Is it safe to combine Remeron (mirtazapine) with venlafaxine?

Combining Mirtazapine with Venlafaxine

The combination of mirtazapine (Remeron) and venlafaxine is generally safe and can be used together, particularly in treatment-resistant depression, though it should not be first-line therapy and requires monitoring for serotonin syndrome and increased adverse effects. 1, 2

When This Combination Is Appropriate

Sequential monotherapy switching should be attempted before combination therapy. The American College of Physicians recommends trying venlafaxine or sertraline as monotherapy switches first when initial antidepressant treatment fails, rather than immediately combining medications 1. However, when monotherapy approaches have been exhausted, the venlafaxine-mirtazapine combination becomes a reasonable option 3, 4.

Clinical Evidence for Combination Use

The combination has demonstrated efficacy in treatment-resistant depression:

• Response rates of 44% at 4 weeks and 50% at 8 weeks were observed in patients with persistent depressive illness who had failed an average of 2.5 previous antidepressant trials 3
• At 6 months, 56% of patients showed significant clinical response (75% of those still receiving treatment) 3
• A prospective case series showed 81.8% response rate and 27.3% remission rate after approximately 8 weeks of combination treatment in patients who had failed at least one prior antidepressant trial 4

However, the largest randomized controlled trial (CO-MED study with 665 patients) found no superiority of venlafaxine-mirtazapine combination over escitalopram monotherapy, with remission rates of 37.7% versus 38.8% at 12 weeks 2. This suggests the combination may be most useful in specific treatment-resistant populations rather than as routine first-step therapy.

Safety Considerations and Monitoring

Serotonin Syndrome Risk

The primary safety concern is serotonin syndrome, though it remains rare with this specific combination. 5 The risk increases when additional serotonergic agents are added:

• One case report documented serotonin syndrome when tramadol was added to a patient already taking venlafaxine and mirtazapine, presenting with agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever 5
• Avoid combining with MAOIs (contraindicated due to serotonin syndrome risk) 6
• Monitor for symptoms: agitation, confusion, tremor, myoclonus, hyperreflexia, diaphoresis, hyperthermia, and autonomic instability 5

Common Adverse Effects

The venlafaxine-mirtazapine combination has a higher adverse effect burden than monotherapy:

• Mean 5.7 worsening adverse events versus 4.7 with escitalopram monotherapy 2
• Most common side effects: sedation (19%) and weight gain (19%) 3
• Nearly half of patients (45%) experience significant side effects, though only 5-14% discontinue due to adverse effects 3, 4
• Sustained hypertension and increased blood pressure can occur with venlafaxine, particularly at doses >150mg 6

Required Monitoring

• Blood pressure and pulse monitoring is essential, especially with venlafaxine doses above 150mg 6
• Height and weight tracking to monitor for weight gain 6
• Reassess symptoms at 2,4, and 8 weeks after initiating combination 1
• Monitor for behavioral activation, hypomania, or mania 6
• Screen for suicidal ideation, particularly in patients under age 24 6

Dosing Strategy

Clinical response typically occurs at moderate to high doses of both agents 3:

• Venlafaxine extended-release: Start 37.5-75mg daily, titrate to 150-300mg daily 1, 2
• Mirtazapine: Titrate up to 45mg daily 2, 3
• Allow 6-8 weeks at therapeutic doses before declaring treatment failure, as 38% of patients don't respond to initial therapy 1

Critical Caveats

Discontinuation syndrome is a significant concern with both medications. Both venlafaxine and mirtazapine require slow tapering when discontinuing to avoid withdrawal symptoms 6. Venlafaxine has been particularly associated with discontinuation symptoms and has higher overdose fatality risk compared to other SNRIs 6.

This combination should not replace evidence-based first-line treatments. The American College of Physicians guidelines emphasize that second-generation antidepressants generally do not differ significantly in efficacy for acute-phase major depressive disorder 6, making the added adverse effect burden of combination therapy unjustified as initial treatment.