Antidepressant Toxicity

Updated: Apr 12, 2015
  • Author: Jeena Jacob, MD, PharmD; Chief Editor: Asim Tarabar, MD  more...
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Overview

Practice Essentials

Overuse of tricyclic antidepressants (TCAs) is a major cause of both non-fatal and fatal drug poisoning in the world. TCA toxicity can be caused by either an acute ingestion or a chronic ingestion. See the image below.

Toxicity, antidepressant. ECG shows the terminal R Toxicity, antidepressant. ECG shows the terminal R wave in aVR and the widened QRS complex associated with tricyclic antidepressant (TCA) toxicity.

Signs and symptoms

Clinical symptoms of antidepressant toxicity often progress rapidly and unpredictably. Many times, patients present asymptomatically or minimally symptomatic and progress to life-threatening cardiovascular and neurologic toxicity within an hour.

Toxicity typically presents as symptoms affecting the autonomic nervous system, central nervous system, and the heart.

Anticholinergic symptoms may include dry mouth and skin, urinary retention, and decreased gastric motility or ileus.

CNS symptoms include altered mental status, delirium, and headache. More severe symptoms include psychotic behavior, hallucinations, and seizures.

Cardiac findings include cardiac dysrhythmias, hypotension, and conduction block.

See Clinical Presentation for more detail.

Diagnosis

Electrocardiography has great utility in predicting the severity of toxicity and is the single most important test to determine diagnosis and prognosis. Prospective studies of patients with TCA overdose show that the sensitivity of an R-wave greater than or equal to 3 mm in aVR can predict toxicity. Rightward deviation of QRS vector (a negative deflection in lead 1 and a positive final deflection in lead aVR) is associated with TCA toxicity.

A chest radiograph should be obtained if there is evidence of hypoxia, aspiration or ARDS.

See Workup for more detail.

Management

Immediate evaluation is imperative for any patient presenting with a suspected tricyclic overdose. Intravenous access should be obtained, and the patient should be connected to a cardiac monitor. If the patient presents with CNS depression, intubation should be considered. An ECG should be obtained, and basic laboratory studies, including electrolytes and glucose levels, should be sent.

Activated charcoal is not always indicated for TCA ingestions. In cases of altered mental status, the benefits of charcoal need to be weighed against the risk of aspiration. Therefore, prior to charcoal administration, the airway needs to be secured in patients with an altered mental status.

See Treatment and Medication for more detail.

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Background

Tricyclic antidepressants (TCAs) were one of the most important causes of mortality resulting from poisoning until 1993 and still continue to be a major cause of death from self-poisoning. Although selective serotonin reuptake inhibitors (SSRIs) have overtaken them to become first-line therapy for depression, TCAs remain widely prescribed for depression and an increasing number of other indications including anxiety disorders, attention deficit disorder, pediatric enuresis, and chronic pain syndromes. In 2012,cyclic antidepressant overdoses were involved in 2.4% of all fatalities reported to US poison centers.

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Pathophysiology

TCAs have long been thought to exert their therapeutic effects by inhibiting the presynaptic reuptake of biogenic amines, primarily serotonin and norepinephrine. TCAs can be structurally divided into secondary and tertiary amines. The secondary amines exert more selective effects on norepinephrine reuptake, whereas tertiary amines are more potent reuptake inhibitors of serotonin.

In addition to their effects on these receptor systems, TCAs affect many other receptor systems, resulting in many of their toxic effects. They are antagonists at muscarinic acetylcholine receptors, peripheral alpha-adrenergic receptors, and histamine receptors. The cardiovascular toxicity, which is the most common cause of morbidity and mortality from TCAs, is related to their membrane-stabilizing effect through sodium channel blockade and alpha-adrenergic blockade. The effects of these drugs on vascular tone, myocardial action potential, and the autonomic nervous system can cause severe hypotension, dysrhythmias, and conduction delays.

TCAs bind to and inhibit the movement of sodium ions into the fast sodium channel thereby slowing phase O depolarization in the His-Purkinje system and ventricular myocytes. This results in slowed cardiac conduction by slowing the propagation of ventricular depolarization which is manifested as a prolonged QRS on the ECG. The right bundle branch is affected disproportionately by the conduction delay because it has a longer refractory period thereby resulting in a rightward shift of the terminal QRS axis and the right bundle-branch block (RBBB) pattern that is seen on the ECG of some patients who are exposed to TCAs (a characteristic ECG is shown in the image below).

Toxicity, antidepressant. ECG shows the terminal R Toxicity, antidepressant. ECG shows the terminal R wave in aVR and the widened QRS complex associated with tricyclic antidepressant (TCA) toxicity.

TCAs also block phase 3 repolarization in His-Purkinje myocytes, resulting in prolonged QTc on the ECG. Specifically, TCAs inhibit outward potassium current by blocking potassium channels in phase 3, which ultimately results in prolongation of the QT interval. Prolongation of the QTc usually predisposes to the development of torsades de pointes but in the setting of TCA exposure, it is uncommon because torsades de pointes is more likely to occur in the setting of bradycardia and the anticholinergic effects of these drugs produce offsetting tachycardia.

Refractory hypotension is caused primarily by the inhibition of alpha-1 adrenergic receptors. This hypotension can be exacerbated by hypoxia, acidosis, and volume-depletion. Although initial reuptake inhibition of norepinephrine (NE) in the central and peripheral nervous systems can result in a patient initially presenting with hypertension and tachycardia, prolonged blockade can cause depletion of norepinephrine from the presynaptic nerve terminal, which results in the subsequent development of refractory hypotension and bradycardia in cases of serious overdose. This biphasic result is seen because most norepinephrine is recycled at the nerve terminal for rapid reuse. When this reuptake is blocked, the initial hypertension and tachycardia result. However, with serious overdose, all the available synaptic norepinephrine is depleted, resulting in hypotension.

Sinus tachycardia is the most common cardiac disturbance seen following TCA overdose. Competitive blockade at muscarinic acetylcholine receptors, thought to primarily play a role though norepinephrine reuptake inhibition, contributes to the tachycardia. Wide-complex tachycardia is also observed which results primarily from prolonged antegrade conduction and the ensuing nonuniform conduction leads to reentrant ventricular dysrhythmias.

Neurologic effects of TCAs, including agitation and delirium, primarily result from CNS blockade of muscarinic receptors. TCA seizures usually occur within 1-2 hours of ingestion and are thought to occur secondary to increased concentrations of norepinephrine, interactions with GABA and NMDA-glutamate receptors, antidopaminergic properties, anticholinergic properties, and inhibition of neuronal sodium channels. Uncontrolled seizures can result in severe metabolic acidosis, rhabdomyolysis, hyperthermia, and acute renal failure. Resulting seizure-induced acidosis can also exacerbate cardiovascular toxicity.

Pulmonary complications including acute lung injury, aspiration pneumonitis, and acute respiratory distress syndrome (ARDS) may also be seen. One study showed dose-related vasoconstriction and bronchoconstriction in isolated rat lungs associated with amitriptyline exposure. Acute lung injury can also result from coma, hypotension, pulmonary infection, and excessive fluid administration.

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Frequency

United States

According to the American Association of Poison Control Center's 108,773 antidepressant exposures were reported in 2012. {Ref 3}

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Mortality/Morbidity

Fatalities per antidepressant overdose declined from 73 per 10,000 reported ingestions in 1983 to 32 per 10,000 in 2003 due to the increased use of selective serotonin reuptake inhibitors (SSRIs). However, tricyclic antidepressant (TCA) overdoses had higher rates of hospitalization (78.7% vs 64.7% hospitalized) and much higher fatality rates than did SSRI overdose reports (0.73% vs 0.14% mortality).

In October 2003, the US Food and Drug Administration (FDA) issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. In September 2004, the results of an FDA analysis suggested that the risk of emergent suicidality in children and adolescents taking SSRIs was real. The FDA advisors recommended the following:

  • A "black-box" warning label be placed on all antidepressants, indicating that they increase the risk of suicidal thinking and behavior (suicidality)
  • A patient information sheet (Medication Guide) be provided to the patient and their caregiver with every prescription
  • The results of controlled pediatric trials of depression be included in the labeling for antidepressant drugs

The committees recommended that the products not be contraindicated in the United States because access was important for those who could benefit from them. For more information, see the FDA Statement on Recommendations of the Psychopharmacologic Drugs and Pediatric Advisory Committees.

Some studies have shown that the FDA warnings regarding suicide in children on antidepressants may have had the unintended result of a decrease in the rates of diagnosis and treatment of depression, as well as dosing adjustments by physicians. It has also been noted that monitoring of these patients did not increase following the warnings. [1, 2, 3, 4]

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