Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3α-hydroxysteroid dehydrogenase activity

Concentrations of 3 alpha-reduced neuroactive steroids are altered in depression and normalize after antidepressant pharmacotherapy with selective serotonin re-uptake inhibitors (SSRIs). We investigated the impact of mirtazapine on the activity of a key neurosteroidogenic enzyme, the 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), and on the levels of neuroactive steroids in relation to clinical response. A total of 23 drug-free in-patients suffering from a major depressive episode (DSM-IV criteria) underwent 5-week treatment with mirtazapine (45 mg/day). Plasma samples were taken weekly at 0800 and quantified for neuroactive steroids by means of combined gas chromatography/mass spectrometry analysis. Enzyme activity was determined by assessment of steroid conversion rates. Irrespective of clinical outcome, there were significant increases in 3 alpha, 5 alpha-tetrahydroprogesterone, 3 alpha, 5 beta-tetrahydroprogesterone, 5 alpha-dihydroprogesterone, and 5 beta-dihydroprogesterone after mirtazapine treatment, whereas 3 beta, 5 alpha-tetrahydroprogesterone levels were significantly decreased. In vitro investigations demonstrated a dose-dependent inhibitory effect of mirtazapine on the activity of the microsomal 3 alpha-HSD in the oxidative direction (conversion of 3 alpha, 5 alpha-tetrahydroprogesterone to 5 alpha-dihydroprogesterone). Mirtazapine affects neuroactive steroid composition similarly as do SSRIs. The inhibition of the oxidative pathway catalyzed by the microsomal 3 alpha-HSD is compatible with an enhanced formation of 3 alpha-reduced neuroactive steroids. However, the changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of this antidepressant rather than clinical improvement in general.