eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Antidepressant

Author: Jeena Jacob, MD, PharmD, Resident Physician, Department of Emergency Medicine, Yale-New Haven Hospital
Contributor Information and Disclosures

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). 

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. 

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