Aetiology

A lethal dose of tricyclic antidepressant (TCA) is often contained in a typical month's supply, with 2-week doses enough to produce considerable toxicity. Serious toxicity is rare with doses less than 20 mg/kg, but because of variations in metabolism, protein binding, and absorption, the specific amount is unlikely to predict clinical danger.[11]

TCA use has declined due to the availability of selective serotonin reuptake inhibitors (SSRIs), but they continue to account for most deaths attributed to antidepressant overdose each year.[8] Amitriptyline and dosulepin appear to be particularly toxic in overdose, and dosulepin has been associated with an increased risk of seizures and arrhythmias.[2][3]

With SSRIs, ingestion of more than 30 times the normal dose is required to elicit symptoms such as fatigue, tremor, nausea, and vomiting. At more than 75 times of the normal dose, serious effects can occur, including seizures, toxic ECG changes, and decreased consciousness. Most fatalities occur when these drugs are taken in combination with other drugs or alcohol, as toxicity then increases.[12]

Features of serotonin toxicity may also occur if the patient has co-ingested other drugs that increase the effect of serotonin, or is taking one of these drugs therapeutically. These include SSRIs, venlafaxine, monoamine oxidase inhibitors, amfetamines, cocaine, MDMA (ecstasy), linezolid, tramadol, or triptans. The clinical features of serotonin syndrome include hyperpyrexia, impaired consciousness level or agitation, increased muscle tone, and clonus.[13] It is often associated with an elevated creatine kinase level.

Pathophysiology

TCAs are rapidly absorbed, highly protein bound, and have a high lipid solubility, so they are rapidly distributed into tissues. Tissue concentrations in both the brain and myocardium are much greater than blood concentrations. The main pharmacological effects include:[14]

  • Anticholinergic effects at muscarinic receptors

  • Alpha-1 adrenergic receptor antagonism

  • Fast sodium channel blockade

  • Inhibition of pre-synaptic reuptake of noradrenaline (norepinephrine), serotonin, and dopamine

  • Competitive antagonism of histaminergic H1 and H2 receptors

The lethal nature of a TCA overdose results from toxicity to multiple systems through varying mechanisms that cause dysrhythmias, hypotension, and seizures. As muscarinic antagonists, TCAs cause tachycardia. Within the myocardium, TCAs act as fast sodium channel blockers, resulting in delayed AV conduction with widening of the QRS complex on the ECG, QT prolongation, and risk of arrhythmias.

TCAs decrease peripheral vascular resistance through their potent alpha-1 receptor antagonist effect, and cause profound, and often refractory, hypotension. Impaired myocardial contractility, caused by impaired sodium flux into myocardial cells, contributes to hypotension and impaired cardiac output. Acidosis, caused by seizures, worsens cardiac toxicity. When coupled with a wide complex tachycardia, cardiovascular collapse quickly ensues in the absence of supportive measures. Refractory hypotension is the leading cause of in-hospital death from TCA overdose.

Within the central nervous system, TCA overdose causes delirium, lethargy, seizure, and coma. Mental status changes are most likely to be caused by antimuscarinic effects. Seizures result from multiple factors. As in the myocardium, TCAs act as fast sodium channel blockers within the central nervous system. An additional cause for seizures results from direct antagonism of GABA receptors.

Classification

TCA generation

When compared with the first-generation TCAs, second-generation TCAs more selectively inhibit pre-synaptic reuptake of serotonin and dopamine.

First-generation TCAs are tertiary amines and include:

  • Amitriptyline

  • Clomipramine

  • Doxepin

  • Dosulepin

  • Imipramine

  • Trimipramine.

Second-generation TCAs are secondary amines and include:

  • Desipramine

  • Nortriptyline

  • Protriptyline.

Tetracyclic antidepressants are four-ringed structures and include:

  • Amoxapine

  • Maprotiline.

Amitriptyline and dosulepin appear to be particularly toxic in overdose, and dosulepin has been associated with an increased risk of seizures and arrhythmias.[2][3]

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