Neurosteroid Biosynthesis Upregulation: A Novel Promising Therapy for Anxiety Disorders and PTSD

Abstract

Generalized anxiety, panic, and posttraumatic stress disorder (PTSD) are debilitating conditions, which have an incidence of one in ten persons in the general population and epidemiological studies also report that these disorders often occur with depression (1-3). Anxiolytic benzodiazepines, including diazepam and alprazolam, remain the best and most used treatments for these conditions (4-7). However, their therapeutic use is associated with side effects, which include sedation and rapid development of tolerance as well as dependence. This results in severe discontinuation symptoms and often to drug abuse (4-6, 8; 9). In many patients, including patients with PTSD, the pharmacological effects of these drugs are very weak and there is a large number of non-responders (10-12). This has stimulated drug design that for many decades has focused in the development of new more effective therapies for anxiety disorders (13-15). Novel neuronal biomarkers for the pharmacological targets of the next generation of anxiolytic drugs have been discovered. The downregulation of neurosteroid biosynthesis has been implicated in the pathophysiology of anxiety and depressive disorders (reviewed in 16). Decreases in cerebrospinal fluid (clinical studies) and brain content (preclinical studies) of the GABAA receptor-active progesterone derivative, allopregnanolone, have been associated with affective and mood disorders, which includes depression, anxiety spectrum disorders, PTSD, premenstrual dysphoric disorder, schizophrenia, and impulsivity (17-27). Thus, elevating or normalizing the downregulation of brain allopregnanolone levels could be a promising therapeutic strategy for these psychiatric disorders. This prompted investigations to develop new neurosteroidogenic agents to contrast allopregnanolone biosynthesis deficits in anxiety and depression (28-31). We measured allopregnanolone levels in the cerebrospinal fluid (CSF) of PTSD patients assuming that allopregnanolone levels in the CSF reflect the levels of this neurosteroid in the brain (17). Also, in depressed patients, the concentration of allopregnanolone in the CSF was decreased by about 50-60% of the levels measured in non-psychiatric patients (26). The CSF allopregnanolone level decrease is likely induced by a downregulation of the expression of 5┙-reductase type I mRNA in the prefrontal-cortex (area BA9) that we measured in