Altered systemic cortisol metabolism in bipolar disorder and schizophrenia spectrum disorders Nils Eiel Steen a, b, c, * , Paal Methlie d, e , Steinar Lorentzen b, f , Ingrid Dieset a, b , Monica Aas a, b , Mari Nerhus a, b , Marit Haram a, b , Ingrid Agartz a, b, g , Ingrid Melle a, b , Jens P. Berg b, h, i , Ole A. Andreassen a, b a KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway b Institute of Clinical Medicine, University of Oslo, Oslo, Norway c Drammen District Psychiatric Center, Clinic of Mental Health and Addiction, Vestre Viken Hospital Trust, Drammen, Norway d Institute of Medicine, University of Bergen, Bergen, Norway e Hormone Laboratory, Haukeland University Hospital, Bergen, Norway f Department of Research and Development, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway g Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway h Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway i Hormone Laboratory, Oslo University Hospital, Oslo, Norway article info Article history: Received 10 June 2013 Received in revised form 23 January 2014 Accepted 27 January 2014 Keywords: Severe mental disorders Psychosis 5a reductase 5b reductase 11b-Hydroxysteroid dehydrogenase Hypothalamic-pituitary-adrenal-axis abstract Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is suggested as a pathophysiological factor in bipolar disorder and schizophrenia. Increased clearance of cortisol was recently indicated as a component in the HPA axis hyperdrive. The aim of the present study was to test the model of increased cortisol metabolism in a new replication sample separately and combined with a previously published sample of bipolar disorder and schizophrenia. Spot urine was sampled from 212 healthy controls (HC) and 221 patients with a schizophrenia spectrum disorder (SCZ, n ¼ 115) and bipolar disorder (BD, n ¼ 106). Of these, a subsample of 169 HC and 155 patients was included in a previous report. Urinary free cortisol, cortisone and their metabolites were measured, and the activities of 5a-reductase, 5b- reductase and 11b-HSD were estimated and analyzed for differences between groups. In the new sample, there was increased enzyme activity in SCZ for 5b-reductase (p ¼ 0.024 vs HC; p ¼ 0.027 vs BD) and 11b- HSD2 (p ¼ 0.014 vs HC; p ¼ 0.004 vs BD). In the combined sample, there was increased activity in SCZ for 5a-reductase (p < 0.001 vs HC; p ¼ 0.020 vs BD), 5b-reductase (p < 0.001 vs HC; p ¼ 0.045 vs BD) and 11b-HSD2 (p < 0.001 vs HC; p ¼ 0.043 vs BD), and in BD for 5b-reductase (p ¼ 0.002), 11b-HSD2 (p ¼ 0.039) and 5a-reductase (trend, p ¼ 0.084) (all vs HC). The findings confirm increased systemic cortisol metabolism in BD and SCZ. This is most consistent in SCZ, with BD taking an intermediate po- sition. The design makes it impossible to determine the direction of the effect. However, the findings merit further study of cortisol metabolism as a possible component in the HPA axis dysfunction and pathophysiology of BD and SCZ. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction Bipolar disorder and schizophrenia are severe mental disorders with overlapping symptomatology and genetic determinants in common (Lichtenstein et al., 2009). The underlying pathophysio- logical mechanisms are largely unknown. However, a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis has been implicated in both conditions (Corcoran et al., 2003; Daban et al., 2005). The HPA axis is closely regulated by central mechanisms involving the limbic system and hypothalamus. Signals reach the paraventricular nucleus (PVN) of the hypothalamus from limbic structures. Secretion of corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) from neurons of the PVN triggers release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. ACTH travels in the blood and stimulates cortisol secre- tion from the adrenal cortex. Cortisol regulates the activity on the higher levels of the axis by negative feedback effects (Herman et al., * Corresponding author. Drammen District Psychiatric Center, Vestre Viken Hospital Trust, 3004 Drammen, Norway. Tel.: þ47 328 61 800; fax: þ47 328 61 801. E-mail address: n.e.steen@medisin.uio.no (N.E. Steen). Contents lists available at ScienceDirect Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires 0022-3956/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpsychires.2014.01.017 Journal of Psychiatric Research 52 (2014) 57e62