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.
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
, have minor structural
differences from traditional cyclic antidepressants but have similar
toxicity in overdose and thus are discussed in this chapter.
a muscle relaxant that is almost structurally identical to amitriptyline
but lacks antidepressant activity.2
Table 171-0.1 Cyclic Antidepressants
and Related Drugs
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