Role of the Blood-Brain Barrier in Stress Resilience: Investigating New Pathways Towards Pharmacological Augmentation of Stress Resilience

NCT06965868 | Not Yet Recruiting DMC

• 1 other identifier: NEURON_RV-064 - PHASR-PP
• Study Type: interventional
• Target: 122
• Locations: 3 countries
• Sites: 3

Brief Summary

The goal of this clinical trial is to better understand the relationship between blood-brain barrier (BBB) function and stress resilience and to investigate a potential causal role for BBB function in stress resilience in humans. The researchers will look for particpants that are young adults to answer the following questions to reach our goal:

• Is better BBB integrity, measured with neuroimaging, associated with better stress resilience in the short term and in the long term?
• Does the administration of Metformin improve BBB integrity?
• Is improved BBB integrity a possible link between Metformin and better short- and long-term stress resilience? The participants will do the following during our study:
• Participants will fill in online surveys on stressor exposure and mental health once every four weeks over 36 weeks
• Participants will visit the study site 4 times:
• The first time for a screening process which includes questionnaires, a medical exam and a blood sample.
• The next 2 visits will include a blood sample, a medical exam, an MRI scan and a list of questionnaires
• The last visit will include another blood sample, a medical exam and a list of questionnaires.
• Between visit 2 and 3, the participant will take either Metformin or Placebo

Conditions

Stress Resilience; Blood-Brain Barrier Integrity; Mental Health

Keywords

Stress Resilience; Blood Brain Barrier; Emerging Adults; BBB integrity; at-risk; prospective; placebo-controlled; University Students; Metformin

Outcome Measures

Primary Outcomes (1)

• Average stressor reactivity (SR) score in the 'early follow-up' study phase

  SR is the residual deviation of an individual from the sample's normative relation between stressor exposure (E) and mental health problems (P). A positive residual indicates more mental health problems than expected based on the normative E-P relationship. A negative residual (negative SR score) indicates less mental health problems than expected. Hence, SR is an inverse continuous expression of an individual's resilience.

  From week 13 after enrollment (T4) until week 24 after enrollment (T6)

Secondary Outcomes (1)

• Whole-brain Blood-Brain Barrier Integrity, assessed with neuroimaging at T0 and T3

  Week 1 after enrollment (T0), before the Experimental Manipulation phase, and week 12 after enrollment (T3), at the end of the Experimental Manipulation phase

Other Outcomes (1)

• Average stressor reactivity (SR) score in the 'whole follow-up' study phase

  From week 13 (T4) after enrollment until week 36 after enrollment (T9).

Study Arms (2)

Metformin

OTHER

Metformin is used as an experimental tool in the attempt to enhance inter-individual variation in Blood-Brain Barrier integrity in the study sample.

Drug: Metformin

Placebo

PLACEBO COMPARATOR

Placebo will be given as a control intervention.

Drug: Placebo

Interventions

Metformin DRUG

The Metformin intervention will be self-administred capsules, taken during a 12-week period: Four weeks of dose increase; first and second week 500 mg once daily, third and fourth week 500mg twice daily. Full-dose administration (850 mg twice daily) for eight weeks.

Metformin

Placebo DRUG

This intervention will be self-administered placebo capsules

Placebo

Eligibility Criteria

• Age: 18 Years - 25 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Absence of mental disorder diagnosis.
• University students.
• GHQ-28 \> 20
• Three or more adverse life events acc. to LE list in the past
• Beck Depression Inventory (BDI) ≤ 14 \& Columbia-Suicide Severity Rating Scale (C-SSRS) ≤ 1. Thereby concurrent depression and suicidality are excluded.
• Age 18 to 25 years
• Ability of participant to understand character and individual consequences of the study (MMSE Folstein \> 28)
• Signed and dated informed consent of participant

You may not qualify if:

• Life-time and current diagnosis of any severe mental disorder determined by M.I.N.I. diagnostic interview.
• Known history of brain injuries or neurodevelopmental disorder.
• Evidence of neurodegenerative disorder (e.g., Parkinson).
• Multimorbidity or significant organ (esp. liver or renal) dysfunction or manifest diabetes or substance abuse (esp. alcohol).
• Contraindication to metformin such as renal insufficiency (Creatinin-Clearance\< 60ml/min), recent (\<3 month) ischemic events (e.g. myocardial infarction or stroke).
• Women of childbearing age, who do not practice a medically accepted contraception (i.e., systematic contraceptives, diaphragm, condoms with spermicide, sexual abstinence) during the study and during a 2 years post-study period and who do not present a negative pregnancy test (serum or urine).
• History of hypersensitivity to the study drug, to any drug with similar chemical structure, or to any excipient present in the pharmaceutical form of the study drug.
• Diabetes type 2 (would result in interference with the experimental manipulation)
• Participation in other studies employing a drug during the present study or within the last three months.
• Current use of antidiabetic, weight-loss, or psychoactive medication or substances.
• Pacemaker, implanted medical pumps, implanted cardiac catheters or acute or unstable heart disease (angina pectoris).
• Intracranial implant (aneurysm clips, shunts, stimulators, cochlear implants or electrodes) or other metallic objects inside or near the head (mouth excluded) that cannot be removed.
• Claustrophobia or another contraindication to MRI.
• Insufficient German language skills.

Sponsors & Collaborators

• Leibniz-Institut für Resilienzforschung (LIR) gGmbH: lead
• University of Latvia: collaborator
• University of Zurich: collaborator
• Johannes Gutenberg University Mainz: collaborator
• University of Warsaw: collaborator

Study Sites (3)

Universitätsmedizin der Johannes Gutenberg-Universität Mainz (UM)

Mainz, Rhineland-Palatinate, 55131, Germany

Location

University of Warsaw

Warsaw, 00-927, Poland

Location

University Zurich (UZH)

Zurich, CH-8032, Switzerland

Location

Related Publications (4)

• Kalisch R, Muller MB, Tuscher O. A conceptual framework for the neurobiological study of resilience. Behav Brain Sci. 2015;38:e92. doi: 10.1017/S0140525X1400082X. Epub 2014 Aug 27.

  PMID: 25158686 BACKGROUND

• Cathomas F, Holt LM, Parise EM, Liu J, Murrough JW, Casaccia P, Nestler EJ, Russo SJ. Beyond the neuron: Role of non-neuronal cells in stress disorders. Neuron. 2022 Apr 6;110(7):1116-1138. doi: 10.1016/j.neuron.2022.01.033. Epub 2022 Feb 18.

  PMID: 35182484 BACKGROUND

• Vennin C, Hewel C, Todorov H, Wendelmuth M, Radyushkin K, Heimbach A, Horenko I, Ayash S, Muller MB, Schweiger S, Gerber S, Lutz B. A Resilience Related Glial-Neurovascular Network Is Transcriptionally Activated after Chronic Social Defeat in Male Mice. Cells. 2022 Oct 27;11(21):3405. doi: 10.3390/cells11213405.

  PMID: 36359800 BACKGROUND

• Shao X, Ma SJ, Casey M, D'Orazio L, Ringman JM, Wang DJJ. Mapping water exchange across the blood-brain barrier using 3D diffusion-prepared arterial spin labeled perfusion MRI. Magn Reson Med. 2019 May;81(5):3065-3079. doi: 10.1002/mrm.27632. Epub 2018 Dec 18.

  PMID: 30561821 BACKGROUND

MeSH Terms

Conditions

Psychological Well-Being

Interventions

Metformin

Condition Hierarchy (Ancestors)

Personal Satisfaction; Behavior

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Raffael Kalisch, Prof. Dr.

  Leibniz Institute for Resilience Research gGmbH (LIR)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Frédérique M.W Maas, MSc

CONTACT

+49 155 1060 7971; Frederique.Maas@lir-mainz.de

Raffael Kalisch, Prof. Dr.

CONTACT

+49 (0)6131 178419; raffael.kalisch@lir-mainz.de

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. Raffael Kalisch

Model Details: Prospective, randomized, parallel-group, placebo-controlled, double-blind, multi-center experimental study

Study Record Dates

• First Submitted: April 24, 2025
• First Posted: May 11, 2025
• Study Start: June 1, 2025
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027
• Last Updated: May 11, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: All anonymized data will be made openly accessible through public depositories (in particular, OSF) upon publication or at latest two years after the termination of the project and will remain accessible for at least ten years upon completion of the study.
• Access Criteria: Collaborators can get access to the pseudonymized data under the supervision of a Data Use and Access Committee (DUAC). All anonymized data will be made openly accessible through public depositories (in particular, OSF).

Locations

CH (1); PL (1); DE (1)