January 30, 2020

Antidepressant toxicity

Mirtazapine

  • Novel tetracyclic antidepressant
  • Risk assessment
    • Relatively minor effects even after large overdoses
    • Children: Accidental ingestions up to 100mg are benign
  • Toxic mechanism
    • Centrally acting alpha-2 antagonist that enhances serotonin and Na release
    • Also acts as 5-HT2/3 and H1 receptor antagonist
  • Toxicokinetics
    • Absorption – Rapid
    • Distribution – >100L/kg. 85% protein bound
    • Metabolism – Hepatic cytP450 2D6/3A4 
    • Elimination – Metabolites excreted in urine. Significant first-pass effect. Half-life 20-40 hours

Mirtazapine

  • Clinical features
    • If symptomatic, onset is within 4 hours
    • Mild tachycardia, hypertension and drowsiness with large OD
    • CNS depression more likely if >1000mg but rarely severe
  • Management
    • Supportive care
  • Disposition
    • Asymptomatic with normal ECG at 4 hours – d/c
  • Handy tip
    • Seizures, coma or significant alteration in vitals suggests another cause

MAOi

  • Irreversible non-selective (MAO-A/B): Phenelzine, tranylcypromine
  • Irreversible MAO-B: Selegiline
  • Reversible MAO-A: Moclobemide
  • Irreversible, non-selective agents more at risk of lethal serotonin syndrome, significant adverse reactions and a withdrawal state

MAOi

  • Risk assessment
    • Moclobemide
      • Minor symptoms regardless of dose if taken alone
      • If taken with any other serotonergic agent – high risk of severe serotonin syndrome regardless of dose
      • Non-lifethreatening serotonin syndrome in <5%
      • QTc prolongation if >3g but TdeP not described
    • Tranylcypromine and phenelzine
      • Dose-dependent, potentially lethal serotonergic and sympathomimetic toxicity
      • Symptoms are delayed and prolonged
      • Phenelzine: >2mg/kg toxic. 4-6mg/kg potentially fatal
      • Tranylcypromine: >1mg/kg toxic. 170mg has caused a fatality
    • Children: 1-2 tabs of phenelzine or tranylcypromine warrant hospital assessment

MAOi

  • Toxic mechanism
    • MAO-A metabolises serotonin, NA and dopamine
    • MAO-B metabolises phenylethylamine and benzylamine at central and peripheral synaptic sites
    • Irreversible blockade needs new enzyme synthesis to re-establish function
    • Irreversible, non-selective agents lead to accumulation of NA, noradrenaline, dopamine and phenylethylamine and subsequent serotonergic and sympathomimetic toxicity that can last for days
  • Toxicokinetics
    • All well absorbed
    • Considerable first-pass metabolism
    • Moderate Vd 1.2L/kg
    • All undergo hepatic metabolism and metabolites excreted in urine

MAOi

  • Clinical features
    • Moclobemide
      • Minor nausea, anxiety, tachycardia
    • Moclobemide with another serotonergic agent
      • Serotonin syndrome within 6-12 hours
    • Phenelzine or tranylcypromine
      • Asymptomatic for 6-12 hours
      • Restlessness, agitation, tachycardia, involuntary movements, grimacing, clonus, hyperreflexia
      • Rapid decline in conscious state
      • Muscle rigidity with resultant respiratory compromise, rhabdo, respiratory acidosis and hyperthermia
      • Autonomic instability
      • DIC and MODS
      • Can last days
    • Tyramine reaction
      • After ingestion of tyramine-containing food e.g. cheese, severe occipital headache, pronounced hypertension/sweating/agitation/mydriasis and sometimes chest pain
      • Can be complicated by hypertensive crisis with ICH, rhabdo, AKI and DIC

MAOi

  • Screening Ix
  • Serial ECG (moclobemide) q6h
    • If QT >450ms, continue monitoring
  • Management
    • Resus
    • HTN and tachycardia – Titrated IV benzodiazepines
      • Beta-blockers CI due to unopposed alpha risk
      • For severe HTN consider infusion of GTN, SNIP or phentolamine
    • Seizures and agitated delirium – IV benzodiazepines
    • Treat hyperthermia aggressively > 39.5
    • Life-threatening serotonin syndrome requires paralysis, I&V

MAOi

  • Decontamination
    • Moclobemide – AC not indicated as good outcomes
    • If present within 2 hours and well after >1mg/kg tranylcypromine or >2mg/kg phenelzine – 50g AC
    • Give to all intubated patients
  • Antidotes
    • Trial of cyproheptadine if symptoms consistent with mild-to-moderate serotonin syndrome refractory to benzodiazepines
    • 8mg PO/NG q8h
  • Disposition
    • If well at 12 hours, can discharge
  • Handy tips
    • Aggressively manage hyperthermia in setting of MAOi
    • Failure to observe patient for 12 hours following MAOi with missed serotonin syndrome onset

SSRI

  • Common but usually benign
  • Citalopram and escitalopram are unique in causing dose-dependent QT prolongation
  • Risk assessment
    • Mild serotonin syndrome in <20% and lasts <12 hours
    • Seizures in <4% and more likely with citalopram
    • >600mg citalopram or >300mg escitalopram is associated with QT prolongation but rarely TdeP
    • Co-ingestion of other serotonergic agents greatly increases the risk of severe serotonin syndrome
  • Children: Up to 3 tablets is benign

SSRI

  • Toxicokinetics
    • Rapidly absorbed, highly protein bound, large Vd
    • Undergo hepatic metabolism to less active metabolites excreted in urine
    • Didesmethylcitalopram is the citalopram metabolite thought to be responsible for QT prolongation
    • Elimination half-lives around 24 hours
  • Clinical features
    • Minor symptoms within 4 hours and lasting <12
    • Mild serotonin syndrome
    • Severe only if coingested serotonergic agents
    • Seizures in 2% of citalopram/escitalopram OD heralded by serotonin syndrome
      • Short-lived and easily controlled

SSRI

  • Serial ECG
    • If >600mg citalopram or >300mg escitalopram ECG on arrival and continue cardiac monitoring for at least 8 hours
    • Monitoring to continue until under nomogram
    • If >1000mg citalopram or >500mg escitalopram, continue monitoring for 12 hours
  • Management
    • General support
    • Seizures treated with benzos
    • Serotonin syndrome – Titrated benzos
    • Cyproheptadine 8mg q8h PO if mild-moderate serotonin syndrome refractory to benzos
    • Monitor and treat hyperthermia

SSRI

  • Decontamination
    • If within 4 hours of administration and taken >600mg citalopram or >300mg escitalopram – 50g AC
    • OD with other SSRI’s do not warrant AC unless co-ingestants
  • Disposition
    • Cardiac monitoring as above for toxic doses of citalopram/escitalopram
    • All others if well at 6 hours with normal ECG – d/c
  • Handy tips
    • Coma suggests co-ingestant or complication
  • Pitfall – Failure to administer adequate benzos

TCA

  • Amitryptyline, clomipramine, dothiepin, doxepin, imipramine, notryptiline, trimipramine
  • Amitryptiline and dothiepin particularly severe
  • Clomipramine less toxic and behaves more like an SSRI
  • Risk assessment
    • Onset of severe toxicity usually within 2 hours
    • Seizures and myoclonus more common with dothiepin
    • <5mg/kg: Minimal symptoms
    • 5-10mg/kg: Drowsiness and mild anticholinergic effects
    • >10mg/kg is potentially life-threatening with coma, hypotension, seizures, cardiac dysrhythmias within 2-4 hours. Anticholinergic effects likely but often masked by coma
    • >30mg/kg: Severe toxicity with pH-dependent cardiotoxicity and coma >24 hours
  • Children: >10mg/kg is potentially lethal
  • Responsible for nearly half of all fatalities due to antidepressants

TCA

  • Toxic mechanism
    • NA and 5-HT reuptake inhibitors + GABA-A receptor blockers
    • Myocardial toxicity due to fast sodium channel blockade (Type 1A)
    • Also M1, H1, peripheral post-synaptic alpha-1 receptor blockers
    • Reversible K channel inhibition and direct myocardial depression
    • Antihistamine and anticholinergic – ALOC agitation, delirium, coma
    • Anticholinergic and GABA-A antagonism – Seizures
    • Antimuscarinic and alpha blockade – Tachycardia and vasodilation
  • Toxicokinetics
    • Rapidly absorbed with peak levels at 2 hours
    • Anticholinergic effects can cause delayed gastric emptying and prolong time to peak
    • Peak cardiac effects 1-4 hours
    • Highly protein bound, large Vd 5-20L/kg
    • Hepatic cytP450 2D6 to active metabolites

TCA

  • Clinical features
    • CNS
      • Sedation, coma usually before CVS signs. Seizures. Anticholinergic delirium often obscured by coma
    • CVS 
      • Sinus tachy, mild hypertension, hypotension, broad-complex tachydysrhythmias, broad-complex bradycardia per—arrest
    • Anticholinergic
      • Agitation, delirium, mydriasis, dry skin, flushed, tachycardia, urinary retention, ileus, myoclonus
    • Cardiotoxicity does NOT occur without neurotoxicity
      • If prolonged QRS without coma, consider pre-existing conduction delay

TCA

  • ECG
    • Prolonged QRS
      • >100ms predictive of seizures
      • >160ms predictive of VT
    • Large terminal R wave in aVR (>3mm 81% sensitive and 73% specific for development of seizures or arrhythmia)
    • R/S ratio >0.7 in aVR
    • QT prolongation
      • Due to QRS prolongation and JT interval is typically normal
    • Prolonged PR
    • AV block
    • Ventricular ectopy
    • Non-specific ST-T wave changes
    • Brugada pattern – RBBB with downsloping ST elevation in V1-3
    • Right axis deviation
      • Seen as right bundle more sensitive to blockade with subsequent delayed right ventricular activation

TCA

  • ECG prediction (Buckley et al)
    • QTS, QTc and terminal R/S ratio >0.7 are strongest predictors of arrhythmia but not strong enough to be used in isolation
    • Only terminal R/S ratio remained statistically significant after adjustment for QRS duration
    • Boenhert and Lovejoy widely quoted but not borne out in literature
      • QRS <=100ms indicates negligible risk of seizures or arrhythmia
      • QRS >=100ms and <160ms moderate risk
      • QRS >= 160ms indicates high risk of both

TCA

  • Management
    • Cardiac monitoring until resolution of toxicity
    • At any sign of reduced GCS <12 – I&V with hyperventilation
    • Neurotoxicity precedes cardiac instability, therefore, if giving bicarb only use as a temporizing measure around immediate intubation and hyperventilation
    • Bicarb and hyperventilation only required for QRS widening or ventricular dysrhythmias
      • Target pH 7.5-7.55 and narrowing QRS complex
    • Ventricular dysrhythmias
      • Sodium bicarb 100mmol (2mmol/kg) IV q1-2min until perfusing rhythm targeting pH 7.5-7.55
      • Lignocaine third-line 1.5mg/kg IV when pH 7.5
      • Amiodarone and beta-blockers are CI
      • Can consider hypertonic saline also
    • Fluid boluses, bicarb and adrenaline/noradrenaline infusions for hypotension
    • Seizures managed with benzos (not phenytoin – Na channel blocker)
    • Haemodialysis not recommended as not dialyzable (EXTRIP)

TCA

  • Decontamination
    • AC not indicated for <10mg/kg
    • If >10mg/kg, administer after intubation
  • Disposition
    • If well at 6 hours, can d/c
  • Handy tips
    • Resuscitation efforts do not cease until I&V, hyperventilation, bicarbed and pH 7.5-7.55
    • Numerous reports of good outcomes despite prolonged resuscitation
    • Above interventions should ensure survival of all patients who arrive alive or peri-arrest
  • Pitfalls
    • Insufficient bicarb dosing

Venlafaxine and Desvenlafaxine

  • Potent SNRI’s
  • Can cause seizures and cardiotoxicity
  • Risk assessment
    • 14% of patients have seizures but incidence is dose-dependent (vs. <4% of SSRI overdose)
      • <1.5g: Risk of seizures <5%
      • <3g: Risk of seizures <10%
        >3g: Risk of seizures >30%
      • >4.5g: Risk of seizures 100%. Hypotension, QRS and QT prolongation
      • >7g: Hypotension, LV dysfunction
    • Onset of seizures can be delayed up to 16 hours
    • Pre-existing seizure disorder increases risk of this
    • High-risk of serotonin syndrome if other serotonergic agent taken

SNRI

  • Toxic mechanism
    • SNRI’s + rate-dependent Na channel blocking activity
    • Weak dopamine reuptake inhibition and no activity at H1/M1/Alpha-1
    • Do not inhibit MAO
  • Toxicokinetics
    • Venlafaxine
      • Well absorbed, high first-pass metabolism, BA 50%
      • All XR and peak levels at 6-8 hours
      • Vd 5-7L/kg
      • Half-life 15 hours
    • Desvenlafaxine
      • Well absorbed, BA 80%
      • Vd 3-4L/kg
      • 45% excreted unchanged in urine and rest glucuronide conjugation in liver
      • Half-life 11 hours

SNRI

  • Clinical features
    • Onset of clinical features can be delayed 6-12 hours
    • Dysphoria, mydriasis, sweating, tremor, tachycardia (up to 160/min) heralds onset of toxicity and possible seizures
    • Seizures are generalised and short-duration
    • Coma is not a feature
    • Hypotension can occur with very large overdoses and is also delayed
    • Minor QRS and QT prolongation can occur but unlikely to be associated with dysrhythmias unless massive OD
    • Usually resolves within 24 hours

SNRI

  • Ix
    • Screening BSL, ECG para
    • CK for rhabdo
  • Management
    • Increasing agitation, tachy, tremor – titrated IV benzos until gentle sedation and HR <100 as prevents seizure activity
    • Treat hyperthermia aggressively
    • Treat serotonin syndrome if arises
  • Decontamination
    • AC if presents within 2 hours of >4.5g dose
    • WBI if >8g venlafaxine -> I&V if necessary to do this
    • Not indicated if late presenter as risk of seizures increased at this point

SNRI

  • Disposition
    • Must observe all patients with IV in situ for 16 hours and until symptom free
    • If <4.5g, cardiac monitoring is not required after first 6 hours provided ECG is normal
    • If >4.5g, continue monitoring for 12 hours at least
  • Handy tips
    • Early benzos are crucial
    • Coma suggests alternative cause
  • Pitfalls
    • Failure to anticipate and prepare for delayed seizures
    • Failure to give early benzos
    • AC around time of seizure

Bupropion

  • Used for nicotine addiction in XR formulation
  • High risk of seizures with any overdose
  • First seizure usually within 2-8 hours but can be delayed up to 24 hours
  • Risk of seizures increased if pre-existing seizure disorder, or co-ingestion of other central sympathomimetics or serotonergic drugs
  • Severe cardiotoxicity if >9g
  • Children: Any dose >10mg/kg needs assessment

Bupropion

  • Any dose: Seizures, tachycardia, hypertension, tremors, agitation, hallucination
  • >4.5g: Seizure risk 50% and usually within 8 hours
  • >9g: Seizures universal. Haemodynamic instability, prolonged QRS/QT, ventricular dysrhythmias. Fatal without good supportive are

Bupropion

  • Toxic mechanism
    • Monocyclic antidepressant that increases CNS excitatory amines by inhibiting NA and dopamine reuptake
    • Also minimal serotonin reuptake inhibition and moderate anticholinergic effect
    • Sodium channel blocker
  • Toxicokinetics
    • Well absorbed, peak levels at 2-3 hours
    • Large Vd 20L/kg
    • Metabolites to active metabolites
    • Renal excretion of active metabolites

Bupropion

  • If >4.5g, repeat ECG every 2 hours and remain on cardiac monitoring
  • Tachycardia on arrival predicts seizure
  • ECG on all patients on arrival and at 12 hours
  • Management
    • Early intubation if >9g
    • Treat seizures with Iv diazepam
    • Broad-complex tachy – Intubation, hyperventilation, bicarb as for TCA
  • Decontamination
    • AC once airway secured

Bupropion

  • Disposition
    • Observe all patients with IV in place for 24 hours and until symptom free
  • Handy tip
    • Early prophylactic benzo dosing to achieve calm and HR <100 can prevent seizures
  • Pitfalls
    • Failure to anticipate and prepare for delayed seizures
    • Failure to administer adequate benzos
    • AC at time of seizure

Last Updated on October 14, 2020 by Andrew Crofton

Andrew Crofton
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