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 ...