Tricyclic Antidepressant Toxicity in Pediatrics

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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. 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 the following:

The most commonly prescribed cyclic antidepressants include the following:

Cyclic antidepressants have a narrow therapeutic window, which increases 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 few decades, the prescription of selective serotonin reuptake inhibitors (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 fact, according to poison center data, cyclic antidepressants continue to contribute disproportionately to mortality for antidepressant overdoses. For example, the American Association of Poison Control Centers reported that in 2014, tetracyclic and tricyclic antidepressants accounted for 5724 of the 46,517 single exposures to antidepressants (12%), but for 13 of the 32 deaths (41%). ^[1]

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 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 toxic effects of cyclic antidepressants are related to the following four 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 dysrhythmias 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.

The 2013 American Association of Poison Control Centers (AAPCC) annual report on toxic exposures in the United States included 46,517 single exposures to antidepressants and 111,985 case mentions. Of single exposures, 5724 were due to tetracyclic and tricyclic antidepressants, with 13 related deaths. Single exposures to cyclic antidepressants were reported in 1819 pediatric patients. Of cases in which the patient’s age was known, 799 occurred in children younger than 6 years, 242 in those 6 to 12 years old, and 776 occurred in teenagers. ^[1]

According to poison center data, cyclic antidepressants toxicity contribute disproportionately to mortality from antidepressant exposures. Although cyclic antidepressants accounted for approximately 12% of reported single exposures to antidepressants in 2013, they accounted for approximately 49% of deaths (20 of 41 total deaths). ^[1] Cyclic antidepressants were the most common cause of overdose-related fatalities until the 1990s, 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]

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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Derrick Lung, MD, MPH Physician, Department of Emergency Medicine, San Mateo Medical Center; Assistant Clinical Professor, Division of Clinical Pharmacology, Department of Medicine, San Francisco General Hospital; Assistant Medical Director, California Poison Control System, San Francisco Division

Derrick Lung, MD, MPH is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children’s Medical Center

Disclosure: Received salary from Merck for employment.

Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children’s Hospital of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, Wisconsin Medical Society

Disclosure: Nothing to disclose.

Michael E Mullins, MD Assistant Professor, Division of Emergency Medicine, Washington University in St Louis School of Medicine; Attending Physician, Emergency Department, Barnes-Jewish Hospital

Michael E Mullins, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians

Disclosure: Received stock ownership from Johnson & Johnson for none; Received stock ownership from Savient Pharmaceuticals for none.

Heidi Connolly, MD Associate Professor of Pediatrics and Psychiatry, University of Rochester School of Medicine and Dentistry; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center

Heidi Connolly, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Christopher I Doty, MD, FACEP, FAAEM Assistant Professor of Emergency Medicine, Residency Program Director, Department of Emergency Medicine, Kings County Hospital Center, State University of New York Downstate Medical Center

Christopher I Doty, MD, FACEP, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, Council of Emergency Medicine Residency Directors, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Frank A Maffei, MD, FAAP Associate Professor of Pediatrics, Temple University School of Medicine; Medical Director, Pediatric Intensive Care Unit, Janet Weis Children’s Hospital at Geisinger Health System

Frank A Maffei, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Samara Soghoian, MD, MA Clinical Assistant Professor of Emergency Medicine, New York University School of Medicine, Bellevue Hospital Center

Samara Soghoian, MD, MA is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Rashida Y White-McCrimmon, MD Resident Physician, Department of Emergency Medicine, Kings County Hospital Center, State University of New York Downstate Medical Center

Rashida Y White-McCrimmon, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, and Emergency Medicine Residents Association

Disclosure: Nothing to disclose.

Tricyclic Antidepressant Toxicity in Pediatrics

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