eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Antidepressant

Jeena Jacob, MD, PharmD, Resident Physician, Department of Emergency Medicine, Yale-New Haven Hospital

Updated: Nov 13, 2008

Introduction

Background

Tricyclic antidepressants (TCAs) were one of the most important causes of mortality resulting from poisoning until 1993 and continue to be responsible for more deaths per prescription than all the other antidepressants put together. 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 2006, about 6000 cyclic antidepressant overdoses were reported with 4% resulting in serious adverse outcomes including death. 

Pathophysiology

TCAs have long been thought to exert their therapeutic effects by inhibiting the presynaptic reuptake of biogenic amines, primarily serotonin and norepinephrine. However, newer evidence points to additional therapeutic effect stemming from TCA-induced changes in the sensitivity of central serotonergic and beta-adrenergic receptors as well as changes in gene expression within neurons. 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, histamine receptors. They also affect central Media file 1). 

Toxicity, antidepressant. ECG shows the terminal R wave in aVR and the widened QRS complex associated with tricyclic antidepressant (TCA) toxicity.

Refractory hypotension, caused primarily by the inhibition of alpha1-adrenergic receptors, is one of the most common causes of mortality seen with TCA overdose. 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, also contributes to the tachycardia. Wide-complex tachycardia is also observed, and it results primarily from prolonged antegrade conduction and the ensuing nonuniform conduction leads to reentrant ventricular dysrhythmias. 

One study suggests a link between chronic TCA drug use and myocardial injury as increased myocardial uptake of monoclonal antimyosin antibody, a known marker for myocardial damage, was demonstrated in adults undergoing long-term amitriptyline treatment. 

Neurologic effects of TCAs, including agitation and delirium, primarily result from CNS blockade of muscarinic receptors. TCA seizures, although rare, 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. Seizures are seen in approximately 13% of fatal cases of TCA overdose and uncontrolled seizures can result in severe metabolic acidosis, rhabdomyolysis, hyperthermia, and acute renal failure. Resulting seizure-induced acidosis can also exacerbate cardiovascular toxicity. 

TCA exposure can also manifest as other anticholinergic effects including dilated pupils, dry mouth, dry flushed skin, urinary retention, and ileus. 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. 

Syncope and sudden death in patients taking therapeutic doses of TCAs has been described in case reports. Possible mechanisms include torsades secondary to QTc prolongation, advanced AV conduction delays, blood pressure fluctuations, and ventricular tachycardia. It is recommended that TCAs not be given to children with a resting QTc >450 msec or bundle branch block. The Brugada pattern, which is  caused by genetic defects in sodium channels and is associated with sudden death, has been described in patients taking TCAs in therapeutic doses as well as with overdose. However, in one study of intentional TCA overdose patients, the presence of the Brugada ECG pattern was associated with seizures, hypotension, and a widened QRS but not sudden death.  

Frequency

United States

According to the American Association of Poison Control Center's 5,830 cyclic antidepressant exposures were reported in 2006. Of these cyclic antidepressant exposures, 1,483 were intentional overdoses, 1,936 (33%) were treated at a health care facility, 203 (3.5%) resulted in major toxicity, and 6 (0.1%) resulted in death.¹

Mortality/Morbidity

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). Most cases of in-hospital fatality are secondary to refractory hypotension.

Clinical

History

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.

Physical

• CNS findings
  • Early manifestations include altered mental status, delirium, 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.
  • Myoclonus and/or choreoathetosis should not be confused with or treated as seizures.
  • Other findings include ileus; urinary retention; hyperthermia; and dry, flushed skin from anticholinergic effect. 
• Cardiac findings
  • 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
  • Acute lung injury
  • Hypoventilation
  • Aspiration pneumonitis secondary to CNS depression
  • Acute respiratory distress syndrome (ARDS)
  • Hypoxia caused by hypoventilation, aspiration, and capillary leakage
• Anticholinergic findings
  • Tachycardia
  • Hypothermia
  • Agitation (early)
  • CNS depression 
  • Mydriasis
  • Dry skin and/or mucous membranes
  • Hyperthermia
  • Decreased gastric motility/ileus
  • Urinary retention

Causes

Tricyclic antidepressant toxicity can be caused by either an acute ingestion or a chronic ingestion. Acute ingestions most often occur in patients who are chronically on this class of medications. Toxicity secondary to chronic ingestions usually presents with symptomatology that is an exaggeration of the usual side effects of tricyclics. 

Differential Diagnoses

Other Problems to Be Considered

Antimalarial toxicity (eg, chloroquine, primaquine)
Chloral hydrate toxicity
Intrinsic cardiac disease (other causes of conduction disturbances, dysrhythmias, hypotension)
Intrinsic neurologic disease (other causes of seizures, altered mental status)

Workup

Laboratory Studies

• 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. A toxicology screen may be helpful if concurrent ingestion is possible or if symptoms are not fully explained by tricyclic antidepressants (TCAs). 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.
• Serum pH
  • 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.

Imaging Studies

• Obtain a chest radiograph after intubation or if evidence of hypoxia, aspiration, or ARDS is present.

Other Tests

An ECG has great utility in predicting the severity of toxicity.

• ECG is the single most important test to determine diagnosis and prognosis.
• Several studies have shown that a QRS duration greater than 100 milliseconds on an ECG is associated with an increased incidence of seizures, coma, need for intubation, hypotension, and dysrhythmias.  
• Prospective studies of patients with TCA overdose show that the sensitivity of an R-wave greater than 3 mm in aVR is similar to the sensitivity of a QRS=100 msec. Prospective data suggest that the typical period of QRS prolongation after severe tricyclic antidepressant ingestion is 12-18 hours but may be as long as 3 days. 
• 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.
• Case reports have described ECGs in TCA toxicity mimicking acute myocardial infarction and the Brugada syndrome. One study found that 17% of patients that presented with TCA poisoning and ECG changes had Brugada pattern on ECG, which is a manifestation of intraventricular conduction disturbances.
• 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.

Procedures

• Endotracheal intubation
  • 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.
  • The patient should be hyperventilated after intubation. Check proper placement with a chest radiograph. The target PaCO₂ is 30 mm Hg by ABG following intubation.
• Gastric lavage
  • After the patient's airway, breathing, and circulation are secured, gastric lavage can be initiated in the symptomatic patient with an intentional overdose within 1.5-2 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.
• Only anecdotal evidence supports the efficacy of an intra-aortic balloon pump (IABP) for intractable hypotension.

Treatment

Prehospital 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. Flumazenil administration is contraindicated following TCA overdose.

Emergency Department Care

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. If the patient is presenting with altered mental status, an arterial blood gas measurement should be obtained.

• 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.
  • Animal studies show a benefit to using hypertonic saline to reverse cardiotoxicity, but the doses for TCA poisoning have never been evaluated in humans. One case report describes the successful use of 7.5% NaCl to treat refractory hypotension and QRS widening. This modality could be considered in refractory cases but should not supersede treatment with NaHCO₃.
  • Vasopressors are recommended for refractory hypotension.
• Convulsions
  • Benzodiazepines

Consultations

• Consider consulting a regional poison control center or medical toxicologist.
• Patients with abnormal vital signs or mental status changes will need intensive care unit (ICU) care, which may require the consultation of an intensivist.

Medication

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. Norepinephrine has been reported to reverse refractory hypotension. A few recent reports also support a trial of vasopressin for refractory hypotension. Narcan or thiamine and immediate measurement of serum glucose concentration are indicated for any patients with altered mental status, such as that which occurs with TCA toxicity.

Contraindicated medications include flumazenil, beta-blockers, calcium channel blockers, and class IA (procainamide, quinidine, disopyramide, moricizine), class IC (flecainide, propafenone), and possibly class III (bretylium, amiodarone, sotalol) antidysrhythmics.

GI decontaminant

Activated charcoal is indicated for all TCA ingestions unless bowel obstruction, ileus, or perforation is suspected, even when a patient presents late following ingestion. Since the anticholinergic effects of TCAs delay gastric emptying and slow GI motility, this may allow efficacy for charcoal when administered relatively late postingestion. 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.

Activated charcoal (Liqui-Char)

Binds TCAs, limiting absorption and speeding elimination. Clinical benefit of multiple doses has not been demonstrated clearly and is not recommended.

Dosing

Adult

1 g/kg PO/NGT initial (may be administered with sorbitol or comparable cathartic or in aqueous solution)

Pediatric

1 g/kg PO (typical 12.5-25 g)
<2 years: Use aqueous charcoal without cathartic

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases adsorptive properties)

Contraindications

Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies; unprotected airway and absent gag reflex

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not very effective in poisonings of ethanol, methanol, and iron salts; can be effectively administered in early stages of gastric lavage; gastric lavage returns are black; intubate before administration in altered mental status

Cardiovascular agents

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. Animal studies show that TCA Fab effectively reduces hypotension, shortens QRS duration, and improves survival in TCA-poisoned animals, and one study by Heard et al in humans involving 7 patients showed that the use of TCA Fab was associated with a fall in serum free TCA levels with none of the patients in the study developing worsening signs of TCA toxicity.²  Further studies are still needed to evaluate the routine use of TCA Fab in humans.

Sodium bicarbonate (Neut)

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. Following bolus administration, an IV drip may be prepared with 3 ampules of bicarbonate in 1 L of D5W, run at 150-250 mL/h (monitor pH = 7.45-7.55). Maintain serum potassium levels (see Precautions below). Resolution of QRS widening is a reasonable endpoint for NaHCO₃ administration. However, since it may recur, patients who have had QRS widening need to be on a cardiac monitor that is being continuously monitored.

Dosing

Adult

1-2 mEq/kg IV bolus, followed by an IV drip of 1000 mL of D5W to which 100-150 mEq of sodium bicarbonate has been added; initiate drip rate at 3 times maintenance IVF rate and titrate drip rate to urinary pH (target >8)

Pediatric

Administer as in adults

Interactions

Urinary alkalinization, induced by increased sodium bicarbonate concentrations, may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines, pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine; may inactivate sympathomimetic agents (eg, epinephrine, norepinephrine)

Contraindications

Documented hypersensitivity; alkalosis (pH >7.5); volume overload; severe hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause alkalosis, therefore monitor serum pH; may also cause decreased plasma potassium, hypocalcemia, and hypernatremia, though these are rare; serum potassium level must be >4 mEq/L because urinary alkalinization cannot occur in the presence of hypokalemia; caution in electrolyte imbalances such as in patients with CHF, cirrhosis, edema, corticosteroid use, or renal failure; when administering, avoid extravasation, which can cause tissue necrosis

Norepinephrine (Levophed)

Norepinephrine is the drug of choice. Other vasopressors may also be used, but norepinephrine has been reported to reverse hypotension that was refractory to other agents. This is thought to be because severe TCA toxicity causes depletion of synaptic norepinephrine that can then only be reversed with exogenous norepinephrine administration. 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.

Dosing

Adult

0.05-0.15 mcg/kg/min IV infusion; titrate to effect

Pediatric

0.1-1 mcg/kg/min IV infusion; titrate to effect

Interactions

Chlorpromazine enhances the pressor response of norepinephrine by blocking the reflex bradycardia caused by norepinephrine

Contraindications

Documented hypersensitivity; peripheral, mesenteric, or other vascular thrombosis; ischemia may be increased and the area of the infarct extended; uncorrected hypovolemia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Correct blood volume depletion, if possible, before administering; extravasation may cause severe tissue necrosis and, thus, should be administered into a large vein; caution in occlusive vascular disease; consider risk vs benefit if hypercapnia is present

Epinephrine (Adrenaline)

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.

Dosing

Adult

1-10 mcg/min IV; titrate dose to desired effect; severe cardiac dysfunction may require doses >10 mcg/min (up to 0.1 mcg/kg/min)

Pediatric

0.1-1 mcg/kg/min IV; titrate dose to desired effect

Interactions

Increases toxicity of beta-blocking and alpha-blocking agents and halogenated inhalational anesthetics

Contraindications

Documented hypersensitivity; cardiac arrhythmias; angle-closure glaucoma; local anesthesia in areas such as fingers or toes because vasoconstriction may produce sloughing of tissue; do not use during labor (may delay second stage of labor)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in elderly patients, prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, and cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias. Correct blood volume depletion, if possible, before administering

Phenylephrine (Neo-Synephrine)

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.

Dosing

Adult

100-180 mcg/min IV; decrease to 40-60 mcg/min when pressure stabilizes

Pediatric

0.1 mg/min IV infusion or 3 mg/m² body surface area IM/SC q1-2h prn; decrease to 0.04-0.06 mg/min when pressure stabilizes

Interactions

Bretylium may potentiate action of vasopressors on adrenergic receptors, possibly resulting in arrhythmias; MAOIs may significantly enhance adrenergic effects, and pressor response may be increased 2- to 3-fold
Guanethidine may increase pressor response of direct-acting vasopressors, possibly resulting in severe hypertension

Contraindications

Documented hypersensitivity; severe hypertension; ventricular tachycardia; uncorrected hypovolemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in elderly patients, hyperthyroidism, myocardial disease, bradycardia, partial heart block, or severe arteriosclerosis; with hypovolemia, phenylephrine use is not a substitute for replacement of blood, fluids with electrolytes, and plasma (these should be restored promptly when loss has occurred)

Lidocaine (Xylocaine)

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.

Dosing

Adult

1.5 mg/kg slow IV push over 2-3 min, loading dose; may repeat q5min up to 300 mg/h; if successful, begin infusion at 1-4 mg/min

Pediatric

1 mg/kg slow IV push, drip at 10-50 mcg/kg/min

Interactions

Coadministration with cimetidine or beta-blockers, increases toxicity; coadministration with procainamide and tocainide may result in additive cardiodepressant action; may increase effects of succinylcholine

Contraindications

Documented hypersensitivity to amide-type local anesthetics; avoid in Adams-Stokes syndrome and Wolff-Parkinson-White syndrome; avoid in severe sinoatrial, AV, or intraventricular block, if artificial pacemaker not in place

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Use a solution without preservatives; caution in heart failure, hepatic disease, hypoxia, hypovolemia, shock, respiratory-depression, and bradycardia; may increase risk of CNS and cardiac adverse effects in elderly patients; high plasma concentrations can cause seizures, heart block, and AV conduction abnormalities

Anticonvulsants

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. Flumazenil is contraindicated in treatment of TCA toxicity.

Lorazepam (Ativan)

Increasing the action of GABA, a major inhibitory neurotransmitter, may depress all levels of CNS, including limbic and reticular formation. DOC because of more prolonged anticonvulsant effects than diazepam or midazolam (4-6 h vs 1-3 h). Has an excellent safety profile.

Dosing

Adult

0.05-0.1 mg/kg (2-7 mg) IV/IM initial over 1-2 min

Pediatric

Children: 0.05 mg/kg IV (range, 0.02-0.1 mg/kg)
Adolescents: Administer as in adults
Status epilepticus:
Adolescents: 0.07 mg/kg; not to exceed 4 mg, slowly over 2-5 min, with second dose in 10-15 min if needed
Infants and children: 0.1 mg/kg over 2-5 min, second dose of 0.05 mg/kg IV at 10-15 min if needed; not to exceed 4 mg/dose
Neonates: 0.05 mg/kg over 2-5 min; may repeat in 10-15 min if needed

Interactions

Toxicity in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs

Contraindications

Documented hypersensitivity; preexisting CNS depression with an unsecured airway; hypotension; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor for respiratory depression and secure the airway if compromised; contains benzyl alcohol, which may be toxic to infants in high doses; caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, Parkinson disease, or patients who may have inhibition of benzodiazepine metabolism and clearance (eg, using nicotine, taking cimetidine)

Diazepam (Valium)

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

Dosing

Adult

2-10 mg IV q10-15min until symptoms resolve; not to exceed 30 mg

Pediatric

30 days to 5 years: 0.05-0.3 mg/kg/dose IV over 2-3 min (slowly) q15-30 min until symptoms resolve; not to exceed 5 mg
>5 years: 1 mg/dose IV over 2-3 min (slowly) q2-5min until symptoms resolve; not to exceed 10 mg

Interactions

Increases toxicity in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; hypotension; acute narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with other CNS depressants, low albumin levels, or renal and hepatic disease (may increase toxicity); monitor for respiratory depression with high or repeated doses; as with other CNS depressants, the airway needs to be secured if compromised

Phenobarbital (Barbita, Luminal)

Not used often because of the preferable safety profile of benzodiazepines but an effective antiseizure medication.

Dosing

Adult

120 mg IV over 10 min, then 5 mg/min up to 500-600 mg/d total

Pediatric

15-20 mg/kg IV load; 1-6 mg/kg/dose q15-30min prn maintenance

Interactions

May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects, hypotension, and fatality; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities also may occur)

Contraindications

Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritic patients

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor for respiratory depression and secure the airway if compromised; monitor for hypotension; with prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema

Follow-up

Further Inpatient Care

• Patients being treated for antidepressant toxicity may need repeat boluses of bicarbonate or drip and will require cardiac monitoring and ICU care if admitted.

Complications

Complications of antidepressant toxicity may include the following:

• CNS sequelae
• Seizures
• Dysrhythmias
• Hypotension

Prognosis

• Prognosis generally is favorable without long-term CNS or cardiovascular sequelae in patients who survive initial toxicity. Most fatalities occur within the first 24 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 following 6 hours of emergency department observation are unlikely to develop toxicity.

Patient Education

• For excellent patient education resources, visit eMedicine's Poisoning - First Aid and Emergency Center, Mental Health and Behavior Center, and Substance Abuse Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

Miscellaneous

Medicolegal Pitfalls

• Failure to appreciate the possibility of rapid deterioration
• Failure to provide sufficient cardiac monitoring, IV access, and observation
• Failure to administer sodium bicarbonate (indicated for QRS widening, dysrhythmia, cardiac blocks, shock)
• Failure to administer activated charcoal to the unstable patient
• Failure to aggressively manage the airway

Multimedia

Media file 1: Toxicity, antidepressant. ECG shows the terminal R wave in aVR and the widened QRS complex associated with tricyclic antidepressant (TCA) toxicity.

References

1. Bronstein AC, Spyker DA, Cantilena LR Jr, et al. 2006 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS). Clin Toxicol (Phila). Dec 2007;45(8):815-917. [Medline]. [Full Text].

2. Heard K, Dart RC, Bogdan G, et al. A preliminary study of tricyclic antidepressant (TCA) ovine FAB for TCA toxicity. Clin Toxicol (Phila). 2006;44(3):275-81. [Medline].

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Keywords

antidepressant toxicity, antidepressant overdose, tricyclic antidepressants, TCAs, cyclic antidepressants, antidepressant poisoning, TCA toxicity, TCA overdose, TCA exposure, treatment of depression

Contributor Information and Disclosures

Author

Jeena Jacob, MD, PharmD, Resident Physician, Department of Emergency Medicine, Yale-New Haven Hospital
Jeena Jacob, MD, PharmD is a member of the following medical societies: American Medical Association, Emergency Medicine Residents Association, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School
David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center
Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Eric Legome, MD, and Craig Smollin, MD, to the development and writing of this article.

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