Combining Mirtazapine (Remeron) and Sertraline in Treatment-Resistant Depression
The combination of mirtazapine and sertraline can be used in treatment-resistant depression, though the evidence for this specific combination is limited and shows modest benefit at best. The largest trial (MIR study) found only a small, non-clinically significant reduction in depression scores when adding mirtazapine to SSRIs/SNRIs, with higher withdrawal rates due to adverse effects 1.
Evidence for Combination Therapy
Efficacy Data
The MIR randomized controlled trial (480 patients) added mirtazapine 15-30 mg to existing SSRI/SNRI therapy in treatment-resistant depression and found a difference of only -1.83 points on the BDI-II at 12 weeks, which was smaller than the minimum clinically important difference and not statistically significant (p=0.087) 1.
This modest benefit diminished further over time, with essentially no difference by 12 months 1.
More participants withdrew from mirtazapine due to adverse effects (46 vs. 9 participants), and the combination was not cost-effective 1.
Mechanism and Rationale
Mirtazapine works through dual enhancement of noradrenergic and serotonin 5-HT1 receptor-mediated neurotransmission, which differs mechanistically from SSRIs like sertraline 2.
Mirtazapine has shown faster onset of action (as early as 1 week) compared to some SSRIs in monotherapy trials 2, 3.
The drug is well-tolerated with minimal anticholinergic effects and lacks the gastrointestinal and sexual dysfunction commonly seen with SSRIs 2, 3.
Practical Prescribing Approach
When to Consider This Combination
Use this combination only after:
- Confirming adequate trial of sertraline alone (at least 6-8 weeks at therapeutic dose) 4
- Verifying medication adherence 1
- Ensuring sertraline is at maximum tolerated dose (up to 200 mg/day) 4
Dosing Strategy
- Start mirtazapine at 7.5-15 mg at bedtime while continuing sertraline 4, 1
- Increase to 30 mg after 2 weeks if tolerated 4, 1
- Maximum mirtazapine dose is 30-45 mg/day 4, 5
Monitoring Requirements
- Assess for serotonin syndrome symptoms: tremor, diarrhea, delirium, neuromuscular rigidity, hyperthermia 4
- Monitor for increased sedation, weight gain, and increased appetite (common with mirtazapine) 4, 2
- Evaluate response at 4-8 weeks using standardized depression scales 4
Important Safety Considerations
Serotonin Syndrome Risk
Combining two serotonergic agents increases risk of serotonin syndrome, which occurs in 14-16% of SSRI overdoses 4.
The combination must be ceased immediately if symptoms develop 6.
This risk is lower with mirtazapine than with other combinations (such as SSRI + SNRI) due to mirtazapine's unique mechanism 2.
Drug Interactions
Mirtazapine is unlikely to inhibit metabolism of sertraline, as it has minimal effect on CYP1A2, CYP2D6, or CYP3A4 enzymes 2.
Sertraline has less effect on metabolism of other medications compared to other SSRIs 4.
Alternative Strategies for Treatment-Resistant Depression
If the mirtazapine-sertraline combination fails or is not tolerated, consider:
Switching to a different monotherapy (bupropion, venlafaxine, or another SSRI) - the STAR*D trial showed 1 in 4 patients achieved remission with switching, with no difference between agents 4.
SNRIs like venlafaxine may be slightly more effective than SSRIs but have higher discontinuation rates due to nausea and vomiting 4.
Augmentation with lithium (150-300 mg/day targeting blood levels 0.2-0.6 mEq/L) 4.
Special Populations
Older Adults
Both sertraline and mirtazapine are preferred agents in older patients with depression 4.
Mirtazapine's sedating effects and appetite stimulation may be beneficial in elderly patients with insomnia and poor appetite 4.
Use lower starting doses and monitor for increased sedation and falls risk 4.
Common Pitfalls to Avoid
Do not combine without first ensuring adequate trial of monotherapy - 38% of patients don't respond to initial antidepressant, but switching may be as effective as combining 4.
Do not ignore the high withdrawal rate - nearly 20% of patients discontinued mirtazapine due to adverse effects in the MIR trial 1.
Do not expect dramatic improvement - the evidence shows only modest benefit that may not be clinically meaningful 1.
Do not use this as first-line therapy - all second-generation antidepressants are equally effective for treatment-naive patients 4.