Tricyclic Antidepressant Toxicity

Updated: Jul 13, 2016
  • Author: Vivian Tsai, MD, MPH, FACEP; Chief Editor: Asim Tarabar, MD  more...
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Most of the cyclic antidepressants (CAs) contain a 3-ring molecular structure. CAs were first used in the 1950s to treat clinical depression. The first report of the adverse effects of tricyclic antidepressant (TCA) overdose came within 2 years of their entry into clinical use. [1]

Despite the increasing popularity of the selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, CAs continue to play an important role in the treatment of enuresis, obsessive-compulsive disorder, attention deficit hyperactivity disorder, school phobia, and separation anxiety in the pediatric population. In adults, indications for CAs include depression, neuralgic pain, chronic pain, and migraine prophylaxis. Some of the more commonly prescribed CAs include amitriptyline, desipramine, imipramine, nortriptyline, doxepin, clomipramine, and protriptyline. Maprotiline, a tetracyclic compound, and amoxapine, a dibenzoxapine, are newer compounds that have a slightly different structure and toxicologic profile.

There is also a potential for TCA abuse and misuse outside of clinical indications and dosages. Subjects who admitted to the misuse of TCAs in a published case series have described effects of TCAs ranging from "a more sociable state" to a "'high' with euphoria, confusion, hallucinations, and a distorted sense of time". [2]



The CAs are well absorbed orally and undergo significant first-pass metabolism in the liver. They have a large volume of distribution and have long half-lives that generally exceed 24 hours. After the CAs are metabolized in the liver via glucuronic acid conjugation, they are then excreted through the kidneys.

The toxic effects of tricyclics are results of the following 4 main pharmacologic properties:

  1. Inhibition of norepinephrine and serotonin reuptake at nerve terminals
  2. Anticholinergic action
  3. Direct alpha-adrenergic blockade
  4. Membrane-stabilizing effect on the myocardium by blocking the cardiac myocyte fast sodium channels

TCAs may also penetrate into the central nervous system (CNS). Given the appropriate dosage, a particular CA exerts its therapeutic antidepressant effects by increasing biogenic amines such as norepinephrine and serotonin at nerve terminals. The same mechanism is thought to be responsible for seizure occurrence in CA overdose. Altered mental status is also frequently seen in CA overdose and is mainly attributed to anticholinergic and antihistaminergic properties of CAs.

The effects of CA overdose on the cardiovascular system result mainly from the impediment of the cardiac conduction system. CAs, like the class IA antiarrhythmics, decrease the sodium influx through the fast sodium channels and consequently decrease the slope of phase 0, leading to the widened QRS complex that is typically seen on ECGs of individuals with CA poisoning. An in vitro study reported that CAs also directly decrease myocardial contractility in a dose-dependent manner. [3] Profound hypotension is sometimes seen in CA overdose and is mainly due to the well-recognized anti–alpha-adrenergic effect of the CAs; however, these direct myocardial depressive effects may also contribute to the severe hypotension seen in CA toxicity.




United States

In the 2014 American Association of Poison Control Centers' National Poison Data System Annual report, TCAs accounted for 4418 single exposures and 12 deaths. The CA most frequently ingested was amitriptyline, with 2790 exposures and seven deaths, followed by doxepin (561 exposures, three deaths) and nortriptyline (524 exposures, no deaths). In addition, the tetracyclic antidepressants maprotiline and mirtazapine accounted for 1274 single exposures and one death. [4]


Fatality before reaching a healthcare facility occurs in approximately 70% of patients attempting suicide with CAs. CA were the number one cause of fatality from drug ingestion until the last decade when they were surpassed by analgesics. Only 2-3% of CA overdose cases that reach a healthcare facility result in death.


CA toxicity occurs in both men and women. However, the incidence of CA exposure is greater in women than in men because women are at a higher risk for suicide attempts.


CA toxicity occurs at all ages. Incidence of CA toxicity is most prevalent in persons aged 20-29 years. This again reflects the demographics of suicidal attempts.