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Tricyclic Antidepressant Toxicity

Tricyclic Antidepressant Toxicity

Article Author:
Muhammad Khalid
Article Editor:
Muhammad Waseem
7/21/2020 10:54:11 PM
For CME on this topic:
Tricyclic Antidepressant Toxicity CME
PubMed Link:
Tricyclic Antidepressant Toxicity


Tricyclic antidepressants (TCAs) were introduced in the late 1950s for the treatment of depression. However, with the advent of selective serotonin reuptake inhibitors (SSRIs) and other new antidepressants, the use of TCAs has become limited, although it is still used to treat depression that has not responded to treatment with less toxic agents. In adults, TCAs are also used in migraine headache prophylaxis, treatment of neuralgic pain, including the pain associated with Ciguatera poisoning, and obsessive-compulsive disorder. In children, TCAs have been used to treat nocturnal enuresis. Despite the current limited use of TCAs, the curve for TCA-overdose associated hospitalization and fatality is on the rise.[1][2][3][4]


Since TCAs are mostly used for treating patients with chronic pain and neuropsychiatric disorders, toxicity and overdoses are mostly seen in these patients, who are taking them for these debilitating diseases. These drugs are commonly prescribed for these diseases, and therefore are readily available to these patients.


According to the database, TCA overdose accounted for 1.12 exposures per 10,000 population in 1992. Recently, the trend for antidepressant overdose has shifted more towards SSRIs. However, the rate of hospitalization is higher in cases of TCA overdose compared to SSRI, because of the narrower therapeutic index with TCAs.


Tricyclic antidepressants impose their therapeutic effects by inhibiting presynaptic reuptake of norepinephrine and serotonin in the central nervous system (CNS). This effect in the CNS can cause seizures. TCAs are weakly basic, and an acidic environment facilitates the formation of the ionized form and potentiates this effect. In cases of toxicity, TCAs block a number of receptors, including peripheral alpha-adrenergic, histaminic, muscarinic, and central serotonin receptors. Blockade of alpha-adrenergic receptors can cause hypotension. Blockade of muscarinic receptors can cause signs of anticholinergic toxicity, such as tachycardia, fever, dry mouth and skin, decreased bowel sounds, and altered mental status. Blockade of histamine receptors can also cause altered mental status. TCAs can cause cardiac toxicity. Blockade of fast sodium channels in myocardial cells slows the action potential and provides a membrane stabilizing effect. The characteristic QRS prolongation seen in TCA overdose occurs secondary to prolongation of phase “0” of the myocardial action potential. This effect can lead to heart block and bradycardia. QT prolongation seen in cases of TCA overdose occurs due to potassium channel blockade that may potentially cause torsades de pointes. TCAs can also exert a quinidine-like toxic effect on the myocardium that can cause decreased cardiac contractility and hypotension.[5][6][7]


TCAs are rapidly absorbed in the gastrointestinal tract. However, following an overdose, owing to the inherent anticholinergic effects, TCAs may decrease the gastrointestinal motility and cause delayed absorption and toxicity. Coingestion of other anticholinergic medications may cause more erratic absorption. TCAs have a long elimination half-life as these drugs are largely bound to the plasma protein and highly lipid-soluble. Renal excretion occurs after significant first-pass hepatic metabolism. TCAs are primarily metabolized by CYP2D6, and the enzyme inducers and inhibitors of this pathway may alter their metabolism. Toxicity may occur because of the primary compound or its metabolite. Respiratory or metabolic acidosis may increase the unbound fraction of TCA and may potentiate the harmful effects. Signs of toxicity usually appear within 2 hours’ post-ingestion. If 6 hours post-ingestion, there are no signs of toxicity seen both clinically and on the electrocardiogram, and the patient has normal bowel sounds, then most likely, the patient has not taken a significant overdose and can be medically cleared for psychiatric evaluation if needed. Once significant toxicity occurs, it usually lasts for 24-48 hours. However, there are case reports of significant toxicity due to Amitriptyline that lasted up to 5 days post-ingestion.

History and Physical

All patients with suspected TCA overdose should be immediately evaluated, and a 12 lead EKG should be obtained. The therapeutic index of TCAs is narrow, and therefore, the ingestion of 10 to 20 mg/kg is potentially life-threatening. Symptoms usually start in 30 to 40 minutes, and signs of toxicity are usually clinically apparent within 2 hours, but delayed toxicity may occur. History of co-ingestion or access to other medications, including acetaminophen and aspirin, is essential. Close attention to the patient’s vital signs and repeated physical examination for evidence of an anticholinergic toxidrome, cardiac toxicity, and neurologic toxicity should be done and will help guide proper management.


Cardiovascular, anticholinergic, and neurologic manifestations are common. Vital signs may be abnormal. The patient may not be able to protect his or her airway. Respiratory depression may occur. Sinus tachycardia is commonly present due to anticholinergic toxicity, but more dangerous tachydysrhythmias and even bradycardia with or without heart block can occur. Hypotension can occur due to dehydration, cardiac toxicity, and alpha-adrenergic blockade. The patient may often demonstrate anticholinergic toxicity, such as fever, dilated pupils, dry mouth, dry, warm skin, decreased bowel sounds, and altered mental status. The patient may be agitated or seizing, or the patient may have decreased mental status, and may even become comatose. An EKG should be obtained early in the management of these patients, and any evidence of sodium and/or potassium channel blockade should be promptly addressed. Prolongation of QRS, due to sodium channel blockade of more than 100 milliseconds, is predictive of seizures while QRS > 160 milliseconds is predictive of arrhythmia. An R/S ratio in AVR of 0.7 or more and an R wave in the AVR lead more than 3 mm is strongly predictive of seizures and arrhythmias. In addition to basic lab investigations, including levels of possible co-investments, such as acetaminophen and aspirin, a CT scan of the head to rule out other causes of altered mental status should be done if clinically indicated. It should be noted that TCA levels do not correlate with toxicity, but may be helpful in diagnosing an unknown overdose when the clinical symptoms and signs point to a possible TCA ingestion. Any sign of toxicity warrants admission in an intensive care setting for at least 24 hours. Asymptomatic patients should be continuously monitored for signs of toxicity, changes in vital signs, and EKG for at least 6 hours.[8][9][10][11]

Treatment / Management

Proper management of airway, breathing, and circulation is critical in cases of TCA poisoning. Gastrointestinal decontamination by activated charcoal should be done only if conditions are appropriate and the airway is protected. Charcoal decontamination may be effective up to 2 hours’ post-ingestion, especially if the bowel sounds are diminished. Every effort should be made to minimize the formation of acidosis, as acidosis may increase cardiac and neurologic toxicity. Seizures usually respond to benzodiazepines, but in cases of refractory seizures, prompt administration of anticonvulsants, such as phenobarbital or propofol, or even general anesthesia, should be considered. Sodium bicarbonate should be given to hemodynamically unstable patients, patients with seizures, and patients with QRS prolongation of more than 100 msec. Sodium bicarbonate is given as a bolus of 1 meq/kg, followed by an intravenous infusion containing sodium bicarbonate. The aim of this therapy is to narrow the QRS and to keep the serum pH between 7.5 and 7.55. Hypotensive patients should be treated with IV fluids and sodium bicarbonate, and if their hypotension does not respond to this, alpha-adrenergic agents, such as norepinephrine, should be used. Sodium bicarbonate should be used to treat dysrhythmias associated with QRS widening. Temporary pacemakers have been used to treat refractory symptomatic bradycardias not responsive to sodium bicarbonate. Physostigmine, Type 1A, Type 1C, and Type 3 Anti-dysrhythmic agents should be strictly avoided, as should Flumazenil. Intralipid emulsion treatment should be considered in hemodynamically unstable patients with overdoses of lipophilic TCAs. Since TCA are highly protein bound with an extensive volume of distribution, enhanced elimination with dialysis and hemoperfusion is not effective.

Differential Diagnosis

  • Antidepressant toxicity
  • Child abuse
  • Encephalitis
  • Febrile seizures
  • Heat exhaustion and heat stroke
  • Hyperkalemia in emergency medicine
  • Hypocalcemia
  • Isoniazid toxicity
  • MDMA toxicity
  • Metabolic acidosis in emergency medicine

Enhancing Healthcare Team Outcomes

Tricyclic antidepressant toxicity can be life-threatening and is best managed by an interprofessional team that consists of an emergency department physician, nurse practitioner, poison control specialist, cardiologist, neurologist, and an emergency or critical care nurse. As with all cases of poisoning, proper management of airway, breathing, and circulation is critical in cases of TCA poisoning. Gastrointestinal decontamination by activated charcoal should be done only if conditions are appropriate and the airway is protected. Sodium bicarbonate should be given to hemodynamically unstable patients, patients with seizures, and patients with QRS prolongation of more than 100 msec. Some patients may even require temporary pacing for bradycardia. Hydration and close monitoring in an ICU setting are recommended. It is vital to make sure that the patient has no other co-ingestants in the systemic circulation.  For patients managed promptly, the outcomes are good. However, if treatment is delayed or the patient has ingested multiple other agents, the prognosis is guarded. Before discharge, if attempted suicide is suspected, the patient should be referred to a mental health counselor. Parents should be urged to keep all medications in a locked cabinet away from the reach of children.[12][13][Level 5]


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