Augmentation Strategy for Depression with Duloxetine
For patients with depression who have inadequate response to duloxetine monotherapy, augmentation with bupropion is the most strongly supported strategy based on the highest quality evidence. 1
Primary Augmentation Recommendation: Bupropion
Add bupropion SR (sustained-release) to ongoing duloxetine therapy when duloxetine alone fails to achieve remission after 8 weeks at therapeutic doses (60-120 mg daily). 1
Evidence Supporting Bupropion Augmentation:
- The landmark STAR*D trial demonstrated that bupropion SR augmentation achieved equivalent efficacy to buspirone augmentation, but with significantly superior tolerability (12.5% vs. 20.6% discontinuation due to adverse events, P < 0.001). 1
- Bupropion has the best tolerability profile among medication augmentation options for duloxetine. 1
- This strategy is endorsed by the American College of Physicians as having the strongest evidence base. 1
Practical Dosing for Bupropion Augmentation:
- Start bupropion SR at 150 mg once daily in the morning, then increase to 150 mg twice daily (300 mg total) after one week if tolerated. 1
- Continue duloxetine at its current therapeutic dose (typically 60-120 mg daily). 2
Alternative Augmentation Options
Aripiprazole (Second-Line):
- Consider aripiprazole augmentation if bupropion is contraindicated or not tolerated. 1
- One trial showed numerically higher remission rates with aripiprazole augmentation compared to bupropion (55.4% vs. 34.0%, P = 0.031), though this study had higher risk of bias. 1
- Start at 2-5 mg daily and titrate based on response and tolerability.
Mirtazapine (Third-Line):
- Mirtazapine augmentation is a viable alternative, as trials showed no difference between switching to mirtazapine versus augmenting with it. 1
- This suggests augmentation is as effective as switching for this agent. 1
- Start at 15 mg at bedtime and increase to 30-45 mg as needed.
When to Switch Instead of Augment
Switch to a different antidepressant rather than augment if:
- No response after 8 weeks at therapeutic duloxetine doses (60-120 mg daily). 1
- Intolerable side effects from duloxetine, particularly sustained hypertension (duloxetine commonly increases blood pressure and pulse). 2, 1, 3
- Severe adverse effects including hepatotoxicity (monitor for right upper quadrant pain, jaundice, dark urine, elevated transaminases). 2, 3
Switching Options (All Equally Effective):
The STAR*D trial found no efficacy differences when switching to: 1
- Bupropion SR
- Escitalopram
- Sertraline
- Venlafaxine
Critical Monitoring Requirements
Cardiovascular Monitoring:
- Monitor blood pressure and pulse regularly throughout duloxetine treatment, as it can cause sustained hypertension and tachycardia. 2, 1, 3
- Check blood pressure before starting duloxetine, during dose titration, and periodically during maintenance. 3
Serotonin Syndrome Risk:
- Assess for serotonin syndrome when combining duloxetine with other serotonergic agents (including bupropion, though risk is lower than with SSRIs). 1, 3
- Monitor for mental status changes, autonomic instability, neuromuscular symptoms, and gastrointestinal symptoms. 3
Suicidality Screening:
- Screen for suicidal ideation at every visit, especially in patients under age 24 and during the first weeks after medication changes or dose adjustments. 2, 1, 3
- Risk is highest during initial treatment and dose changes. 3
Treatment Response Assessment:
- Evaluate treatment response after 8 weeks of adequate dosing before declaring treatment failure. 1
- Use standardized rating scales (HAM-D, PHQ-9) to objectively track response. 2
Hepatic Monitoring:
- Monitor for signs of liver injury: right upper quadrant pain, jaundice, dark urine, hepatomegaly. 2, 3
- Duloxetine is contraindicated in patients with substantial alcohol use or chronic liver disease. 3
Critical Safety Considerations and Pitfalls
Absolute Contraindications:
- Never combine duloxetine with MAOIs (including linezolid or IV methylene blue) due to serotonin syndrome risk. 1, 3
- Allow 5 days after stopping duloxetine before starting an MAOI. 3
- Allow 14 days after stopping an MAOI before starting duloxetine. 3
Discontinuation Management:
- Avoid abrupt discontinuation of duloxetine when switching medications. 1, 3
- Taper slowly over 1-2 weeks to prevent discontinuation syndrome (dizziness, nausea, headache, paresthesias, irritability). 2, 3
Drug Interactions:
- Duloxetine is a moderate CYP2D6 inhibitor: it increases desipramine AUC 3-fold and can affect other CYP2D6 substrates. 3
- Monitor closely when combining with drugs metabolized by CYP2D6 (e.g., certain antipsychotics, beta-blockers, tricyclic antidepressants). 3
Bleeding Risk:
- Increased bleeding risk when duloxetine is combined with NSAIDs, aspirin, or anticoagulants (including warfarin). 3
- Counsel patients about this risk and monitor for signs of bleeding. 3
Orthostatic Hypotension and Falls:
- Risk of orthostatic hypotension, syncope, and falls, particularly in elderly patients and during the first week of therapy or after dose increases. 3
- Risk increases with concomitant antihypertensives or CYP1A2 inhibitors. 3
- Consider dose reduction if symptomatic orthostatic hypotension occurs. 3
Common Pitfalls to Avoid
Do not assume all augmentation strategies are equal: Bupropion has the best evidence and tolerability profile among medication augmentation options. 1
Do not overlook cognitive therapy augmentation: The STAR*D trial showed cognitive therapy augmentation had similar efficacy to medication augmentation, with numerically lower discontinuation rates (9.2% vs. 18.8%, P = 0.086). 1
Do not continue ineffective treatment beyond 8 weeks: If there is less than 30% symptom reduction after 8 weeks at therapeutic doses, switch or augment rather than continuing the same regimen. 2, 1
Do not ignore blood pressure monitoring: Duloxetine commonly causes sustained hypertension, which may necessitate discontinuation. 2, 1, 3
Do not combine with heavy alcohol use: Duloxetine with heavy alcohol intake may cause severe liver injury. 3