This study tests the effect of a treatment called COMP360 for adults with treatment-resistant depression (TRD), which is a kind of depression that doesn't get better with regular treatments. The study will include 568 adults who have tried other medicines without success. It will last up to 16 weeks, including 3-10 weeks for checking if participants are eligible and 6 weeks for follow-up after receiving the treatment.

Participants will receive COMP360 in different doses: 25 mg, 10 mg, or 1 mg. They must be at least 18 years old and have major depression, without any other serious mental health issues like schizophrenia or bipolar disorder. The study is double-blind, meaning neither the participants nor the researchers know who gets which dose, to ensure fairness.

• Participants should not have used certain therapies like electroconvulsive therapy recently.
• They will receive psychological support during the study.
• Participants must stop any medications that are not allowed in the study.