> Table of Contents > Serotonin Syndrome
Serotonin Syndrome
Neela Bhajandas, PharmD
Michael C. Barros, PharmD, BCPS, BCACP
Paul N. Williams, MD, FACP
image BASICS
DESCRIPTION
  • A potentially life-threatening adverse drug reaction that results from excessive stimulation of peripheral and CNS serotonergic receptors
  • It is a concentration-dependent toxicity that can develop in any individual who has ingested drug combinations that synergistically increase synaptic 5-HT.
  • Serotonin toxicity occurs in three main settings: (i) therapeutic drug use, which often results in mild to moderate symptoms; (ii) intentional overdose of a single serotonergic agent, which typically leads to moderate symptoms; and (iii) as the result of a drug interaction between numerous serotonergic agents (most commonly, selective serotonin reuptake inhibitors [SSRIs] and monoamine oxidase inhibitors [MAOIs]), most often associated with severe serotonin toxicity.
  • Classically characterized by a triad of symptoms that include mental status change, neuromuscular abnormalities, and autonomic hyperactivity
  • Onset is usually within 24 hours with 60% of cases occurring within 6 hours of exposure to, or change in, dosing of a serotonergic agent. Rarely, cases have been reported weeks after discontinuation of serotonergic agents.
Geriatric Considerations
Elderly are at increased risk given use of multiple meds.
Pediatric Considerations
  • Serotonin syndrome has similar manifestations in children and adults.
  • General management is unchanged in children, other than medication dosing.
Pregnancy Considerations
  • 3rd-trimester exposure to SSRIs has been associated with transient neonatal complications that may reflect either acute drug withdrawal or serotonergic toxicity.
  • Symptoms in neonates may include tremors, increased muscle tone, jitteriness, shivering, feeding/digestive disturbances, irritability, agitation, sleep disturbances, increased reflexes, excessive crying, and respiratory disturbances.
EPIDEMIOLOGY
Seen in about 14-16% of SSRI overdose patients
Incidence
  • In 2008, there were 106,336 adverse events reported with antidepressant use including 28 deaths. Most of these were associated with SSRIs, either alone or in combination with other drugs. SSRIs alone were responsible for adverse events in 18.8% of cases, with 55.7% due to intentional causes, 39.5% unintentional, and remainder of causes unknown. Of patients reporting adverse effects with SSRIs, 46.6% had symptoms requiring hospitalization, and significant toxic effects occurred in 90 patients with 2 resultant deaths (1)[A].
  • The incidence of serotonin syndrome is rising because serotonergic agents are increasingly used in clinical practice and in combination with other serotonergic agents.
  • Predominant age: affects all age groups
  • Predominant sex: male = female
ETIOLOGY AND PATHOPHYSIOLOGY
  • The result of excessive stimulation in peripheral and CNS serotonergic receptors
  • Risk is mediated in a dose-related manner to the action of 5-HT/5-HT agonists on 5HT-1a and/or 5HT-2a receptors. The development mechanism of the syndrome is unknown.
  • It is hypothesized that the degree of serotonin elevation in blood plasma has to be 10-15% times above baseline levels to result in serotonin toxicity (2)[A].
  • A number of drugs are associated with the serotonin syndrome, which usually involves combination with an SSRI. These include SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline); MAOIs; SNRIs (duloxetine, venlafaxine, desvenlafaxine); tricyclic antidepressants (e.g., amitriptyline); other antidepressants (buspirone, nefazodone, trazodone); lithium; triptans; anticonvulsants (Depakote); analgesics (fentanyl, meperidine, pentazocine, tramadol); antibiotics (linezolid [weak MAOI], ritonavir); over-the-counter (OTC) cough medications (dextromethorphan); some antipsychotics (risperidone, olanzapine); antiemetics (ondansetron, granisetron); other medications, such as metoclopramide, cyclobenzaprine, L-dopa; dietary supplements (tryptophan); herbal supplements (St. John's wort, nutmeg); methylene blue; and drugs of abuse (e.g., methylenedioxymethamphetamine [MDMA], cocaine, D-lysergic acid diethylamide [LSD], and amphetamine).
  • Initially, patients can develop a peripheral tremor, confusion, and ataxia; systemic signs are next (e.g., agitation, diaphoresis, hyperreflexia, and shivering). If it worsens, the severe signs of fever, jerking, and diarrhea may develop. Serotonin syndrome can last from hours to days after the offending agents are stopped and supportive care is initiated.
  • Drug interactions are most often the cause of severe cases of serotonin syndrome. Many of the same classes of medications listed earlier are involved, especially MAOIs (including linezolid) with SSRIs.
Genetics
Unknown
RISK FACTORS
  • Serotonergic agents
  • Reported following ingestion of a single agent. However, the greatest number of adverse events has been shown to be associated with SSRIs in combination with other substances, and the combination of SSRIs and MAOIs carries the greatest risk for developing serotonin toxicity.
GENERAL PREVENTION
  • Consider drug-drug interactions when a multidrug regimen is required and avoid if possible.
  • Caution patients about taking SSRIs with OTC medications (e.g., dextromethorphan) or herbal supplements (e.g., St. John's wort) prior to consulting a physician.
  • Clinician education
  • Continual improvement in use of health information technology
image DIAGNOSIS
  • Serotonin syndrome is a clinical diagnosis.
  • Epidemiologic data suggest that up to 85% of practitioners are unaware of serotonin syndrome.
  • Hunter Toxicity Criteria Decision Rules aid in the diagnosis of clinically significant serotonin toxicity (sensitivity, 84%; specificity, 97%).
  • To fulfill Hunter criteria, a patient must have taken a serotonergic agent and have one of the following:
    • Spontaneous clonus
    • Inducible clonus plus agitation/diaphoresis
    • Ocular clonus plus agitation/diaphoresis
    • Tremor and hyperreflexia
    • Hypertonia
    • Temperature >38°C plus ocular clonus/inducible clonus (3)[A]
PHYSICAL EXAM
  • Vital signs: tachycardia, hypertension, and hyperthermia (severe cases)
  • Neuromuscular findings (seen in over half of patients with serotonin syndrome)
    • Hyperreflexia (greater in lower extremities)
    • Clonus (involuntary muscle contractions, most commonly tested by flexing foot upward rapidly; includes ocular)
    • Myoclonus (greater in lower extremities)
    • Tremor (greater in lower extremities)
    • Hypertonia
    • Bilateral Babinski sign
    • Akathisia
    • Tonic-clonic seizures (severe cases)
    • Autonomic signs
      • Diaphoresis
      • Mydriasis
      • Flushing
      • Dry mucous membranes
      • Vomiting, diarrhea, increased bowel sounds
      • Mental status changes: anxiety, disorientation, delirium (4)[A]
      • Severe cases have led to altered level of consciousness, rhabdomyolysis, metabolic acidosis, and disseminated intravascular coagulation (DIC).
DIFFERENTIAL DIAGNOSIS
  • Neuroleptic malignant syndrome (NMS)
  • Anticholinergic fever (e.g., benztropine, diphenhydramine, oxybutynin, nifedipine, famotidine, atropine, scopolamine; plant poisoning from belladonna/“deadly nightshade,” datura, henbane, mandrake, brugmansia)
  • Malignant hyperthermia
  • Heat stroke
  • P.963

  • CNS infection (meningitis, encephalitis)
  • Sympathomimetic toxicity
  • Nonconvulsive seizures
  • Hyperthyroidism
  • Tetanus
  • Acute baclofen withdrawal
DIAGNOSTIC TESTS & INTERPRETATION
  • Serum serotonin levels do not correlate with clinical findings.
  • Nonspecific lab findings that may develop include the following:
    • Elevated WBC count
    • Elevated creatine phosphokinase (CK or CPK)
    • Decreased serum bicarbonate
    • Elevated hepatic transaminases
  • In severe cases, the following complications may develop:
    • DIC
    • Metabolic acidosis
    • Rhabdomyolysis
    • Renal failure
    • Myoglobinuria
    • Acute respiratory distress syndrome (ARDS) (4)[A]
image TREATMENT
  • Discontinue all serotonergic agents.
  • Supportive care is the mainstay of therapy. This includes administration of oxygen and aggressive IV fluids, continuous cardiac monitoring, and correction of vital signs.
    • Benzodiazepines may be effective for the management of agitation in patients with serotonin syndrome.
    • Administration of serotonin antagonists: Cyproheptadine (histamine and serotonin antagonist) may be useful if supportive measures and sedation (benzodiazepines) are unable to control agitation and correct vital signs.
  • Mild cases (afebrile, tachycardia, shivering, diaphoresis, mydriasis, hyperreflexia, intermittent tremor or myoclonus)
    • Discontinue precipitating agent(s).
    • Supportive care
    • Sedation
  • Moderate cases (temperature >38°C, autonomic instability, mydriasis, hyperactive bowel sounds, diarrhea, diaphoresis, ocular clonus, hyperreflexia, tremor, mild agitation, or hypervigilance)
    • Discontinue precipitating agent(s).
    • Supportive care
    • Sedation
    • Aggressive treatment of autonomic instability
    • Treatment with cyproheptadine should be initiated if agitation and vital sign abnormalities are unimproved with benzodiazepines and supportive care.
    • Hypotension from MAOI interactions should be treated with low doses of direct-acting sympathomimetics (e.g., norepinephrine, phenylephrine, epinephrine); indirect serotonin agonists, such as dopamine, should be avoided.
    • Severe hypertension and tachycardia should be treated with short-acting agents, such as nitroprusside or esmolol.
    • Avoid use of longer acting agents, such as propranolol.
  • Severe cases (temperature >41.1°C, autonomic instability, delirium, muscular rigidity, and hypertonicity)
    • Discontinue precipitating agent(s).
    • Immediate sedation
    • Endotracheal intubation as clinically indicated
    • Paralysis as clinically indicated (maintained with nondepolarizing continuous paralytic agents such as vecuronium, cisatracurium, rocuronium)
    • Antipyretic medications are not effective (4)[A]; the increased body temperature is due to muscle activity, not an alteration in the hypothalamic set point.
MEDICATION
  • Activated charcoal: may be used in patients who intentionally overdose on serotonergic agents (3)[A]
  • Benzodiazepines: may be used to manage agitation in serotonin syndrome and also may correct mild increases in BP and heart rate. Use with caution in patients with delirium, given the known paradoxical effect of exacerbating delirium.
  • Cyproheptadine (Periactin): Consider use if benzodiazepines and supportive measures are unable to control agitation and correct vital signs:
    • Adults: initial dose 12 mg PO (can also be crushed and given via nasogastric [NG] tube) followed by 2 mg q2h until clinical response observed; 12 to 32 mg of drug may be required in a 24-hour period.
    • Children
      • <2 years: 0.06 mg/kg q6h
      • 2 to 6 years: 2 mg q6h
      • 7 to 14 years: 4 mg q6h
    • Unlikely to be effective in patients who have received activated charcoal.
  • Use of antipsychotics with 5-HT2A antagonist activity, such as olanzapine and chlorpromazine, is not recommended (4)[A].
ISSUES FOR REFERRAL
  • Psychiatry: for assistance with medication management and follow-up care (inpatient psychiatric care vs. outpatient psychiatric follow-up)
  • Toxicology/clinical pharmacology service
  • Poison control center
INPATIENT CONSIDERATIONS
Patients with known/suspected serotonin syndrome should be admitted to a medical inpatient unit for observation.
Discharge Criteria
  • Mental status has returned to baseline.
  • Stable vital signs
  • No increase in clonus
  • Close patient follow-up is ensured.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • In mild cases of serotonin toxicity, address risks and benefits of restarting offending agents. Serotonergic medications need to be titrated slowly, and patients must have close outpatient follow-up with physician.
  • If patient developed severe serotonin syndrome, the offending agent should likely not be resumed unless precipitant for serotonin syndrome is found (e.g., combination with another serotonin agonist); the patient can be carefully monitored, or there is clear benefit versus risk of restarting the medication.
PROGNOSIS
  • Generally favorable with early recognition of the syndrome and prompt initiation of treatment
  • Most cases resolve within 24 hours of discontinuation of serotonergic agents; this can be longer depending on the drug's half-life:
    • MAOIs can result in toxicity for several days.
    • SSRIs can result in toxicity for up to several weeks after discontinuation.
  • ICU admission is often indicated in severe cases.
REFERENCES
1. Bronstein AC, Spyker DA, Cantilena LR Jr, et al. 2008 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th annual report. Clin Toxicol (Phila). 2009;47(10):911-1084.
2. Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010;81(9):1139-1142.
3. Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635-642.
4. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
Additional Reading
&NA;
  • Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust. 2007;187(6):361-365.
  • McAllen KJ, Schwartz DR. Adverse drug reactions resulting in hyperthermia in the intensive care unit. Crit Care Med. 2010;38(6 Suppl):S244-S252.
Codes
&NA;
ICD10
G25.79 Other drug induced movement disorders
Clinical Pearls
&NA;
Consider serotonin syndrome in patients with recent use of a serotonergic agent (particularly if multiple proserotonergic agents are involved) presenting with unexplained tachycardia, hypertension, hyperthermia, clonus, hyperreflexia, and change in mental status.