Cyclic antidepressants were the first-generation of drugs developed to treat depression. Their use for treating depression has declined greatly as safer agents have been developed. Cyclic antidepressants are now occasionally used to treat obsessive-compulsive disorder, attention-deficit disorder, panic and phobia disorders, anxiety disorders, and a variety of other conditions.
In 2013, cyclic antidepressants were the most commonly identified antidepressants associated with overdose-related deaths.1,2 Roughly half of all cyclic antidepressant exposures involve other drugs as well, and most co-ingestants increase the incidence and severity of cyclic antidepressant overdose toxicity.
Eight cyclic antidepressants are currently available in the United States (Table 177-1), with more agents available in other countries. Therapy is initially started at the lowest therapeutic level and slowly increased until the desired therapeutic response is achieved. This approach allows patients to become acclimated to adverse effects such as sedation and dry mucous membranes. Two related antidepressants, amoxapine and maprotiline, have structural differences from traditional cyclic antidepressants but have similar toxicity in overdose. Cyclobenzaprine is a muscle relaxant that is almost structurally identical to amitriptyline but lacks antidepressant activity, and serious toxicity from overdose is rare.3
TABLE 177-1Cyclic Antidepressants and Related Drugs ||Download (.pdf) TABLE 177-1 Cyclic Antidepressants and Related Drugs
|Generic Name ||Typical Adult Outpatient Daily Dose (milligrams) ||Recommended Maximal Adult Outpatient Daily Dose (milligrams) ||Active Metabolites |
|Amitriptyline ||75–150 ||300 ||Nortriptyline |
|Amoxapine* ||50–300 ||400 || |
|Clomipramine ||25–50 ||250 ||Desmethylclomipramine |
|Cyclobenzaprine* ||15–30 ||30 ||None |
|Desipramine ||75–200 ||300 ||None |
|Doxepin ||75–300 ||300 ||Desmethyldoxepin |
|Imipramine ||75–200 ||300 ||Desipramine |
|Maprotiline* ||75–150 ||225 ||Desmethylmaprotiline |
|Nortriptyline ||75–150 ||150 ||None |
|Protriptyline ||15–60 ||60 ||None |
|Trimipramine ||75–200 ||300 ||Desmethyltrimipramine |
Cyclic antidepressant–related drug toxicity can occur at therapeutic dosages from one or more of seven possible mechanisms (Table 177-2).
TABLE 177-2Mechanisms for Cyclic Antidepressant Drug Toxicity at Therapeutic Dosages ||Download (.pdf) TABLE 177-2 Mechanisms for Cyclic Antidepressant Drug Toxicity at Therapeutic Dosages
Administration of high therapeutic dosages to naive individuals
Drug interactions with medications sharing similar pharmacologic actions
Elevated levels of cyclic antidepressants due to genetically slow hepatic metabolism
Drug interactions with other medications that inhibit hepatic metabolism (cytochrome P-450 system)
Additional toxicity from other active ingredients (e.g., antipsychotics) contained in some combination cyclic antidepressant formulations
Preexisting cardiovascular or CNS disease that predisposes patients to toxicity
Development of serotonin syndrome, usually in combination with serotoninergic medications
The cyclic antidepressants are named after their chemical structure, which consists of a three-ring central structure plus a side chain, thus the common term tricyclic antidepressants. Maprotiline is a tetracyclic (also termed a heterocyclic), with a four-ring central structure plus a side chain. Cyclic antidepressants are subdivided into two categories: tertiary and secondary ...