TY - JOUR
T1 - Glucocorticoid Receptor (GR) antagonism as disease-modifying treatment for MDD with childhood trauma
T2 - protocol of the RESET-medication randomized controlled trial
AU - Linsen, F.
AU - Broeder, C.
AU - Sep, M. S. C.
AU - Verhoeven, J. E.
AU - Bet, P. M.
AU - Penninx, B. W. J. H.
AU - Meijer, O. C.
AU - Vinkers, C. H.
N1 - Funding Information: The RESET-medication study is supported by funds from the Netherlands Brain Foundation (Hersenstichting). Study medication is made available by Corcept Therapeutics, Inc (TSB, JB), Menlo Park. The study is an investigator-initiated study with the Amsterdam UMC, location VUmc, as study sponsor. The study funders had no role in the design of the study, the collection, analysis and interpretation of the data, or in the preparation, review, or approval of the manuscript. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Background: Major depressive disorder (MDD) is a heterogeneous psychiatric disorder. Childhood trauma (CT, emotional/physical/sexual abuse or neglect before the age of 18) is one of the largest and most consistent risk factors for development and poor course of MDD. Overactivity of the HPA-axis and the stress hormone cortisol is thought to play a role in the vulnerability for MDD following exposure to CT. Rodent experiments showed that antagonism of the glucocorticoid receptor (GR) at adult age reversed the effects of early life stress. Similarly, we aim to target MDD in individuals with CT exposure using the GR antagonist mifepristone. Methods: The RESET-medication study is a placebo-controlled double-blind randomized controlled trial (RCT) which aims to include 158 adults with MDD and CT. Participants will be randomized (1:1) to a 7-day treatment arm of mifepristone (1200 mg/day) or a control arm (placebo). Participants are allowed to receive usual care for MDD including antidepressants. Measurements include three face-to-face meetings at baseline (T0), day 8 (T1), week 6 (T2), and two online follow-up meetings at 12 weeks (T3) and 6 months (T4). A subgroup of participants (N = 80) are included in a fMRI sub-study (T0, T2). The main study outcome will be depressive symptom severity as measured with the Inventory of Depressive Symptomatology—Self Rated (IDS-SR) at T2. Secondary outcomes include, among others, depressive symptom severity at other time points, disability, anxiety, sleep and subjective stress. To address underlying mechanisms mifepristone plasma levels, cortisol, inflammation, epigenetic regulation and fMRI measurements are obtained. Discussion: The RESET-medication study will provide clinical evidence whether GR antagonism is a disease-modifying treatment for MDD in individuals exposed to CT. If effective, this hypothesis-driven approach may extend to other psychiatric disorders where CT plays an important role. Trial registration: The trial protocol has been registered 01–02-2022 on ClinicalTrials.gov with ID “NCT05217758”.
AB - Background: Major depressive disorder (MDD) is a heterogeneous psychiatric disorder. Childhood trauma (CT, emotional/physical/sexual abuse or neglect before the age of 18) is one of the largest and most consistent risk factors for development and poor course of MDD. Overactivity of the HPA-axis and the stress hormone cortisol is thought to play a role in the vulnerability for MDD following exposure to CT. Rodent experiments showed that antagonism of the glucocorticoid receptor (GR) at adult age reversed the effects of early life stress. Similarly, we aim to target MDD in individuals with CT exposure using the GR antagonist mifepristone. Methods: The RESET-medication study is a placebo-controlled double-blind randomized controlled trial (RCT) which aims to include 158 adults with MDD and CT. Participants will be randomized (1:1) to a 7-day treatment arm of mifepristone (1200 mg/day) or a control arm (placebo). Participants are allowed to receive usual care for MDD including antidepressants. Measurements include three face-to-face meetings at baseline (T0), day 8 (T1), week 6 (T2), and two online follow-up meetings at 12 weeks (T3) and 6 months (T4). A subgroup of participants (N = 80) are included in a fMRI sub-study (T0, T2). The main study outcome will be depressive symptom severity as measured with the Inventory of Depressive Symptomatology—Self Rated (IDS-SR) at T2. Secondary outcomes include, among others, depressive symptom severity at other time points, disability, anxiety, sleep and subjective stress. To address underlying mechanisms mifepristone plasma levels, cortisol, inflammation, epigenetic regulation and fMRI measurements are obtained. Discussion: The RESET-medication study will provide clinical evidence whether GR antagonism is a disease-modifying treatment for MDD in individuals exposed to CT. If effective, this hypothesis-driven approach may extend to other psychiatric disorders where CT plays an important role. Trial registration: The trial protocol has been registered 01–02-2022 on ClinicalTrials.gov with ID “NCT05217758”.
KW - Childhood trauma
KW - Glucocorticoid receptor
KW - Major depressive disorder
KW - Mifepristone
KW - Randomized controlled trial
UR - http://www.scopus.com/inward/record.url?scp=85159159496&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s12888-023-04830-9
DO - https://doi.org/10.1186/s12888-023-04830-9
M3 - Article
C2 - 37170109
SN - 1471-244X
VL - 23
JO - BMC psychiatry
JF - BMC psychiatry
IS - 1
M1 - 331
ER -