Can mirtazapine and escitalopram (selective serotonin reuptake inhibitor (SSRI)) be given together to an adult patient with treatment-resistant depression?

Combining Mirtazapine and Escitalopram for Treatment-Resistant Depression

Direct Answer

Yes, mirtazapine and escitalopram can be given together, but the evidence for this specific combination in treatment-resistant depression is limited and does not demonstrate convincing clinical benefit. The largest and most rigorous trial found no clinically meaningful improvement when adding mirtazapine to SSRIs or SNRIs, with higher withdrawal rates due to adverse effects 1.

Evidence Quality and Strength

The MIR Trial: Highest Quality Evidence

The 2018 MIR randomized controlled trial (n=480) specifically evaluated adding mirtazapine to ongoing SSRI/SNRI therapy in treatment-resistant depression 1. This study found:

• No clinically meaningful benefit: The difference in depression scores at 12 weeks was -1.83 points on the BDI-II (95% CI -3.92 to 0.27), which was smaller than the minimum clinically important difference and the confidence interval included no effect 1
• Higher discontinuation rates: 46 patients in the mirtazapine group withdrew due to mild adverse effects versus only 9 in the placebo group 1
• Not cost-effective: Adding mirtazapine was not a cost-effective use of NHS resources 1
• Diminishing effect over time: Any small benefit observed at 12 weeks became even smaller at 24 weeks and disappeared entirely by 12 months 1

Supporting Evidence for Combination Therapy

Despite the MIR trial's negative findings, older observational data suggests some patients may respond 2:

• A 2007 case series (n=32) of venlafaxine-mirtazapine combination showed 50% response at 8 weeks and 56% at 6 months, though this was uncontrolled and used venlafaxine rather than escitalopram 2
• Historical reviews suggest mirtazapine may be effective as augmentation therapy in refractory depression, though this evidence is preliminary 3, 4

Clinical Decision Algorithm

When to Consider This Combination

Consider adding mirtazapine to escitalopram only if:

1. The patient has failed adequate trials (6+ weeks at therapeutic dose) of at least 2 different antidepressants 1
2. Specific target symptoms are present that mirtazapine addresses:
   • Severe insomnia requiring pharmacologic intervention 5, 6
   • Significant anxiety symptoms 6, 3
   • Poor appetite or weight loss 3, 4
3. The patient understands the limited evidence for benefit and accepts the risk of adverse effects 1

When to Avoid This Combination

Do not combine if:

• The patient is concerned about weight gain or sedation (the most common adverse effects) 3, 4, 2
• First-line treatment options have not been exhausted (switching to another SSRI, SNRI, or bupropion should be tried first) 5
• Cost is a significant concern, as combination therapy is not cost-effective 1

Practical Implementation

Dosing Strategy

If proceeding with combination therapy 1, 2:

• Start mirtazapine at 15 mg at bedtime for 2 weeks
• Increase to 30 mg at bedtime if tolerated
• Continue escitalopram at current therapeutic dose
• Clinical response typically requires moderate to high doses of both agents 2

Monitoring Requirements

Assess at 4 weeks for:

• Depression symptom improvement (expect 44% response rate at best) 2
• Adverse effects, particularly sedation (19% incidence) and weight gain (19% incidence) 2
• Medication adherence

Reassess at 8-12 weeks:

• If no response by 12 weeks, discontinue mirtazapine as further benefit is unlikely 1
• If partial response, continue and reassess at 6 months 2

Safety Considerations

Serotonin Syndrome Risk

While theoretically possible when combining serotonergic agents, mirtazapine's mechanism (alpha-2 antagonism enhancing serotonin release via 5-HT1 receptors) differs from SSRIs 3, 4. Monitor for:

• Agitation, confusion, tremor
• Hyperthermia, diaphoresis
• Neuromuscular hyperactivity

Drug Interactions

Mirtazapine has low potential for cytochrome P450 interactions and is unlikely to affect escitalopram metabolism 3, 4. This is one theoretical advantage of this combination over alternatives.

Alternative Strategies with Stronger Evidence

First-Line Alternatives to Combination Therapy

The American College of Physicians recommends these options before combining antidepressants 5:

1. Switch to a different antidepressant: Bupropion, venlafaxine, or another SSRI (25% achieve remission with switching) 5
2. Augment with cognitive behavioral therapy: Equally effective as medication augmentation with better long-term outcomes 5
3. Augment with bupropion: Similar efficacy to mirtazapine augmentation but different side effect profile 5

When Mirtazapine Monotherapy is Preferred

Mirtazapine as a single agent (not combined) is a valid first-line option when 6:

• Rapid onset of action is needed (faster than SSRIs) 6
• Depression is accompanied by insomnia 6
• Patient is elderly (specifically recommended for this population) 6

Critical Caveats

The combination is commonly used in clinical practice despite limited evidence - both general practitioners and patients expressed concerns about adding a second antidepressant in the MIR trial 1. This reflects the gap between practice patterns and evidence-based medicine in treatment-resistant depression.

Treatment-resistant depression remains an area of unmet need - the MIR trial authors note that more promising interventions include augmentation with atypical antipsychotics and transcranial magnetic stimulation rather than antidepressant combinations 1.