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Cyclic antidepressants are considered first-generation antidepressants, along with monamine oxidase inhibitors (see Chapter 173, Monamine Oxidase Inhibitors). Although they have different mechanisms of action, both classes have in common a nonspecific pharmacologic approach to treating depression, low therapeutic index, troublesome side effects, and the potential to produce severe toxicity in overdose. Second-generation antidepressants (see Chapter 172, Atypical Antidepressants, Serotonin Reuptake Inhibitors, and Serotonin Syndrome) have been developed over the past 30 years with more specific mechanisms of action, higher therapeutic index, fewer side effects, and considerably greater safety in overdose compared with the first-generation antidepressants. Although cyclic antidepressants are currently considered second-line therapy for treating major depression, they are frequently used in treating other psychiatric and medical conditions such as obsessive-compulsive disorder, attention-deficit disorder, panic and phobia disorders, anxiety disorders, eating disorders, insomnia, chronic pain syndromes, fibromyalgia, irritable bowel syndrome, peripheral neuropathies, and nocturnal enuresis, as well as for migraine headache prophylaxis and drug-withdrawal therapy in selected cases. Cyclic antidepressants are often used in pediatric and adolescent patients, but their benefit must be balanced against the U.S. Food and Drug Administration warning that all antidepressants have the potential to increase the risk of suicidal thinking and behavior in patients <24 years of age.

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Over 102,000 human exposures to antidepressants were reported to U.S. poison control centers in 2008, and 11,000 of those exposures involved cyclic antidepressants.1 Antidepressants were the third most common cause of drug-related fatalities, with cyclic antidepressants being the most commonly identified class of antidepressants to cause overdose-related deaths.1 Roughly half of all cyclic antidepressant exposures involve other drugs as well. This is an important consideration, because coingestants typically increase the incidence and severity of cyclic antidepressant overdose toxicity. Most single-drug cyclic antidepressant exposures occur in young adults, are intentional, require treatment at a health care facility, and have a 75% chance of causing some degree of clinical toxicity. Currently eight cyclic antidepressants are available in the U.S. (Table 171-0.1), but many more agents are available in other countries. The five cyclic antidepressants most commonly involved in drug-related exposures reported in 2008 are amitriptyline (55%), nortriptyline (9%), doxepin (8%), imipramine (5%), and desipramine(1%).1 Therapeutic dosages of cyclic antidepressants are highly variable as evidenced by the wide range of adult daily dosages in outpatient treatment recommendations. Initial cyclic antidepressant therapy should always be started at the lowest therapeutic dosage and then be slowly increased until the desired therapeutic response is achieved. This approach allows most patients to become acclimated to the typical cyclic antidepressant–induced adverse effects such as sedation and dry mucous membranes. Two related antidepressants, amoxapine and maprotiline , have minor structural differences from traditional cyclic antidepressants but have similar toxicity in overdose and thus are discussed in this chapter. Cyclobenzaprine is a muscle relaxant that is almost structurally identical to amitriptyline but lacks antidepressant activity.2

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Table Graphic Jump Location
Table 171-0.1 Cyclic Antidepressants and Related Drugs 

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