This chapter focuses on the economic impact of treatment non-response in major depressive disorders (MDD). Patient responses to initial therapy for MDD fall into four basic outcome categories. The frequency and health-care costs are associated with all four treatment outcome categories. The cost of treatment non-response is best measured relative to the costs experienced by patients who succeed on their initial course of therapy. The costs of non-response are measured relative to the costs patterns achieved by patients with an adequate course of therapy in terms of dose and duration. Multivariate ordinary least-squares (OLS) regression analyses were used to investigate the impact of the patient's drug use profile on health-care costs. The antidepressant drug therapy outcomes achieved by newly treated California Medicaid (Medi-Cal) patients are presented in the chapter. An adequate course of therapy on the initial antidepressant therapy prescribed was achieved by 17.1% of all treated patients.