Concentrations of 3α-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery

Background: There is preclinical and clinical evidence that plasma concentrations of 3α-hydroxy-5α-pregnan-20-one (3α,5α-tetrahydroprogesterone; 3α,5α-THP), a neuroactive steroid that is a positive allosteric modulator of the GABAA receptor, are altered in depression and normalize as a result of antidepressant treatment. However, no data are available on the concentrations of 3α,21-dihydroxy-5α-pregnan-20-one (3α,5α-tetrahydrodeoxycorticosterone; 3α,5α-THDOC), another GABA ergic neuroactive steroid, in depression. Methods: We studied nine depressed patients before and after treatment with various antidepressants and compared them to healthy matched control subjects. Blood samples were quantified by means of a highly sensitive combined gas chromatography/mass spectrometry analysis. Results: Compared to control subjects, plasma concentrations of 3α,5α-THDOC and its precursor 5α-dihydrodeoxycorticosterone (5α-DHDOC) were increased in depressed patients and were not significantly influenced by antidepressant treatment. However, 3α,5α-THP plasma concentrations were decreased in depression and clinically effective antidepressant treatment was accompanied by an increase of 3α,5α-THP concentrations in these patients. Conclusions: Our results provide the first evidence for a differential alteration in the plasma concentrations of the 3α-reduced neuroactive steroids 3α,5α-THDOC and 3α,5α-THP in major depression, which is only partially reversed by successful antidepressant treatment.