Drug-drug interactions are well documented and are known to change pharmacokinetic properties of an agent, affecting efficacy and increasing the risk for side effects or adverse events. While clinical trial and laboratory data assess the mechanism of these interactions, a compelling part of the picture is missing, the clinical and economic consequences associated with these events. OBJECTIVES: The purpose of this analysis was to identify changes in incurred charges related to the treatment of depression with respect to the concurrent use of drugs with interaction potential. METHODS: Complete medical and pharmacy claim records were collected for patients with depression by using an episoding methodology. Data collection began with the episode start and continued for 1 year. For patients with the use of specific antidepressants, cohorts were formed using the presence of concurrent use with other prescription drugs having documented interaction potential. Total depression related expenditures for patients with concurrent drug use were collected and compared to a matched patient group. RESULTS: A total of 4,655 patients were selected for observation, 1,681 had evidence of at least one (1) instance of co-administration of interacting agents. Of all patients, fluoxetine users had the greatest percentage of co-administration (39.9%) and bupropion users had the least amount (7.9%). When observing incurred healthcare charges, the average total yearly charges for treating depression were 35% higher for patients with the presence of drug co-administration than compared to matched patient group ($2,513 vs. $1,860, respectively, p<0.001). Service categories that were major drivers included professional visits, testing, outpatient facility, and prescription drugs. CONCLUSIONS: The presence of antidepressant drug co-administration seems to correlate with increased charges specific to the treatment of depression. This information is a compelling indicator that drug interactions are clinically significant and have serious economic consequences. Careful selection of antidepressants can avoid additional resource utilization.