Serotonin Syndrome

Aka: Serotonin Syndrome

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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 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 (e.g. Olanzapine or Zyprexa)
    2. Stimulant Medications
      1. Methylphenidate (Ritalin)
      2. Sibutramine (Meridia)
    3. Antiemetics
      1. Metoclopramide (Reglan)
      2. Ondansetron (Zofran)
      3. Droperidol (Inapsine)
    4. Migraine and Seizure Medications
      1. Triptans (e.g. SumatriptanImitrex)
      2. Ergot Alkaloids
      3. Valproic Acid (Depakote, Depakene)
      4. Carbamazepine (Tegretol)
    5. Synthetic Opioid Analgesics
      1. Tramadol (Ultram)
      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)
    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

V. 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

VI. 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 [PubMed]
  4. Exclude other possible causes
    1. Infectious, metabolic, Substance Abuse or withdrawal
    2. No recent Neuroleptic changes

VII. Differential Diagnosis

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

VIII. Management

  1. Discontinue Serotoninergic medication
  2. Provide supportive care
  3. Treat muscle rigidity, Tremor and hyperthermia
    1. First line
      1. Benzodiazepines
    2. Refractory (severe, critically ill patients)
      1. Intubation
      2. Sedation and Paralytic Agents
  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
    2. Avoid antipyretics
      1. Hyperthermia of Serotonin Syndrome is due to increased muscle activity (not the Hypothalamus)

IX. 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

X. 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. Ables (2010) Am Fam Physician 81(9): 1139-42 [PubMed]
  4. Bodner (1995) Neurology 45:219-23 [PubMed]
  5. Brown (1996) Ann Pharmacother 30:529-33 [PubMed]
  6. Corkeron (1995) Med J Aust 163:481-2 [PubMed]
  7. Erner (2003) Pain Med 4(1): 63-74 [PubMed]
  8. Iqbal (2012) Ann Clin Psychiatry 24(4): 310-8 [PubMed]
  9. Kovich (2015) Am Fam Physician 92(2): 94-100 [PubMed]
  10. Mills (1995) Am Fam Physician 52(5):1475-82 [PubMed]

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Ontology: Malignant Carcinoid Syndrome (C0024586)

Definition (NCI) A syndrome characterized by signs and symptoms caused by advanced carcinoid tumors. They include skin flushing, diarrhea, wheezing, and tachycardia.
Definition (NCI_NCI-GLOSS) A combination of symptoms caused by the release of serotonin and other substances from carcinoid tumors of the gastrointestinal tract. Symptoms may include flushing of the face, flat angiomas (small collections of dilated blood vessels) of the skin, diarrhea, bronchial spasms, rapid pulse, and sudden drops in blood pressure.
Definition (MSH) A symptom complex associated with CARCINOID TUMOR and characterized by attacks of severe flushing of the skin, diarrheal watery stools, bronchoconstriction, sudden drops in blood pressure, edema, and ascites. The carcinoid tumors are usually located in the gastrointestinal tract and metastasize to the liver. Symptoms are caused by tumor secretion of serotonin, prostaglandins, and other biologically active substances. Cardiac manifestations constitute CARCINOID HEART DISEASE. (Dorland, 27th ed; Stedman, 25th ed)
Concepts Disease or Syndrome (T047)
MSH D008303
ICD9 259.2
ICD10 E34.0
SnomedCT 109950000, 190580007, 154717002, 35868009
English Carcinoid Syndrome, Malignant, Carcinoid Syndromes, Malignant, Malignant Carcinoid Syndrome, Malignant Carcinoid Syndromes, Syndromes, Malignant Carcinoid, CARCINOID SYNDROME, Syndrome, Malignant Carcinoid, carcinoid syndrome (diagnosis), carcinoid syndrome, Malignant Carcinoid Syndrome [Disease/Finding], serotonin syndrome, malignant carcinoid syndrome, carcinoids syndrome, syndrome serotonin, Hormonal tumor (disorder), Malignant carcinoid syndrome, Serotonin syndrome, Carcinoid syndrome, Hormone secretion by carcinoid tumor, Excessive serotonin secretion, Hormone secretion by carcinoid tumour, Carcinoid syndrome (disorder), Hormonal tumor, Hormonal tumour, carcinoid; hormone secretion, tumor, carcinoid; syndrome, hormone secretion; carcinoid tumor, secretion; carcinoid tumor, hormone, syndrome; carcinoid, Carcinoid Syndrome, Hormone secretion by carcinoid tumors
Italian Sindrome carcinoide, Sindrome da carcinoide maligno
Japanese カルチノイド症候群, ｶﾙﾁﾉｲﾄﾞｼｮｳｺｳｸﾞﾝ
Swedish Malignt karcinoidsyndrom
Czech maligní karcinoidní syndrom, Karcinoidní syndrom
Finnish Pahanlaatuinen karsinoidioireyhtymä
Russian KARTSINOID ZLOKACHESTVENNYI, КАРЦИНОИД ЗЛОКАЧЕСТВЕННЫЙ
Korean 카르시노이드 증후군
Polish Zespół rakowiaka
Hungarian Carcinoid syndroma
Norwegian Malignt karsinoid-syndrom
Portuguese Síndrome do Carcinoide Maligno, Síndrome carcinóide
Spanish tumor hormonal, tumor hormonal (trastorno), secreción de hormonas por el tumor carcinoide, síndrome carcinoide (trastorno), síndrome carcinoide, síndrome de serotonina, síndrome serotoninérgico, Síndrome carcinoide, Síndrome Carcinoide Maligno
Dutch carcinoïd; hormoonsecretie, tumor, carcinoïd; syndroom, hormoonsecretie; carcinoïdtumor, secretie; carcinoïdtumor, hormoon, syndroom; carcinoïd, Carcinoïdsyndroom, carcinoïdsyndroom, Carcinoïdsyndroom, maligne, Maligne carcinoïdsyndroom, Syndroom, maligne carcinoïd-
German Karzinoid-Syndrom, Malignes Karzinoidsyndrom, Cassidy-Scholte-Syndrom, Karzinoidsyndrom, Biörck-Thorson-Syndrom
French Carcinoïdose, Syndrome carcinoïde, Syndrome carcinoïde malin, Syndrome de Björk
Derived from the NIH UMLS (Unified Medical Language System)

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