• Reference [5]
Symptom Prevalence
Tachycardia / Bradycardia 85%
Hypertension / Hypotension 76%
Confusion / Consciousness impairment 64%
Fever
(Temp > 38°C or 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 or 106.0°F)
9%



  • Reference [5]
Sternbach diagnostic criteria
Serotonin syndrome is diagnosed if ≥ 3 of the below symptoms are present
  • Symptoms must occur with the addition of, or an increase in a known serotonergic agent
  • Other etiologies (e.g. infectious, metabolic, drugs) must be ruled out
  • If a neuroleptic agent was started or increased prior to the onset of symptoms, neuroleptic malignant syndrome is a possibility

    Symptoms
    • 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
  • Symptoms must occur with the addition of, or an increase in a known serotonergic agent
  • Other etiologies (e.g. infectious, metabolic, drugs) must be ruled out
  • 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
  • Symptoms must occur in the presence of a serotonergic agent

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







  • Includes dextromethorphan, triptans, antiemetics, SNRIs, and agents inhibiting the metabolism of antidepressants
  • Reference [5]
Most common cause of serotonin syndrome in a review of 299 cases
Suspected cause Proportion of 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%



  • Reference [1,2]
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)