1. The authors examined the effect of total sleep deprivation (SD) in combination with nortriptyline in 20 patients with major depressive disorder (MDD). Patients underwent a 36-hour SD procedure followed by nortriptyline started on the evening after SD, with ratings for two weeks. 2. Eleven (55%) patients were responders; they showed a rapid and sustained remission after SD, whereas non-responders demonstrated the delayed results expected with nortriptyline. 3. High initial depression scores and absence of depersonalization were associated with response to SD, while being female and middle insomnia were associated with response to the combined regimen. 4. The combination of SD with antidepressants proves to be an effective and safe treatment modality. © 1992.