Study protocol: role of the blood-brain barrier in stress resilience: investigating new pathways towards Pharmacological augmentation of stress resilience (a PHASR-PP project study).

BACKGROUND: Preclinical research indicates that the integrity of the blood-brain barrier (BBB) is an important resilience factor. Further, there is preclinical evidence suggesting that the mTOR pathway regulates BBB function and that pharmacological inhibition of this pathway may improve stress resilience. METHODS: Translating these results to the human, we aim to establish a prospective association between BBB integrity and stress resilience in stressor-exposed individuals at risk to develop stress-related mental health problems. Using an observational study design, we primarily exploit assumed natural inter-individual variation in BBB integrity, assessed with neuroimaging, which we attempt to relate to inter-individual variation in stress resilience. We hypothesize that better whole-brain BBB integrity predicts better stress resilience. As a further measure to maximize sensitivity, we attempt to enhance inter-individual variation in BBB integrity by administering the indirect mTOR pathway inhibitor metformin to half of the participants, using a randomized parallel-group placebo-controlled double-blind multi-centre experimental design. This experimental-interventional approach also allows us to ask whether metformin improves whole-brain BBB integrity and whether this in turn improves stress resilience, via mediation analysis. Such a finding would suggest a causal role for BBB integrity in stress resilience. In additional analyses, blood-based biomarkers and regional neuroimaging metrics are used as measures of BBB integrity, and the influence of socio-demographic, anamnestic, psycho-social, immunological, metabolic, and other neuroimaging variables on BBB function and stress resilience is also considered. DISCUSSION: The study may, for the first time, delineate a relationship between BBB function and stress resilience in humans and potentially implicate BBB integrity as a causal factor in resilience. Findings may inform the development of novel pharmacological strategies to improve BBB function and stress resilience, to be investigated in follow-up studies. TRIAL REGISTRATION: Registered under National Library of Medicine under the number NCT06965868 (https//clinicaltrials.gov/study/NCT06965868, initial registration date 04/24/2025, study start date 01/02/2026).