Symptoms and Clinical Findings of Serotonin Syndrome
Serotonin syndrome presents with a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities, with the Hunter criteria being the recommended diagnostic standard requiring a patient to have taken a serotonergic drug within the past 5 weeks and exhibiting specific symptoms. 1
Clinical Presentation
Serotonin syndrome manifests across a spectrum of severity from mild to life-threatening. The classic triad includes:
Mental Status Changes
- Anxiety
- Agitation
- Confusion
- Altered consciousness
Autonomic Hyperactivity
- Hyperthermia (temperature >38°C)
- Tachycardia
- Diaphoresis (excessive sweating)
- Blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic change within 24 hours)
- Flushing
- Urinary incontinence
Neuromuscular Abnormalities
- Hyperreflexia
- Clonus (spontaneous, inducible, or ocular)
- Tremor
- Muscle rigidity
- Myoclonus
- Positive Babinski sign
- Chorea
- Trismus (jaw clenching)
- Oculogyric crisis
Diagnostic Criteria: Hunter Criteria
The Hunter criteria are considered the gold standard for diagnosis 1, 2. A diagnosis requires:
- Recent use of a serotonergic agent (within 5 weeks)
- At least ONE of the following:
- Spontaneous clonus
- Inducible clonus PLUS agitation or diaphoresis
- Ocular clonus PLUS agitation or diaphoresis
- Tremor AND hyperreflexia
- Hypertonia AND temperature >38°C AND ocular or inducible clonus
Severity Classification
- Mild: Serotonergic features that may not concern the patient (mild tremor, hyperreflexia)
- Moderate: Significant distress requiring treatment but not life-threatening
- Severe: Medical emergency with rapid onset of severe hyperthermia (>41°C), muscle rigidity, and multiple organ failure 1, 3
Laboratory Findings
While not diagnostic, the following laboratory abnormalities may be present:
- Leukocytosis (15,000-30,000 cells/mm³)
- Elevated creatine kinase (≥4 times upper limit of normal)
- Electrolyte abnormalities consistent with dehydration
- Elevated liver enzymes
- Metabolic acidosis 4, 1
Complications
If not promptly treated, serotonin syndrome can lead to:
- Rhabdomyolysis
- Renal failure
- Disseminated intravascular coagulation
- Seizures
- Death (approximately 11% mortality rate without proper treatment) 1
Common Pitfalls and Caveats
- Variable presentation: One of the greatest challenges in diagnosis is the extremely variable presentation 4
- Misdiagnosis: Often confused with neuroleptic malignant syndrome, malignant hyperthermia, or anticholinergic toxicity
- Medication history: Critical to obtain a complete medication history, including over-the-counter medications, herbal supplements, and illicit drugs 1, 5
- Rapid progression: Symptoms can progress rapidly from mild to severe, requiring immediate intervention
- Polypharmacy risk: The risk significantly increases when combining multiple serotonergic medications, particularly MAOIs with any serotonergic drug 1
Early recognition and prompt discontinuation of serotonergic agents are crucial to prevent significant morbidity and mortality. The presence of clonus (spontaneous, inducible, or ocular) is particularly specific for serotonin syndrome and should prompt immediate action 2, 3.