AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Most of the cyclic antidepressants (CAs) contain a 3-ring molecular structure. CAs were first used in the 1950s to treat clinical depression. The first report of the adverse effects of tricyclic overdose came within 2 years of their clinical use.

Despite the increasing popularity of the selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, CAs continue to play an important role in the treatment of enuresis, obsessive-compulsive disorder, attention deficit hyperactivity disorder, school phobia, and separation anxiety in the pediatric population. In adults, indications for CAs include depression, neuralgic pain, chronic pain, and migraine prophylaxis. Some of the more commonly prescribed CAs include amitriptyline, desipramine, imipramine, nortriptyline, doxepin, clomipramine, and protriptyline. Maprotiline, a tetracyclic compound, and amoxapine, a dibenzoxapine, are newer compounds that have a slightly different structure and toxicologic profile.

Pathophysiology

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

Tricyclic antidepressants (TCAs) may also penetrate into the 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 ECGs of individuals with CA poisoning. An in vitro study reported that CAs also directly decrease myocardial contractility in a dose-dependent manner.¹ Profound hypotension is sometimes seen in CA overdose and is mainly due to the well-recognized anti–alpha-adrenergic effect of the CAs; however, these direct myocardial depressive effects may also contribute to the severe hypotension seen in CA toxicity.

Frequency

United States

Antidepressants are the third leading cause of toxic exposures in 2004 after analgesics and sedatives. In the 2004 Toxic Exposure Surveillance System (TESS) national report, 12,270 cases of CA exposures and 86 CA-related deaths were reported.² The CA most frequently ingested is amitriptyline, followed by doxepin and nortriptyline. Amitriptyline exposure is associated with the most number of deaths among the various CAs.

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

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.

Age

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

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 higher incidence of seizures, maprotiline exhibits more severe cardiac toxicity. Determine status in the following systems:

• Cardiovascular
• • Palpitation
  • Chest pain
  • Hypotension
• CNS
• • Convulsion
  • Decrease mental status
  • Respiratory depression
  • Drowsiness
  • Coma
• Peripheral autonomic system
• • Dry mouth
  • Dry skin
  • Urinary retention
  • Blurred vision

Physical

Physical findings are usually consistent with the anticholinergic toxidrome and quinidinelike cardiotoxicity.

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

Causes

• Unintentional ingestion (most common cause in pediatric population)
• Intentional ingestion; suicidal ideation

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Brugada syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• 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.
• Because multisubstance ingestion is common, routine screening for other potentially treatable toxins is recommended (eg, acetaminophen). Request for the other serum toxicologic levels should be guided based on the clinical picture. For example, in patients with acidosis, assess for aspirin, ethylene glycol, and methanol.
• Assess the following:
• • Electrolyte, BUN, and creatinine levels 
  • Anion gap
  • CBC count
  • Alcohol level
  • ABGs for evaluation of acidosis or hypoxia
• Point-of-care qualitative urine immunoassays are available. They detect the presence of CA in the body. Test results are positive for most TCAs in the subtheraputic-to-toxic range, with the exception of clomipramine. False positives due to cross-reactivity occur in patients who are also taking cyclobenzaprine. These tests are helpful when patients' medication lists are unknown and CA toxicity is suspected based on history, clinical presentation, and ECG findings. However, in patients known to take TCAs, the urine immunoassays are of limited use because the result does not correlate with serum CA levels.³

Imaging Studies

• 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.

Other Tests

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

• Measurement of limb-leads QRS duration 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).
• 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%.
• 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.⁴
• 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; AV 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).
• A Brugada pattern was seen using ECG in 17% of patients with TCA toxicity in a retrospective study completed by Monteban-Kooistra et al.⁵ The ECG finding abnormalities resolved after administration of sodium bicarbonate.
• Early recognition of conduction disturbances is important in suspected CA poisoning.

Procedures

• GI decontamination may be helpful within the first several hours postingestion because CAs can slow gastric emptying through the 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.⁶ Usually, lavage is recommended for patients who developed significant toxicity requiring endotracheal intubation and who presented after relatively recent ingestion (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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

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.

Emergency Department Care

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 ECG are all essential measures.

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.

• Airway: Endotracheal intubation may be necessary in patients who present with seizures or who are in a comatose state for airway protection.
• Hyperventilation: The use of hyperventilation is controversial. It has been recommended traditionally for the resultant alkaline state hyperventilation achieves. Alkalinization is thought to increase protein binding of CA and promote CA excretion, thereby decreasing cardiotoxicity. However, a randomized controlled animal study shows that hyperventilation has little effect on reversing CA toxicity.⁷
• Hypotension
• • Normal saline intravenous fluids are indicated for CA-induced hypotension.
  • For hypotension refractory to intravenous saline, vasopressors with alpha-agonist effect (eg, Neo-Synephrine, norepinephrine) may be used.
• GI decontamination: Once the patient is stabilized, activated charcoal can be considered.
• Intravenous sodium bicarbonate
• • Serum alkalinization with intravenous sodium bicarbonate has been the mainstay of therapy in CA-induced cardiovascular toxicity. Prolonged QRS is most often the indication for serum alkalinization in CA toxicity. Not all physicians agree on what the duration of QRS should be in order for them to institute 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 cut off for intravenous sodium bicarbonate. Evidence suggests the reversal of toxic effects of CA (eg, QRS prolongation, myocardial depression) following serum alkalization and sodium loading with sodium bicarbonate.
  • Animal studies have shown hypertonic saline to be effective in reversing CA toxicity.⁷ However, no study adequately compared the efficacy of hypertonic saline versus sodium bicarbonate. Sodium loading may be the most important factor in the reversal of the symptoms of cyclic antidepressant toxicity.
• Benzodiazepines: 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.
• Hemodialysis or hemoperfusion: 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.
• Physostigmine: This is a short-acting cholinesterase inhibitor used for the reversal of anticholinergic symptoms. It should not be used in treating CA toxicity because of the reported cases of physostigmine-induced seizures and asystole.

Consultations

• Poison control center
• Toxicologist
• Cardiologist for pacemaker placement and arrhythmia management, when indicated
• ICU admission for patients with cardiovascular and/or neurologic manifestations of CA toxicity

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: GI decontaminant

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

Drug Category: Cardiovascular agents

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.

Drug Category: Anticonvulsants

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

Drug Category: Miscellaneous

Magnesium sulfate has been successfully used in an overdose with refractory ventricular fibrillation.⁸ Animal studies have shown that magnesium sulphate converted ventricular tachycardia to sinus rhythm in 9 of 10 rats.⁹

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Level of conscious and ECG changes at presentation are the most sensitive clinical predictors of serious complications.
• Cyclic antidepressant (CA) toxicity typically lasts 24-48 hours following a significant overdose. However, studies have reported prolonged CA toxicity as long as 4-5 days.¹⁰ Amitriptyline is the drug most commonly implicated in these cases.
• Consider ICU admission for any ECG changes.
• Admission to a monitored bed is appropriate for patients exhibiting only anticholinergic symptoms and no cardiac manifestations.

Complications

• Seizures
• Dysrhythmias

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The use of physostigmine in cyclic antidepressant (CA) poisoning has been associated with complete heart block, asystole, and hypotension.
• Ipecac syrup is not recommended as the procedure in GI decontamination because of the possibility that patients 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 benzodiazepines overdose with concomitant CAs exposure can precipitate seizures.

Special Concerns

• ECG is a highly sensitive tool and can be used to rule out CA toxicity. However, it is not specific enough to be used alone to diagnose CA overdose. Widening of QRS complex can be used as a rough guide in determining the prognosis of TCA poisoning (eg, seizures, dysrhythmias). However, characteristic ECG changes in addition to clinical presentation (anticholinergic toxidrome, seizures, hypotension, tachycardia) seen with CAs can be an adjunction in diagnosing CA toxicity.
• Lidocaine, when used to treat ventricular arrhythmia, should be administered with caution to avoid precipitating seizures.
• 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.
• 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.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Heard K, Cain BS, Dart RC, Cairns CB. Tricyclic antidepressants directly depress human myocardial mechanical function independent of effects on the conduction system. Acad Emerg Med. Dec 2001;8(12):1122-7. [Medline].
2. Watson WA, Litovitz TL, Rodgers GC, et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 2005;23(5):589-666. [Medline].
3. Mealanson SE., Lewandrowski EL., Griggs DA., Flood JG. Interpreting Tricyclic Antidepressnt Measurements in Urine in an Emergency Department Setting: Comparison of Two Qualitative Point-Of-Care Urine Tricyclic Antidepressant Drug Immunoassays with Quantitative serum Chromatographic Analysis. Journal of Analytical Toxiciology. June 2007;31:270-275. [Medline].
4. Liebelt EL, Francis PD, Woolf AD. ECG lead aVR versus QRS interval in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. Ann Emerg Med. Aug 1995;26(2):195-201. [Medline].
5. Monteban-Kooistra WE, van den Berg MP, Tulleken JE. Brugada electrocardiographic pattern elicited by cyclic antidepressants overdose. Intensive Care Med. Feb 2006;32(2):281-5. [Medline]. [Full Text].
6. Christophersen AB, Levin D, Hoegberg LC, Angelo HR, Kampmann JP. Activated charcoal alone or after gastric lavage: a simulated large paracetamol intoxication. Br J Clin Pharmacol. Mar 2002;53(3):312-7. [Medline].
7. McCabe JL, Cobaugh DJ, Menegazzi JJ, Fata J. Experimental tricyclic antidepressant toxicity: a randomized, controlled comparison of hypertonic saline solution, sodium bicarbonate, and hyperventilation. Ann Emerg Med. Sep 1998;32(3 Pt 1):329-33. [Medline].
8. Knudsen K, Abrahamsson J. Magnesium sulphate in the treatment of ventricular fibrillation in amitriptyline poisoning. Eur Heart J. May 1997;18(5):881-2. [Medline].
9. Knudsen K, Abrahamsson J. Effects of magnesium sulfate and lidocaine in the treatment of ventricular arrhythmias in experimental amitriptyline poisoning in the rat. Crit Care Med. Mar 1994;22(3):494-8. [Medline].
10. O'Connor N, Greene S, Dargan P, Wyncoll D, Jones A. Prolonged clinical effects in modified-release amitriptyline poisoning. Clin Toxicol (Phila). 2006;44(1):77-80. [Medline].
11. Boehnert MT, Lovejoy FH Jr. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med. Aug 22 1985;313(8):474-9. [Medline].
12. Frommer DA, Kulig KW, Marx JA, Rumack B. Tricyclic antidepressant overdose. A review. JAMA. Jan 23-30 1987;257(4):521-6. [Medline].
13. Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emerg Med J. Jul 2001;18(4):236-41. [Medline]. [Full Text].
14. Liebelt EL, Francis PD. Cyclic antidepressants. In: Goldfrank's Toxicologic Emergencies. 2002.
15. Newton EH, Shih RD, Hoffman RS. Cyclic antidepressant overdose: a review of current management strategies. Am J Emerg Med. May 1994;12(3):376-9. [Medline].
16. Pimentel L, Trommer L. Cyclic antidepressant overdoses. A review. Emerg Med Clin North Am. May 1994;12(2):533-47. [Medline].
17. Roberge RJ, Krenzelok EP. Prolonged coma and loss of brainstem reflexes following amitriptyline overdose. Vet Hum Toxicol. Feb 2001;43(1):42-4. [Medline].
18. Rosenbaum TG, Kou M. Are one or two dangerous? Tricyclic antidepressant exposure in toddlers. J Emerg Med. Feb 2005;28(2):169-74. [Medline].
19. Seger DL, Hantsch C, Zavoral T, Wrenn K. Variability of recommendations for serum alkalinization in tricyclic antidepressant overdose: a survey of U.S. Poison Center medical directors. J Toxicol Clin Toxicol. 2003;41(4):331-8. [Medline].
20. Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning: cardiovascular toxicity. Toxicol Rev. 2005;24(3):205-14. [Medline].

Article Last Updated: Jun 10, 2008