In this study, we profiled the function of IL-18 in the central nervous system as follows: (1) IL-18 was found in the cytoplasm of human neurons; (2) 16 genes expressed in the PFC of Il18−/− mice were shared with a CMS model of depression; (3) TTR in the brain, including the PFC, was a mediator associated with depression in IL-18 deficiency; and (4) AHSG in the serum was associated with the dysregulation of physiological homeostasis, such as energy imbalance or immune impairment. Here, TTR is linked to major depressive disorder.