- USES: Mirtazapine is used to treat major depressive disorders. PHARMACOLOGY: Mirtazapine is a tetracyclic antidepressant belonging to the piperazinoazepine group of compounds. Evidence indicates that mirtazapine may enhance central noradrenergic and serotonergic activity, possibly through its antagonist activity at central presynaptic alpha2-adrenergic inhibitory autoreceptors and heteroreceptors. It is a potent 5-HT2 and 5-HT3 receptor antagonist, a histamine (H1) receptor antagonist, a moderate peripheral alpha-1 adrenergic antagonist, and a moderate muscarinic receptor antagonist. TOXICOLOGY: Mirtazapine produces sedative effects due to potent histamine (H1) receptor antagonism, orthostatic hypotension due to moderate alpha-1 adrenergic receptor antagonism, and relatively low incidence of anticholinergic side effects due to a moderate muscarinic receptor antagonism. EPIDEMIOLOGY: Overdose is rare. OVERDOSE: Overdose of mirtazapine alone with no co-ingestants is associated with only mild clinical symptoms. Reported overdose effects have included drowsiness, disorientation, tremor, headache, impaired memory, tachycardia, bradycardia, hypotension, hypertension, nausea, vomiting, ataxia, miosis, blurred vision, hepatitis, and rhabdomyolysis. ADVERSE EFFECTS: COMMON: Somnolence, dizziness, constipation. OTHER EFFECTS: Dry mouth, dizziness, disorientation, impaired memory, nausea, vomiting, orthostatic hypotension, hyponatremia, arthralgia, and myalgia. RARE: Severe skin reactions (eg, bullous dermatitis, erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis), elevated liver enzymes, pancreatitis, agranulocytosis, pancytopenia, anemia, thrombocytopenia, leukopenia, lymphocytosis, lymphadenopathy, seizures, and restless leg syndrome. Potentially life-threatening serotonin syndrome and neuroleptic malignant syndrome have been reported in patients receiving mirtazapine therapy. The risk is increased with concomitant use of SSRIs, serotonin norepinephrine reuptake inhibitors (SNRI), triptans, and MAOIs (contraindicated).
Range of Toxicity:
- TOXICITY: Severe toxicity is unlikely from mirtazapine alone. Adults have ingested up to 4.5 grams and recovered with supportive care. An accidental overdose of 60 mg in a 3-year-old child resulted in tachycardia. The child was alert, responsive, and interactive and recovered with no adverse sequelae. A 34-month-old girl developed somnolence, nausea, and vomiting after ingesting 165 mg of mirtazapine (15 mg/kg). THERAPEUTIC: ADULT: 15 mg/day as a single dose orally; may increase in dose every 1 to 2 weeks to a maximum dose of 45 mg/day. PEDIATRIC: Safety and efficacy in pediatric patients have not been established.
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Treat mild hyponatremia with water restriction and/or 0.9% sodium chloride. MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. Treat severe hypotension with IV fluids, dopamine, or norepinephrine. Manage severe hyponatremia with 0.9% sodium chloride; 3% sodium chloride may be necessary in patients with severe hyponatremia. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Although rare, treat neuroleptic malignant syndrome with oral bromocriptine, IV benzodiazepines in conjunction with cooling and other supportive measures. Consider dantrolene in severe cases.
- Decontamination: PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration. HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is alert and able to maintain airway.
- Airway management: Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression or seizures.
- Antidote: None.
- Hyponatremia: Evaluate for hyponatremia and associated symptoms. Patients with mild symptoms can be managed with water restriction. Patients with moderate to severe symptoms should receive 0.9% sodium chloride (rarely 3% NaCl in patients with very severe symptoms). The goal is slow correction; the serum sodium should not increase more than 2 mEq/L/hour in any 4-hour period or more than 15 mEq/L per day. Rapid correction may cause central pontine myelinolysis. Monitor serum electrolytes, fluid intake and output, and urine volume and electrolytes.
- Seizure: Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
- Neuroleptic malignant syndrome: Oral bromocriptine, IV benzodiazepines in conjunction with cooling and other supportive measures. Consider dantrolene in severe cases.
- Serotonin syndrome: Primary treatment is sedation with IV benzodiazepines, and cooling measures. CYPROHEPTADINE: A serotonin antagonist with high affinity for the 5-HT2 receptors; effective for milder cases of serotonin syndrome. Dose: ADULT: 12 mg orally or nasogastric tube, followed by 4 to 8 mg every 4 to 6 hours. CHILD: 0.25 mg/kg/day orally or nasogastric tube divided every 6 hours, maximum dose 12 mg/day. CHLORPROMAZINE: A phenothiazine antipsychotic with 5-HT2 antagonist activity; indicated in severe serotonin syndrome cases. Dose: 12.5 to 50 mg IV, followed by 25 to 50 mg every 6 hours. It is NOT generally recommended because it may cause severe hypotension. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with nondepolarizing agents.
- Rhabdomyolysis: Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.
- Monitoring of patient: Plasma concentrations are not readily available or clinically useful in the management of overdose. Monitor vital signs and mental status. Monitor CBC with differential with platelet count, serum electrolytes, and liver enzymes in symptomatic patients. Monitor CK, renal function, and urine output in patients with rhabdomyolysis. Monitor for clinical evidence of neuroleptic malignant syndrome and serotonin syndrome following an overdose.
- Enhanced elimination procedure: Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding of mirtazapine.
- Patient disposition: HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home. OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolytes and fluid balance. Patients that remain asymptomatic can be discharged. ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with severe neutropenia should be admitted to the hospital. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.