Best Antidepressant for Depression Without Weight Gain
Bupropion is the optimal first-line antidepressant for patients concerned about weight gain, as it is the only antidepressant consistently associated with weight loss rather than weight gain. 1
Primary Recommendation: Bupropion
Bupropion promotes weight loss through appetite suppression and reduced food cravings, with 23% of patients losing ≥5 lbs compared to only 11% on placebo in long-term trials. 1, 2
The FDA approves bupropion for chronic weight management (in combination with naltrexone as Contrave), underscoring its weight-loss properties. 1
In a 52-week study, patients with higher baseline BMI experienced greater weight loss: those with BMI ≥30 lost a mean of 2.4 kg, while those with BMI 22-26 lost 0.6 kg. 3
Bupropion demonstrates equivalent antidepressant efficacy to SSRIs like escitalopram and fluoxetine, while offering superior weight and sexual dysfunction profiles. 4, 5
Important Contraindications to Bupropion
Avoid bupropion in patients with seizure disorders or eating disorders (bulimia/anorexia), as it lowers the seizure threshold. 6, 2
Do not use within 14 days of monoamine oxidase inhibitors. 2
Use caution in patients with uncontrolled hypertension, as bupropion can increase blood pressure. 6
Second-Line Weight-Neutral Options
If bupropion is contraindicated, consider these alternatives:
Fluoxetine and sertraline cause initial modest weight loss (approximately 0.5-1 kg) that transitions to weight neutrality with long-term use. 1, 7
In a large comparative effectiveness study of 183,118 patients, bupropion showed 0.22 kg less weight gain than sertraline at 6 months, with 15% reduced risk of gaining ≥5% of baseline weight. 8
Sertraline demonstrated mean weight differences of approximately 1 kg less than placebo in pediatric trials, though this effect diminished with chronic use. 7
Vortioxetine represents another weight-neutral option when SSRIs are preferred. 1
Antidepressants to Absolutely Avoid
Paroxetine has the highest risk of weight gain among all SSRIs and should be avoided in weight-concerned patients. 1, 8
Mirtazapine causes significant weight gain through potent appetite stimulation and should never be used when weight is a concern. 1
Amitriptyline carries the greatest weight gain risk among tricyclic antidepressants. 1
Duloxetine shows higher weight gain than sertraline (0.34 kg more at 6 months) and carries 10-15% higher risk of gaining ≥5% baseline weight. 8
Clinical Decision Algorithm
First choice: Bupropion (if no seizure disorder, eating disorder, or uncontrolled hypertension) 1
Second choice: Sertraline or fluoxetine (weight-neutral SSRIs with initial weight loss) 1, 8
Third choice: Vortioxetine (weight-neutral alternative SSRI) 1
Never use: Paroxetine, mirtazapine, amitriptyline, or MAOIs in weight-concerned patients 1
Monitoring Requirements
Monitor weight at baseline, monthly for the first 3 months, then quarterly during continued treatment. 9
Regular weight monitoring is particularly important in pediatric patients on long-term SSRI treatment. 7
Assess for neuropsychiatric adverse effects with bupropion, including suicidal thoughts, especially in patients younger than 24 years. 2
Common Pitfalls to Avoid
Do not assume all SSRIs have identical weight effects—paroxetine causes significant weight gain while fluoxetine and sertraline are weight-neutral, demonstrating critical within-class differences. 1, 10
The weight-loss effect of fluoxetine and sertraline diminishes with chronic use (beyond 6-12 months), transitioning to weight neutrality rather than continued weight loss. 1, 7
Bupropion's weight-loss effects are dose-dependent and more pronounced in patients with higher baseline BMI. 2, 3