Tricyclic Antidepressant Toxicity in Pediatrics

Updated: Mar 18, 2020
  • Author: Derrick Lung, MD, MPH; Chief Editor: Stephen L Thornton, MD  more...
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Overview

Practice Essentials

Cyclic antidepressants (CAs) have been used in the treatment of major depression since the late 1950s. Originally termed tricyclic antidepressants (TCAs), they are more accurately called cyclic antidepressants because some newer members of this class have a four-ring structure. Cyclic antidepressants have a narrow therapeutic window, which increases their likelihood for toxicity. [1]

In 2018, the US Food and Drug Administration (FDA) issued a public health advisory that directed manufacturers of all antidepressant drugs, including TCAs, to revise the labeling for their products to include a boxed warning and expanded warning statements alerting health care providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents. [2]

The risk of suicidality associated with these drugs was identified based on a combined analysis of short-term (up to 4mo), placebo-controlled trials of 9 antidepressant drugs in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients on drug therapy was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. [2]

On the basis of those data, the FDA determined that the following points are appropriate for inclusion in the boxed warning [2] :

  • Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders.
  • Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.
  • Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.
  • Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.
  • A statement regarding whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).

Only fluoxetine (Prozac) is FDA approved for use in treating major depressive disorder (MDD) in pediatric patients. The selective serotonin reuptake inhibitors (SSRIs) Prozac, sertraline (Zoloft), and fluvoxamine (Luvox) and the cyclic antidepressant clomipramine (Anafranil) are approved for OCD in pediatric patients. None of the drugs is approved for other psychiatric indications in children. [2]

In the past few decades, the prescription of SSRIs for the treatment of depression has far surpassed that of cyclic antidepressants. However, the decreased use of cyclic antidepressants for depression has in part been attenuated by expanded applications for these agents, such as treatment of chronic pain syndromes. In the pediatric population, they are commonly prescribed for the treatment of the following:

The most commonly prescribed cyclic antidepressants include the following:

  • Amitriptyline
  • Desipramine
  • Imipramine
  • Nortriptyline
  • Doxepin
  • Clomipramine

Onset of symptoms of cyclic antidepressant toxicity typically occurs within 2 hours and typically begins with antimuscarinic effects. Major cardiovascular and central nervous system (CNS)  complications typically occur within the first 6 hours after exposure. See Presentation and Workup. Pharmacologic therapy in patients with CA toxicity is directed toward the cardiac and CNS effects. Sodium bicarbonate therapy is the cornerstone of treatment for cyclic antidepressant–induced conduction disturbances, ventricular dysrhythmias, and hypotension. See Treatment and Medication.

For patient education information, see First Aid for Poisoning in Children and Child Safety Proofing.

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Pathophysiology

Cyclic antidepressants are named for their three-ring or four-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 antimuscarinic 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 toxic effects of cyclic antidepressants are related to the following four pharmacologic effects:

  • Antimuscarinic 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 antimuscarinic 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 dysrhythmias or asystole.  Fast sodium channel blockade may also contribute to development of seizures.

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.

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Epidemiology

The 2018 annual report of the American Association of Poison Control Centers National Poison Data System(AAPCC-NPDS) reported 1521 tetracyclic and 3969 tricyclic antidepressant exposures (from a total of 56,891 antidepressant single exposures). Of tetracyclic and tricyclic antidepressant exposures combined, 3500 occurred in adults age 20 years and older; 915 occurred in adolescents aged 13-19 years, and 675 ocurred in children younger than 6 years. The lowest number of exposures (228) were seen in children aged 6-12. [4]

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. 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.

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Prognosis

Cyclic antidepressants contribute disproportionately to mortality for antidepressant overdoses. The American Association of Poison Control Centers reported that in 2018, tetracyclic and tricyclic antidepressants accounted for 5490 of the 56,891 single exposures to antidepressants (10%), but for 25 of the 50 deaths (50%). [4]

Approximately 70% of intentional cyclic antidepressant overdoses may be fatal prior to arrival in the ED. However, among patients who present for medical treatment, serious complications are rare compared with the total number of toxic ingestions, and in-hospital mortality is as low as 2-3%. With early recognition and aggressive treatment, a good outcome can be expected.

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, [5]  and skin hyperpigmentation. [6]  Some of these ADRs may be responsible for the increased risk of falls, with associated morbidity, seen among elderly patients taking cyclic antidepressants. A prospective cohort study noted an association between cyclic antidepressant use and an increased risk of coronary heart disease. [7]

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. [8]

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