DepressionPharmacologyRapid Response

Serotonin syndrome

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By: Trae Stewart, PhD, MPH, MSN, MN, MS, PMHNP-BC, APRN

Early recognition and quick action prevent poor outcome

Takeaways:

  • Serotonin syndrome manifests with a combination of cognitive, autonomic, and somatic symptoms, including agitation, tachycardia, hyperreflexia, tremors, and hyperthermia, typically arising from the use or combination of serotonergic medications.
  • Effective management involves the immediate discontinuation of serotonergic agents, administration of supportive care such as I.V. fluids and benzodiazepines, and the use of serotonin antagonists like cyproheptadine in severe cases.
  • Prompt recognition and intervention are crucial for preventing severe complications such as rhabdomyolysis and multi-organ failure.

MICHELLE ANDERSON*, a 54-year-old woman, arrives at the ED with flu-like symptoms, including fatigue, muscle aches, and a mild fever. Her medical history includes depression, which she manages with a selective serotonin reuptake inhibitor (SSRI), and recurrent migraines treated with a triptan. Two days earlier, Ms. Anderson sprained her ankle and received a prescription for tramadol.

On the day of her ED visit, Ms. Anderson experienced a migraine and took her usual triptan. Paul, the ED nurse, notes the patient’s restlessness and mild tremors. Ms. Anderson’s vital signs are HR 98 bpm, BP 140/90 mmHg, temperature 99.2° F, RR 24, and SpO2 95%.

Symptom escalation

Ms. Anderson becomes increasingly confused, agitated, and tachycardic, while also exhibiting hyperreflexia (exaggerated reflex responses). Hyperreflexia can lead to uncontrolled muscle contractions, which increase energy demand and heat production in muscles, causing mechanical stress, ischemia, and cellular disruption. This cascade results in rhabdomyolysis (breakdown of muscle fibers with release of myoglobin, potassium, and creatine kinase into the bloodstream). Myoglobin can damage kidneys and elevate potassium, ultimately resulting in life-threatening cardiac arrhythmias.

Paul implements continuous cardiac monitoring and increases vital sign frequency. He recognizes the possibility of serotonin syndrome and holds tramadol and triptan, which, in combination with the patient’s SSRI, may have synergistically elevated her serotonin levels. Her vital signs are now HR 130, BP 160/106 mmHg, temperature 101.2° F, RR 34, and SpO2 92%

Paul administers oxygen at 3 L/min via nasal and initiates an I.V. for hydration as ordered to manage hyperthermia and prevent rhabdomyolysis. He administers lorazepam 2 mg I.V. to control agitation and muscle rigidity and then prepares cyproheptadine, an antihistamine with 5-HT2A antagonistic properties. He administers an initial dose of 12 mg orally, followed by 2 mg every hour as needed. However, Ms. Anderson’s symptoms intensify. Paul calls the rapid response team (RRT).

Taking action

The RRT provides aggressive hydration with I.V. normal saline at 100 mL/hr, administers additional benzodiazepines to maintain muscle relaxation, and continues cyproheptadine to antagonize excessive serotonin activity.

Given Ms. Anderson’s persistent tachycardia and hypertension, the team monitors her cardiovascular status closely, ready to administer beta-blockers if necessary. To prevent potential respiratory compromise, the RRT decides to intubate the patient.

Education

Serotonin regulates mood, cognition, and various physiological functions, including thermoregulation and neuromuscular activity. Levels that surpass normal limits disrupt neurotransmitter balance, leading to a range of symptoms.

Serotonin syndrome is a potentially life-threatening condition caused by excessive accumulation of serotonin in the central nervous system. It occurs when medications or combinations of medications overstimulate serotonin receptors, especially the 5-HT1A and 5-HT2A subtypes.

Outcome

Ms. Anderson’s symptoms subside, and her vital signs stabilize. After 48 hours in acute care, Ms. Anderson is transferred back to primary care for ongoing management. Before discharge, the provider discontinues cyproheptadine and the nurse offers Ms. Anderson education about how to avoid toxic levels of serotonin. Paul’s quick recognition of Ms. Anderson’s deterioration and the RRT’s swift action prevented progression to severe complications and a potentially catastrophic outcome.

About serotonin syndrome

Serotonin syndrome can develop rapidly, often within hours of starting or increasing a serotonergic agent. Symptoms include
the following:

Autonomic

  • Diaphoresis
  • Diarrhea
  • Hypertension
  • Hyperthermia
  • Mydriasis
  • Nausea and vomiting
  • Shivering
  • Tachycardia
Cognitive

  • Agitation
  • Coma
  • Confusion
  • Hallucinations
Somatic (Neuromuscular)

  • Clonus
  • Hyperreflexia
  • Muscle rigidity
  • Rhabdomyolysis
  • Seizures
  • Tremors

Medications associated with serotonin syndrome

Drug Class
Examples
Mechanism of Action
Antiemetics
Granisetron, metoclopramide,ondansetron
Serotonin receptor agonism (5-HT3)
Antiepileptics
Carbamazepine, valproate
Enhance serotonin signaling via indirect mechanisms
Atypical antidepressants
Bupropion, mirtazapine, nefazodone, trazodone
Modulate serotonin activity via diverse mechanisms
Illicit drugs
Cathinones, cocaine, LSD, MDMA(ecstasy)
Increase serotonin release or agonize serotonin receptors
Inhibitors of serotonin metabolism
MAOIs (isocarboxazid, linezolid, moclobemide, phenelzine, rasagiline, selegiline, tedizolid, tranylcypromine)
Prevent serotonin breakdown by inhibiting monoamine oxidase
Inhibitors of serotonin reuptake
SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)
Block reuptake of serotonin into presynaptic neurons
SNRIs (duloxetine, milnacipran, venlafaxine)
Increase serotonin and norepinephrine levels
Mood stabilizers
Lithium
Enhance serotonin release
Opiates
Fentanyl, meperidine, methadone,tapentadol, tramadol
Enhance serotonin release or inhibit reuptake
Serotonin precursors
Tryptophan
Increase serotonin synthesis
Supplements
St. John’s Wort, 5-HTP (Griffonia simplicifolia plant)*
Inhibit serotonin reuptake and metabolism
Tricyclic antidepressants
Amitriptyline, amoxapine, clomipramine, imipramine, nortriptyline, trimipramine
Inhibit serotonin and norepinephrine reuptake
Triptans
Eletriptan, rizatriptan, sumatriptan, zolmitriptan
5-HT1B/1D receptor agonists
Miscellaneous Medications
Methylene blue, procarbazine
MAOI-like effects

*Individuals who accidentally or intentionally take large amounts of 5-HTP (5-Hydroxytryptophan) dietary supplements, in addition to prescribed serotonergic medications, put themselves at significant risk of developing serotonin syndrome.
5-HTP, a naturally occurring amino acid and chemical precursor to serotonin (5-HT), is derived from L-tryptophan, an essential amino acid found in food. It’s commonly sold over-the-counter as, or as an ingredient in, a supplement (such as St. John’s Wort). Once ingested, 5-HTP is converted into serotonin in the brain, potentially increasing serotonin levels.

Differential diagnoses

Serotonin syndrome can be confused with other conditions, including the following:

Condition
Key features
Differentiating characteristics
Anticholinergic toxicity
Altered mental status (agitation, anxiety, seizures), dry mucosa, erythematous skin, urinary retention
Absence of clonus, dry skin/mucosa, no diaphoresis(dry presentation), no hyperreflexia, normal reflexes
Antidepressant discontinuation syndrome
Malaise, nausea, sleep/mood changes, transient symptoms lasting less than a week
No clonus or hyperreflexia, related to abrupt antidepressant cessation, spontaneous resolution in under a week
Hyperactive delirium
Altered mental status, agitation, diaphoresis, hypertension, tachycardia, tremor
No hyperreflexia or clonus, often seen in elderly patients or with withdrawal states
Hyperthyroidism/thyroid storm
Agitation, fever, heat intolerance, tachycardia, tremor, weight loss
Elevated thyroid hormones (T3, T4), low TSH, no clonus or hyperreflexia
Malignant hyperthermia
Elevated CO₂ levels, hyperthermia, mottled skin, muscle rigidity, tachycardia, tachypnoea
Genetic predisposition, hyporeflexia, mortis-like rigidity, no clonus or hyperreflexia, triggered by volatile anesthetics or succinylcholine
Neuroleptic malignant syndrome
Altered mental status, autonomic dysfunction, hyperthermia, rigidity (lead-pipe or cogwheel)
Absence of clonus, bradykinesia, gradual onset (7–10 days), hyporeflexia, prolonged duration even after discontinuation of offending drug
Nonconvulsive status epilepticus
Altered mental status, intermittent agitation, possible autonomic instability
EEG abnormalities confirm diagnosis, no clonus or hyperreflexia
Rhabdomyolysis
Dark urine (myoglobinuria), elevated creatine kinase, muscle pain, weakness
Muscle injury typically due to trauma or prolonged immobility, no hyperreflexia or clonus
Sepsis
Altered mental status, fever, possible hypotension, signs of infection (such as elevated WBC), tachycardia
No clonus or hyperreflexia, positive infectious source, systemic inflammatory markers

Differential diagnoses

Management of serotonin syndrome includes immediate cessation of offending agents and supportive care. If serotonin
syndrome remains unrecognized or untreated, it can swiftly progress to irreversible organ damage and death.

Cyproheptadine reduces serotonin syndrome symptoms such as hyperthermia, neuromuscular excitation, and autonomic
instability. It’s preferred over chlorpromazine to avoid risks like orthostatic hypotension and worsening hyperthermia.
Cyproheptadine may be administered up to a maximum of 32 mg in 24 hours, followed by a maintenance dose of 8 mg every
6 hours.

*Name is fictitious.

Trae Stewart is a professor of nursing at Massachusetts College of Pharmacy & Health Sciences in Boston and a psychiatric-mental health nurse practitioner at PsychMatters in Las Vegas, Nevada.

American Nurse Journal. 2025; 20(10). Doi: 10.51256/ANJ102546

References

Agrawal U, Yihang Q, Jingping W. Therapeutic considerations in chronic serotonin syndrome: A case report. Transl Perioper Pain Med. 2022;9(1):1-5. doi:10.31480/2330-4871/160

Chiew AL, Buckley NA. The serotonin toxidrome: Shortfalls of current diagnostic criteria for related syndromes. Clin Toxicol. 2022;60(2):143-58. doi:10.1080/15563650.2021.1993242

Kulkarni RR, Kulkarni PR. Linezolid-induced near-fatal serotonin syndrome during escitalopram therapy: Case report and review of literature. Indian J Psychol Med. 2013;35(3):303-6. doi:10.4103/0253-7176.122245

Mikkelsen N, Damkier P, Arnspang Pedersen S. Serotonin syndrome—A focused review. Basic Clin Pharmacol Toxicol. 2023;133(2):124-9. doi:10.1111/bcpt.13912

Morarasu S, Coman AE, Bologa C, et al. Recognition and management of serotonin toxidrome in the emergency department—Case based review. J Pers Med. 2022;12(12):2069. doi:10.3390/jpm12122069

Nagy A, Nasir A, Haque M, Judge R, Lee J. Therapeutic cyproheptadine regimen in serotonin syndrome: Complications after cardiovascular surgery. Clin Case Rep. 2023;11(7):e7720. doi:10.1002/ccr3.7720

Shakoor M, Ayub S, Ahad A, Ayub Z. Transient serotonin syndrome caused by concurrent use of tramadol and selective serotonin reuptake inhibitor. Am J Case Rep. 2014;15:562-4. doi:10.12659/ajcr.892264

Key words: serotonin syndrome, SSRI, tramadol, clinical management

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