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Serotonin Syndrome (SS)

Serotonin Syndrome (SS)

Serotonin syndrome (SS) is a potentially life-threatening condition caused by excessive accumulation of serotonin in the nervous system, typically due to the use or interaction of serotonergic drugs. It can range from mild symptoms like shivering and diarrhea to severe manifestations such as muscle rigidity, high fever, seizures, and even death if untreated16.

Causes

• Most often occurs when two or more drugs that increase serotonin levels are taken together, such as combining antidepressants (SSRIs, SNRIs, MAOIs) with migraine medications (triptans), opioid painkillers, or certain supplements.
• It can also result from overdose or rapid dose escalation of serotonergic drugs.
• Common drugs implicated include:
  • Selective Serotonin Reuptake Inhibitors (SSRIs): e.g., fluoxetine, sertraline, citalopram
  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): e.g., venlafaxine, duloxetine
  • Monoamine Oxidase Inhibitors (MAOIs): e.g., phenelzine, tranylcypromine
  • Other agents: tramadol, fentanyl, buspirone, dextromethorphan, triptans, certain herbs (e.g., ginseng), and illicit drugs1356.

Pathophysiology

• Excess serotonin leads to overstimulation of central and peripheral serotonin receptors, particularly 5-HT1A and 5-HT2A receptors.
• This overstimulation disrupts normal neurotransmission, causing autonomic, neuromuscular, and cognitive symptoms.
• The syndrome usually develops within 24 hours of medication changes affecting serotonin metabolism, synthesis, release, or receptor activation4.

Symptoms

• Cognitive/Behavioral: Agitation, confusion, restlessness, hallucinations, delirium
• Autonomic: Rapid heart rate, high blood pressure, hyperthermia, sweating, shivering, diarrhea
• Neuromuscular: Tremor, muscle rigidity, hyperreflexia (especially in lower limbs), clonus (involuntary muscle contractions), seizures
• Symptoms typically appear quickly, often within hours of drug initiation or dose increase145.

Diagnosis

• Based on clinical history of serotonergic drug exposure and characteristic symptoms.
• No specific laboratory test confirms serotonin syndrome; diagnosis is clinical.
• Differential diagnosis includes neuroleptic malignant syndrome, anticholinergic toxicity, infection, and malignant hyperthermia56.

Treatment

• Immediate discontinuation of all serotonergic agents.
• Supportive care including hydration, oxygen, and monitoring of vital signs.
• Sedation with benzodiazepines (e.g., diazepam, lorazepam) to control agitation and muscle stiffness.
• Serotonin antagonists such as cyproheptadine may be used in moderate to severe cases.
• Severe cases may require intensive care with temperature control and management of complications257.
• Symptoms often resolve within 24 to 72 hours after stopping offending agents.

Summary Table

Aspect	Details
Cause	Excess serotonin from drug interactions, overdose, or dose changes
Common Drugs	SSRIs, SNRIs, MAOIs, tramadol, fentanyl, triptans, dextromethorphan, herbal supplements
Onset	Usually within 24 hours of serotonergic drug change
Symptoms	Agitation, confusion, hyperthermia, tachycardia, muscle rigidity, tremor, clonus, diarrhea
Diagnosis	Clinical, based on history and symptoms
Treatment	Stop serotonergic drugs, supportive care, benzodiazepines, cyproheptadine, ICU care if severe

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References

1. Mayo Clinic. Serotonin syndrome – Symptoms & causes. 2024.
   https://www.mayoclinic.org/diseases-conditions/serotonin-syndrome/symptoms-causes/syc-20354758
2. Cleveland Clinic. Serotonin Syndrome: Causes, Symptoms & Treatment.
   https://my.clevelandclinic.org/health/diseases/17687-serotonin-syndrome
3. WebMD. Serotonin Syndrome: Causes, Symptoms, and Treatment. 2023.
   https://www.webmd.com/brain/serotonin-syndrome-causes-symptoms-treatments
4. StatPearls. Serotonin Syndrome. 2024.
   https://www.ncbi.nlm.nih.gov/books/NBK482377/
5. MedlinePlus. Serotonin syndrome. 2024.
   https://medlineplus.gov/ency/article/007272.htm
6. MSD Manuals. Serotonin Syndrome. 2023.
   https://www.msdmanuals.com/home/injuries-and-poisoning/heat-disorders/serotonin-syndrome
7. Mayo Clinic. Serotonin syndrome – Diagnosis & treatment.
   https://www.mayoclinic.org/diseases-conditions/serotonin-syndrome/diagnosis-treatment/drc-20354764

Serotonin syndrome is a medical emergency caused by excessive serotonergic activity, requiring prompt recognition, discontinuation of offending agents, and supportive care to prevent serious complications.