The present study was designed to investigate the effect of chronic treatment with a SSRI (fluoxetine) and a tri-cyclic antidepressant (imipramine) on depressive-like behavior, endothelial dysfunction, glucose homeostasis, lipid profile, and vascular expression of TLR4, TNF-α and IL-1β in diabetic and non-diabetic rats exposed to chronic restraint stress, experimental model of depression, in a trial to justify the preference of one antidepressant agent over the other for management of comorbid depression in diabetic subjects. Here, IL1B is linked to major depressive disorder.