Best Medication to Add with Duloxetine for Depression
When duloxetine monotherapy fails to achieve remission in major depressive disorder, augmentation with bupropion is the most strongly supported strategy based on the highest quality evidence.
Second-Step Treatment Strategy: Augmentation vs. Switching
The 2023 American College of Physicians guideline, analyzing the landmark STAR*D trial, found that augmentation and switching strategies show similar efficacy when initial antidepressant treatment fails 1. However, augmentation allows you to maintain any partial benefit already achieved with duloxetine.
Bupropion as First-Line Augmentation
- Bupropion SR augmentation demonstrated equivalent efficacy to buspirone augmentation in the STAR*D trial, but with significantly better tolerability (12.5% vs. 20.6% discontinuation due to adverse events, P < 0.001) 1
- A 2012 head-to-head comparison showed that switching SSRI-resistant patients to either duloxetine or bupropion produced response rates of 60-70% and remission rates of 30-40%, with no significant differences between agents 2
- Bupropion's mechanism (dopamine/norepinephrine reuptake inhibition) complements duloxetine's serotonin/norepinephrine action, providing broader neurotransmitter coverage 2
Alternative Augmentation Options
If bupropion is contraindicated or ineffective:
- Aripiprazole augmentation showed numerically higher remission rates than bupropion (55.4% vs. 34.0%, P = 0.031) in one trial, though this study had higher risk of bias 1
- Mirtazapine augmentation can be considered, as trials showed no difference between switching to mirtazapine versus augmenting with it, suggesting augmentation is a viable strategy 1
When to Consider Switching Instead
Switch to a different antidepressant if:
- No response after 8 weeks at therapeutic duloxetine doses 3
- Intolerable side effects from duloxetine (particularly sustained hypertension, given duloxetine's propensity to increase blood pressure) 3
The STAR*D trial found no efficacy differences between switching to bupropion SR, escitalopram, sertraline, or venlafaxine 1. However, escitalopram may offer better tolerability than duloxetine (lower dropout rates: OR 1.62,95% CI 1.01-2.62) 4.
Critical Monitoring Considerations
When augmenting duloxetine:
- Monitor blood pressure and pulse regularly, as duloxetine can cause sustained hypertension 3
- Assess for serotonin syndrome risk, particularly when combining serotonergic agents 3
- Screen for suicidal ideation, especially in patients under age 24 and during the first weeks after medication changes 3
- Evaluate treatment response after 8 weeks of adequate dosing before declaring treatment failure 3
Common Pitfalls to Avoid
- Do not combine duloxetine with MAOIs due to serotonin syndrome risk 3
- Avoid abrupt discontinuation of duloxetine if switching; taper slowly to prevent discontinuation syndrome 3
- Do not assume all augmentation strategies are equal; bupropion has the best tolerability profile among medication augmentation options 1
- Recognize that cognitive therapy augmentation showed similar efficacy to medication augmentation in STAR*D, with numerically lower discontinuation rates (9.2% vs. 18.8%, P = 0.086) 1