Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. Stimulation of the postsynaptic 5-HT1A and 5-HT2A receptors has been implicated in serotonin syndrome, often due to a medication. The selective serotonin reuptake inhibitors (SSRIs) are perhaps the most commonly implicated group of medications associated with serotonin syndrome. However, serotonin syndrome has been seen in cases of drug interactions, as well as intentional overdoses of numerous drugs. In the central nervous system (CNS), serotonin modulates attention, behavior, and thermoregulation. In the peripheral nervous system serotonin is involved in regulating gastrointestinal motility, vasoconstriction, uterine contraction, and bronchoconstriction. Understanding the role of serotonin the in the body can help understand the clinical manifestations seen in serotonin syndrome.

Clinical manifestations of serotonin syndrome often include mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. Mental status changes can include anxiety, agitated delirium, restlessness, and disorientation. Autonomic manifestations can include diaphoresis, tachycardia, hyperthermia, hypertension, vomiting, and diarrhea. Neuromuscular hyperactivity can manifest as tremor, muscle rigidity, myoclonus, hyperreflexia, and bilateral Babinski sign, mostly affecting the lower extremities. 




●Slow, continuous, horizontal eye movements (referred to as ocular clonus)

●Dilated pupils



●Deep tendon hyperreflexia (common)

●Inducible or spontaneous muscle clonus (common)

●Muscle rigidity

●Bilateral Babinski signs

●Dry mucus membranes

●Flushed skin and diaphoresis

●Increased bowel sounds  

Agents that Can Precipitate Serotonin Syndrome

  • Cocaine
  • MDMA
  • Tramadol
  • Cyclobenzaprine
  • Dextromethorphan
  • St. John’s Wort
  • MAOI
  • Fentanyl

Diagnosis of serotonin syndrome is based on clinical findings. The Hunter Toxicity Criteria Decision Rules is the most accurate decision tool (84% sensitive and 97% specific). To fulfill the Hunter Criteria, a patient must have taken a serotonergic agent and meet ONE of the following conditions:

Spontaneous clonus

Inducible clonus PLUS agitation or diaphoresis

Ocular clonus PLUS agitation or diaphoresis

Tremor PLUS hyperreflexia

Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus

Treatment for serotonin syndrome involves supportive care, discontinuing the offending agent, and providing the antidote. Sedation with benzodiazepines is important for controlling agitation as well as correcting mild increases in blood pressure and heart rate. Haloperidol and Droperidol should be avoided; these drugs have anticholinergic properties that inhibit sweating and dissipation of body heat.  Hypertension and tachycardia should be managed with short acting agents such as esmolol or nitroprusside. Controlling hyperthermia is extremely important as it can minimize severe complications of serotonin syndrome, including seizures, DIC and ventricular tachycardia. There is no role for antipyretics in treatment of hyperthermia secondary to serotonin syndrome. The hyperthermia is caused by increased muscular activity as opposed to an alteration of the hypothalamic temperature set point.

If supportive care fail to improve vital signs and decrease agitation, Cyproheptadine can be administered. The dosage for serotonin syndrome is 12mg orally, followed by 2mg every 2 hours until clinical improvement. Cyproheptadine is only available in oral form.

Disposition: Patients with severe serotonin syndrome require ICU monitoring. Symptoms typically resolve within 24 hours after removal of the offending agent. However, longer acting formulations can cause symptoms to be prolonged. Once symptoms resolve, it is safe to discharge these patients with close follow up. It is important to have a risk/benefit discussion with their prescriber about continuing/discontinuing the offending agent.

Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 2003; 96:635.

May 2024