ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacoepidemiology
This article is part of the Research TopicInnovative Approaches in Pharmacovigilance: Enhancing Detection and Analysis of Adverse Drug Reactions in Clinical and Real-World SettingsView all 5 articles
Disproportionality analysis of safety signals for milnacipran and levomilnacipran: a pharmacovigilance study using the FDA Adverse Event Reporting System
Provisionally accepted
- 1Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, China
- 2Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, China
- 3Wuhan Mental Health Center, Wuhan, China
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Background: Major depressive disorder (MDD) is a global health concern, with serotonin-norepinephrine reuptake inhibitors (SNRIs) constituting a mainstay of the psychopharmacological approach to its clinical management. Milnacipran and levomilnacipran are SNRIs with distinct serotonin/norepinephrine reuptake ratios. Their real-world adverse event (AE) profiles and sex-specific patterns remain incompletely characterized owing to limitations of small-scale clinical trials. Methods: Utilizing the FAERS database, adverse event signals were identified for milnacipran (2,752 cases) and levomilnacipran (715 cases) through the methods of Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS). Sex-stratified analyses were also conducted, employing a modified ROR approach. Results: Female patients predominated in AE reports (milnacipran: 79.61%; levomilnacipran: 64.48%). At the level of System Organ Class, milnacipran exhibited significant signals in vascular disorders (EBGM05=2.16), while levomilnacipran demonstrated stronger signals in psychiatric (EBGM05=3.45), reproductive (EBGM05=8.65), and renal/urinary systems (EBGM05=2.39). Out of 26 shared Preferred Terms, painful ejaculation and urinary retention showed the largest disparities (levomilnacipran risk higher). Sex-specific signals included female-predominant nausea (milnacipran) and suicidal ideation (levomilnacipran), and male-predominant urinary retention (both agents). Conclusion: This real-world pharmacovigilance study has highlighted the distinct adverse event profiles of milnacipran and levomilnacipran, with a particular emphasis on sex-specific reactions. This differentiation supports the adoption of precision prescribing strategies and addresses the limitations often encountered in traditional clinical trial data.
Keywords: milnacipran, Levomilnacipran, adverse events, FAERS, pharmacovigilance analysis, sex differences
Received: 07 Oct 2025; Accepted: 30 Nov 2025.
Copyright: © 2025 Huang, Zhang, Zhou, Wang, Zhang, Li and Xiao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Tao Huang
Junli Xiao
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