Dehydroepiandrosterone (DHEA) as augmentation of standard antidepressants in treatmentresistantdepression: a randomized controlled trial (DHEA-DE)

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Major Depressive Disorder (MDD) is one of the most pressing health problems worldwide and among the top five leading causes for years lived with disability among all medical diseases. About half of the depressed patients do not respond to initial antidepressant treatment defined as “stage 1 of treatment-resistant depression (TRD)”.A systematic review showed an association of TRD with lower patient health-related quality of life and higher medical costs compared to MDD. A Cochrane review of pharmacological interventions in TRD concluded that there is an urgent need for new treatment approaches in TRD that are safe and effective.In this respect, dehydroepiandrosterone (DHEA) is a promising treatment option.DHEA is an endogenous steroid hormone mostly released from the adrenal gland but it is also produced within the brain and acts as a neurosteroid. DHEA has been metaanalytically shown to elicit antidepressive effects and to be safe in MDD in pilot randomized controlled trials and for depressive symptoms in patients with other medical diseases. Furthermore, another meta-analysis and our own data have shown that DHEA levels are decreased in depressed patients. However, no confirmatory trial of add-on DHEA treatment in TRD has been conducted so far.Therefore, the primary aim of this proposal is to examine whether add-on DHEA tostandard antidepressant medication improves depression to a greater extent than addon placebo in patients with TRD over 6 weeks. In eight centers, we will randomize n = 320 patients (18 – 65 years) to either add-on DHEA or add-on placebo while every patient will continue standard antidepressant medication. The primary analysis will compare changes in the clinician-rated Montgomery-Asberg-Depression Rating Scale (MADRS) from baseline to week 6 between the DHEA and placebo group by means of a Gaussian linear model for repeated measures (intent-to-treat-sample). Key secondary endpoints include response (defined as 50% MADRS score reduction from baseline), remission (defined as MADRS score < 10), and change in self-report Beck Depression Inventory scores from baseline to week 6.In sum, we propose to examine oral DHEA as a safe and promising treatment option in TRD in a confirmatory manner. This approach could help the individual patient by relieving depressive symptoms and could reduce the burden of TRD as a public health issue.