OBJECTIVES To compare economic outcomes of MDD patients who were treated with a patented SSRI (escitalopram, citalopram, sertraline, or paroxetine controlled-release) and were switched to a generic SSRI for non-medical reasons vs. those continuing on the patented SSRI.“Therapeutic substitution,” defined as change from a branded product to a different generic compound in the same class, is a common practice encouraged by low co-pay for the generic products. METHODS Adult MDD patients from the Ingenix Impact Database (2003-2007) were considered “switchers” if they were treated with a patented SSRI and switched to a generic SSRI. Those who had an MDD-related urgent care (hospitalization or emergency room) or psychotherapy visit in the seven days prior to switching were excluded. Patients who remained on the patented SSRI (“non-switchers”) were matched 1:1 to switchers. All-cause, mental health and MDD-related urgent care costs over six months were compared between switchers and non-switchers and regression models controlled for baseline differences. A subgroup analysis was conducted for patients treated with escitalopram. RESULTS The study included 4449 matched pairs, 3304 (74%) of whom started on escitalopram. Compared to non-switchers, switchers had higher risks of all-cause and mental health-related urgent care use (OR=1.15 and 1.34, respectively, P <0.01) and higher risk-adjusted MDD-related medical costs ($222, P<0.05). In escitalopram subgroup analyses, compared to non-switchers, switchers from escitalopram had even higher risks of all-cause (OR=1.21) and mental health-related urgent care use (OR=1.41, both P <0.01) and higher MDD-related medical costs ($151, P <0.05). CONCLUSIONS Compared to patients who continued on escitalopram or patented SSRIs, patients who switched to a generic SSRI incurred more urgent care resource use and higher MDD-related health care costs. The effects of “therapeutic substitution” should be carefully examined because increasing utilization of drugs with lower acquisition costs may not be a cost-saving strategy, when total health care costs are considered.