Adding an Antidepressant to Escitalopram (Lexapro)
Primary Recommendation
When escitalopram monotherapy fails to achieve adequate response, add bupropion as the preferred augmentation strategy, as this combination works through complementary mechanisms (SSRI plus dopamine/norepinephrine reuptake inhibition) and is specifically supported by guideline evidence for treatment-resistant depression. 1
Evidence-Based Augmentation Strategy
First-Line Augmentation: Bupropion
Bupropion is the preferred agent to add to escitalopram because it works through different neurotransmitter systems (dopamine and norepinephrine) rather than serotonin, providing complementary antidepressant effects without redundancy 2, 1
The American College of Physicians specifically supports combining bupropion with SSRIs like escitalopram for patients who failed initial SSRI monotherapy 1
This combination has a favorable safety profile with no additive sedative effects, no increased fall risk, and lower sexual dysfunction compared to SSRI monotherapy 2
No significant pharmacokinetic interactions exist between escitalopram and bupropion based on their distinct metabolic pathways 1
Dosing Protocol for Combination Therapy
Standard Adult Dosing:
- Continue escitalopram at current dose (typically 10-20 mg daily) 3
- Add bupropion SR starting at 150 mg daily, can increase to 300-400 mg daily as tolerated 2
Elderly Patient Dosing (Age >60):
- Start escitalopram at 5 mg daily (50% of standard adult dose) 2
- Start bupropion SR at 100 mg daily (lower than standard 150 mg) 2
- Increase doses gradually with small increments at intervals of at least one week 2
- Maximum escitalopram dose is reduced for patients older than 60 years 3, 2
Critical Safety Monitoring
Cardiac Considerations:
- Escitalopram causes dose-dependent QT prolongation, with FDA and EMA limiting maximum recommended doses 3
- For patients >60 years, maximum escitalopram dose is further reduced due to cardiac risk 3
- Obtain baseline ECG if cardiac risk factors present before initiating or increasing doses 3
Seizure Risk:
- Bupropion lowers seizure threshold; use with extreme caution in patients with seizure history 2
Suicide Risk Monitoring:
- All SSRIs increase risk of suicide attempts compared to placebo 3
- Risk is highest during first 1-2 months of treatment and when starting at higher doses 3
- Schedule follow-up within 1 week of adding medication, then at 2-4 weeks 3, 1
- Monitor for agitation, irritability, or unusual behavioral changes indicating worsening depression 3
Alternative Augmentation Strategies
If Bupropion is Contraindicated:
The evidence does not strongly support specific second-line augmentation agents, but consider:
- Another SSRI or SNRI may be added, though this increases serotonin syndrome risk and provides redundant mechanisms 1
- Switching rather than augmenting may be more appropriate if no response to escitalopram 3
Common Pitfalls to Avoid
Do not use excessive dosing in elderly patients who require approximately 50% of standard adult starting doses due to age-related pharmacokinetic changes 2
Do not abruptly discontinue either medication if changes are needed; both escitalopram and bupropion require gradual tapering to avoid discontinuation syndromes 3, 2
Monitor for hyponatremia with SSRI use, particularly in older adults (0.5-12% risk) 2
Adjust bupropion SR dose in renal or hepatic disease, while escitalopram requires no adjustment for these conditions 2
Watch for cognitive side effects as escitalopram may cause memory impairment in some patients 1
When to Modify Treatment
- If no adequate response after 6-12 weeks at therapeutic doses, consider switching antidepressants rather than further augmentation 3
- 38% of patients do not achieve treatment response and 54% do not achieve remission with second-generation antidepressants during 6-12 weeks 3
- Reassess treatment strategy if patient experiences intolerable adverse effects or shows signs of clinical worsening 3