Tricyclic Antidepressant Toxicity

The CAs are well absorbed orally and undergo significant first-pass metabolism in the liver. They have a large volume of distribution and have long half-lives that generally exceed 24 hours. After the CAs are metabolized in the liver via glucuronic acid conjugation, they are then excreted through the kidneys.

The toxic effects of tricyclics are results of the following 4 main pharmacologic properties:

1. Inhibition of norepinephrine and serotonin reuptake at nerve terminals
2. Anticholinergic action
3. Direct alpha-adrenergic blockade
4. Membrane-stabilizing effect on the myocardium by blocking the cardiac myocyte fast sodium channels

TCAs also penetrate into the central nervous system (CNS). Given the appropriate dosage, a particular CA exerts its therapeutic antidepressant effects by increasing biogenic amines such as norepinephrine and serotonin at nerve terminals. The same mechanism is thought to be responsible for seizure occurrence in CA overdose. Altered mental status is also frequently seen in CA overdose and is mainly attributed to anticholinergic and antihistaminergic properties of CAs.

The effects of CA overdose on the cardiovascular system result mainly from the impediment of the cardiac conduction system. CAs, like the class IA antiarrhythmics, decrease the sodium influx through the fast sodium channels and consequently decrease the slope of phase 0, leading to the widened QRS complex that is typically seen on electrocardiograms of individuals with CA poisoning. An in vitro study reported that CAs also directly decrease myocardial contractility in a dose-dependent manner.[3]  

Frequency

United States

In the 2021,  American Association of Poison Control Centers' National Poison Data System Annual report, TCAs accounted for 4705 single exposures and 15 deaths. The CA most frequently ingested was amitriptyline, with 2106 exposures and five deaths, followed by doxepin (556 exposures and one death) and nortriptyline (372 exposures, 1 death). In addition, of the tetracyclic antidepressants, mirtazapine accounted for 1613 single exposures and no deaths.[4]

Mortality/Morbidity

Fatality before reaching a healthcare facility occurs in approximately 70% of patients attempting suicide with CAs. CA were the number one cause of fatality from drug ingestion until the last decade, when they were surpassed by analgesics. Only 2-3% of CA overdose cases that reach a healthcare facility result in death.

Sex- and age-related demographics

CA toxicity occurs in both men and women. However, the incidence of CA exposure is greater in women than in men because women are at a higher risk for suicide attempts.

CA toxicity occurs at all ages. Incidence of CA toxicity is most prevalent in persons aged 20-29 years. This again reflects the demographics of suicidal attempts.

History of suicidal ideation, prior suicide attempts, circumstances around ingestion, intended cyclic antidepressant (CA) usage, co-ingestants, time of ingestion, and dose ingested should be obtained from the patient directly and also from the patient's family.

CA exposure in children is common. The potentially lethal dose (with desipramine, imipramine, or amitriptyline) is as low as 15 mg/kg. Toddlers can exceed this threshold with only 1-2 pills and should be evaluated in the emergency department.[5]

Onset of symptoms typically occurs within 2 hours of ingestion, which corresponds to the peak CA serum level, which may range from 2-12 hours.

Determining which specific CA is involved may be helpful. Although amoxapine is associated with a higher incidence of seizures, maprotiline causes more severe cardiac toxicity.

Cardiovascular manifestations may include the following:

• Palpitation
• Chest pain
• Hypotension

Central nervous system manifestations may include the following:

• Convulsion
• Decrease mental status
• Respiratory depression
• Drowsiness
• Coma

Peripheral autonomic system manifestations may include the following:

• Dry mouth
• Dry skin
• Urinary retention
• Blurred vision

Physical findings are usually consistent with the anticholinergic toxidrome and quinidine-like cardiotoxicity, and may include the following:

• Tachycardia
• Hypotension and orthostasis
• Fever
• Altered mental status
• Ileus
• Absent bowel sounds
• Rigidity
• Dry skin and mucous membranes
• Mydriasis

Studies have shown that serum cyclic antidepressant (CA) level does not correlate well with severity of CA toxicity and is a poor predictor of clinical outcome. However, because multisubstance ingestion is common, routine screening for other potentially treatable toxicants is recommended (eg, acetaminophen, aspirin). Requests for the other serum toxicologic levels should be based on the clinical picture. For example, in patients with acidosis, assess for aspirin, ethylene glycol, and methanol.

Assess the following:

• Electrolyte, blood urea nitrogen (BUN), and creatinine levels
• Anion gap (see the Anion Gap calculator)
• Complete blood cell count (CBC)
• Blood alcohol level
• Arterial blood gases (ABGs) for evaluation of acidosis or hypoxia

Point-of-care qualitative urine immunoassays for CA are available but are of limited clinical utility. Test results are positive for most tricyclic antidepressants in the subtherapeutic-to-toxic range, with the exception of clomipramine; therefore a positive result does not imply CA toxicity. False-positive results also occur due to cross-reactivity with other polycyclic medications. A urine immunoassay may be helpful when the patient's medications are unknown and CA toxicity is suspected on the basis of history, clinical presentation, and ECG findings.[6]

Chest radiography should be performed in cases of suspected aspiration or when respiratory symptoms are noted and may be used to rule out other causes of fever, tachycardia, and altered mental status.

Electrocardiography (ECG) is a highly sensitive tool, and a normal result can be used to rule out clinically significant CA toxicity. However, ECG is not specific enough to be used alone to diagnose CA overdose. However, characteristic ECG changes can be a valuable adjunct to typical clinical features (anticholinergic toxidrome, seizures, hypotension, tachycardia) in diagnosing CA toxicity.

ECG features of CA toxicity are as follows:

• Sinus tachycardia is the most common ECG finding in CA toxicity.

• Measurement of QRS duration in limb leads can be used to assess the severity of CA exposure. A QRS interval greater than 100 milliseconds is the basis for treatment with bicarbonate (alkalinization).

• Widening of the QRS complex can be used as a rough guide in determining the prognosis of TCA poisoning (eg, seizures, dysrhythmias). Patients with a QRS interval less than 100 milliseconds are unlikely to develop seizures and arrhythmias. Patients with a QRS interval greater than 100 milliseconds have up to a 34% chance of developing seizures and up to a 14% chance of developing a life-threatening cardiac arrhythmia. With a QRS complex greater than 160 milliseconds, the chance of ventricular arrhythmias increases to 50%.[7]

• The amplitude of the R wave in lead aVR and the ratio of the R/S waves in aVR are greater in patients who developed seizures or dysrhythmias.

• According to Liebelt et al, when the R wave in aVR equals 3 mm or more, the sensitivity and specificity for subsequent development of seizures or arrhythmias are 81% and 73%, respectively.[8]

• ECG findings that can be observed in CA toxicity include sinus tachycardia; prolongation of the PR, QRS, and QTc intervals; nonspecific ST-segment and T-wave changes; atrioventricular block; right-axis deviation of the terminal 40-millisecond vector of the QRS complex in the frontal plane; and the Brugada pattern (downsloping ST-segment elevation in leads V1-V3 in association with right bundle branch block).[9]

• A Brugada pattern was seen using ECG in 17% of patients with TCA toxicity in a retrospective study completed by Monteban-Kooistra et al.[10] The ECG finding abnormalities resolved after administration of sodium bicarbonate.

• A study of 98 consecutive cases of CA intoxication in France found that the mortality rate was 6.7% among patients with the Brugada pattern and 2.4% among patients without it. However, the difference was not statistically significant (P=0.39).[11]

• Early recognition of conduction disturbances is important in suspected CA poisoning.

Endotracheal intubation is necessary in a patient who is obtunded and unable to protect the airway. Intravenous access should be established as soon as possible. Administer intravenous fluid if the patient is hypotensive. Prompt transport of the patient to the nearest emergency department is implicit.

Evidence-based management guidelines for tricyclic antidepressant (TCA) poisoning are available from the American Association of Poison Control Centers (AAPCC). This guideline is outlined for poison control center personnel to assist in prehospital triage and management of patients with possible TCA ingestion/overdose. A brief summary of the prehospital evidence-based consensus management guideline is as follows[12] :

• Patients with suspected self-harm or who are the victims of malicious administration of a TCA should be referred to an emergency department (ED) immediately (Grade D).

• Referral to an ED with close monitoring of clinical status and vital signs en route is recommended for (1) patients with acute TCA ingestions who are younger than 6 years, (2) patients with underlying conditions such as convulsions or cardiac arrhythmias, and (3) co-ingestion of other drugs with TCAs (Grade D).

• Referral to an ED is recommended for patients who are symptomatic after a TCA ingestion (Grade B).

• Ingestion of either an amount that exceeds the usual maximum single therapeutic dose or an amount equal to or greater than the lowest reported toxic dose would warrant consideration of referral to an ED (Grades B/C).

• Do not induce emesis (Grade D).

• The risk-to-benefit ratio of prehospital activated charcoal for TCA poisoning is unknown. Activated charcoal administration should only be carried out by health professionals and only if no contraindications are present. Do not delay transportation in order to administer activated charcoal (Grades B/D).

• Asymptomatic patients are unlikely to develop symptoms if the ingestion took place more than 6 hours before the initial call to a poison control center. These patients do not need referral to an ED facility (Grade C).

• Follow-up calls to determine the outcome for a TCA ingestion ideally should be made within 4 hours of the initial call to a poison control center and at appropriate intervals thereafter based on the clinical judgment of the poison control center staff (Grade D).

• An ECG/rhythm strip, if available, should be checked during the prehospital assessment of a patient with TCA overdose. A QRS duration longer than 100 msec is an indicator that the patient should be immediately stabilized, given sodium bicarbonate if there is a protocol for its use, and transported to an ED (Grade B).

• Symptomatic patients with TCA poisoning might require prehospital interventions in accordance with standard ACLS guidelines (Grade D).

• Administration of sodium bicarbonate might be beneficial for patients with severe or life-threatening TCA toxicity if a prehospital protocol exists for its use (Grades B/D).

• Benzodiazepines are recommended for TCA-associated convulsions (Grade D).

• Flumazenil is not recommended for patients with TCA poisoning (Grade D).

Refer to the AAPCC guideline for complete details.[12]

The greatest risk of seizures and arrhythmias occurs within the first 6-8 hours of cyclic antidepressant (CA) ingestion. The treatment of an asymptomatic patient with a history of CA ingestion is mainly supportive therapy. For all patients with possible CA toxicity, airway protection, ventilation and oxygenation, intravenous fluids, cardiac monitoring, and performing electrocardiography (ECG) are all essential measures. The patient should be admitted to the ICU if hemodynamic instability and ECG changes are observed.

Consider early gastric decontamination using charcoal if the patient presents within 2 hours of ingestion.

Once suicidal ideation is ruled out and the patient remains asymptomatic for 6-8 hours postingestion without any ECG changes, the patient may be discharged home. If suicidal ideation is present, evaluation for admission to a psychiatric facility is mandatory.

Treatment considerations include the following:

• Airway: Endotracheal intubation may be necessary for airway protection in patients who present with seizures or who are comatose.

• Hyperventilation: The use of hyperventilation is controversial. It has been recommended traditionally for the alkaline state it produces. Alkalinization is thought to increase protein binding of CA and promote CA excretion, thereby decreasing cardiotoxicity. However, a randomized controlled animal study found that hyperventilation has little effect on reversing CA toxicity.[13]

• Hypotension: Intravenous infusion of normal saline is indicated for CA-induced hypotension. For hypotension refractory to intravenous saline, vasopressors may be used.

• Gastrointestinal (GI) decontamination: Once the patient is stabilized, activated charcoal can be considered.

• Intravenous sodium bicarbonate

GI decontamination may be helpful within the first several hours postingestion because CAs can slow gastric emptying through their anticholinergic activity.

Gastric lavage may be helpful in recovering and identifying the CA ingested. However, one study that compared the use of gastric lavage and activated charcoal versus charcoal alone showed no benefit in clinical outcome.[14] Usually, lavage is recommended for patients who developed significant toxicity requiring endotracheal intubation and who presented relatively soon after ingestion (within several hours).

Activated charcoal reduces the absorption of CAs. It may also be beneficial in cases of multisubstance ingestion. It should be administered only in patients who are able to protect the airway.

Endotracheal intubation is indicated if the patient cannot adequately maintain a safe airway.

Serum alkalinization with intravenous sodium bicarbonate has been the mainstay of therapy in CA-induced cardiovascular toxicity. QRS prolongation is most often the indication for serum alkalinization in CA toxicity. Not all physicians agree on what duration of QRS should be the indication for starting intravenous sodium bicarbonate therapy. However, about 88% of the poison control directors in the United States use a QRS of 100 milliseconds or greater as the threshold for use of intravenous sodium bicarbonate.[15]

Evidence suggests the reversal of toxic effects of CA (eg, QRS prolongation, myocardial depression) following serum alkalization and sodium loading with sodium bicarbonate. Sodium bicarbonate may be initially administered as an intravenous bolus at a dose of 1 - 2 mEq/kg. Serial ECG performed before and after administration of bicarbonate may be used to determine if cardiac conduction abnormalities are responsive to the therapy. Boluses of sodium bicarbonate may be repeated to treat cardiac conduction abnormalities and impaired contractility, with a maximum target blood pH of 7.50 - 7.55.

Alternatively, a bicarbonate infusion may be initiated after the bolus by adding 3 ampules of sodium bicarbonate (50 mEq each for a total of 150 mEq) to 1 L of 5% dextrose in water (D5W) and infusing at 1.5 - 2 times the maintenance rate. The same maximum target blood pH of 7.50 - 7.55 should be used for bicarbonate infusions. In patients who can not tolerate the volume of fluid associated with an infusion (eg, those with congestive heart failure, renal impairment, or end-stage renal disease), use of repeated boluses may be preferable.

Ventricular bradyarrhythmias, due to depressed atrioventricular conduction and automaticity, can be treated by placement of a temporary pacemaker. Alternatively, consider the use of a chronotropic agent.

Lidocaine, when used to treat ventricular arrhythmia, should be administered with caution to avoid precipitating seizures.

Intravenous lipid emulsion (ILE) has demonstrated efficacy in the treatment of local anesthetic agent–induced cardiotoxicity, in laboratory studies.[16] The theorized mechanism of action of ILE is the creation of "lipid sink" in the intravascular compartment, sequestering lipophilic drugs and reducing bioavailability.[17] No clinical studies have been done on ILE in the treatment of CA toxicity; however, case reports from Europe and New Zealand describe successful resuscitation using ILE therapy in patients demonstrating severe CA cardiotoxicity.[18, 19]

In the case studies published, ILE was used with success in patients with severe hemodynamic instability and QRS widening. ILE may be administered in a 1.5 mL/kg or 100 mL bolus (in adults) over 1 minute. This bolus may be repeated for patients in cardiac arrest or with recurrent toxicity. Alternatively, the bolus may be followed with an ILE infusion at 0.25 mL/kg/min for 30 - 60 minutes.[20]  

The seizures in CA toxicity are usually self-limited. The treatment of choice for prolonged or recurrent seizures in CA toxicity is a benzodiazepine. Most CA-induced seizures are usually brief and resolve prior to the administration of anticonvulsants. General anesthesia should be reserved for patients with status epilepticus who are unresponsive to the standard treatment regimen (eg, benzodiazepines, barbiturates, propofol). This may prevent hyperthermia and rhabdomyolysis.

A case study reported successful use of ILE therapy to treat refactory status seizures following ingestion of 3.0g of amozapine. In this case, seizures persisted after diazepam was administered.  Levetiracetam and phenobarbital were also administered with no effect. ILE was injected for over 1 minute with the patient's status seizures ceasing after 2 minutes. Within an hour after ILE, the seizures recurred and ILE was again administered. The seizures stopped and did not recur.[21]

The use of hypertonic saline in CA toxicity remains controversial. Although 7.5% hypertonic saline has been shown to correct hypotension and QRS widening in severe CA overdose in a swine model,[13] limited evidence supports the use of hypertonic saline in CA toxicity in humans. No study has adequately compared the efficacy of hypertonic saline versus sodium bicarbonate, and sodium loading may be the most important factor in the reversal of the symptoms of cyclic antidepressant toxicity.

Because of the large volume of distribution and high protein-binding characteristics of CAs, hemodialysis has not been shown to be effective in the treatment of CA overdose.

The following drugs should be avoided in patients with CA toxicity:

• The use of physostigmine in CA poisoning has been associated with complete heart block, asystole, and hypotension

• Inducing emesis with ipecac syrup is not recommended for GI decontamination because of the possibility that the patient may experience sudden neurologic deterioration (eg, lethargy, seizures) and aspirate

• The use of type IA and IC antidysrhythmics or other sodium channel blockade agents may exacerbate toxic effects of CAs on the myocardium

• The use of flumazenil for reversal of benzodiazepine overdose with concomitant CAs exposure can precipitate seizures

Level of consciousness and ECG changes at presentation are the most sensitive clinical predictors of serious complications. Consider intensive care unit admission for any patient with ECG changes. Admission to a monitored bed is appropriate for patients exhibiting only anticholinergic symptoms and no cardiac manifestations.

CA toxicity typically lasts 24-48 hours following a significant overdose. However, studies have reported prolonged CA toxicity lasting as long as 4-5 days.[22]  Amitriptyline is the drug most commonly implicated in these cases.

Poison control center and toxicologist consultation may be helpful in diagnosing and treating tricyclic antidepressant toxicity. A cardiologist should be consulted for pacemaker placement and arrhythmia management, when indicated. ICU admission is needed for patients with cardiovascular and/or neurologic manifestations.

Treatment of cyclic antidepressant (CA) toxicity focuses on airway management, dysrhythmias, seizures, and hypotension. Sodium bicarbonate, benzodiazepines, and norepinephrine are the drugs of choice for these complications.

Class Summary

This agent prevents further absorption of drug and other co-ingestants from the GI tract.

Activated charcoal (Liqui-Char)

Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. May be administered with or without cathartic (eg, Sorbitol 70%), except in young pediatric patients, where electrolyte imbalance may be of concern. Does not dissolve in water.

For maximum effect, administer within 30 min of ingesting poison.

Class Summary

Sodium bicarbonate is indicated for QRS intervals greater than 100 milliseconds, seizures, acidosis (pH level < 7), hypotension, cardiac arrest, or dysrhythmia. Antidysrhythmic agents may be helpful. However, avoid certain drugs that exacerbate the cardiac effects of CAs, such as quinidine and procainamide (class IA), flecainide (class IC), and bretylium and amiodarone (class III). Vasopressors are used for the treatment of hypotension not corrected by intravenous fluids.

Sodium bicarbonate (Neut)

First-line therapy for QRS interval >100 milliseconds or if dysrhythmias are present. Correction of acidosis promotes protein binding of CA and improves myocardial contractility. Doses or IV drip may be administered with a pH goal of 7.5-7.55. Monitor and replace potassium as needed to prevent hypokalemia.

Lidocaine (Xylocaine)

Class IB antiarrhythmic that increases electrical stimulation threshold of ventricle, suppressing automaticity of conduction through tissue. Second DOC for CA dysrhythmias.

Norepinephrine (Levophed)

Stimulates beta1- and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood-flow increases. DOC to treat hypotension refractory to fluid resuscitation in CA toxicity. Dopamine is second-line and less effective.

Class Summary

Benzodiazepines are preferred for treatment of seizures. Do not use barbiturates in patients with hypotension. Do not use phenytoin in patients with dysrhythmias.

Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life (longer than diazepam).

By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Monitoring patient's blood pressure after administering dose is important. Adjust prn.

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Shorter acting than lorazepam.

Midazolam (Versed)

Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose.

Phenobarbital (Barbita, Luminal)

Used for seizures not responding to benzodiazepines. Significant respiratory depression; patient may require endotracheal intubation.

Class Summary

Magnesium sulfate has been successfully used in an overdose with refractory ventricular fibrillation.[23]  In an animal study, magnesium sulfate converted ventricular tachycardia to sinus rhythm in 9 of 10 rats.[24]

Magnesium sulfate

Given parenterally, magnesium decreases acetylcholine in motor nerve terminals and acts on myocardium by slowing the rate of sinoatrial node impulse formation and prolonging conduction time. May be helpful in treating ventricular fibrillation in TCA toxicity, but further study is needed.