatric Research 44 (2010) 339–346 Contents lists available at ScienceDirect Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/jpsychires Modulation of the mineralocorticoid receptor as add-on treatment in depression: A randomized, double-blind, placebo-controlled proof-of-concept study Christian Otte a,*, Kim Hinkelmann a, Steffen Moritz a, Alexander Yassouridis b, Holger Jahn a, Klaus Wiedemann a, Michael Kellner a a Department of Psychiatry and Psychotherapy, University Hospital Hamburg-Eppendorf, Germany b Max Planck Institute of Psychiatry, Munich, Germany article info abstract Article history: Preclinical and clinical studies have suggested a role of the mineralocorticoid receptor (MR) in the Received 31 August 2009 response to antidepressants. We tested in a proof-of-concept study whether adding fludrocortisone (an Received in revised form 5 October 2009 MR agonist) or spironolactone (an MR antagonist) accelerates onset of action and improves efficacy of Accepted 10 October 2009 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 Keywords: fludrocortisone (0.2 mg/d, n = 24) or spironolactone (100 mg/d, n = 27) or placebo (n = 13) for the first Depression Cortisol 3 weeks during a 5-week treatment with escitalopram. Mineralocorticoid receptor No differences in mean HAMD change scores and in time to response emerged between treatments. HPA axis However, among the responders, patients treated with fludrocortisone responded faster (Breslow test, Stress p = 0.05). The mean number of days to response was 16.0 ± 2.6 days vs. placebo 22.2 ± 2.0 vs. spironolac- Antidepressants tone 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 fludrocorti- sone, 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. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction creased activity of the hypothalamus–pituitary–adrenal (HPA) axis leading to elevated cortisol is involved in the pathophysiology of Depression has been identified by the World Health Organiza- depression rendering the HPA axis a plausible target for novel anti- tion (WHO) as one of the top 10 health problems worldwide in depressive medication (Nemeroff and Owens, 2002; Holsboer and 2007 (WHO, 2007). Despite advances in the treatment of depres- Ising, 2008; Pariante and Lightman, 2008; Schatzberg and Lindley, sion, insufficient response to antidepressants and their delayed on- 2008). Accordingly, several studies have examined whether target- set of action still represent major therapeutic obstacles (Nemeroff ing the HPA axis might exert antidepressive effects. Main strategies and Owens, 2002). Therefore, there is an urgent need to develop involved (1) glucocorticoid receptor (GR) antagonists, such as mife- therapies that act faster and improve response and remission (Insel pristone (Belanoff et al., 2002; DeBattista et al., 2006), (2) antago- and Charney, 2003; NIMH, 2003). Accordingly, a recent consensus nists of Corticotropin-Releasing Hormone (CRH) (Zobel et al., 2000; meeting called for more early-stage, well-designed proof-of-con- Binneman et al., 2008; Holsboer and Ising, 2008), or (3) steroid cept studies (Gelenberg et al., 2008). synthesis inhibitors, such as metyrapone (Jahn et al., 2004) or keto- Most of today’s antidepressants elicit their effects through conazole (Wolkowitz et al., 1999). However, these trials have monoaminergic mechanisms. However, evidence suggests that in- yielded equivocal results with regard to efficacy. For example, a re- cent study found that a CRH antagonist was less efficacious than sertraline (Binneman et al., 2008). A recent Cochrane review sum- marized these findings and concluded that targeting the HPA axis * Corresponding author. Address: University Hospital Hamburg-Eppendorf, in the treatment of depression is at the proof-of-concept stage Department of Psychiatry and Psychotherapy, Martinistrasse 52, 20246 Hamburg, Germany. Tel.: +49 40 42803 4677; fax: +49 40 42803 8021. and warrants further investigation to establish clinical utility E-mail address: [email protected] (C. Otte). (Gallagher et al., 2008). 0022-3956/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2009.10.006 340 C. Otte et al. / Journal of Psychiatric Research 44 (2010) 339–346 Cortisol, the effector hormone of the HPA axis in humans, exerts 17-item version (HAMD-17); (3) age from 18 to 70 years; (4) at its action via two different receptor systems: mineralocorticoid least 5 days free from antidepressants, antipsychotics, mood stabi- receptors (MR) are restricted in anatomical localization and mainly lizers, and other medications influencing HPA activity, and (5) no located in the hippocampus, while GR are expressed throughout treatment with fluoxetine or injectabtle antipsychotics for at least the brain (de Kloet et al., 2005). There is preclinical and clinical 30 days. Criteria for exclusion were (1) dementia, schizophrenia or evidence that MR are involved in the pathophysiology of depres- schizoaffective disorder, bipolar disorder, substance depen- sion, making them also an interesting target for new antidepres- dence < 6 months, (2) serious medical conditions, especially those sant treatment options (de Kloet et al., 2005; Kellner and associated with adrenal insufficiency; steroid use or well-known Wiedemann, 2008). impact on HPA activity, (3) pregnancy, nursing, or not using a reli- Clinical studies examining MR function in depression revealed able method of birth control, and 4) any contraindication for flu- equivocal results. Some studies point to a diminished MR function drocortisone, spironolactone, or escitalopram. in depression. Depressed patients who committed suicide showed The study was approved by the local ethics committee. After decreased MR expression in hippocampus and prefrontal cortex complete description of the study to the subjects, written informed (Lopez et al., 1998, 2003). Furthermore, preliminary data suggested consent was obtained. that adding the MR antagonist spironolactone for the first 10 days of treatment diminished the antidepressive effects of amitriptyline 2.2. Procedures and medication after 3 weeks (Holsboer, 1999). Finally, animal studies demon- strated that antidepressants upregulate central MR (Brady et al., Following baseline assessments, 64 subjects who met inclusion 1991; Seckl and Fink, 1992; Reul et al., 1993; Barden et al., 1995; criteria entered a 3-week, double-blind treatment period with Yau et al., 1995; Yau et al., 2002). All of these studies would suggest either spironolactone (50 mg given orally two times a day = that stimulating MR function might be a promising approach to 100 mg/d) or fludrocortisone (0.1 mg given orally two times a improve antidepressant treatment. day = 0.2 mg/d), or placebo (two times a day) at 8:00 h and On the other hand, there are also studies that suggest an in- 20:00 h. In addition, standard antidepressant treatment with escit- creased MR function in depression (Young et al., 2003), up-regu- alopram was started in parallel with a fixed dose (10 mg/d) for the lated MR gene expression in the hypothalamus of depressed first week and could then be increased during the following weeks. patients (Wang et al., 2008), down-regulation of hippocampal MR After day 21, patients continued to take escitalopram, but in response to antidepressants (Yau et al., 2001), anxiolytic effects fludrocortisone, spironolactone, or placebo medication was of blocking MR in animals (Korte et al., 1995; Smythe et al., 1997; stopped. The study period ended after 5 weeks to ensure that pos- Bitran et al., 1998), and anxiogenic effects of the MR agonist aldo- sible discontinuation effects would be captured. Fludrocortisone sterone (Hlavacova and Jezova, 2008). Furthermore, spironolactone and spironolactone were capsuled, and identical placebo capsules improved mood in premenstrual syndrome (O’Brien et al., 1979; were produced. The concomitant use of lorazepam and/or zolpi- Wang et al., 1995), in bulimia nervosa (Wernze, 2000), and reduced dem/zopiclon was allowed throughout the study period, whereas residual symptoms in euthymic patients with bipolar disorder any use of antipsychotics or mood stabilizers was not permitted. (Juruena et al., 2008). These studies suggest that blocking MR Allocation codes were provided in sealed envelopes for each might be more promising from a therapeutic perspective. patient at the pharmacy of University Hospital Hamburg, where Given the rationale that derived from previous studies for both formulation and blinding were conducted. The randomization stimulating and blocking the MR, we examined in a proof-of-con- was organized using the PLAN procedure from the SAS/STAT soft- cept study whether adding spironolactone (an MR antagonist) or ware (SAS Institute Inc., Cary, NC). Randomization was stratified fludrocortisone (an MR agonist) to escitalopram, a standard selec- for sex. tive serotonin reuptake inhibitor,