How can I safely restart bupropion (Wellbutrin) in an adult (≥18 years) after prior discontinuation, ensuring no seizure disorder, eating disorder, recent monoamine‑oxidase inhibitor use, uncontrolled hypertension, pregnancy or breastfeeding, and what are the appropriate initial dose, titration schedule, maximum dose, and monitoring parameters?

Restarting Bupropion: Evidence-Based Protocol

Pre-Restart Safety Screening

Before restarting bupropion, verify the absence of all absolute contraindications:

• Seizure history or predisposing conditions (prior seizure disorder, head trauma, brain tumor, stroke, eating disorders [bulimia/anorexia], or abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs) 1, 2
• Current MAOI use or within 14 days of MAOI discontinuation (includes phenelzine, isocarboxazid, linezolid, or methylene blue) 1, 2
• Uncontrolled hypertension (≥140/90 mm Hg or ≥130/80 mm Hg in high-risk patients) 1
• Pregnancy or breastfeeding (limited data suggest possible cardiovascular defects; case reports of seizures in breastfed infants warrant caution) 1
• Moderate-to-severe hepatic impairment (Child-Pugh score ≥7) or end-stage renal disease 1, 2

Initial Dosing and Titration Schedule

For major depressive disorder, use the following restart protocol:

• Days 1–3: Bupropion SR 150 mg once daily in the morning 1, 2
• Day 4 onward: Increase to 150 mg twice daily (300 mg total) if tolerated 1, 2
• Second dose timing: Administer the second dose before 3 PM to minimize insomnia risk 1

For bupropion XL formulation:

• Days 1–4: 150 mg once daily in the morning 1, 2
• Day 5 onward: Increase to 300 mg once daily in the morning 1, 2

For older adults (≥65 years):

• Start at 50% of standard dose: 37.5 mg every morning 1
• Titrate gradually: Increase by 37.5 mg every 3 days as tolerated 1
• Maximum dose: 150 mg twice daily (300 mg total) 1

Maximum Dose Limits

To maintain seizure risk at 0.1% (1 in 1,000), never exceed:

• Bupropion SR: 400 mg per day 1
• Bupropion XL: 450 mg per day 1, 2
• For smoking cessation: 300 mg per day maximum 1

Dose Adjustments for Renal or Hepatic Impairment

Moderate-to-severe renal impairment (eGFR <90 mL/min):

• Reduce total daily dose by 50% (e.g., 150 mg once daily instead of 300 mg) 1
• Bupropion and its metabolites accumulate renally; close monitoring is required 1

Moderate-to-severe hepatic impairment (Child-Pugh 7–15):

• Maximum dose is 150 mg every other day 1, 2

Mild hepatic impairment (Child-Pugh 5–6):

• Reduce dose and/or frequency 1, 2

Critical Monitoring Parameters

During weeks 1–2 (highest-risk period):

• Suicidal ideation and behavioral changes (especially in patients <24 years; risk is greatest in the first 1–2 months) 1
• Blood pressure and heart rate (bupropion can elevate both parameters) 1
• Agitation or activation (bupropion has activating properties that may worsen agitation) 1

Throughout the first 12 weeks:

• Monitor blood pressure and heart rate periodically 1
• Assess for neuropsychiatric adverse effects (agitation, restlessness, behavioral changes) 1

At 6–8 weeks:

• Formally assess therapeutic response 1
• If no adequate response, consider dose adjustment, augmentation, or switching 1

Common Side Effects and Management

Most frequent adverse events (typically transient):

• Insomnia (manage by ensuring second dose is before 3 PM; occurs more frequently than placebo) 1, 3
• Dry mouth (occurs more frequently than placebo; usually resolves without intervention) 1, 3
• Headache, nausea, anxiety (occur at similar rates to placebo) 3

Seizure risk at therapeutic doses:

• 0.06%–0.1% (1 in 1,000) at 300 mg/day when patients are properly screened 1, 3, 4
• Risk increases markedly above 450 mg/day or with rapid dose escalation 1

Severe hypersensitivity reactions:

• 0.1% (1 in 1,000) incidence of urticaria or angioedema 1

Expected Timeline for Clinical Effect

Energy and activation:

• May improve within the first few weeks 1

Full antidepressant response:

• Requires 6–8 weeks at therapeutic doses 1
• Do not discontinue prematurely before 6–8 weeks unless significant adverse effects occur 1

Treatment modification:

• If no adequate response by 6–8 weeks, modify treatment (increase dose, augment with SSRI, or switch) 1

Discontinuation Protocol

When stopping bupropion XL 300 mg once daily:

• Taper to 150 mg once daily before discontinuation 1, 2
• Gradual dose reduction minimizes potential withdrawal symptoms 1

Clinical Advantages of Bupropion

Bupropion offers distinct benefits over SSRIs:

• Significantly lower rates of sexual dysfunction compared to SSRIs (e.g., escitalopram, paroxetine) 1, 5
• Minimal weight gain or modest weight loss (unlike many other antidepressants) 1
• Lower rates of sedation than SSRIs 1
• Particularly beneficial for patients with low energy, apathy, or hypersomnia due to activating properties 1
• Dual benefit for patients with comorbid depression and nicotine dependence 1

Critical Pitfalls to Avoid

• Do not restart bupropion without screening for seizure risk factors (history of seizures, eating disorders, abrupt alcohol/benzodiazepine withdrawal) 1, 2
• Do not exceed 450 mg/day (seizure risk rises markedly above this threshold) 1, 2
• Do not combine with MAOIs or initiate within 14 days of MAOI discontinuation 1, 2
• Do not skip intensive monitoring during weeks 1–2 (highest risk for emergent suicidal ideation, especially in patients <24 years) 1
• Do not administer the second dose after 3 PM (increases insomnia risk) 1
• Do not use in patients with uncontrolled hypertension (bupropion can elevate blood pressure) 1