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The newer antidepressants are commonly referred to as atypical, heterocyclic, or second-generation antidepressants. These terms distinguish them from the more traditional monoamine oxidase inhibitors and cyclic antidepressants. This distinction is important, because newer antidepressants are more selective in their pharmacologic activity and have a much different clinical presentation in overdose. As a group, the newer antidepressants are the most popular form of psychopharmacologic therapy for the treatment of major depression, obsessive-compulsive disorder, panic disorders, and eating disorders.

The American Association of Poison Control Centers reported that antidepressants were the third most common cause of poison-related fatalities and were responsible for roughly 4% of all phone calls to regional poison control centers during 2008.1 Fortunately, the newer antidepressants produced less severe toxicity in overdose and are associated with fewer fatalities than either cyclic antidepressants or monamine oxidase inhibitors. In 2008, there were over 57,000 selective serotonin reuptake inhibitor (SSRI) and trazodone exposures with only two reported fatalities. This favorable overdose profile is tempered by the U.S. Food and Drug Administration black box warning regarding the use of SSRIs by patients <24 years of age due to increased suicidal ideation and behavior.

The newer antidepressants are a heterogeneous group of drugs that differ significantly in chemical structure, mechanism of action, pharmacokinetic characteristics, and adverse effect profile. Nonetheless, they also share many important similarities:

1. Almost all antidepressants possess serotoninergic activity and, especially in combination with other serotonergic agents, have the potential to produce serotonin syndrome. Thus they carry specific warnings about this syndrome, particularly against their combination with monamine oxidase inhibitors and other high-potency agents (Table 172-1).

2. Most atypical antidepressants do not significantly inhibit cardiac sodium, calcium, or potassium ion channels, which in large part explains their greater safety in overdose compared with cyclic antidepressants. However, they have been reported on rare occasion to be associated with the same ECG conduction abnormalities typically seen with cyclic antidepressants, which allows for the possibility of cardiotoxicity following larger overdoses of the newer antidepressants.

3. These agents do not inhibit monoamine oxidase activity and are not associated with tyramine-like reactions. This permits the use of indirect sympathomimetics if needed for blood pressure support.

4. These agents have negligible affinity for acetylcholine, dopamine, γ-aminobutyric acid, glutamate, and β-adrenergic receptors. Although their exact mechanism of action remains poorly understood, it is traditionally attributed to inhibition of neurotransmitter reuptake or interruption of negative feedback loops.

5. Newer antidepressants (except bupropion, see Bupropion below) appear to have a much higher safety margin than the monamine oxidase inhibitors and cyclic antidepressants. Nonetheless, they can still cause fatalities, especially at very high doses or when combined with other drugs. There are extremely limited human data on the “typical” presentation or optimal management of toxicity with these agents. Some patients may just need to be observed, whereas others ...

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