REVIEW IN SEROTONIN SYNDROME MANAGEMENT

Diagnosis, Prevention and management of serotonin syndrome are described in a review for family physicians published in the May 1 issue of the American Family Physician.
"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," write Adrienne Z. Ables, PharmD, and Raju Nagubilli, MD, from Spartanburg Family Medicine Residency Program in Spartanburg, South Carolina. "This syndrome was first described in the literature during the 1960s in studies of single and combination therapy with antidepressant medications. Potential mechanisms of serotonin syndrome include increased serotonin synthesis or release; reduced serotonin uptake or metabolism; and direct serotonin receptor activation."
Symptoms of excessive serotonergic activity in the nervous system include mental status changes, autonomic instability, and neuromuscular hyperactivity, usually caused by exposure to multiple serotonergic drugs or excessive exposure to a single serotonin-augmenting drug.
Intentional self-poisoning with serotonergic agents has also been reported, as well as serotonin syndrome occurring when drugs that inhibit the cytochrome P450 2D6 and/or cytochrome P450 3A4 isoenzymes are added to therapeutic regimens of selective serotonin reuptake inhibitors (SSRIs).
Specific agents that may be implicated in serotonin syndrome include amphetamines and their derivatives (ecstasy, dextroamphetamine, methamphetamine, and sibutramine), analgesics (cyclobenzaprine, fentanyl, meperidine, tramadol), antidepressants/mood stabilizers (buspirone, lithium), monoamine oxidase inhibitors (such as phenelzine), SSRIs (such as fluoxetine), serotonin-norepinephrine reuptake inhibitors (such as venlafaxine), serotonin 2A receptor blockers (such as trazodone), St. John's wort, tricyclic antidepressants, antiemetics (metoclopramide, ondansetron), and antimigraine drugs (carbamazepine, ergot alkaloids, triptans, and valproic acid).
Miscellaneous agents that may cause serotonin syndrome include cocaine, dextromethorphan, linezolid, l-tryptophan, and 5-hydroxytryptophan.
Criteria for Identifying Serotonin Syndrome
It is important for clinicians to be able to recognize serotonin toxicity because the prognosis is favorable if complications are managed appropriately. The term serotonin syndrome usually is reserved for severe toxicity.
The Hunter Serotonin Toxicity Criteria are used to diagnose serotonin syndrome. Diagnosis by these criteria requires at least 1 of the following characteristic 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.
Differential diagnosis of serotonin syndrome includes anticholinergic syndrome, malignant hyperthermia, and neuroleptic malignant syndrome.
Most cases of serotonin syndrome are mild, and patients usually respond to withdrawal of the offending agent and supportive care. Agitation and tremor may be treated with benzodiazepines, and cyproheptadine may be used as an antidote.
For moderate or severe cases of serotonin syndrome, patients should be hospitalized, and neuromuscular paralysis, sedation, and intubation may be indicated for critically ill patients.
Key Recommendations for Practice
Specific key clinical recommendations for practice, and their accompanying level of evidence rating, include the following:
• To prevent serotonin syndrome, clinicians must be aware of the toxic potential of serotonergic agents (level of evidence, C). Education and use of drug interaction software may help promote awareness.
• Serotonin syndrome should be identified and diagnosed with use of established criteria (level of evidence, C). Compared with Sternbach's criteria, the Hunter Serotonin Toxicity Criteria are more sensitive and specific in diagnosing serotonin syndrome.
• First-line treatment of serotonin syndrome is to withdraw the offending drugs and to provide supportive care (level of evidence, C).
• On the basis of case reports, moderate to severe cases of serotonin syndrome may be treated with cyproheptadine (level of evidence, C).
"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 review authors write. "The reported incidence may also reflect an increasing diagnostic awareness of the syndrome.... Prevention of serotonin syndrome begins with awareness by physicians and patients of the potential for toxicity from serotonergic drugs."
The review authors have disclosed no relevant financial relationships.
Am Family Physician. 2010;81:1139-1142. Abstract

Additional Resource

More information on serotonin syndrome and SSRI toxicity is available on eMedicine

CLINICAL CONTEXT
With a higher number of serotonergic medications available, the incidence of serotonin syndrome has been increasing. In 2005, there were 48,279 cases of serotonin syndrome reported to US Poison Control Centers, 18% of which were judged to be moderate or severe cases.

Although wider use of psychotropic medications at least partially explains the increasing incidence of serotonin syndrome, nonpsychotropic medications also contribute to the syndrome. These medications include tramadol, metoclopramide, triptans, valproic acid, linezolid, and dextromethorphan. Drugs of abuse, such as methamphetamine and cocaine, can also contribute to the development of serotonin syndrome.

The current review describes the diagnosis and management of serotonin syndrome.
STUDY HIGHLIGHTS

• Serotonin syndrome most commonly develops when other serotonergic medications are added to therapeutic SSRI regimens, when dosages are changed, or in an overdose of serotonergic agents.
• There are no published guidelines regarding the prevention of serotonin syndrome.
• Most patients with serotonin syndrome experience symptoms for 6 to 24 hours, although the onset of symptoms can be within minutes of drug ingestion.
• The Hunter Serotonin Toxicity Criteria are more sensitive and specific than Sternbach's criteria. The diagnosis of serotonin toxicity with the Hunter criteria includes at least 1 of the following signs to be present:
o Spontaneous clonus
o Inducible clonus with agitation or diaphoresis
o Ocular clonus with agitation or diaphoresis
o Tremor and hyperreflexia
o Hypertonia, temperature above 38°C, and ocular or inducible clonus
• The primary differential diagnosis of serotonin syndrome includes anticholinergic syndrome, malignant hyperthermia, and neuroleptic malignant syndrome.
• There are no specific laboratory tests to diagnose serotonin syndrome.
• Mild cases of serotonin syndrome generally resolve within 24 to 72 hours after removal of the causative drugs.
• Patients with moderate to severe serotonin syndrome, defined as hypertonicity, hyperthermia, autonomic instability, or progressive cognitive changes, should be hospitalized.
• Benzodiazepines may be used to control agitation and tremor in serotonin syndrome.
• Cyproheptadine is a serotonin 2A antagonist. It is the most widely used antidote for serotonin syndrome, although it is not an evidence-based treatment. The usual starting dose is 12 mg, followed by an additional 2 mg every 2 hours as long as symptoms continue. After the patient is stabilized, cyproheptadine may be continued at a dose of 8 mg every 6 hours.
Clinical Implications
Nonpsychotropic medications that can promote serotonin syndrome include tramadol, metoclopramide, triptans, valproic acid, linezolid, and dextromethorphan.
The Hunter Serotonin Toxicity Criteria require that at least 1 of the following signs be present to diagnose serotonin toxicity: spontaneous clonus; inducible clonus with agitation or diaphoresis; ocular clonus with agitation or diaphoresis; tremor and hyperreflexia; or hypertonia, temperature above 38°C, and ocular or inducible clonus.