This study is testing a nasal spray called esketamine to help adults with treatment-resistant depression. This means they have tried at least two different antidepressants, but they didn’t work well enough. The study will compare how well esketamine works compared to a fake spray (placebo) in improving depression symptoms. Esketamine will come in doses of 56 mg and 84 mg.

• Duration: Participants will take part in the study for several weeks, with regular check-ups.
• Eligibility: Participants must have depression without psychotic features and not have used esketamine before.
• Compensation: Participants may be compensated for their time and travel.

Participants must be comfortable using a nasal spray and women of childbearing age must have a negative pregnancy test. People who have used esketamine, had certain treatments like electroconvulsive therapy, or have severe substance problems might not be able to join. The study aims to see if esketamine can help when other treatments haven't worked.