What SSRI (Selective Serotonin Reuptake Inhibitor) is safer to use with Wellbutrin SR (Bupropion) 150 mg BID (Twice a Day) and aspirin?

SSRI Selection with Wellbutrin SR 150 mg BID and Aspirin

Sertraline or citalopram/escitalopram are the safest SSRI choices when combined with Wellbutrin SR 150 mg BID and aspirin, with sertraline having the most favorable drug interaction profile and citalopram/escitalopram having the least effect on cytochrome P450 enzymes.

Primary Recommendation: Sertraline

Sertraline is the preferred SSRI in this combination due to its minimal effect on metabolism of other medications compared to other SSRIs 1. This is particularly important when combining with bupropion (Wellbutrin), as drug-drug interactions through cytochrome P450 pathways can increase risks.

Key Safety Considerations:

• Sertraline has less effect on CYP450 metabolism compared to fluoxetine, paroxetine, and fluvoxamine, reducing the risk of elevated bupropion levels 1
• Well-tolerated profile with proven efficacy when used alongside other medications 1
• Starting dose: 25-50 mg daily, maximum 200 mg daily 1

Alternative: Citalopram/Escitalopram

Citalopram and escitalopram have the least effect on CYP450 isoenzymes compared with other SSRIs and therefore have a lower propensity for drug interactions 1.

Important Caveats:

• Citalopram maximum dose is 40 mg/day due to QT prolongation risk associated with Torsade de Pointes, ventricular tachycardia, and sudden death at higher doses 1
• Avoid in patients with long QT syndrome 1
• Starting dose: 10 mg daily 1

Critical Safety Warnings for This Combination

Bleeding Risk with Aspirin

Abnormal bleeding can occur with SSRIs, especially with concomitant administration of aspirin or nonsteroidal anti-inflammatory drugs 1. Rare bleeding events include:

• Ecchymosis
• Hematoma
• Epistaxis
• Petechiae
• Hemorrhage 1

Monitor patients closely for signs of bleeding, particularly during the first weeks of combined therapy.

Serotonin Syndrome Risk

Caution must be exercised when combining two or more serotonergic drugs, including bupropion (which has mild serotonergic effects) and SSRIs 1. While bupropion primarily inhibits noradrenaline and dopamine reuptake, it has milder effects on serotonergic activity 2.

Serotonin syndrome symptoms can arise within 24-48 hours after combining medications 1:

• Mental status changes (confusion, agitation, anxiety)
• Neuromuscular hyperactivity (tremors, clonus, hyperreflexia, muscle rigidity)
• Autonomic hyperactivity (hypertension, tachycardia, diaphoresis, vomiting, diarrhea)
• Advanced symptoms: fever, seizures, arrhythmias, unconsciousness 1

Start the SSRI at a low dose, increase slowly, and monitor closely for symptoms, especially in the first 24-48 hours after dosage changes 1.

CYP2D6 Interaction Concern

Bupropion has well-established specific inhibition of the cytochrome P450 2D6 pathway, which can increase blood levels of SSRIs and tricyclic antidepressants 2. This is why SSRIs with less CYP450 involvement are preferred.

SSRIs to AVOID in This Combination

Paroxetine - NOT RECOMMENDED

• More anticholinergic than other SSRIs 1
• Higher rates of sexual dysfunction than other SSRIs 1
• Associated with increased risk of suicidal thinking or behavior compared to other SSRIs 1
• Interacts with drugs metabolized by CYP2D6 1
• Associated with discontinuation syndrome 1

Fluoxetine - NOT RECOMMENDED

• Very long half-life with side effects that may not manifest for weeks 1
• Interacts with drugs metabolized by CYP2D6 1
• Activating properties may compound bupropion's activating effects 1

Fluvoxamine - NOT RECOMMENDED

• Greatest potential for drug-drug interactions among SSRIs 1
• Interacts with drugs metabolized by CYP1A2, CYP2C19, CYP2C9, CYP3A4, and CYP2D6 1
• Associated with discontinuation syndrome 1

Practical Prescribing Algorithm

1. First choice: Sertraline 25-50 mg daily 1

   • Increase by 25-50 mg every 1-2 weeks as tolerated
   • Maximum 200 mg daily
   • Monitor for bleeding given aspirin co-administration

2. Second choice: Escitalopram 10 mg daily 1

   • Maximum 20 mg daily (avoid exceeding 40 mg for citalopram)
   • Monitor ECG if cardiac risk factors present

3. Monitor closely for:

   • Serotonin syndrome symptoms in first 24-48 hours after starting or dose changes 1
   • Bleeding complications given aspirin use 1
   • Behavioral activation/agitation (may occur with either medication) 1

4. Educate patients about:

   • Signs of bleeding to report immediately
   • Early symptoms of serotonin syndrome
   • Importance of not missing doses to avoid discontinuation syndrome

Clinical Evidence Supporting Combination

The combination of bupropion-SR and SSRIs has been studied and found to be effective and well-tolerated 3, 4. In an open pilot study, the combination of escitalopram and bupropion-SR showed remission rates of 50% with low treatment-emergent adverse events 3. Only 6% of participants discontinued due to side effects 3.

Bupropion SR combined with SSRIs in patients maintained on SSRI treatment showed no evidence of emergent depression and minimal weight gain 4. Additionally, 16% of subjects spontaneously reported improvement in SSRI-associated sexual dysfunction when bupropion was added 4.