Patients, ages 18 to 65 with a diagnosis of major depressive disorder, currently depressed without psychotic features will be recruited into this study. This experimental proof-of-concept study has two Study Phases. Study Phase I consists of total sleep deprivation. Responders to total sleep deprivation who subsequently relapse will enter Study Phase II. Study Phase II is a double-blind crossover administration of either intravenous yohimbine or saline solution during REM sleep.