Can a patient with depression or anxiety mix Lexapro (escitalopram) and Wellbutrin (bupropion)?

Can Patients Mix Lexapro and Wellbutrin?

Yes, patients can safely combine Lexapro (escitalopram) and Wellbutrin (bupropion) for depression or anxiety, and this is a well-established, guideline-supported treatment strategy. 1, 2

Evidence Supporting Combination Therapy

The American College of Physicians recognizes combining bupropion with SSRIs like escitalopram as an established augmentation strategy for depression that has failed to respond adequately to monotherapy. 1, 2 This combination works through complementary mechanisms—escitalopram affects serotonin pathways while bupropion works via noradrenergic and dopaminergic systems. 1

Low-quality evidence demonstrates that augmenting SSRIs with bupropion decreases depression severity more effectively than augmentation with buspirone. 1 Importantly, discontinuation rates due to adverse events were actually lower with bupropion augmentation (12.5%) compared to buspirone (20.6%, P < 0.001), suggesting a favorable safety profile. 1

Clinical Advantages of This Combination

• Sexual dysfunction mitigation: Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs and can actually reverse SSRI-associated sexual side effects. 1, 3 This makes the combination particularly advantageous for patients experiencing this common SSRI side effect. 2

• Weight considerations: Bupropion is associated with minimal weight gain or even weight loss, unlike many other antidepressants. 1

• Energy and motivation: Bupropion's activating properties can improve energy levels and reduce apathy, complementing escitalopram's effects. 1

Dosing Strategy

Standard dosing for combination therapy:

• Escitalopram: 10-20 mg daily 2
• Bupropion SR: 150 mg twice daily (300 mg total daily) 1, 2
• Bupropion XL: 300 mg once daily in the morning 1

For initiating bupropion in patients already on escitalopram:

• Start bupropion at 37.5 mg every morning 1
• Increase by 37.5 mg every 3 days as tolerated 1
• Target dose: 150 mg twice daily (maximum 300 mg/day) 1
• Administer second dose before 3 PM to minimize insomnia risk 1

Critical Safety Considerations

Absolute Contraindications for Bupropion

• History of seizure disorder or any condition predisposing to seizures 1, 2, 4
• Current or recent (within 14 days) MAOI use 1, 4
• Eating disorders (bulimia or anorexia nervosa) due to increased seizure risk 1
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs 1
• Uncontrolled hypertension 1

Seizure Risk Management

The maximum dose of bupropion must not exceed 450 mg/day to maintain seizure risk at 0.1% (1 in 1,000). 1 Both medications can potentially lower the seizure threshold, though this is primarily a concern with bupropion at higher doses. 2 For the combination therapy, standard therapeutic doses (bupropion 300 mg/day, escitalopram 10-20 mg/day) are safe when contraindications are absent. 2

Serotonin Syndrome Monitoring

While combining these medications is safe, monitor for serotonin syndrome, particularly during treatment initiation. 3, 4 Key features include:

• Mental status changes (agitation, hallucinations, delirium) 3, 4
• Autonomic instability (tachycardia, labile blood pressure, hyperthermia) 3, 4
• Neuromuscular symptoms (tremor, rigidity, myoclonus, hyperreflexia) 3, 4
• Advanced symptoms (fever, seizures, unconsciousness) 3

Cardiovascular Monitoring

• Monitor blood pressure and heart rate periodically, especially in the first 12 weeks, as bupropion can elevate both parameters. 1
• Escitalopram carries risk of QT prolongation; do not exceed 40 mg/day (20 mg/day in adults >60 years). 3

Common Side Effects of Combination Therapy

Most frequent side effects: 3

• Gastrointestinal: nausea (most common reason for discontinuation), vomiting, diarrhea, constipation 3
• Neurological: headache, dizziness, tremor, insomnia 3
• Other: dry mouth, fatigue, sweating, agitation 3

Special Population Considerations

Hepatic impairment:

• Moderate to severe: Maximum bupropion dose 150 mg daily 1

Renal impairment:

• Moderate to severe (GFR <90 mL/min): Reduce bupropion total daily dose by 50% 1

Older adults:

• Start bupropion at 37.5 mg every morning, increase by 37.5 mg every 3 days 1
• Maximum dose: 150 mg twice daily (300 mg total) 1

Patients under 24 years:

• Close monitoring required for increased suicidal thoughts, particularly during first 1-2 months of treatment 1, 4

Treatment Timeline and Monitoring

• Initial monitoring: Begin within 1-2 weeks of initiation for worsening depression, suicidal ideation, or behavioral changes 1
• Efficacy assessment: Allow 6-8 weeks at adequate doses before determining treatment response 1, 2
• Early energy improvement: Bupropion may produce more rapid improvement in energy levels within the first few weeks 1

When to Use This Combination

Preferred scenarios:

1. Partial response to escitalopram monotherapy after 6-8 weeks 2
2. SSRI-induced sexual dysfunction requiring mitigation 3, 2
3. Depression with prominent low energy, apathy, or hypersomnia 1
4. Concerns about weight gain with antidepressant therapy 1
5. Comorbid depression and smoking cessation needs 1

Drug Interaction Considerations

• Escitalopram has minimal CYP450 interactions, making it preferable to citalopram when combining with bupropion. 3
• The combination of escitalopram and bupropion does not have significant pharmacokinetic interactions that would preclude their use together. 1
• Neither medication should be combined with MAOIs due to risk of hypertensive crisis or serotonin syndrome. 2, 4

Clinical Evidence Nuance

While one randomized controlled trial found that initial combination therapy did not outperform monotherapy in speed or rate of remission 5, this contrasts with naturalistic cohort data showing combination therapy superior to switching monotherapy (28% vs. 7% remission rate, p <0.05). 6 The key distinction: combination therapy is most beneficial as an augmentation strategy after inadequate monotherapy response, not necessarily as initial treatment. 1, 2 An open-label pilot study demonstrated 50% remission rates with the combination in chronic/recurrent depression, significantly higher than typical SSRI monotherapy. 7