Serotonin syndrome can occur with therapeutic drug use, self-poisoning, or, most commonly, unintended drug interactions when 2 serotonergic drugs are used (see table ). It can occur in all age groups.
Complications in severe serotonin syndrome can include metabolic acidosis Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly... read more , rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is a clinical syndrome involving the breakdown of skeletal muscle tissue. Symptoms and signs include muscle weakness, myalgias, and reddish-brown urine, although this triad is... read more , seizures Seizure Disorders A seizure is an abnormal, unregulated electrical discharge that occurs within the brain’s cortical gray matter and transiently interrupts normal brain function. A seizure typically causes altered... read more , acute kidney injury Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more , and disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more (DIC). Causes of these complications probably include severe hyperthermia and excessive muscle activity.
(See also Overview of Heat Illness Overview of Heat Illness Heat illness encompasses a number of disorders ranging in severity from muscle cramps and heat exhaustion to heatstroke (which can be a life-threatening emergency). Current estimates of heat-related... read more .)
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 Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome is characterized by altered mental status, muscle rigidity, hyperthermia, and autonomic hyperactivity that occur when certain neuroleptic drugs are used. Clinically... read more 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
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Treatment of Serotonin Syndrome
Supportive measures
Sometimes cyproheptadine
When serotonin syndrome is recognized and treated promptly, the prognosis is usually good (1 Key Points 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... read more ).
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 Treatment Heatstroke is hyperthermia accompanied by a systemic inflammatory response causing multiple organ dysfunction that may result in death. Symptoms include temperature > 40° C and altered mental... read more ). Neuromuscular blockade with appropriate sedation, muscle paralysis, and other supportive measures may be necessary. Drug treatment of autonomic abnormalities (eg, hypertension, tachycardia) should be with shorter-acting drugs (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 (12 mg, then 2 mg every 2 hours until response occurs).
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. 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.
Treat complications aggressively and consider cyproheptadine.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
cyproheptadine |
Periactin |
nitroprusside |
NIPRIDE RTU , Nitropress |
esmolol |
Brevibloc |
