MIRTAZAPINE
Clinical safety rating: safe
Animal studies have demonstrated safety
Mirtazapine is a tetracyclic antidepressant that acts as an antagonist at presynaptic α2-adrenergic receptors, leading to increased norepinephrine and serotonin release. It also antagonizes 5-HT2 and 5-HT3 receptors, and histamine H1 receptors. It does not inhibit monoamine oxidase.
| Metabolism | Extensively metabolized in the liver via CYP2D6, CYP1A2, and CYP3A4; metabolites include demethylated and hydroxylated products. Major metabolites: 8-hydroxymirtazapine and N-desmethylmirtazapine. |
| Excretion | Renal (75% as metabolites, <4% unchanged) and fecal (25% via bile); total clearance 0.43 L/min. |
| Half-life | 20-40 hours (mean 30 h); allows once-daily dosing; prolonged in elderly (up to 50 h) and hepatic impairment. |
| Protein binding | 85% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 11.1 L/kg (0.8-1.2 L/kg as reported range); extensive tissue distribution. |
| Bioavailability | 50% after oral administration, due to first-pass metabolism. |
| Onset of Action | Oral: antidepressant effects begin within 1-2 weeks; anxiolytic effect may appear within first week. Maximal benefit at 4-6 weeks. |
| Duration of Action | 24 hours due to long half-life; once-daily dosing maintains steady-state. Clinical effect persists for weeks after discontinuation. |
Initial: 15 mg orally once daily at bedtime; titrate up to 45 mg/day as tolerated. Maintenance: 15-45 mg/day.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment needed for mild to moderate renal impairment. For severe renal impairment (CrCl < 30 mL/min): consider dose reduction (e.g., 50% of usual dose) due to decreased clearance; use with caution. |
| Liver impairment | Child-Pugh Class A and B: no specific dose adjustment; use with caution. Child-Pugh Class C: contraindicated due to risk of increased exposure and adverse effects. |
| Pediatric use | Not approved for patients < 18 years; safety and efficacy not established. Limited data: 15-30 mg daily in adolescents with depression, starting at 15 mg. |
| Geriatric use | Initial dose 7.5 mg orally once daily, titrate slowly; maximum recommended dose 30 mg/day due to increased sensitivity and risk of sedation, falls, and hyponatremia. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants may enhance sedative effects Can cause significant weight gain and somnolence.
| Breastfeeding | Mirtazapine is excreted in breast milk with an M/P ratio of approximately 1.1. Relative infant dose = 1-3% of maternal weight-adjusted dose. No adverse effects reported in exposed infants; American Academy of Pediatrics considers it compatible with breastfeeding. |
| Teratogenic Risk | First trimester: Limited human data; animal studies show no teratogenicity at clinically relevant doses. Second/third trimester: Risk of poor neonatal adaptation syndrome (irritability, respiratory distress) if used near term; no major malformations reported. |
■ FDA Black Box Warning
Increased risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders.
| Common Effects | Sedation |
| Serious Effects |
["Concomitant use with MAOIs (including linezolid or intravenous methylene blue)","Serotonin syndrome risk with MAOIs; contraindicated within 14 days of MAOI use","Known hypersensitivity to mirtazapine or any component","Use in combination with other drugs that cause QT prolongation (if contraindicated)"]
| Precautions | ["Suicidality risk in children, adolescents, and young adults","Serotonin syndrome (especially with other serotonergic drugs)","Agranulocytosis (rare)","Somnolence/sedation","Increased appetite and weight gain","Orthostatic hypotension","QT prolongation (caution in cardiac disease)","Monitor for manic/hypomanic episodes","May impair cognitive and motor performance"] |
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| Fetal Monitoring |
| Monitor maternal weight, blood glucose, and blood pressure due to potential weight gain and metabolic effects. For neonate, observe for signs of poor neonatal adaptation syndrome (agitation, cyanosis, apnea) for the first 48 hours after delivery. |
| Fertility Effects | No known adverse effects on fertility in humans. In animal studies, no impairment of fertility was observed at doses up to 20 times the maximum recommended human dose. |