Serotonin syndrome

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Pathophysiology - Serotonin Overload

  • Core Defect: A functional excess of serotonin ($5-HT$) at the synaptic cleft, leading to widespread effects in the central and peripheral nervous systems.
  • Primary Mechanism: Intense, non-physiological stimulation of postsynaptic serotonin receptors.
    • $5-HT_{2A}$ Receptors: Overactivation is strongly linked to the most severe symptoms, including neuromuscular hyperactivity (e.g., clonus, rigidity) and hyperthermia.
    • $5-HT_{1A}$ Receptors: Stimulation contributes to cognitive and behavioral changes like agitation and confusion.

⭐ While multiple serotonergic agents are a classic cause, serotonin syndrome can be precipitated by a single agent, especially after a dose increase.

Causative Agents - The Usual Suspects

Increased serotonin from various sources can trigger this syndrome. Combining drugs from different classes significantly elevates the risk, especially with MAOIs.

Drug ClassExamples
SSRIsSertraline, Fluoxetine, Citalopram
SNRIsVenlafaxine, Duloxetine
MAOIsSelegiline, Phenelzine, Tranylcypromine
TCAsAmitriptyline, Imipramine, Clomipramine
OpioidsTramadol, Fentanyl, Meperidine
TriptansSumatriptan, Rizatriptan
OtherLinezolid, Dextromethorphan, St. John's Wort

Clinical Features - The Serotonin Triad

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  • Cognitive/Mental Status Changes
    • Agitation, restlessness
    • Confusion, delirium
  • Autonomic Hyperactivity
    • Fever, diaphoresis (sweating)
    • Tachycardia, hypertension
    • Mydriasis (dilated pupils)
  • Neuromuscular Excitation
    • Clonus (inducible or spontaneous)
    • Hyperreflexia (brisk reflexes)
    • Tremor, myoclonus

⭐ Spontaneous or inducible clonus, especially in the lower extremities, is a highly specific and key diagnostic finding for serotonin syndrome.

📌 Mnemonic: SHIVERS

  • Shivering
  • Hyperreflexia
  • Increased temperature
  • Vital sign instability
  • Encephalopathy
  • Restlessness
  • Sweating

Diagnosis & Management - Spotting and Stopping

  • Diagnosis: Primarily clinical, using the Hunter Toxicity Criteria. Requires history of serotonergic agent use plus one of the following:
    • Spontaneous clonus
    • Inducible clonus PLUS agitation or diaphoresis
    • Ocular clonus PLUS agitation or diaphoresis
    • Tremor PLUS hyperreflexia
    • Hypertonia PLUS temperature > 38°C

⭐ Cyproheptadine is a key antidote, but supportive care and discontinuation of the causative agent are the most critical first steps in management.

High‑Yield Points - ⚡ Biggest Takeaways

  • Results from excess serotonergic activity, typically from combining drugs like SSRIs with MAOIs.
  • Classic triad: autonomic dysfunction (hyperthermia, diaphoresis), neuromuscular hyperactivity, and altered mental status.
  • Hyperreflexia and clonus, especially in the lower extremities, are key diagnostic clues.
  • Onset is rapid, occurring within hours of a medication change.
  • Management requires stopping the offending agent and providing supportive care.
  • Cyproheptadine is the antidote for moderate-to-severe cases.

Practice Questions: Serotonin syndrome

Test your understanding with these related questions

A 65-year-old man presents to the emergency department with confusion and a change in his behavior. The patient was in his usual state of health 3 days ago. He became more confused and agitated this morning thus prompting his presentation. The patient has a past medical history of depression, hypertension, diabetes, and Parkinson disease and is currently taking fluoxetine, lisinopril, insulin, metformin, and selegiline (recently added to his medication regimen for worsening Parkinson symptoms). He also takes oxycodone and clonazepam for pain and anxiety; however, he ran out of these medications last night. His temperature is 101°F (38.3°C), blood pressure is 111/78 mmHg, pulse is 117/min, respirations are 22/min, and oxygen saturation is 99% on room air. Physical exam is notable for an irritable, sweaty, and confused elderly man. Neurological exam reveals hyperreflexia of the lower extremities and clonus. Which of the following is the most likely etiology of this patient’s symptoms?

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Flashcards: Serotonin syndrome

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First Aid Pharmacology: Neuro/Psych MAO inhibitors may cause CNS _____ (stimulation or depression)

TAP TO REVEAL ANSWER

First Aid Pharmacology: Neuro/Psych MAO inhibitors may cause CNS _____ (stimulation or depression)

stimulation

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