Epidemiologic Trends in Tianeptine (“Zaza”) Use: A Retrospective Cohort Analysis from the TriNetX Global Collaborative Network (2010-2024)

Background Tianeptine, often marketed as “Zaza,” “Red,” and “Tianaa,” is an atypical tricyclic antidepressant (TCA) with unique serotonergic and opioid receptor activity. While it is approved in some countries for major depressive disorder (MDD) and other conditions, it is not FDA-approved in the U.S. due to its potential for misuse and dependence. In recent years, cases of recreational use, withdrawal symptoms, and overdose events have increased, raising public health concerns. Despite these concerns, large-scale data on Tianeptine’s incidence and prevalence remain limited. Objective This study aims to analyze the incidence and prevalence of Tianeptine use within a large patient cohort using de-identified electronic health record (EHR) data from the TriNetX Global Collaborative Network. By examining demographic trends and comparing two time periods (2010-2017 vs. 2018-2024), we assess changes in usage patterns over time. Methods A retrospective cohort study was conducted using de-identified EHR data obtained from the TriNetX Global Collaborative Network. TriNetX is a federated, cloud-based health research network that provides aggregated, longitudinal health information from 141 healthcare organizations representing over 125,000,000 unique patients across the United States and partner institutions located in Europe, Asia, and South America. This study analyzed data from 129,740,865 patients between January 1, 2010, and December 31, 2024. Incidence and prevalence of Tianeptine use were analyzed across age, sex, race, and ethnicity. Patients with documented Tianeptine use were identified, and trends were compared across two timeframes (2010-2017 vs. 2018-2024). Because TriNetX data are aggregated from participating health systems, individual-level data cannot be accessed or exported by researchers. Results Between 2010–2017 and 2018–2024, the incidence and prevalence of Tianeptine-related encounters in a healthcare population significantly increased, with incidence proportion rising from 0.576 to 4.30 cases per 100,000 individuals, and the incidence rate increasing from 0.045 to 0.431 cases per 100,000 person-days. Tianeptine-related encounters were initially concentrated among adults aged ≥85 years; however, the incidence proportion in this group declined by 54% in the later period. In contrast, incidence increased among individuals aged 70–84 years, with the most pronounced rise observed in the 70–74 subgroup. Additionally, new cases have emerged in adolescents (10–19 years) and young adults (20–24 years). Conclusion Tianeptine-related healthcare encounters have increased over the past decade, with shifting age demographics and emerging cases in younger populations. These findings highlight the need for increased clinical awareness, improved surveillance, and further research into patterns of misuse and associated health outcomes.Given its opioid-like effects and potential dependence, these findings highlight the need for stronger regulatory oversight, improved clinical awareness, and targeted public health interventions. The results contribute to ongoing policy discussions and emphasize the importance of further research on Tianeptine misuse and treatment strategies.