What is the next best step for a patient with a history of depression and anxiety, previously treated with Prozac (fluoxetine) without improvement, now on Wellbutrin (bupropion) 300 mg, who continues to experience anxiety and nausea?

Management of Persistent Anxiety on Bupropion 300mg

Add an SSRI or SNRI to the existing bupropion regimen rather than switching medications, as augmentation with bupropion demonstrates superior efficacy compared to other augmentation strategies and avoids discontinuation symptoms. 1

Understanding the Clinical Situation

Bupropion is an activating antidepressant that works through noradrenergic and dopaminergic pathways, but it lacks serotonergic activity—which is crucial for treating anxiety disorders. 2 This patient's persistent anxiety despite adequate bupropion dosing (300mg) indicates the need for a serotonergic agent rather than further dose escalation. 1

The nausea is likely multifactorial: anxiety itself commonly causes nausea, and bupropion can contribute to gastrointestinal side effects. 3

Recommended Treatment Algorithm

Primary Strategy: Augment with an SSRI or SNRI

Add sertraline, escitalopram, or another SSRI/SNRI to the current bupropion 300mg regimen. 1 This combination addresses depression through complementary mechanisms while specifically targeting the anxiety component through serotonergic pathways. 1

Evidence supporting augmentation over switching:

• Augmenting SSRIs with bupropion (or vice versa) decreases depression severity more effectively than augmentation with buspirone 1
• Similar remission rates (30.3%) when augmenting with bupropion versus buspirone, but bupropion showed significantly lower discontinuation rates due to adverse events (12.5% vs. 20.6%, P < 0.001) 1
• Augmentation is equally effective as switching to another antidepressant but avoids discontinuation symptoms 1

Addressing the Anxiety-Related Nausea

For immediate symptom relief while the SSRI takes effect (6-8 weeks), consider:

• Short-term benzodiazepine use: Alprazolam 0.25-0.5mg orally three times daily, or lorazepam, can address both anxiety and anticipatory nausea 4
• Start with 0.25mg in this patient given the complexity of the regimen 4
• Use only as a bridge therapy for 2-4 weeks while the SSRI reaches therapeutic levels 5
• Gradually taper once anxiety improves 4

For nausea specifically:

• If nausea persists despite anxiety improvement, consider ondansetron 4-8mg as needed 4
• Rule out other causes: medication side effects, gastritis, or gastrointestinal pathology 4

Critical Safety Monitoring

Monitor closely for:

• Worsening anxiety, agitation, or suicidal ideation, especially in the first 1-2 weeks after adding the SSRI 1, 3
• Serotonin syndrome when combining bupropion with SSRIs/SNRIs (tremor, diarrhea, delirium, neuromuscular rigidity, hyperthermia) 4
• Blood pressure elevation, as bupropion can increase blood pressure 1

Timeline for Response Assessment

Allow 6-8 weeks at adequate doses before determining treatment response. 1 Energy levels may improve within the first few weeks, but full anxiolytic effects of the added SSRI typically require 4-6 weeks. 1

Alternative Considerations if Augmentation Fails

If no adequate response occurs after 6-8 weeks of combination therapy:

• Consider switching from bupropion to an SSRI or SNRI monotherapy at higher doses 6
• Duloxetine 60-120mg daily has shown 60-70% response rates in SSRI-resistant depression 6
• Venlafaxine is another option, though it has slightly higher rates of nausea and vomiting compared to SSRIs 4

Common Pitfalls to Avoid

Do not:

• Increase bupropion above 300mg for anxiety—this will likely worsen anxiety symptoms due to its activating properties 1, 2
• Use bupropion monotherapy for primary anxiety disorders, as it lacks serotonergic activity 5, 2
• Prescribe benzodiazepines long-term without a clear taper plan 5
• Discontinue bupropion abruptly if switching medications 3

Do:

• Maintain bupropion at 300mg while adding the SSRI/SNRI 1
• Educate the patient that full response may take 6-8 weeks 1
• Schedule follow-up within 1-2 weeks to assess for worsening symptoms 1