Can fluoxetine (Prozac) and mirtazapine (Remeron) be taken together?

Fluoxetine and Mirtazapine Combination Therapy

Fluoxetine and mirtazapine can be safely taken together, but caution must be exercised due to the potential risk of serotonin syndrome, especially when initiating the combination. 1

Pharmacological Rationale

Fluoxetine (an SSRI) and mirtazapine (an atypical antidepressant) work through different mechanisms:

• Fluoxetine: Selectively inhibits serotonin reuptake
• Mirtazapine: Acts as an antagonist at presynaptic α2-adrenergic receptors and certain serotonin receptors (5-HT2 and 5-HT3)

This combination may be particularly beneficial for treatment-resistant depression due to their complementary mechanisms of action.

Efficacy Evidence

• Research suggests that combining mirtazapine with SSRIs like fluoxetine may improve response rates compared to monotherapy 2
• Mirtazapine has a faster onset of action compared to SSRIs like fluoxetine, which may provide earlier symptom relief 1
• The combination may be particularly helpful for patients with depression accompanied by anxiety or insomnia due to mirtazapine's sedative properties 1

Safety Considerations

Serotonin Syndrome Risk

While the combination can be used, there is a potential risk of serotonin syndrome, characterized by:

• Mental status changes (confusion, agitation)
• Neuromuscular hyperactivity (tremors, clonus, hyperreflexia)
• Autonomic hyperactivity (hypertension, tachycardia, diaphoresis) 1

Case reports have documented serotonin syndrome with similar combinations (e.g., fluvoxamine and mirtazapine) 3, although fluoxetine and mirtazapine specifically have been used together in clinical trials without major safety concerns 2.

Pharmacokinetic Interactions

• Fluoxetine is a potent inhibitor of CYP2D6 and moderate inhibitor of CYP3A4, which may increase mirtazapine concentrations
• Similar interactions have been documented between fluvoxamine and mirtazapine, where fluvoxamine increased mirtazapine concentrations three- to fourfold 4

Practical Recommendations

1. Start with lower doses:

   • Begin with lower doses of both medications when using them in combination
   • Consider starting mirtazapine at 7.5-15mg at bedtime

2. Monitor closely for:

   • Signs of serotonin syndrome, especially within the first 24-48 hours after combining or changing doses 1
   • Sedation (mirtazapine can cause significant sedation, especially at lower doses)
   • Weight gain (mirtazapine may increase appetite)

3. Dose adjustments:

   • Adjust doses based on clinical response and side effects
   • Be aware that fluoxetine may increase mirtazapine blood levels, potentially requiring lower mirtazapine doses

4. Contraindications:

   • Do not combine either medication with MAOIs due to high risk of serotonin syndrome 1
   • Use with caution in patients taking other serotonergic medications

Conclusion

The combination of fluoxetine and mirtazapine can be an effective strategy for treatment-resistant depression, but requires careful monitoring for potential interactions and side effects, particularly serotonin syndrome. The complementary mechanisms may provide benefits for patients who haven't responded adequately to monotherapy.