Mirtazapine

Mechanism

Chemical and Commercial Profile

Common trade names: Rexer, Motivan, Vastat.
Group: Tetracyclic antidepressant, adrenergic/serotonergic modulator.

Mechanism of Action

Mirtazapine does not inhibit the reuptake of serotonin or norepinephrine at the level of membrane transporters. Its therapeutic effect lies in:

1. Antagonism of presynaptic α₂-adrenergic autoreceptors and heteroreceptors: This disinhibits and significantly increases the release of norepinephrine and serotonin into the synaptic cleft.
2. Selective antagonism of 5-HT₂ and 5-HT₃ receptors: By blocking these secondary pathways, free serotonin is redirected exclusively to the 5-HT_1A receptors, enhancing the anxiolytic and pure antidepressant response without inducing adverse effects typical of diffuse serotonergic stimulation (avoiding sexual dysfunction, nausea or agitation).
3. Antagonism of high-affinity H₁ histaminergic receptors: Explains its marked sedative and sleep-inducing effect at low doses.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid after oral intake; 50% bioavailability. C_max in 2 hours.
• Distribution: Protein binding of 85%.
• Metabolism: Hepatic through demethylation and hydroxylation via CYP2D6, CYP1A2 and CYP3A4. The metabolite desmethylmirtazapine retains weak pharmacological activity.
• Excretion: Renal (75%) and biliary (15%).
• Half-life (t_1/2): 20 to 40 hours; ideal for a single daily nighttime administration.

Indicators and dose

Indications

• Moderate to severe major depression, especially that accompanied by severe sleep insomnia, psychomotor anxiety and secondary anorexia.
• Off-label: Post-traumatic stress disorder (PTSD), refractory primary insomnia, refractory pruritus of cholestatic or uremic origin.

Dosage and Settings

• Adults: Start with 15 mg at night; maintenance range of 30 mg to 45 mg/day.
• Kidney Failure:
  • Cl_Cr [15-30 ml/min]: Reduce the theoretical dose by 30%.
  • Cl_Cr < 15 ml/min: Reduce the theoretical dose by 50%.
• Liver Failure: Moderate to severe: Reduce initial dose to 15 mg/day and schedule slow increases by monitoring liver enzymes.

Security

Contraindications

• Simultaneous use with MAOIs (minimum safety interval of 14 days).
• History of idiopathic severe agranulocytosis or neutropenia.

Adverse Effects (ADR)

The sedation paradox of mirtazapine

At a dose of 15 mg/day, mirtazapine exerts potent sedation mediated by the dominant H₁ antihistamine blockade. However, by increasing the dose to 30-45 mg/day, the stimulation of central noradrenergic neurotransmission through α₂ antagonism compensates and counteracts the sedative effect, resulting in a drug that is less sleep-inducing and more activating at high doses.

• Very common (>10%): Residual daytime sleepiness, dry mouth, increased appetite (dual antagonism H₁ and 5-HT_2C), substantial weight gain.
• Frequent (1%-10%): Orthostatic dizziness, constipation, peripheral edema due to mild hydrosaline retention.
• Rare or serious (<0.1%): Febrile neutropenia or agranulocytosis (requires immediate hematological control if the patient has fever or odynophagia), suicidal ideation in young people, restless legs syndrome.

Clinical Interactions

• CNS depressants: Marked synergy with alcohol, benzodiazepines and opiates.
• Potent inducers: Carbamazepine and phenytoin increase the clearance of mirtazapine by 50-60%, requiring doubling its theoretical dose.

Pregnancy and Breastfeeding

FDA Category: C. Limited human data; no consistent teratogenic effects have been reported. Breastfeeding: Compatible with caution. Its excretion in breast milk is extremely low (Relative Infant Dose <1.5%), making it a safe alternative for postpartum depression if sleep induction is required.