Serotonin Syndrome

See Also

Background
History

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

Epidemiology

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

Etiology

Excessive Serotonin levels at the receptor sites
Associated with combinations of Serotoninergic drugs
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. Sumatriptan Imitrex)
  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

Risk Factors

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
Cytochrome P450 Drug Interactions or specific patient Phenotypes making them more susceptible to Serotonin Syndrome
Medical conditions that decrease the available monoamine oxidase
1. Hypertension
2. Atherosclerosis
3. Hyperlipidemia

Diagnosis

Mental Status Changes
1. Confusion or Disorientation (51%)
2. Agitation or irritability (34%)
3. Coma or unresponsiveness (29%)
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%)
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]
Exclude other possible causes
1. Infectious, metabolic, Substance Abuse or withdrawal
2. No recent Neuroleptic changes

Differential Diagnosis

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

Management

Discontinue Serotoninergic medication
Provide supportive care
Treat Muscle rigidity, Tremor and hyperthermia
1. First line
  1. Benzodiazepines
2. Refractory (severe, critically ill patients)
  1. Intubation
  2. Sedation and Paralytic Agents
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
Other medications that have been used for Serotonin Syndrome symptom control
1. Propranolol
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)

Course

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

References

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