Tricyclic antidepressants taken in overdose by suicidal patients often cause life-threatening poisoning. Currently available tricyclic antidepressants are described in Table II-8. Amitriptyline is also marketed in combination with chlordiazepoxide or perphenazine. Cyclobenzaprine, a centrally acting muscle relaxant, is structurally related to the tricyclic antidepressants but exhibits minimal cardiotoxic and variable CNS effects. Newer, noncyclic antidepressants are discussed. Monoamine oxidase inhibitors are discussed.

Tricyclic antidepressant toxicity affects primarily the cardiovascular and central nervous systems.

1. Cardiovascular effects. Several mechanisms contribute to cardiovascular toxicity:
   1. Anticholinergic effects and inhibition of neuronal reuptake of catecholamines result in tachycardia and mild hypertension.
   2. Peripheral alpha-adrenergic blockade causes vasodilation and contributes to hypotension.
   3. Membrane-depressant (quinidine-like) effects cause myocardial depression and cardiac conduction disturbances by inhibition of the fast sodium channel that initiates the cardiac cell action potential. Metabolic or respiratory acidosis may contribute to cardiotoxicity by further inhibiting the fast sodium channel.
2. Central nervous system effects. These effects result in part from anticholinergic toxicity (eg, sedation and coma), but seizures are probably a result of inhibition of reuptake of norepinephrine or serotonin in the brain or other central effects.
3. Pharmacokinetics. Anticholinergic effects of these drugs may delay gastric emptying, resulting in slow or erratic absorption. Most of these drugs are extensively bound to body tissues and plasma proteins, resulting in very large volumes of distribution and long elimination half-lives. Tricyclic antidepressants are metabolized primarily by the liver, with only a small fraction excreted unchanged in the urine. Active metabolites may contribute to toxicity; several drugs are metabolized to other well-known tricyclic antidepressants (eg, amitriptyline to nortriptyline, imipramine to desipramine). See also Table II-63.

Most of the tricyclic antidepressants have a narrow therapeutic index, so that doses of less than 10 times the therapeutic daily dose may produce severe toxicity. In general, ingestion of 10-20 mg/kg is potentially life-threatening.

Tricyclic antidepressant poisoning may produce any of three major toxic syndromes: anticholinergic effects, cardiovascular effects, and seizures. Hyponatremia is also common. Depending on the dose and the drug, patients may experience some or all of these toxic effects. Symptoms usually begin within 30-40 minutes of ingestion but may be delayed owing to slow and erratic gut absorption. Patients who are awake initially may abruptly lose consciousness or develop seizures without warning.

1. Anticholinergic effects include sedation, delirium, coma, dilated pupils, dry skin and mucous membranes, diminished sweating, tachycardia, diminished or absent bowel sounds, functional bowel obstruction, and urinary retention. Myoclonic muscle jerking is common with anticholinergic intoxication and may be mistaken for seizure activity.
2. Cardiovascular toxicity manifests as abnormal cardiac conduction, arrhythmias, and hypotension.
   1. Typical electrocardiographic findings include sinus tachycardia with prolongation of the PR, QRS, and QT intervals. A prominent terminal R wave is often seen in lead aVR. Various degrees of atrioventricular (AV) block may be seen. Brugada pattern (down-sloping ST-segment elevation in V1-V3 in association with a right bundle branch block) has also been reported.
      1. Prolongation of the QRS complex to 0.12 seconds or longer, a terminal R wave of 3 mm or more in aVR, and a terminal R wave/S wave ratio of 0.7 or more in aVR are fairly reliable predictors of serious cardiovascular and neurologic toxicity (except in the case of amoxapine, which causes seizures and coma with no change in the QRS interval).
      2. Sinus tachycardia accompanied by QRS-interval prolongation may resemble ventricular tachycardia (see Figure I-3). True ventricular tachycardia and fibrillation may also occur.
      3. Atypical or polymorphous ventricular tachycardia (torsade de pointes; see Figure I-7) associated with QT-interval prolongation may occur with therapeutic dosing but is uncommon in overdose.
      4. Development of bradyarrhythmias usually indicates a severely poisoned heart and carries a poor prognosis.
   2. Hypotension caused by venodilation is common and usually mild. In severe cases, hypotension results from myocardial depression and may be refractory to treatment; some patients die with progressive, intractable cardiogenic shock. Pulmonary edema is also common in severe poisonings.
3. Seizures are common with tricyclic antidepressant toxicity and may be recurrent or persistent. The muscular hyperactivity from seizures and myoclonic jerking, combined with diminished sweating, can lead to severe hyperthermia, resulting in rhabdomyolysis, brain damage, multisystem failure, and death.
4. Death from tricyclic antidepressant overdose usually occurs within a few hours of admission and may result from ventricular fibrillation, intractable cardiogenic shock, or status epilepticus with hyperthermia. Sudden death several days after apparent recovery has been reported occasionally, but in all such cases, there was evidence of continuing cardiac toxicity within 24 hours of death.

Tricyclic antidepressant poisoning should be suspected in any patient with lethargy, coma, or seizures accompanied by QRS-interval prolongation or a terminal R wave in aVR of greater than 3 mm.

1. Specific levels
   1. Plasma levels of some of the tricyclic antidepressants can be measured by clinical laboratories. Therapeutic concentrations are usually less than 0.3 mg/L (300 ng/mL). Total concentrations of parent drug plus active metabolite of 1 mg/L (1,000 ng/mL) or greater usually are associated with serious poisoning. Generally, plasma levels are not used in emergency management because the QRS interval and clinical manifestations of overdose are reliable and more readily available indicators of toxicity.
   2. Most tricyclics are detectable on comprehensive urine toxicology screening. Some rapid immunologic techniques are available and have sufficiently broad cross-reactivity to detect several tricyclics. However, use of these assays for rapid screening in the hospital laboratory is not recommended because they may miss some important drugs and give false-positive results for other drugs (eg, cyclobenzaprine or diphenhydramine) that are present in therapeutic concentrations. Because diphenhydramine is widely used, it causes many more false-positive than true-positive tricyclic antidepressant results, leading to significant diagnostic ambiguity.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, creatine kinase (CK), urinalysis for myoglobin, arterial blood gases or oximetry, 12-lead ECG and continuous ECG monitoring, and chest radiography.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary. Caution: Respiratory arrest can occur abruptly and without warning.
   2. Treat coma, seizures, hyperthermia, hypotension, and arrhythmias if they occur. Note: Do not use procainamide or other type Ia or Ic antiarrhythmic agents for ventricular tachycardia because these drugs may aggravate cardiotoxicity.
   3. Consider cardiac pacing for bradyarrhythmias and high-degree AV block, and overdrive pacing for torsade de pointes.
   4. Mechanical support of the circulation (eg, cardiopulmonary bypass or veno-arterial extracorporeal membrane oxygenation [ECMO]) may be useful (based on anecdotal reports) in stabilizing patients with refractory shock, allowing time for the body to eliminate some of the drug.
   5. If seizures are not immediately controlled with usual anticonvulsants, paralyze the patient with a neuromuscular blocker to prevent hyperthermia. Uncontrolled hyperthermia may induce further seizures and lactic acidosis, aggravating cardiotoxicity. Note: Paralysis abolishes the muscular manifestations of seizures but has no effect on brain seizure activity. After paralysis, electroencephalographic (EEG) monitoring is necessary to determine the efficacy of anticonvulsant therapy.
   6. Continuously monitor the temperature, other vital signs, and ECG in asymptomatic patients for a minimum of 6 hours, and admit patients to an intensive care setting for at least 24 hours if there are any signs of toxicity.
   7. If the patient is resuscitated after cardiac arrest, therapeutic hypothermia has been suggested to be beneficial in a case report.
2. Specific drugs and antidotes
   1. In patients with QRS-interval prolongation or hypotension, administer sodium bicarbonate, 1-2 mEq/kg IV, and repeat as needed to maintain arterial pH between 7.45 and 7.55. Sodium bicarbonate may reverse membrane-depressant effects by increasing extracellular sodium concentrations and by a direct effect of pH on the fast sodium channel. Hypertonic sodium chloride has similar effects in animal studies and some human case reports.
   2. When cardiotoxicity persists despite treatment with sodium bicarbonate, the use of lidocaine can be considered, although human evidence of efficacy is limited. Lidocaine competes with tricyclic antidepressants for binding at the sodium channel but binds for a shorter period of time and thus may reverse some of sodium channel blockade.
   3. For severe tricyclic overdose with refractory ventricular arrhythmias and/or shock, the use of intravenous lipid emulsion therapy may be beneficial.
   4. Hyperventilation, by inducing a respiratory alkalosis (or reversing respiratory acidosis), may also be of benefit but works only transiently and may provoke seizures.
   5. Although physostigmine may reverse anticholinergic features of tricyclic antidepressant toxicity, it should not be administered routinely to patients with tricyclic antidepressant poisoning; it may aggravate conduction disturbances, causing asystole; further impair myocardial contractility, worsening hypotension; and contribute to seizures.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly, but it should be considered for large ingestions (eg, >20-30 mg/kg).
4. Enhanced elimination. Owing to extensive tissue and protein binding with a resulting large volume of distribution, dialysis and hemoperfusion are not effective. Although repeat-dose charcoal has been reported to accelerate tricyclic antidepressant elimination, the data are not convincing.