What is serotonin syndrome?

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From the Guidelines

Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonin levels in the body, typically resulting from medication interactions, and requires immediate medical attention. The syndrome occurs when two or more serotonergic medications are combined, such as SSRIs, SNRIs, MAOIs, certain pain medications, or illicit drugs 1. Symptoms develop rapidly and include mental status changes (agitation, confusion), autonomic instability (high fever, sweating, rapid heart rate), and neuromuscular abnormalities (tremor, rigidity, hyperreflexia) 1.

Key Characteristics

  • The condition is characterized by excessive serotonin levels, which can lead to overstimulation of receptors in the central and peripheral nervous systems, particularly 5-HT1A and 5-HT2A receptors 1.
  • Symptoms can range from mild to severe and include altered mental status, autonomic dysfunction, and neuromuscular abnormalities, as well as abnormal vital signs such as fever, hypertension, and tachycardia 1.
  • Treatment involves discontinuing the offending medications, supportive care, and in severe cases, administering serotonin antagonists like cyproheptadine (typically 12mg initially, followed by 2mg every 2 hours until symptoms improve) 1.

Treatment Considerations

  • Benzodiazepines may be used for agitation and muscle rigidity 1.
  • Prevention is crucial by maintaining careful medication records and avoiding combinations of serotonergic drugs 1.
  • The mortality rate is approximately 11%, with significant morbidity and mortality associated with serotonin syndrome, highlighting the importance of prompt recognition and treatment 1.

Diagnostic Criteria

  • Clinical diagnostic criteria for serotonin syndrome have been proposed, with Hunter criteria being most commonly used 1.
  • Testing may be obtained on the basis of clinical suspicion and may include a complete blood cell count, electrolytes, serum urea nitrogen, creatinine, arterial blood gas, hepatic transaminases, creatine kinase, urinalysis, toxicology screens, coagulation studies, electrocardiography, EEG, and brain imaging studies 1.

From the Research

Definition and Causes of Serotonin Syndrome

  • Serotonin syndrome (SS) is a drug-induced clinical syndrome resulting from increased serotonergic activity in the central nervous system 2
  • It is characterized by a dose-relevant spectrum of clinical findings related to the level of free serotonin (5-hydroxytryptamine [5-HT]), or 5-HT receptor activation (predominantly the 5-HT1A and 5-HT2A subtypes) 3
  • The syndrome is produced most often by the concurrent use of two or more drugs that increase brainstem serotonin activity 4
  • It can also occur after the initiation of a single serotonergic drug in a susceptible individual, the addition of a second or third agent to long-standing doses of a maintenance serotonergic drug, or after an overdose 3

Clinical Features of Serotonin Syndrome

  • The clinical features of SS include alterations in mental status, autonomic instability, and neuromuscular abnormalities such as tremor, hyperreflexia, or myoclonus 5
  • Common clinical features include hyperreflexia, clonus, tachycardia, tremor, rigidity, increased bowel sound, diaphoresis, fever, hypertension, and myoclonus 6
  • The syndrome can range from mild to severe, with severe cases being potentially life-threatening 3

Treatment of Serotonin Syndrome

  • The treatment for SS involves the administration of a serotonin antagonist, such as cyproheptadine 6, 5
  • Discontinuation of drug therapy and supportive care alone may also be effective in treating SS 4
  • The role of specific serotonin receptor antagonists, such as cyproheptadine, in the treatment of SS remains to be delineated, and its use should be considered an adjunct to supportive care 5

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Serotonin syndrome controversies: A need for consensus.

World journal of critical care medicine, 2024

Research

Serotonin syndrome.

American family physician, 1995

Research

Treatment of the serotonin syndrome with cyproheptadine.

The Journal of emergency medicine, 1998

Research

Cyproheptadine in serotonin syndrome: A retrospective study.

Journal of family medicine and primary care, 2024

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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