Can you take trazodone, mirtazapine, and Cymbalta (duloxetine) together?

Combining Trazodone, Mirtazapine, and Duloxetine (Cymbalta)

Taking trazodone, mirtazapine, and duloxetine (Cymbalta) together is not recommended due to the significant risk of serotonin syndrome, which can be life-threatening. This combination of three serotonergic antidepressants substantially increases the risk of adverse effects without clear evidence of additional therapeutic benefit.

Risks of This Combination

Serotonin Syndrome Risk

• All three medications affect serotonergic neurotransmission through different mechanisms:

  • Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI)
  • Mirtazapine affects serotonergic transmission through 5-HT receptor modulation
  • Trazodone has serotonergic effects including 5-HT reuptake inhibition

• Signs and symptoms of serotonin syndrome include:

  • Mental status changes (agitation, hallucinations, delirium, coma)
  • Autonomic instability (tachycardia, labile blood pressure, dizziness, diaphoresis)
  • Neuromuscular symptoms (tremor, rigidity, myoclonus)
  • Gastrointestinal symptoms (nausea, vomiting, diarrhea) 1

Additional Safety Concerns

• Excessive sedation and CNS depression from the combined sedative effects of all three medications 2, 3
• Increased risk of QTc prolongation, particularly with mirtazapine 1
• Potential for additive anticholinergic effects
• Increased risk of hyponatremia 4
• Potential for drug interactions through CYP450 enzyme system 4

Evidence Against This Combination

The American Academy of Sleep Medicine clinical guideline states: "No research studies have been conducted to specifically examine such combinations [of multiple antidepressants]" 2. While the guideline mentions that combinations of two different classes may improve efficacy while minimizing toxicity, it does not support using three antidepressants simultaneously.

The FDA labeling for duloxetine specifically warns about the risk of serotonin syndrome when combined with other serotonergic drugs, and recommends monitoring for symptoms if concomitant use is clinically warranted 4.

Alternative Approaches

If the goal is to treat depression with insomnia:

1. Single agent approach: Consider using just mirtazapine, which has both antidepressant and strong sedative properties, particularly at lower doses (7.5-15mg) 3

2. Two-medication approach:

   • Duloxetine for antidepressant effect + low-dose trazodone for sleep
   • OR mirtazapine for sleep/depression + duloxetine for additional antidepressant effect

3. Non-antidepressant sleep aid: If using duloxetine as the primary antidepressant, consider a non-serotonergic sleep medication instead of adding both trazodone and mirtazapine

Monitoring If Combination Is Used

If, despite these warnings, this combination is deemed clinically necessary:

1. Start with the lowest possible doses of each medication
2. Introduce medications one at a time with at least 1-2 weeks between additions
3. Monitor closely for signs of serotonin syndrome, especially during initiation and dose changes
4. Check blood pressure, heart rate, and sodium levels regularly
5. Educate the patient about warning signs requiring immediate medical attention
6. Consider ECG monitoring for QTc prolongation

Conclusion

While there may be rare clinical scenarios where multiple antidepressants are considered, the triple combination of trazodone, mirtazapine, and duloxetine carries substantial risks without established benefits. The risk-benefit ratio strongly favors alternative approaches with fewer medications or different combinations.