Early morning sleep deprivation (patient awake from 0200 to 2200 hours) produces a same-day antidepressant effect in approximately one-half of patients with major depression. Unfortunately, these antidepressant effects are short-lived and patients usually relapse to baseline depression levels within 48 hours. Recent work suggests, however, that the use of lithium with early morning sleep deprivation sustains this rapid antidepressant effect and makes it clinically useful. In a 30-day study, we compared the abilities of four different treatments (lithium plus early morning sleep deprivation, lithium plus a control sleep deprivation procedure, and desipramine with either of the two sleep manipulations) to induce a rapid (next-day) and sustained antidepressant response in 16 depressed patients. Lithium plus early morning sleep deprivation produced a quicker response than lithium with the control sleep deprivation, and the response was sustained for at least 30 days. In this design, however, lithium/early morning sleep deprivation was no faster than either of the two desipramine/sleep deprivation conditions in inducing remission. These results support the results of previous studies and suggest further investigation of this novel sleep/pharmacologic intervention is warranted.