What is the recommended approach when adding a Selective Serotonin Reuptake Inhibitor (SSRI) to bupropion (Wellbutrin)?

Adding an SSRI to Wellbutrin (Bupropion)

Combining bupropion with an SSRI is a well-established and generally safe strategy that can be used either to augment inadequate antidepressant response or to counteract SSRI-induced sexual dysfunction, with 54% of patients showing significant improvement when bupropion is added to existing SSRI therapy. 1, 2

Clinical Indications for Combination Therapy

The combination of bupropion and SSRIs serves two distinct clinical purposes:

For Treatment-Resistant Depression

• Adding bupropion to an existing SSRI produces response rates of 54% in patients who failed to achieve adequate response to SSRI monotherapy, defined as a 50% or more reduction in depression rating scales 1
• This augmentation strategy is more effective than adding buspirone to SSRIs for decreasing depression severity 3
• The combination addresses depression through complementary mechanisms: SSRIs modulate serotonin while bupropion works via noradrenergic and dopaminergic pathways 3

For SSRI-Induced Sexual Dysfunction

• Controlled studies support bupropion's effectiveness in reversing antidepressant-associated sexual dysfunction when added to ongoing SSRI therapy 2
• Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs when used as monotherapy 3

Practical Dosing Strategy

Initial Titration

• Start bupropion at 37.5 mg every morning, increasing by 37.5 mg every 3 days as tolerated 3
• Alternative approach: Start with 150 mg once daily for 3 days, then increase to 150 mg twice daily 3
• The second dose must be administered before 3 PM to minimize insomnia risk 3

Target and Maximum Dosing

• Target dose is typically 150 mg twice daily (300 mg total daily) 3, 4
• Maximum dose should not exceed 300 mg per day when combining with SSRIs to maintain seizure risk at 0.1% 3

Critical Safety Considerations

Absolute Contraindications

• Active seizure disorder or any condition that lowers seizure threshold 3, 4
• Current or recent (within 14 days) MAOI use 3
• Eating disorders (bulimia or anorexia nervosa) due to increased seizure risk 3
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 3
• Uncontrolled hypertension 3

Theoretical Drug Interaction

• While there is a theoretical risk of serotonin syndrome when combining bupropion with SSRIs, no incidents were reported in phase 3 studies 5
• Despite this reassuring safety profile, clinicians should remain vigilant for signs of serotonin syndrome, particularly during dose escalation 4

Monitoring Requirements

• Baseline and periodic vital signs monitoring, especially blood pressure and heart rate during the first 12 weeks 3, 4
• Close monitoring for neuropsychiatric effects including suicidal ideation, particularly in patients under 24 years old during the first 1-2 months 3
• Assessment for seizure activity, especially if dose escalation occurs 4

Timeline for Clinical Response

When Augmenting for Depression

• Allow 6-8 weeks at an adequate dose before determining treatment response 3
• Begin monitoring therapeutic response and adverse effects within 1-2 weeks of initiation 3
• Energy levels may improve more rapidly with bupropion, sometimes within the first few weeks 3

When Treating Sexual Dysfunction

• Response to bupropion for SSRI-induced sexual dysfunction may occur more quickly than antidepressant augmentation effects 2

Special Population Considerations

Hepatic Impairment

• For moderate to severe hepatic impairment, the total daily dose should not exceed 150 mg daily 3

Renal Impairment

• For moderate to severe renal impairment (GFR <90 mL/min), reduce the total daily dose by half 3

Older Adults

• Start with lower doses (approximately 50% of standard dose) due to increased risk of adverse reactions 3

Clinical Pearls and Common Pitfalls

Patient Selection

• Bupropion augmentation is particularly beneficial for patients with depression characterized by low energy, apathy, or hypersomnia due to its activating properties 3
• Patients concerned about sexual dysfunction or weight gain are ideal candidates for bupropion combination therapy 3
• In anxious depression, SSRIs may have a modest advantage over bupropion monotherapy (6% difference in response rates), but this does not preclude combination therapy 6

Tolerability Profile

• Combination therapy with bupropion and SSRIs is generally well tolerated, even in geriatric and medically frail patients 7
• The combination was well tolerated in 25 patients across various age groups and medical conditions 7

Formulation Considerations

• Monitor patients closely when switching between brand and generic formulations or between SR and XL formulations, as historical bioequivalence issues may lead to loss of antidepressant effect 3

Timing Optimization

• Administer the first dose in the morning to leverage bupropion's activating properties 3
• The second dose before 3 PM prevents sleep disturbances 3