Post-SSRI Sexual Dysfunction (PSSD): A comprehensive review of epidemiology, pathophysiology, and clinical management

Background Selective serotonin reuptake inhibitors (SSRIs) are first-line treatments for depression but are associated with significant sexual side effects. Post-SSRI Sexual Dysfunction (PSSD) describes a persistent syndrome of sexual dysfunction, including genital anesthesia and anhedonia, that continues or emerges after drug cessation. Despite recent warnings from regulatory bodies like the EMA, PSSD remains under-recognized. Methods A systematic review was conducted using PubMed, Web of Science, and Scopus databases up to April 2024. Studies focusing on PSSD pathophysiology, diagnostic criteria, and therapeutic interventions were analyzed. Results Prevalence estimates suggest persistent symptoms in up to 74% of affected cohorts beyond 6 months. The pathophysiology is multifactorial, involving 5-HT1A receptor desensitization, neurosteroid (allopregnanolone) depletion via 5α-reductase inhibition, and epigenetic silencing of dopaminergic reward circuits. Diagnosis is clinical, based on 2022 standardized criteria, distinguishing PSSD from depressive relapse by specific somatic symptoms like genital numbness. No FDA-approved treatments exist, though off-label use of dopamine agonists and low-power laser therapy shows preliminary promise. Conclusion PSSD is a severe iatrogenic condition requiring heightened pharmacovigilance. Future research must prioritize biomarker identification and prospective trials for targeted neurosteroid therapies.