In a patient who wants to quit smoking and is newly diagnosed with major depressive disorder, which medication can be initiated to treat both conditions?

Bupropion is the Medication of Choice

Bupropion should be initiated to simultaneously treat both smoking cessation and major depressive disorder in this patient. 1, 2

Rationale for Bupropion Selection

Bupropion is the only medication among the four options that holds FDA approval for both major depressive disorder and smoking cessation, making it uniquely suited to address both conditions with a single agent. 1, 3 The drug works through norepinephrine and dopamine reuptake inhibition rather than serotonergic mechanisms, distinguishing it from typical antidepressants. 2

Dual-Indication Evidence

• For depression: Bupropion demonstrates remission rates of 42–49% in major depressive disorder, equivalent to SSRI efficacy. 1
• For smoking cessation: Bupropion increases 12-month abstinence rates by approximately 9–10 percentage points above placebo (≈19% quit rate versus 11% with placebo). 1
• Combined benefit: The medication is particularly advantageous for patients requiring treatment of both depression and nicotine dependence simultaneously, addressing both conditions through complementary dopaminergic and noradrenergic pathways. 1, 4

Why Not the Other Options?

• Varenicline is FDA-approved only for smoking cessation, not for depression treatment. 5
• Vortioxetine is approved only for major depressive disorder, not for smoking cessation. 1
• Vilazodone is approved only for major depressive disorder, not for smoking cessation. 1

Dosing Protocol

Standard Titration Schedule

• Days 1–3: Start bupropion SR 150 mg once daily in the morning. 1
• Day 4 onward: Increase to 150 mg twice daily (300 mg total daily dose) if tolerated. 1
• Maximum dose: Do not exceed 300 mg/day for smoking cessation to maintain seizure risk at approximately 0.1%. 1

Timing Considerations

• Begin bupropion 1–2 weeks before the target quit date to establish therapeutic drug levels before the cessation attempt. 1
• Administer the second daily dose before 3 PM to minimize insomnia risk, as bupropion has activating properties. 1

Treatment Duration

• Continue therapy for 7–12 weeks after the quit date, with formal efficacy assessment after this period. 1
• For depression: Allow 6–8 weeks at therapeutic doses before determining treatment response. 1

Critical Safety Screening Before Initiation

Absolute Contraindications (Must Rule Out)

• Seizure history or predisposing conditions: Any history of seizures, epilepsy, stroke, brain tumor, head trauma, or conditions that lower seizure threshold. 6, 3
• Eating disorders: Current or past anorexia nervosa or bulimia nervosa. 3
• MAOI use: Current use or use within the preceding 14 days. 3
• Abrupt discontinuation of CNS depressants: Recent abrupt cessation of alcohol, benzodiazepines, or antiepileptic drugs. 1, 3

Relative Contraindications and Precautions

• Uncontrolled hypertension: Bupropion can elevate blood pressure and heart rate; measure baseline blood pressure and monitor periodically, especially during the first 12 weeks. 1
• Hepatic impairment: For moderate to severe hepatic impairment, maximum dose is 150 mg daily. 1
• Renal impairment: For moderate to severe renal impairment (GFR <90 mL/min), reduce total daily dose by 50%. 1

Monitoring Requirements

Early Phase (Weeks 1–2)

• Assess for suicidal ideation, agitation, irritability, or unusual behavioral changes within 1–2 weeks of initiation, as the risk of suicide attempts is highest during the first 1–2 months of antidepressant therapy. 1, 7 This is especially critical because the patient is newly diagnosed with MDD and the FDA black-box warning applies to all patients under 24 years of age. 1, 3

Ongoing Monitoring

• Blood pressure and heart rate: Monitor periodically, especially in the first 12 weeks, as bupropion can cause elevations. 1
• Depressive symptoms: Assess therapeutic response at 6–8 weeks; if inadequate, consider dose adjustment or augmentation strategies. 1
• Smoking status: Track abstinence with self-report and expired carbon monoxide measurements. 8

Advantages of Bupropion in This Clinical Context

Side-Effect Profile Benefits

• Significantly lower rates of sexual dysfunction compared to SSRIs (a common concern with antidepressants). 1
• Minimal weight gain or even modest weight loss, unlike many other antidepressants. 1
• Lower rates of sedation than SSRIs, with activating properties that may benefit patients with low energy or apathy. 1

Special Considerations for Depression with Smoking

• Smokers with depression are less likely to achieve abstinence even with pharmacotherapy, but bupropion addresses both conditions. 9
• History of major depression does not diminish bupropion's smoking-cessation efficacy; the drug is equally effective regardless of psychiatric history. 4
• Increases in depressive symptoms during early abstinence predict return to smoking, making concurrent depression treatment essential. 4

Common Pitfalls to Avoid

• Do not skip the 1–2 week lead-in period before the quit date—therapeutic drug levels must be established before attempting cessation. 1
• Do not exceed 300 mg/day for smoking cessation—higher doses markedly increase seizure risk. 1
• Do not overlook the intensive monitoring window in weeks 1–2—this period carries the highest risk for emergent suicidal ideation. 1, 7
• Do not assume "low-dose" bupropion is safe in patients with seizure history—the contraindication is absolute, not dose-dependent. 6

Augmentation Strategy if Needed

If smoking cessation proves difficult with bupropion alone after 7–12 weeks, add nicotine replacement therapy (NRT) such as a 21 mg patch plus short-acting NRT (gum or lozenge) for breakthrough cravings. 1 The combination of bupropion plus NRT achieves the highest abstinence rates (35.5% at 12 months) compared to bupropion alone (30.3%), though the difference is not statistically significant. 1