What antidepressant has the least risk of weight gain?

Antidepressant with Least Weight Gain

Bupropion is the only antidepressant consistently associated with weight loss rather than weight gain, making it the optimal choice when weight concerns are a priority. 1, 2, 3

First-Line Recommendation: Bupropion

• Bupropion 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 (up to 6 months). 3
• This is the only antidepressant FDA-approved for chronic weight management (in combination with naltrexone as Contrave). 1
• Typical weight loss is dose-dependent: 14% of patients on 300 mg/day and 19% on 400 mg/day lost >5 lbs versus only 6% on placebo. 3

Critical Caveat for Bupropion

• Bupropion is activating and can exacerbate anxiety or be inappropriate for bipolar disorder patients. 1, 4
• Do not use in patients with seizure disorders, eating disorders, or those abruptly discontinuing alcohol/benzodiazepines. 3

Second-Line Options: Weight-Neutral SSRIs

If bupropion is contraindicated due to anxiety or bipolar disorder:

Fluoxetine and Sertraline

• These SSRIs cause initial weight loss (first 4 weeks) followed by weight neutrality with long-term use. 1, 2
• Fluoxetine shows mean weight decrease of 0.4 kg during acute treatment (4 weeks), with subsequent weight gain during continuation therapy similar to placebo and related to recovery from depression rather than the medication itself. 5
• Long-term data (50 weeks) confirms weight gain on fluoxetine is not different from placebo after remission. 5

Citalopram

• Citalopram demonstrates less weight gain than escitalopram, paroxetine, or duloxetine. 4
• Consider this as a middle-ground option when bupropion and fluoxetine/sertraline are not suitable. 4

Antidepressants to AVOID for Weight-Concerned Patients

Highest Risk SSRIs

• Paroxetine has the highest risk of weight gain among all SSRIs. 1, 2, 4

Highest Risk Tricyclics

• Amitriptyline carries the greatest weight gain risk among tricyclic antidepressants. 1, 6
• Weight gain with amitriptyline is mediated through antihistamine H1 receptor antagonism in the hypothalamus. 6

Other High-Risk Agents

• Mirtazapine, lithium, and monoamine oxidase inhibitors are closely associated with significant weight gain. 1
• Mirtazapine specifically noted for weight gain in clinical guidelines. 1

Practical Algorithm

Step 1: Assess for contraindications to bupropion (anxiety, bipolar disorder, seizure history, eating disorders)

• If no contraindications → Start bupropion 1, 3
• If contraindicated → Proceed to Step 2

Step 2: Consider fluoxetine or sertraline as weight-neutral alternatives 1, 2

• If patient has prominent anxiety → Choose sertraline over fluoxetine
• If neither tolerated → Consider citalopram 4

Step 3: If switching from weight-promoting antidepressant:

• Monitor weight closely during first month; >2 kg gain or ≥7% of initial body weight warrants intervention. 6
• Implement dietary counseling and physical activity recommendations at treatment initiation. 2

Adjunctive Weight Management Strategies

If patient must remain on weight-promoting antidepressant for clinical reasons:

• Consider adding metformin 1000 mg/day or topiramate 100 mg/day to counter weight gain effects. 6
• Lifestyle modifications including balanced diet and regular physical activity can help limit weight gain. 6