Background: While case reports and clinical trials reported withdrawal syndrome after reduction and/or discontinuation of antidepressant drugs, no large study has been conducted to compare the risk between the different antidepressants. Methods: Using data recorded from January 1st, 1988, and December 31st, 2020 in VigiBase®, the World Health Organization's Global Individual Case Safety Reports database, we performed disproportionality analysis to investigate the risk of reporting withdrawal syndrome in patients treated by short half-life antidepressants compared with patients treated by long half-life antidepressants. In addition, we aimed to better inform clinical practice by comparing 15 antidepressants for the risk of reporting withdrawal syndrome. Results: Among the 338,498 reports with antidepressants of interest, we found 15,507 cases of withdrawal syndrome. Short half-lives antidepressants were associated with an increased risk of reporting a withdrawal syndrome compared to long half-life antidepressants (ROR 5.38; 95% CI 5.16-5.61). The risk was higher for 18-44 years old (ROR 6.88; 95% CI 6.17-7.62), women (ROR 1.38; 95% CI 1.33-1.43) and patients treated with Paroxetine, Desvenlafaxine, Venlafaxine and Duloxetine. Limitations: The limitations of this study stem from the case-reporting process. Conclusions: This large observational study in a real-world setting suggests that the use of short half-life antidepressants increases the risk of reporting withdrawal syndrome compared to long half-life antidepressants. Among the most common antidepressants, paroxetine and serotonin-noradrenaline reuptake inhibitors are associated with a greater risk of reporting withdrawal syndrome, while agomelatine and vortioxetine present a lower risk. Additional studies are needed to corroborate our results.