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.
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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.
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.
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).
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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.
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]
Clinical symptoms of antidepressant toxicity often progress rapidly and unpredictably, and many times, patients present asymptomatically or minimally symptomatic and progress to life-threatening cardiovascular and neurologic toxicity within an hour.
Central nervous system (CNS) findings are as follows:
Early manifestations include altered mental status, psychotic behavior, delirium and agitation (from anticholinergic effect), and hallucinations. These symptoms can later proceed rapidly to lethargy, stupor, and coma.
Seizures are usually generalized and often occur within 1-2 hours of ingestion. Seizures occurs in 4% of patients with overdose and in 13% of fatal cases. CNS depression and seizures result from mixed effects including those of neuronal fast sodium channel blockade; reuptake inhibition of monoaminergic neurotransmitters; and blockade of H1-histamine, muscarinic, GABA, and NMDA-glutamate receptors.
Other findings include ileus; urinary retention; hyperthermia; and dry, flushed skin from anticholinergic effect.
Cardiac findings are as follows:
Hypotension as a result of dysrhythmias or alpha-adrenergic blockade with a possible, lesser role played by cardiac conduction abnormalities and direct myocardial depression, autonomic neuron neurotransmitter depletion (caused by reuptake blockade), and capillary leakage
Dysrhythmias
Conduction block
Slowed ventricular conduction and resulting dysrhythmias from blockade of fast sodium channels
Tachycardia caused by muscarinic anticholinergic effects
Hypertension (early) caused by inhibition of norepinephrine reuptake
Pulmonary findings are as follows:
Acute lung injury
Hypoventilation
Aspiration pneumonitis secondary to CNS depression
Acute respiratory distress syndrome (ARDS)
Hypoxia caused by hypoventilation, aspiration, and capillary leakage
Tricyclic antidepressant toxicity can be caused by either an acute ingestion or a chronic ingestion. Toxicity secondary to chronic ingestions usually presents with symptomatology that is an exaggeration of the usual side effects of tricyclics.
Quantitative screening or tricyclic serum concentrations are of minimal utility in the acute setting because serum levels do not correlate with acute toxicity secondary to pharmacologic properties such as large volume of distribution, pH-dependent protein binding, wide intrapatient variability of terminal elimination half-lives, and prolonged distribution phases. An abbreviated screen for acetaminophen and aspirin coingestants usually is sufficient.
Electrolytes and glucose levels should be used to screen for anion gap acidosis that exists with other ingestions and to look for metabolic disturbances that can alter mental status, cause seizures, or change the ECG. See the Anion Gap calculator.
Blood gas analysis should be obtained to check pH, with an attempt to maintain an alkaline environment (pH = 7.45-7.55). Acidemia allows a greater degree of fast sodium channel binding by the TCA and produces a wider QRS on the ECG.
Aggressively manage airway for patients who present agitated or with a decreased level of consciousness. For these patients, endotracheal intubation may be required before gastric lavage or activated charcoal to prevent aspiration.
Consider hyperventilation after intubation as a method of serum alkalinization. It is not as effective as sodium bicarbonate as a single method of alkalinization. If performed, carefully, monitor the patient's pH levels.
After the patient's airway, breathing, and circulation are secured, gastric lavage can be initiated in the symptomatic patient with an intentional overdose within 2 hours after ingestion.
If the patient exhibits declining mental status, the intubation should be performed first. Activated charcoal should be administered if the benefit of charcoal administration outweighs the risk of aspiration.
A central venous line may be helpful in administering medication and monitoring fluid status.
Hemodialysis
Hemodialysis and hemoperfusion are not effective and are not recommended for TCA poisoning.
The poor efficacy of hemodialysis probably is because only a small amount of free TCA is present in the serum. TCA is highly bound to serum proteins and tissues, with a large volume of distribution.
ECG has great utility in predicting the severity of toxicity. Indeed, ECG is the single most important test to determine diagnosis and prognosis. One study reported that 33% of patients with a QRS interval of 100 milliseconds or more developed seizures, and 14% developed ventricular dysrhythmias. For patients with a QRS of 160 milliseconds or more, 50% developed ventricular dysrhythmias. Other significant ECG findings include the following:
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.
Sinus tachycardia is a typical but nonspecific early sign of TCA toxicity.
Dysrhythmias are also nonspecific to TCA toxicity but important to respond to.
Ventricular tachycardia is the most common lethal dysrhythmia.
Torsade de pointes is uncommon in overdose but may occur in patients taking therapeutic doses.
Bradycardia and asystole are usually preterminal rhythms, although patients have been resuscitated from these with aggressive supportive care.
Closely monitor vital signs and cardiovascular, neurological, and respiratory status in addition to ECG monitoring. Rapidly transport all patients with possible TCA ingestion to the hospital because clinical deterioration often occurs rapidly after overdose. Although the effectiveness of out-of hospital activated charcoal has not been studied in the prehospital setting, because of the aspiration risk involved, it is not routinely recommended. Aggressive airway support is vital.
Immediate evaluation is imperative for any patient presenting with a suspected tricyclic antidepressant (TCA) 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. Seizures are treated with benzodiazepines.
Dysrhythmias
Sodium bicarbonate is the first-line therapy if TCA ingestion is known or strongly suspected. Sodium bicarbonate should be considered in life-threatening circumstances in the prehospital setting if there is a protocol for its use.
Procainamide, quinidine, beta-blockers, and calcium channel blockers are contraindicated.
Hypotension
Hypotension is treated with sodium bicarbonate and intravenous fluids. Vasopressors are recommended for refractory hypotension.
Hypertonic saline 3% can be administered to reverse cardiotoxicity in patients not responsive to sodium bicarbonate. This modality could be considered in refractory cases but should not supersede treatment with NaHCO3.
Consider consulting a regional poison control center or medical toxicologist.
Patients with abnormal vital signs or mental status changes may need intensive care unit (ICU) care, which may require the consultation of an intensivist.
The mainstay of specific treatment of significant TCA-related toxicity is NaHCO3 administered in conjunction with supportive care, including aggressive airway support, antiseizure, vasopressor, and dysrhythmic medications. Indications for NaHCO3 administration include QRS widening, hypotension, dysrhythmias, and seizures that are associated with QRS widening. NaHCO3 replaces lidocaine as the drug of choice for ventricular tachycardia following TCA overdose in a variation of the usual ACLS guidelines. Hypotension with evidence of shock not responsive to judicious fluid therapy and sodium bicarbonate are indications for pressors.
Contraindicated medications include beta-blockers, calcium channel blockers, and class IA (procainamide, quinidine, disopyramide, moricizine), class IC (flecainide, propafenone), and possibly class III (bretylium, amiodarone, sotalol) antidysrhythmics.
Activated charcoal is not routinely indicated. 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. Since the anticholinergic effects of TCAs delay gastric emptying and slow GI motility, this may allow efficacy for charcoal when administered relatively late postingestion.
Clinical Context:
First-line drug for cardiovascular morbidity in TCA poisoning. Provides exogenous sodium to overcome the competitive fast sodium channel blockade produced by TCA, and produces an alkalemia (or reverses acidemia) that mitigates the fast sodium channel blockade by TCA.
Indicated for QRS widening, dysrhythmias, hypotension, and seizures that are associated with QRS widening. Patient can be monitored and given boluses of bicarbonate prn if QRS widening and block resolves with initial treatment. Maintain serum potassium levels (see Precautions below). Resolution of QRS widening is a reasonable endpoint for NaHCO3 administration. However, because it may recur, patients who have had QRS widening need to be on a cardiac monitor that is being continuously monitored.
Clinical Context:
Other vasopressors may also be used. Norepinephrine's vasopressive effect is from its alpha alpha-adrenergic agonist properties. Vasopressors are indicated for persistent hypotension not responsive to judicious fluid loading and sodium bicarbonate.
Clinical Context:
Has alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypertension, and vascular permeability. Beta-agonist effects of epinephrine include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.
Clinical Context:
Strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity that produces vasoconstriction of arterioles in the body. Increases peripheral venous return. Generally not used as a first-line agent. Correct volume deficits before administration.
Clinical Context:
Secondary to NaHCO3 for dysrhythmias due to TCA toxicity. Class IB antiarrhythmic that increases electrical stimulation threshold of the ventricle, suppressing automaticity of conduction through the tissue. Second-line agent for treatment of ventricular dysrhythmias.
Serum alkalinization with NaHCO3 is the first-line and most effective therapy for arrhythmias. Vasopressors can be useful in correcting hypotension. Lidocaine is the second-line agent behind alkalinization for arrhythmias. Class IA and IC antiarrhythmic agents (eg, procainamide, disopyramide, quinidine, flecainide, encainide) are contraindicated, as are beta-blockers and calcium channel blockers.
Clinical Context:
Increasing the action of GABA, a major inhibitory neurotransmitter, may depress all levels of CNS, including limbic and reticular formation.
Most seizures are short, self-limited, and may resolve before treatment can be administered; however, if prolonged greater than several minutes or repetitive, treatment is indicated. Controversy exists about the indications for sodium bicarbonate with seizures. A trial of NaHCO3 is recommended for seizures that are associated with QRS widening, after benzodiazepine treatment. If seizures are refractory to all treatment, paralysis is indicated to stop motor activity and resultant metabolic acidosis. Benzodiazepines may calm a patient presenting with agitation secondary to the anticholinergic effects. However, their use may exacerbate CNS depression from TCA overdose, so their use for this indication must be accompanied by aggressive monitoring and management of the airway.
Prognosis is generally favorable without long-term CNS or cardiovascular sequelae in patients who survive initial toxicity. Patients show clinical signs of toxicity in the first 6 hours; survival beyond this time suggests a favorable prognosis unless severe hypoxia or hypotension were present before initial treatment.
A small subset may have prolonged neurologic sequelae after status seizures or persistent hypotension.
Patients who remain asymptomatic without medical intervention following 6 hours of emergency department observation receive GI decontamination and have normal EKG findings with normal QRS duration may be medically cleared.
For patient education resources, see the First Aid and Injuries Center and Mental Health Center. Also see patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.
Jeena Jacob, MD, PharmD, Associate Director, Medical Toxicology Fellowship, North Shore University Hospital; Assistant Professor of Emergency Medicine, Hofstra North Shore-LIJ School of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Theodore I Benzer, MD, PhD, Assistant Professor in Medicine, Harvard Medical School; Director of the ED Observation Unit, Director of Toxicology, Chair of Quality and Safety, Department of Emergency Medicine, Massachusetts General Hospital
Disclosure: Nothing to disclose.
Specialty Editors
John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals
Disclosure: Nothing to disclose.
Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.
Additional Contributors
David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Eric Legome, MD, and Craig Smollin, MD, to the development and writing of this article.
Cassels C. FDA Suicide Warnings Change Antidepressant Prescribing Patterns, but Physicians Ignore Monitoring Recommendations. Medscape Today. Available at http://www.medscape.com/viewarticle/715952. Accessed: February 8, 2010.
Cassels C. FDA Suicide Warnings About Antidepressants Cut Rates of Depression Diagnosis and TreatmentExperts Call for FDA to Reconsider Black-Box Warning on Antidepressants. Medscape Today. Available at http://www.medscape.com/viewarticle/704235. Accessed: February 8, 2010.
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