Transcriptomic activation of immune cell trafficking predicts antidepressant response to minocycline

Although inflammation has been suggested as a promising therapeutic target for major depressive disorder (MDD), uncertainty remains about how to recognise individuals who may benefit from anti-inflammatory treatments. Transcriptomic profiles provide an important tool to identify relevant biological mechanisms associated with response. In this study, we investigate: i) the ability of transcriptomic profiles to predict antidepressant response to anti-inflammatory treatment with minocycline, and ii) the effect of minocycline on transcriptomic profiles based on the antidepressant response. We included n = 36 MDD antidepressant non-responders who took part in the 4-week double-blind, randomised, placebo-controlled, MINocycline in DEPression (MINDEP) trial (n = 17 on minocycline and n = 19 on placebo). We performed RNA-sequencing and pathway analyses in whole-blood samples collected at baseline and end of treatment (4-week follow-up). We investigated differences between responders and non-responders at baseline and follow-up, separately in the minocycline and placebo groups. At baseline, 227 transcripts were differentially expressed between responders and non-responders to minocycline (FDR < 0.1), vs. 11 transcripts in the placebo group. Pathway analyses of differentially regulated transcripts in minocycline responders (p < 0.05, |FC| > 2, FDR < 0.1) revealed activation of immune pathways with evidence of immune cell trafficking signatures (p < 0.05, |z-score| ≥ 2), with upregulation of immunoglobulin and downregulation of T-cell receptor transcripts. In contrast, there were no significant transcriptomic differences between responders and non-responders at week 4. A differential transcriptomic regulation, with activation of immune cell trafficking pathways, predicts antidepressant response to minocycline (but not placebo). The recognition of this molecular profile may guide future trials in immunopsychiatry and support a personalised clinical approach in MDD.