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. This evidence concerns the gene IL18 and depressive symptom measurement.