What is serotonin syndrome?

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Serotonin syndrome is described in the literature as a potentially serious drug-related condition characterized by a number of mental, autonomic and neuromuscular changes.1 Although serotonin syndrome can cause death, the condition is mild in most persons, and with supportive care alone they tend to recover completely. The syndrome, first described in animal models in the 1950s, was referred to as the "serotonin behavioral" or "hyperactivity syndrome."1 Reports of serotonin syndrome in humans followed, and have become increasingly frequent since the 1960s. The earliest reports involved persons who were taking monoamine oxidase inhibitors (MAOIs). Some of the early reports included patients who were also taking tryptophan, a serotonin precursor.1,2

Serotonin syndrome is most often reported in patients taking two or more medications that increase CNS serotonin levels by different mechanisms. The most common drug combinations associated with serotonin syndrome involve the MAOIs, selective serotonin reuptake inhibitors (SSRIs), and the tricyclic antidepressants.3 Because of the dramatic rise in the use of SSRIs, it is predicted that emergency room physicians are going to encounter the serotonin syndrome more frequently than in the past.1

Serotonin Syndrome Risk Factors

Risk factors for the development of serotonin syndrome are unclear, but some trends are becoming apparent as more cases appear in the literature. Some researchers have suggested that peripheral vascular disease and atherosclerosis may lead to severe vasospasm and hypertension in the presence of elevated serotonin levels. This seems paradoxical, since in peripheral areas of the body serotonin usually causes vasodilation. However, in patients with vascular disease serotonin can lead to profound vasoconstriction.6

Another risk factor relates to drug metabolism rate. Slow metabolizers of SSRIs (approximately 7% of the population) may produce higher than normal levels of these antidepressants in the blood. A slow metabolizer receiving an SSRI in combination with another agent that raises serotonin levels is therefore at increased risk of developing serotonin syndrome.6

Clinical Features and Differential Diagnosis

Mental status changes are the most frequently reported symptoms associated with serotonin syndrome.2 Other commonly reported features include motor abnormalities, cardiovascular changes, gastrointestinal problems and miscellaneous changes such as diaphoresis and fever (TABLE 1).2,4 Martin refers to three categories of symptoms that are present: altered mental status, autonomic dysfunction and neuromuscular abnormalities.1 Sporer indicates that at least three of the following must be present for a diagnosis: mental status changes, agitation, myoclonus, hyperreflexia, fever (hyperpyrexia), shivering, diaphoresis, ataxia and diarrhea in the setting of a recent addition or increase in dose of an agent that raises serotonin levels. Sporer also points out that there should be no other obvious causes of the confusion and/or fever, and that no antipsychotic medications have been used or increased in dose prior to the onset of symptoms.3

Poisonings and other diseases, such as neuroleptic malignant syndrome (NMS), can cause symptoms that are very similar to serotonin syndrome (TABLE 3). Martin offers suggestions that may be useful in differentiating serotonin syndrome from these conditions. One is an observation that bromocriptine has been proposed as a treatment for NMS and a cause or precipitant of serotonin syndrome. Another is that NMS occurs from prolonged exposure to neuroleptic agents or withdrawal of dopamine agonists, and there is lead-pipe rigidity with NMS, in contrast to myoclonus or hyperreflexia seen in persons with serotonin syndrome.

Medications Linked with Serotonin Syndrome

Causative agents associated with serotonin syndrome include those that: increase serotonin synthesis (L-tryptophan); decrease serotonin metabolism (MAOIs); increase serotonin release; inhibit serotonin uptake (SSRIs); and stimulate certain serotonin receptors directly, and provide a nonspecific increase in serotonin activity (TABLE 2).

The largest number of cases reported in the literature and the most serious consequences of serotonin syndrome have resulted from use of the MAOIs.3 Most cases were reported when an MAOI was used in conjunction with meperidine, tryptophan, dextromethorphan (an ingredient in many over-the-counter products), a tricyclic antidepressant, or an SSRI antidepressant.2,3 The long half-life (SSRIs) and duration of effect (irreversible MAOIs) seen with some of these medications increase the possibility of serotonin syndrome occurring several weeks after these drugs have been discontinued.1 It is important to note that serotonin syndrome has been precipitated by medications that are not usually thought of as being serotonergic. One author asserts that both meperidine and dextromethorphan are "notorious for precipitating acute serotonin syndrome."4

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What is serotonin syndrome?

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