Management of Serotonin Syndrome
The management of serotonin syndrome requires immediate discontinuation of all serotonergic agents, supportive care including IV fluids, benzodiazepines for agitation control, and cyproheptadine administration for moderate to severe cases. 1
Diagnosis
Before initiating treatment, confirm diagnosis using the Hunter criteria (84% sensitivity, 97% specificity):
- Patient has taken a serotonergic drug within the past 5 weeks
- Plus one of the following:
- Spontaneous clonus
- Inducible clonus with agitation or diaphoresis
- Ocular clonus with agitation or diaphoresis
- Tremor and hyperreflexia
- Hypertonia, temperature >38°C, and ocular or inducible clonus 1
Management Algorithm
Step 1: Discontinue Offending Agents
- Immediately stop all serotonergic medications
- Common culprits include SSRIs, SNRIs, TCAs, MAOIs, opioids, antiemetics, and antimigraine drugs 1
Step 2: Supportive Care (All Cases)
- Administer IV fluids
- Monitor vital signs
- Control agitation with benzodiazepines (first-line) 1, 2
- Avoid physical restraints as they may worsen hyperthermia and lactic acidosis 1
Step 3: Pharmacological Management Based on Severity
Mild Cases:
- Supportive care and benzodiazepines are usually sufficient
- Symptoms typically resolve within 24-72 hours after discontinuation of serotonergic agents 2, 3
Moderate to Severe Cases:
- Administer cyproheptadine (serotonin 5-HT2A antagonist) 1, 4
- Adult dosing: Initial dose of 12 mg orally (three 4 mg tablets)
- Maintenance: 4-8 mg every 6 hours as needed
- Maximum daily dose: 32 mg 1, 4
- Pediatric dosing (based on FDA label):
- Ages 2-6 years: 0.25 mg/kg/day or 8 mg/m², not to exceed 12 mg/day
- Ages 7-14 years: 4 mg two or three times daily, not to exceed 16 mg/day 4
- Alternative: Chlorpromazine (if cyproheptadine unavailable) 1
Step 4: Management of Severe Cases (Temperature >41°C)
- Consider neuromuscular paralysis with non-depolarizing agents
- Intubation and mechanical ventilation (required in approximately 25% of severe cases) 1
- ICU admission for close monitoring 5
Monitoring for Complications
Monitor for and treat:
- Rhabdomyolysis
- Metabolic acidosis
- Elevated liver enzymes
- Renal failure
- Seizures
- Disseminated intravascular coagulation 1, 6
Prognosis and Recovery
- With prompt recognition and treatment, prognosis is generally favorable 2, 3
- Fever typically resolves within 1-3 days but may take up to 7 days 1
- Without proper treatment, mortality rate is approximately 11% 1
Important Clinical Pearls
- Benzodiazepines are the first-line treatment for agitation and can help with muscle rigidity 1, 2
- Cyproheptadine is eliminated more slowly in patients with renal insufficiency; dose adjustments may be necessary 4
- Avoid combining MAOIs with any other serotonergic medications 1
- Exercise caution when combining two or more non-MAOI serotonergic drugs 1
- Serotonin syndrome is not an idiosyncratic reaction but a predictable and preventable pharmacological effect 3
- The condition can be confused with neuroleptic malignant syndrome, malignant hyperthermia, or anticholinergic toxicity; careful differentiation is essential 5, 6