Combination of Bupropion and Mirtazapine for Treatment-Resistant Depression
The combination of bupropion (Wellbutrin) and mirtazapine primarily treats treatment-resistant major depressive disorder (MDD), particularly in patients with accompanying symptoms of anxiety, insomnia, and sexual dysfunction. This combination leverages complementary mechanisms of action to address multiple neurotransmitter systems that may be dysregulated in complex depression cases.
Mechanism of Action and Complementary Effects
Bupropion: Acts primarily as a dopamine-norepinephrine reuptake inhibitor with minimal effect on serotonin 1, 2
- Provides activation, energy, and motivation improvement
- Associated with less sexual dysfunction than SSRIs/SNRIs
- Particularly helpful for fatigue and concentration difficulties
Mirtazapine: Acts as an α2-adrenergic antagonist and 5-HT2/5-HT3 receptor antagonist 3, 4
- Enhances both noradrenergic and serotonergic neurotransmission
- Provides anxiolytic and sleep-promoting effects
- Has a faster onset of action compared to many antidepressants
Clinical Applications
Treatment-Resistant Depression
The combination is particularly valuable for patients who have failed to respond adequately to first-line antidepressant monotherapy:
Evidence from the STAR*D trial showed that approximately 38% of patients do not achieve treatment response during 6-12 weeks of treatment with second-generation antidepressants, and 54% do not achieve remission 5
When initial therapy fails, adding a second agent with a different mechanism of action can be effective, with about 25% of patients becoming symptom-free after medication changes 5
Depression with Specific Symptom Clusters
This combination is particularly effective for depression accompanied by:
Anxiety: Mirtazapine provides anxiolytic effects through 5-HT2A antagonism 4
Sleep disturbances: Mirtazapine's histamine H1 receptor antagonism promotes improved sleep quality and faster onset 6, 4
Sexual dysfunction: Bupropion can help counteract the sexual side effects often seen with other antidepressants 7, 2
Fatigue and low energy: Bupropion's dopaminergic effects can improve energy, motivation, and concentration 8, 2
Advantages of This Combination
Faster onset of action: Mirtazapine has demonstrated a significantly faster onset of action compared to SSRIs, with noticeable effects within the first 1-2 weeks 5, 9
Complementary side effect profiles: Bupropion's activating properties can offset mirtazapine's sedative effects 9
Broader neurotransmitter coverage: The combination addresses norepinephrine, dopamine, and serotonin systems through different mechanisms 9
Important Considerations and Precautions
Dosing:
Contraindications:
Monitoring:
- Watch for rare but serious side effects including seizures with bupropion and agranulocytosis with mirtazapine
- Monitor for changes in blood pressure, heart rate, and weight
Clinical Pearls
This combination may be particularly useful when a patient has partially responded to either medication alone but continues to have residual symptoms
Mirtazapine is best administered at bedtime due to its sedative properties, while bupropion should be given in the morning to minimize insomnia risk 6
The combination may be weight-neutral overall, as bupropion's tendency to suppress appetite may offset mirtazapine's tendency to increase appetite 9
While this combination is not explicitly endorsed in guidelines as first-line therapy, it represents a rational approach for treatment-resistant depression based on complementary mechanisms of action
When initiating this combination, start with one medication first, stabilize the dose, then add the second medication to better identify the source of any side effects that may emerge