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Which of the following medications is MOST likely to be an effective treatment for serotonin syndrome?
A. Ondansetron X
B. Cyproheptadine ✔
C. Methylene blue X
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Serotonin toxicity, or serotonin syndrome, causes a myriad of symptoms, most commonly affecting the autonomic nervous system. These symptoms lead to neuromuscular dysfunction and mental status changes. In its most severe form, serotonin syndrome can lead to critical illness and even death. Symptoms include:
Serotonin syndrome shares many symptoms with other disorders. The differential diagnosis includes neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic toxicity, and sympathomimetic drug toxicity (Table 1).
Table 1. Differentiating serotonin syndrome among common presentations. Used in accordance with the Creative Commons Attribution 4.0 International license, from Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013;13(4):533-540. © 2013 The Authors.
Serotonin syndrome is typically precipitated by medications that affect the amount of circulating serotonin. This can occur by several mechanisms, including inhibition of serotonin reuptake or metabolism, increased synthesis or release of serotonin, or activation of serotonin receptors. In addition, the inhibition of cytochrome P450 enzymes may lead to an accumulation of serotonergic medications. A multitude of medications have been implicated in causing serotonin syndrome (Table 2).
Table 2. Mechanisms of serotonin syndrome and the drugs associated with each. Used in accordance with the Creative Commons Attribution 4.0 International license, from Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013;13(4):533-540. © 2013 The Authors.
Serotonin (5-hydroxytryptamine [5-HT]) is formed by the decarboxylation and hydroxylation of tryptophan. There are at least 7 receptors to which 5-HT can bind. The most important 5-HT receptors related to serotonin syndrome seem to be 5-HT1A and 5-HT2A, and antagonism of those receptors has been associated with an improvement in the symptoms associated with serotonin syndrome. Conversely, blockade of other 5-HT receptors has been associated with a higher risk of developing serotonin syndrome. For example, ondansetron, a 5-HT3 receptor antagonist, may induce or worsen serotonin syndrome. Methylene blue has been associated with exacerbation of serotonin syndrome when combined with serotonergic agents due to its monoamine oxidase inhibitory action.
Treatment of serotonin syndrome includes discontinuing the offending agents and addressing the resulting symptoms. Cyproheptadine is a 5-HT2A receptor antagonist (as well as a histamine-1 receptor blocker) that is frequently employed when symptoms are moderate to severe. Although cyproheptadine may provide symptomatic relief, it is not thought to shorten the course of serotonin syndrome. Another 5-HT receptor antagonist, chlorpromazine, may be useful but is typically avoided due to its risk of orthostatic hypotension in this potentially unstable patient population. The benzodiazepine, diazepam, has been used to blunt the hyperadrenergic symptoms associated with serotonergic syndrome. Observation in the hospital is recommended during the treatment of serotonin syndrome, and patients with severe symptoms should be monitored in an intensive care setting.
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Date of last update: September 18, 2024
