To assess the trends of drug expenditure, utilization and price of SSRIs and SNRIs antidepressants in the U.S. Medicaid program, and to highlight the market share of SSRI and SNRI and the effect of generic drug entry on Medicaid drug expenditure. A retrospective descriptive data analysis was conducted for this study. A national pharmacy summary data for study brand and generic drugs were retrieved from the Medicaid State Outpatient Drug Utilization Data collected by the U.S. Center of Medicaid/Medicare Services. The study covered the period between 1991 and 2018. Study drugs include 12 different SSRI and SNRI brands and their generics available in the market, such as Citalopram, Escitalopram, Paroxetine, Fluoxetine, Sertraline, Venlafaxine, Desvenlafaxine, Duloxetine, and Levomilnacipran. Data were analyzed annually and categorized by total prescriptions (utilization), total reimbursement (spending) and cost per prescription as the proxy of price for each drug. From 1991 to 2018, total prescription of SSRI and SNRI drugs rose by 3001%. Total Medicaid spending on SSRIs & SNRIs increased from $64.5 million to $2 billion in 2004, then decreased steadily until reached $755 million in 2018. SSRIs average utilization market share was 87% compared to 13% of SNRIs’ utilization market share. About 72% of total Medicaid spending on the two groups goes to SSRIs, remaining 28% for SNRIs. SSRI and SNRI brands’ prices increased overtime. On the contrary, generics price was steadily decreased overtime. SSRIs' and SNRIs' utilization increased dramatically over the last 30 years. The utilization shifted from brand to generic drugs resulting in less spending but high utilization due to their low generic drug price. SSRI generics captured most of the prescription market in Medicaid programs in the past 10 years. Generic substitution demonstrated to be a meaningful cost-containment policy for Medicaid programs.