Up to two thirds of patients with major unipolar depression will not respond to the first medication prescribed. Depression may be considered resistant to treatment when at least two trials with antidepressants from different pharmacologic classes (adequate in dose, duration, and compliance) fail to produce a significant clinical improvement. Evidence regarding the effectiveness of psychotherapy for treatment-resistant depression is limited. A recent high-quality trial found that patients who did not respond to citalopram and who received cognitive behavior therapy (with or without continued citalopram) had similar response and remission rates to those who received other medication regimens. Initial remission rates in that trial were 37 percent, and even after three additional trials of different drugs or cognitive behavior therapy, the cumulative remission rate was only 67 percent. In general, patients who require more treatment steps have higher relapse rates, and fewer than one half of patients achieve sustained remission. No treatment strategy appears to be better than another. Electroconvulsive therapy is effective as short-term therapy of treatment-resistant depression. There is no good-quality evidence that vagal nerve stimulation is an effective treatment for this condition.