Chapter 68: Cyclic Antidepressants

HISTORY AND EPIDEMIOLOGY

The term cyclic antidepressant (CA) refers to a group of pharmacologically related xenobiotics used for treatment of depression, neuralgic pain, migraines, enuresis, and attention deficit hyperactivity disorder (ADHD). Most CAs have at least three rings in their chemical structure. They include the traditional tricyclic antidepressants (TCAs) imipramine, desipramine, amitriptyline, nortriptyline, doxepin, trimipramine, protriptyline, and ­clomipramine, as well as other cyclic compounds such as the tetracyclic, maprotiline and the dibenzoxapine amoxapine, antidepressants.

Imipramine was the first TCA used for treatment of depression in the late 1950s. However, the synthesis of iminodibenzyl, the “tricyclic” core of ­imipramine, and the description of its chemical characteristics date back to 1889. Structurally related to the phenothiazines, imipramine was originally ­developed as a hypnotic for agitated or psychotic patients and was serendipitously found to alleviate depression. From the 1960s until the late 1980s, the TCAs were the major pharmacologic treatment for depression in the United States. However, by the early 1960s, cardiovascular and central nervous system (CNS) toxicities were recognized as major complications in patients with TCA overdoses. The newer CAs developed in the 1980s and 1990s were designed to decrease some of the adverse effects of older TCAs, improve the therapeutic index, and reduce the incidence of serious toxicity. The epidemiology of CA poisoning has evolved significantly in the past 30 years, resulting in great part from the introduction of the selective serotonin reuptake inhibitors (SSRIs and SSNRIs) and other newer antidepressants for the treatment of depression. Although the use of CAs for depression has decreased, other medical indications, including chronic pain, sleep disorders, obsessive-compulsive disorder, and, particularly in children, enuresis and ADHD, have emerged, resulting in their continued use.^19,87 The antidepressants are a leading cause of drug-related self-poisonings in the developed world, primarily because of their ready availability to people with depression or chronic pain who by virtue of their diseases are at high risk for overdose. However, despite the increase in SSRI use and overdose, patients with TCA overdoses continue to have a higher incidence of hospitalization and fatality than do those with SSRI overdose and continue to be among the leading xenobiotics associated with fatality reported to poison control centers (Chap. 130).

Despite the emergence of the SSRIs in the early 1990s, TCAs are still frequently prescribed by pediatric office-based practices for many of the conditions noted earlier. Since the October 2004 US Food and Drug Administration boxed warning about the increased risk of suicidal behavior associated with antidepressant use, several reports describe significant declines in antidepressant dispensing in children compared with historical trends.²⁵ Nevertheless, CA poisoning likely will continue to be among the most lethal unintentional drug ingestions in younger children because only one or two adult-strength pills can produce serious clinical effects in young children.

PHARMACOLOGY

The TCAs are classified into tertiary and secondary amines based on the presence of ...