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

Concentrations of 3α-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 3α-hydroxysteroid dehydrogenase (3α-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 3α,5α-tetrahydroprogesterone, 3α,5β-tetrahydroprogesterone, 5α-dihydroprogesterone, and 5β-dihydroprogesterone after mirtazapine treatment, whereas 3β,5α-tetrahydroprogesterone levels were significantly decreased. In vitro investigations demonstrated a dose-dependent inhibitory effect of mirtazapine on the activity of the microsomal 3α-HSD in the oxidative direction (conversion of 3α,5α-tetrahydroprogesterone to 5α-dihydroprogesterone). Mirtazapine affects neuroactive steroid composition similarly as do SSRIs. The inhibition of the oxidative pathway catalyzed by the microsomal 3α-HSD is compatible with an enhanced formation of 3α-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.Molecular Psychiatry (2006) 11, 261–272. doi:10.1038/sj.mp.4001782; published online 13 December 2005 [ABSTRACT FROM AUTHOR]