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Key Points

  • Cyclic antidepressants remain a leading cause of poisoning-related fatalities among psychoactive medications.

  • Patients will frequently present with minimal signs and symptoms only to abruptly decompensate from life-threatening cardiovascular and central nervous system toxicity.

  • Cardiovascular toxicity (specifically refractory hypotension) is the leading cause of morbidity and mortality in cyclic antidepressant overdose.

  • Hypertonic sodium bicarbonate should be given in 1–2 mEq/kg boluses to reverse the wide-complex dysrhythmias commonly encountered with cyclic antidepressant poisoning.


Cyclic antidepressants (CA) consist of a group of pharmacologically related medications that were initially developed in the late 1950s for the treatment of patients with severe depression. Although used less frequently for this purpose, their role has expanded to include the management of various alternative conditions including neuralgic pain, migraine headaches, enuresis, and attention deficit hyperactivity disorder. Traditional cyclic antidepressants have a chemical structure built on a 3-ring nucleus and include such medications such as amitriptyline, nortriptyline, doxepin, imipramine, and clomipramine. Antidepressants have historically remained a leading cause of pharmacologic self-poisoning owing to their near ubiquitous availability to a depressed patient population inherently at risk for self-harming behavior. Although the introduction of selective serotonin reuptake inhibitors (SSRIs) has decreased the overall incidence of CA poisonings, CA overdoses continue to account for a greater morbidity and mortality given their increased potential for significant toxicologic complications, especially in pediatric patients.

Cyclic antidepressants are nonselective agents that exhibit a wide array of pharmacologic effects with considerable variations in potency. The majority of clinical findings associated with CA poisoning can be attributed to ≥1 of the following pharmacologic actions:

  • Competitive inhibition of acetylcholine at central and peripheral muscarinic (but not nicotinic) receptors

  • Inhibition of α-adrenergic receptors

  • Inhibition of norepinephrine and serotonin uptake

  • Sodium channel blockade

  • Antagonism of GABA-A receptors

Although it is the inhibition of norepinephrine and serotonin uptake that is believed to account for the antidepressant effects of these agents, the alternative actions just listed account for the significant toxicity associated with CA overdose, with sodium channel blockade being the most important factor contributing to patient mortality.

Clinical Presentation


Patients commonly present to the emergency department with minimal clinical findings only to develop life-threatening cardiovascular and central nervous system (CNS) manifestations within the timespan of a few hours. Co-ingestants are not uncommon in patients with CA overdoses, and this possibility must always be investigated.

Attempt to determine the exact amount of drug ingested, as the cyclic antidepressants have a rather narrow therapeutic window, and small excursions beyond the usual therapeutic range (2–4 mg/kg) may result in significant toxicity. Acute ingestions of more than 10–20 mg/kg will cause significant cardiovascular and CNS disturbances owing to the blockade of cardiac sodium channels and inhibition of CNS GABA-A receptors, respectively. Toxicity in children has been reported with ingestions as low ...

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