Mirtazapine for Anxiety: Starting Dose, Mechanism, and Side Effects
The recommended starting dose of mirtazapine for anxiety is 15 mg once daily at bedtime, though some guidelines suggest starting as low as 7.5 mg in elderly or frail patients. 1, 2
Starting Dose and Titration
- Begin with 15 mg orally once daily, preferably in the evening prior to sleep 1
- For elderly, debilitated, or frail patients, consider starting at 7.5 mg at bedtime 2
- If inadequate response occurs, increase the dose up to a maximum of 45 mg per day 1
- Do not make dose changes more frequently than every 1-2 weeks to allow sufficient time for evaluation of response 1
- Steady-state plasma levels are achieved within 5 days, though clinical response typically requires 2-4 weeks 3, 4
Important caveat: While anxiety symptoms may improve within the first week of treatment, full therapeutic assessment requires 6-8 weeks 5, 3. This is particularly relevant since mirtazapine is FDA-approved for major depressive disorder, not specifically for anxiety as a standalone indication 1.
Mechanism of Action for Anxiety
Mirtazapine works through a unique dual mechanism that differs from SSRIs:
- Blocks presynaptic alpha-2 adrenergic autoreceptors and heteroreceptors, which increases release of both norepinephrine and serotonin 1, 3
- Antagonizes postsynaptic 5-HT2 and 5-HT3 serotonin receptors while leaving 5-HT1A receptors unaffected, resulting in enhanced 5-HT1A-mediated serotonergic transmission 3, 6
- Blocks histamine H1 receptors, which contributes to its sedating and anxiolytic properties 1, 7
- The net result is increased noradrenergic activity combined with specific serotonergic activity, particularly at 5-HT1A receptors 1, 3
This mechanism is particularly effective when anxiety is accompanied by insomnia or sleep disturbances, as the H1 antagonism provides prominent sedative effects 2, 5, 7. The American Family Physician specifically notes that mirtazapine is "potent, well-tolerated, and promotes sleep" making it especially useful for anxiety with comorbid insomnia 5.
Side Effects Profile
Most Common Side Effects:
- Somnolence/sedation (most frequently reported, though paradoxically may be less frequent at higher doses) 1, 3, 7
- Increased appetite and weight gain 1, 3, 7
- Dry mouth 5, 6
- Dizziness 7, 8
- Constipation or diarrhea 5
Advantages Over Other Antidepressants:
- Minimal to no sexual dysfunction, unlike SSRIs 3, 6
- No significant gastrointestinal symptoms (nausea, diarrhea) that are common with SSRIs 3
- Minimal cardiovascular and anticholinergic effects 3
- No significant QTc prolongation at therapeutic doses 1
Important Safety Considerations:
- Screen for bipolar disorder before initiating treatment, as antidepressants can precipitate mania 1
- Gradually taper when discontinuing rather than stopping abruptly to minimize withdrawal symptoms 1
- Reduce dose in elderly patients due to decreased oral clearance 1
- Adjust dose with strong CYP3A4 inhibitors or inducers (e.g., decrease dose with ketoconazole, increase with carbamazepine) 1
- Allow at least 14 days between discontinuing an MAOI and starting mirtazapine, and vice versa 1
Metabolic Considerations:
- Weight gain occurs more frequently than with other antidepressants and should be expected 5
- Transient elevations in cholesterol levels and liver function tests may occur 4
- The sedation and appetite effects are attributed to H1 receptor antagonism, particularly at lower doses 7
Clinical pearl: The sedating effects make bedtime dosing ideal, and this side effect can be therapeutically advantageous in anxious patients with insomnia 2, 5, 3. However, patients should be counseled about potential next-day sedation, especially during the first 1-2 weeks of treatment 3.