From the FDA Drug Label
Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of mirtazapine tablets with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Serotonin Syndrome — The development of a potentially life–threatening serotonin syndrome may occur with SNRIs and SSRIs, including Prozac treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs).
Combination of Mirtazapine and SSRIs: The combination of mirtazapine and SSRIs, such as fluoxetine, may increase the risk of serotonin syndrome, a potentially life-threatening condition.
- Key Considerations:
- Concomitant use of serotonergic drugs may increase the risk of serotonin syndrome.
- Patients should be cautioned about the risk of serotonin syndrome and instructed to report any symptoms to their healthcare provider.
- The development of serotonin syndrome may occur with concomitant use of serotonergic drugs, including triptans, and with drugs that impair metabolism of serotonin, including MAOIs.
- Clinical Decision: The combination of mirtazapine and fluoxetine should be used with caution and careful monitoring for signs and symptoms of serotonin syndrome 1 2.
From the Research
Mirtazapine can be safely combined with selective serotonin reuptake inhibitors (SSRIs) like fluoxetine for treating depression, with the most recent and highest quality study suggesting that the combination is effective and well-tolerated 3. The combination of mirtazapine and SSRIs, such as fluoxetine, is particularly useful for patients who haven't responded adequately to single-agent therapy.
- Typical dosing involves standard SSRI dosing (such as fluoxetine 20-40mg daily) along with mirtazapine 15-45mg at bedtime.
- The combination works well because these medications have complementary mechanisms of action - SSRIs increase serotonin levels by blocking reuptake, while mirtazapine enhances both serotonin and norepinephrine neurotransmission through different receptor interactions.
- This combination may provide better symptom relief, particularly for patients with depression accompanied by anxiety, insomnia, or poor appetite, as mirtazapine's sedating and appetite-stimulating properties can counteract SSRI-induced insomnia or appetite suppression. However, patients should be monitored for potential side effects including increased sedation, weight gain, and rarely, serotonin syndrome, as noted in studies such as 4 and 5. The most recent study 3 suggests that the lower range of the licensed dose of SSRIs, such as fluoxetine, achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression, which supports the use of this combination. It is essential to initiate this combination under medical supervision with regular follow-up to assess effectiveness and manage any side effects, as recommended by various studies, including 6.