What anxiety medication pairs well with Wellbutrin (bupropion) with the least amount of side effects?

Anxiety Medication Pairing with Bupropion (Wellbutrin)

SSRIs (particularly sertraline or citalopram/escitalopram) are the best anxiety medications to combine with bupropion, offering complementary mechanisms with minimal drug interactions and well-established safety profiles. 1, 2

Primary Recommendation: SSRIs

Sertraline (Zoloft) or citalopram/escitalopram (Celexa/Lexapro) are the optimal first-line choices for combining with bupropion when treating comorbid anxiety and depression 3, 1:

• Sertraline is well-tolerated and has less effect on metabolism of other medications compared to other SSRIs, minimizing drug-drug interaction concerns 3
• Citalopram/escitalopram have the least effect on CYP450 isoenzymes and thus the lowest propensity for drug interactions among SSRIs 3
• Combination therapy with bupropion and SSRIs is generally well-tolerated, can boost antidepressant response, and reduces SSRI-associated sexual side effects 1

Evidence Supporting SSRI + Bupropion Combination

The combination addresses anxiety through complementary mechanisms 1, 2:

• Bupropion does not worsen anxiety contrary to clinical belief—propensity-matched studies show no difference in anxiety outcomes between SSRI monotherapy and bupropion monotherapy over 12 weeks 4
• Bupropion and SSRIs demonstrate comparable anxiolytic efficacy in major depressive disorder with anxiety symptoms 2
• Open-label and controlled studies support effectiveness of bupropion combined with SSRIs for treatment-resistant depression and to reverse SSRI-associated sexual dysfunction 1

Alternative Options

SNRIs (Second-Line)

Venlafaxine or duloxetine can be considered if SSRIs are ineffective 3:

• SNRIs improve anxiety symptoms in children/adolescents (high strength of evidence for clinician-reported outcomes) 3
• Venlafaxine has the least effect on CYP450 system compared to other SNRIs, reducing interaction potential 3
• Caution: Monitor blood pressure and pulse, as both bupropion and SNRIs can increase these parameters 3

Buspirone (For Mild-Moderate Anxiety)

Buspirone is an option for augmentation in mild-to-moderate anxiety 3, 5:

• Initial dose: 5 mg twice daily, maximum 20 mg three times daily 3
• Takes 2-4 weeks to become effective 3
• In head-to-head augmentation trials, bupropion showed greater symptom reduction and lower dropout rates due to intolerance compared to buspirone (12.5% vs 20.6%) 5

Medications to Avoid

Do NOT combine bupropion with 3:

• MAO inhibitors: Contraindicated due to increased risk of hypertensive reactions 3
• Benzodiazepines for long-term use: No evidence supports routine combination; reserve for acute situations only 3

Dosing Considerations

Starting the Combination

When adding an SSRI to existing bupropion therapy 3:

• Sertraline: Start 25-50 mg daily, maximum 200 mg daily 3
• Citalopram: Start 10 mg daily, maximum 40 mg daily (avoid exceeding 40 mg due to QT prolongation risk) 3
• Escitalopram: Start 5-10 mg daily, maximum 20 mg daily 3

Bupropion Dosing

If initiating bupropion 3:

• Start 37.5-150 mg once daily in morning 3
• Increase by 37.5-150 mg every 3 days as tolerated 3
• Maximum 150 mg twice daily (300 mg total daily) 3
• Give second dose before 3 PM to minimize insomnia risk 3

Safety Monitoring

Key Adverse Effects to Monitor

Common side effects of the combination 3, 1:

• SSRI-related: Nausea, diarrhea, headache, sexual dysfunction, insomnia 3
• Bupropion-related: Agitation, dry mouth, insomnia, headache, tremor 3, 6
• Seizure risk: Bupropion is contraindicated in patients with seizure disorders or brain metastases 3

Critical Warnings

Monitor for serotonin syndrome when combining serotonergic agents 3:

• Symptoms include mental status changes, autonomic hyperactivity, neuromuscular abnormalities 3
• Risk is low with SSRI + bupropion (bupropion has no serotonergic activity) but monitor nonetheless 6

Psychiatric monitoring 3:

• Watch for worsening depression, suicidal ideation (especially in patients <24 years) 3
• Anxiety and depression occurred in 0.1-5.4% of patients on bupropion in clinical trials 3

Clinical Advantages of This Combination

The SSRI + bupropion combination offers specific benefits 1, 5:

• Complementary mechanisms: SSRIs provide serotonergic anxiolysis while bupropion adds norepinephrine/dopamine activity without worsening anxiety 1, 2
• Reduced sexual dysfunction: Bupropion can ameliorate SSRI-induced sexual side effects 1, 5
• Enhanced antidepressant response: Effective for patients refractory to monotherapy 1, 5
• Lower discontinuation rates: Better tolerability profile than other augmentation strategies 5