Antidepressants Associated with Weight Loss
Bupropion is the primary antidepressant with consistent weight loss properties, demonstrating a pooled weight loss of 2.77 kg at 6-12 months when used as monotherapy, and is the only antidepressant shown to consistently promote weight loss rather than weight gain or weight neutrality. 1
Primary Recommendation: Bupropion
Bupropion should be the first-line antidepressant choice when weight loss is a treatment priority, as it is the only agent in its class with documented weight-reducing effects across multiple formulations and indications. 1, 2
Evidence for Weight Loss
Monotherapy for depression: Bupropion produces a mean weight loss of 2.77 kg over 6-12 months in patients with major depressive disorder. 1
In obese patients with depressive symptoms: Bupropion SR 300-400 mg/day resulted in 4.4 kg (4.6% of baseline weight) loss versus 1.7 kg (1.8%) with placebo over 26 weeks, with 40% of patients losing ≥5% of baseline weight compared to 16% on placebo. 3
FDA-approved combination therapy: Naltrexone/bupropion extended-release is FDA-approved specifically for obesity treatment, demonstrating 6.1% weight loss versus 1.3% with placebo at 56 weeks, with 48% of patients achieving ≥5% weight loss. 1
Mechanism of Action
Bupropion functions as a dopamine and norepinephrine reuptake inhibitor, modulating central reward pathways triggered by food and suppressing appetite while reducing food cravings. 1
Dosing Considerations
- Standard antidepressant dosing ranges from 300-400 mg/day in sustained or extended-release formulations. 4, 3
- Weight loss effects are dose-related, with higher doses (400 mg/day) showing greater weight reduction (19% lost >5 lbs) compared to 300 mg/day (14% lost >5 lbs). 4
Ideal Candidates
Bupropion is particularly appropriate for patients with:
- Concomitant depression requiring treatment 1
- Desire to quit smoking (dual FDA approval) 1
- Food cravings or addictive eating behaviors 1
- Concerns about sexual dysfunction from other antidepressants 5, 6
- History of weight gain on other psychotropic medications 1
Contraindications and Cautions
Avoid bupropion in patients with:
- Uncontrolled hypertension 1
- History of seizures or conditions predisposing to seizures (anorexia, bulimia nervosa) 1
- Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs 1
- Current use of MAO inhibitors or opioids 1
Black box warning: Monitor for suicidal thoughts in young adults during the first few months of treatment, though no evidence of suicidality was reported in phase 3 obesity studies. 1
Common Side Effects
The most frequent adverse effects include nausea, constipation, headache, dizziness, insomnia, and dry mouth. 1, 4 Notably, bupropion has very low rates of sexual dysfunction and is more likely to cause weight loss than gain. 5
Secondary Option: Fluoxetine (High-Dose)
Fluoxetine at 60 mg daily (higher than standard antidepressant dosing of 20 mg) demonstrates weight loss of 4.74 kg at 6 months and 3.15 kg at 12 months. 1 However, this represents short-term weight loss only; fluoxetine becomes weight-neutral with long-term use. 1
This option is less preferable than bupropion because the weight loss effect is temporary and requires supra-therapeutic antidepressant dosing. 1
Weight-Neutral Alternatives
If bupropion is contraindicated, sertraline and fluoxetine at standard antidepressant doses (20 mg) are weight-neutral with long-term use, making them preferable to weight-gaining alternatives like paroxetine, mirtazapine, or tricyclic antidepressants. 1
Clinical Pitfalls to Avoid
- Do not use sertraline expecting weight loss: Despite one small study, evidence is insufficient to recommend sertraline for weight reduction. 1
- Do not prescribe paroxetine or mirtazapine: These are associated with the greatest weight gain risk within their respective classes. 1
- Recognize that most SSRIs cause weight neutrality at best: Only bupropion consistently promotes weight loss as a long-term effect. 1, 2
- Monitor for seizure risk: Bupropion lowers seizure threshold, particularly at doses >400 mg/day or in susceptible populations. 1