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DHEA metabolism to the neurosteroid androsterone: a possible mechanism of DHEA’s antidepressant action

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An Erratum to this article was published on 14 August 2015

Abstract

Background

Alterations in neurosteroid secretion have been implicated in the efficacy of antidepressants. In a previous study, the adrenal androgen DHEA, a precursor of the neurosteroid androsterone, produced antidepressant and libido-enhancing effects in patients with midlife depression. To investigate the mechanisms underlying DHEA’s behavioral effects in this same patient group, we examined plasma levels of four additional neurosteroids implicated in the regulation of affective behavior.

Methods

Blood samples were assayed for neurosteroids in men (n = 13) and women (n = 10) with midlife depression who previously participated in a crossover study in which DHEA and placebo were administered for 6 weeks each. Depression severity was measured by the Center for Epidemiologic Studies Depression Scale (CES-D). Plasma levels of androsterone (ADT), allopregnanolone, pregnanolone, and pregnenolone were measured by GC-MS at baseline and week 6 of each treatment phase. Data were analyzed with repeated measures analysis of variance (ANOVA-R) and Bonferroni t tests.

Results

ADT levels (but not allopregnanolone, pregnanolone, and pregnenolone) increased after DHEA but not after placebo (F 2,42 = 3.3, p < 0.05). Post-DHEA ADT levels were higher in women than men [t 63 = 2.9, p < 0.05]. However, in both men and women who met criteria for clinical response on the CES-D, baseline ADT levels significantly increased post-DHEA, and the magnitude of the ADT increase post-DHEA treatment was similar in men and women. Consequently, it was the non-responders who accounted for the sex difference in post-DHEA plasma ADT levels, a difference that was driven by values in two women (the only female non-responders).

Conclusions

The small sample size notwithstanding, these data emphasize the potential behavioral relevance of ADT in humans, which may include contribution to the antidepressant effects of DHEA.

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Conflict of interest

This work was written as part of Drs. Ben Dor and Schmidt’s official duties as Government employees. The views expressed in this article do not necessarily represent the views of the NIMH, NIH, HHS, the Department of Veterans Affairs, or the US Government. This work was supported by the National Institute of Mental Health Intramural Research Program, the VA Mid-Atlantic MIRECC, and a VA Career Development Transition Award. The NIMH had no further role in study design, the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Dr. Rubinow is a funded member of the Editorial Board for a Servier sponsored journal (Dialogues in Clinical Neuroscience). Dr. Marx is an applicant or co-applicant on pending patent applications focusing on the use of neurosteroids and derivatives for CNS disorders and for lowering cholesterol, no patents issued and no licensing in place (VA 208 waiver in place). None of the other authors have any disclosures to report.

Author contribution

Drs. Schmidt and Rubinow designed the study and wrote the protocol. Drs. Ben Dor and Schmidt managed the literature searches and analyses. Drs. Ben Dor and Schmdit undertook the statistical analysis, and Dr. Ben Dor wrote the first draft of the manuscript. Dr. Marx conducted neurosteroid quantifications and contributed to the manuscript. All authors contributed to and have approved the final manuscript.

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Correspondence to Peter J. Schmidt.

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Dor, R.B., Marx, C.E., Shampine, L.J. et al. DHEA metabolism to the neurosteroid androsterone: a possible mechanism of DHEA’s antidepressant action. Psychopharmacology 232, 3375–3383 (2015). https://doi.org/10.1007/s00213-015-3991-1

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  • DOI: https://doi.org/10.1007/s00213-015-3991-1

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