Serotonin Syndrome & NMS

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Serotonin Syndrome

Serotonin Syndrome is also known as serotonin toxicity caused by increased serotonergic activity leading to a classic triad of AMS, autonomic hyperactivity, and neuromuscular abnormalities

Causative agents (all lead to stimulation of 5-HT receptors)

  • Antidepressants (SSRIs, SNRIs and MAOIs) - most common

  • Analgesics (fentanyl, methadone, and tramadol)

  • Antiemetics (ondansetron and metoclopramide)

  • Cold medications (dextromethorphan and pseudoephedrine)

  • Illicit substances (cocaine, ecstasy, methamphetamine, LSD)

  • Others (triptans, ergots, bromocriptine, linezolid, carbamazepine, cyclobenzaprine and methylene blue)

History to Gather

  • Detailed medication history including new medications, change in dosing, illicit substance use, and supplementation.

  • Timing of ingestion - syndrome presents within 6-24 hours of intake

Physical Exam Findings

  • Vital sign abnormalities: tachycardia, hypertension, hyperthermia

  • General: confused or agitated, tremulous

  • HEENT: ocular clonus, mydriasis

  • Skin: diaphoresis

  • GI: vomiting and diarrhea

  • Neuro: hyperreflexia and muscle clonus

Evaluation

  • Clinical diagnosis using Hunter Serotonin Toxicity Criteria

  • Lab workup:

    • CBC - commonly have leukocytosis

    • BMP - assess for electrolyte abnormalities and renal dysfunction

    • CK - assess for rhabdomyolysis

    • VBG (in more severe cases) - may develop acidosis

Management

Mainstay treatment: discontinue causative agent supportive care

  • IVF if dehydrated

  • External cooling measures, as antipyretics are ineffective

  • O2 as needed

  • Benzodiazepines for agitation (Dexmedetomidine for more severe cases, limited evidence

Other considerations:

  • For severe/refractory autonomic instability - esmolol, nicardipine or nitroprusside for extreme hypertension refractory to pain/agitation control

  • Pressors for hypotension (avoid dopamine)

  • Serotonergic receptor antagonists - rarely used clinically

    • Cyproheptadine - no controlled studies and limited evidence, only available orally

      • Has been showed to improve symptoms in mild cases

      • 12 mg initially followed by 2mg q2hr

    • Chlorpromazine - very limited evidence, can be given IM

      • Risk of hypotension and dystonic reactions

      • Do not give if NMS is on differential

Disposition

Cases can range from mild, only requiring observation, to severe, requiring ICU level care. Generally, patients recover fully. The duration of symptoms depends on the causative agent and its pharmacology. Patients can be safely discharged when vital signs have normalized and patient has returned to mental status baseline with no signs of hyperreflexia or clonus.

Hunter Serotonin Toxicity Criteria (Sensitivity: 84% Specificity: 97%)

Must have recent exposure to a serotonergic drug plus 1 of the following:

  • Spontaneous clonus

  • Inducible clonus AND (agitation or

  • diaphoresis)

  • Ocular Clonus AND (agitation or

  • diaphoresis)

  • Tremor AND hyperreflexia

  • Hypertonia AND temperature >38 AND

  • (ocular clonus or inducible clonus)

Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome - caused by dopamine antagonism or rapid withdrawal of dopamine agonist medications, leading to AMS, muscle rigidity, fever, and autonomic instability. Between 0.01-0.04% of all patients treated with antipsychotics develop NMS

Causative agents

  • Intoxication with the following:

    • All antipsychotics

    • Antiemetics (Droperidol,

    • Domperidone, Metoclopramide,

    • Promethazine, Prochlorperazine)

    • Others (Tetrabenazine, Reserpine, Amoxapine, Diatrizoate, Lithium,

    • Phenelzine, Dosulepin, Trimipramine, Desipramine)

  • Rapid withdrawal from the following:

    • Levodopa

    • Amantadine

    • Tolcapone

History - Detailed medication history including new medications, change in dosing, illicit substance use, and supplementation.

Physical Exam

  • Vital sign abnormalities: tachycardia, hypertension, hyperthermia

  • General: confused or agitated, tremulous

  • Skin: diaphoresis

  • Neuro: “lead pipe” rigidity, dystonia, dysphagia, dysarthria

Evaluation

Clinical diagnosis - International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome is helpful

Lab workup

  • CBC - commonly have leukocytosis

  • CMP - assess for electrolyte abnormalities, liver dysfunction, and renal dysfunction

  • CK - assess for rhabdomyolysis

  • VBG (in more severe cases) - may develop acidosis

Management

  • Discontinue causative agent if dopamine antagonist toxicity or restart dopaminergic agent if rapid withdrawal is the cause of NMS

  • Supportive care

    • IVF if dehydrated

    • External cooling measures, as antipyretics are ineffective

    • O2 as needed

    • Benzodiazepines for agitation

  • Specific pharmacotherapy (controversial):

    • Bromocriptine or amantadine: dopaminergic agents, some meta-analysis and case reports show decreased mortality in severe cases

    • Bromocriptine: 2.5mg PO q8-12hr, max dose 45mg/day

    • Amantadine: 100mg PO initially; max dose 200mg q12hr

    • Dantrolene: muscle relaxant for cases with extreme rigidity, use in combination (not as monotherapy) with dopaminergic agents in severe cases

      • 1-2.5 mg/kg initially followed by 1mg/kg q6hrs

Disposition

NMS can be very severe and usually requires ICU level care.

Potential complications include dysrhythmias, respiratory failure, DIC, seizures, and hepatic failure. Workup for complications should be initiated on a case by case basis.

International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome > 74 points (out of 100) used to determine presence of NMS (Sensitivity: 69.6% Specificity: 90.7%)

  • Exposure to a dopamine antagonist or withdrawal of a dopamine agonist in the prior 72 hours: 20 points

  • Hyperthermia (>100.4 F or >38C) on at least two occasions, measured orally: 18 points

  • Rigidity: 17 points

  • Mental status alteration (reduced or fluctuating level of consciousness): 13 points

  • Creatinine kinase elevation at least four times the upper limit of normal: 10 points

  • Sympathetic nervous system lability, defined as at least two of the below: 10 points

  • Blood pressure elevation (systolic or diastolic >25% above baseline)

  • Blood pressure fluctuation (>25% systolic or >20% diastolic change in 24 hours)

  • Diaphoresis

  • Urinary incontinence

  • Hypermetabolic state (defined as heart rate increase >25% above baseline and respiratory rate increase >50% above baseline): 5 points

  • Negative evaluation for other toxic, metabolic, infectious, or neurologic causes: 7 points

Differentiating Serotonin Syndrome and NMS

References

  1. Chiew AL, Isbister GK. Management of serotonin syndrome (toxicity). Br J Clin Pharmacol. 2024; 1-8. doi:10.1111/bcp.16152

  2. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 2003; 96:635–642. 

  3. Gillman PK. Successful treatment of serotonin syndrome with chlorpromazine. Med J Aust 1996; 165:345–346. 

  4. Gurrera RJ, Mortillaro G, Velamoor V, Caroff SN. A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome. J Clin Psychopharmacol. 2017 Feb;37(1):67-71. doi: 10.1097/JCP.0000000000000640. PMID: 28027111. 

  5. Iqbal MM, Basil MJ, Kaplan J, Iqbal MT. Overview of serotonin syndrome. Ann Clin Psychiatry 2012; 24:310–318. 

  6. Kornhuber J, Weller M: Neuroleptic malignant syndrome. Curr Opin Neurol 1994, 7:353-357. 


  7. Kuhlwilm L, Schönfeldt-Lecuona C, Gahr M, Connemann BJ, Keller F, Sartorius A. The neuroleptic malignant syndrome-a systematic case series analysis focusing on therapy regimes and outcome. Acta Psychiatr Scand. 2020 Sep;142(3):233-241. doi: 10.1111/acps.13215. Epub 2020 Aug 2. PMID: 32659853.

  8. Nguyen H, Pan A, Smollin C, Cantrell LF, Kearney T. An 11-year retrospective review of cyproheptadine use in serotonin syndrome cases reported to the California Poison Control System. J Clin Pharm Ther. 2019; 44(2): 327-334. doi:10.1111/jcpt.12796 

  9. Reulbach, U., Dütsch, C., Biermann, T. et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care 11, R4 (2007). https://doi.org/10.1186/cc5148

  10. Strawn, J. R., Keck, P. E., & Caroff, S. N. (2007). Neuroleptic Malignant Syndrome. American Journal of Psychiatry, 164(6), 870–876. https://doi.org/10.1176/ajp.2007.164.6.870

  11. Simon LV, Torrico TJ, Keenaghan M. Serotonin Syndrome. [Updated 2024 Mar 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482377/

  12. Simon LV, Hashmi MF, Callahan AL. Neuroleptic Malignant Syndrome. [Updated 2023 Apr 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482282/

Authorship

Written by, Graphics by: Victoria Martell, MD PGY-1, University of Cincinnati Department of Emergency Medicine

Peer Review, Editing, Posting by: Jeffery Hill, MD MEd, Associate Professor, University of Cincinnati Department of Emergency Medicine

Cite as: Martell, V., Hill, J., Serotonin Syndrome & NMS. TamingtheSRU. www. tamingthesru.com/blog/core-content/serotonin-syndrome-amp-nms. 1/5/2025.