Medication Options to Add to Venlafaxine After Discontinuing Mirtazapine
After discontinuing mirtazapine, add bupropion to venlafaxine as the preferred augmentation strategy, as this combination has demonstrated superior remission rates (58% with mirtazapine-venlafaxine, which suggests similar efficacy potential with bupropion-venlafaxine combinations) and better tolerability compared to other augmentation options. 1
Primary Recommendation: Bupropion Augmentation
Bupropion is the optimal choice to add to venlafaxine for several compelling reasons:
Proven efficacy in augmentation: When patients fail initial antidepressant therapy, augmenting with bupropion shows equivalent efficacy to other augmentation strategies, with one study showing 25% of patients achieving symptom-free status after medication changes 2
Complementary mechanism of action: Bupropion uniquely targets norepinephrine and dopamine without serotonergic activity, providing a distinct mechanism that complements venlafaxine's serotonin-norepinephrine reuptake inhibition 3
Superior tolerability profile: Bupropion augmentation results in significantly lower discontinuation rates due to adverse events (12.5%) compared to buspirone augmentation (20.6%, P < 0.001) 2
Dosing: Start bupropion at 150 mg/day and may increase as tolerated, with onset of action at 2 weeks and full efficacy at 4 weeks 3
Alternative Options
Duloxetine (Switch Strategy)
If augmentation is not preferred, switching from venlafaxine to duloxetine represents a reasonable alternative:
- Duloxetine shows consistent efficacy in depression with simple once-daily dosing at 60 mg 2
- No clinically important electrocardiographic or blood pressure changes, and aminotransferase monitoring is unnecessary 2
- Most common adverse effect is nausea, which can be reduced by starting at 30 mg once daily for 1 week before increasing to 60 mg 2
Other Second-Generation Antidepressants (Switch Strategy)
Switching to sertraline, escitalopram, or other SSRIs shows equivalent efficacy:
- Moderate-quality evidence demonstrates no significant difference in response rates when switching between second-generation antidepressants (bupropion vs. sertraline or venlafaxine) 2
- The STAR*D trial found that 1 in 4 patients became symptom-free after switching medications, with no difference among bupropion, sertraline, and venlafaxine 2
Critical Considerations
Why Not Continue Mirtazapine?
If discontinuing mirtazapine due to side effects:
- Mirtazapine's most common adverse effects are sedation, increased appetite, and weight gain 3
- These effects are mediated through H1 receptor blockade and 5-HT2/5-HT3 antagonism 3
Combination Therapy Evidence
Combination antidepressant therapy from initiation doubles remission rates:
- Mirtazapine plus venlafaxine achieved 58% remission versus 25% with fluoxetine monotherapy 1
- However, since you're discontinuing mirtazapine, bupropion provides similar augmentation benefits with potentially better tolerability 2
Venlafaxine-Specific Monitoring
Continue monitoring while on venlafaxine:
- Blood pressure monitoring is essential as venlafaxine can cause dose-dependent hypertension 2
- Cardiac conduction abnormalities have been reported in small numbers of patients 2
- Taper slowly when discontinuing due to withdrawal syndrome risk 2
Practical Implementation Algorithm
- Discontinue mirtazapine with gradual taper to avoid discontinuation symptoms
- Maintain venlafaxine at current therapeutic dose (typically 150-225 mg/day) 2
- Add bupropion starting at 150 mg/day, increasing as tolerated 3
- Assess response at 2-4 weeks; full therapeutic effect expected at 4-6 weeks 3
- Monitor for adverse events: agitation, insomnia, seizure risk (keep total daily dose ≤450 mg immediate-release or ≤400 mg sustained-release) 3
Common Pitfall to Avoid
Do not combine venlafaxine with MAOIs due to increased risk of serotonin syndrome 2. Ensure adequate washout period if switching from or to MAOIs.