TBM (Applied Biomedical Research with a Primary Societal finality) project: INSTA-MD: INflammation-based Stratification for immune- Targeted Augmentation in Major Depressive disorder

Current treatment strategies for major depressive disorder (MDD) are insufficient, and up to 60% of MDD patients do not remit after two consecutive trials of first-line antidepressants. Immune dysregulation is both a feature and a cause of MDD, and approximately 30% of MDD patients display an immune-mediated subtype. This immune-mediated MDD is associated with poor response to treatment as usual and needs targeted intervention. Celecoxib and minocycline have emerged as the preferred compounds for first-line immune-targeted augmentation. Both show moderate-tolarge treatment effects with good acceptability in the total MDD population. C-reactive protein (CRP) is a readily accessible trait marker of MDD and can be used to identify patients with immune-mediated MDD. Proof-of-concept studies suggest that hsCRP can be used as a stratification tool to predict response to immune-targeted augmentation in MDD. The current INSTA-MD project will prepare the clinical implementation of immune-targeted augmentation in patients with immune-mediated MDD: 1) A multicentre, 12-week, double-blind RCT of immune-targeted augmentation in patients with MDD (n=240). Disproportionate stratified sampling will be based on baseline hsCRP levels (low= < 3 mg/L; high= ≥ 3 mg/L). Participants in each hsCRP stratum will be randomised to augmentation treatment with either minocycline, celecoxib, or placebo. 2) Development of treatment ecommendations (a) the identification and screening of immune-mediated MDD & (b) the integration of immunetargeted augmentation in primary care. Recommendations will be disseminated among researchers/clinicians/caretakers/patients, in Flanders, Belgium and Europa. A joint European guidance paper will be created. P: immune-mediated subtype of MDD I: TAU + immune-targeted augmentation with CXB or MCO C: TAU + placebo O: (1) reduction in depressive symptoms; (2) improvement in MDD remission rates