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)
Abstract
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…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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