The prevalence of major depressive disorder (MDD) in pancreatic cancer (PC) has been reported up to 7 times higher than the general population. Despite repeated studies that show worse quality of life, survival outcomes, and treatment compliance in cancer patients with depression, baseline antidepressant use ranges from 15% to 27%. A meta-analysis of 6 prospective trials specific to PC estimates that 43% of patients with PC experience depression after diagnosis. This is especially alarming in patients with PC, who may experience a prodrome of symptoms including depression and loss of drive. In fact, this prodrome of symptoms may very well be due to an overexpression of indoleamine 2,3-dioxgenase, an enzyme in the kynurenine pathway that leads to serotonin depletion and the buildup of cytotoxic metabolites in the brain. In this literature review, we outline all previous studies pertinent to PC and depression, as well as the molecular underpinnings that may contribute to states of depression, and report on previous randomized control trials in cancer populations that investigate the use of antidepressants to treat depressive symptoms and improve quality of life both prophylactically and after the onset of major depressive disorder. In addition, we detail a case report outlining the precipitous decline in health in 1 patient with PC and depression.