Fluoxetine decreases concentrations of 3a,5a- tetrahydrodeoxycorticosterone (THDOC) in major depression Andreas Stro¨hle a, *, Augusto Pasini b , Elena Romeo b , Bettina Hermann a , Gianfranco Spalletta b , Flavia di Michele c , Florian Holsboer a , Rainer Rupprecht a, d a Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804, Munich, Germany b Universita` degli Studi di Roma Tor Vergata, Department of Neuroscience, Via Tor Vergata 135, 00133, Rome, Italy c IRCCS Santa Lucia, Rome, Italy d Ludwig Maximilian University, Department of Psychiatry, Nussbaumstrasse 7, 80336, Munich, Germany Received 19 January 2000; accepted 26 January 2000 Abstract There is evidence for a dierential alteration in the concentrations of 3a-reduced neuroactive steroids in major depression. Because it has been suggested that fluoxetine may shift the activity of the 3a-hydroxysteroid oxidoreductase towards the reductive direction, treatment of major depression may be accompanied by a further increase in plasma 3a,5a- tetrahydrodeoxycorticosterone (THDOC) concentration. We studied eight male depressed patients before and after treatment with fluoxetine and compared them to healthy age-matched control subjects. Blood samples were quantified for 3a,5a- tetrahydroprogesterone, 3a,5b-tetrahydroprogesterone (THP) and THDOC by means of a highly sensitive combined gas chromatography/mass spectrometry analysis. Compared to control subjects, concentrations of THDOC were higher in depressed patients and decreased after fluoxetine treatment. In contrast, THP concentrations were lower in depressed patients and increased after fluoxetine treatment. Our results give further evidence for a disequilibrium of 3a-reduced neuroactive steroids in major depression, which is normalized by treatment with fluoxetine. 7 2000 Elsevier Science Ltd. All rights reserved. Keywords: Neuroactive steroids; Depression; Antidepressants; Neurosteroids; THDOC; THP; Fluoxetine 1. Introduction The neuroactive steroids 3a,5a-tetrahydroprogester- one, 3a,5b-tetrahydro-progesterone (THP) and 3a,5a- tetrahydrodeoxycorticosterone (THDOC) are potent allosteric modulators of the GABA A receptors (Majewska et al., 1986; Paul and Purdy 1992) and may regulate gene expression via the progesterone receptor after intracellular oxidation into 5a-dihydroprogester- one (5a-DHP) and 5a-dihydrodeoxycorticosterone (5(- DHDOC) (Rupprecht et al., 1993; Rupprecht and Holsboer, 1999). The 5a-reductase and 3a-hydroxy- steroid oxidoreductase catalyze the conversion of pro- gesterone into 3a,5a-THP and into 3a,5a-THDOC (Karavolas and Hodges 1990; Celotti et al., 1992). Recent data suggest a causal role of 3a-reduced neu- roactive steroids in the pathogensis of major de- pression and its treatment: plasma and cerebrospinal fluid concentrations of (Guidotti and Costa 1998) and its stereoisomer 3a,5b-THP are decreased during de- pression and normalize during long term treatment with selective serotonin reuptake inhibitors (SSRI) (Romeo et al., 1998; Uzunova et al., 1998) or other antidepressants (Romeo et al., 1998; Stro¨hle et al., 1999). This leads to the suggestion that SSRIs could be considered as prototypic molecules which constitute a new class of drugs acting on neurosteroid brain bio- synthesis and being devoid of significant side eects Journal of Psychiatric Research 34 (2000) 183–186 0022-3956/00/$ - see front matter 7 2000 Elsevier Science Ltd. All rights reserved. PII: S0022-3956(00)00006-6 www.elsevier.com/locate/jpsychires * Corresponding author. Tel.: +49-89-30622-233; fax: +49-89- 30622-605. E-mail address: stroehle@mpipsykl.mpg.de (A. Stro¨hle).