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Atypical and serotonergic antidepressants are commonly referred to as newer or second-generation antidepressants to distinguish them from the first-generation monoamine oxidase inhibitors and cyclic antidepressants. As a group, these antidepressants are the most popular form of psychopharmacologic therapy for the treatment of major depression, obsessive-compulsive disorder, panic disorders, and eating disorders.1 These antidepressants produce less severe toxicity in overdose and are associated with fewer fatalities than either cyclic antidepressants or monoamine oxidase inhibitors.2–4 This favorable overdose profile is tempered by the U.S. Food and Drug Administration black box warning regarding the use of some agents by patients <24 years old due to increased suicidal ideation and behavior.

This group of antidepressants is a heterogeneous collection of drugs that differ significantly in chemical structure, mechanism of action, pharmacokinetic characteristics, and adverse effect profile.1 Nonetheless, they also share many important similarities.

Most possess serotonergic activity and, especially in combination with other serotonergic agents, have the potential to produce serotonin syndrome. These agents have negligible affinity for acetylcholine, dopamine, γ-aminobutyric acid, glutamate, and β-adrenergic receptors. These agents do not inhibit monoamine oxidase activity and are not associated with tyramine-like reactions. Most of these antidepressants do not significantly inhibit cardiac sodium, calcium, or potassium ion channels. Although their exact mechanism of action remains poorly understood, it is traditionally attributed to inhibition of neurotransmitter reuptake or interruption of negative feedback loops.

These antidepressants are metabolized primarily by hepatic enzyme systems (cytochrome P450 pathways). If two drugs are given that interact with a common metabolic pathway, drug levels can increase or decrease depending on the interaction. In addition, hepatic dysfunction can lead to elevated drug levels and subsequent drug toxicity. These antidepressants are not detected by routine hospital serum and urine drug screens. Specialty laboratories can measure parent drug and metabolite plasma levels, but this information is useful only for the confirmation of suspected drug overdose and does not affect patient management.



The atypical antidepressants have chemical structures different from each other and from the other antidepressant classes (Table 178-1). They possess some unique clinical features at therapeutic doses and with overdoses.

TABLE 178-1Atypical Antidepressants


Bupropion has a monocyclic phenylaminoketone chemical structure that resembles the phenylethylamines (e.g., amphetamine), but does not produce stimulant effects or drug-addictive behavior at therapeutic dosages. The therapeutic mechanism of action of bupropion is primarily inhibition of neuronal reuptake of norepinephrine ...

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