Abstract
Background Selective serotonin reuptake inhibitors (SSRIs) represent the cornerstone of modern antidepressant therapy, yet critical knowledge gaps persist regarding their comparative real-world safety profiles. This evidence deficit has profound implications for clinical decision-making and patient outcomes. Methods We conducted a comprehensive pharmacovigilance analysis utilizing VigiBase, the WHO global database of individual case safety reports, encompassing over 342,000 reports for six major SSRIs (sertraline, fluoxetine, paroxetine, citalopram, escitalopram, and fluvoxamine). Disproportionality analysis using information component (IC) values was performed across seven clinically relevant safety domains: anticholinergic effects, sexual dysfunction, metabolic effects, extrapyramidal symptoms, sleep disturbances, withdrawal syndrome, and cardiac conduction abnormalities. Results Significant heterogeneity in safety profiles was observed among SSRIs, with clear correlations between pharmacodynamic properties and adverse event patterns. Paroxetine demonstrated the highest rates of anticholinergic effects, sexual dysfunction, weight gain, and withdrawal syndrome, correlating with its high muscarinic M1 receptor binding affinity (Ki = 108 nM). Citalopram showed elevated cardiac conduction abnormalities, while fluoxetine exhibited increased extrapyramidal symptoms. A strong inverse relationship was observed between SSRI half-life and withdrawal syndrome reporting. Conclusions This analysis reveals that SSRIs exhibit distinct safety profiles that correlate with their pharmacodynamic properties, challenging the traditional view of these medications as a homogeneous therapeutic class. These findings support precision prescribing approaches based on individual patient risk factors and provide mechanistic insights for evidence-based SSRI selection.