Serotonin Syndrome

1. See Also
   1. Serotonin
   2. Neurotransmitter Physiology
   3. Neuroleptic Malignant Syndrome
   4. Malignant Hyperthermia
2. 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
3. Etiology
   1. Excessive Serotonin levels at the receptor sites
   2. Associated with combinations of Serotoninergic drugs
   3. Exacerbated by drugs that increase Serotonin levels
      1. Psychiatric medications
         1. Selective Serotonin Reuptake Inhibitors - SSRI (e.g. Paroxetine - Paxil)
         2. Serotonin-Norepinephrine Reuptake Inhibitors - SNRI (e.g. Venlafaxine - Effexor)
         3. MAO inhibitors (e.g. Phenelzine or Nardil)
         4. Tricyclic Antidepressants (e.g. Amitriptyline)
         5. Lithium
         6. Buspar
         7. Trazodone
         8. Some Antipsychotic medications
      2. Stimulant Medications
         1. Methylphenidate (Ritalin)
         2. Sibutramine (Meridia)
      3. Antiemetics
         1. Metoclopramide (Reglan)
         2. Ondansetron (Zofran)
      4. Migraine and Seizure Medications
         1. Triptans (e.g. SumatriptanImitrex)
         2. Ergot Alkaloids
         3. Valproic Acid (Depakote)
         4. Carbamazepine (Tegretol)
      5. Analgesics
         1. Tramadol (Ultram)
         2. Cyclobenzaprine (Flexeril)
         3. Meperidine (Demerol)
         4. Fentanyl (Duragesic)
      6. Herbals and supplements
         1. St. John's Wort
         2. Ginkgo Biloba
      7. Miscellaneous medications
         1. Dextromethorphan
         2. Cocaine
         3. 3,4-methylenedioxmethamphetamine (Ecstacy)
         4. Methamphetamine
         5. Linezolid (Zyvox) - MAO inhibitor effect
         6. L-Tryptophan
         7. 5-Hydroxytryptophan (dietary supplement) - Serotonin precursor
4. Risk Factors
   1. Medications with serotonergic effects (see above)
      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 making them more susceptible to Serotonin Syndrome
   3. Medical conditions that decrease the available monoamine oxidase
      1. Hypertension
      2. Atherosclerosis
      3. Hyperlipidemia
5. Diagnosis
   1. Mental Status Changes
      1. Confusion or disorientation (51%)
      2. Agitation or irritability (34%)
      3. Coma or unresponsiveness (29%)
   2. Autonomic changes
      1. Fever or hyperthermia (45%)
      2. Diaphoresis (45%)
      3. Sinus Tachycardia (36%)
      4. Hypertension (35%)
      5. Mydriasis (28%) or unreactive pupils (20%)
      6. Tachypnea (26%)
      7. Nausea (23%)
   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
   4. Exclude other possible causes
      1. Infectious, metabolic, Substance Abuse or withdrawal
      2. No recent Neuroleptic changes
6. Differential Diagnosis
   1. Anticholinergic Syndrome
   2. Malignant Hyperthermia
   3. Neuroleptic Malignant Syndrome
7. Management
   1. Discontinue Serotoninergic medication
   2. Provide supportive care
   3. Treat muscle rigidity, Tremor and hyperthermia
      1. First line: Benzodiazepines
      2. Refractory: Paralytic Agents (severe, critically ill patients)
   4. Consider Serotonin antagonists
      1. Cyproheptadine (Periactin)
         1. Initial protocol
            1. Bolus: 12 mg oral bolus dose for 1 dose
            2. Continued symptoms: 2 mg every 2 hours until symptoms controlled
         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
8. 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
9. References
   1. Nordt and Swadron in Majoewsky (2012) EM:RAP 12(2): 3
   2. Ables (2010) Am Fam Physician 81(9): 1139-42
   3. Erner (2003) Pain Med 4(1): 63-74
   4. Mills (1995) Am Fam Physician 52(5):1475-82
   5. Corkeron (1995) Med J Aust 163:481-2
   6. Brown (1996) Ann Pharmacother 30:529-33
   7. Bodner (1995) Neurology 45:219-23