Serotonin syndrome is a potentially life-threatening condition caused by large increases in serotonergic activity due to exposure to serotonin agonists. Defining symptoms include altered mental status, autonomic instability, and neuromuscular abnormalities (tremors, myoclonus).
- Exact incidence is unknown due to:
- Lack of confirmatory testing
- Wide spectrum of severity
- Cases appear to be increasing:
- Increased awareness of disease by providers
- Increased use of serotonergic medication
Serotonin syndrome occurs secondary to use of therapeutic medication, drug interactions, or overdose.
- Psychiatric drugs:
- Selective serotonin reuptake inhibitors (SSRIs): most common cause
- Serotonin-norepinephrine reuptake inhibitors (SNRIs)
- Serotonin modulators (trazodone)
- Monoamine oxidase inhibitors (tranylcypromine, phenelzine, isocarboxazid, selegiline)
- Tricyclic antidepressants (TCAs)
- Nonpsychiatric drugs:
- Illicit drugs:
- MDMA/ecstasy/molly (3,4-Methylenedioxymethamphetamine)
- LSD (lysergic acid diethylamide)
- Supplements/herbal medication:
- St. John’s wort
Serotonin syndrome occurs from any combination of drugs that have the net effect of increasing serotonergic neurotransmission.
- Stimulation of postsynaptic 5-HT1A and 5-HT2A receptors
- Serotonin (5-HT) receptors normally found in the CNS regulate:
- Serotonin (5-HT) receptors found in the peripheral nervous system (PNS) regulate:
- GI motility
- Uterine contraction
- Mental status changes
- Unstable blood pressures (usually elevated)
- Increased bowel sounds
- Mental status change
- Increased reflexes
Serotonin syndrome is clinically diagnosed (serum serotonin levels have no correlation to symptoms or toxicity). Multiple diagnostic criteria have been developed, with the Hunter Serotonin Toxicity Criteria being the most accurate.
Hunter Serotonin Toxicity Criteria
Patient must have taken a serotonergic drug and be positive for 1 of the following criteria:
- Spontaneous clonus
- Inducible clonus + agitation or diaphoresis
- Ocular clonus + agitation or diaphoresis
- Tremor + hyperreflexia
- Hypertonia + hyperthermia (> 38°C (> 100.4°F)) + ocular/inducible clonus
Serotonin syndrome often resolves within 24 hours of discontinuing the serotonergic agent and initiating care.
- Discontinuation of all serotonergic agents
- Supportive care to normalize vital signs:
- Control fever:
- Cooling blankets
- Ice packs
- Oxygen: intubate, if severe altered mental status
- IV fluids
- Maintain appropriate blood pressure: benzodiazepines to lower elevated pressure and control agitation
- Control fever:
- Antidote therapy: cyproheptadine (5-HT2 receptor antagonist)
- Rhabdomyolysis and myoglobinuria
- Disseminated intravascular coagulation (DIC)
- Metabolic acidosis
- Acute renal failure
It is important to distinguish between serotonin syndrome, malignant hyperthermia, and neuroleptic malignant syndrome.
- Neuroleptic malignant syndrome (NMS): rare, idiosyncratic, and potentially life-threatening reaction to neuroleptic (e.g., antipsychotic) drugs. Very similar to serotonin syndrome, but without the GI symptoms and more muscle rigidity. Treated similarly to serotonin syndrome, by discontinuing causative drugs and offering supportive care.
- Malignant hyperthermia: rare complication triggered by certain inhaled anesthetics or paralytics. Suspect in operating room or anesthesia procedure. Treatment is nearly same as NMS and clinically indistinguishable except for drugs triggering the syndrome.
- Boyer EW, Shannon M. (2005). The serotonin syndrome. N Engl J Med. https://pubmed.ncbi.nlm.nih.gov/15784664/
- Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. (2003). The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. https://pubmed.ncbi.nlm.nih.gov/12925718/
- Sternbach H. (1991). The serotonin syndrome. Am J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/2035713/