I. What every physician needs to know.

Serotonin syndrome should probably be termed “serotonin toxicity” as it is a predictable consequence of drugs that increase the serotonergic activity in the brain and at peripheral serotonin receptors. Symptoms can range from mild to severe based on the degree of toxicity. Serotonin receptors and the consequences of excess serotonin acting on these receptors are summarized as follows (see Table I).

Table I.
Serotonin receptor subtype Action related to serotonin toxicity
5-HT1A Neuronal inhibition, regulation of sleep, feeding, thermoregulation, anxiety, depression
5-HT1D Locomotion, muscle tone
5-HT2A Neuronal excitation, learning, peripheral vasoconstriction, platelet aggregation
5-HT2B Stomach contraction
5-HT3 Nausea and vomiting, anxiety
5-HT4 Gastrointestinal motility

Excess stimulation of receptors leading to serotonin syndrome can occur via:

  • Increased production of serotonin which is derived from tryptophan;

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  • Increased neuronal release of serotonin;

  • Reduced re-uptake of serotonin from the neuronal synapse or;

  • Reduced metabolism of serotonin that normally occurs through the monoamine oxidase pathway.

Direct stimulation of serotonin receptors may also have a mechanistic role. Decreased metabolism of serotonergic drugs, as can be seen with cytochrome P450 inhibition in patients taking selective serotonin reuptake inhibitors (SSRIs), is another mechanism for developing serotonin syndrome. Most cases occur in patients receiving multiple agents that effect serotonin activity or from significant exposure to certain serotonergic drugs. There is individual patient variation in these mechanisms that accounts for differences in vulnerability to serotonin toxicity.

Serotonin toxicity (serotonin syndrome) manifests predictable clinical findings based on receptor activation. The clinical findings form a triad of mental status changes, autonomic instability and neuromuscular hyperactivity.

II. Diagnostic Confirmation: Are you sure your patient has serotonin syndrome?

The diagnosis of serotonin syndrome is a clinical diagnosis based on mental status changes, neuromuscular hyperactivity, and autonomic instability in a patient with serotonergic drug exposure. There is no specific laboratory test that identifies serotonin syndrome and serotonin levels do not correlate with toxicity. An accurate history, medication review, and physical exam is critical. Diagnosis should be made by using the Hunter Serotonin Toxicity Criteria (sensitivity 84% and specificity 97% compared to gold standard diagnosis by a clinical toxicologist), which is more sensitive and specific than the earlier developed Sternbach’s criteria..

The Hunter Serotonin Toxicity Criteria are as follows:

  • Has the patient been exposed to a serotonergic agent within the past five weeks? If no, the patient does not have serotonin toxicity.

  • Does the patient have any of the following symptoms or combinations of symptoms?

    Spontaneous clonus.

    Ocular clonus and either agitation or diaphoresis.

    Inducible clonus and either agitation or diaphoresis.

    Tremor and hyperreflexia.

    Muscle rigidity, temperature greater than 38 degrees Celsius (100.4 Fahrenheit), and either ocular or inducible clonus.

If a patient has exposure to a serotonergic agent and any of the above findings, the diagnosis of serotonin toxicity is made. If none of these symptoms is present, the patient does not have serotonin toxicity.

A. History Part I: Pattern Recognition.

Key clinical findings include exposure to a serotonergic agent or combination of serotonergic agents, generally that have been recently initiated or increased in dosage. Many drugs have been associated with serotonin syndrome. Although the most common causes involve SSRIs and monoamine oxidase (MAO) inhibitors, medication review should include prescription and over-the-counter drugs, illicit substances, and dietary supplements. The following table, drawn from several recent narrative reviews, provides a compendium of agents that have been associated with serotonin toxicity (see Table II).

Table II.
Mechanism Drugs that may cause serotonin toxicity Drug combinations that have been associated with severe serotonin toxicity
Increased serotonin production L-tryptophan L-tryptophan + MAO inhibitor (MAOI)
Increased serotonin release from neurons AmphetaminesNMDA (“Ecstasy”)CocaineOpioids (oxycodone, buprenorphine)Tramadol Amphetamines + MAO inhibitorNMDA + MAOINMDA + SSRI
5-HT1A agonism BuspironeLSDDihydroergotamineTriptansMirtazapine Paroxetine + buspirone
Decreased serotonin reuptake SSRIsFluoxetineSertralineParoxetineCitalopramEscitalopramFluvoxamineVenlafaxineDuloxetineClomipramine, imipramineTramadol, meperidine, methadone, fentanylDextromethorphanSt. John’s wartOdansetronGranisetron Analgesics + MAOI or SSRIClomipramine + MAOISSRIs or venlafaxine + MAOISSRIs, venlafaxine, bupropion
MAO inhibition MAOISelegilineLinezolidMethylene blue Linezolid + SSRI

Serotonin toxicity results in mental status changes, autonomic instability and increased neuromuscular activity. Toxicity presents on a spectrum of clinical findings ranging from mild to life-threatening symptoms (see Table III). Progression of symptoms can occur rapidly. Onset of symptoms can help differentiate serotonin toxicity from other competing diagnoses. Symptoms can develop within minutes of drug exposure and roughly 60% of patients will present within six to twenty-four hours after first medication use, change in dosing, or overdose.

Table III.
Mild symptoms AkathisiaTremorTachycardiaDiaphoresis or shiveringAnxiety
Moderate symptoms Altered mental status

Easily startled

Confusion

Agitation and hypervigilance

Inducible clonusOcular clonus (slow, continuous lateral eye movements)Fever up to 41 degrees CelsiusDiarrhea
Severe symptoms Sustained or spontaneous clonusMuscular hypertonicity, lower extremities > upper Hyperthermia, often temperature greater than 41 degrees Celsius (105.8 degrees Fahrenheit)Delirium or comaSevere myoclonusMarked hyperreflexia

B. History Part 2: Prevalence.

Serotonin toxicity is not an idiosyncratic reaction, but rather, a somewhat predictable consequence of drugs that result in excess serotonin action on central nervous system receptors and on peripheral serotonergic receptors. The incidence of serotonin syndrome has increased with the growing number of serotonergic drugs in use and increased awareness of toxicity. The true incidence is not well known in part because the condition is may go undiagnosed or unrecognized, especially in mild cases. Among patients who overdose on SSRIs, serotonin toxicity occurs in about 15%.

C. History Part 3: Competing diagnoses that can mimic serotonin syndrome.

The primary differential diagnosis when considering serotonin syndrome includes neuroleptic malignant syndrome (NMS), malignant hyperthermia, and anti-cholinergic toxicity. Diagnosis can be made based on medication exposure history and findings on physical exam. Correct diagnosis is critical, as treatments for NMS and malignant hyperthermia may precipitate severe serotonin toxicity.

Differentiating serotonin syndrome from mimics (See Table IV).

Table IV.
Competing diagnoses Distinguishing features
Serotonin toxicity Relatively abrupt onset (within hours of drug exposure or dosage increase)Shivering is common, but less prominent with competing diagnosesOther clinical features listed above
Neuroleptic malignant syndrome Slower development (over days)Usually akinetic with muscular rigidityDecreased levels of consciousnessMutism more common than the rambling speech often seen with serotonin toxicityDecreased bowel soundsBradyreflexia
Anticholinergic syndrome Use of tricyclic antidepressants or other anticholinergic drugsDry mouthBlurred visionMydriasisFlushed skin (erythematous skin appearance)Decreased bowel soundsAgitation/deliriumTachycardiaHyperthermiaUrinary retention
Malignant hyperthermia Administration of halogenated inhalational anesthetics or depolarizing muscle relaxantsDiaphoresisMottled skin with patches of bright red flushingAgitationDecreased bowel soundsMuscular rigidity, “rigor mortis-like”Hyporeflexia

Other diagnoses that might be considered include encephalitis, meningitis, sepsis, thyroid storm, sympathomimetic overdose, serotonergic discontinuation syndrome, delirium tremens, tetanus, heat stroke, baclofen withdrawal. In addition to history, examination, and drug exposure review, laboratory work-up and diagnostic testing may be used to rule out these etiologies.

D. Physical Examination Findings.

Physical exam is aimed at confirming serotonin syndrome and evaluating for alternative etiologies. Focused physical examination should include the following:

  • Deep-tendon reflexes: Hyperreflexia, often greater in the lower extremities than upper extremities. Muscle rigidity seen in severe toxicity may mask hyperreflexia.

  • Clonus: Spontaneous, inducible, and ocular nystagmus (continuous lateral movement of the eyes), often greater in the lower extremities than upper extremities. Muscle rigidity seen in severe toxicity may mask clonus.

  • Evaluation of tremor: Tremor or shivering, often greater in lower extremities than upper extremities.

  • Muscle tone: Muscle rigidity and hypertonicity in severe cases of toxicity.

  • Mental status: Expect agitation, confusion, hypervigilance, pressured speech, delirium.

  • Evaluation of pupil size: Mydriasis.

  • Dryness of the oral mucosa: Relatively normal.

  • Bowel sounds: Hyperactive, possibly with diarrhea.

  • Skin color: Diaphoresis with normal skin color.

  • Vital signs: Hypertension, tachycardia, and temperature > 100.4F/38C. Higher temperatures and rapidly fluctuating heart rate and blood pressures can be seen in severe cases.

E. What diagnostic tests should be performed?

There are no specific diagnostic tests for serotonin toxicity. Urine or serum toxicology may establish the presence of potential contributing drugs if the history is unobtainable or deemed unreliable.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The diagnosis is a clinical diagnosis in patients who have been exposed to agents or medications known to be associated with serotonin toxicity. Laboratory tests should be considered based on the history, examination and suspicion for complications or co-existing conditions.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No imaging studies are required to make the diagnosis of serotonin toxicity. Brain imaging could be considered if there is doubt about the diagnosis with suspicion for an intracranial process, but is not necessary in the absence of corresponding physical findings on exam.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) is over-utilized to evaluate change in mental status in patients whose history is highly suggestive of serotonin toxicity and whose physical findings are diagnostic of the condition (see above). The diagnosis is not a so-called diagnosis of exclusion.

III. Default Management.

  • Withdraw the offending serotonergic agents.

  • Supportive management:

    Mild cases resolve within 24-72 hours with simple cessation of offending drugs – Benzodiazepines may be used for agitation or tremor if needed. Observe patient for at least 6 hours.

    Moderate serotonin toxicity – Admit to hospital. Intravenous fluids to address hemodynamic abnormalities. Control agitation with benzodiazepines. Physical restraints should be avoided because they worsen muscle contraction that is driving lactic acidosis and hyperthermia. For severe agitation or hyperthermia, consider administration of 5-HT2A antagonists. Cyproheptadine orally or by nasogastric tube, 12 mg initially, followed by 2 mg every two hours for persistent symptoms. A maintenance dosing of 8 mg every six hours can be continued once the patient is stable. Olanzapine 10 mg sublingual may be considered although evidence limited.

    Severe serotonin toxicity – Admit to intensive care unit. Supportive measures as noted above. Patients may require sedation, intubation, and paralysis for control of muscle rigidity and severe hyperthermia. Succinylcholine should not be used for paralysis due to the risk of hyperkalemia from rhabdomyolysis. In addition, consider chlorpromazine 50-100 mg intramuscular injection if unable to use cyproheptadine. Hypotension should be managed with fluids, direct-acting sympathomimetics (norepinephrine, phenylephrine, epinephrine) in low doses. Severe hypertension should be managed with nitroprusside or esmolol, as opposed to longer acting agents, given the labile autonomic state.

  • Control of hyperthermia: The goal is to eliminate excess muscle activity that is driving the hyperthermia.

    Benzodiazepines in moderate cases.

    Severe cases may require intubation, mechanical ventilation and immediate paralysis using non-depolarizing agents such as vecuronium.

    Antipyretic agents such as acetaminophen are of no utility as the hyperthermia is not due to hypothalamic set point changes.

A. Immediate management.

Supportive management – see above.

Laboratory studies:

  • Creatine phosphokinase (CPK) – muscle hyperactivity places the patient at risk for rhabdomyolysis.

  • Electrolytes, BUN, creatinine – due to concern for hyperkalemia and renal dysfunction from rhabdomyolysis.

B. Physical Examination Tips to Guide Management.

Follow mental status, vital signs, urine output, degree of anxiety/agitation, and degree of muscle rigidity.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Electrolytes, renal function, CPK (if initially elevated).

D. Long-term management.

Caution regarding use of medications known to be associated with serotonin syndrome or toxicity although the toxicity is a predictable response to drugs or drug combinations known to increase serotonin levels. Therefore, antidepressants with less serotonergic effect could be employed after an adequate washout period for the original offending agents.

E. Common Pitfalls and Side-Effects of Management.

Most common pitfall in management is failure to recognize serotonin toxicity and to promptly withdraw offending agents. Additionally, control of muscle hyperactivity is key to management of hyperthermia and to lessening risk for significant rhabdomyolysis.

IV. Management with Co-Morbidities.

N/A

A. Renal Insufficiency.

Higher incidences of serotonin syndrome have been seen in patients with end stage renal disease on hemodialysis who are taking SSRIs. However, no change in management is needed in end stage renal disease, except for, meticulous attention to fluids and urine output.

B. Liver Insufficiency.

No change in management, although would be vigilant for more severe lactic acidosis in setting of muscle hyperactivity.

C. Systolic and Diastolic Heart Failure.

No major change in management, except careful attention to fluids and aggressive control of hyperthermia through control of muscle hyperactivity.

D. Coronary Artery Disease or Peripheral Vascular Disease.

  • Control muscle hyperactivity to reduce hyperthermia.

  • Careful management of autonomic instability (hypo- or hypertension). See above.

E. Diabetes or other Endocrine issues.

No change in management.

F. Malignancy.

No change in management.

G. Immunosuppression (HIV, chronic steroids, etc.)

No change in management. Consider that linezolid and ritonavir have been associated with serotonin toxicity when combined with other serotonergic agents.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in management.

I. Gastrointestinal or Nutrition Issues.

Diarrhea is expected with moderate or severe serotonin toxicity.

J. Hematologic or Coagulation Issues.

No change in management.

K. Dementia or Psychiatric Illness/Treatment.

Management of depression or dementia will require careful consultation with psychiatry regarding medications associated with less serotonergic activity.

V. Transitions of Care.

A. Sign-out Considerations While Hospitalized.

  • Patients require frequent clinical assessment as there are no laboratory parameters to assess the degree of muscle hyperactivity, alteration in mental status, hyperthermia, or autonomic instability.

  • New medication starts should be carefully assessed for possible serotoninergic activity.

  • For patients with initially elevated CPK, follow CPK approximately every 8-12 hours to assure peaked.

  • Hypertension should be managed with short-acting agents (e.g., esmolol or nitroprusside) given autonomic liability.

  • Hypotension should be managed with IV fluids, norepinephrine or phenylephrine at low doses.

B. Anticipated Length of Stay.

Mild serotonin toxicity may not require hospitalization, but if hospitalized, expect resolution of symptoms within 24-72 hours. More severe toxicity has unpredictable length of stay but may be as short as 3-4 days.

C. When is the Patient Ready for Discharge?

  • Agitation and confusion have fully resolved.

  • Muscle rigidity resolved.

  • Renal function stable.

D. Arranging for Clinic Follow-up

Patient should be seen in clinic within two weeks for follow-up, reassessment of medications.

1. When should clinic follow up be arranged and with whom?

General medicine, within two weeks (although there are no clear guidelines).

2. What tests should be conducted prior to discharge to enable best clinic first visit?

No additional tests except those listed above for management.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

CPK, blood urea nitrogen (BUN) and creatinine if these were abnormal during hospital stay. None if no initial laboratory abnormalities.

E. Placement Considerations.

Functional assessment as muscle rigidity improves.

F. Prognosis and Patient Counseling.

The patient (and family) should be aware of the diagnosis of “serotonin syndrome” and should convey this information to providers considering new medications in the future.

In general, if the patient’s presentation was due to drug interaction and the plan is to re-start SSRIs in the future, the patient should avoid dextromethorphan (e.g., “Robitussin DM”), meperidine (“Demerol”), and Linezolid. For migraine patients, there should be careful consideration of triptans as therapy, although the literature is mixed on whether or not there is an association with serotonin toxicity.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

See above for precautions regarding future medications.

What’s the Evidence?

Ables, AZ, Nagubilli, R. “Prevention, recognition, and management of serotonin syndrome”. Am Fam Physician. vol. 81. 2010. pp. 1139-42.

Boyer, EW, Shannon, M. “The serotonin syndrome”. N Engl J Med. vol. 352. 2005. pp. 1112-20.

Dunkley, EJ, Isbister, GK, Sibbritt, D, Dawson, AH, Whyte, IM. “The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity”. QJM. vol. 96. 2003. pp. 635-42.

Frank, C. “Recognition and treatment of serotonin syndrome”. Can Fam Physician. vol. 54. 2008. pp. 988-92.

Gillman, PK. “Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review”. Headache. vol. 50. 2010. pp. 264-72.

Guo, SL, Wu, TJ, Liu, CC, Ng, CC, Chien, CC, Sun, HL. “Meperidine-induced serotonin syndrome in a susceptible patient”. Br J Anaesth. vol. 103. 2009. pp. 369-70.

Isbister, GK, Buckley, NA, Whyte, IM. “Serotonin toxicity: a practical approach to diagnosis and treatment”. Med J Aust. vol. 187. 2007. pp. 361-5.

Rastogi, R, Swarm, RA, Patel, TA. “Case scenario: opioid association with serotonin syndrome: implications to the practitioners”. Anesthesiology. vol. 115. 2011. pp. 1291-8.

Lawrence, KR, Adra, M, Gillman, PK. “Serotonin toxicity associated with the use of linezolid: a review of postmarketing data”. Clin Infect Dis..

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