Treatment of Mood Disorders: Tricyclic Antidepressants
Although no longer considered as first-line therapy, TCAs are still commonly used as initial treatment because of their familiarity. This heterocyclic class includes both the tricyclic and the tetracyclic compounds. Their efficacy has been known for decades, and they are widely used for the treatment of depression as well as panic disorders, generalized anxiety disorder, posttraumatic stress disorder, obsessive-compulsive disorder, eating disorders, and chronic pain disorders. Concern with the use of TCAs, especially in the medically ill, involves their adverse effects and theoretical evidence of increased mortality in patients with ischemic heart disease or arrhythmia.

The most common side effects of the TCAs are alterations of the cholinergic, histaminergic, and adrenergic pathways. Muscarinic blockade may result in dry mouth, constipation, urinary retention, tachycardia, exacerbation of closed angle glaucoma, and confusion and delirium in the elderly. Antihistaminic activity can cause somnolence, fatigue, weight gain, and gastrointestinal side effects. The α₁-adrenergic activity in TCAs may lead to orthostatic hypotension.

Conventional TCA therapy may pose significant risk to the cardiac patient because of an adverse effect on the cardiac conduction system. Through inhibition of the fast sodium channels of cardiac cells, TCAs may increase the PR interval and QRS duration and prolong the QTc interval. This slowing of cardiac conduction can increase the possibility of arrhythmias. Previously it was believed that tricyclics were more likely to possess antiarrhythmic activity than to be arrhythmogenic. This theory was based on studies involving imipramine hydrochloride and nortriptyline and their quinidine-like effect on cardiac conduction. The results of the Cardiac Arrhythmia Suppression Trial (CAST) study stimulated a reconsideration of this conventional thinking. This landmark study was the first to demonstrate increased mortality in post-MI patients being treated with Type 1c antiarrhythmic agents. Extrapolating these data to include TCAs because of their similar activity on conduction led to the postulate that TCAs as well could lead to an increased occurrence of death in post-MI patients. This has lead to recommendations that TCAs should be avoided in patients with preexisting arrhythmias (including first-, second-, and third-degree heart block and atrial fibrillation) and bundle branch block and in patients being treated with a Type 1c antiarrhythmic agent.