Efficacy of inflammation-based stratification for add-on celecoxib or minocycline in major depressive disorder: Protocol of the INSTA-MD double-blind placebo-controlled randomised clinical trial

Different lines of evidence confirm the involvement of the immune system in the pathophysiology of major depressive disorder. Up to 30% of depressed patients present with an immune-mediated subtype, characterized by peripheral inflammation (high-sensitive C-reactive protein (hsCRP) ≥ 3 mg/l) and an atypical symptom profile with fatigue, anhedonia, increased appetite, and hypersomnia. This immune-mediated subtype of MDD is associated with poorer response to first-line antidepressant treatment. Consequently, strategies for immune-targeted augmentation should be prioritised towards patients with this subtype. Meta-analyses have shown modest but heterogeneous treatment effects with immune-targeted augmentation in unstratified MDD cohorts, with celecoxib and minocycline as most promising first-line treatment options. However, no study has prospectively evaluated the effectiveness of a priori stratification by baseline inflammation levels for add-on celecoxib or minocycline in MDD. The INSTA-MD trial is a multicentre, 12-week, randomised, double-blind, placebo-controlled, parallel-group stratified clinical trial of adjunctive minocycline or celecoxib to treatment-as-usual for patients with MDD. Two hundred forty adult patients with Major Depressive Disorder who failed to remit with one or two trials of antidepressant treatment will be enrolled and allocated to high-hsCRP (hsCRP ≥3 mg/L) or low-hsCRP (hsCRP