Is bupropion (Wellbutrin) a suitable augmentation for an adult on a selective serotonin reuptake inhibitor (SSRI) or serotonin‑norepinephrine reuptake inhibitor (SNRI) who still has low energy, fatigue, and lack of motivation, assuming no history of seizures, eating disorders, or uncontrolled hypertension?

Bupropion Augmentation for Low Energy on SSRI/SNRI Therapy

Yes, bupropion (Wellbutrin) is an excellent augmentation choice for adults on SSRIs or SNRIs who continue to experience low energy, fatigue, and lack of motivation, provided seizure disorders, eating disorders, and uncontrolled hypertension have been ruled out. 1

Why Bupropion Works for Residual Energy Deficits

Bupropion's norepinephrine-dopamine reuptake inhibition provides complementary pharmacological activity to serotonergic antidepressants, specifically targeting the motivational and energy symptoms that SSRIs/SNRIs often fail to address. 1, 2 This dual mechanism addresses both dopaminergic/noradrenergic and serotonergic pathways simultaneously. 1

The drug's activating properties make it particularly beneficial for patients with depression characterized by low energy, apathy, or hypersomnia. 1 Energy improvements may appear within the first few weeks, though full antidepressant response requires 6–8 weeks at therapeutic doses. 1

Evidence Supporting Augmentation Strategy

Bupropion augmentation of SSRIs demonstrates superior efficacy compared to other augmentation options. In the STAR*D trial, adding bupropion to citalopram achieved approximately 30% remission rates in patients who failed initial SSRI monotherapy. 1, 3 Critically, bupropion augmentation resulted in significantly lower discontinuation rates (12.5%) compared to buspirone augmentation (20.6%; P < 0.001), indicating better tolerability while delivering comparable efficacy. 1, 3

Multiple open-label and controlled trials support this strategy. One prospective trial showed 54% of patients responded when bupropion SR was added to SSRIs or venlafaxine. 4 A randomized controlled study demonstrated 60% remission rates with bupropion augmentation versus 24% with SSRI continuation alone. 5

Dosing Protocol

Start bupropion SR at 150 mg once daily in the morning for 3 days, then increase to 150 mg twice daily (300 mg total) if tolerated. 1 The maximum dose is 400 mg/day for SR formulation or 450 mg/day for XL formulation. 1

Administer the second dose before 3 PM to minimize insomnia risk, as bupropion has activating properties. 1 For older adults (>65 years), start at 37.5 mg every morning and increase by 37.5 mg every 3 days as tolerated, with a maximum of 300 mg/day. 1

Allow 6–8 weeks at therapeutic doses before declaring treatment failure. 1

Mandatory Pre-Treatment Screening

Absolute contraindications that must be ruled out: 1, 6

• Seizure history or any condition predisposing to seizures (head trauma, brain tumor, stroke, epilepsy)
• Current or past eating disorders (anorexia nervosa, bulimia)
• Uncontrolled hypertension (≥140/90 mm Hg or ≥130/80 mm Hg in high-risk patients)
• Current MAOI use or within 14 days of MAOI discontinuation
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs
• Moderate to severe hepatic impairment (maximum 150 mg/day if present)
• Moderate to severe renal impairment (reduce dose by 50% if GFR <90 mL/min)

Critical Monitoring Requirements

During the first 1–2 weeks after initiation, monitor intensively for: 1, 3

• Suicidal ideation and behavioral changes, especially in patients under 24 years (highest risk period for suicide attempts)
• Serotonin syndrome signs within the first 24–48 hours: mental status changes (confusion, agitation), neuromuscular hyperactivity (tremor, clonus, hyperreflexia), autonomic hyperactivity (hypertension, tachycardia, diaphoresis). Advanced symptoms (fever, seizures, arrhythmias, unconsciousness) require immediate hospitalization. 3
• Blood pressure and heart rate, particularly in the first 12 weeks, as bupropion can elevate both parameters 1
• Increased agitation or restlessness, as bupropion is an activating medication 1

Additional Clinical Advantages

Bupropion offers significant tolerability benefits over continuing SSRI/SNRI monotherapy: 1

• Significantly lower rates of sexual dysfunction compared to SSRIs (escitalopram, paroxetine)
• Minimal weight gain or potential weight loss, unlike many other antidepressants
• Lower rates of sedation than SSRIs
• No addiction potential, tolerance, or cognitive impairment 3

Common Pitfalls to Avoid

Do not combine bupropion with MAOIs or initiate within 14 days of MAOI discontinuation. 1, 6

Do not exceed 450 mg/day total dose, as seizure risk increases markedly above this threshold (approximately 0.1% at 300 mg/day). 1

Do not miss early signs of serotonin syndrome by attributing symptoms to worsening depression or anxiety. 3

Do not discontinue SSRIs abruptly when adding bupropion; maintain the existing SSRI dose during augmentation. 3

Do not declare treatment failure before 6–8 weeks at therapeutic bupropion doses (minimum 300 mg/day for most adults). 1

Alternative if Bupropion Fails or Is Contraindicated

If bupropion augmentation produces inadequate response after 6–8 weeks, consider adding cognitive-behavioral therapy (CBT) rather than further dose escalation. 1 Combination CBT plus medication is superior to either modality alone. 1

If bupropion is contraindicated due to seizure history or eating disorders, buspirone augmentation (20 mg three times daily) is the next evidence-based option, though it has higher discontinuation rates. 3