Augmenting Bupropion in Major Depressive Disorder
When bupropion monotherapy fails to achieve adequate response after 6-8 weeks, augment with an SSRI or SNRI rather than switching to another antidepressant. 1
Evidence for Augmentation Strategies
Bupropion Plus SSRI/SNRI Augmentation
Adding an SSRI or SNRI to existing bupropion therapy demonstrates superior efficacy compared to other augmentation strategies. The STAR*D trial found similar remission rates when augmenting citalopram with bupropion (30.3%) versus buspirone, but bupropion showed significantly lower discontinuation rates due to adverse events (12.5% vs. 20.6%, P < 0.001). 1
Bupropion augmentation of SSRIs reduces depression severity more effectively than buspirone augmentation in patients who failed initial SSRI monotherapy. 1
Open-label studies demonstrate that 54% of patients who were partial or non-responders to SSRIs achieved response (≥50% reduction in depression scores) when bupropion SR 150-300 mg/day was added. 2
The combination is generally well-tolerated and addresses complementary mechanisms: SSRIs target serotonin while bupropion affects norepinephrine and dopamine pathways. 3
Switching vs. Augmentation: The Evidence
Augmentation with bupropion is equally effective as switching to another antidepressant, but may be preferred to avoid discontinuation symptoms. 1
Two trials with 1,231 participants found no difference in efficacy or safety between switching from paroxetine or sertraline to mirtazapine versus augmenting with mirtazapine. 1
The STAR*D trial showed no significant differences in response or remission when switching from citalopram to bupropion SR, sertraline, or venlafaxine XR (response rates 21-28%). 1
Practical Augmentation Protocol
Dosing Strategy for Augmentation
Start bupropion SR at 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) if tolerated. 4
Administer the first dose in the morning and the second dose before 3 PM to minimize insomnia risk. 4
Maximum dose is 400 mg/day for SR formulation or 450 mg/day for XL formulation. 4
Allow 6-8 weeks at therapeutic dose before determining treatment response. 4
Alternative Augmentation: Adding NRT for Smoking Cessation
For patients who smoke, augment bupropion with nicotine replacement therapy (NRT) to address both depression and smoking cessation. 1
A double-blind RCT showed the highest abstinence rates at 12 months with bupropion plus NRT (35.5%) compared to bupropion alone (30.3%), though the difference was not statistically significant. 1
This combination is particularly beneficial for patients with comorbid depression and nicotine dependence. 1
Critical Safety Considerations
Seizure Risk Management
The maximum dose must not exceed 450 mg/day to maintain seizure risk at 0.1%. 1
Absolute contraindications include: seizure disorders, eating disorders (bulimia/anorexia), abrupt discontinuation of alcohol/benzodiazepines/barbiturates/antiepileptic drugs, and concurrent MAOI use. 4, 5
Use extreme caution when combining with other drugs that lower seizure threshold (antipsychotics, other antidepressants, theophylline, systemic corticosteroids). 5
Drug Interactions Requiring Dose Adjustment
Bupropion inhibits CYP2D6, requiring dose reduction of concomitant medications metabolized by this pathway. 5
Drugs requiring dose reduction include: venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline, haloperidol, risperidone, metoprolol, propafenone, and flecainide. 5
Critical warning: Bupropion may reduce efficacy of tamoxifen by inhibiting its metabolic activation via CYP2D6. 4, 5
CYP2B6 inhibitors (ticlopidine, clopidogrel) increase bupropion exposure and may require dose adjustment based on clinical response. 5
Monitoring Requirements
Monitor blood pressure and heart rate periodically, especially during the first 12 weeks, as bupropion can cause elevations in both parameters. 4
Screen for suicidal ideation at baseline and monitor closely during the first 1-2 months, particularly in patients under 24 years old. 4
Assess for neuropsychiatric adverse effects including agitation, restlessness, and behavioral changes. 1
Special Populations
Hepatic and Renal Impairment
For moderate to severe hepatic impairment, reduce maximum dose to 150 mg daily (one tablet). 4
For moderate to severe renal impairment (GFR <90 mL/min), reduce total daily dose by 50%. 4
Avoid in end-stage renal disease. 4
Cardiovascular Considerations
Uncontrolled hypertension is a contraindication to bupropion use. 4
- Blood pressure must be controlled before initiating therapy and monitored throughout treatment. 4
Common Pitfalls to Avoid
Do not combine bupropion with MAOIs or use within 14 days of discontinuing MAOIs due to risk of hypertensive crisis. 4, 5
Do not exceed maximum daily doses (400 mg SR, 450 mg XL) as seizure risk increases significantly above these thresholds. 4
Do not administer the second daily dose after 3 PM as this significantly increases insomnia risk. 4
Do not discontinue treatment before 6-8 weeks unless significant adverse effects occur, as premature discontinuation prevents adequate assessment of efficacy. 4
Do not overlook dopaminergic interactions: When combining with levodopa or amantadine, monitor for CNS toxicity including restlessness, agitation, tremor, ataxia, and dizziness. 5