Antidepressants with Low Seizure Risk and Minimal Weight Gain
For patients requiring an antidepressant without significant seizure threshold lowering or weight gain, bupropion is the optimal first choice, followed by sertraline or fluoxetine as alternatives. 1, 2
Primary Recommendation: Bupropion
Bupropion stands alone as the only antidepressant consistently associated with weight loss rather than weight gain, with 23% of patients losing ≥5 lbs compared to 11% on placebo in long-term trials. 1, 2 It promotes weight loss through appetite suppression and reduced food cravings. 1
Seizure Risk Profile
- Bupropion has a low seizure risk (0.0%-0.4%) at therapeutic doses, similar to newer antidepressants and not substantially different from the general population incidence (0.07%-0.09%). 3
- Critical caveat: Bupropion should not be used in patients with seizure disorders or those at high risk for seizures. 1
- The medication is activating and may exacerbate anxiety or be inappropriate for bipolar disorder. 1
Alternative Options: SSRIs with Favorable Profiles
Sertraline
- Weight profile: Initially causes modest weight loss, then becomes weight-neutral with long-term use. 2, 4
- Seizure risk: Very low (0.0%-0.4%), among the safest antidepressants for seizure risk. 3, 5
- A 2024 target trial emulation study of 183,118 patients found sertraline had minimal weight change at 6 months, serving as the reference comparator. 6
- FDA labeling notes weight loss in pediatric populations, with approximately 1 kg less weight gain compared to placebo. 7
Fluoxetine
- Weight profile: Causes initial weight loss followed by weight neutrality with long-term treatment. 2, 4
- Seizure risk: Very low, among the safest antidepressants. 3, 5
- In the 2024 comparative study, fluoxetine showed a non-significant weight difference of -0.07 kg compared to sertraline at 6 months. 6
- Long-term data (26-32 weeks) demonstrated modest but non-significant weight decrease. 8
Venlafaxine
- Weight profile: Generally weight-neutral to slight weight loss due to nausea and decreased appetite. 4
- Seizure risk: Low, comparable to other newer antidepressants. 3
- The 2024 study showed only 0.17 kg more weight gain than sertraline at 6 months. 6
Antidepressants to Avoid
Highest Weight Gain Risk
- Paroxetine: Highest weight gain risk among all SSRIs, with 0.37 kg more gain than sertraline at 6 months and 10-15% higher risk of gaining ≥5% baseline weight. 2, 4, 6, 8
- Mirtazapine: Closely associated with significant weight gain and promotes appetite. 1, 2, 4
- Amitriptyline: Greatest weight gain risk among tricyclic antidepressants. 2
Higher Seizure Risk
- Tricyclic antidepressants (including amitriptyline, imipramine): Seizure risk of 0.4% to 1-2% at therapeutic doses, substantially higher than newer agents. 3, 5
Clinical Decision Algorithm
First-line: Prescribe bupropion unless contraindications exist (seizure history, eating disorders, bipolar disorder, severe anxiety). 1, 2
If bupropion contraindicated: Choose sertraline or fluoxetine based on side effect profile preferences (sertraline has less drug-drug interactions). 2, 3
If SNRI needed: Venlafaxine is the most weight-neutral option in this class. 4, 6
Screen for seizure predisposition before prescribing any antidepressant: previous seizures, alcohol/sedative withdrawal, multiple concomitant medications, brain injury, or metabolic abnormalities. 3, 5
Important Caveats
- Escitalopram and duloxetine cause modest weight gain (0.34-0.41 kg more than sertraline at 6 months) and should be avoided if weight is a primary concern. 6
- Citalopram causes minimal weight gain (0.12 kg more than sertraline) and may be acceptable if other options fail. 6
- Avoid paroxetine entirely in weight-sensitive patients—it consistently demonstrates the highest weight gain across multiple studies. 2, 6, 8
- Seizure risk increases with higher doses and blood levels for all antidepressants, so use the lowest effective dose. 3, 5
- A significant proportion of antidepressant-related seizures occur in predisposed individuals, making screening essential. 5