For a 50‑year‑old menopausal woman with a history of methamphetamine and crack use, severe depression on sertraline 100 mg and a GLP‑1 agonist for cravings, should I first optimize sertraline and screen for bipolar disorder before adding bupropion, and what is the appropriate bupropion (including bupropion/naltrexone) dosing regimen to treat depression and cravings?

Optimize Sertraline and Screen for Bipolar Disorder Before Adding Bupropion; Bupropion-Naltrexone Dosing for Depression and Cravings

Before adding bupropion, increase sertraline to 100–200 mg daily over 2–4 weeks and complete a formal bipolar disorder assessment, because antidepressants can precipitate mania in undiagnosed bipolar disorder and this patient's stimulant-associated "hypomania" requires clarification. 1, 2, 3

Critical Pre-Treatment Steps

Complete Bipolar Disorder Screening

• Screen for personal and family history of bipolar disorder, prior manic/hypomanic episodes unrelated to stimulant use, and risk factors including family history of suicide or bipolar disorder. The distinction between stimulant-induced activation and true hypomania is essential because bupropion can precipitate manic episodes in bipolar disorder. 2, 3
• If bipolar disorder is confirmed, do not use bupropion or sertraline monotherapy—first-line treatment requires mood stabilizers (lithium, valproate, lamotrigine) or atypical antipsychotics (quetiapine, aripiprazole, lurasidone, cariprazine). 4, 3
• Antidepressants without mood stabilizers carry significant risk of mood destabilization and can induce rapid cycling in bipolar disorder. 4, 3

Optimize Sertraline First

• Increase sertraline from 100 mg to 150–200 mg daily in 50 mg increments at weekly intervals, because 50 mg is the starting dose but many patients require higher doses for full therapeutic effect. 5, 6, 7
• Allow 6–8 weeks at the optimized sertraline dose (150–200 mg) before determining treatment response, as this represents the standard timeline for antidepressant efficacy assessment. 1, 5
• Sertraline demonstrates equivalent efficacy to other SSRIs in depression and is well-tolerated in patients with comorbid medical conditions including substance use history. 6, 7

Bupropion Addition Strategy (If Sertraline Optimization Fails)

When to Add Bupropion

• Add bupropion only after confirming bipolar disorder is ruled out and sertraline at 150–200 mg for 6–8 weeks has produced inadequate response. 1, 3
• The combination of sertraline and bupropion addresses depression through complementary mechanisms (serotonergic via sertraline; noradrenergic/dopaminergic via bupropion) and has demonstrated efficacy in treatment-resistant depression. 8

Bupropion Dosing Protocol

• Start bupropion SR 37.5 mg every morning, increase by 37.5 mg every 3 days as tolerated, targeting 150 mg twice daily (300 mg total daily). 1
• Administer the first dose in the morning and the second dose before 3 PM to minimize insomnia risk. 1
• Maximum dose is 400 mg/day for SR formulation; do not exceed this to maintain seizure risk at 0.1%. 1, 2

Critical Safety Screening Before Bupropion

• Absolute contraindications include: 1, 2
  • History of seizure disorder or conditions predisposing to seizures (head trauma, brain tumor, stroke)
  • Current or recent MAOI use (within 14 days)
  • Eating disorders (bulimia, anorexia nervosa)—increased seizure risk
  • Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs
  • Uncontrolled hypertension
  • Moderate to severe hepatic or renal impairment (requires dose reduction)
• Measure baseline blood pressure and heart rate—bupropion can elevate both parameters, requiring monitoring especially in the first 12 weeks. 1, 2

Monitoring During Bupropion Initiation

• Assess for suicidal ideation, agitation, irritability, or behavioral changes within 1–2 weeks of starting bupropion, as the risk of suicide attempts is highest in the first 1–2 months of antidepressant therapy. 1
• Monitor blood pressure and heart rate periodically, especially during the first 12 weeks. 1, 2
• Allow 6–8 weeks at therapeutic bupropion dose (300 mg/day) before assessing full response. 1

Bupropion-Naltrexone Combination for Cravings

When to Consider Bupropion-Naltrexone

• Bupropion-naltrexone ER is appropriate for this patient's methamphetamine and crack cocaine cravings, addressing both depression and substance use through complementary opioid-blocking (naltrexone) and dopaminergic/noradrenergic (bupropion) mechanisms. 4, 1
• This combination is FDA-approved for obesity but has evidence supporting efficacy in alcohol dependence and may benefit stimulant cravings. 4, 1

Bupropion-Naltrexone Dosing Schedule

• Week 1: Naltrexone 8 mg/bupropion 90 mg once daily in the morning 1
• Week 2: Naltrexone 8 mg/bupropion 90 mg twice daily 1
• Week 3: Naltrexone 16 mg/bupropion 180 mg in the morning + naltrexone 8 mg/bupropion 90 mg in the evening 1
• Week 4 and beyond: Naltrexone 16 mg/bupropion 180 mg twice daily (maintenance dose) 1
• Maximum bupropion dose in this combination is 360 mg/day—do not exceed to minimize seizure and cardiovascular risk. 1

Critical Contraindications for Naltrexone-Bupropion

• Absolutely contraindicated if patient is taking any opioid medications (including Suboxone, methadone, tramadol)—naltrexone will precipitate severe opioid withdrawal. 1
• Contraindicated in uncontrolled hypertension—this combination can significantly elevate blood pressure and heart rate. 1, 2
• Contraindicated in moderate to severe hepatic impairment—naltrexone can cause hepatocellular injury; maximum dose is 150 mg bupropion daily in hepatic impairment. 1
• Contraindicated in moderate to severe renal impairment—reduce bupropion dose by 50% if GFR <90 mL/min; avoid in end-stage renal disease. 1

Monitoring for Bupropion-Naltrexone

• Measure blood pressure and heart rate at baseline and every 2–4 weeks for the first 12 weeks, then periodically thereafter. 1, 2
• Obtain baseline liver function tests and monitor periodically during naltrexone treatment. 1
• Assess for neuropsychiatric adverse effects including agitation, anxiety, and suicidal ideation, especially in the first 1–2 months. 1
• If blood pressure exceeds 130/80 mm Hg or becomes uncontrolled, reduce dose or discontinue the combination. 1

Alternative Strategy: Bupropion Monotherapy + Behavioral Support

If Naltrexone Is Contraindicated

• Use bupropion SR 150 mg twice daily (300 mg total) as monotherapy for both depression and stimulant cravings, as bupropion has demonstrated efficacy for methamphetamine dependence, particularly in patients with low-to-moderate baseline use. 1
• Combine bupropion with intensive behavioral support (structured counseling, definite quit date, weekly follow-up for at least 4 weeks) to maximize abstinence rates. 1

Expected Timeline and Efficacy

• Bupropion's activating properties may improve energy, apathy, and motivation within 2–4 weeks, though full antidepressant effect requires 6–8 weeks. 1
• For substance use cravings, assess efficacy after 7–12 weeks of treatment at therapeutic dose. 1
• Approximately 38% of patients fail an initial antidepressant trial; switching or augmentation after 6–8 weeks yields remission in about 25% of these patients. 1

Clinical Advantages of This Approach

Why Optimize Sertraline First

• Sertraline at 100 mg may be subtherapeutic—the optimal dose for most patients is 150–200 mg daily, and increasing the dose is safer than adding a second agent before ruling out bipolar disorder. 5, 6, 7
• Sertraline has low potential for drug interactions and requires no dose adjustment based on age alone, making it ideal for this 50-year-old patient. 6, 7

Why Bupropion Is Appropriate for This Patient

• Bupropion addresses the patient's specific symptom profile: moderate depression with anergia (stays in bed, difficulty getting up), which responds better to bupropion's activating dopaminergic/noradrenergic effects than to SSRIs alone. 1
• Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs (a common SSRI side effect that may affect adherence). 1
• Bupropion is associated with minimal weight gain or modest weight loss, unlike many antidepressants. 1
• Bupropion has demonstrated efficacy for stimulant cravings, particularly methamphetamine, making it ideal for this patient's substance use history. 1

Why Bupropion-Naltrexone May Be Superior

• The combination addresses both depression and cravings through complementary mechanisms without known pharmacokinetic interactions. 1
• Naltrexone is a first-line pharmacologic option for alcohol dependence and may benefit stimulant cravings through opioid-receptor blockade. 4, 1
• The fixed-dose combination ensures adherence and provides a unified approach to treat both conditions. 1

Common Pitfalls to Avoid

• Do not add bupropion before completing bipolar disorder screening—antidepressants can precipitate mania in undiagnosed bipolar disorder, and this patient's stimulant-associated "hypomania" requires clarification. 4, 2, 3
• Do not add bupropion before optimizing sertraline to 150–200 mg for 6–8 weeks—premature polypharmacy increases side effects and complicates assessment. 1, 5
• Do not use naltrexone-bupropion if the patient is taking any opioid medications—naltrexone will precipitate severe withdrawal. 1
• Do not exceed bupropion 300 mg/day for monotherapy or 360 mg/day in the naltrexone-bupropion combination—seizure risk increases markedly above these thresholds. 1, 2
• Do not skip intensive monitoring during weeks 1–2 after starting bupropion—this period carries the highest risk for emergent suicidal ideation. 1
• Do not use bupropion-naltrexone in uncontrolled hypertension—measure baseline blood pressure and monitor closely, as this combination can significantly elevate blood pressure. 1, 2
• Do not discontinue the GLP-1 medication abruptly when starting bupropion-naltrexone—overlap the medications during the 4-week titration period to maintain craving control, then taper the GLP-1 as bupropion-naltrexone reaches therapeutic dose. 1