Our study provides the first rationale for testing specific P2X7 antagonists such as CE-224,535 or JNJ-54175446, which were assessed without success for the treatment of rheumatoid arthritis (NCT00628095) and are under evaluation for the treatment of major depressive disorders (NCT04116606), respectively, alone or in combination with specific antagonists of NLRP3 such as Tranilast or Dapansutrile, which were assessed for the treatment of Cryopyrin-Associated Periodic Syndrome (CAPS) (NCT03923140) or systolic heart failures (NCT03534297), respectively. The gene discussed is P2RX7; the disease is major depressive disorder.