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.
The tricyclic compounds are also effective when used for maintenance treatment. Early studies demonstrated that maintenance treatment with a tricyclic would reduce the relapse rate associated with placebo by about 50% (Davis 1976). These studies, however, usually employed low doses. Subsequently, the Pittsburgh group found that imipramine, at full dose, effectively maintained nearly 80% of the depressed patients for a 3-year period compared with 10% of those on placebo (Frank et al. 1990). In this study, maintenance psychotherapy had an intermediate effect, with about 30% of the patients remaining well. Although this seminal study demonstrated the impressive value of maintenance treatment with full-dose imipramine, the magnitude of the findings may reflect characteristics of the sample treated. The sample comprised patients with recurrent depression who might have been expected to do poorly on placebo. In addition, the patients selected for the study had a history of symptom-free periods between prior episodes, suggesting that these patients might be more likely (than patients with a history of residual symptoms) to have a complete response to treatment. In practice, clinicians may encounter patients with chronic depression, patients with residual symptoms, or patients with comorbid medical and psychiatric disorders. For such patients, drug treatment may be more effective than placebo, but the actual number of patients whose depression remains in remission may be lower.
The U.S. Food and Drug Administration (FDA) has approved all of the tricyclic and tetracyclic compounds discussed in this chapter for the treatment of depression with the exception of clomipramine. In Europe, clomipramine is also used for depression; in fact, it is regarded by many as the most potent antidepressant.
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