Introduction
Mirtazapine is a tetracyclic antidepressant (TeCA) that was first approved by the FDA in 1996. It is classified as a noradrenergic and specific serotonergic antidepressant (NaSSA) and represents a distinct pharmacological approach to treating depression. Unlike selective serotonin reuptake inhibitors (SSRIs), mirtazapine's unique mechanism provides an alternative treatment option, particularly for patients who cannot tolerate SSRI side effects or who have specific symptom profiles.
Mechanism of Action
Mirtazapine exerts its antidepressant effects through dual modulation of monoaminergic systems. It acts as a potent antagonist at central presynaptic α₂-adrenergic autoreceptors and heteroreceptors, which enhances noradrenergic and serotonergic neurotransmission. Additionally, mirtazapine is a potent antagonist of 5-HT₂ and 5-HT₃ receptors, which contributes to its anxiolytic effects and reduced incidence of serotonin-related side effects. The drug also has significant histamine H₁ receptor antagonism, which accounts for its sedative properties.
Indications
- FDA-approved for the treatment of major depressive disorder (MDD)
- Off-label uses include:
- Generalized anxiety disorder - Post-traumatic stress disorder - Insomnia (particularly with comorbid depression) - Appetite stimulation in cachexic patients - Antiemetic effects in chemotherapy-induced nausea
Dosage and Administration
Initial dose: 15 mg orally once daily at bedtime Dose titration: May increase to 30-45 mg daily based on response and tolerance Maximum dose: 45 mg daily Special populations:- Geriatric patients: Consider lower starting dose (7.5 mg)
- Hepatic impairment: Use caution, consider dose reduction
- Renal impairment (CrCl <30 mL/min): Use caution
- Pediatric patients: Not recommended under age 18
Pharmacokinetics
Absorption: Well absorbed orally, bioavailability approximately 50% Distribution: Volume of distribution ~4.5 L/kg, protein binding ~85% Metabolism: Extensive hepatic metabolism via CYP450 enzymes (primarily CYP1A2, CYP2D6, CYP3A4) Elimination: Half-life 20-40 hours, excreted primarily in urine (75%) and feces (15%)Contraindications
- Known hypersensitivity to mirtazapine or any component of the formulation
- Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI therapy
- Patients with severe hepatic impairment
Warnings and Precautions
- Suicidal ideation: Monitor for worsening depression or emergence of suicidal thoughts
- Serotonin syndrome: Risk increased with concomitant serotonergic drugs
- Agranulocytosis: Rare but serious blood dyscrasia reported
- Metabolic effects: Weight gain, hypercholesterolemia, and hypertriglyceridemia may occur
- QT prolongation: Use caution in patients with risk factors for QT prolongation
- Withdrawal symptoms: Taper gradually when discontinuing after prolonged use
Drug Interactions
- MAOIs: Contraindicated due to risk of serotonin syndrome
- CNS depressants: Enhanced sedative effects with alcohol, benzodiazepines, opioids
- Strong CYP3A4 inhibitors: May increase mirtazapine levels (e.g., ketoconazole)
- Strong CYP3A4 inducers: May decrease mirtazapine levels (e.g., carbamazepine)
- Serotonergic drugs: Increased risk of serotonin syndrome with tramadol, linezolid
Adverse Effects
Common (≥10%):- Somnolence (54%)
- Increased appetite (17%)
- Weight gain (12%)
- Dry mouth (25%)
- Constipation (13%)
- Agranulocytosis
- Seizures
- Serotonin syndrome
- Orthostatic hypotension
- Hyponatremia
- Suicidal ideation
Monitoring Parameters
- Mental status and suicide risk assessment at initiation and regularly thereafter
- Body weight at baseline and periodically during treatment
- Complete blood count if signs of infection develop
- Lipid profile periodically with long-term use
- Liver function tests in patients with hepatic impairment
- Therapeutic response after 4-6 weeks of treatment
Patient Education
- Take medication at bedtime due to sedative effects
- Do not abruptly discontinue medication; taper under medical supervision
- Avoid alcohol and other CNS depressants
- Report any signs of infection (fever, sore throat) immediately
- Be aware of potential weight gain and discuss dietary strategies
- Do not take with MAOIs or within 14 days of stopping MAOI therapy
- Use caution when driving or operating machinery until response is known
- Inform all healthcare providers about mirtazapine use
References
1. FDA Prescribing Information: Remeron (mirtazapine) Tablets 2. Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528 3. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001;7(3):249-264 4. Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors: serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord. 1998;51(3):215-235 5. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366