Safety Concerns, Mechanistic Pathways, and Knowledge Gaps in the Clinical Use of Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for the management of depressive and anxiety disorders and represent one of the most significant pharmacological advances in psychiatry. SSRIs are effective and better tolerated than older antidepressants; however, long-term safety issues, interactions, and withdrawal effects remain a concern. This review combines data from clinical trials, safety databases, and biological studies to provide a clear overview of the safety of SSRIs. The key risks include gastrointestinal bleeding, sexual dysfunction, hyponatremia, serotonin syndrome, discontinuation syndromes, and cardiovascular complications. Recent studies have reported lesser-known problems, such as akathisia, post-SSRI sexual dysfunction, metabolic issues, and possible effects on cognition. Large-scale pharmacovigilance analyses, such as those of the WHO VigiBase and Food and Drug Administration Adverse Event Reporting System, demonstrate that certain SSRIs carry disproportionate reporting signals, underscoring the need for individualized prescribing and long-term monitoring. This review further discusses the genetic and pharmacogenomic determinants of treatment response, as well as special population risks, such as those in the elderly, adolescents, and pregnant women, and regulatory measures aimed at mitigating harm. By critically integrating clinical, mechanistic, and real-world evidence, this review identifies significant knowledge gaps, particularly concerning long-term safety and understudied populations, and offers recommendations for future research. Clinicians should adopt a patient-centered risk-benefit evaluation, balancing therapeutic efficacy with safety concerns.