Mirtazapine for Major Depressive Disorder
Mirtazapine is a second-generation antidepressant that works by blocking presynaptic alpha-2 adrenergic receptors and postsynaptic serotonin receptors (5-HT2 and 5-HT3), making it effective for treating major depressive disorder with a potentially faster onset of action than other antidepressants. 1, 2
Mechanism of Action
- Mirtazapine enhances both noradrenergic and serotonergic neurotransmission through its unique mechanism as an antagonist at central presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors 3
- It specifically enhances serotonergic transmission via 5-HT1 receptors while blocking 5-HT2 and 5-HT3 receptors, which helps reduce serotonin-related side effects 2
- Mirtazapine also acts as an antagonist of histamine (H1) receptors, peripheral α1-adrenergic receptors, and muscarinic receptors, which explains some of its clinical effects like sedation 3
Clinical Efficacy
- Mirtazapine is FDA-approved for the treatment of major depressive disorder in adults 3
- It has demonstrated efficacy equivalent to tricyclic antidepressants (amitriptyline, clomipramine, and doxepin) in clinical trials 1, 2
- Evidence suggests mirtazapine may have a faster onset of action than selective serotonin reuptake inhibitors (SSRIs), with noticeable improvements as early as 1-2 weeks of treatment 4, 5
- Mirtazapine has shown a significantly faster onset of action compared to citalopram, fluoxetine, paroxetine, and sertraline, though after 4 weeks, most response rates become similar 4
Dosing and Administration
- The recommended starting dosage is 15 mg/day administered as a single dose at bedtime 1
- Dose can be adjusted based on clinical response, with an effective dose range of 15-45 mg/day 5
- Mirtazapine has a half-life of about 20-40 hours, making it suitable for once-daily dosing 3
- For elderly patients, dose adjustments may be necessary as oral clearance is reduced compared to younger patients 3
Adverse Effects
- The most common adverse effects include somnolence (sedation), increased appetite, weight gain, and dizziness 1, 6
- Somnolence, the most commonly reported side effect, appears to be less frequent at higher dosages 2
- Unlike many other antidepressants, mirtazapine does not appear to be associated with sexual dysfunction 2
- Mirtazapine increases the risks of dry mouth and increased appetite but may decrease the risk of headaches compared to placebo 6
Special Considerations
- Mirtazapine may be particularly beneficial for patients with depression accompanied by anxiety symptoms, insomnia, or appetite/weight loss 2, 7
- The American College of Physicians recommends assessing patient status, therapeutic response, and adverse effects within 1-2 weeks of initiating therapy 4
- If patients do not have an adequate response within 6-8 weeks, treatment modification should be considered 4
- Treatment should continue for 4-9 months after a satisfactory response for patients with a first episode of major depression, and longer for those with multiple episodes 4
Monitoring and Follow-up
- Regular monitoring for therapeutic response and adverse effects should begin within 1-2 weeks of starting treatment 4
- Weight should be monitored regularly due to the potential for weight gain 6
- Assess for improvement in depressive symptoms, including mood, sleep, appetite, and energy levels 4
- For patients who do not achieve adequate response (approximately 38% of patients do not achieve response and 54% do not achieve remission with second-generation antidepressants), consider switching to another antidepressant 4
Drug Interactions
- Mirtazapine is metabolized by CYP1A2, CYP2D6, and CYP3A4 enzymes but is not a potent inhibitor or inducer of these enzymes 3, 2
- It has a low potential for interactions with drugs metabolized by CYP2D6, making it potentially useful for patients requiring multiple medications 7
- Caution should be exercised when combining with other CNS depressants due to potential additive sedative effects 1