The efficacy of the tricyclic and tetracyclic compounds in major depression is well established. The evidence for their effectiveness has been reviewed previously (Agency for Health Care Policy and Research 1993; Davis and Glassman 1989). Imipramine is the most extensively studied tricyclic antidepressant, in part because for many years it was the standard agent against which other new drugs were compared. In 30 of 44 placebo-controlled studies, imipramine was more effective than placebo. If data from these studies are combined, 65% of 1,334 patients completing treatment with imipramine were substantially improved, whereas 30% of those on placebo improved. Intention-to-treat response rates for placebo-controlled studies of imipramine in outpatients were 51% for imipramine and 30% for placebo (Agency for Health Care Policy and Research 1993). In most comparison studies, the other tricyclic and tetracyclic antidepressants have been found to be comparable to imipramine in efficacy.