REStoring mood after Early life Trauma - Glucocorticoid Receptor (GR) blockade as disease-modifying treatment for depression with childhood trauma

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. We 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 favourable 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, we aim to investigate whether we can target the biological
sequelae of excessive stress due to CT by blocking the glucocorticoid receptor
(GR) using the generic drug mifepristone.

To investigate whether mifepristone (7-day, 1200 mg/day) added to treatment as
usual (TAU), is more efficacious than placebo in reducing depressive symptom
severity (Inventory of Depressive Symptoms-Self Rated questionnaire; IDS-SR) in
patients with CT-related depression, 6 weeks after the start of the
intervention.

The fMRI substudy aims to clarify the neurobiological effects of mifepristone
treatment on stress reactivity in CT-related depression, these effects will be
assessed acutely and later during recovery following a psychosocial stress
test, the Trier Social Stress Test (TSST).

Placebo-controlled double-blind randomized controlled trial (RCT), with
randomization into two treatment arms (1:1)

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.

For more information see document B2.5 risicoclassificatie.

Before the IC is signed, there will be a telephone screening (20 minutes) to
discuss the exclusion criteria with the potential participant. During the
telephone screening, the subjects will firstly be informed about the content
and purpose of the screening, and what will happen with the data. Subjects will
be asked for verbal consent to record the data.

For screening purposes, the participant is asked for the presence of a primary
diagnosis of PTSD/ASD or other psychiatric disorder, possible initiation of
depression treatment, medication use and chronic adrenal insufficiency.
Additionally, women will also be asked if they are willing to use non-hormonal
contraception (if fertile), are pregnant and have a history of vaginal bleeding
and uterine symptoms.
During the telephone screening, no questions are asked about the seriousness of
the depressive symptoms and the childhood trauma.

The IC is signed at the start of the physical visit of the baseline visit (T0).

Once participants are included, they are asked to come by the research location
3 times: at baseline (T0): 1,5 hours (+ 1 hr at home questionnaires),
post-intervention (T1), 8 days after randomization: 1 hour (+ 0,5 hr at home
questionnaires), post-intervention (T2), 6 weeks after randomization: 1 hour
(+ 0,5 hr at home questionnaires). Two follow up measurements are performed via
video calling and online questionnaires: 45 minutes. Study medication will be
dispensed after the baseline measurements and taken once daily for 7
consecutive days at home. Clinical measurements (5x) consist of questionnaires,
clinical interviews, blood samples (T0, T1, T2), hair samples (T0, T2) and
saliva samples (T0-T3, taken at home by participants themselves).

A subgroup of participants (n=80, 40 per intervention group) will be asked to
participate in an (f)MRI sub-study at baseline (T0) and post-intervention (T2;
2hr per scan session). This sub-study consists of a stress paradigm, the Trier
Social Stress test (TSST), followed by fMRI scans directly (0-40 minutes
after stressor offset) and later (60-100 minutes after stressor offset). The
TSST is a validated and standardized test to induce mild psychosocial stress in
a laboratory setting. It involves a speech test and a short arithmetic test
that does not lead to extreme perceived stress levels. Additionally, repeated
saliva sampling (5x) and extra questionnaires are filled in (PANAS, VAS, STAI,
DARS) to further assess stress-induced related factors.

The physical load for this study consists of taking blood three times from the
test subjects. These blood samples may be painful or cause bruising. 16 mL of
blood is taken from the patient per measurement moment. This amount does not
cause any problems in adults. By way of comparison: 500 ml of blood is taken at
a time from the blood bank. If participating in the fMRI sub-study, the
participant must lie still twice (baseline + post-intervention) for 2x 60
minutes (1h break in between) in a narrow space (fMRI), which may be perceived
as uncomfortable. The stress test (TSST) prior to the fMRI scans has often been
applied without any known lasting disadvantageous effects, including a recent
study using the TSST in combination with (f)MRI in a clinical population
(patients with bipolar disorder). This study showed no detrimental effects of
the combination of stress and the MRI scanner.

Questions about depressive complaints and childhood trauma can be experienced
as personal and unpleasant for the test subject in this study.
However, previous research has shown that patients generally do not feel
uncomfortable when asked about their depressive symptoms and any suicidal
thoughts and that they even consider it positive that attention is paid to
their mood (Dazzi et al., 2014). Other research has shown that trauma-related
research in adults can lead to low to moderate levels of stress. However, this
same study showed that participants generally perceive their participation as
positive and beneficial and do not regret it (Jaffe et al., 2015).

The use of mifepristone can cause moderate damage, but the chance of this is
minimized by means of strict exclusion criteria. Previous studies in psychotic
depression showed no serious side effects and were limited to mild/moderate
side effects and were similar to placebo. This also applied to higher doses of
1200 mg/day. The investigational actions involve a negligible risk to the
safety of the subjects and the risk of harm is small. The physical and
psychological burden for the test subjects is small, however since this patient
population is regarded as vulnerable, the current study is classified as a
'moderate' risk.