Combining Mirtazapine and Sertraline
The combination of mirtazapine and sertraline can be used together with caution, but requires careful monitoring for serotonin syndrome, particularly during the first 24-48 hours after initiation or dose changes, as both are serotonergic agents that increase the risk of this potentially life-threatening condition. 1
Key Safety Considerations
Serotonin Syndrome Risk
When combining two non-MAOI serotonergic drugs like mirtazapine and sertraline, start the second agent at a low dose, increase slowly, and monitor closely for symptoms, especially in the first 24-48 hours after dosage changes. 1
The FDA drug label for mirtazapine explicitly warns that "the concomitant use of serotonergic drugs with mirtazapine tablets increases the risk of serotonin syndrome" and specifically lists SSRIs (including sertraline) as examples of drugs that increase this risk. 2 Similarly, the sertraline label warns about serotonin syndrome when used with other serotonergic drugs. 3
Monitor for these serotonin syndrome symptoms:
- Mental status changes: confusion, agitation, anxiety, hallucinations, delirium, coma 1, 2, 3
- Neuromuscular hyperactivity: tremors, clonus, hyperreflexia, muscle rigidity, myoclonus 1, 2, 3
- Autonomic hyperactivity: hypertension, tachycardia, arrhythmias, tachypnea, diaphoresis, shivering, vomiting, diarrhea 1, 2, 3
- Advanced symptoms: fever, seizures, arrhythmias, unconsciousness (potentially fatal) 1
Clinical Evidence on Combination Therapy
The MIR trial (2018), the highest quality study on this specific combination, found no clinically important benefit when adding mirtazapine to SSRIs/SNRIs in treatment-resistant depression. 4 At 12 weeks, the difference in depression scores was only -1.83 points (95% CI -3.92 to 0.27), smaller than the minimum clinically important difference, and this benefit diminished further at 24 weeks and 12 months. 4
More participants in the mirtazapine combination group withdrew due to adverse events (46 vs. 9 participants), and the combination was not cost-effective. 4
Practical Prescribing Algorithm
If you decide to combine these medications despite limited efficacy evidence:
Ensure the patient is stable on sertraline first - confirm adequate dose and duration (at least 6 weeks) 4
Start mirtazapine at 15 mg daily at bedtime (lower than standard starting dose for monotherapy) 1, 2
Monitor intensively for the first 48 hours after starting and after any dose increase 1
Increase to 30 mg after 2 weeks only if tolerated and no signs of serotonin syndrome 2, 4
Discontinue both medications immediately if serotonin syndrome symptoms emerge and provide supportive care with continuous cardiac monitoring 1, 2, 3
Additional Safety Concerns
QTc prolongation: Both medications can prolong the QTc interval, increasing risk when combined. 1, 2 Exercise caution in patients with cardiovascular disease or family history of QT prolongation. 2
Drug interactions: Sertraline may interact with drugs metabolized by CYP2D6. 1 Monitor for increased side effects if the patient is on other medications metabolized by this pathway. 1
Weight gain and sedation: Mirtazapine commonly causes increased appetite, weight gain, and sedation. 2, 5 In pediatric trials, 49% of patients gained ≥7% body weight. 2
Important Caveats
Mirtazapine alone has been shown to have faster onset of action (2-4 weeks) compared to SSRIs like sertraline, but efficacy equalizes after 4 weeks. 1 This suggests that switching rather than combining might be equally effective with fewer risks.
There is evidence that mirtazapine may have lower serotonergic potency than previously thought - it cannot precipitate serotonin toxicity in overdose when used alone and may not cause serotonin syndrome when mixed with MAOIs in the same way other serotonergic drugs do. 6 However, this does not eliminate risk when combined with potent SSRIs like sertraline.
Inform patients about the increased risk and ensure they understand warning signs of serotonin syndrome that require immediate medical attention. 2, 3