Comprehensive Guide to Mirtazapine
Mirtazapine is a unique antidepressant with a distinct receptor binding profile that offers faster onset of action compared to SSRIs, making it particularly valuable for patients with depression accompanied by sleep disturbances, anxiety, or poor appetite. 1, 2
Indications and FDA-Approved Uses
- Major Depressive Disorder (MDD) - Primary FDA-approved indication 2
- Particularly effective in depression with:
Off-Label Uses
- Anxiety disorders including:
- Post-traumatic stress disorder (PTSD)
- Panic disorder
- Social anxiety disorder 3
- Obsessive-compulsive disorder (OCD)
- Undifferentiated somatoform disorder
- Adjunctive therapy in schizophrenia
- Insomnia (commonly used at lower doses) 3, 4
- Combination therapy with other antidepressants for treatment-resistant depression 5
Pharmacodynamics (Receptor Binding Profile)
Mirtazapine has a unique mechanism of action as a noradrenergic and specific serotonergic antidepressant (NaSSA) 3:
- α2-adrenergic receptor antagonist: Blocks presynaptic auto-receptors and heteroreceptors, increasing norepinephrine and serotonin release 2, 6
- 5-HT2 and 5-HT3 receptor antagonist: Blocks these receptors directly, reducing serotonin-related side effects like nausea, sexual dysfunction, and anxiety 2, 7
- H1-histamine receptor antagonist: Strong binding, responsible for sedation and increased appetite 2, 6
- 5-HT1A receptor: Indirect enhancement of 5-HT1A-mediated neurotransmission 6
- α1-adrenergic receptor antagonist: Moderate binding, can cause orthostatic hypotension 2
- Muscarinic receptor antagonist: Weak binding, minimal anticholinergic effects 2, 6
- No significant affinity for dopamine receptors 2
Pharmacokinetics
- Absorption: ~50% bioavailability; peak plasma concentrations reached in 2 hours 2
- Distribution: 85% protein-bound 2
- Metabolism:
- Extensively metabolized in the liver via:
- Demethylation and hydroxylation followed by glucuronide conjugation
- CYP2D6 and CYP1A2 involved in 8-hydroxy metabolite formation
- CYP3A4 responsible for N-desmethyl and N-oxide metabolite formation 2
- Several metabolites have pharmacological activity but at low plasma levels 2
- Extensively metabolized in the liver via:
- Elimination:
- Half-life: 20-40 hours (longer in females: 37 hours vs. 26 hours in males)
- 75% excreted in urine, 15% in feces
- Steady state reached within 5 days 2
Dosing and Administration
- Starting dose: 15 mg once daily at bedtime
- Therapeutic dose range: 15-45 mg daily
- Titration: Can increase to 30 mg after 1-2 weeks if needed, then to 45 mg if necessary
- Administration: Once daily dosing (typically at bedtime due to sedative effects) 2, 6
- Special populations:
- Elderly: Lower starting dose (7.5-15 mg) due to reduced clearance (40% lower in elderly males, 10% lower in elderly females)
- Hepatic impairment: 30% decrease in clearance; use lower doses
- Renal impairment: 30-50% decrease in clearance depending on severity; use lower doses 2
Clinical Efficacy
- Onset of action: Significantly faster than SSRIs, with effects often seen within 1-2 weeks 1, 7
- Efficacy: Comparable to tricyclic antidepressants and SSRIs for treating depression 1, 3
- Response rates: Similar to other antidepressants after 4-6 weeks of treatment 1
- Unique benefits:
Adverse Effects
Common adverse effects:
- Sedation/somnolence (most common, dose-dependent, may decrease at higher doses) 2, 7
- Increased appetite and weight gain (10-15% of patients) 2, 7
- Dry mouth (25% of patients) 4
- Dizziness 2
- Constipation 2
Less common but important adverse effects:
- Elevated cholesterol levels (3-4% increase) 6
- Transient elevations in liver enzymes 6
- Rare but serious hematological effects: agranulocytosis, neutropenia (monitor CBC if symptoms develop) 1
Drug Interactions
Significant interactions:
- Warfarin: Mirtazapine increases INR by approximately 0.2 2
- CYP3A4 inhibitors (e.g., ketoconazole): Increase mirtazapine levels by 40-50% 2
- CYP enzyme inducers (e.g., carbamazepine, phenytoin): Decrease mirtazapine levels by 45-60% 2
- MAO inhibitors: Contraindicated due to risk of serotonin syndrome 5
- Alcohol and CNS depressants: Additive sedation and cognitive/motor impairment 2
- QTc-prolonging medications: Potential increased risk of arrhythmias 2
- Cimetidine: Increases mirtazapine AUC by >50% 2
Special Considerations
Genetic polymorphisms:
- CYP2D6 poor metabolizers (5-8% of Caucasians) may have increased risk of adverse effects
- CYP2D6 ultrarapid metabolizers (1-7% of Caucasians) may have subtherapeutic plasma concentrations 1
Combination therapy:
- May be combined with trazodone for enhanced sleep benefits
- Potential benefit when combined with other antidepressants for treatment-resistant depression 5
Safety in overdose:
- Generally safer than TCAs in overdose
- Excessive sedation is the primary symptom 6
Discontinuation:
- Gradual tapering recommended to minimize withdrawal symptoms
- Consider tapering over 10-14 days after successful treatment 5
Practical Clinical Pearls
- Consider mirtazapine as first-line for depression with prominent insomnia, anxiety, or poor appetite
- The sedative effects are most pronounced at lower doses (15 mg) due to predominant H1 receptor binding; at higher doses (30-45 mg), the noradrenergic effects become more prominent
- Morning dosing may be considered if excessive daytime sedation occurs with bedtime dosing
- Weight gain can be beneficial in underweight or elderly patients but may be problematic in others
- Monitor for rare but serious hematological effects, especially if fever, sore throat, or other signs of infection develop
- Consider therapeutic drug monitoring in cases of suspected non-response due to ultrarapid metabolism or excessive side effects due to poor metabolism
Mirtazapine's unique receptor profile and faster onset of action make it a valuable option in the antidepressant armamentarium, particularly for patients with comorbid sleep disturbances or anxiety.