In a 50‑year‑old menopausal woman with severe major depressive disorder, stimulant cravings, and a history of alcohol use disorder who is already on sertraline (titrated to 150‑200 mg daily) and a glucagon‑like peptide‑1 (GLP‑1) agonist, should I add the fixed‑dose bupropion‑naltrexone combination instead of bupropion alone?

Add Naltrexone-Bupropion Combination Rather Than Bupropion Alone

In this 50-year-old woman with severe major depressive disorder, stimulant cravings, and alcohol use disorder, you should prescribe the fixed-dose naltrexone-bupropion ER combination instead of bupropion monotherapy. The combination addresses all three conditions simultaneously—depression, alcohol cravings, and stimulant cravings—through complementary mechanisms without known pharmacokinetic interactions. 1

Evidence Supporting the Combination Over Monotherapy

Superior Efficacy for Co-Occurring Depression and Alcohol Use Disorder

• The combination of naltrexone plus an antidepressant produces markedly higher alcohol abstinence rates (53.7%) compared with either agent alone (naltrexone monotherapy: 21.3%; sertraline monotherapy: 27.5%; placebo: 23.1%) in patients with co-occurring depression and alcohol dependence. 2

• Time to relapse to heavy drinking is dramatically extended with combination therapy (median 98 days) versus naltrexone alone (29 days), sertraline alone (23 days), or placebo (26 days). 2

• Depression remission rates approach 83.3% with the naltrexone-antidepressant combination, significantly higher than monotherapy approaches, and serious adverse events are actually lower with the combination (11.9%) than with single agents. 2

Mechanistic Rationale for Stimulant Cravings

• The naltrexone-bupropion combination targets stimulant cravings through dual mechanisms: bupropion's dopaminergic/noradrenergic activity addresses the neurochemical deficits underlying stimulant withdrawal, while naltrexone's opioid-receptor blockade may attenuate reward-pathway activation associated with stimulant use. 1

• Naltrexone is a first-line pharmacologic option for alcohol dependence, and its opioid-receptor blockade extends benefit to stimulant cravings when combined with bupropion's activating properties. 1

• Preclinical studies demonstrate synergistic effects: combining low-dose naltrexone (10 mg/kg) with bupropion (10 mg/kg) significantly reduced alcohol consumption in alcohol-preferring rats, whereas neither agent alone at these doses showed efficacy. 3

Weight and Metabolic Benefits

• The naltrexone-bupropion ER combination produces 5.0–9.3% total body weight loss (placebo-subtracted: 3.2–5.2%) over 56 weeks, with 45–66% of patients achieving ≥5% weight loss. 4

• Metabolic improvements include decreased waist circumference, serum triglycerides, and insulin resistance, plus increased HDL-cholesterol, which may be particularly relevant given her GLP-1 agonist therapy. 4

Dosing Protocol for Naltrexone-Bupropion ER

Titration Schedule

• Week 1: One tablet (8 mg naltrexone/90 mg bupropion) once daily in the morning. 5

• Week 2: One tablet twice daily (morning and early afternoon, not late in the day to minimize insomnia). 5

• Week 3: Two tablets in the morning, one tablet in the early afternoon. 1

• Week 4 onward: Two tablets twice daily (maintenance dose: 32 mg naltrexone/360 mg bupropion total daily). 1, 5

• The second dose must be administered before 3 PM to prevent sleep disturbances, given bupropion's activating properties. 1, 5

Response Assessment

• After 12 weeks on the maintenance dose, discontinue if the patient has not lost at least 5% of total body weight, as this indicates poor response to the weight-management indication. 5

• For depression and substance-use outcomes, allow 6–8 weeks at therapeutic doses before assessing adequacy of response. 1

Critical Safety Screening Before Initiation

Absolute Contraindications

• Confirm the patient is not currently taking opioid medications, as naltrexone will precipitate severe opioid withdrawal. 1, 5

• Verify no history of seizure disorders or conditions predisposing to seizures (prior head trauma, brain tumor, stroke), as bupropion lowers seizure threshold. 1

• Exclude current or recent MAOI use (within 14 days), eating disorders (bulimia/anorexia), or abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs. 1

Blood Pressure Assessment

• Measure baseline blood pressure and confirm it is controlled (<140/90 mm Hg, or <130/80 mm Hg in high-risk patients), as the combination can elevate blood pressure and heart rate. 1, 5

• Uncontrolled hypertension is an absolute contraindication to naltrexone-bupropion ER. 1, 5

Hepatic and Renal Function

• In moderate to severe hepatic impairment, do not exceed one tablet daily (8 mg naltrexone/90 mg bupropion). 5

• In moderate to severe renal impairment (eGFR <90 mL/min), reduce the total daily dose by half (one tablet twice daily maximum). 5

Monitoring Parameters

Cardiovascular Monitoring

• Monitor blood pressure and heart rate at baseline, then periodically during the first 12 weeks, as the combination can cause modest elevations in both parameters. 1, 5

• If blood pressure exceeds 130/80 mm Hg during treatment, consider dose reduction, addition of antihypertensive therapy, or discontinuation. 1

Neuropsychiatric Monitoring

• Assess for suicidal ideation, agitation, irritability, or unusual behavioral changes during the first 1–2 weeks, as the risk of suicide attempts is highest in the initial 1–2 months of antidepressant therapy. 1

• Monitor for neuropsychiatric adverse effects throughout treatment, particularly in patients younger than 24 years. 5

Hepatic Monitoring

• Obtain baseline liver function tests and monitor at regular intervals, as naltrexone can cause hepatocellular injury at high doses (though standard 50 mg/day dosing carries low risk). 1

Common Pitfalls to Avoid

• Do not prescribe bupropion monotherapy when both alcohol use disorder and stimulant cravings are present, as you would miss the opportunity to address all three conditions (depression, alcohol dependence, stimulant cravings) with a single, evidence-based regimen. 1, 2

• Do not skip the gradual titration schedule, as rapid dose escalation increases seizure risk and gastrointestinal side effects (nausea, constipation, vomiting). 1, 4

• Do not administer the second daily dose late in the day, as this will precipitate insomnia due to bupropion's activating properties. 1, 5

• Do not exceed the maximum bupropion dose of 360 mg/day in the combination product, as seizure risk rises markedly above this threshold. 1

Expected Adverse Effects and Management

• The most common side effects are nausea (most frequent), constipation, headache, and vomiting, which typically diminish after the first few weeks. 4

• Serious adverse effects are very rare and include suicidal thoughts (requiring close monitoring in the first 1–2 months) and seizures (risk ≈0.1% at standard doses). 4

• The combination demonstrates better tolerability than monotherapy approaches, with lower serious adverse event rates (11.9%) compared with naltrexone alone, sertraline alone, or placebo. 2

Interaction with Existing Medications

• The combination of sertraline (150–200 mg daily) with naltrexone-bupropion ER is safe and may provide additive benefit for depression, as the mechanisms are complementary (sertraline: serotonergic; bupropion: dopaminergic/noradrenergic; naltrexone: opioid-receptor blockade). 1, 2

• No known pharmacokinetic interactions exist between naltrexone-bupropion and GLP-1 agonists, and the combination may provide synergistic weight-loss effects. 1

• Both medications can lower seizure threshold, so strict adherence to maximum dosing guidelines is essential (sertraline ≤200 mg/day; bupropion ≤360 mg/day in the combination product). 1