Tricyclic Antidepressants: An Underutilized Treatment? Part I

HISTORY AND BACKGROUND The development of antidepressant medications began in the 1950s with the serendipitous discovery of monoamine oxidase inhibitors (MAOIs) and the tertiary amine class of tricyclic antidepressants (TCAs). Imipramine, the first marketed TCA, was introduced in 1957 as the result of an effort to improve on the phenothiazines. It was subsequently demonstrated to have antidepressant but not antipsychotic effects. The classification of TCAs is based on the molecular structure of 2 benzene rings joined by a 7-member ring containing nitrogen, oxygen, or only carbons. TCAs slow the rate of neuronal reuptake of serotonin and norepinephrine, increasing synaptic levels of both monoamines. TCAs also block histaminic, muscarinic, and 1 -adrenergic receptor sites, accounting for the unwanted adverse effects of weight gain, drowsiness, dry mouth, constipation, and orthostasis (Table 1). Their blockade of sodium channels in myocardial tissue makes these agents proarrhythmic and potentially lethal in overdose. The secondary amines are derived by demethylating the tertiary amines. The secondary amines primarily block norepinephrine reuptake. Compared with the tertiary amines, they have a lower affinity for histaminic, cholinergic, and 1 -adrenergic receptors, and are generally better tolerated. Their affinity for myocardial sodium channels, however, still renders these drugs dangerous in overdose. The toxic-to-therapeutic ratio is well established with the secondary amines. Serum blood levels can be monitored to optimize efficacy while minimizing adverse effects. After participating in this activity, the psychiatrist should be better able to: • Evaluate the role for tricyclic antidepressants in the treatment of major depression. • Assess the adverse effects and risks when using tricyclic antidepressants. • Use tricyclic antidepressants in treatment strategies for patients with depression.