Can You Take Zepbound with Wellbutrin and Sertraline?
Yes, you can take Zepbound (tirzepatide) for weight loss while taking Wellbutrin (bupropion) and sertraline for depression—there are no known contraindications to this combination, and your current antidepressant regimen is actually favorable from a weight management perspective.
Why This Combination Is Reasonable
Your Antidepressants Have Favorable Weight Profiles
Sertraline is weight-neutral with long-term use, showing weight loss only in short-term studies but minimal weight changes over extended treatment periods 1.
Bupropion consistently promotes weight loss through appetite suppression and reduced food cravings, making it the only antidepressant that actively supports weight reduction 1.
Studies comparing these medications show bupropion causes mean weight loss of 2.77 kg at 6-12 months 1, while sertraline produces small, non-significant weight decreases (-0.79 kg) 2.
No Drug-Drug Interactions
Zepbound (tirzepatide) is a GLP-1/GIP receptor agonist that works through completely different mechanisms than your antidepressants 1.
Bupropion affects dopamine/norepinephrine reuptake, while sertraline affects serotonin reuptake—neither pathway interacts with tirzepatide's incretin-based mechanism 1.
The combination of bupropion and sertraline itself is well-established as safe and effective, even in treatment-refractory depression 3.
Practical Considerations
Monitoring Requirements
Gastrointestinal side effects from Zepbound (nausea, delayed gastric emptying) may be more noticeable initially but typically improve with gradual dose titration 1.
Track your weight regularly, as the combined effect of bupropion's appetite suppression and tirzepatide's satiety enhancement could produce more substantial weight loss than either alone 1, 4.
Monitor mood stability, though no evidence suggests tirzepatide negatively impacts depression treatment 1.
Optimizing Your Regimen
Your current antidepressant combination is actually ideal for someone pursuing weight loss, as you're avoiding weight-promoting agents like paroxetine or mirtazapine 1, 5.
If you experience increased nausea from Zepbound, this is unrelated to your antidepressants and should be managed through slower dose escalation 1.
Weight loss from this combination should be proportional to your baseline BMI, with greater losses expected at higher starting weights 6, 4.
Common Pitfalls to Avoid
Don't discontinue your antidepressants thinking Zepbound alone will address mood—depression requires continued psychiatric medication management 1.
Don't attribute all side effects to drug interactions—nausea and GI symptoms are expected with GLP-1 agonists and typically resolve within weeks 1.
If sexual dysfunction occurs, this is more likely from sertraline than from bupropion or tirzepatide, as sertraline causes significantly more orgasmic dysfunction 2, 7.