What is the recommended dose of mirtazapine (Remeron) for treating hyperemesis gravidarum?

Mirtazapine Dosing for Hyperemesis Gravidarum

Mirtazapine 30 mg orally once daily (preferably at bedtime) is the recommended dose for treating refractory hyperemesis gravidarum based on published case series, though this represents off-label use as mirtazapine is not included in current guideline-recommended treatment algorithms. 1

Position in Treatment Algorithm

Mirtazapine should be reserved for severe, refractory cases that have failed standard therapies, not as first- or second-line treatment:

• First-line therapy: Doxylamine-pyridoxine combination is the preferred initial antiemetic, safe throughout pregnancy 2, 3
• Second-line therapy: Metoclopramide is preferred when antihistamines fail, or ondansetron (though use ondansetron cautiously before 10 weeks gestation due to potential cardiac defect concerns) 2, 3
• Third-line therapy: Methylprednisolone 16 mg IV every 8 hours for severe cases unresponsive to other agents 2
• Refractory cases: Mirtazapine may be considered when conventional antiemetics (metoclopramide, promethazine, ondansetron) have failed 4, 1

Specific Dosing Protocol

The evidence supports 30 mg daily as the effective dose:

• Start mirtazapine 30 mg orally once daily, preferably in the evening prior to sleep 1
• Response typically occurs within 24 hours of initiation 1
• Continue treatment for approximately 1 week initially, though duration can extend throughout pregnancy if needed 1
• The FDA-approved starting dose for depression is 15 mg daily with titration up to 45 mg maximum, but the hyperemesis gravidarum case series used 30 mg from the start 5, 1

Clinical Evidence and Mechanism

Mirtazapine's antiemetic properties derive from multiple receptor actions:

• Acts on noradrenergic, serotonergic, histaminergic, and muscarinic receptors to produce antiemetic, sedative, and appetite-stimulating effects 4
• All three published cases of severe hyperemesis gravidarum treated with mirtazapine 30 mg daily responded within 24 hours and were able to resume oral diet within days 1
• These were patients with dehydration, ketonuria, hypokalemia, and weight loss who had failed metoclopramide and promethazine 1

Safety Considerations

Mirtazapine is not associated with increased risk of birth defects:

• Not associated with independent increased risk of congenital malformations based on pregnancy registry data 4
• All three infants in the published case series were healthy newborns 1
• However, current hyperemesis gravidarum guidelines do not include mirtazapine in their treatment algorithms, reflecting the limited evidence base (only case reports, no controlled trials) 2, 3

Important Caveats

• Screen for bipolar disorder before initiating any antidepressant including mirtazapine, as it may precipitate mania 5
• Drug interactions: Decrease mirtazapine dose with strong CYP3A4 inhibitors (ketoconazole, clarithromycin) or cimetidine; increase dose with strong CYP3A inducers (carbamazepine, phenytoin) 5
• Discontinuation: Taper gradually rather than stopping abruptly to avoid withdrawal symptoms 5
• Evidence limitation: The recommendation is based solely on case reports (3 patients total); a randomized controlled trial protocol exists but results are not yet published 6, 1

When to Consider Mirtazapine

Use mirtazapine only after documenting failure of:

• Doxylamine-pyridoxine combination 2
• Metoclopramide or ondansetron 2
• Methylprednisolone (if appropriate for gestational age) 2
• Consider gabapentin as an alternative refractory-case option, which showed 52% greater reduction in symptoms compared to standard therapy in a small randomized trial 7