Does combining Mirtazapine (Remeron) with Bupropion (Wellbutrin) lessen appetite effects?

Does Combining Mirtazapine with Bupropion Lessen Appetite Effects?

Combining bupropion (Wellbutrin) with mirtazapine (Remeron) can theoretically counterbalance mirtazapine's appetite-stimulating effects, though this combination lacks direct clinical trial evidence and the net effect on appetite will vary based on individual patient response and dosing.

Mechanism-Based Rationale

The pharmacologic profiles of these medications suggest opposing effects on appetite:

Mirtazapine's Appetite-Stimulating Properties

• Mirtazapine potently promotes appetite and weight gain through antagonism of 5-HT2 and 5-HT3 receptors, plus histamine H1 receptor blockade 1
• Sedation, increased appetite, and weight gain are more common with mirtazapine than placebo, with these effects mediated primarily through H1 receptor antagonism 2
• Clinical studies demonstrate mean weight gains of 1.93-2.11 kg (3.9-4.6% of body weight) within 3-6 months in patients with Alzheimer's disease 3
• The appetite stimulation is considered a therapeutic effect when treating cachexia or anorexia, but an adverse effect in weight-neutral depression treatment 1, 4

Bupropion's Appetite-Suppressing Properties

• Bupropion is the only antidepressant consistently associated with weight loss through dopamine and norepinephrine reuptake inhibition that suppresses appetite and reduces food cravings 1
• Bupropion modulates central reward pathways triggered by food, making it activating rather than sedating 1
• When combined with naltrexone, bupropion achieves 6.1% weight loss versus 1.3% with placebo, demonstrating robust anorectic effects 1, 5

Clinical Considerations for the Combination

Potential Counterbalancing Effects

• The opposing mechanisms suggest bupropion may partially offset mirtazapine's appetite stimulation, though no controlled trials have directly studied this specific drug-drug interaction on appetite outcomes 1
• The net effect depends on relative dosing: higher mirtazapine doses (30-45 mg) produce more pronounced appetite effects, while therapeutic bupropion doses (300-450 mg total daily) provide consistent anorectic activity 1, 2

Practical Prescribing Strategy

• If weight neutrality is the goal, start bupropion first (titrate to 150 mg twice daily) before adding low-dose mirtazapine (7.5-15 mg at bedtime) to minimize sedation while preserving antidepressant synergy 1
• Monitor weight monthly during the first 3 months, as individual responses vary significantly based on genetic factors affecting drug metabolism 6
• This combination is sometimes used clinically as "California rocket fuel" for treatment-resistant depression, where the appetite effects may balance but sedation from mirtazapine and activation from bupropion can complement each other 1

Important Caveats

• Bupropion should not be used in patients with seizure disorders, eating disorders (anorexia/bulimia), or those requiring opioid therapy, as these are absolute contraindications 1, 5
• The combination may increase seizure risk if bupropion exceeds 450 mg/day immediate-release or 400 mg/day sustained-release formulations 6
• Mirtazapine's sedating effects are dose-dependent and paradoxically may decrease at higher doses (above 30 mg), while appetite stimulation persists 2, 4

Alternative Approaches

If appetite suppression is specifically desired:

• Consider bupropion monotherapy (150-300 mg daily) as first-line, which consistently promotes weight loss without the competing appetite effects of mirtazapine 1
• If sedation is needed without appetite stimulation, trazodone (50-100 mg at bedtime) provides sleep benefits with minimal weight effects 6
• For patients requiring both antidepressant efficacy and weight management, SSRIs like fluoxetine or sertraline are weight-neutral long-term 1