Serotonin Syndrome

ByDavid Tanen, MD, David Geffen School of Medicine at UCLA
Reviewed/Revised Mar 2023
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Serotonin syndrome is a potentially life-threatening condition resulting from increased central nervous system serotonergic activity that is usually drug related. Symptoms may include mental status changes, hyperthermia, and autonomic and neuromuscular hyperactivity. Diagnosis is clinical. Treatment is supportive.

Serotonin syndrome can occur with therapeutic drug use, self-poisoning, or, most commonly, unintended drug interactions when 2 serotonergic drugs are used (see table Drugs That Can Cause Serotonin Syndrome). It can occur in all age groups.

Complications in severe serotonin syndrome can include metabolic acidosis, rhabdomyolysis, seizures, acute kidney injury, and disseminated intravascular coagulation (DIC). Causes of these complications probably include severe hyperthermia and excessive muscle activity.

(See also Overview of Heat Illness.)


Symptoms and Signs of 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 drug. 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 drugs that have a long half-life or active metabolites (eg, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors).

Diagnosis of Serotonin Syndrome

  • Clinical criteria

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). These criteria require that patients have taken a serotonergic drug and have one of the following:

  • Muscle hypertonia

  • Spontaneous clonus

  • Tremor plus hyperreflexia

  • Ocular or inducible clonus, plus either agitation, diaphoresis, or 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 drugs, rapid onset (eg, within 24 hours), and hyperreflexia, in contrast to the often decreased reflex responses in neuroleptic malignant syndrome.

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, prothrombin time, testing for urine myoglobin) may be necessary to identify complications in severe serotonin syndrome.

Pearls & Pitfalls

  • Among patients with hyperthermia, altered mental status, autonomic hyperactivity, and muscular rigidity factors that favor serotonin syndrome over neuroleptic malignant syndrome include use of serotonergic drugs, onset within 24 hours, and hyperreflexia

Treatment of Serotonin Syndrome

  • Supportive measures

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

All serotonergic drugs should be stopped. Mild symptoms are often relieved with sedation using a benzodiazepine, with resolution occurring in 24 to 72 hours. 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

Consultation with a toxicologist is encouraged and can be accomplished by calling the United States Poison Control Network (1-800-222-1222).

Treatment reference

  1. 1. Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med 352(11):1112-20, 2005. doi: 10.1056/NEJMra041867 Erratum in: N Engl J Med 356(23):2437, 2007. Erratum in: N Engl J Med 361(17):1714, 2009.

Key Points

  • Drugs that increase serotonergic activity can lead to hyperthermia and neuromuscular hyperactivity, with complications of metabolic acidosis, rhabdomyolysis, seizures, acute kidney injury, and disseminated intravascular coagulation (DIC).

  • The diagnosis is likely if patients have taken a serotonergic drug and have muscle hypertonia; spontaneous clonus; tremor plus hyperreflexia; or the combination of ocular or inducible clonus; plus either agitation, diaphoresis, or temperature > 38° C.

  • Serotonin syndrome can often be differentiated from neuroleptic malignant syndrome by use of serotonergic drugs, rapid onset (eg, within 24 hours of its drug trigger), and hyperreflexia.

  • Stop all serotonergic drugs and give a benzodiazepine.

Drugs Mentioned In This Article
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