Prevention, Diagnosis, and Management of Serotonin Syndrome



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Am Fam Physician. 2010 May 1;81(9):1139-1142.

Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonergic activity in the nervous system. It is characterized by mental status changes, autonomic instability, and neuromuscular hyperactivity. Most reported cases of serotonin syndrome are in patients using multiple serotonergic drugs or who have had considerable exposure to a single serotonin-augmenting drug. Diagnosis is made using the Hunter Serotonin Toxicity Criteria, which require the presence of one of the following classical features or groups of features: spontaneous clonus; inducible clonus with agitation or diaphoresis; ocular clonus with agitation or diaphoresis; tremor and hyperreflexia; or hypertonia, temperature above 100.4° F (38° C), and ocular or inducible clonus. Most cases of serotonin syndrome are mild and may be treated by withdrawal of the offending agent and supportive care. Benzodiazepines may be used to treat agitation and tremor. Cyproheptadine may be used as an antidote. Patients with moderate or severe cases of serotonin syndrome require hospitalization. Critically ill patients may require neuromuscular paralysis, sedation, and intubation. If serotonin syndrome is recognized and complications are managed appropriately, the prognosis is favorable.

Serotonin syndrome is a potentially life-threatening set of symptoms caused by serotonin toxicity, and usually involves a combination of drugs that increase serotonergic transmission. This syndrome was first described in the literature during the 1960s in studies of single and combination therapy with antidepressant medications.1 Potential mechanisms of serotonin syndrome include increased serotonin synthesis or release; reduced serotonin uptake or metabolism; and direct serotonin receptor activation.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References Comments

Prevention of serotonin syndrome requires clinical awareness of the toxic potential of serotonergic agents.

C

1

Education and use of drug interaction software may be helpful

Established criteria should be used to identify and diagnose serotonin syndrome.

C

1, 14

Hunter Serotonin Toxicity Criteria are more sensitive and specific than Sternbach's criteria in diagnosing serotonin syndrome

First-line management of serotonin syndrome involves withdrawal of the offending drugs and provision of supportive care.

C

19

Cyproheptadine may be used to treat moderate to severe cases of serotonin syndrome.

C

19, 20

Based on case reports


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References Comments

Prevention of serotonin syndrome requires clinical awareness of the toxic potential of serotonergic agents.

C

1

Education and use of drug interaction software may be helpful

Established criteria should be used to identify and diagnose serotonin syndrome.

C

1, 14

Hunter Serotonin Toxicity Criteria are more sensitive and specific than Sternbach's criteria in diagnosing serotonin syndrome

First-line management of serotonin syndrome involves withdrawal of the offending drugs and provision of supportive care.

C

19

Cyproheptadine may be used to treat moderate to severe cases of serotonin syndrome.

C

19, 20

Based on case reports


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

Definition and Etiology

Serotonin syndrome is defined as excessive serotonergic activity in the central and peripheral nervous systems. Classical clinical features include a combination of mental status changes, autonomic instability, and neuromuscular hyperactivity.24 The intensity of clinical findings reflects the degree of serotonin toxicity. The term “serotonin syndrome” usually refers to the severe end of the toxicity spectrum.

Serotonin syndrome can occur with any increase in serotonergic neurotransmission. The majority of cases are iatrogenic from synergistic medication use, although cases of intentional self-poisoning with serotonergic agents also occur.5,6 Another mechanism for development of serotonin syndrome is the addition of drugs that inhibit the cytochrome P450 2D6 and/or 3A4 (CYP3A4) isoenzymes to therapeutic regimens of selective serotonin reuptake inhibitors (SSRIs). In one case report, serotonin syndrome was precipitated in a 12-year-old patient taking a stable dosage of sertraline (Zoloft) when erythromycin, a CYP3A4 inhibitor, was also prescribed.7 A remarkable number of drugs from different classes have been implicated as causing serotonin syndrome (Table 1).1,3,810 Most reported cases are in patients taking multiple serotonergic agents or who have had considerable exposure to a single serotonin-augmenting drug.11

Table 1.

Medications that May Contribute to Serotonin Syndrome

Amphetamines and derivatives 3,4-methylenedioxymethamphetamine (Ecstasy) Dextroamphetamine Methamphetamine Sibutramine (Meridia) Analgesics Cyclobenzaprine (Flexeril) Fentanyl (Duragesic) Meperidine (Demerol) Tramadol (Ultram) Antidepressants/mood stabilizers Buspirone (Buspar) Lithium Monoamine oxidase inhibitors (e.g., phenelzine [Nardil]) Selective serotonin reuptake inhibitors (e.g., fluoxetine [Prozac]) Serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine [Effexor]) Serotonin 2A receptor blockers (e.g., trazodone) St. John's wort (Hypericum perforatum) Tricyclic antidepressants (e.g., amitriptyline, nortriptyline [Pamelor]) Antiemetics Metoclopramide (Reglan) Ondansetron (Zofran) Antimigraine drugs Carbamazepine (Tegretol) Ergot alkaloids Triptans Valproic acid (Depakene) Miscellaneous Cocaine Dextromethorphan Linezolid (Zyvox) L-tryptophan 5-hydroxytryptophan


Information from references 1, 3, and 8 through 10.

Table 1.   Medications that May Contribute to Serotonin Syndrome

View Table

Table 1.

Medications that May Contribute to Serotonin Syndrome

Amphetamines and derivatives 3,4-methylenedioxymethamphetamine (Ecstasy) Dextroamphetamine Methamphetamine Sibutramine (Meridia) Analgesics Cyclobenzaprine (Flexeril) Fentanyl (Duragesic) Meperidine (Demerol) Tramadol (Ultram) Antidepressants/mood stabilizers Buspirone (Buspar) Lithium Monoamine oxidase inhibitors (e.g., phenelzine [Nardil]) Selective serotonin reuptake inhibitors (e.g., fluoxetine [Prozac]) Serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine [Effexor]) Serotonin 2A receptor blockers (e.g., trazodone) St. John's wort (Hypericum perforatum) Tricyclic antidepressants (e.g., amitriptyline, nortriptyline [Pamelor]) Antiemetics Metoclopramide (Reglan) Ondansetron (Zofran) Antimigraine drugs Carbamazepine (Tegretol) Ergot alkaloids Triptans Valproic acid (Depakene) Miscellaneous Cocaine Dextromethorphan Linezolid (Zyvox) L-tryptophan 5-hydroxytryptophan


Information from references 1, 3, and 8 through 10.

Incidence

The incidence of serotonin syndrome is rising, reflecting the growing number of serotonergic drugs available and the increased use of these agents in clinical practice. The reported incidence may also reflect an increasing diagnostic awareness of the syndrome (Table 2).12,13 Because many cases go unrecognized, the true incidence of serotonin syndrome is unknown.

Table 2.

SSRI Ingestions Reported to U.S. Poison Control Centers

Ingestions 2002 2005

Total exposures reported

46,244

48,279

Moderate to major effects*

7,349 (16 percent)

8,585 (18 percent)

Deaths

93 (0.2 percent)

118 (0.2 percent)


SSRI = selective serotonin reuptake inhibitor.

*—Moderate effects are defined as prolonged, pronounced, or systemic effects requiring treatment but are not considered life threatening. Major effects are defined as signs or symptoms that are life threatening or that lead to significant disability.

Information from references 12 and 13.

Table 2.   SSRI Ingestions Reported to U.S. Poison Control Centers

View Table

Table 2.

SSRI Ingestions Reported to U.S. Poison Control Centers

Ingestions 2002 2005

Total exposures reported

46,244

48,279

Moderate to major effects*

7,349 (16 percent)

8,585 (18 percent)

Deaths

93 (0.2 percent)

118 (0.2 percent)


SSRI = selective serotonin reuptake inhibitor.

*—Moderate effects are defined as prolonged, pronounced, or systemic effects requiring treatment but are not considered life threatening. Major effects are defined as signs or symptoms that are life threatening or that lead to significant disability.

Information from references 12 and 13.

Prevention

Prevention of serotonin syndrome begins with awareness by physicians and patients of the potential for toxicity from serotonergic drugs.1 Avoiding the combined use of serotonin-augmenting drugs is essential. Physicians should modify prescribing practices to minimize coprescription of drugs known to have a high probability of inducing serotonin syndrome. A computerized ordering system and medical software can check for possible interactions when multi-drug regimens are required. Currently, there are no established guidelines for the prevention of serotonin syndrome. Eventually, the application of pharmacogenomic principles may help identify and protect patients at risk of serotonin syndrome before the administration of serotonergic agents.

Diagnosis

The diagnosis of serotonin syndrome depends on identifying autonomic instability, neuromuscular signs, and cognitive-behavioral changes in the presence of serotonergic medication use (Table 31,3,8,14).1,14 Symptoms occur most commonly after serotonergic medications are added to therapeutic SSRI regimens, when dosages are changed, or after an overdose of serotonergic agents. Symptoms can develop rapidly, often within minutes of drug ingestion, although most patients present within six to 24 hours after a medication change or overdose.15  It is important to note that serotonergic agents include nonprescription drugs, illicit drugs, and diet supplements (Table 1).1,3,810 A complete and accurate medication history is critical when making the diagnosis.

Table 3.

Signs and Symptoms of Serotonin Syndrome

Agitation (restlessness)*

Diaphoresis*

Diarrhea*

Disseminated intravascular coagulation†

Fever above 100.4° F (38° C)

Hyperreflexia*

Incoordination (ataxia)*

Mental status changes

Confusion*

Hypomania*

Multi-organ failure†

Myoclonus*

Ocular clonus

Rhabdomyolysis†

Shivering*

Tonic-clonic seizures†

Tremor*


*—Sternbach's diagnostic criteria require three of 10 signs and symptoms.

†—Extremely severe cases.

Information from references 1, 3, 8, and 14.

Table 3.   Signs and Symptoms of Serotonin Syndrome

View Table

Table 3.

Signs and Symptoms of Serotonin Syndrome

Agitation (restlessness)*

Diaphoresis*

Diarrhea*

Disseminated intravascular coagulation†

Fever above 100.4° F (38° C)

Hyperreflexia*

Incoordination (ataxia)*

Mental status changes

Confusion*

Hypomania*

Multi-organ failure†

Myoclonus*

Ocular clonus

Rhabdomyolysis†

Shivering*

Tonic-clonic seizures†

Tremor*


*—Sternbach's diagnostic criteria require three of 10 signs and symptoms.

†—Extremely severe cases.

Information from references 1, 3, 8, and 14.

The clinical manifestations of serotonin syndrome are highly variable. The diagnosis should be based on the Hunter Serotonin Toxicity Criteria or Sternbach's criteria, although Hunter's criteria are more sensitive (84 versus 75 percent) and more specific (97 versus 96 percent) than Sternbach's.14 Hunter's criteria use decision rules for predicting serotonin toxicity in patients who are known to have taken a serotonergic agent (Figure 1).14 Diagnosis with Hunter's criteria requires one of the following features or groups of features: spontaneous clonus; inducible clonus with agitation or diaphoresis; ocular clonus with agitation or diaphoresis; tremor and hyperreflexia; or hypertonia, temperature above 100.4°F (38°C), and ocular or inducible clonus. Sternbach's criteria require three of 10 clinical features coincident with an addition or recent increase of known serotonergic drugs to an established medication regimen (Table 31,3,8,14). It is necessary to rule out initiation or change of dosage of dopaminergic drugs and other possibilities, such as infection, metabolic disorder, substance intoxication, or withdrawal.1,3,4,8,16

Hunter's Decision Rules for Diagnosis of Serotonin Toxicity

Figure 1.

Hunter's decision rules for diagnosis of serotonin toxicity.

Adapted with permission from Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria; simple and accurate diagnositc decision rules for serotonin toxicity. QJM. 2003;96(9):639.

View Large

Hunter's Decision Rules for Diagnosis of Serotonin Toxicity


Figure 1.

Hunter's decision rules for diagnosis of serotonin toxicity.

Adapted with permission from Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria; simple and accurate diagnositc decision rules for serotonin toxicity. QJM. 2003;96(9):639.

Hunter's Decision Rules for Diagnosis of Serotonin Toxicity


Figure 1.

Hunter's decision rules for diagnosis of serotonin toxicity.

Adapted with permission from Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria; simple and accurate diagnositc decision rules for serotonin toxicity. QJM. 2003;96(9):639.

The primary differential diagnosis of serotonin syndrome includes anticholinergic syndrome, malignant hyperthermia, and neuroleptic malignant syndrome (Table 4).8,14,17,18 An accurate history of the drugs or substances ingested is helpful in ruling out these conditions. Other potential diagnoses may include tetanus, overdose of sympathomimetic drugs, meningitis, encephalitis, thyroid storm, heat stroke, delirium tremens, or sepsis.8,14,17,18 Laboratory tests and other diagnostic tests, such as imaging studies, may be ordered based on physical examination and medication history.3,8 There are no specific laboratory tests to diagnose serotonin syndrome; laboratory and other diagnostic testing are used to rule out alternative explanations of symptoms.

Table 4.

Differential Diagnosis of Serotonin Syndrome

Clinical condition History Vital signs Clinical features

Anticholinergic syndrome

Use of tricyclic antidepressants or other anticholinergic drugs

Tachycardia, tachypnea, hyperthermia (usually 102.2°F [39°C] or below)

Dry mouth, blurred vision, mydriasis, flushed skin, agitation/delirium, decreased bowel sounds

Malignant hyperthermia

Administration of halogenated inhalational anesthetics or depolarizing muscle relaxants

Hypertension, tachycardia, tachypnea, hyperthermia (up to 114.8°F [46°C])

Diaphoresis, mottled skin, agitation, decreased bowel sounds, muscular rigidity, hyporeflexia

Neuroleptic malignant syndrome

Ingestion of antipsychotic medications

Hypertension, tachycardia, tachypnea, hyperthermia (above 105.8°F [41°C])

Sialorrhea, diaphoresis, pallor, stupor, mutism, coma, normal or decreased bowel sounds, lead-pipe rigidity, bradyreflexia


Information from references 8, 14, 17, and 18.

Table 4.   Differential Diagnosis of Serotonin Syndrome

View Table

Table 4.

Differential Diagnosis of Serotonin Syndrome

Clinical condition History Vital signs Clinical features

Anticholinergic syndrome

Use of tricyclic antidepressants or other anticholinergic drugs

Tachycardia, tachypnea, hyperthermia (usually 102.2°F [39°C] or below)

Dry mouth, blurred vision, mydriasis, flushed skin, agitation/delirium, decreased bowel sounds

Malignant hyperthermia

Administration of halogenated inhalational anesthetics or depolarizing muscle relaxants

Hypertension, tachycardia, tachypnea, hyperthermia (up to 114.8°F [46°C])

Diaphoresis, mottled skin, agitation, decreased bowel sounds, muscular rigidity, hyporeflexia

Neuroleptic malignant syndrome

Ingestion of antipsychotic medications

Hypertension, tachycardia, tachypnea, hyperthermia (above 105.8°F [41°C])

Sialorrhea, diaphoresis, pallor, stupor, mutism, coma, normal or decreased bowel sounds, lead-pipe rigidity, bradyreflexia


Information from references 8, 14, 17, and 18.

Management

When serotonin syndrome is recognized promptly and its complications are treated appropriately, the prognosis is generally favorable. First-line management involves withdrawal of the offending serotonergic drugs and provision of supportive care. The intensity of treatment depends on the severity of the syndrome.19 Mild cases generally resolve within 24 to 72 hours with conservative therapy and removal of the causative drugs. Most patients with mild cases do not require hospital admission. Patients with moderate to severe cases involving hypertonicity, hyperthermia, autonomic instability, or progressive cognitive changes require hospitalization.3,8 Benzodiazepines may be used for control of agitation and tremor. Patients may also benefit from cyproheptadine, olanzapine (Zyprexa), or chlorpromazine. Chlorpromazine and olanzapine are not routinely used because of the potential for adverse effects and toxicity. Cyproheptadine, a serotonin 2A antagonist, is usually recommended and is the most widely used antidote.19,20 An initial dose of 12 mg should be considered, followed by an additional 2 mg every two hours if symptoms continue. After the patient is stabilized, a maintenance dosage of 8 mg every six hours may be administered. Although cyproheptadine is widely used, definitive evidence is lacking on its effectiveness in serotonin syndrome. The mainstays of therapy in managing hyperthermia and increased muscle rigidity in severely ill patients are neuromuscular paralysis, sedation, and possible intubation.

The Authors

ADRIENNE Z. ABLES, PharmD, is an associate professor at the Spartanburg Family Medicine Residency Program in Spartanburg, S.C.

RAJU NAGUBILLI, MD, is a family medicine resident at Spartanburg Family Medicine Residency Program.

Address correspondence to Adrienne Z. Ables, PharmD, Spartanburg Family Medicine Residency Program, 853 N. Church St., Ste. 510, Spartanburg, SC 29303 (e-mail: azables@srhs.com). Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

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5. Fraser J, South M. Life-threatening fluvoxamine overdose in a 4-year-old child. Intensive Care Med. 1999;25(5):548.

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7. Lee DO, Lee CD. Serotonin syndrome in a child associated with erythromycin and sertraline. Pharmacotherapy. 1999;19(7):894–896.

8. Jones D, Story DA. Serotonin syndrome and the anaesthetist. Anaesth Intensive Care. 2005;33(2):181–187.

9. Wooltorton E. Triptan migraine treatments and antidepressants: risk of serotonin syndrome. CMAJ. 2006;175(8):874.

10. Huang V, Gortney JS. Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists. Pharmacotherapy. 2006;26(12):1784–1793.

11. Nelson LS, Erdman AR, Booze LL, et al. Selective serotonin reuptake inhibitor poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2007;45(4):315–332.

12. Watson WA, Litovitz TL, Rodgers GC Jr, et al. 2002 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2003;21(5):353–421.

13. Lai MW, Klein-Schwartz W, Rodgers GC, et al. 2005 Annual Report of the American Association of Poison Control Centers' national poisoning and exopsure database. Clin Toxicol (Phila). 2006;44(6–7):803–932.

14. 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. 2003;96(9):635–642.

15. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine (Baltimore). 2000;79(4):201–209.

16. Mackay FJ, Dunn NR, Mann RD. Antidepressants and the serotonin syndrome in general practice. Br J Gen Pract. 1999;49(448):871–874.

17. Ali SZ, Taguchi A, Rosenberg H. Malignant hyperthermia. Best Pract Res Clin Anaesthesiol. 2003;17(4):519–533.

18. Guzé BH, Baxter LR Jr. Current concepts. Neuroleptic malignant syndrome. N Engl J Med. 1985;313(3):163–166.

19. Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol. 1999;13(1):100–109.

20. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med. 1998;16(4):615–619.

This is one in a series of “Clinical Pharmacology” articles coordinated by Allen F. Shaughnessy, PharmD, Tufts University Family Medicine Residency at Cambridge Health Alliance, Malden, Mass.


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