Tricyclic Antidepressant Toxicity in Pediatrics 

Cyclic antidepressants (CAs) have been used in the treatment of major depression since the late 1950s. Originally termed tricyclic antidepressants (TCAs), they are now more accurately called cyclic antidepressants because some newer members of this class have a 4-ring structure. They are also currently used in the treatment of chronic pain syndromes and for migraine prophylaxis. In the pediatric population, they are commonly prescribed for the treatment of enuresis, obsessive-compulsive disorder, attention deficit hyperactivity disorder, school phobia, and separation anxiety. The most commonly prescribed cyclic antidepressants include amitriptyline, desipramine, imipramine, nortriptyline, doxepin, and clomipramine.

Cyclic antidepressants have a narrow therapeutic window, increasing their likelihood for toxicity. The clinical features of cyclic overdose were first reported in 1959, only 2 years after they began to be used clinically. In the past decade, the prescription of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression has far surpassed that of cyclic antidepressants. However the prescription of cyclic antidepressants and the incidence of cyclic antidepressant toxicity is now actually on the rise due to increasing use of cyclic antidepressants in the therapy of chronic pain syndromes.

Cyclic antidepressants remain second only to analgesics as the most common drugs implicated in overdose fatalities. Some evidence suggests that cyclic antidepressants are associated with more overdose fatalities per number of prescriptions issued than other antidepressant classes.

Cyclic antidepressants are named for their 3-ring or 4-ring aromatic (heterocyclic) structure. They are rapidly absorbed in the GI tract and undergo first-pass metabolism in the liver. Conjugates are then renally eliminated. Cyclic antidepressants are very lipophilic and highly protein-bound, leading to large volumes of distribution. They have long elimination half-lives that often exceed 24 hours (>31-46 h for amitriptyline). In an overdose, altered pharmacokinetics may prolong elimination and increase toxic effects. Cyclic antidepressants have significant anticholinergic effects that can delay gastric emptying. Additionally, the acidosis that results from respiratory depression and hypotension reduces protein-binding, resulting in higher serum levels of active free drug.

Although the exact therapeutic mechanism of cyclic antidepressants is not known, it is most likely related to decreased central norepinephrine and serotonin reuptake, resulting in increased levels of these biogenic amines in the brain. The therapeutic dose for most cyclic antidepressants in children is 5-10 mg/kg/d, and toxicity may be observed at doses of 10-20 mg/kg/d. Significant adverse effects are generally seen only with doses greater than 20 mg/kg/d. The toxic effects of cyclic antidepressants are related to the following 4 pharmacologic effects:

• Anticholinergic effects
• Direct alpha-adrenergic blockade
• Inhibition of norepinephrine and serotonin reuptake
• Blockade of fast sodium channels in myocardial cells, resulting in quinidinelike membrane-stabilizing effects

The most serious adverse effects of cyclic antidepressant toxicity are due to CNS effects and cardiovascular instability. Depressed mental status is generally caused by the antihistamine and anticholinergic properties of cyclic antidepressants, whereas seizures are thought to be due to increased CNS levels of biogenic amines. Life-threatening cardiovascular complications are due to impaired conduction from fast sodium channel blockade. This decreases the slope of phase zero depolarization, widens the QRS complex, and prolongs the PR and QT intervals. Impaired cardiac conduction may lead to heart block and unstable ventricular arrhythmias or asystole. cyclic antidepressants have also been shown to directly depress myocardial contractility. However, the profound hypotension seen in serious cyclic antidepressant poisoning is primarily due to vasodilatation from direct alpha-adrenergic blockade.

Frequency

United States

The 2004 American Association of Poison Control Centers (AAPCC) annual report on toxic exposures in the United States included 103,155 reported cases of antidepressant toxicity; 12,269 were due to heterocyclic agents, with a total of 86 deaths.^[1] Cyclic antidepressants poisoning was reported in 2,948 children. Of these cases, 1,355 occurred in children younger than 6 years, while another 1,593 occurred in children aged 6-19 years.

Among antidepressant agents, cyclic antidepressants were the third most common class implicated in toxic exposures. SSRIs were the most common antidepressants taken in toxic doses. This is most likely due to the frequency with which they are prescribed.

Mortality/Morbidity

Cyclic antidepressants toxicity accounts for approximately 12% of reported toxic exposures for antidepressants but accounts for approximately 29% of deaths due to antidepressant poisoning. Cyclic antidepressants were the most common cause of overdose-related fatalities until the past decade, when analgesics surpassed them as a class.

In addition to acute poisoning from intentional or unintentional overdose, several well-documented adverse drug reactions (ADRs) are associated with tricyclic antidepressant use, including sedation, insomnia, orthostatic hypotension, cardiac dysrhythmias, movement disorders,^[2] and skin hyperpigmentation.^[3] Some of these ADRs may be responsible for the increased risk of falls, with associated morbidity, seen among elderly patients taking cyclic antidepressants. A recent prospective cohort study noted an association between cyclic antidepressant use and an increased risk of coronary heart disease.^[4]

Some of the morbidity associated with cyclic antidepressant ADRs may be linked to genetic variations in the CYP2D6 enzyme, which is important for the hepatic metabolism of this class of medication.^[5]

Sex

The incidence of cyclic antidepressants poisoning is higher in women than in men. This most likely reflects a higher rate of depression and suicide attempts among women.

Age

The distribution of toxic cyclic antidepressant exposures in children is bimodal, with peaks in early childhood and the later teenaged years. Accidental exposure is typically seen in toddlers, whereas adolescents tend to present with intentional overdoses.