What anxiety medications, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), can be paired with bupropion without causing significant cognitive slowing?

Anxiety Medications Compatible with Bupropion Without Cognitive Slowing

SSRIs (selective serotonin reuptake inhibitors) are the preferred anxiety medications to combine with bupropion, as they do not cause cognitive slowing and this combination is well-tolerated with evidence supporting enhanced efficacy. 1

Primary Recommendation: SSRIs

SSRIs should be the first-line choice for anxiety treatment when paired with bupropion. The combination is generally well tolerated and can boost antidepressant response without causing cognitive impairment 1. Specific SSRIs that can be safely combined include:

• Sertraline - Well-studied in combination with bupropion, showing similar efficacy in augmentation strategies 2
• Citalopram/Escitalopram - Successfully combined in major trials (STAR*D study) with bupropion for augmentation 2
• Fluoxetine - Demonstrated safe combination profile 2
• Paroxetine - Can be combined, though has higher discontinuation syndrome risk 2
• Fluvoxamine - Effective for anxiety, though has more drug-drug interaction potential via multiple CYP450 pathways 2

Key Evidence

The STAR*D trial demonstrated that augmenting citalopram with bupropion SR showed similar efficacy to other augmentation strategies, with lower discontinuation rates due to adverse events (12.5%) compared to buspirone (20.6%) 2. This suggests bupropion combinations are well-tolerated.

Animal models and clinical evidence indicate that bupropion enhances the serotonergic system when combined with SSRIs, providing synergistic antidepressant and anxiolytic effects 3.

Alternative Option: SNRIs

SNRIs (serotonin-norepinephrine reuptake inhibitors) can be offered as a second-line option when combined with bupropion 2. Specific agents include:

• Venlafaxine extended-release - Successfully combined with bupropion in both clinical trials and case reports, showing synergistic reduction in depressive and anxiety symptoms 2, 4
• Duloxetine - Can be switched to or combined, though less data available 2

A case report demonstrated that venlafaxine 150 mg three times daily combined with bupropion 100 mg three times daily significantly reduced depressive symptoms (p < 0.002) and increased social function (p < 0.002) over 8 months in treatment-resistant depression 4.

Medications to Avoid

Buspirone should be avoided as an augmentation agent with bupropion, as it shows significantly higher discontinuation rates due to adverse events (20.6% vs. 12.5%) compared to bupropion augmentation alone 2.

Benzodiazepines are not recommended as they cause cognitive slowing, sedation, and carry risks of dependence - contradicting the goal of avoiding cognitive impairment.

Important Drug Interaction Considerations

CYP2D6 Inhibition

Bupropion inhibits CYP2D6, which can increase concentrations of certain SSRIs 5:

• Paroxetine, fluoxetine, and sertraline are metabolized by CYP2D6 - consider dose reduction when combining 5
• Citalopram/escitalopram have the least CYP450 effects and may have lower interaction potential 2

Seizure Risk

Bupropion lowers seizure threshold - dose cautiously and avoid exceeding maximum recommended doses when combining with other medications 5. The risk is dose-dependent, so use the lowest effective doses of both agents.

Serotonin Syndrome Risk

When combining bupropion with SSRIs or SNRIs, monitor for serotonin syndrome symptoms: mental status changes, neuromuscular hyperactivity (tremors, clonus, hyperreflexia), and autonomic hyperactivity (hypertension, tachycardia, diaphoresis) 2. Start the second agent at a low dose and increase slowly, monitoring especially in the first 24-48 hours after dosage changes 2.

Practical Implementation Algorithm

1. Start with an SSRI monotherapy for anxiety (sertraline, escitalopram, or fluoxetine preferred) 2
2. If partial response after 6-12 weeks, add bupropion starting at low dose (150 mg SR daily or 150 mg XL daily) 1
3. Titrate bupropion slowly to 300-450 mg daily as tolerated, monitoring for activation, anxiety, or seizure risk 5
4. Consider SSRI dose reduction if using paroxetine, fluoxetine, or sertraline due to CYP2D6 inhibition by bupropion 5
5. If SSRI fails or is not tolerated, switch to SNRI (venlafaxine XR) and combine with bupropion using same approach 4

Cognitive Effects Profile

Neither SSRIs nor bupropion cause cognitive slowing - in fact, bupropion's dopaminergic and noradrenergic effects may enhance alertness and concentration 6. The combination avoids the sedation and cognitive impairment seen with benzodiazepines or certain tricyclic antidepressants 2.

SSRIs are associated with improved anxiety symptoms without cognitive dulling in children and adults 2. Common side effects are gastrointestinal (nausea, diarrhea) and activation (initial anxiety, insomnia), not cognitive slowing 2.