Mirtazapine Tapering Guide
mirtazapine
Boxed Warning
Suicidality risk in children, adolescents, and young adults under 25 during initial treatment.
Overview
Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) approved for major depressive disorder. It has a unique mechanism that does not involve reuptake inhibition. It is known for sedation and appetite stimulation, especially at lower doses.
7.5mg, 15mg, 30mg, 45mg
Tablets: 7.5mg, 15mg, 30mg, 45mg; Orally disintegrating tablets (SolTab): 15mg, 30mg, 45mg
Category C (risk cannot be ruled out)
Mechanism of Action
Antagonist at central alpha-2 adrenergic autoreceptors and heteroreceptors, increasing noradrenergic and serotonergic neurotransmission. Also antagonizes 5-HT2A, 5-HT2C, 5-HT3, and histamine H1 receptors. The strong H1 antagonism causes sedation and weight gain.
Taper Notes
Rebound insomnia is the predominant withdrawal feature, driven by histamine H1 unmasking. Sedation is paradoxically stronger at lower doses (where H1 antagonism dominates over noradrenergic activation). Tablets can be split or dissolved in water for fine titration.
Maudsley Deprescribing Guidance
Aqueous suspension (dissolving tablets in water) permits precise sub-tablet doses. Distinguish rebound histaminergic insomnia from depressive relapse by symptom timing — rebound emerges within days of reduction; relapse develops over weeks.
Common Withdrawal Symptoms
Interactions & Safety
Drug Interactions
- MAOIs — contraindicated (serotonin syndrome risk)
- Serotonergic drugs increase serotonin syndrome risk
- CYP3A4 inhibitors (ketoconazole) may increase mirtazapine levels
Food Interactions
- Food has minimal effect on absorption
- Avoid alcohol (additive CNS depression)
Contraindications
- MAOIs within 14 days
- Known hypersensitivity to mirtazapine
Toxicity
Relatively low toxicity in overdose compared to TCAs. Agranulocytosis/neutropenia rarely reported. Weight gain and metabolic effects. Serotonin syndrome possible with serotonergic combinations.
Pharmacokinetics
ADME Profile
Rapidly and completely absorbed. Bioavailability ~50%. Tmax ~2 hours. Food has minimal effect on absorption.
~4.5 L/kg
Extensively metabolized hepatically via CYP2D6, CYP3A4, and CYP1A2 to demethyl and hydroxylated metabolites, which have minimal pharmacological activity.
Renal (~75%) and fecal (~15%). Less than 5% excreted unchanged in urine.
~85%
~230 mL/min (apparent oral clearance)
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