Antidepressant Toxicity 

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.

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 gamma-aminobutyric acid (GABA), N -methyl-D-aspartate (NMDA), and dopamine receptors. The cardiovascular toxicity, which is the most common cause of morbidity and mortality from TCAs, is related to their membrane-stabilizing effect through sodium channel blockade and alpha-adrenergic blockade. The effects of these drugs on vascular tone, myocardial action potential, and the autonomic nervous system can cause severe hypotension, dysrhythmias, and conduction delays.

TCAs bind to and inhibit the movement of sodium ions into the fast sodium channel thereby slowing phase O depolarization in the His-Purkinje system and ventricular myocytes. This results in slowed cardiac conduction by slowing the propagation of ventricular depolarization which is manifested as a prolonged QRS on the ECG. The right bundle branch is affected disproportionately by the conduction delay because it has a longer refractory period thereby resulting in a rightward shift of the terminal QRS axis and the right bundle-branch block (RBBB) pattern that is seen on the ECG of some patients who are exposed to TCAs (a characteristic ECG is shown in the image below).

TCAs also block phase 3 repolarization in His-Purkinje myocytes, resulting in prolonged QTc on the ECG. Specifically, TCAs inhibit outward potassium current by blocking potassium channels in phase 3, which ultimately results in prolongation of the QT interval. Prolongation of the QTc usually predisposes to the development of torsades de pointes but in the setting of TCA exposure, it is uncommon because torsades de pointes is more likely to occur in the setting of bradycardia and the anticholinergic effects of these drugs produce offsetting tachycardia.

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.

In October 2003, the US Food and Drug Administration (FDA) issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. In September 2004, the results of an FDA analysis suggested that the risk of emergent suicidality in children and adolescents taking SSRIs was real. The FDA advisors recommended the following:

• A "black-box" warning label be placed on all antidepressants, indicating that they increase the risk of suicidal thinking and behavior (suicidality)
• A patient information sheet (Medication Guide) be provided to the patient and their caregiver with every prescription
• The results of controlled pediatric trials of depression be included in the labeling for antidepressant drugs

The committees recommended that the products not be contraindicated in the United States because access was important for those who could benefit from them. For more information, see the FDA Statement on Recommendations of the Psychopharmacologic Drugs and Pediatric Advisory Committees.

Some studies have shown that the FDA warnings regarding suicide in children on antidepressants may have had the unintended result of a decrease in the rates of diagnosis and treatment of depression, as well as dosing adjustments by physicians. It has also been noted that monitoring of these patients did not increase following the warnings.^{[2, 3, 4, 5]}