What are the clinical presentations of Serotonin (5-hydroxytryptamine) syndrome?

From the Guidelines

Serotonin syndrome presents as a potentially life-threatening condition characterized by a triad of cognitive-behavioral changes, autonomic instability, and neuromuscular abnormalities, with symptoms developing within minutes to hours after exposure to proserotonergic drugs. The clinical presentation of serotonin syndrome can vary, but it often includes agitation, restlessness, anxiety, and confusion, accompanied by dilated pupils, sweating, shivering, and diarrhea 1. As the syndrome progresses, patients may develop high fever (often >41.1°C), tachycardia, hypertension, and hyperreflexia, with distinctive neuromuscular findings such as clonus, muscle rigidity, and tremor. In severe cases, patients can develop seizures, metabolic acidosis, rhabdomyolysis, renal failure, and disseminated intravascular coagulation 1.

Key Features of Serotonin Syndrome

• Cognitive-behavioral changes: agitation, restlessness, anxiety, and confusion
• Autonomic instability: hypertension, tachycardia, hyperthermia, and diaphoresis
• Neuromuscular abnormalities: clonus, muscle rigidity, tremor, and hyperreflexia
• Gastrointestinal symptoms: diarrhea and hyperactive bowel sounds
• Other symptoms: mydriasis, sialorrhea, and elevated creatine kinase

Diagnosis and Treatment

The diagnosis of serotonin syndrome is clinical, and there are no pathognomonic laboratory or radiographic findings 1. The Hunter criteria are commonly used to diagnose serotonin syndrome, and treatment involves discontinuing the precipitating agent, providing supportive care, and possibly using benzodiazepines for agitation or cyproheptadine as a serotonin antagonist in moderate to severe cases 1. Immediate discontinuation of all serotonergic agents is essential, along with supportive care and possibly benzodiazepines for agitation or cyproheptadine (12-24mg daily in divided doses) as a serotonin antagonist in moderate to severe cases.

Severity and Mortality

Serotonin syndrome can be severe, with a mortality rate of approximately 11%, and significant morbidity and mortality associated with the condition 1. Severe cases are characterized by rhabdomyolysis, metabolic acidosis, elevated serum aminotransferase, renal failure, seizures, and disseminated intravascular coagulation 1. Approximately one-quarter of patients are treated with intubation, mechanical ventilation, and admission to an ICU 1.

From the Research

Presentation of Serotonin Syndrome

Serotonin syndrome (SS) is a rare and potentially life-threatening toxic state caused by an adverse drug reaction that leads to excessive central and peripheral serotonergic activity 2. The clinical manifestations of SS are diverse and nonspecific, which may lead to misdiagnosis.

• The syndrome classically consists of a triad of signs and symptoms broadly characterized as:
  • Alteration of mental status
  • Abnormalities of neuromuscular tone
  • Autonomic hyperactivity
• However, all 3 triads of SS may not occur simultaneously 2.
• SS can range in severity from mild to life-threatening, with most cases being mild and resolving with prompt recognition and supportive care 2.
• Common clinical features of SS include:
  • Neuromuscular abnormalities, such as tremor, hyperreflexia, or myoclonus 3
  • Autonomic hyperactivity, such as tachycardia, hypertension, or diaphoresis 4
  • Mental state changes, such as altered mental status or agitation 5
• Other clinical features that may be present in SS include:
  • Hyperreflexia 4
  • Clonus 4
  • Rigidity 4
  • Increased bowel sound 4
  • Fever 4
  • Myoclonus 4

Severity of Serotonin Syndrome

The severity of SS can vary, with some cases being mild and easily managed, while others can be life-threatening 2.

• Severe SS is usually precipitated by the simultaneous initiation of 2 or more serotonergic drugs, but the syndrome can also occur after the initiation of a single serotonergic drug in a susceptible individual 5.
• The combination of a monoamine oxidase inhibitor (MAOI) with serotonergic drugs is especially dangerous and may lead to the most severe form of the syndrome, and occasionally death 5.

Diagnosis and Treatment

The diagnosis of SS requires a history of exposure to agents active at serotonin receptors and the presence of alterations in mental status, autonomic instability, and neuromuscular abnormalities 3.

• Treatment of SS involves withdrawal of the offending agent(s), aggressive supportive care to treat hyperthermia and autonomic dysfunction, and occasionally the administration of serotonin antagonists, such as cyproheptadine or chlorpromazine 2.
• Cyproheptadine has been shown to be effective in treating SS, with most patients showing at least some response to the medication within 24 hours 4.