Review The complex roles of neurosteroids in depression and anxiety disorders Patrizia Longone a, * , Rainer Rupprecht b , Gaia A. Manieri c , Giorgio Bernardi a,d , Elena Romeo a,d , Augusto Pasini d a Molecular Neurobiology and Experimental Neurology, Santa Lucia Foundation, Scientific Institute, Rome, Italy b Psychiatry Department, Ludwig-Maximilian University, Munich, Germany c Neurology Department, La Sapienza University, Rome, Italy d Neurosciences Department, Tor Vergata University, Rome, Italy Received 15 February 2007; received in revised form 19 September 2007; accepted 1 October 2007 Available online 6 October 2007 Abstract The role of neurosteroids in neuropsychiatric disorders has been thoroughly investigated in many research studies that have stressed their significant pathophysiological function in neuropsychiatry. In this review, we will focus mainly on the steroids active on the GABA A receptors studied in anxiety and depression. The aim is to discuss the controversial results reported in research on anxiety and depressive disorders. We suggest the combined use of biological parameters linked to psychopathological dimensions to make more homogeneous diagnoses and to develop more precise therapies for the treatment of depression and anxiety disorders. We discuss the role of neurosteroids in the pathophysiology and therapy of anxiety and depression. Finally, we consider the possibility of using quantification of mRNA expression of steroidogenic enzymes from peripheral sources in neuropsychiatry. # 2007 Elsevier Ltd. All rights reserved. Keywords: Neurosteroids; Anxiety; Depression; GC–MS; Lymphocytes 1. Introduction The action of steroids is based on their concentrations and on the specificity of tissue receptors. Steroids, which modulate several biological mechanisms, are important for the regulation of body homeostasis. In the central nervous system (CNS), locally produced steroids (neurosteroids) and hormonal steroids, which have crossed the blood–brain barrier, control glial and neuronal cell responses through genomic mechanisms or membrane-receptor modulation (Compagnone and Mellon, 2000; Baulieu et al., 2001; Lambert et al., 2003; Rupprecht and Holsboer, 2001). Neurosteroid levels are altered in many neuropsychiatric and neurodegenerative disorders such as mood and anxiety disorders, schizophrenia, Alzheimer’s and Parkinson’s disease (Guidotti and Costa, 1998; Romeo et al., 1998; Uzunova et al., 1998; di Michele et al., 2003; Schumacher et al., 2003; Strous et al., 2003; Brambilla et al., 2004; Marx et al., 2006). This indicates that distorted neurosteroid regulation may be more related to the psychopathological dimensions present in different pathologies than to a particular syndrome (Dubrovsky, 2004, 2006). Central and peripheral fluids show the same concentration trends as neurosteroids. One reason for this is that most of them can easily cross the blood–brain barrier and reach an equilibrium between the two compartments. In order to have a clearer understanding of their role we believe it is important to evaluate neurosteroid levels in biological fluids as well as the expression of their biosynthetic enzymes. This review will focus on the pathophysiological role of neurosteroids that act on GABA A receptors in anxiety and mood disorders. They include progesterone (PROG), www.elsevier.com/locate/neuint Available online at www.sciencedirect.com Neurochemistry International 52 (2008) 596–601 Abbreviations: GABA A , type A g-aminobutyric acid receptors; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; GC/MS, gas chromatography/mass spectrometry; PROG, progesterone; PREG, pregne- nolone; PREGS, pregnenolone sulfate; THDOC, tetrahydrodeoxycorticoster- one; 3a-HSD, 3a-hydroxysteroidehydrogenase; 3a,5a-THP, 3a,5a- tetrahydroprogesterone. * Corresponding author at: Molecular Neurobiology Unit, Santa Lucia Foun- dation, 00143 Via del Fosso di Fiorano 64/65, Italy. Tel.: +39 06 501703151; fax: +39 06 501703302. E-mail address: p.longone@hsantalucia.it (P. Longone). 0197-0186/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2007.10.001