The tricyclic drugs were the mainstay of treatment for depression for three decades. Although the second-generation antidepressants appear to be better tolerated, no new agent has been shown to be more effective than the tricyclics, and if anything, there has been concern that the new agents may be less effective. The tricyclics were "dirty" drugs; that is, they had multiple actions. Although their side effects have been emphasized, these multiple actions may have contributed to their efficacy. Not only does amitriptyline block uptake of 5-HT, but its metabolite blocks uptake of norepinephrine, and in addition, amitriptyline is a 5-HT2 antagonist. The principal drawback of this class of agents is the risk of serious cardiac adverse effects. They can aggravate arrhythmia in patients with preexisting conduction delay. They also may increase the risk of sudden death in children and in patients with ischemic heart disease. Moreover, a week's supply of medication taken in overdose could be fatal. As noted, even though the use of the tricyclics has diminished, amitriptyline remains a common cause of death by overdose in the United States. Because of these adverse effects, it is unlikely that there will be a resurgence of interest in the tricyclics. Nevertheless, the efficacy of these agents across a range of disorders, including pain, suggests the possible advantage of antidepressant drugs with multiple actions.

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