Are mirtazapine and Cymbalta (duloxetine) contraindicated when used together?

Mirtazapine and Duloxetine (Cymbalta) Combination Safety

Mirtazapine and duloxetine (Cymbalta) are not absolutely contraindicated when used together, but this combination requires careful monitoring due to potential serotonergic effects and should generally be avoided unless under specialist supervision.

Pharmacological Considerations

Mechanism of Action

• Duloxetine (Cymbalta): Serotonin-norepinephrine reuptake inhibitor (SNRI) that increases both serotonin and norepinephrine levels
• Mirtazapine: Noradrenergic and specific serotonergic antidepressant (NaSSA) that enhances noradrenergic neurotransmission and indirectly increases serotonergic neurotransmission while blocking 5-HT2 and 5-HT3 receptors 1

Potential Risks

1. Serotonin Syndrome Risk:

   • The combination can potentially lead to excessive serotonergic activity
   • Case reports document serotonin syndrome with mirtazapine combined with other serotonergic agents 2, 3
   • Symptoms include agitation, confusion, hyperthermia, myoclonus, hyperreflexia, and autonomic instability

2. Additive Side Effects:

   • Both medications can cause sedation, dizziness, and weight gain
   • Combined use may amplify these effects

Evidence Assessment

The evidence regarding this specific combination is limited, but several guidelines provide relevant information:

• The American Heart Association's 2024 statement mentions that mirtazapine appears safe in cardiovascular disease and can be used for sleep and appetite stimulation, while SNRIs like duloxetine have slightly higher discontinuation rates due to adverse effects compared to SSRIs 4

• While not explicitly addressing this combination, clinical guidelines acknowledge that combinations of antidepressants from different classes may be used in clinical practice 4

• Case reports have documented serotonin syndrome with mirtazapine combined with other serotonergic medications, suggesting caution with this combination 2, 3

Clinical Decision Algorithm

When to Consider This Combination:

1. Treatment-resistant depression not responding to single-agent therapy
2. Specific symptom targeting (e.g., using mirtazapine's sedative and appetite-stimulating properties alongside duloxetine's pain relief effects)

When to Avoid This Combination:

1. History of serotonin syndrome
2. Significant hepatic or renal impairment
3. Elderly patients with multiple comorbidities
4. Patients on other serotonergic medications

Monitoring Requirements If Used:

• Initial phase: Weekly monitoring for signs of serotonin syndrome
• Education: Inform patients about warning signs (confusion, agitation, tremor, sweating, fever)
• Start low: Begin with lower doses of both medications
• Titrate slowly: Increase doses gradually with close monitoring

Safer Alternatives

If combination antidepressant therapy is needed:

• Mirtazapine + SSRI (particularly sertraline, which has minimal drug interactions) 5
• Bupropion + SSRI/SNRI (different mechanism with less serotonergic overlap)
• Augmentation strategies with non-antidepressants (e.g., atypical antipsychotics)

Conclusion

While not absolutely contraindicated, the combination of mirtazapine and duloxetine should be approached with caution due to the theoretical risk of serotonin syndrome and additive side effects. Alternative combinations with better documented safety profiles should be considered first, and if this combination is deemed necessary, close monitoring is essential, particularly during initiation and dose adjustments.