title: Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity.
abstract: Concentrations of 3alpha-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 3alpha-hydroxysteroid dehydrogenase (3alpha-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 3alpha,5alpha-tetrahydroprogesterone, 3alpha,5beta-tetrahydroprogesterone, 5alpha-dihydroprogesterone, and 5beta-dihydroprogesterone after mirtazapine treatment, whereas 3beta,5alpha-tetrahydroprogesterone levels were significantly decreased. In vitro investigations demonstrated a dose-dependent inhibitory effect of mirtazapine on the activity of the microsomal 3alpha-HSD in the oxidative direction (conversion of 3alpha,5alpha-tetrahydroprogesterone to 5alpha-dihydroprogesterone). Mirtazapine affects neuroactive steroid composition similarly as do SSRIs. The inhibition of the oxidative pathway catalyzed by the microsomal 3alpha-HSD is compatible with an enhanced formation of 3alpha-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.
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schüle
authors.forename: E
authors.initials: E
authors.lastname: Romeo
authors.forename: D P
authors.initials: DP
authors.lastname: Uzunov
authors.forename: D
authors.initials: D
authors.lastname: Eser
authors.forename: F
authors.initials: F
authors.lastname: di Michele
authors.forename: T C
authors.initials: TC
authors.lastname: Baghai
authors.forename: A
authors.initials: A
authors.lastname: Pasini
authors.forename: M
authors.initials: M
authors.lastname: Schwarz
authors.forename: H
authors.initials: H
authors.lastname: Kempter
authors.forename: R
authors.initials: R
authors.lastname: Rupprecht
mesh_terms: D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D003866:Depressive Disorder / Q000097:blood*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008875:Middle Aged; D000078785:Mirtazapine; D013256:Steroids / Q000097:blood*; D016896:Treatment Outcome
chemical_list: D000929:Antidepressive Agents, Tricyclic; D013256:Steroids; D008803:Mianserin; D000078785:Mirtazapine; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)