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Abstract

Background: Certain metabolites of progesterone such as 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP; allopregnanolone) and 3alpha,5beta-THP (pregnanolone) are potent, positive allosteric modulators of gamma-aminobutyric acid type A receptors. Although animal studies suggest anxiolytic properties of these endogenous modulators of central nervous excitability, no clinical data indicate whether they are also involved in the pathophysiology of anxiety disorders and panic attacks. Methods: We quantified the concentrations of 3alpha,5alpha-THP, 3alpha,5beta-THP, the isomer 3beta,5alpha- THP, and their precursors in the plasma of 10 patients with panic disorder and matched control subjects during panic attacks induced by means of sodium lactate and cholecystokinin tetrapeptide administration, using a highly sensitive gas chromatography-mass spectrometry analysis. Results: Panic attacks induced by sodium lactate and cholecystokinin tetrapeptide in patients with panic disorder were accompanied by pronounced decreases in the concentrations of 3alpha,5alpha- THP and 3alpha,5beta-THP and a concomitant increase in the concentrations of the functional antagonistic isomer 3beta,5alpha-THP, findings that are compatible with a decreased gamma-aminobutyric acid-ergic tone. No changes in neuroactive steroid concentrations were observed after placebo administration in patients with panic disorder or after placebo, sodium lactate, or cholecystokinin tetrapeptide administration in controls. Conclusions: The association between changes in plasma neuroactive steroid concentrations and experimentally induced panic attacks and the well- documented pharmacological properties of these compounds as gamma-amino-butyric acid type A receptor modulators suggest that neuroactive steroids may play a role in the pathophysiology of panic attacks in patients with panic disorde