What weight‑neutral medication can I switch a 32‑year‑old woman with moderate major depressive disorder and generalized anxiety, currently on sertraline 75 mg with 40‑lb weight gain and inadequate response, and who cannot tolerate buspirone, to?

Weight-Neutral Antidepressant for Treatment-Resistant Depression with Sertraline-Induced Weight Gain

Switch to bupropion SR 150 mg twice daily (or XL 300 mg once daily) as your primary antidepressant, as it is the only antidepressant consistently associated with weight loss rather than weight gain and is effective for both depression and anxiety. 1

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Evidence-Based Rationale for Bupropion

Bupropion is the optimal choice when weight concerns are a priority because it promotes weight loss through appetite suppression and reduced food cravings, with clinical trial data showing 23% of patients losing ≥5 lbs compared to only 11% on placebo in long-term trials. 1 The FDA has even approved bupropion (in combination with naltrexone as Contrave) for chronic weight management, underscoring its weight-loss properties. 1

In a large real-world study of 183,118 patients, bupropion was associated with 0.22 kg less weight gain at 6 months compared to sertraline (the medication your patient is currently taking), and showed a 15% reduced risk for gaining at least 5% of baseline weight. 2 This makes bupropion the clear winner among antidepressants for patients with weight concerns. 1, 2

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Why Sertraline Failed and What to Avoid

Your patient's current medication, sertraline 75 mg, causes short-term weight loss that transitions to weight neutrality with chronic use—but individual variations occur, and this patient has gained 40 pounds. 1 Sertraline is generally considered weight-neutral to modest loss in most patients, but clearly this patient is an exception. 1

Medications to absolutely avoid in this patient:

• Paroxetine has the highest risk of weight gain among all SSRIs and would be the worst choice. 1
• Mirtazapine is closely associated with significant weight gain and would exacerbate the problem. 1, 3
• Duloxetine shows higher weight gain than sertraline (0.34 kg more at 6 months). 2
• Tricyclic antidepressants (especially amitriptyline) carry the greatest weight gain risk. 1

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Bupropion Dosing Protocol

Initial Dosing

Start with bupropion SR 150 mg once daily for 3 days, then increase to 150 mg twice daily if tolerated. 4 The first dose should be taken in the morning, and the second dose must be given before 3 PM to minimize insomnia risk. 4

Alternatively, bupropion XL 150 mg once daily in the morning can be started, then increased to 300 mg once daily after one week. 4 The XL formulation offers once-daily dosing convenience.

Target Dose

The standard therapeutic dose for major depressive disorder is 300 mg/day (either 150 mg SR twice daily or 300 mg XL once daily). 4 The maximum dose is 400 mg/day for SR or 450 mg/day for XL, but start conservatively. 4

Titration Strategy

Begin with 37.5 mg every morning and increase by 37.5 mg every 3 days as tolerated if the patient is sensitive to medication side effects or on multiple psychotropic medications. 4 This gradual approach minimizes adverse effects while reaching therapeutic levels.

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Critical Safety Screening Before Starting Bupropion

Absolute contraindications that must be ruled out: 1, 4

• Seizure disorders or any condition predisposing to seizures (bupropion lowers seizure threshold)
• Eating disorders (bulimia or anorexia nervosa) due to increased seizure risk
• Current or recent MAOI use (within 14 days)
• Uncontrolled hypertension (bupropion can elevate blood pressure)
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs (increases seizure risk)

Relative contraindications requiring caution: 4

• Moderate to severe hepatic impairment (maximum dose 150 mg daily)
• Moderate to severe renal impairment (reduce total daily dose by 50%)

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Monitoring Requirements

Baseline Assessment

Before starting bupropion, obtain: 4

• Blood pressure and heart rate (bupropion can cause elevations)
• Mental status examination focusing on suicidal ideation (especially critical in patients <24 years old)

Ongoing Monitoring

• Blood pressure and heart rate periodically, especially during the first 12 weeks 4
• Monitor for neuropsychiatric adverse effects, including agitation, restlessness, and behavioral changes 4
• Assess for suicidal ideation within 1-2 weeks of initiation, as the risk for suicide attempts is greatest during the first 1-2 months of treatment 4
• Allow 6-8 weeks at an adequate dose before determining treatment response 4

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Expected Timeline for Response

Initial improvement in energy levels may occur within the first few weeks, as bupropion has activating properties. 4 However, full antidepressant response requires 6-8 weeks at therapeutic doses. 4 If no adequate response occurs by 6-8 weeks, consider dose adjustment or alternative strategies. 4

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Efficacy for Both Depression and Anxiety

While bupropion is FDA-approved for major depressive disorder, the presence of comorbid anxiety does not appear to significantly affect its comparative efficacy based on STAR*D trial analyses. 4 This patient's anxiety should not preclude bupropion use.

Bupropion demonstrates equivalent efficacy to SSRIs and SNRIs for major depressive disorder, with response rates of approximately 42-49% remission. 4 Importantly, bupropion has significantly lower rates of sexual dysfunction compared to SSRIs, which is an additional advantage. 4

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Addressing the Buspirone Intolerance

The patient tried buspirone but had side effects. Buspirone augmentation of SSRIs is less effective than bupropion augmentation and has significantly higher discontinuation rates due to adverse events (20.6% vs. 12.5%, P < 0.001). 4 Switching to bupropion monotherapy avoids the need for buspirone entirely.

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Transition Strategy from Sertraline to Bupropion

Immediate initiation of bupropion after stopping sertraline is safe—no washout period is needed because neither drug is an MAOI. 4 However, consider a brief cross-taper to minimize discontinuation symptoms:

1. Start bupropion SR 150 mg once daily while continuing sertraline 75 mg for 3-7 days
2. Increase bupropion to 150 mg twice daily and reduce sertraline to 50 mg for 3-7 days
3. Continue bupropion 150 mg twice daily and reduce sertraline to 25 mg for 3-7 days
4. Discontinue sertraline and maintain bupropion 150 mg twice daily

This approach prevents a therapeutic gap while minimizing withdrawal symptoms from sertraline.

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Alternative Weight-Neutral Options (If Bupropion Fails or Is Contraindicated)

If bupropion cannot be used due to contraindications or intolerance, consider these weight-neutral alternatives:

Vortioxetine

Vortioxetine is a weight-neutral option that can be considered when weight is a significant concern. 1 However, it lacks the weight-loss advantage of bupropion.

Fluoxetine

Fluoxetine typically causes modest weight loss during initial treatment, followed by weight neutrality with long-term use, making it one of the preferred SSRIs when weight concerns are present. 1 It ranks as one of the most weight-favorable SSRIs. 1

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Common Pitfalls to Avoid

1. Never exceed 450 mg/day total dose to maintain seizure risk at 0.1%. 4
2. Never give the second dose of bupropion SR after 3 PM, as this increases insomnia risk. 4
3. Do not discontinue bupropion abruptly—taper gradually if discontinuation is needed. 4
4. Do not combine with MAOIs or initiate within 14 days of MAOI discontinuation. 4
5. Do not skip the intensive monitoring window during weeks 1-2, as this period carries the highest risk for emergent suicidal ideation. 4
6. Do not conclude treatment failure before 6-8 weeks at therapeutic doses. 4

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Adjunctive Weight Management Strategies

If the patient requires additional weight management support while on bupropion, consider:

Phentermine/topiramate ER (7.5/46 mg, escalating to 15/92 mg if needed) as adjunctive therapy for patients with weight gain attributable to antidepressants, achieving 7.8-9.8% weight loss in clinical trials. 1 However, this should only be considered if bupropion alone does not reverse the weight gain after an adequate trial.

Metformin can be added if metabolic concerns develop, though this is typically reserved for patients on antipsychotics with poor cardiometabolic profiles. 5

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Summary Algorithm

1. Confirm no contraindications to bupropion (seizure history, eating disorders, uncontrolled hypertension, recent MAOI use)
2. Obtain baseline blood pressure and assess suicidal ideation
3. Start bupropion SR 150 mg once daily for 3 days, then increase to 150 mg twice daily (or start XL 150 mg daily, increase to 300 mg daily after 1 week)
4. Cross-taper with sertraline over 2-3 weeks to minimize discontinuation symptoms
5. Monitor blood pressure, mood, and suicidal ideation weekly for the first month
6. Assess response at 6-8 weeks—expect weight loss and improved depression/anxiety
7. If inadequate response at 8 weeks, consider increasing to 300 mg SR twice daily (or 450 mg XL daily) or adding cognitive behavioral therapy

Bupropion is the evidence-based, guideline-supported choice for this patient with depression, anxiety, and significant antidepressant-induced weight gain. 1, 2