Serotonin Syndrome

In most cases, serotonin syndrome manifests within 24 hours, and usually within 6 hours, of a change in dose or initiation of a medication. Manifestations can range widely in severity. They can be grouped into the following categories:

• Mental status alterations: Anxiety, agitation and restlessness, easy startling, delirium

• Autonomic hyperactivity: Tachycardia, hypertension, hyperthermia, diaphoresis, shivering, vomiting, diarrhea

• Neuromuscular hyperactivity: Tremor, muscle hypertonia or rigidity, myoclonus, hyperreflexia, clonus (including ocular clonus), extensor plantar responses

Neuromuscular hyperactivity may be more pronounced in the lower than the upper extremities.

Symptoms usually resolve in 24 hours, but symptoms may last longer after use of medications that have a long half-life or active metabolites (eg, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors).

• Primarily history and physical examination

Diagnosis of serotonin syndrome is clinical. Various explicit criteria have been proposed.

The Hunter criteria are currently preferred because of ease of use and high accuracy (almost 85% sensitivity and > 95% specificity compared with diagnosis by a toxicologist) (1, 2). These criteria require that patients have taken a serotonergic medication and have one of the following:

• Spontaneous clonus

• Tremor and hyperreflexia

• Ocular or inducible clonus, plus agitation or diaphoresis, or hypertonia and temperature > 38° C

Systemic infections, drug or alcohol withdrawal syndromes, and toxicity caused by sympathomimetic or anticholinergic drugs should also be considered in the differential diagnosis. Differentiation of serotonin syndrome from neuroleptic malignant syndrome may be difficult because symptoms (eg, muscle rigidity, hyperthermia, autonomic hyperactivity, altered mental status) overlap. Clues to serotonin syndrome include use of serotonergic medications, rapid onset (eg, within 24 hours), and hyperreflexia, in contrast to the often decreased reflex responses in neuroleptic malignant syndrome (2).

There are no confirmatory tests, but patients should have testing to exclude other disorders (eg, cerebrospinal fluid analysis for possible central nervous system infection, urine testing for drugs of abuse). Also, some tests (eg, serum electrolytes, platelet count, renal function tests, creatine kinase, coagulation panel, urine myoglobin) may be necessary to identify complications in severe serotonin syndrome.

• Discontinue serotonergic medications

• Supportive measures

• Sometimes cyproheptadineSometimes cyproheptadine

When serotonin syndrome is recognized and treated promptly, the prognosis is usually good (1).

All serotonergic medications should be discontinued. Mild symptoms are often relieved with sedation using a benzodiazepine, with resolution occurring in 24 to 72 hours. Dexmedetomidine can be considered in refractory cases. Its mechanism as an alpha-2 agonist may treat the underlying pathophysiology of excess serotonin, as well as act as a sedative agent (All serotonergic medications should be discontinued. Mild symptoms are often relieved with sedation using a benzodiazepine, with resolution occurring in 24 to 72 hours. Dexmedetomidine can be considered in refractory cases. Its mechanism as an alpha-2 agonist may treat the underlying pathophysiology of excess serotonin, as well as act as a sedative agent (2, 3). If symptoms resolve more rapidly, patients should be observed for at least several hours. However, most patients require hospitalization for further testing, treatment, and monitoring.

In severe cases, admission to an intensive care unit is required. Hyperthermia is treated by cooling (see Heatstroke: Treatment). Neuromuscular blockade with appropriate sedation, muscle paralysis, and other supportive measures may be necessary. Pharmacologic treatment of autonomic abnormalities (eg, hypertension, tachycardia) should be with shorter-acting medications (eg, nitroprusside, esmolol) because autonomic effects can change rapidly.). Neuromuscular blockade with appropriate sedation, muscle paralysis, and other supportive measures may be necessary. Pharmacologic treatment of autonomic abnormalities (eg, hypertension, tachycardia) should be with shorter-acting medications (eg, nitroprusside, esmolol) because autonomic effects can change rapidly.

If symptoms persist despite supportive measures, the serotonin antagonist cyproheptadine can be given orally or, after crushing, via nasogastric tube, but evidence for this treatment is of low quality (If symptoms persist despite supportive measures, the serotonin antagonist cyproheptadine can be given orally or, after crushing, via nasogastric tube, but evidence for this treatment is of low quality (4, 5).

Consultation with a toxicologist is encouraged and can be accomplished in the United States by calling America's Poison Centers (1-800-222-1222). Expert assistance is also available from the online tool atPoisonHelp.org.