RESET-medication Glucocorticoid Receptor (GR) Blockade as Disease Modifying Treatment for Depression With Childhood Trauma

Study Overview
=================
Brief Summary
-----------------
Depression is a recurrent debilitating psychiatric disorder with a lifetime prevalence of 20%. Even though antidepressants and psychotherapy are often effective, a substantial proportion of patients does not respond to currently used evidence-based treatments. The heterogeneous nature of depressive symptoms is a major obstacle for the development of novel effective treatments, and targeted treatments for depression are currently lacking. The investigators propose a targeted disease-modifying treatment for the clinically distinct form of depression related to childhood trauma (CT, emotional/ physical/sexual abuse or neglect before the age of18). CT-related depression is critically different from non-CT depression: it emerges earlier in life with more severe and recurrent symptoms and less favorable responses to treatment. With an average 25% prevalence in depression, there is a large and unmet need for therapeutic strategies to treat depression in individuals with substantial CT. The GR is the major cortisol receptor in the brain and rodent studies have shown that GR blockade at adult age can reverse the effects of early-life adversity. Therefore, GR blockade is a potential novel treatment for CT-related depression but this has never been investigated. Based on the underlying stress neurobiology, the aim is to investigate whether the biological sequelae of excessive stress due to CT can be targeted by blocking the glucocorticoid receptor (GR) using the generic drug mifepristone.

Detailed Description
-----------------
Rationale: Depression is a recurrent debilitating psychiatric disorder with a lifetime prevalence of 20%. Even though antidepressants and psychotherapy are often effective, a substantial proportion of patients does not respond to currently used evidence-based treatments. The heterogeneous nature of depressive symptoms is a major obstacle for the development of novel effective treatments, and targeted treatments for depression are currently lacking. The investigators propose a targeted disease-modifying treatment for the clinically distinct form of depression related to childhood trauma (CT, emotional/physical/sexual abuse or neglect before the age of 18). CT-related depression is critically different from non-CT depression: it emerges earlier in life with more severe and recurrent symptoms and less favorable responses to treatment. With an average 25% prevalence in depression, there is a large and unmet need for therapeutic strategies to treat depression in individuals with substantial CT. Based on the underlying stress neurobiology, the aim is to investigate whether the biological sequelae of excessive stress due to CT can be targeted by blocking the glucocorticoid receptor (GR) using the generic drug mifepristone. The GR is the major cortisol receptor in the brain and rodent studies have shown that GR blockade at adult age can reverse the effects of early-life adversity. Therefore, GR blockade is a potential novel treatment for CT-related depression but this has never been investigated. Objective: The investigators will test the hypothesis that treatment with the GR-antagonist mifepristone is more effective than placebo to reduce depressive symptom severity in CT-related depression. Study design: Placebo-controlled double-blind randomized controlled trial (RCT). Study population: 158 adult patients (male/female, 18+ years), with depression and moderate to severe childhood trauma (CT). Intervention: Patients are randomized to treatment with the GR antagonist mifepristone (1200 mg/day for 7 days, n=79) or placebo (daily for 7 days, n=79), with both groups receiving usual care for depression. Main study parameters/endpoints: Improvement of depressive symptoms, as measured with the Inventory of Depressive Symptomatology - Self Rated (IDS-SR, continuous scale) questionnaire, 6 weeks after the start of the intervention. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: For screening, online questionnaires will be completed requiring 10 minutes. After inclusion and randomization, the experimental protocol consists of three face-to- face meetings at baseline (T0, 2,5hrs), week 1 (T1, 1hr), week 6 (T2, 1hr), and two online follow-up meetings at 12 weeks (T3, 0.75hr) and 6 months (T4, 0.75hr). Study medication will be dispensed after the baseline measurements and taken once daily for 7 consecutive days. Clinical measurements consist of clinical interviews, questionnaires, blood and saliva samples (T0, T1, T2), and hair samples (T0, T2). A subgroup of participants (n=60, 30 per intervention group) will be asked to participate in (f)MRI scans at baseline (T0) and post-intervention (T2;1hr per scan session). Mifepristone has been clinically used for Cushing's syndrome (antiglucocorticoid effects) and termination of pregnancy (anti-progesterone effects) for several decades. Mifepristone is generally well-tolerated, and several double-blind studies using the identical duration and dose have shown (7 days, 1200 mg) that the safety profile of mifepristone is comparable to that of placebo treatment, and study dropouts due to side effects were higher for placebo (1.6%) than for mifepristone (1.4%). The most common adverse events (AEs) were nausea, headache, dizziness, and a dry mouth and were comparable between the mifepristone and placebo groups. With regard to mifepristone's progesterone receptor activity and its indication for pregnancy termination, in the current RCT women of childbearing potential (WOCBP) who do not agree to use a non-hormonal contraceptive method (e.g. condom) during the intervention and up to 1 month after the intervention, are strictly excluded from participating in this study. Since mifepristone may interfere with the effectiveness of hormonal contraceptive methods, a non-hormonal method (e.g. condom) should be used, also in case of continued hormonal contraceptive use during the intervention and up to 1 month after the intervention. Thus, besides men and non-WOCBP, WOCBP can only participate if not currently breastfeeding, with confirmed negative pregnancy test and use of a non-hormonal contraceptive method.

Official Title
-----------------
RESET-medication: Glucocorticoid Receptor (GR) Blockade as Diseasemodifying Treatment for Depression With Childhood Trauma

Conditions
-----------------
Major Depressive Disorder, Childhood Trauma

Intervention / Treatment
-----------------
* Drug: Mifepristone
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Mastery of Dutch language Age of ≥ 18 years of age and able to give written IC Participant agrees to be randomized Moderate to severe depression; score ≥ 26 on the Inventory of Depressive Symptoms-Self Report (IDS-SR) DSM-5 diagnosis of major depression disorder (MDD), confirmed with clinical interview (M.I.N.I.-S) Moderate to severe childhood trauma (CT) before the age of 18; Score above validated cut-off for moderate to severe CT on one or more of the following domains using the Childhood Trauma Questionnaire (CTQ): physical neglect: score ≥ 10 emotional neglect: score ≥ 15 sexual abuse: score ≥ 8 physical abuse: score ≥ 10 emotional abuse: score ≥ 13 Exclusion Criteria: Primary diagnosis of post-traumatic stress disorder (PTSD) or Acute Stress Disorder (ASD) Lifetime diagnosis of borderline personality disorder (BPD) Other lifetime severe psychiatric comorbidity (e.g. bipolar disorder, schizophrenia) or current alcohol/drug dependence that requires clinical attention. Start of other forms of depression treatment in the week before or after the start of the intervention. Female participant being a WOCBP and who does not want to use a non-hormonal contraceptive method (e.g. condom) during the intervention period and up to 1 month after the intervention. Female participants that are pregnant or breastfeeding. Female participants that have a history of unexplained vaginal bleeding or endometrial changes. Chronic adrenal insufficiency (contraindication for mifepristone). Current use of: Medications containing CYP3A4-inhibitors Medications containing CYP3A4-inductors Glucocorticoid antagonists within 1 week before possible start of trial treatment. Systemic corticosteroids. Topical corticosteroid treatment are acceptable, with the exception of inhaled corticosteroids (inhalators).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mifepristone<br>Glucocorticoid Receptor (GR) blockade using the generic drug mifepristone | Drug: Mifepristone<br>* 1200 mg/day, once daily, 7 days<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo, once daily, 7 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depressive symptom severity at post-treatment | Depressive symptom severity in patients with CT-related depression, measured with the Inventory of Depressive Symptomatology - Self Report (IDS-SR, with a total score ranging from 0 to 84, where higher scores indicate higher severity of depressive symptoms) | 6 weeks after the start of the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depressive symptom severity at short-term | Depressive symptom severity in patients with CT-related depression, measured with the Inventory of Depressive Symptomatology - Self Report (IDS-SR, with a total score ranging from 0 to 84, where higher scores indicate higher severity of depressive symptoms) | 8 days after the start of the intervention | 
| Depressive symptom severity at long-term | Depressive symptom severity in patients with CT-related depression, measured with the Inventory of Depressive Symptomatology - Self Report (IDS-SR, with a total score ranging from 0 to 84, where higher scores indicate higher severity of depressive symptoms) | 3 months and 6 months after the start of the intervention | 
| Remission in CT-related depression | The presence or absence of DSM-5 Major Depressive Disorder (MDD), identified using the Major Depressive Disorder (MDD) section of the Mini International Neuropsychiatric Interview (M.I.N.I.-S). | Up to 6 months after the start of the intervention | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RESET, childhood maltreatment, early life stress, Glucocorticoid Receptor (GR)