Tricyclic And Tetracyclic Drugs Introduction

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 norepinephrine and serotonin. Indeed, this "psychopharmacological bridge" suggested that alterations of these neurotransmitters might cause depression (Bunney and Davis 1965; Prange 1965; Schildkraut 1965). The tricyclics were extensively studied, and through this study the field developed several principles for the management of depressive illness. For example, in addition to understanding the need for adequate dose and duration during acute treatment, the importance of continuation treatment was described. The adverse events associated with these agents required that psychiatrists become familiar with a variety of syndromes, such as anticholinergic delirium, delayed cardiac conduction, precipitation of acute glaucoma, and orthostatic hypotension. The observation that tricyclic plasma concentrations varied widely stimulated interest in understanding the metabolism of tricyclics. The field was introduced to the concepts of polymorphisms in the mephenytoin and debrisoquine pathways (later relabeled the cytochrome P450 [CYP] 2C19 and 2D6 pathways), which in part explained the widely varying blood levels. Knowledge of the widely varying drug concentrations raised questions about the relationships of clinical activity and drug concentrations. Although effects of antipsychotics and a few other drugs on tricyclic plasma levels had been described in the 1970s, it was the observation of the effect of fluoxetine on desipramine coupled with the aggressive marketing of the selective serotonin reuptake inhibitors (SSRIs) that greatly expanded our awareness of and knowledge about drug interactions. Finally, our knowledge of how these drugs worked became the basis for the discovery of new drugs such as the SSRIs.

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