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Serotonin Toxicity (Hunter Criteria)

Serotonin Toxicity (Hunter Criteria): Suspected serotonin toxicity → Identify all serotonergic drugs → Hunter criteria met? → Criteria met: stop ALL ser...

Pathway Overview

16 steps

Algorithm Steps

16 total

  1. 01Start

    Suspected serotonin toxicity

    Serotonergic drug (overdose, interaction, new drug or dose increase) with new neuromuscular, autonomic or mental state signs.

  2. 02Action

    Identify all serotonergic drugs

    Severe toxicity almost always follows a combination, most often an MAOI (including moclobemide) with an SSRI or SNRI.

    • SSRIs; SNRIs (venlafaxine, desvenlafaxine, duloxetine); clomipramine, imipramine
    • MAOIs: phenelzine, tranylcypromine, moclobemide; also linezolid and methylene blue
    • Opioids: tramadol, tapentadol, pethidine, fentanyl, dextromethorphan
    • MDMA, amphetamines, lithium, St John's wort, tryptophan
    • Antipsychotic started or dose increased: consider NMS instead
  3. 03Decision

    Hunter criteria met?

    Serotonergic drug plus any ONE: spontaneous clonus; inducible or ocular clonus with agitation or sweating; tremor with hyperreflexia; hypertonia, temperature above 38 °C and ocular or inducible clonus. Derived in overdose. Stable dose (low risk): count only spontaneous clonus, ocular clonus with agitation or sweating, or rigidity with temperature above 38 °C and clonus, after other causes are excluded.

    • Spontaneous clonus
    • Inducible clonus AND (agitation OR diaphoresis)
    • Ocular clonus AND (agitation OR diaphoresis)
    • Tremor AND hyperreflexia
    • Hypertonia AND temperature above 38 °C AND (ocular OR inducible clonus)
  4. If Yes
    1. 04Warning

      Criteria met: stop ALL serotonergic drugs

      Serotonin toxicity likely. It can increase over some hours after an overdose: reassess often.

      • Stop every serotonergic drug, including OTC, herbal and illicit
      • Overdose within 1 h: consider activated charcoal only if the airway is safe
      • Advice: clinical toxicologist or Poisons Information Centre 13 11 26
    2. 05Warning

      Do not use: suxamethonium, physical restraint, bromocriptine

      These can worsen the toxicity or its complications.

      • Suxamethonium: hyperkalaemia risk with rhabdomyolysis; use a non-depolarising agent
      • Physical restraint without sedation worsens hyperthermia and acidosis; sedate instead
      • Bromocriptine can worsen toxicity. Dantrolene and propranolol: no proven benefit (give dantrolene if malignant hyperthermia)
    3. 06Decision

      Severe? Temperature rising fast or increasing rigidity

      Severe: temperature 38.5 °C or more and rising, or increasing muscle rigidity (truncal rigidity, opisthotonus, sustained clonus).

    4. If Yes
      1. 07Warning

        Severe: emergency. Cool, sedate, intubate and paralyse

        Can progress to multiorgan failure within hours. Supportive care comes before any antidote. Volatile anaesthetic or suxamethonium in the last hours: treat as malignant hyperthermia (stop the trigger, dantrolene per local MH protocol).

        • Temperature above 39 °C with agitation, reduced consciousness, rigidity or no response to cooling: sedate, intubate and paralyse early (non-depolarising agent)
        • Active cooling: fans with water spray, ice packs, cooling blanket. Antipyretics do not work
        • ICU; stop all serotonergic drugs; clinical toxicologist advice
      2. 08Action

        Severe: ICU support and complications

        NMS possible (antipsychotic started or increased, bradykinesia, no clonus): do NOT give chlorpromazine.

        • IV benzodiazepine to reduce muscle activity
        • IV fluids; treat rhabdomyolysis, hyperkalaemia, acidosis and DIC
        • Hypotension after an MAOI: pressor response can be exaggerated; avoid ephedrine; titrate small vasopressor doses
        • Chlorpromazine only on toxicologist advice; give IV fluid first (causes hypotension)
        • Cyproheptadine via NG tube: no proven benefit in severe toxicity
        • Long-acting drugs or MAOIs: sedation and ventilation may be needed for longer
      3. 09Action

        Monitor for progression and complications

        Moderate and severe toxicity.

        • Temperature, muscle tone and clonus: repeat often
        • CK, potassium, creatinine: rhabdomyolysis and renal failure
        • Liver function and coagulation if severe (liver failure, DIC)
        • ECG: QT prolongation (for example citalopram overdose)
      4. 10Outcome

        Recovery, discharge and prevention

        Most improve within 24 h of stopping the drug; longer with long-acting drugs or MAOIs. Deliberate overdose: suicide risk assessment before discharge.

        • Deliberate overdose: mental health and suicide risk assessment before discharge
        • Record the drug combination as an adverse drug reaction
        • Before restarting, review each drug and allow washout
        • Fluoxetine to MAOI: wait at least 5 weeks. MAOI to fluoxetine: at least 14 days
        • Tell the patient which drugs and OTC products to avoid
      If No
      1. 11Decision

        Moderate? Distressing signs that need treatment

        Moderate: marked clonus, agitation, tachycardia or fever that is not rising fast; distressing but not life-threatening. Mild: tremor or hyperreflexia with little distress.

      2. If Yes
        1. 12Action

          Moderate: admit and sedate with a benzodiazepine

          Observe at least 6 h (12 h after slow-release venlafaxine). Escalate at once if temperature rises or rigidity develops.

          • Diazepam or midazolam, titrated to calm (lorazepam if used locally)
          • Opioids, alcohol or other sedatives on board: titrate slowly and watch airway and breathing
          • IV fluids as needed
          • Cyproheptadine may ease symptoms: see next step
        2. 13Action

          Moderate, adult: consider oral cyproheptadine

          5-HT2A antagonist. No controlled trials; main effect is sedation. Oral or NG only; less useful after activated charcoal. Child: dose on toxicologist advice.

          • Adult: 12 mg orally or via NG tube
          • Then 2 mg every 2 h while symptoms continue
          • Maintenance: 8 mg every 6 h
          • Maximum 32 mg in 24 h (and no more than 0.5 mg/kg/day)
          • Australian tablets: 4 mg
        3. Path rejoins step 09Shared downstream outcome
        If No
        1. 14Action

          Mild: stop or reduce the drug, supportive care

          Tremor, hyperreflexia or mild anxiety that does not distress the patient. Cyproheptadine is not needed.

          • Stop or reduce the serotonergic drug(s)
          • Benzodiazepine (for example oral diazepam) if anxious or agitated
          • After an overdose, keep observing: toxicity can increase over some hours
          • Escalate if clonus, agitation or temperature increase
        2. Path rejoins step 10Shared downstream outcome
    If No
    1. 15Decision

      Rigidity with temperature above 38 °C?

      Rigidity can hide clonus, so Hunter criteria can miss severe toxicity, mostly after an MAOI plus another serotonergic drug. Also consider malignant hyperthermia (anaesthetic in the last hours) and NMS (antipsychotic).

    2. If Yes
      1. Path rejoins step 07Shared downstream outcome
      If No
      1. 16End

        Criteria not met: look for another cause

        Consider NMS (antipsychotic, lead-pipe rigidity, no clonus), anticholinergic or sympathomimetic toxicity, infection. Reassess often after an overdose. Stable therapeutic dose with mild signs: withhold or reduce the drug.

        • NMS: antipsychotic started or increased; bradykinesia, lead-pipe rigidity, no clonus
        • Anticholinergic toxicity: dry skin, absent bowel sounds, no clonus
        • Malignant hyperthermia: anaesthetic exposure
        • Sympathomimetic toxicity
        • CNS infection, sepsis, non-convulsive seizures, baclofen withdrawal

Guideline Source

Chiew AL, Isbister GK. Management of serotonin syndrome (toxicity). Br J Clin Pharmacol 2025;91(3):654-661 (with Hunter Serotonin Toxicity Criteria, QJM 2003)

DOI: 10.1111/bcp.16152View Guideline

Clinical Safety Information

Clinical Decision Support — Not a Substitute for Clinical Judgment

Individual patient factors may require deviation from these recommendations.

Known Limitations

  • Hunter criteria were derived in overdose: they can miss severe rigidity and over-diagnose side effects on stable doses
  • Cyproheptadine and chlorpromazine have no controlled-trial evidence; supportive care comes first
  • Doses are for adults; children and pregnancy are not specifically addressed
  • Sources differ on the severe temperature threshold (38.5 to 40 °C); act on a rising trend and rigidity

Contraindicated Populations

Children: doses are for adults; get paediatric toxicology advice (Poisons Information Centre 13 11 26)

Applicable Regions

AUUSEUGlobal

AU: Poisons Information Centre 13 11 26 (24 h). Lorazepam injection is on the ARTG, but diazepam and midazolam are used more often in Australian toxicology practice. Cyproheptadine is available as 4 mg tablets.

Version 2Next review: 2027-09-30

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Frequently Asked Questions

What is the Serotonin Toxicity (Hunter Criteria)?

The Serotonin Toxicity (Hunter Criteria) is a emergency clinical algorithm for Psychiatry. It provides a structured decision tree to guide clinical decision-making, based on Chiew AL, Isbister GK. Management of serotonin syndrome (toxicity). Br J Clin Pharmacol 2025;91(3):654-661 (with Hunter Serotonin Toxicity Criteria, QJM 2003).

What guideline is the Serotonin Toxicity (Hunter Criteria) based on?

This algorithm is based on Chiew AL, Isbister GK. Management of serotonin syndrome (toxicity). Br J Clin Pharmacol 2025;91(3):654-661 (with Hunter Serotonin Toxicity Criteria, QJM 2003) (DOI: 10.1111/bcp.16152).

What are the limitations of the Serotonin Toxicity (Hunter Criteria)?

Known limitations include: Hunter criteria were derived in overdose: they can miss severe rigidity and over-diagnose side effects on stable doses; Cyproheptadine and chlorpromazine have no controlled-trial evidence; supportive care comes first; Doses are for adults; children and pregnancy are not specifically addressed; Sources differ on the severe temperature threshold (38.5 to 40 °C); act on a rising trend and rigidity. Individual patient factors may require deviation from these recommendations.

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