In this study, researchers are testing a medicine called **lumateperone** to help people with **Major Depressive Disorder** (MDD), which is a serious type of depression. This study is for people aged 18 to 65 who haven’t improved much with their current antidepressant treatments (ADT). The study has three parts: a **Screening Period** up to 2 weeks to check if you can join; a **Treatment Period** for 6 weeks where you get either lumateperone or a placebo (a pill with no medicine); and a **Safety Follow-up Period** for 1 week to check on your health after treatment. You might get a chance to try a new treatment that could help your depression, but you won’t know if you’re taking the real medicine or the placebo. **Key Points:** - **Duration**: Up to 9 weeks total with 3 study periods. - **Treatment**: 6 weeks of either lumateperone or placebo. - **Eligibility**: Must have tried at least two antidepressants without much success. Participating could help find new treatments for MDD, but there's no guarantee you'll receive the active medication.