Merck Manual

Please confirm that you are a health care professional

honeypot link

Serotonin Syndrome

By

David Tanen

, MD, David Geffen School of Medicine at UCLA

Last full review/revision Feb 2021| Content last modified Feb 2021
Click here for Patient Education
Topic Resources

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 Drugs That Can Cause Serotonin Syndrome 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 ). 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.

Table
icon

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.

Treatment of Serotonin Syndrome

  • Supportive measures

  • Sometimes cyproheptadine

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 and often death. Symptoms include temperature > 40° C and altered mental status... 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
ANECTINE, QUELICIN
MARPLAN
ZYVOX
NARDIL
ELDEPRYL
PARNATE
WELLBUTRIN, ZYBAN
No US brand name
No US brand name
EFFEXOR XR
CELEXA
LEXAPRO
PROZAC, SARAFEM
LUVOX
PAXIL
ZOLOFT
INBRIJA
No US brand name
No US brand name
No US brand name
NORPRAMIN
ZONALON
TOFRANIL
No US brand name
PAMELOR
VIVACTIL
No US brand name
ADDERALL XR 10
No US brand name
TENUATE
No US brand names
DESOXYN
HALDOL
ADASUVE
No US brand name
ORAP
No US brand name
CONCERTA, RITALIN
No US brand name
ADIPEX-P
ABILIFY
CLOZARIL
ZYPREXA
INVEGA
SEROQUEL
RISPERDAL
GEODON
INAPSINE
REGLAN
COMPRO
PROMETHEGAN
AXERT
RELPAX
FROVA
AMERGE
MAXALT
IMITREX
ZOMIG
BUPRENEX
ACTIQ, DURAGESIC, SUBLIMAZE
HYSINGLA ER
DEMEROL
OXYCONTIN
TALWIN
ULTRAM
No US brand name
CHLOR-TRIMETON
DELSYM
SANCUSO
LITHOBID
ZOFRAN
NORVIR
LIORESAL
No US brand name
DANTRIUM
PARLODEL
No US brand name
NITROPRESS
BREVIBLOC
VALIUM
ATIVAN
AMIDATE
DIPRIVAN
Click here for Patient Education
NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
Professionals also read
Test your knowledge
Hypothermia
A male patient who is homeless is brought to the emergency department (ED) after he was found disoriented and confused on the street during winter. Physical examination on route to the ED showed unreactive pupils and bradycardia. Currently, the patient is irritable and his speech is slurred. Which of the following is the most appropriate initial step in diagnosis? 
Download the Manuals App iOS ANDROID
Download the Manuals App iOS ANDROID
Download the Manuals App iOS ANDROID
Download the Manuals App iOS ANDROID
Download the Manuals App iOS ANDROID
Download the Manuals App iOS ANDROID

Also of Interest

Download the Manuals App iOS ANDROID
Download the Manuals App iOS ANDROID
Download the Manuals App iOS ANDROID
TOP