Can mirtazapine be added to Effexor (venlafaxine)?

Combining Mirtazapine with Venlafaxine (Effexor)

Yes, mirtazapine can be safely added to venlafaxine (Effexor) as a combination therapy for treatment-resistant depression, with studies showing response rates of 44-50% at 4-8 weeks and up to 75% at 6 months for patients who failed previous antidepressant trials. 1, 2

Rationale for Combination

This combination is particularly effective because:

• Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI)
• Mirtazapine works through different mechanisms (α2-adrenergic antagonism and 5-HT2/5-HT3 receptor blockade)
• The synergistic actions target multiple neurotransmitter systems simultaneously

Dosing Recommendations

1. Starting dose for mirtazapine: 15 mg once daily at bedtime 3
2. Titration: Increase according to response and tolerability
3. Target dose: Up to 45 mg once daily 3
4. Continue venlafaxine: Maintain current effective dose

Benefits of Adding Mirtazapine

• Faster onset of action: Mirtazapine has demonstrated significantly faster onset compared to SSRIs 3
• Complementary effects: May address symptoms not fully controlled by venlafaxine alone
• Sleep improvement: Sedating properties help with insomnia 4
• Appetite stimulation: Beneficial for patients with poor appetite 3

Monitoring for Side Effects

• Common side effects of mirtazapine 3:

  • Sleep disorders (initially sedation)
  • Constipation or diarrhea
  • Increased appetite and weight gain
  • Headache and fatigue

• Important safety concern: Risk of serotonin syndrome when combining these medications 5

  • Monitor for: agitation, confusion, shivering, diaphoresis, myoclonus, hyperreflexia, tachycardia, and fever
  • Particularly important when adding other serotonergic medications (e.g., tramadol)

Drug Interactions

• Contraindicated with MAOIs: Do not use this combination within 14 days of MAOI use 6
• Other serotonergic drugs: Use caution when adding other medications that affect serotonin 6
• CYP3A inhibitors/inducers: May require dose adjustments of mirtazapine 6

Evidence for Efficacy

• A prospective case series of 22 patients with treatment-resistant depression showed 2:

  • Response rate of 81.8% after approximately 8 weeks
  • Remission rate of 27.3%
  • Only one patient unable to tolerate the combination

• Another study of 32 patients with persistent depression showed 1:

  • 44% response rate at 4 weeks
  • 50% response rate at 8 weeks
  • 56% significant response at 6 months (75% of those still on treatment)

Cardiovascular Considerations

For patients with cardiovascular disease, this combination requires careful monitoring as:

• Mirtazapine has been shown to be safe in cardiovascular disease 3
• Venlafaxine may cause hypertension at higher doses 3

Conclusion

The venlafaxine-mirtazapine combination is a well-established approach for treatment-resistant depression with good efficacy data. The complementary mechanisms of action provide synergistic effects while addressing different symptom clusters. Close monitoring for serotonin syndrome is essential, particularly when initiating therapy or adjusting doses.