Overview

Major depressive disorder (MDD) is a major contributor to impaired health worldwide. Initial antidepressant treatment of MDD does not lead to response in up to 50 % of patients. TRD (Treatment Resistant Depression) is associated with increased rates of recurrence, mortality as well as increased treating costs compared to MDD. Treatment op-tions for TRD remain limited with lithium, quetiapine and esketamine being the only recommended and approved augmentation strategies in the EU. Dehydroepiandrosterone (DHEA), an endogenous steroid hormone, is a promising, safe and tolerable adjunctive treatment op-tion. DHEA has been meta-analytically shown to elicit antidepressant effects and to be safe both in MDD and for depressive symptoms in other medical diseases. However, previous RCTs (Randomized con-trolled trial) were small and no study has yet tested the antidepressant potential of adjunct treatment with DHEA in patients with TRD.

Primary objective To determine whether add-on 100 mg/d DHEA to continued standard antidepressant medication improves depression to a greater extent than add-on placebo in subjects with treatment-resistant depression.

Secondary objectives To determine whether add-on 100 mg/d DHEA to continued standard antidepressant medication improves response rates, remission rates, patients' impression of change, clinician's impression of severity and change, quality of life, social functioning and self-report depression se-verity to a greater extent than adjunct placebo in subjects with TRD. Furthermore, changes in glucose, glycosylated hemoglobin (HbA1c), total, HDL- and LDL-cholesterol, C-reactive protein (CRP), and inter-leukin-6 levels from baseline to week 6 will be determined.

Eligibility

Inclusion Criteria:

• Patient provided written informed consent

  -,The patient is capable of giving consent (has sufficient knowledge of German and clearly understands the nature, significance and scope, including risks, of the medical procedure)

• The patients is aged between 18 and 75 years (≥ 18 and ≤ 75)
• The patient has an episode of major depression according to DSM 5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edi-tion)
• The patient has treatment-resistant depression (TRD), defined as non-response to at least one 4-week antidepressant treatment trial (including the current treatment) in the index episode (correspond-ing to level 1 resistance to treatment failure according to the Maudsley staging method)
• The patient has a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥ 20
• The patient is receiving antidepressant medication (SSRI or SNRI or tricyclic antidepressant or mirtazapine or bupropion) for at least 4 weeks, the dosage is at least at the approved minimum thera-peutic dosage and has been unchanged for at least 14 days prior to screening visit.
• The patient had less than three (\<3) treatment attempts with anti-depressants in the current MDE (current treatment attempts not in-cluded).

Exclusion Criteria:

• Exclusion Criteria Related to psychiatric diagnosis
• The patient has current clinically significant suicidal ideation with intent, corresponding to a score of 4 or 5 for ideation on the C-SSRS, or a suicidal attempt within the past 6 months, as indicated by the C-SSRS at screening visit
• The patient fulfills the criteria for psychotic depression according to DSM-5
• The patient meets the criteria for schizophrenia, schizoaffective disorder or bipolar disorder in M.I.N.I according to DSM-5
• The patient meets the criteria for a dependency disorder in the M.I.N.I. for DSM-5
• The patient has dementia or moderate to severe cognitive impair-ment. Exclusion Criteria Related to IMP
• The Patient is currently taking DHEA or has taken it within the last 14 days prior to screening visit.
• The patients is currently taking hormone replacement therapy with sex hormones (other than contraceptives)
• The patient has undiagnosed genital bleeding
• The patient has untreated endometrial hyperplasia The patient has or has had sex hormone-dependent cancer (e.g. breast cancer, ovarian cancer, endometrial cancer, prostate can-cer)
• The patient is allergic or has contraindication to DHEA or lactulose and cellulose
• The patient has previous diagnosis of chronic kidney disease stage G3b (or higher) or GFR \< 30 ml/min.
• The patient has diagnosis of prostatic hyperplasia. Exclusion Criteria Related to standard antidepressant medication (AxMP)
• The Patient is taking antidepressants other than those listed as in-clusion criterion (SSRI, SNRI, tricyclic antidepressants, bupropion, mirtazapine)
• The patient is taking psychotropic medication, e.g. antipsychotics, anticonvulsants, lithium or Johannis herbs. Allowed substances in-clude benzodiazepines, non-benzodiazepines (Zopiclon, Zolpidem or Eszopiclon) and antidepressants listed under inclusion criteria.
• The patient is using non-selective, irreversible MAO inhibitors (e.g. tranylcypromine) or selective, reversible MAO-A inhibitors (e.g. moclobemide) or the reversible non-selective MAO inhibitor line-zolid
• The patient has insulin-dependent diabetes mellitus General Safety Exclusion Criteria
• The patient has an untreated and unstable general medical condi-tion (e.g. hypertension with end organ damage or hypertensive de-railment)
• The patient has a medical history of liver failure and/or bilirubin above 3 times the normal range and reduced total protein
• The patient is pregnant or breastfeeding.
• The patient of childbearing age shows an unwillingness to use an effective contraceptive method (defined as a Pearl Index \< 1)
• The patient currently has or has a history of venous thromboembo-lism (VTE) (deep vein thrombosis, pulmonary embolism)
• The patient currently has or has a history of arterial thromboem-bolic disease (e.g. angina pectoris, myocardial infarction, stroke)
• The patient has a thrombophilic disease (e.g. protein C, protein S or antithrombin deficiency)
• The patient has porphyria
• The patient has clinically significant untreated hypothyroidism
• The patient has clinically significant abnormalities in the 12-lead ECG (e.g. prolongation of the QTc interval ≥ 500 ms) as performed during screening visit
• The patient is a vulnerable person (defined as: persons deprived their liberty, confined to an institution by court or administrative or-der, persons that may have Insufficient power, intelligence, educa-tion, resources, strength, or other needed attributes to protect their own interests, or unable to explicitly give consent)
• The patient might be dependent on representative of the sponsor, the investigator or the trial site The patient is currently participating in another interventional clini-cal trial.

Laboratory Exclusion Criteria

• The patient's laboratory values show clinically significant abnor-malities
• The patient currently has liver disease with liver-specific levels out-side the age- and gender-specific reference intervals \[elevations of GOT or GPT above 3 times the upper normal value (ULN)\]