ECT is highly effective and patients that receive this modality often present with severe forms of major depression. Early relapse is perhaps the most critical clinical problem in the use of ECT. In unipolar patients, the current standard is to use continuation monotherapy with a heterocyclic (HCA) or other antidepressant for relapse prevention following ECT. This practice is largely based on three studies conducted in England in the 1960's. Besides methodological flaws, the relevance of this work to present practice is questionable. ECT was frequently a 'first-choice' treatment and standards for adequate pharmacotherapy have changed considerably. Resistance to adequate trials of antidepressants is now the primary indication for ECT and the same class of antidepressant medication that patients failed during the acute episode is commonly used as continuation therapy following ECT. The efficacy of this practice has never been substantiated. In an earlier naturalistic study, we found that the relapse rate was twice as high in patients who had failed one or more adequate preECT HCA trials, compared to patients who came to ECT without any adequate medication trials. Adequacy of postECT pharmacotherapy was only marginally related to relapse. In related research, we have also suggested that medication resistance is a strong predictor of ECT short-term outcome. Using the R10 mechanism, we propose to complete a multi-center study that re-evaluates continuation pharmacotherapy in ECT responders. The study is conducted at the New York State Psychiatric Institute, University of Iowa, and Western Psychiatric Institute and Clinic. A parallel group, random assignment, double-blind design is used to test the relative efficacies of placebo, nortriptyline, and combination nortriptyline-lithium carbonate treatments in preventing relapse following ECT response in primary unipolar patients. It was hypothesized at the outset that nortriptyline alone was of limited benefit for many patients and less effective than its combination with lithium. The interim data document remarkably high relapse rates both with placebo and nortriptyline, and substantial efficacy for the combination treatment. In addition, a larger sample is prospectively evaluated regarding clinical features and treatment history, with standardization of ECT administration across sites. The hypothesis is tested that medication resistance is a potent predictor of ECT efficacy, and, when considered, is responsible for the apparent association of better ECT response in depressed patients with psychosis. This study should have important implications for when ECT is considered during the treatment of the acute depressive episode and, most critically, in establishing an efficacious pharmacological strategy for relapse prevention.