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Original Research

Increased Systemic Cortisol Metabolism in Patients With Schizophrenia and Bipolar Disorder: A Mechanism for Increased Stress Vulnerability?

Nils Eiel Steen, MD; Paal Methlie, MD; Steinar Lorentzen, MD, PhD; Sigrun Hope, MD; Elizabeth A. Barrett, PsyD; Sara Larsson, PsyD; Erlend Mork, PsyD; Bjørg Almås, PhD; Kristian Løvås, MD, PhD; Ingrid Agartz, MD, PhD; Ingrid Melle, MD, PhD; Jens P. Berg, MD, PhD; and Ole A. Andreassen, MD, PhD

Published: February 8, 2011

Article Abstract

Objective: The hypothalamic-pituitary-adrenal (HPA) axis seems dysregulated and part of the pathophysiology in bipolar disorder and schizophrenia, but the underlying mechanisms are unknown. Recent evidence indicates that systemic cortisol metabolism influences blood cortisol levels and HPA axis functioning. Our objective was to estimate systemic cortisol metabolism by means of the activity of 5α-reductase, 5β-reductase, and 11β-hydroxysteroid dehydrogenase (11β-HSD) in patients with bipolar disorder and schizophrenia spectrum disorders compared to healthy controls.

Method: Inpatients and outpatients aged 18 to 65 years with DSM-IV bipolar disorder (n = 69) or schizophrenia (n = 87) were consecutively recruited to the catchment area-based Thematically Organized Psychosis Research (TOP) study. Healthy controls (n = 169) were randomly selected from statistical records from the same catchment area and were contacted by letter inviting them to participate. Spot urine samples were collected in a cross-sectional manner from November 2006 to November 2008. Urinary free cortisol and cortisone and their metabolites were analyzed with liquid chromatography tandem mass spectrometry and used as indicators of 5α-reductase, 5β-reductase, and 11β-HSD activity.

Results: The combined patient group had increased activity of 5α-reductase, 5β-reductase, and 11β-HSD2 (all P < .001) compared to controls. Elevated systemic cortisol metabolism was present in both schizophrenia (5α-reductase, 5β-reductase, and 11β-HSD2; all P < .001) and bipolar disorder (5α-reductase [P = .016], 5β-reductase [P = .001], and 11β-HSD2 [P = .007]).

Conclusions: The results indicate increased activity of cortisol metabolism in patients with bipolar disorder and schizophrenia compared to healthy controls and suggest that increased systemic cortisol metabolism is involved in the pathophysiology and stress vulnerability in these severe mental disorders. The findings should be explored further in terms of potential new drug targets, and they add to the physiologic rationale for stress coping strategies in these patient groups.

J Clin Psychiatry

Submitted: February 19, 2010; accepted March 29, 2010.

Online ahead of print: February 8, 2011 (doi:10.4088/JCP.10m06068yel).

Corresponding author: Nils Eiel Steen, MD, Department of Mental Health and Addiction, Oslo University Hospital, 0514 Oslo, Norway (

Volume: 72

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