What is serotonin syndrome?

From the Guidelines

Serotonin syndrome is a life-threatening condition characterized by mental status changes, autonomic hyperactivity, and neuromuscular abnormalities, typically caused by excessive serotonin levels resulting from medication interactions or overdose. The clinical presentation of serotonin syndrome can be extremely variable, making diagnosis challenging 1. According to the modified Dunkley criteria, the diagnosis can be made if the patient has taken a serotonergic drug within the last 5 weeks and has any of the following: tremor and hyperreflexia; spontaneous clonus; muscle rigidity, temperature >38°C, and either ocular clonus or inducible clonus; ocular clonus and either agitation or diaphoresis; or inducible clonus and either agitation or diaphoresis 1.

Key Characteristics

• Mental status changes, such as agitation and confusion
• Autonomic instability, including high fever, sweating, and rapid heart rate
• Neuromuscular abnormalities, such as tremors, muscle rigidity, and hyperreflexia

Treatment Considerations

Treatment often involves discontinuing the precipitating agent and providing supportive care, which may include benzodiazepines for agitation, cooling measures for hyperthermia, and in severe cases, serotonin antagonists like cyproheptadine 1. The pediatric dosage of cyproheptadine is usually 0.25 mg/kg per day, while the adult dosage is typically 12 to 24 mg over 24 hours 1.

Important Considerations

• The condition can progress to seizures, respiratory failure, and death if not promptly treated
• The mortality rate is approximately 11%, with significant morbidity and mortality associated with serotonin syndrome 1
• Clinical diagnostic criteria, such as the Hunter criteria, can be used to diagnose serotonin syndrome, but there are no pathognomonic laboratory or radiographic findings 1

From the FDA Drug Label

Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including sertraline, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Serotonin syndrome is a potentially life-threatening condition that can occur with the use of certain medications, including sertraline, especially when used in combination with other serotonergic drugs.

• Symptoms of serotonin syndrome may include:
  • Mental status changes (agitation, hallucinations, delirium, coma)
  • Autonomic instability (tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia)
  • Neuromuscular symptoms (tremor, rigidity, myoclonus, hyperreflexia, incoordination)
  • Seizures
  • Gastrointestinal symptoms (nausea, vomiting, diarrhea) 2 2

From the Research

Definition and Causes of Serotonin Syndrome

• Serotonin syndrome (SS) is a rare and potentially life-threatening toxic state caused by an adverse drug reaction that leads to excessive central and peripheral serotonergic activity 3.
• This excessive serotonin hyperstimulation may be secondary to a standard therapeutic dose of a single agent, inadvertent interactions between various drugs, intentionally or unintentionally excessive use of particular drugs, deliberate self-harm, or recreational use of certain drugs 3.
• SS commonly occurs after the use of serotonergic agents alone or in combination with monoamine oxidase inhibitors 3.

Clinical Features and Diagnosis

• SS classically consists of a triad of signs and symptoms broadly characterized as alteration of mental status, abnormalities of neuromuscular tone, and autonomic hyperactivity 3.
• However, all 3 triads of SS may not occur simultaneously, and clinical manifestations are diverse and nonspecific, which may lead to misdiagnosis 3.
• The serotonin syndrome is characterized by alterations in cognition, behavior, autonomic nervous system function, and neuromuscular activity 4.
• The difference between this syndrome and the occurrence of adverse effects caused by serotonin reuptake inhibitors alone is the clustering of the signs and symptoms, their severity, and their duration 4.

Management and Prevention

• Management of SS involves withdrawal of the offending agent(s), aggressive supportive care to treat hyperthermia and autonomic dysfunction, and occasionally the administration of serotonin antagonists--cyproheptadine or chlorpromazine 3.
• Patients with moderate and severe cases of SS require inpatient hospitalization 3.
• The use of specific serotonin receptor antagonists such as cyproheptadine in the treatment of the serotonin syndrome remains to be delineated, but its use should be considered an adjunct to supportive care 5.
• To reduce the occurrence, morbidity, and mortality of the serotonin syndrome, it must be both prevented by prudent pharmacotherapy and given prompt recognition when it is present 4.