What is Serotonin Syndrome

Serotonin Syndrome (PRESS Syndrome)

Serotonin syndrome is a potentially life-threatening condition characterized by excessive serotonergic activity in the nervous system, manifesting as a triad of mental status changes, autonomic instability, and neuromuscular hyperactivity. 1, 2

Definition and Pathophysiology

Serotonin syndrome occurs due to excessive serotonin stimulation in the central and peripheral nervous system, typically resulting from:

• Use of a single serotonergic agent at high doses
• Inadvertent interactions between multiple serotonergic medications
• Combination of serotonergic agents with monoamine oxidase inhibitors (MAOIs)
• Intentional or unintentional overdose of serotonergic medications 3

Clinical Presentation

The classic triad of symptoms includes:

1. Mental Status Changes:

   • Agitation
   • Confusion
   • Delirium
   • Hallucinations

2. Autonomic Instability:

   • Hyperthermia (temperature >38°C)
   • Tachycardia
   • Hypertension
   • Diaphoresis
   • Flushing

3. Neuromuscular Abnormalities:

   • Tremor
   • Muscle rigidity
   • Hyperreflexia
   • Clonus (spontaneous, inducible, or ocular)
   • Myoclonus 1, 2

Diagnostic Criteria

The Hunter Serotonin Toxicity Criteria are the diagnostic standard, requiring:

• Patient has taken a serotonergic drug within the past 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 1, 2

Common Causative Agents

• Selective Serotonin Reuptake Inhibitors (SSRIs)
• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
• Monoamine Oxidase Inhibitors (MAOIs)
• Tricyclic Antidepressants (TCAs)
• Opioids (particularly tramadol, meperidine)
• Certain antibiotics (linezolid)
• Over-the-counter medications containing dextromethorphan
• Herbal supplements (St. John's Wort) 3, 4

Management

1. Immediate discontinuation of all serotonergic agents - this is the most critical first step 1

2. Supportive care:

   • IV fluid administration
   • External cooling for hyperthermia
   • Cardiac monitoring
   • Respiratory support if needed 1

3. Pharmacological interventions:

   • Benzodiazepines for agitation and tremor
   • Cyproheptadine (a serotonin antagonist) for moderate to severe cases
   • Severe cases may require neuromuscular paralysis, sedation, and intubation 1, 2

Severity and Prognosis

• Mild cases: Resolve with discontinuation of offending agents and supportive care
• Moderate to severe cases: Require hospitalization and more aggressive management
• Mortality rate: Approximately 11% for untreated cases 1
• Potential complications: Rhabdomyolysis, renal failure, disseminated intravascular coagulation, seizures, and death 1

Differentiation from Similar Conditions

Serotonin syndrome must be differentiated from neuroleptic malignant syndrome (NMS), which presents similarly but is caused by dopamine antagonism rather than serotonin excess. Key differences:

• NMS typically develops more slowly (days to weeks)
• NMS features more prominent "lead-pipe" rigidity
• NMS lacks the clonus and hyperreflexia characteristic of serotonin syndrome 1, 5

Prevention

Serotonin syndrome is highly preventable through:

• Careful medication reconciliation
• Avoiding combinations of serotonergic agents
• Particular caution when prescribing MAOIs with other serotonergic medications
• Patient education about potential drug interactions 3, 4

Special Considerations

In patients with underlying movement disorders like Parkinson's disease, diagnosis can be challenging as tremor may be attributed to the underlying condition rather than serotonin syndrome. A high index of suspicion is essential in these patients when serotonergic medications are involved 6.