**Study Summary** This study is comparing two treatments for people with treatment-resistant depression (TRD). One treatment is **Esketamine (Spravato®)**, a nasal spray approved by the FDA. The other is **ketamine**, given through an IV (drip into the arm), which is not FDA-approved for depression. The study will test how well each treatment works, how comfortable people are using them, and how well they handle any side effects. It will also try to find out which treatment might work better for different people. **Key Points:** 1. The study lasts for 5 years and involves 400 participants, with 200 in each treatment group. 2. Participants must be 18 or older, have tried at least two antidepressants without success, and have moderate to severe depression. 3. Women must use effective birth control during the study and can't donate eggs. Before joining, make sure you understand the study's requirements, including not driving after treatment and arranging a ride home. Always talk to your doctor before participating in any study.