Global burden of antidepressant-associated seizures from 1967 to 2023: A comparative analysis of the international pharmacovigilance database

Background: Although antidepressants have been implicated in seizure risk, comprehensive safety data examining this risk across different antidepressants remains limited. Methods: Data from Vigibase, an international pharmacovigilance database, encompassing 131,255,418 reports from 1967 to 2023, was analyzed. Reporting odds ratio (ROR) and information component (IC) were calculates to identify disproportionate associations between 17 antidepressants and seizures. Results: Among 2,275,638 reports on antidepressants, 23,331 reported seizures. Antidepressants as a whole were associated with higher reporting frequency of seizures compared with all medications. Among antidepressant classes, tricyclic antidepressants (TCA; ROR [95 % CI]: 2.71 [2.58–2.84]; IC [IC0.25] 1.42 [1.34]), were the most frequently reported in combination with seizures, followed by selective serotonin reuptake inhibitors (SSRIs; 2.27 [2.22–2.32]; 1.16 [1.13]) and serotonin-norepinephrine reuptake inhibitors (SNRIs; 1.31 [1.27–1.36]; 0.39 [0.33]). Regarding individual antidepressants, agomelatine and desvenlafaxine were the only medications without a significant disproportionate association with seizures. Among the remaining antidepressants, bupropion (8.57 [8.34–8.80]; 3.04 [3.00]) and clomipramine (4.69 [4.29–5.13]; 2.20 [2.05]) had the highest disproportionality measure estimates, whereas vortioxetine and duloxetine had the lowest disproportionality in reporting. Escitalopram (2.17 [2.04–2.31]; 1.11 [1.01]), the active enantiomer of citalopram, and desvenlafaxine (0.93 [0.82–1.05]; −0.11 [−0.31]), the active metabolite of venlafaxine, were less frequently reported for seizures compared to their parent compounds. Conclusion: Our findings align with earlier studies indicating that SNRIs and SSRIs carry a lower risk of seizures, whereas bupropion and clomipramine are linked to a higher risk. Agomelatine, vortioxetine, and SNRIs like desvenlafaxine and duloxetine may potentially be safe alternatives.