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serotonin syndrome (serotonism)

Etiology: 1) excess serotonin or increased sensitivity to serotonin 2) increased serotonin production - L tyrptophan, cocaine, amphetamines, phentermine 3) inhibition of serotonin reuptake - SSRI, SNRI, tricyclic antidepressants (TCA), bupropion, nefazodone, trazodone, dextromethorphan, meperidine, pentazocine, St John's wort, tramadol, phentermine, granisetron, ondansetron, chlopheniramine 4) inhibition of serotonin metabolism - monoamine oxidase inhibitors, linezolid, isocarboxazid, phenelzine, selegine, tranylcypromine, buspirone, rasagiline, safinamide 5) increased serotonin release - dextromethorphan, meperidine, oxycodone, L-dopa, amphetamines, phentermine, methyleledioxymethamphetamine (MDMA, Ecstasy), mirtazapine 6) serotonin receptor agonists - buspirone, lysergic acid diethylamide (LSD), meperidine, fentanyl, lithium, metoclopramide, dihydroergotamine, triptans, mirtazapine, trazodone, ondansetron, granisetron, dolasetron, palonosetron 7) inhibition of elimination of serotonin via inhibition of cyt P450 isozymes - CYP2D6 - inhibitors: fluoxetine, sertraline - substrates: dextromethorphan, oxycodone, phentermine, risperidone, tramadol - CYP3A4 - inhibitors: ciprofloxacin, ritonavir - substrates: methadone, oxycodone, venlafaxine - CYP2C19 - inhibitors: fluconazole - substrates: citalopram 8) generally occurs when 2 or more drugs that affect the serotonin system through different mechanisms are prescribed [3] - monoamine oxidase inhibitors (MAOi) with SSRI, SNRI, TCA, opiates - SSRI with MAOi, SNRI, TCA, opiates, or triptans - fluoxetine with carbamazepine, phentermine, fentanyl - SNRI with MAOi, TCA, opiates, or triptans - venlafaxine with lithium carbonate, calcineurin inhibitors, mirtazqpine, or tranylcypromine - venlafaxine with mirtazapine & tramadol, amitriptyline & meperidine, methadone & fluoxetine or sertraline, tramadole & trazodone & quetiapine - opiates with MAOi, SSRI, SNRI or triptans - tramadol with mirtazapine & olanzapine - dextromethorphan with SSRI, amitriptyline, or chlorpheniramine - dextromethorphan with risperidone & amitriptyline - olanzapine with lithium carbonate & citalopram - risperidone with fluoxetine or paroxetine - ciprofloxacin with venlafaxine & methadone - fluconazole with citalopram - linezolid with SSRI or tapentodol Pathology: - autonomic hyperactivity - hemodynamic changes - neuromuscular disorder - mental status changes - potentially life-threatening [10] Clinical manifestations: 1) mild: a) nausea/vomiting b) flushing c) sweating, diaphoresis 2) headache 3) dizziness 4) agitation, restlessness, anxiety 5) confusion, inattention 6) ataxia 7) neuromuscular hyperexcitability a) myoclonus (spontaneous clonus), muscle twitching, muscle rigidity - especially lower extremities b) hyperreflexia c) tremor d) shivering e) hyperthermia, due to excessive muscular activity - temperature may be > 105.8 F (41C) [10] 8) ocular clonus - slow continuous horizontal eye movements 9) hypertension or hypotension 10) tachycardia, tachypnea 12) diarrhea (late manifestation) 12) mydriasis 13) onset within 24 hours of initiating or increasing dose of offending agent - average onset < 12 hours [10] 14) gastrointestinal prodrome, hyperactive bowel sounds 15) sleep disturbance [10] Complications: - disseminated intravascular coagulation - rhabdomyolysis - multiple organ failure - shock - coma [10] Diagnostic criteria: - see Hunter criteria Management: 1) discontinuation of offending agent(s) 2) most cases resolve in 24-72 hours 3) supportive care - oxygen therapy - intravenous fluids - cardiac monitoring, including QTc & QRS duration [10] - external cooling if temperature > 40 C - esmolol for hypertension 4) activated charcoal to assist with gastrointestinal decontamination may be considered 5) severe cases a) sedation, paralyzing agents, mechanical ventilation may be required in cases of recent exposure b) benzodiazepine c) serotonin antagonists have been used (no strong supporting evidence for their use) - cyproheptadine, chlorpromazine 6) antipyretic therapy NOT recommended

General

syndrome

References

  1. Kaiser Permanente, Northern California Regional Pharmacy & Therapeutics Committee
  2. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
  3. Prescriber's Letter 13(9): 2006 Serotonin Syndrome Detail-Document#: 220905 (subscription needed) http://www.prescribersletter.com
  4. Medical Knowledge Self Assessment Program (MKSAP) 14, 17. American College of Physicians, Philadelphia 2006. 2015
  5. Prescriber's Letter 16(10): 2009 Facts About Serotonin Syndrome Detail-Document#: 251026 (subscription needed) http://www.prescribersletter.com
  6. Gillman PK. Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review. Headache. 2010 Feb;50(2):264-72 PMID: 19925619
  7. Werneke U, Jamshidi F, Taylor DM, Ott M. Conundrums in neurology: diagnosing serotonin syndrome - a meta-analysis of cases. BMC Neurol. 2016 Jul 12;16:97. doi: 10.1186/s12883-016-0616-1. PMID: 27406219 Free PMC Article
  8. Dobry Y, Rice T, Sher L. Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors. Int J Adolesc Med Health. 2013;25(3):193-9. Review. PMID: 24006318
  9. Paauw DS Why Is Serotonin Syndrome on the Rise? Medscape - Dec 02, 2020 https://www.medscape.com/viewarticle/941567
  10. Sinert RH Fast Five Quis: Serotonin Syndrome Medscape. 2121. June 4. https://reference.medscape.com/viewarticle/951841 - Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17;352(11):1112-20 PMID: 15784664 Review https://www.nejm.org/doi/10.1056/NEJMra041867
  11. Khan SS, Cole SP. Serotonin Syndrome. Medscape. 2020. Sept 21 https://emedicine.medscape.com/article/2500075-overview
  12. Foong AL, Grindrod KA, Patel T et al. Demystifying serotonin syndrome (or serotonin toxicity). Can Fam Physician. 2018;64(10):720-727 PMID: 30315014 PMCID: PMC6184959 Free PMC article
  13. Scotton WJ, Hill LJ, Williams AC et al. Serotonin syndrome: pathophysiology, clinical features, management, and potential future directions. Int J Tryptophan Res. 2019;12:1178646919873925 PMID: 31523132 PMCID: PMC6734608 Free PMC article https://journals.sagepub.com/doi/10.1177/1178646919873925
  14. Uddin MF, Alweis R, Shah SR et al. Controversies in serotonin syndrome diagnosis and management: a review. J Clin Diagn Res. 2017;11(9):OE05-OE07 PMID: 29207768 PMCID: PMC5713790 Free PMC article https://jcdr.net/article_fulltext.asp?issn=0973-709x&year=2017&volume=11&issue=9&page=OE05&issn=0973-709x&id=10696
  15. Malcolm B, Thomas K. Serotonin toxicity of serotonergic psychedelics. Psychopharmacology (Berl). 2021. PMID: 34251464