Serotonin syndrome is a potentially life-threatening condition resulting from increased CNS 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 4: Heat Illness: 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 renal failure, and disseminated intravascular coagulation. Causes probably include severe hyperthermia and muscle activity.

Table 4
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Drugs That Can Cause Serotonin Syndrome Class Drugs Antidepressants: Monoamine oxidase inhibitors IsocarboxazidSome Trade Names MARPLAN Click for Drug Monograph LinezolidSome Trade Names ZYVOX Click for Drug Monograph PhenelzineSome Trade Names NARDIL Click for Drug Monograph TranylcypromineSome Trade Names PARNATE Click for Drug Monograph Antidepressants: Serotonin-norepinephrineSome Trade Names LEVOPHED Click for Drug Monograph reuptake inhibitors BupropionSome Trade Names WELLBUTRIN ZYBAN Click for Drug Monograph NefazodoneSome Trade Names SERZONE Click for Drug Monograph TrazodoneSome Trade Names DESYREL Click for Drug Monograph VenlafaxineSome Trade Names EFFEXOR Click for Drug Monograph Antidepressants: SSRIs CitalopramSome Trade Names CELEXA Click for Drug Monograph EscitalopramSome Trade Names LEXAPRO Click for Drug Monograph FluoxetineSome Trade Names PROZAC SARAFEM Click for Drug Monograph FluvoxamineSome Trade Names LUVOX Click for Drug Monograph ParoxetineSome Trade Names PAXIL Click for Drug Monograph SertralineSome Trade Names ZOLOFT Click for Drug Monograph Antidepressants: Tricyclic antidepressants AmitriptylineSome Trade Names ELAVIL ENDEP Click for Drug Monograph AmoxapineSome Trade Names ASENDIN Click for Drug Monograph DesipramineSome Trade Names NORPRAMIN Click for Drug Monograph DoxepinSome Trade Names SINEQUAN ZONALON Click for Drug Monograph ImipramineSome Trade Names TOFRANIL Click for Drug Monograph MaprotilineSome Trade Names No US trade name Click for Drug Monograph NortriptylineSome Trade Names AVENTYL Click for Drug Monograph ProtriptylineSome Trade Names VIVACTIL Click for Drug Monograph TrimipramineSome Trade Names SURMONTIL Click for Drug Monograph CNS stimulants Amphetamine Cocaine Diethylpropion Methamphetamine 3,4-Methylenedioxyamphetamine (MDA) 3,4-Methylenedioxymethamphetamine (MDMA, or Ecstasy) MethylphenidateSome Trade Names CONCERTA RITALIN Click for Drug Monograph PhentermineSome Trade Names ADIPEX-P IONAMIN Click for Drug Monograph SibutramineSome Trade Names MERIDIA Hallucinogens Lysergic acid diethylamide (LSD) 5-Methoxy-diisopropyltryptamine Herbs Nutmeg Panax (Asian or American) ginseng St John's wort Syrian rue 5-Hydroxytryptamine (5-HT1) agonists (triptans) AlmotriptanSome Trade Names AXERT Click for Drug Monograph EletriptanSome Trade Names RELPAX Click for Drug Monograph FrovatriptanSome Trade Names FROVA Click for Drug Monograph NaratriptanSome Trade Names AMERGE Click for Drug Monograph RizatriptanSome Trade Names MAXALT Click for Drug Monograph SumatriptanSome Trade Names IMITREX Click for Drug Monograph ZolmitriptanSome Trade Names ZOMIG Click for Drug Monograph Opioids BuprenorphineSome Trade Names BUPRENEX SUBUTEX Click for Drug Monograph FentanylSome Trade Names ACTIQ DURAGESIC SUBLIMAZE Click for Drug Monograph Hydrocodone MeperidineSome Trade Names DEMEROL Click for Drug Monograph OxycodoneSome Trade Names OXYCONTIN OXYIR Click for Drug Monograph PentazocineSome Trade Names TALWIN Click for Drug Monograph Pethidine TramadolSome Trade Names ULTRAM Click for Drug Monograph Others BuspironeSome Trade Names BUSPAR Click for Drug Monograph ChlorpheniramineSome Trade Names CHLOR-TRIMETON Click for Drug Monograph DextromethorphanSome Trade Names BENYLIN DM DELSYM DEXALONE Click for Drug Monograph GranisetronSome Trade Names KYTRIL Click for Drug Monograph 5-Hydroxytryptophan Levodopa LinezolidSome Trade Names ZYVOX Click for Drug Monograph LithiumSome Trade Names ESKALITH LITHOBID LITHONATE Click for Drug Monograph MetoclopramideSome Trade Names REGLAN Click for Drug Monograph OlanzapineSome Trade Names ZYPREXA Click for Drug Monograph OndansetronSome Trade Names ZOFRAN Click for Drug Monograph RisperidoneSome Trade Names RISPERDAL Click for Drug Monograph RitonavirSome Trade Names NORVIR Click for Drug Monograph Tryptophan ValproateSome Trade Names DEPAKENE Click for Drug Monograph

Symptoms and Signs

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 h, but symptoms may last longer after use of drugs that have a long half-life or active metabolites (eg, monoamine oxidase inhibitors, SSRIs).

Diagnosis

• Clinical criteria

Diagnosis 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 (see Heat Illness: 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 h), 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, CSF analysis for possible CNS infection, urine testing for drugs of abuse). Also, some tests (eg, serum electrolytes, platelet count, renal function tests, CK, PT, testing for urine myoglobin) may be necessary to identify complications in severe serotonin syndrome.

Treatment

• Supportive measures
• Sometimes cyproheptadineSome Trade Names
  PERIACTIN
  Click for Drug Monograph
  

All serotonergic drugs should be stopped. Mild symptoms are often relieved with sedation using a benzodiazepine. If symptoms rapidly resolve, patients should be observed for at least several hours. Most will require hospitalization for further testing, treatment, and monitoring.

In severe cases, admission to an ICU is required. Hyperthermia is treated by cooling (see Heat Illness: Treatment). 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, nitroprussideSome Trade Names
NIPRIDE
Click for Drug Monograph
, esmololSome Trade Names
BREVIBLOC
Click for Drug Monograph
) because autonomic effects can change rapidly.

If symptoms persist despite supportive measures, the serotonin antagonist cyproheptadineSome Trade Names
PERIACTIN
Click for Drug Monograph
can be given orally or, after crushing, via NGT (12 mg, then 2 mg q 2 h until response occurs). DantroleneSome Trade Names
DANTRIUM
Click for Drug Monograph
is not recommended.

Consultation with a toxicologist is encouraged and can be accomplished by calling the United States Poison Control Network (1-800-222-1222) or accessing the WHO's list of international poison centers (http://www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html).

Last full review/revision February 2010 by James P. Knochel, MD

Content last modified May 2012