SNRI Overdose

Serotonin noradrenaline reuptake inhibitor overdose, mainly with venlafaxine, causes serotonin toxicity, seizures, hypertension, tachycardia and, in large ingestions, sodium channel blockade with QRS widening and cardiac arrest. It is more dangerous than SSRI overdose.

Venlafaxine is associated with more deaths and severe poisoning than most other newer antidepressants. Serious toxicity is likely above 1 g, and seizures above 2 to 3 g. Duloxetine and desvenlafaxine are less toxic.

Risk factors for harm. Modified release formulations (delayed peak and delayed seizures), co-ingestion, cardiac disease and large doses.

Course. Effects begin within 2 to 6 hours and peak at up to 12 hours for modified release products; seizures can occur up to 24 hours.

Pathophysiology.

Inhibition of serotonin and noradrenaline reuptake causes sympathetic and serotonergic excess, and at high doses sodium channel blockade slows conduction and reduces contractility.

Alpha adrenergic effects cause hypertension and tachycardia early, and vasodilatory shock may follow.

• Tachycardia, hypertension, mydriasis, agitation, tremor and diaphoresis.
• Serotonin toxicity: clonus, hyperreflexia, hyperthermia and diarrhoea.
• Seizures (often delayed), coma, QRS widening and ventricular arrhythmia, hypotension and cardiac arrest.
• Rhabdomyolysis and hyponatraemia.

Red flags.

• QRS over 100 ms or R wave in aVR over 3 mm.
• Seizures, coma or temperature over 38.5 degrees Celsius.
• Persistent hypotension or arrhythmia.

• History of drug, formulation, dose, time and co-ingestants.
• ECG on arrival and repeated at least every 2 hours for 6 hours; QRS and QTc measurement.
• Electrolytes, glucose, creatine kinase, renal and liver function, venous gas with lactate, paracetamol level.
• Clinical assessment for serotonin toxicity (inducible clonus, hyperreflexia).

Differential diagnosis. SSRI overdose, tricyclic antidepressant overdose, sympathomimetic toxicity, anticholinergic toxicity, MAOI interaction and neuroleptic malignant syndrome.

• Activated charcoal 50 g orally once (1 g/kg, maximum 50 g, in children) within 2 hours for modified release products if the airway is protected. Monitor the airway for aspiration. Avoid with reduced consciousness, ileus or gastrointestinal obstruction; no renal or hepatic adjustment; acceptable in pregnancy.
• Intravenous access, cardiac monitoring and observation for at least 24 hours for modified release venlafaxine over 1 g.
• QRS over 100 ms or arrhythmia: sodium bicarbonate 8.4% 1 to 2 mmol/kg (1 to 2 mL/kg) intravenously over several minutes, repeated until QRS is under 100 ms. Maximum serum pH 7.55 and sodium 150 mmol/L. Monitor ECG, pH, potassium and sodium; replace potassium to keep it over 4.0 mmol/L; avoid in heart failure with fluid overload.
• Seizures: lorazepam 0.1 mg/kg intravenously (maximum 4 mg for each dose) over 2 minutes, repeated once after 5 to 10 minutes if seizures continue. Maximum 8 mg in total. Monitor breathing, oxygen saturation, blood pressure and sedation. Use lower doses in older adults, respiratory disease and hepatic impairment; no renal adjustment; use only when needed in pregnancy.
• Agitation and serotonin toxicity: diazepam 5 to 10 mg intravenously, repeated every 5 to 10 minutes as needed. Maximum 30 mg in the first hour without specialist review. Monitor breathing, oxygen saturation and blood pressure. Use lower doses in older adults, respiratory disease and hepatic impairment; use only when needed in pregnancy.
• Cyproheptadine 12 mg orally or via nasogastric tube once, then 2 mg every 2 hours until symptoms settle, then 8 mg every 6 hours, for moderate to severe serotonin toxicity. Maximum 32 mg daily. Monitor sedation and blood pressure. Avoid in glaucoma, urinary retention and with monoamine oxidase inhibitors; reduce dose in hepatic and renal impairment.
• Hypotension: fluids first, then noradrenaline 0.05 micrograms/kg/minute intravenously, titrated to a mean arterial pressure of 65 mmHg or higher. Maximum 1 microgram/kg/minute. Monitor blood pressure, extravasation and arrhythmia; give by central line; use caution in cardiac disease.
• Cardiac arrest: advanced life support with repeated sodium bicarbonate, and consider intravenous lipid emulsion or extracorporeal support in refractory cases (specialist).
• Avoid beta blockers and flumazenil.

Monitoring. Continuous ECG, temperature, urine output, creatine kinase, electrolytes and gas.

Referral and escalation. Poisons information centre for all significant ingestions; intensive care for QRS widening, seizures or shock.

Special groups. Children: lower thresholds for admission. Pregnancy: the same treatment applies.