What antidepressants do not significantly lower the seizure threshold?

Antidepressants with Lower Seizure Risk

SSRIs (particularly fluoxetine and duloxetine), mirtazapine, and trazodone have the lowest seizure risk among antidepressants, while bupropion carries weak evidence of increased seizure risk and should be avoided in seizure-prone patients. 1

Safest Options (Negligible to Low Risk)

First-Line Choices

• Fluoxetine has negligible seizure risk (0.0%-0.4%) at therapeutic doses 2, 3, 4
• Duloxetine demonstrates negligible seizure risk and showed no incremental risk compared to bupropion (OR 0.94; 95% CI 0.75-1.22) 5, 4
• Mirtazapine carries at most moderate but still low risk (>0.1% under regular doses) 4
• Trazodone has low seizure potential at therapeutic doses 2, 4

Additional Safe Options

• Sertraline has lower seizure risk than tricyclics (0.0%-0.4%) but showed modest increase compared to bupropion in elderly patients 2, 3, 4
• Fluvoxamine demonstrates low seizure risk comparable to other safer SSRIs 2

Antidepressants to Avoid in Seizure-Prone Patients

Highest Risk

• Bupropion has weak evidence of association with increased seizure risk, making it a poor choice for patients with seizure concerns 1
• Escitalopram carries the highest risk among second-generation antidepressants (adjusted OR 1.79; 95% CI 1.42-2.25 compared to bupropion) 5, 4
• Citalopram shows elevated risk (adjusted OR 1.67; 95% CI 1.35-2.07 compared to bupropion) 5, 4

Moderate Risk

• Clomipramine (tricyclic) has the highest evidence for moderate risk among all antidepressants 4
• Amitriptyline and other tricyclics carry 0.4%-2% seizure risk at effective therapeutic doses, significantly higher than newer agents 2, 3, 4
• Venlafaxine demonstrates at most moderate but still low risk 4

Clinical Decision Algorithm

For patients without seizure history:

• Start with fluoxetine, duloxetine, or mirtazapine as first-line options 2, 3, 4
• Avoid bupropion, escitalopram, and citalopram if other factors suggest seizure vulnerability 1, 5

For patients with seizure history or brain injury:

• Strongly prefer fluoxetine or duloxetine given negligible risk 2, 4
• Absolutely avoid tricyclics (0.4%-2% risk) and bupropion 1, 2, 3
• In brain-injured populations, 19% developed seizures on tricyclics, making them contraindicated 6

For elderly patients (≥65 years):

• Avoid escitalopram and citalopram specifically, as they show highest seizure risk in this population 5
• Fluoxetine and duloxetine remain safest choices 5, 4

Critical Caveats

Dose-dependent risk: Seizure risk increases with higher doses and blood levels for most antidepressants, so comparisons must consider effective therapeutic doses 2, 3

Predisposing factors amplify risk: A significant proportion of antidepressant-related seizures occur in patients with previous seizures, alcohol/sedative withdrawal, or multiple concomitant medications 2, 3

Timing of risk: Seizures typically develop within the first 60 days of treatment, requiring heightened vigilance during this period 5

Overdose considerations: While therapeutic doses of newer antidepressants are relatively safe, overdose significantly increases seizure risk for certain agents 3