**Study Summary:** This study tests a new medicine called **CLE-100 (oral esketamine)** for people with **Major Depressive Disorder (MDD)** who haven't improved with standard antidepressants. **Esketamine** is a type of medicine that may help with depression. The study is **Phase 2**, meaning it's early in testing, and **double-blind**, which means neither the patients nor the researchers know who is getting the real medicine or a **placebo** (a fake treatment). Participants will continue their regular antidepressant and take either CLE-100 or placebo once a day for 4 weeks. After this, they might join a longer, 6-month study where everyone gets CLE-100. **Key Points:** - **Duration:** 4 weeks initially, with an option to continue for 6 months. - **Compensation:** Participants may be compensated for their time. - **Risks:** Possible side effects include increased blood pressure or heart rate. To join, you must be 18-65 years old, have MDD, and have tried at least two other antidepressants without enough improvement. You cannot join if you have a history of certain mental health or substance use disorders.