Mirtazapine

Indications

• FDA-approved only for major depressive disorder in adults, given once daily at bedtime in a range of 15 to 45 mg/day.
• Off-label for insomnia in depression, where its antihistaminic sedation acts on the first night rather than after weeks.
• Off-label for appetite stimulation and weight gain in cancer cachexia, geriatric failure to thrive, and anorexia nervosa.
• Off-label as an augmentation agent added to an SSRI or SNRI, a combination whose additive efficacy is supported by several trials.
• Off-label for chemotherapy-induced and functional nausea, exploiting the same 5-HT3 antagonism that ondansetron uses.
• Off-label for PTSD-related nightmares and insomnia, though prazosin and trauma-focused psychotherapy remain better supported.

Mechanism of action

• Blocks presynaptic alpha-2 autoreceptors and heteroreceptors, releasing the brake on both norepinephrine and serotonin release.
• Potent 5-HT2A, 5-HT2C, and 5-HT3 antagonism channels the increased serotonin toward 5-HT1A transmission rather than the other subtypes.
• Blocking 5-HT2A and 5-HT2C prevents the insomnia, agitation, and sexual dysfunction that follow unopposed serotonin reuptake inhibition.
• Blocking 5-HT3 prevents nausea and diarrhea, which is why mirtazapine is far better tolerated than SSRIs in the gut.
• Potent histamine H1 antagonism produces the sedation and appetite stimulation that dominate at low doses and lessen as the dose rises.

Pharmacokinetics

• Rapidly and completely absorbed with about 50 percent bioavailability after first-pass metabolism; food has minimal effect.
• Half-life is 20 to 40 hours and is longer in women and older adults, comfortably supporting once-daily bedtime dosing.
• Metabolized by CYP2D6, CYP1A2, and CYP3A4, so no single enzyme dominates and interaction risk is only moderate.
• The demethyl metabolite is weakly active and contributes little; steady state is reached in about five days.
• Clearance falls by roughly 30 percent in moderate renal impairment, 50 percent in severe impairment, and about 30 percent in cirrhosis.

Dosing

• Start 15 mg PO at bedtime; some clinicians begin at 7.5 mg when sedation is the main goal or the patient is frail.
• Increase at intervals of no less than one to two weeks toward the usual target of 30 mg/day, with a maximum of 45 mg/day.
• Sedation is often worse at 7.5 to 15 mg than at 30 mg, because noradrenergic activation increases relative to antihistaminic effect.
• Available as 7.5, 15, 30, and 45 mg tablets and as 15, 30, and 45 mg orally disintegrating tablets useful when swallowing is impaired.
• Reduce the dose and titrate slowly in renal or hepatic impairment, where clearance falls by 30 to 50 percent.
• Taper over two to four weeks when stopping, since abrupt cessation can produce nausea, dizziness, agitation, and rebound insomnia.

Adverse effects

• Somnolence occurs in over 50 percent of patients and is the leading reason for discontinuation, particularly at doses below 30 mg/day.
• Increased appetite affects about 17 percent and clinically meaningful weight gain about 12 percent, often several kilograms in the first year.
• Dry mouth, constipation, dizziness, and elevated cholesterol and triglycerides are common and warrant metabolic monitoring.
• Agranulocytosis or severe neutropenia occurred in roughly 1.1 per 1000 patients in premarketing trials, usually within the first two months.
• Sexual dysfunction and gastrointestinal upset are notably rare, which is the main reason to choose mirtazapine over an SSRI.
• QT prolongation and torsades de pointes have been reported, chiefly in overdose or with other QT-prolonging drugs.

Monitoring

• Obtain a complete blood count if fever, sore throat, stomatitis, or other signs of infection develop, and stop the drug pending results.
• Check weight at baseline and every one to three months, and obtain fasting lipids and glucose at baseline and annually.
• Assess suicidality, activation, and daytime sedation weekly for the first four weeks and after each dose change.
• Track sleep and appetite as early markers of effect, since both often improve within days while mood takes weeks.
• Obtain an ECG only in patients with cardiac disease or on other QT-prolonging medications, since routine ECG is not required.

Interactions

• Contraindicated with MAOIs and within 14 days of stopping one, and with linezolid or intravenous methylene blue.
• Additive sedation with benzodiazepines, opioids, alcohol, and antihistamines is the most common clinically relevant interaction.
• Strong CYP3A4 inhibitors such as ketoconazole and ritonavir raise mirtazapine levels, while carbamazepine and rifampin lower them markedly.
• Serotonin syndrome is possible when combined with SSRIs, SNRIs, tramadol, or triptans, although 5-HT2 and 5-HT3 blockade lower the risk.
• Additive QT risk with methadone, antipsychotics, ondansetron, and class III antiarrhythmics warrants attention in medically complex patients.

Special populations

• Pregnancy data are moderate and show no clear teratogenic signal, and its antiemetic action can help hyperemesis-associated depression.
• Relative infant dose in breast milk is under 2 percent, so mirtazapine is generally considered compatible with breastfeeding.
• Not approved in pediatrics, and a controlled pediatric depression trial failed to separate from placebo while producing weight gain.
• Often favored in frail older adults with insomnia, poor appetite, and weight loss, but falls and sedation must be weighed carefully.
• Reduce the dose in renal impairment, where clearance falls by 30 to 50 percent, and in cirrhosis, where it falls by about 30 percent.

Clinical pearls

• Lower doses are more sedating; raising to 30 mg often reduces daytime somnolence rather than worsening it.
• Best antidepressant when insomnia, nausea, and weight loss coexist with depression.
• Get a CBC for any fever or sore throat: agranulocytosis is rare but real, about 1 in 1000.