After 12 weeks of therapy, the metformin group exhibited considerably less depression than the placebo group (LSMD: 3.454; 95 % CI: 4.145-2.76). -Compared to the placebo group, the metformin group also exhibited significantly lower levels of TNF–α, IL-1β, IL-6, IGF-1, MDA, and CRP, as well as significantly higher levels of BDNF and serotonin. This evidence concerns the gene BDNF and major depressive disorder.