Symptom Prevalence
Tachy/bradycardia 85%
Hyper/hypotension 76%
Confusion/
consciousness impairment
64%
Fever
(Temp > 38°C (100.4°F))
60%
Tremor 59%
Hyperreflexia 57%
Agitation/restlessness 56%
Diaphoresis 53%
Rigidity/hypertonicity 45%
Myoclonus 42%
Mydriasis (pupil dilation) 34%
Clonus Spontaneous - 27%
Inducible - 7%
Dyspnea
(RR > 20 or hypoxia)
26%
Diarrhea 15%
Rhabdomyolysis 14%
Insomnia 10%
Hyperthermia
(Temp > 41.1°C (106.0°F))
9%




Sternbach diagnostic criteria
Serotonin syndrome is diagnosed if ≥ 3 of the following symptoms are present. (Must occur with the addition of, or an increase in a known serotonergic agent. Also, other etiologies (e.g. infectious, metabolic, drugs) must be ruled out, and if a neuroleptic agent was started or increased prior to the onset of symptoms, neuroleptic malignant syndrome is a possibility.)

  • Mental status changes
  • Agitation
  • Myoclonus
  • Hyperreflexia
  • Diaphoresis
  • Shivering
  • Tremor
  • Diarrhea
  • Incoordination
  • Fever
Radomski diagnostic criteria
Serotonin syndrome is diagnosed if ≥ 4 major criteria or 3 major criteria + 2 minor criteria are present. (Must occur with the addition of, or an increase in a known serotonergic agent. Also, other etiologies (e.g. infectious, metabolic, drugs) must be ruled out, and if a neuroleptic agent was started or increased prior to the onset of symptoms, neuroleptic malignant syndrome is a possibility.)

Major criteria
  • Consciousness impairment
  • Elevated mood
  • Semicoma/coma
  • Myoclonus
  • Tremor
  • Shivering
  • Rigidity
  • Hyperreflexia
  • Fever
  • Sweating
Minor criteria
  • Restlessness
  • Insomnia
  • Incoordination
  • Dilated pupils
  • Akathisia
  • Tachycardia
  • Tachy/dyspnea
  • Diarrhea
  • Hyper/hypotension
Hunter diagnostic criteria
Serotonin syndrome is present if any one of the following criteria is met (Must occur in the presence of a serotonergic agent)

  • Spontaneous clonus
  • Inducible clonus AND agitation OR diaphoresis
  • Ocular clonus AND agitation OR diaphoresis
  • Tremor AND hyperreflexia
  • Hypertonic AND temperature > 38°C (100.4°F) AND ocular clonus OR inducible clonus







Most common cause of serotonin syndrome
in a review of 299 cases
Combination of antidepressant and opiate 16%
Overdose 15%
Combination of antidepressant and
other serotonergic agent*
13%
Combination of different antidepressants 8%
Combination of antidepressant and linezolid 7%
Changing antidepressants 5%
Combination of antidepressant and
methylene blue
5%
Start of antidepressants 5%
Start/stop second generation antipsychotic
in the presence of another serotonergic agent*
3%




Medications with serotonergic activity
Antibiotics
Anticonvulsants
Antidepressants
  • Selective Serotonin Reuptake Inhibitors (SSRIs)
    • Citalopram (Celexa®)
    • Escitalopram (Lexapro®)
    • Fluoxetine (Prozac®)
    • Fluvoxamine (Luvox®)
    • Paroxetine (Paxil®)
    • Sertraline (Zoloft®)
  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
    • Desvenlafaxine (Pristiq®)
    • Duloxetine (Cymbalta®)
    • Venlafaxine (Effexor®)
  • Norepinephrine-Dopamine Reuptake Inhibitors
    • Bupropion (Wellbutrin®) - based on case reports
  • Tricyclic antidepressants (TCAs)
    • Amitriptyline (Elavil®)
    • Clomipramine (Anafranil®)
    • Desipramine (Norpramin®)
    • Doxepin
    • Imipramine (Tofranil®)
    • Nortriptyline (Pamelor®)
  • Serotonin modulators
    • Trazodone (Desyrel®)
    • Vilazodone (Viibryd®)
  • Other
    • Mirtazapine (Remeron®)
    • Vortioxetine (Brintellix®)
Anti-anxiety
Anti-nausea/vomiting (Antiemetics)
  • Granisetron (Granisol®, Sancuso®)
  • Metoclopramide (Reglan®)
  • Ondansetron (Zofran®)
Bipolar medications
Cough Suppressants
  • Dextromethorphan (DM) - in over-the-counter cough suppressants
Dietary supplements (herbal products)
  • Ginseng
  • Tryptophan
  • St. John's wort - Hypericum perforatum
HIV medications
  • Ritonavir (Kaletra®) - through CYP3A4 inhibition
Illicit drugs
  • Amphetamines
  • Cocaine
  • Ecstasy - MDMA
  • LSD - lysergic acid diethylamide
  • Foxy Methoxy - 5-methoxydiisopropyltryptamine
  • Syrian rue
Migraine medications
  • Almotriptan (Axert®)
  • Dihydroergotamine (Migranal®, D.H.E.-45®)
  • Eletriptan (Relpax®)
  • Ergotamine (Cafergot®)
  • Frovatriptan (Frova®)
  • Naratriptan (Amerge®)
  • Rizatriptan (Maxalt®)
  • Sumatriptan (Imitrex®)
  • Zolmitriptan (Zomig®)
Monoamine oxidase inhibitors (MAOI)
  • Isocarboxazid (Marplan®) - nonselective [type A and B]
  • Linezolid (Zyvox®) - nonselective [type A and B]
  • Moclobemide - selective [type A]
  • Methylene blue
  • Phenelzine (Nardil®) nonselective [type A and B]
  • Procarbazine (Matulane®)
  • Rasagiline (Azilect®) selective [type B]
  • Selegiline (Eldepryl®) selective [type B] at normal doses, nonselective at higher doses
  • Tranylcypromine (Parnate®) nonselective [type A and B]
Muscle relaxers
  • Cyclobenzaprine (Flexeril®)
  • Metaxalone (Skelaxin®) [3,4]
Pain medications
  • Fentanyl (Duragesic®, Actiq®)
  • Meperidine (Demerol®)
  • Pentazocine (Talwin®)
  • Tramadol (Ultram®)
Parkinson's medications
  • Levodopa-carbidopa (Sinemet®) - based on case reports
Stimulants/ADHD medications
  • Amphetamine-dextroamphetamine (Adderall®)
  • Dexmethylphenidate (Focalin®)
  • Dextroamphetamine (Dexedrine®)
  • Methylphenidate (Ritalin®, Concerta®)
Weight loss medications (appetite suppressants)



References: