There is a high coincidence between obesity and psychiatric disorders including depression. Depressive disorders are commonly treated with antidepressants, including the selective serotonin reuptake inhibitor Lexapro (escitalopram). Although candidates for elective Roux-en-Y gastric bypass (RYGB) surgery may be treated with escitalopram, drug dosing strategies are typically not adjusted postoperatively. Therefore, studies are needed to better characterize escitalopram drug concentrations in a postsurgical setting. Turbulent flow-liquid chromatographic-tandem mass spectrometric methods were used to quantify escitalopram concentrations in serum in study participants approved for RYGB. Blood was collected from study subjects 2 weeks before surgery, and 2 and 6 weeks postoperatively, to assess the impact of RYGB on systemic drug concentrations. Twelve samples from 4 study participants were collected and analyzed for serum escitalopram concentrations. Two weeks post-RYGB, although there were minimal changes in each participant's body mass index (<5%), drug concentrations were 33% (4%-71%) decreased as compared with presurgical serum concentrations. There were further decreases in drug concentrations 6 weeks postsurgery. All clinical laboratory values were within normal reference intervals. RYGB significantly alters the gastrointestinal tract and impacts escitalopram drug concentrations, even shortly after surgery.