What is serotonin syndrome?

Serotonin Syndrome Overview

Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonergic activity in the central and peripheral nervous systems, characterized by a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. 1

Pathophysiology

• Serotonin syndrome results from overstimulation of serotonin receptors, particularly 5-HT1A and 5-HT2A subtypes, leading to excessive central and peripheral serotonergic activity 2
• In the CNS, serotonin regulates temperature, attention, and behavior, while peripherally it affects multiple organ systems 1
• The condition is non-idiosyncratic and predictable, meaning it can occur with addition of a new serotonergic drug, increased dosage of an existing drug, or addition of a second serotonergic agent 3, 4

Epidemiology and Risk Factors

• Serotonin syndrome occurs across all age groups, from newborn infants (due to in utero exposure) to older adults 1
• The incidence and mortality have been increasing due to the growing number and use of proserotonergic medications 1
• The mortality rate is approximately 11%, emphasizing the critical importance of prompt recognition 5, 3
• Approximately one-quarter of patients require intubation, mechanical ventilation, and ICU admission 5, 3

Causative Medications

A wide range of medications can precipitate serotonin syndrome, including: 1

• Psychiatric medications: SSRIs, SNRIs (such as venlafaxine 6 and fluoxetine 7), tricyclic antidepressants, MAOIs, anxiolytics
• Analgesics: Opiates (particularly fentanyl 6, 7), tramadol
• Antimigraine drugs: Triptans 6, 7
• Antibiotics: Linezolid 6
• Other agents: Antiemetics, anticonvulsants, anti-Parkinsonism drugs, muscle relaxants, weight-reduction medications
• Non-prescription substances: Over-the-counter medications, herbal supplements (St. John's Wort 6), dietary supplements, and drugs of abuse 1

The combination of MAOIs with other serotonergic drugs is especially dangerous and may lead to the most severe, potentially fatal form of the syndrome. 2

Clinical Presentation

Classic Triad

Mental Status Changes: 1, 8

• Agitated delirium
• Confusion
• Altered consciousness ranging from mild confusion to coma in severe cases

Autonomic Hyperactivity: 1, 8

• Hyperthermia (temperature up to 41.1°C)
• Tachycardia and tachypnea
• Hypertension or blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic change within 24 hours)
• Diaphoresis
• Mydriasis (enlarged pupils)

Neuromuscular Abnormalities: 1, 8

• Myoclonus (present in 57% of cases) 3
• Hyperreflexia (highly diagnostic when present with serotonergic drug use) 5, 3, 8
• Clonus (spontaneous, inducible, or ocular - highly diagnostic) 5, 3, 8
• Muscle rigidity
• Tremor

Timing and Onset

• Symptoms typically develop within minutes to hours, usually 6-24 hours after starting or increasing the dose of a serotonergic medication or adding a second serotonergic agent 5, 3, 8

Important Clinical Considerations

• The presentation is extremely variable, and mild cases may be easily missed 8
• Not all three components of the triad occur simultaneously in every patient 1
• Clonus and hyperreflexia are considered the most diagnostically valuable findings when occurring with serotonergic drug use 5, 3, 8

Diagnosis

Hunter Criteria (Preferred Diagnostic Tool)

The American Academy of Pediatrics recommends using the Hunter Criteria, which have higher sensitivity (84%) and specificity (97%) compared to older Sternbach criteria. 5, 3, 8

Diagnosis requires the presence of a serotonergic agent PLUS one of the following: 5, 3, 8

• Spontaneous clonus
• Inducible clonus with agitation or diaphoresis
• Ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia
• Hypertonia, temperature above 38°C (100.4°F), and ocular or inducible clonus

Modified Dunkley Criteria (Alternative)

• Requires serotonergic drug use within the last 5 weeks plus 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, 8

Laboratory and Imaging

• There are no pathognomonic laboratory or radiographic findings for serotonin syndrome 8
• Laboratory abnormalities may include elevated creatine kinase, leukocytosis, metabolic acidosis, elevated serum aminotransferase, and electrolyte abnormalities 1, 8

Differential Diagnosis

Serotonin syndrome must be differentiated from: 5, 3

• Neuroleptic malignant syndrome (NMS): Associated with dopamine antagonists; typically has slower onset, more severe rigidity ("lead pipe"), and less prominent hyperreflexia/clonus
• Malignant hyperthermia: Triggered by anesthetic agents; genetic predisposition
• Anticholinergic syndrome: Characterized by dry skin (vs. diaphoresis in SS), absent bowel sounds, and mydriasis without hyperreflexia
• Withdrawal syndromes: From alcohol, benzodiazepines, or other substances

Severity Classification

Mild: Mental status changes and mild autonomic symptoms without significant hyperthermia 4, 9

Moderate: More pronounced autonomic instability and neuromuscular findings 4, 9

Severe: Medical emergency characterized by rapid onset of severe hyperthermia (>41.1°C), muscle rigidity, and multiple organ failure 8

Management

Immediate Actions

Discontinue all serotonergic agents immediately - this is the cornerstone of treatment. 5, 3, 4

Supportive Care (All Cases)

• IV fluids: For dehydration, autonomic instability, and prevention/treatment of rhabdomyolysis 1, 5
• Benzodiazepines: First-line treatment for agitation, neuromuscular symptoms, and tremor 1, 5, 3
• External cooling measures: Use cooling blankets for hyperthermia (antipyretics are typically ineffective as fever results from muscular hyperactivity rather than hypothalamic dysregulation) 1, 5, 8
• Avoid physical restraints: They may exacerbate isometric contractions, worsening hyperthermia and lactic acidosis 5, 3

Pharmacologic Antidote

Cyproheptadine (Serotonin Antagonist): 5, 8, 4

• Adult dosing: 12 mg orally initially, then 2 mg every 2 hours until symptom improvement; maintenance dose of 8 mg every 6 hours after initial control
• Pediatric dosing: 0.25 mg/kg per day
• Mechanism: Competitively blocks serotonin at 5-HT2A receptors
• Side effects: Sedation and hypotension (monitor closely)
• The American Academy of Pediatrics specifically recommends cyproheptadine as the antidote of choice for severe serotonin syndrome 8

Severe Cases (ICU Management)

For patients with severe hyperthermia, muscle rigidity, and autonomic instability: 5, 3, 8

• ICU admission with continuous cardiac monitoring
• Aggressive cooling measures
• Consider intubation with sedation and paralysis using non-depolarizing agents (avoid succinylcholine due to risks of hyperkalemia and rhabdomyolysis) 8
• For hemodynamic instability: Use direct-acting sympathomimetic amines (phenylephrine, norepinephrine) rather than indirect agents like dopamine 8

Monitoring for Complications

Watch for the following potentially life-threatening complications: 8

• Rhabdomyolysis with elevated creatine kinase
• Metabolic acidosis
• Renal failure with elevated serum creatinine
• Seizures
• Disseminated intravascular coagulopathy
• Elevated serum aminotransferase indicating liver dysfunction

Critical Pitfalls to Avoid

• Do not restart serotonergic medications too quickly: Allow adequate washout period based on the half-life of the offending agent 6
• Do not use antipyretics alone for fever management: They are ineffective because hyperthermia is due to muscular hyperactivity, not hypothalamic dysregulation 5, 8
• Do not combine MAOIs with other serotonergic drugs: This is contraindicated and can be fatal 6, 7
• Do not miss mild cases: Early recognition prevents progression to severe, life-threatening toxicity 8, 4
• Do not use succinylcholine for paralysis: Risk of hyperkalemia and worsening rhabdomyolysis 8

Drug-Specific Warnings

Venlafaxine (SNRI)

• FDA labeling warns that serotonin syndrome can develop with SNRIs alone but particularly with concomitant use of serotonergic drugs or drugs that impair serotonin metabolism 6
• Concomitant use with MAOIs intended to treat psychiatric disorders is contraindicated 6
• Should not be started in patients being treated with linezolid or intravenous methylene blue 6

Fluoxetine (SSRI)

• FDA labeling emphasizes that serotonin syndrome may occur with SSRIs, particularly with concomitant use of triptans and drugs that impair serotonin metabolism 7
• Concomitant use with MAOIs intended to treat depression is contraindicated 7
• Concomitant use with serotonin precursors (such as tryptophan) is not recommended 7

Prevention Strategies

• Screen medication lists carefully: Identify all serotonergic agents before adding new medications 4, 10
• Educate patients: About signs and symptoms to report immediately 6
• Respect washout periods: When switching between serotonergic agents, particularly MAOIs (typically 2 weeks for most agents, 5 weeks for fluoxetine) 6
• Start low, go slow: When initiating serotonergic medications, especially in combination 10
• Monitor closely: During initial treatment and dose changes 6

Prognosis

• Most cases of serotonin syndrome are mild and resolve with prompt recognition, discontinuation of offending agents, and supportive care 4, 9
• With prompt recognition and appropriate management of complications, even severe cases have a favorable prognosis 4, 9
• Delayed recognition and inadequate management are the most common causes of death 1