What are the benefits of starting someone on Wellbutrin (bupropion) in conjunction with a Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) for treatment-resistant depression?

Benefits of Adding Bupropion to SNRI Therapy

Primary Recommendation

Adding bupropion to an SNRI provides two distinct clinical benefits: augmentation of antidepressant response in treatment-resistant depression (with approximately 56-80% response rates) and mitigation of SNRI-induced sexual dysfunction and somnolence. 1, 2, 3

Augmentation for Treatment-Resistant Depression

Efficacy Data

• Combination therapy with bupropion added to SSRI/SNRI monotherapy converts partial responders to full responders in 56-80% of patients who failed initial antidepressant treatment 2, 3

• In patients inadequately responsive to SNRI monotherapy, adding bupropion achieved response in 80% (12 of 15 patients) compared to only 20% response when added solely for side effect management 2

• The American College of Physicians recognizes that augmenting citalopram (an SSRI) with bupropion decreases depression severity more than augmentation with buspirone, with lower discontinuation rates due to adverse events 1

Mechanistic Rationale

• Bupropion's dopamine-norepinephrine reuptake inhibition provides complementary neurotransmitter coverage when combined with the serotonin-norepinephrine effects of SNRIs 4, 5, 6

• This dual mechanism addresses residual symptoms that may persist with SNRI monotherapy, particularly anhedonia, fatigue, and cognitive symptoms mediated by dopaminergic pathways 4

Management of SNRI-Induced Side Effects

Sexual Dysfunction

• Bupropion is associated with significantly lower rates of sexual adverse events compared to SSRIs and SNRIs, making it the preferred augmentation agent when sexual dysfunction emerges on SNRI therapy 4, 5, 6

• Controlled and open-label studies support bupropion's effectiveness in reversing antidepressant-associated sexual dysfunction when added to SSRI/SNRI treatment 3

Somnolence and Fatigue

• SNRIs commonly cause somnolence and fatigue, while bupropion is activating rather than sedating, providing a counterbalancing effect 7, 4

• The American Academy of Family Physicians notes bupropion may be preferred when sedation is problematic due to its activating properties 7

• This makes the combination particularly valuable for patients experiencing SNRI-induced daytime drowsiness that persists beyond the initial 2-4 week adjustment period 7

Safety and Tolerability Profile

General Tolerability

• Combination therapy with bupropion and SNRIs is generally well tolerated, even in geriatric and medically frail patients 2, 3

• The combination has been used successfully without significant safety concerns in clinical practice, with available data suggesting good tolerability 3

Important Safety Considerations

• Bupropion lowers the seizure threshold with a 0.1% seizure risk, making it contraindicated in patients with seizure history 4

• Common side effects of bupropion include insomnia, dry mouth, headache, nausea, dizziness, constipation, and tremor 4

• Dose adjustments are required for patients with moderate to severe renal or hepatic impairment 4

• Avoid in patients taking MAOIs and use with caution in patients requiring opioid medications due to potential reduced analgesic efficacy 4

Dosing and Monitoring Strategy

Initiation Protocol

• Typical therapeutic dose range for bupropion is 300-450 mg/day with careful titration to minimize adverse effects 4

• Begin monitoring within 1-2 weeks of initiation, with treatment modification if no adequate response within 6-8 weeks 4

Duration of Treatment

• Continue combination treatment for 4-9 months after satisfactory response for first episode; longer duration (years to lifelong) for patients with 2 or more depressive episodes 1, 4

Clinical Decision Algorithm

When to Add Bupropion to SNRI

1. Inadequate response after 6-8 weeks of optimized SNRI monotherapy (primary indication with 80% response rate) 1, 2

2. Emergence of sexual dysfunction on SNRI therapy (supported by controlled trials) 3

3. Persistent somnolence/fatigue despite dose timing adjustments (bupropion's activating properties counterbalance SNRI sedation) 7, 4

4. Comorbid conditions including ADHD or nicotine dependence (bupropion addresses multiple therapeutic targets) 4

Contraindications to Combination

• History of seizure disorder (absolute contraindication) 4

• Current MAOI use (absolute contraindication) 4

• Severe hepatic or renal impairment without dose adjustment 4

Common Pitfalls to Avoid

• Do not add bupropion solely for side effect management in patients with adequate antidepressant response—only 20% respond versus 80% when added for inadequate efficacy 2

• Avoid rapid titration of bupropion, which increases seizure risk; use gradual dose escalation 4

• Do not discontinue SNRI when adding bupropion for augmentation—the combination provides synergistic benefit 8, 3

• Monitor blood pressure and pulse as both SNRIs and bupropion can cause cardiovascular effects 7