Medical Pharmacology: Pharmacology of Antidepressant Drugs

**Serotonin Syndrome¹⁹⁷**
"Serotonergic" medications administration may be associated with a rare but potentially "life-threatening" drug reaction, known as serotonin syndrome or serotonin toxicity.¹⁹⁷ Drugs typically associated with serotonin syndrome usually are categorized as antidepressants; however, some patients without a history of depression may be prescribed these agents for various other disorders. The syndrome is associated with both exposure to a serotonergic drug and some combination of cognitive behavioral change, autonomic nervous system functional change, and altered neuromuscular activity. The extent of abnormality in any one particular area is variable. Activation of a postsynaptic serotonergic receptor subtype, 5-HT_2A , is likely responsible for serotonin syndrome, although other receptor subtypes may be important in explaining the full manifestation of the syndrome. Drugs that inhibit serotonin binding to postsynaptic serotonergic receptors do not induce serotonin syndrome and may be used to treat it. Most cases of serotonin syndrome develop in patients taking serotonergic drugs at the therapeutic level, although about 10% of cases occur following serotonergic drug overdose.¹⁹⁷ Serotonin syndrome onset develops relatively soon following administration of the serotonin agonist such as a monoamine oxidase inhibitor (MAOI) or a specific serotonin reuptake inhibitor (SSRI). Diagnostic challenge:¹⁹⁷ Nonspecific symptomatology represents a challenge to serotonin syndrome diagnosis. Mild cases might be interpreted incorrectly as associated with other medical or psychiatric disorders. More severe cases may be misdiagnosed as neuroleptic malignant syndrome, associated with administration of antipsychotic agents. A concern in the emergent care setting is that in the absence of considering serotonin syndrome risk, serotonin syndrome may actually be induced by administering a serotonergic drug such as meperidine, dextromethorphan or tramadol. Avoiding this type of event, an iatrogenic cause of serotonin syndrome, requires utilization of drug databases and other resources. The incidence and severity of serotonin syndrome has been difficult to document with some studies apparently overestimating and others underestimating his frequency and severity.¹⁹⁷ However, the most commonly found signs and symptoms due to serotonin syndrome are altered mental status, increased muscle tone and hyperthermia. The most common finding in serotonin syndrome is myoclonus, which is an important observation, given that myoclonus is not typically seen in other conditions that would otherwise mimic serotonin syndrome. Muscle rigidity is particularly notable in lower extremities and represents another clinical marker for serotonin syndrome. Even patients exhibiting ataxia should be evaluated for hypertonia in lower extremities. However, focal neurologic findings or one-sided muscle rigidity tends not to be consistent with serotonin syndrome. Presentations include seizures (generalized and typically of short-duration), moderately severe hyperthermia (temperatures >106^oF (41^oC) however may occur). Management of serotonin syndrome begins with discontinuing all serotonergic agents and providing supportive care with about 25% of patients requiring endotracheal intubation and ventilatory support. ^{197,198,199,200,201} Dramatic improvement within about a day of symptom onset appears typical; serotonin syndrome mortality is about 11% and the most common cause of death is severe hyperthermia. Drugs that may be helpful in management of serotonin syndrome include benzodiazepines, which exhibit nonspecific serotonin antagonism, the administration of which may reduce patient discomfort and facilitate muscle relaxation. The most effective anti-serotonergic drug for use in the setting is cyproheptadine. Chlorpromazine administration may be helpful, probably due to its blockade of the 5-HT_2A serotonin receptor subtype. By contrast to cyproheptadine, chlorpromazine is available by the IV route of administration; however, chlorpromazine administration may result in undesired hypotension. The nonspecific muscle relaxant dantroline has been occasionally used in serotonin syndrome treatment although its use typically is restricted mainly to management of malignant hyperthermia. Following recovery, the patient should probably avoid subsequent exposure to serotonergic agents even though the risk of recurrence has not been quantified.

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