Background: Dehydroepiandrosterone (DHEA) and its sulfated ester DHEA-sulfate (DHEA-S), (togetherDHEA[S]), are the most abundant adrenal steroids in humans and are found in blood and the brain, wherethey function as neurosteroids with direct receptor affinities. Preclinical studies suggest that DHEA(S)has antidepressant/neuroprotective properties, and exogenously administered DHEA has shown antide-pressant efficacy in humans. Nonetheless, the role of endogenous DHEA(S) levels in major depressivedisorder (MDD) and antidepressant outcomes remains unclear.Methods: Morning fasting serum DHEA(S) concentrations were determined in 36 healthy, unmedicatedMDD adults with Hamilton Depression (HDRS) ratings ≥17, and 75 healthy controls. MDD participantsthen completed eight weeks of open-label SSRI treatment before DHEA(S) levels were re-sampled; thosewith post-treatment HDRS ratings ≤7 were classified as “Remitters.” Pre- and post-treatment DHEA(S)levels of Remitters and Non-remitters were compared, controlling for age, sex, and BMI.Results: Pre-treatment HDRS ratings did not differ between Remitters and Non-remitters (p = 0.179). Base-line DHEA levels of Remitters were significantly higher than both Non-remitters (p = 0.008) and controls(p = 0.004); baseline DHEA-S levels of Remitters were also higher than Non-remitters (p = 0.040) but didnot significantly differ from controls (p = 0.096). Non-remitters did not significantly differ from con-trols. Post-treatment DHEA(S) levels remained higher in Remitters compared to Non-remitters (DHEA:p = 0.013; DHEA-S: p = 0.040).Conclusions: These data suggest that higher circulating DHEA(S) levels (while unmedicated and aftereight weeks of SSRI treatment) predict SSRI-associated remission in MDD. This raises the possibilitythat endogenous DHEA(S) abundance is a physiological adjunct to SSRI efficacy, as suggested by priorpreclinical and clinical studies
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