Serotonin syndrome

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Serotonin syndrome is a potentially life-threatening condition caused by serotonergic overactivity due to the use of serotonergic drugs. It can be caused by a therapeutic dose or overdose of a serotonergic drug, concomitant use of multiple serotonergic drugs, or interactions with CYP450 inhibitors. Onset is typically rapid, occurring within 24 hours of drug administration. Classic features include autonomic dysfunction, neuromuscular excitability (e.g., rigidity, hyperreflexia), and altered mental status. Increased neuromuscular activity can also lead to hyperthermia. Serotonin syndrome is a clinical diagnosis but laboratory studies may be used to assess for complications such as rhabdomyolysis. Management involves discontinuation of serotonergic drugs and treatment of features of serotonin syndrome (e.g., agitation, hyperthermia). In most cases, symptoms resolve within 24 hours of cessation of serotonergic drugs. In moderate to severe cases, pharmacological treatment with cyproheptadine may be indicated. Patients with features of severe disease, e.g., life-threatening hyperthermia, may also require sedation and intubation.

Serotonin syndrome is a potentially life-threatening condition caused by serotonergic overactivity in patients with exposure to serotonergic drugs.

Serotonergic drugs ^[2]

• Antidepressants (e.g., MAOIs, SSRIs, SNRIs, tricyclic antidepressants, vortioxetine, vilazodone, trazodone)
• Anxiolytics (e.g., buspirone)
• Anticonvulsants (e.g., valproate)
• Opioids (e.g., tramadol, meperidine)
• NMDA receptor antagonists (e.g., dextromethorphan)
• 5-HT₃ receptor antagonists (e.g., ondansetron)
• Serotonin receptor agonists (e.g., triptans, ritonavir)
• Antibiotics (e.g., linezolid)
• Herbal supplements (e.g., St. John's wort, ginseng, tryptophan)
• Recreational stimulants (e.g., MDMA, cocaine)

Risk factors ^[3]

• Concurrent use of:
  • Two or more serotonergic drugs (e.g., an MAOI with an SSRI)
  • One or more serotonergic drug with certain CYP450 inhibitors (e.g., ciprofloxacin) ^[4]
• Switching from one serotonergic drug to another without tapering
• Accidental or intentional overdose
• Patient-specific pharmacokinetic and/or pharmacodynamic factors ^[5]

Concurrent use of multiple serotonergic drugs, or serotonergic drugs plus certain CYP450 inhibitors, increases the risk and severity of serotonin syndrome.

Symptom progression ^[2]

• Onset: acute, typically within 24 hours of administration of the causative drug
• Resolution: rapid, typically within 24 hours of treatment initiation

Presentation ^[2]

• Classic triad
  • Autonomic dysfunction
    • Diaphoresis
    • Tachycardia
    • Hypertension
    • Mydriasis
  • Neuromuscular excitability: can lead to hyperthermia
    • Hyperreflexia
    • Myoclonus
    • Clonus
    • Horizontal ocular clonus
    • Hypertonicity
    • Rigidity (especially in the lower extremities)
  • Altered mental status
    • Delirium
    • Psychomotor agitation
    • Coma
• Other features
  • Nausea, diarrhea, vomiting
  • Anxiety
  • Hypotension (due to MAOI poisoning)
  • Seizure

HAHA! Serotonin syndrome is no joke: Hyperthermia, Autonomic dysfunction, Hyperreflexia, Altered mental status

To differentiate between serotonin syndrome and other drug-induced hyperthermia conditions, remember that only SErotonin Shakes your Extremities (myoclonus and hyperreflexia, mostly of the lower limbs).

General principles^[2][6]

• Serotonin syndrome is a clinical diagnosis.
• Diagnosis is made based on diagnostic criteria, e.g., Hunter serotonin toxicity criteria.
• Laboratory studies may be used to assess for complications related to muscle rigidity and hyperthermia.

Diagnostic criteria ^[7]

Presence of any of the following in patients with exposure to ≥ 1 serotonergic drug :

• Spontaneous clonus
• Inducible clonus or ocular clonus plus ≥ 1 of the following:
  • Agitation
  • Diaphoresis
  • Hypertonia and temperature > 38°C (100.4°F)
• Tremor and hyperreflexia

Laboratory studies ^[2]

• BMP
  • ↑ Creatinine in acute kidney injury
  • ↓ Bicarbonate in metabolic acidosis
• CBC: ↓ platelets, ↓ Hb, ↑ D-dimer, ↑ aPTT, and ↑ PT in DIC
• ↑ CPK in rhabdomyolysis
• Liver chemistries: ↑ transaminases

See also “Differential diagnosis of drug-induced hyperthermia.”

• Toxic and pharmacological
  • Neuroleptic malignant syndrome
  • Malignant hyperthermia
  • Anticholinergic syndrome
  • Antidepressant discontinuation syndrome ^[8]
  • CNS stimulant overdose
  • Alcohol withdrawal syndrome
• Infectious
  • Meningitis
  • Encephalitis
• Endocrine, e.g., thyroid storm

The differential diagnoses listed here are not exhaustive.

All patients ^[2][9]

The goal of management is the stabilization of vital signs.

• Discontinue all serotonergic drugs immediately.
• Provide supportive care; : e.g., oxygen therapy, IV fluid therapy
• Give symptom-specific treatments.
• Determine severity: For moderate to severe and/or refractory cases, consider treatment with an antidote. ^[2][9][10]
  • Mild: tachycardia, hyperreflexia, shivering, diaphoresis, mydriasis, tremor
  • Moderate: agitation, hyperthermia < 40°C (104°F), clonus, diarrhea
  • Severe: hemodynamic instability, agitated delirium, muscle rigidity, hyperthermia ≥ 40°C (104°F), multiorgan failure

Symptom-specific management ^[2][9][11]

• Agitation and excessive muscle activity: Treat with benzodiazepines.
  • Mild symptoms: e.g., low-dose diazepam (off-label) ^[9]
  • Moderate to severe symptoms: higher starting dose, e.g., diazepam (off-label) and repeat doses as needed ^[9]
• Hyperthermia: Initiate active cooling (see “Management of hyperthermia”).
• Autonomic instability: Use short-acting or titratable medications, as rapid changes in blood pressure and heart rate are common. ^[2]
  • Give antihypertensive treatment.
    • Short-acting agents, e.g., esmolol, nitroprusside ^[2]
    • For dosages, see “Intravenous antihypertensives.”
  • Treat MAOI-induced hypotension or shock.
    • Titratable vasopressors, e.g., norepinephrine ^[2]
    • For dosages, see “Inoconstrictor drugs.”

Avoid physical restraints, as they can lead to worsening hyperthermia and lactic acidosis.

Moderate to severe and/or refractory cases ^{[2][6][10][11]}

• Consider treatment with 5-HT_2A receptor antagonists: cyproheptadine (off-label) ^[2][11][12]
• Temperature > 41.1°C: Sedate, paralyze, and intubate patients. ^[2]
  • Use nondepolarizing NMJ blocker as paralytic agent for intubation, e.g., rocuronium. ^[2]
  • See “Endotracheal intubation” for preparation and procedure.

Rule out anticholinergic syndrome prior to administration of cyproheptadine, as cyproheptadine can worsen anticholinergic syndrome. ^[9]

Avoid bromocriptine and dantrolene, as bromocriptine may worsen symptoms of serotonin syndrome and dantrolene has not been shown to be effective. ^[2][11]

Agents other than cyproheptadine, e.g., chlorpromazine, are not currently recommended for the treatment of serotonin syndrome. ^[2][6][10]

Disposition ^[2][9][11]

• Mild to moderate: Admit to hospital for continuous cardiac monitoring.
• Severe: Admit to critical care.

• Rhabdomyolysis
• Acute kidney injury
• Seizures
• Acute respiratory distress syndrome ^[11]
• Disseminated intravascular coagulation

We list the most important complications. The selection is not exhaustive.

• Before prescribing serotonergic drugs: ^[8]
  • Ask patients about any over-the-counter, herbal, and/or recreational drug use.
  • Avoid concurrent use of ≥ 2 high-dose serotonergic drugs (especially the combination of an MAOI and an SSRI).
  • Educate patients on the symptoms of serotonin syndrome.
  • Choose the lowest starting dose and gradually titrate to the minimum effective dose.
• Switching between serotonergic drugs ^[3]
  • Taper and discontinue the current drug before introducing another drug.
  • Gradually increase the dose of the second drug.

Refer to drug monographs or consult a local pharmacist for more information on drug interactions, half-lives, and washout periods. ^[8]