OBJECTIVE: Previous studies have shown that neuroactive steroids modulate anxiety and stress reactivity. However, no data on the possible role of these γ-aminobutyric acidA (GABAA) receptor-modulating neuroactive steroids in patients with anxiety disorders are available. METHOD: The concentrations of 3α,5α-tetrahydroprogesterone (3α,5α-THP), 3α,5β-THP, 3β,5α-THP, and their precursors were studied in the plasma of 10 patients with panic disorder and 10 matched healthy comparison subjects. In addition, the effects of paroxetine treatment on neuroactive steroid concentrations were studied in the panic disorder patients over a 24-week period. RESULTS: Unexpectedly, patients with panic disorder had significantly greater concentrations of the positive allosteric modulators 3α,5α-THP and 3α,5β-THP and significantly lower concentrations of 3β,5α-THP (a functional antagonist for GABAA agonistic steroids), which might result in greater GABAA receptor-mediated neuronal activity. Paroxetine treatment did not affect neuroactive steroid concentrations, which were highly stable over 24 weeks. CONCLUSIONS: Differences in neuroactive steroid composition in patients with panic disorder were the opposite of those seen in patients with major depression and may reflect counterregulative mechanisms against the occurrence of spontaneous panic attacks.