Chapter 9.Tricyclic and Tetracyclic Drugs

The tricyclic antidepressant agents hold an important place in the history of treatments for depression. They were the first class of antidepressant compounds to be widely used in depression and remained the first-line treatment for more than 30 years. The observation of their activity led to theories of drug action involving norepinphrine and serotonin. Indeed, this “psychopharmacological bridge” suggested that alterations of these neurotransmitters might cause depression (Bunney and Davis 1965; Prange 1964; Schildkraut 1965). The tricyclics were extensively studied, and through this study, the field developed several key principles to guide the management of depressive illness. For example, the importance not only of providing an adequate dosage and duration of medication during acute treatment but also of sustaining symptom improvements through the use of continuation treatment became recognized. The adverse events associated with the tricyclics required that psychiatrists become familiar with a variety of syndromes, such as anticholinergic delirium, delayed cardiac conduction, and orthostatic hypotension. The observation that tricyclic plasma concentrations varied widely stimulated interest in the relationship of these drug concentrations to hepatic metabolism and to clinical activity. The field was introduced to the concepts of genetic polymorphisms in the cytochrome P450 (CYP) enzyme system. Finally, our knowledge of how these drugs worked became the basis for the discovery of new drugs such as the selective serotonin reuptake inhibitors (SSRIs).