2018; von Muecke‐Heim et al. 2021). In chronic stress models, P2X7R antagonists consistently blunted depressive‐like behaviors and reversed immune changes (Ribeiro et al. 2019). P2rx7 downregulation in our meta‐analysis and in patients with MDD (Aston et al. 2005) might reflect a homeostatic or compensatory response to chronic overstimulation of this pathway, limiting excessive inflammation. This evidence concerns the gene P2RX7 and major depressive disorder.