Serotonin Syndrome

Aka: Serotonin Syndrome, Serotonergic Medication

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II. Background: History

  1. Libby Zion was a young patient who died of Serotonin Syndrome in 1984 and set historic precedent
    1. Provider education regarding Serotonin Syndrome
    2. Principal case that limited intern and resident shift hours
    3. http://en.wikipedia.org/wiki/Libby_Zion_law

III. Epidemiology

  1. Complicates 14-16% of SSRI Overdoses
    1. Isbister (2004) J Toxicol Clin Toxicol 42(3): 277-85 [PubMed]

IV. Etiology

  1. Excessive Serotonin levels at the 5HT-2A receptor sites
  2. Associated with combinations of Serotoninergic drugs (e.g. SSRI, TCA, MAOI)
  3. Exacerbated by drugs that increase Serotonin levels (see risk factors below)

V. Risk Factors: General

  1. Medications with serotonergic effects (see below)
    1. Combined use of multiple serotonergic drugs
    2. Inadequate washout period between transitioning to a new serotonergic drug
    3. Higher Incidence with Monoamine Oxidase Inhibitors, St. John's Wort and Linezolid
  2. Cytochrome P450 Drug Interactions or specific patient Phenotypes
    1. Increases susceptibility to Serotonin Syndrome
  3. Medical conditions that decrease the available monoamine oxidase
    1. Hypertension
    2. Atherosclerosis
    3. Hyperlipidemia

VI. Risk Factors: Serotonergic Medications

  1. Psychiatric medications
    1. Selective Serotonin Reuptake Inhibitors - SSRI (e.g. Paroxetine/Paxil or Fluoxetine/Prozac)
    2. Serotonin-Norepinephrine Reuptake Inhibitors - SNRI (e.g. Venlafaxine - Effexor)
    3. MAO Inhibitors (e.g. Phenelzine, Selegiline or Nardil)
      1. High risk for Serotonin Syndrome when combined with other serotinergic agents
    4. Tricyclic Antidepressants (e.g. Amitriptyline, Clomipramine, Imipramine)
    5. Lithium
    6. Buspar
    7. Trazodone
      1. Lower risk of Serotonin Syndrome (non-Serotonin 2A stimulation)
    8. Some Antipsychotic Medications (e.g. Olanzapine or Zyprexa)
  2. Stimulant Medications
    1. Methylphenidate (Ritalin)
    2. Sibutramine (Meridia)
  3. Antiemetics
    1. Metoclopramide (Reglan)
    2. Ondansetron (Zofran)
      1. Lower risk of Serotonin Syndrome (non-Serotonin 2A stimulation)
    3. Droperidol (Inapsine)
  4. Migraine and Seizure Medications
    1. Triptans (e.g. SumatriptanImitrex)
      1. Lower risk of Serotonin Syndrome (non-Serotonin 2A stimulation)
    2. Ergot Alkaloids
    3. Valproic Acid (Depakote, Depakene)
    4. Carbamazepine (Tegretol)
  5. Synthetic Opioid Analgesics
    1. Tramadol (Ultram)
      1. Higher risk for Serotonin Syndrome
    2. Meperidine (Demerol)
    3. Fentanyl (Duragesic)
    4. Methadone
    5. Dextromethorphan
    6. Rare case reports with Buprenorphine (Suboxone), Hydromorphone, Oxycodone or Hydrocodone
  6. Muscle Relaxants
    1. Cyclobenzaprine (Flexeril)
    2. Metaxalone (Skelaxin)
  7. Miscellaneous medications
    1. Chlorpheniramine
    2. Linezolid (Zyvox) - MAO Inhibitor effect
    3. Reserpine
    4. Ritonavir (Norvir)
    5. Locaserin (weight loss agent)
  8. Herbals and supplements
    1. St. John's Wort
    2. Ginkgo Biloba
    3. Ginseng
    4. L-Tryptophan
    5. 5-Hydroxytryptophan (dietary supplement) - Serotonin precursor
    6. Yohimbine
  9. Recreational drugs
    1. Cocaine
    2. 3,4-methylenedioxmethamphetamine (Ecstacy)
    3. Methamphetamine

VII. Signs

  1. Mental Status Changes
    1. Confusion or Disorientation (51%)
    2. Agitation or irritability (34%)
    3. Somnolence, coma or unresponsiveness (29%)
  2. Autonomic changes
    1. Fever or hyperthermia (45%)
      1. Muscle hyperactivity and decreased heat dissipation
    2. Diaphoresis (45%)
    3. Sinus Tachycardia (36%)
    4. Hypertension (35%)
    5. Mydriasis (28%) or unreactive pupils (20%)
    6. Tachypnea (26%)
    7. Nausea (23%) or Vomiting
  3. Neuromuscular changes
    1. Myoclonic Jerks (58%)
    2. Hyperreflexia (52%)
    3. Muscle rigidity (51%)
    4. Restlessness or hyperactivity (48%)
    5. Tremor (43%)
    6. Ataxia or Incoordination (40%)
    7. Clonus (23%)
      1. Spontaneous Clonus with a history of Serotoninergic agent use is pathognomonic for Serotonin Syndrome
      2. Dunkley (2003) QJM 96 (9): 635-642 [PubMed]
  4. Exclude other possible causes
    1. Infectious, metabolic, Substance Abuse or withdrawal
    2. No recent Neuroleptic changes

VIII. Precautions

  1. Subtle Serotonin Syndrome presentations are far more common than severe Serotonin Syndrome (e.g. Delirium, hyperthermia)
  2. Remain alert for more subtle findings (e.g. Agitation, diaphoresis, Tremor)
    1. Focus on times of dose increase and times of new medications (especially in combination)

IX. Diagnosis: Hunter Serotonin Criteria

  1. Major Criteria
    1. Ingestion of serotinergic agent
  2. Other Criteria (at least one present)
    1. Tremor AND Hyperreflexia
    2. Spontaneous Clonus
    3. Ocular Clonus or Inducible Clonus AND one of the following
      1. Hypertonia AND Body Temperature > 100.4 F (38 C) OR
      2. Agitation
      3. Diaphoresis
  3. Efficacy
    1. Test Sensitivity: 84%
    2. Test Specificity: 97%
  4. References
    1. Dunkley (2003) QJM 96(9):635-42 +PMID: 12925718 [PubMed]

X. Differential Diagnosis

  1. Meningitis or Encephalitis
  2. Anticholinergic Syndrome
  3. Malignant Hyperthermia
  4. Seizure Disorder
  5. Neuroleptic Malignant Syndrome
    1. Occurs with Dopamine blocking agents
    2. Classic triad of fever, Muscle rigidity and Altered Mental Status

XI. Management

  1. Discontinue Serotoninergic medications
  2. Provide supportive care
  3. Treat Muscle rigidity, Tremor and hyperthermia
    1. First line
      1. Benzodiazepines decrease Agitation and adrenergic stress
    2. Refractory Hyperthermia (severe, critically ill patients)
      1. Active Cooling of Patient
      2. Endotracheal Intubation
      3. Sedation and Paralytic Agents (non-depolarizing Neuromuscular Blockers, e.g. Rocuronium)
  4. Consider serotonin Antagonists
    1. Cyproheptadine (Periactin)
      1. Initial protocol
        1. Bolus: 12 mg oral bolus dose for 1 dose (may be crushed and placed down NG or OG)
        2. Continued symptoms: 2 mg every 2 hours until symptoms controlled
        3. Expect patient sedation with Cyproheptadine dosing
      2. Maintenance protocol (once stabilized)
        1. Dose: 8 mg every 6 hours or 4 mg every 2-4 hours
        2. Maximum: 0.5 mg/kg/day
  5. Other medications that have been used for Serotonin Syndrome symptom control
    1. Propranolol
  6. Precautions
    1. Avoid Antipsychotics (e.g. Haloperidol) as has serotonergic effects and may exacerbate condition
    2. Avoid antipyretics (ineffective)
      1. Hyperthermia of Serotonin Syndrome is due to increased Muscle activity (not the Hypothalamus)

XII. Course

  1. Many cases likely go undiagnosed and resolve spontaneously when patients stop the medications themselves
  2. Resolution after stopping Serotoninergic medication
    1. Within 24 hours in 70% of cases
    2. Within 96 hours in almost all cases
  3. High acuity care
    1. Intensive Care admission in up to 40% of cases
    2. Mechanical Ventilation in up to 25% of cases
  4. Rarely fatal: 11 deaths in literature

XIII. References

  1. Herbert and Jhun in Herbert (2015) EM:Rap 15(4):14
  2. Nordt and Swadron in Majoewsky (2012) EM:Rap 12(2): 3
  3. Otter and Tomaszewski (2018) Crit Dec Emerg Med 32(11): 28
  4. (2022) Presc Lett 29(9): 51-2
  5. Ables (2010) Am Fam Physician 81(9): 1139-42 [PubMed]
  6. Bodner (1995) Neurology 45:219-23 [PubMed]
  7. Brown (1996) Ann Pharmacother 30:529-33 [PubMed]
  8. Corkeron (1995) Med J Aust 163:481-2 [PubMed]
  9. Erner (2003) Pain Med 4(1): 63-74 [PubMed]
  10. Iqbal (2012) Ann Clin Psychiatry 24(4): 310-8 [PubMed]
  11. Kovich (2015) Am Fam Physician 92(2): 94-100 [PubMed]
  12. Mills (1995) Am Fam Physician 52(5):1475-82 [PubMed]

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