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

NCT05217758 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: RESET001
• Study Type: interventional
• Target: 158
• Locations: 1 country
• Sites: 1

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.

Conditions

Major Depressive Disorder; Childhood Trauma

Keywords

RESET; childhood maltreatment; early life stress; Glucocorticoid Receptor (GR)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Depressive symptom severity at short-term

  8 days after the start of the intervention

• Depressive symptom severity at long-term

  3 months and 6 months after the start of the intervention

• Remission in CT-related depression

  Up to 6 months after the start of the intervention

Other Outcomes (9)

• Functional disability

  Up to 6 months after the start of the intervention

• Anxiety symptoms

  Up to 6 months after the start of the intervention

• Insomnia

  Up to 6 months after the start of the intervention

Study Arms (2)

Mifepristone

EXPERIMENTAL

Glucocorticoid Receptor (GR) blockade using the generic drug mifepristone

Drug: Mifepristone

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Mifepristone DRUG

1200 mg/day, once daily, 7 days

Mifepristone

Placebo DRUG

Placebo, once daily, 7 days

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead
• Netherlands Brain Foundation: collaborator
• Corcept Therapeutics: collaborator

Study Sites (1)

Amsterdam UMC, location VUmc

Amsterdam, North Holland, 1081HV, Netherlands

Location

Related Publications (11)

• Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17. doi: 10.1176/ajp.2006.163.11.1905.

  PMID: 17074942 BACKGROUND

• McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM, Kessler RC. Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication II: associations with persistence of DSM-IV disorders. Arch Gen Psychiatry. 2010 Feb;67(2):124-32. doi: 10.1001/archgenpsychiatry.2009.187.

  PMID: 20124112 BACKGROUND

• Teicher MH, Samson JA. Childhood maltreatment and psychopathology: A case for ecophenotypic variants as clinically and neurobiologically distinct subtypes. Am J Psychiatry. 2013 Oct;170(10):1114-33. doi: 10.1176/appi.ajp.2013.12070957.

  PMID: 23982148 BACKGROUND

• Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, Sharma S, Pearson D, Plotsky PM, Meaney MJ. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science. 1997 Sep 12;277(5332):1659-62. doi: 10.1126/science.277.5332.1659.

  PMID: 9287218 BACKGROUND

• Arp JM, Ter Horst JP, Loi M, den Blaauwen J, Bangert E, Fernandez G, Joels M, Oitzl MS, Krugers HJ. Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress. Neurobiol Learn Mem. 2016 Sep;133:30-38. doi: 10.1016/j.nlm.2016.05.009. Epub 2016 May 28.

  PMID: 27246249 BACKGROUND

• Loi M, Sarabdjitsingh RA, Tsouli A, Trinh S, Arp M, Krugers HJ, Karst H, van den Bos R, Joels M. Transient Prepubertal Mifepristone Treatment Normalizes Deficits in Contextual Memory and Neuronal Activity of Adult Male Rats Exposed to Maternal Deprivation. eNeuro. 2017 Nov 2;4(5):ENEURO.0253-17.2017. doi: 10.1523/ENEURO.0253-17.2017. eCollection 2017 Sep-Oct.

  PMID: 29098176 BACKGROUND

• Papilloud A, Veenit V, Tzanoulinou S, Riccio O, Zanoletti O, Guillot de Suduiraut I, Grosse J, Sandi C. Peripubertal stress-induced heightened aggression: modulation of the glucocorticoid receptor in the central amygdala and normalization by mifepristone treatment. Neuropsychopharmacology. 2019 Mar;44(4):674-682. doi: 10.1038/s41386-018-0110-0. Epub 2018 Jun 4.

  PMID: 29941978 BACKGROUND

• Ding J, da Silva MS, Lingeman J, Chen X, Shi Y, Han F, Meijer OC. Late glucocorticoid receptor antagonism changes the outcome of adult life stress. Psychoneuroendocrinology. 2019 Sep;107:169-178. doi: 10.1016/j.psyneuen.2019.05.014. Epub 2019 May 16.

  PMID: 31132569 BACKGROUND

• Zalachoras I, Houtman R, Atucha E, Devos R, Tijssen AM, Hu P, Lockey PM, Datson NA, Belanoff JK, Lucassen PJ, Joels M, de Kloet ER, Roozendaal B, Hunt H, Meijer OC. Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7910-5. doi: 10.1073/pnas.1219411110. Epub 2013 Apr 23.

  PMID: 23613579 BACKGROUND

• Block TS, Kushner H, Kalin N, Nelson C, Belanoff J, Schatzberg A. Combined Analysis of Mifepristone for Psychotic Depression: Plasma Levels Associated With Clinical Response. Biol Psychiatry. 2018 Jul 1;84(1):46-54. doi: 10.1016/j.biopsych.2018.01.008. Epub 2018 Jan 31.

  PMID: 29523415 BACKGROUND

• Linsen F, Broeder C, Sep MSC, Verhoeven JE, Bet PM, Penninx BWJH, Meijer OC, Vinkers CH. Glucocorticoid Receptor (GR) antagonism as disease-modifying treatment for MDD with childhood trauma: protocol of the RESET-medication randomized controlled trial. BMC Psychiatry. 2023 May 11;23(1):331. doi: 10.1186/s12888-023-04830-9.

  PMID: 37170109 DERIVED

Related Links

• Study website

MeSH Terms

Conditions

Depressive Disorder, Major; Stress, Psychological

Interventions

Mifepristone

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Psychiatrist

Study Record Dates

• First Submitted: December 20, 2021
• First Posted: February 1, 2022
• Study Start: December 9, 2021
• Primary Completion: August 9, 2024
• Study Completion: November 12, 2024
• Last Updated: December 6, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Immediately following publication, no end date.
• Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose.

Locations

NL (1)