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

Abstract

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.

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Acknowledgements

The study was performed in the framework of the doctoral thesis of Ms Hilde Kempter, which has been submitted to the Faculty of Medicine, University of Munich. We gratefully acknowledge the expert technical help of Ms Johanna Zach in the measurement of mirtazapine serum concentrations. We also thank Christian Kohler of the Novartis Institutes for BioMedical Research, Basel, Switzerland for the excellent technical assistance with the cytosolic and microsomal 3α-HSD enzymatic assays.

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Correspondence to R Rupprecht.

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Schüle, C., Romeo, E., Uzunov, D. et al. Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3α-hydroxysteroid dehydrogenase activity. Mol Psychiatry 11, 261–272 (2006). https://doi.org/10.1038/sj.mp.4001782

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