In an otherwise healthy adult with major depressive disorder already taking therapeutic bupropion (Wellbutrin) 150‑300 mg daily, what augmentation options can increase energy?

Augmenting Bupropion for Energy in Depression

Add aripiprazole 2.5–10 mg daily to your current bupropion regimen to boost energy and motivation in treatment-resistant depression. This combination targets both dopaminergic and noradrenergic pathways that drive energy and motivation, providing rapid symptom improvement within days to weeks.

Primary Augmentation Strategy: Aripiprazole

Aripiprazole augmentation produces rapid improvement in depressive symptoms—including energy deficits—in patients who remain symptomatic despite adequate bupropion therapy (150–450 mg/day for ≥2 months). 1

Dosing Protocol

• Start aripiprazole at 2.5 mg daily and titrate to 5–10 mg daily based on response and tolerability 1
• Antidepressant effects typically emerge rapidly (within days to 2 weeks) and are sustained for at least 4 months in most patients 1
• The low-dose range (2.5–10 mg) minimizes metabolic and extrapyramidal side effects while preserving efficacy 1

Mechanism and Rationale

• Aripiprazole's partial dopamine agonism complements bupropion's dopamine-norepinephrine reuptake inhibition, creating synergistic enhancement of motivation and energy circuits 1
• This combination is particularly effective when bupropion alone fails to adequately address apathy, low energy, and reduced motivation 2, 3

Monitoring and Safety

• Watch for akathisia (motor restlessness), which responds to dose reduction if it occurs 1
• Monitor for worsening insomnia, though this is uncommon at low doses 1
• Assess response within 2–4 weeks; if inadequate, increase aripiprazole dose before considering alternative strategies 1

Alternative Augmentation: Optimize Bupropion Dosing First

Before adding augmentation, ensure bupropion is dosed at 300–450 mg daily for at least 6–8 weeks. 3, 4

Dose Escalation Strategy

• If currently on bupropion SR 150 mg twice daily (300 mg total), increase to 150 mg three times daily (450 mg total) 3
• For bupropion XL, escalate from 300 mg to 450 mg once daily 3
• The 450 mg dose provides superior antidepressant response compared with 300 mg, particularly for energy and motivation symptoms 4
• Maximum dose is 450 mg/day to maintain seizure risk at 0.1% 3

Expected Timeline

• Energy improvements may appear within 2 weeks at higher bupropion doses, faster than with most antidepressants 3
• Full therapeutic assessment requires 6–8 weeks at the optimized dose 3

When Bupropion Augmentation Is Needed: Add an SSRI

If aripiprazole is contraindicated or refused, augment bupropion with an SSRI (sertraline 100–200 mg or escitalopram 10–20 mg daily) rather than switching agents. 3

Evidence for SSRI + Bupropion Combination

• Adding bupropion to an SSRI (or vice versa) achieves remission in approximately 30% of treatment-resistant patients 3
• This combination has significantly lower discontinuation rates (12.5%) compared with buspirone augmentation (20.6%, P < 0.001) 3
• The dual mechanism addresses both serotonergic and dopaminergic/noradrenergic deficits 3

Practical Implementation

• Start the SSRI at standard doses while maintaining bupropion at 300–450 mg/day 3
• Allow 6–8 weeks of combination therapy before declaring treatment failure 3
• This strategy is superior to switching antidepressants because it preserves any partial benefit from bupropion 3

Specific Energy-Boosting Properties of Bupropion

Bupropion XL 300–450 mg daily specifically targets decreased energy, pleasure, and interest—core symptoms of depression that impair function. 5

Symptom-Specific Efficacy

• Bupropion demonstrates superior improvement in energy, pleasure, and interest domains compared with placebo (p = 0.007 for patient-rated, p < 0.001 for clinician-rated measures) 5
• Remission rates with bupropion XL are 32–41% versus 18–27% with placebo 5
• Mean time to 50% symptom reduction is approximately 2 weeks, with 90% reduction in less than 2 months 6

Tolerability Advantages

• Bupropion causes minimal weight gain or weight loss (3.7% of patients lose ≥7% body weight) 5
• Sexual dysfunction rates are significantly lower than with SSRIs 3, 4
• Most adverse effects are mild to moderate (dry mouth, transient stomach discomfort, headache) 6

Critical Safety Considerations

Absolute Contraindications

• Seizure disorders or any condition predisposing to seizures (head trauma, brain tumor, stroke) 3
• Eating disorders (bulimia, anorexia nervosa) due to increased seizure risk 3
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs 3
• Current MAOI use or within 14 days of MAOI discontinuation 3

Dose-Related Precautions

• Never exceed 450 mg/day total bupropion dose; seizure risk increases markedly above this threshold 3
• For bupropion SR, give the second dose before 3 PM to minimize insomnia risk 2, 3
• In moderate-to-severe hepatic impairment, maximum dose is 150 mg daily 3
• In moderate-to-severe renal impairment, reduce total daily dose by 50% 3

Monitoring Requirements

• Assess for suicidal ideation during the first 1–2 months, especially in patients <24 years 3
• Monitor blood pressure and heart rate periodically, particularly in the first 12 weeks 3
• Watch for agitation or behavioral activation, as bupropion is an activating medication 2, 3

Common Pitfalls to Avoid

• Do not add augmentation before optimizing bupropion to 300–450 mg/day for 6–8 weeks 3
• Do not use bupropion in highly agitated patients; its activating properties may worsen agitation 2, 1
• Do not combine with MAOIs or start within 14 days of MAOI discontinuation 3
• Do not exceed 450 mg/day to avoid seizure risk escalation 3
• Do not discontinue prematurely; energy improvements may emerge within 2 weeks, but full assessment requires 6–8 weeks 3, 6