Mirtazapine

Mirtazapine is a noradrenergic and specific serotonergic antidepressant used for major depression, particularly with insomnia, anxiety or weight loss. It does not inhibit reuptake. It causes little sexual dysfunction and nausea, but sedation and weight gain are common, and it carries a rare risk of agranulocytosis.

Classification. Tetracyclic antidepressant, noradrenergic and specific serotonergic antidepressant.

Mechanism. Blocks central presynaptic alpha-2 adrenoceptors, which increases noradrenaline and serotonin release, and blocks 5-HT2, 5-HT3 and histamine H1 receptors. Antihistamine sedation is strongest at low doses.

Pharmacokinetics. Bioavailability about 50%, unaffected by food. Metabolised by CYP2D6, CYP1A2 and CYP3A4. Half-life about 20 to 40 hours. Clearance falls by about 30% in moderate kidney or liver impairment and by about 50% in severe kidney impairment.

All regimens are oral with no loading dose.

Major depression, adults.

• Start 15 mg at night (7.5 mg in older adults or when sedation is a concern).
• Titration: increase by 15 mg at intervals of 1 to 2 weeks.
• Maintenance 15 to 45 mg daily as a single dose at night. Maximum 45 mg daily.
• Duration: at least 6 months after remission; 2 years or more for recurrent illness.

Adjunct use (specialist or off-label). 7.5 to 30 mg at night for insomnia or poor appetite in cancer, HIV or advanced illness, and as an add-on to an SSRI or SNRI in treatment-resistant depression.

Dose limits. Creatinine clearance under 40 mL/min and moderate to severe liver impairment: start 7.5 mg and titrate cautiously.

Contraindications. MAOI use now or within 14 days of stopping it, hypersensitivity. Caution in epilepsy, cardiac disease, diabetes, narrow-angle glaucoma and urinary retention.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in under 25 years. Agranulocytosis and neutropenia (rare), serotonin syndrome (rare), hyponatraemia, mania, seizures, QT prolongation (uncommon), hepatic injury, severe cutaneous reactions.

Common adverse effects. Sedation, increased appetite, weight gain, dry mouth, dizziness, raised cholesterol and triglycerides, peripheral oedema.

Interactions. Carbamazepine, phenytoin and rifampicin lower levels, and strong CYP3A4 inhibitors (ketoconazole, ritonavir) raise them. Alcohol and sedatives add to sedation. Serotonin syndrome risk rises with tramadol, triptans and linezolid. Warfarin effect can increase, so check INR.

Common prescribing errors. Increasing the dose when sedation is the problem (higher doses are less sedating); missing early signs of neutropenia; not warning about weight gain.

Special groups.

• Pregnancy: limited data; use only if benefit outweighs risk.
• Breastfeeding: low infant levels; acceptable with infant monitoring.
• Children: not advised in under 18 years.
• Older adults: start 7.5 mg; falls and hyponatraemia.
• Kidney impairment: clearance falls; when creatinine clearance is under 40 mL/min start 7.5 mg and titrate cautiously.
• Liver impairment: start 7.5 mg, titrate cautiously and monitor liver tests.

Formulations. Tablets 15 mg, 30 mg and 45 mg; orally disintegrating tablets and oral solution in some regions. Give once daily at night with or without food.

Baseline. Weight, mood history including past mania, suicide risk, sodium in older adults, fasting lipids and glucose in at-risk patients, full blood count in patients with a history of blood disorders.

Monitoring. Review within 1 to 2 weeks and after each dose change for suicidality. Weigh at each review. Counsel patients to report fever, sore throat, mouth ulcers or infection promptly; check a full blood count and stop the drug if neutrophils are low. Check sodium 2 to 4 weeks after starting in high-risk patients; review the need for the drug if sodium falls under 130 mmol/L and stop it if under 125 mmol/L or if symptomatic.

Stopping. Taper over at least 4 weeks.

Referral and escalation. Refer to psychiatry for suicidal intent, psychosis, mania or failure of two adequate courses. Fever with sore throat needs an urgent full blood count.