Mining and analysis of hemorrhagic adverse events signals of SSRIs and SNRIs based on the FAERS database_Chinese Journal of Evidence-Based Medicine

Authors：

LIU Qingyang ^1,2 , YAO Junqi ^1,3 , LU Anmei ^1,4 , HOU Zijing ⁵ ,  YI Zhanmiao ^1,6

1. Department of Pharmacy, Peking University Third Hospital, Beijing 100191, P. R. China;
2. Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, P. R. China;
3. Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing 100005, P. R. China;
4. Department of Pharmacy, Zhaotong Mental Health Center, Zhaotong 657000, P. R. China;
5. Department of Pharmacy, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, P. R. China;
6. Institute for Drug Evaluation, Peking University Health Science Center, Beijing 100191, P. R. China;

Corresponding?author：

YI Zhanmiao, Email: yzm@bjmu.edu.cn

Keywords：

Selective serotonin reuptake inhibitors; Serotonin and norepinephrine reuptake inhibitors; Hemorrhagic disease; Adverse event; Drug interaction

DOI：

10.7507/1672-2531.202508097

Video：

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Objective To analyze the characteristics and risk factors of hemorrhagic adverse events (AEs) associated with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Methods AEs reports with SSRIs/SNRIs as the primary suspected (PS) drugs from the first quarter of 2009 to the third quarter of 2024 in the FAERS database were extracted. Hemorrhagic AEs reports were screened using the MedDRA standard terminology (SMQ). Descriptive statistics were used to analyze patient characteristics, and signal detection was performed using the reporting odds ratio (ROR), proportional reporting ratio (PRR), and the polynomial gamma Poisson distribution reduction method (MGPS). Multiplicative and additive models were used to assess the interaction risk with antiplatelet/anticoagulant drugs. Results A total of 5 073 reports of hemorrhagic AEs associated with SSRIs (6.5%) and 2 740 reports related to SNRIs (4.1%) were included. The proportion of patients aged ≥65 years (P<0.001), the time-to-onset >90 days (P<0.001), reports from healthcare professionals (P<0.001), and serious adverse events (P<0.001) were higher. The gastrointestinal tract and central nervous system were the main bleeding sites for SSRIs, among which sertraline had the most signals for gastrointestinal adverse events, while the central nervous system had the fewest. All positive signals for SNRIs were associated with venlafaxine. Among AEs of various SSRIs/SNRIs combined with other drugs, the proportion of hemorrhagic AEs was higher in the combination with antiplatelet or anticoagulant drugs (P<0.001). Conclusion Hemorrhagic adverse events associated with SSRIs/SNRIs are mostly severe. In clinical practice, it is essential to implement proper pharmaceutical care, focusing on the bleeding risks associated with SSRIs/SNRIs use in elderly patients, those on long-term medication regimens, and patients concurrently using anticoagulants. Individualized medication regimens should be implemented based on the patient's underlying diseases and drug characteristics.

Citation： LIU Qingyang, YAO Junqi, LU Anmei, HOU Zijing, YI Zhanmiao. Mining and analysis of hemorrhagic adverse events signals of SSRIs and SNRIs based on the FAERS database. Chinese Journal of Evidence-Based Medicine, 2026, 26(4): 401-406. doi: 10.7507/1672-2531.202508097 Copy

1.	World Health Organization. World mental health report: transforming mental health for all. 2022.
2.	Institute for Health Mmetrics and Evaluation. Mental health. 2021.
3.	中華醫學會, 中華醫學會雜志社, 中華醫學會全科醫學分會, 等. 抑郁癥基層診療指南(2021年). 中華全科醫師雜志, 2021, 20(12): 1249-1260.
4.	中華醫學會神經病學分會, 中華醫學會神經病學分會腦血管病學組. 中國急性缺血性卒中診治指南2023. 中華神經科雜志, 2024, 57(6): 523-559.
5.	中華醫學會行為醫學分會, 中華醫學會行為醫學分會認知應對治療學組. 抑郁癥治療與管理的專家推薦意見(2022年). 中華行為醫學與腦科學雜志, 2023, 32(3): 193-202.
6.	Zhao Y, Zhang Y, Yang L, et al. Safety profile of selective serotonin reuptake inhibitors in real-world settings: a pharmacovigilance study based on FDA adverse event reporting system. Ann Pharmacother, 2024, 58(11): 1105-1116.
7.	Bixby AL, VandenBerg A, Bostwick JR. Clinical management of bleeding risk with antidepressants. Ann Pharmacother, 2019, 53(2): 186-194.
8.	Jiang HY, Chen HZ, Hu XJ, et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis. Clin Gastroenterol Hepatol, 2015, 13(1): 42-50.
9.	Anglin R, Yuan Y, Moayyedi P, et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol, 2014, 109(6): 811-819.
10.	Hackam DG, Mrkobrada M. Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis. Neurology, 2012, 79(18): 1862-1865.
11.	Renoux C, Vahey S, Dell'Aniello S, et al. Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage. JAMA Neurol, 2017, 74(2): 173-180.
12.	Sch?fer W, Princk C, Kollhorst B, et al. Antidepressants and the risk of hemorrhagic stroke in the elderly: a nested case-control study. Drug Saf, 2019, 42(9): 1081-1089.
13.	Shin JY, Park MJ, Lee SH, et al. Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study. BMJ, 2015, 351: h3517.
14.	Bobo WV, Moore KM, Betcher HK, et al. The association of antidepressants in late pregnancy with postpartum hemorrhage: systematic review of controlled observational studies. J Child Adolesc Psychopharmacol, 2024, 34(10): 428-446.
15.	Singh I, Achuthan S, Chakrabarti A, et al. Influence of pre-operative use of serotonergic antidepressants (SADs) on the risk of bleeding in patients undergoing different surgical interventions: a meta-analysis. Pharmacoepidemiol Drug Saf, 2015, 24(3): 237-245.
16.	Lee MT, Park KY, Kim MS, et al. Concomitant use of NSAIDs or SSRIs with NOACs requires monitoring for bleeding. Yonsei Med J, 2020, 61(9): 741-749.
17.	《口服抗凝藥物治療管理路徑專家共識》編寫組. 口服抗凝藥物治療管理路徑專家共識. 臨床藥物治療雜志, 2024, 22(9): 1-23.
18.	Smith MM, Smith BB, Lahr BD, et al. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are not associated with bleeding or transfusion in cardiac surgical patients. Anesth Analg, 2018, 126(6): 1859-1866.
19.	Laursen SB, Leontiadis GI, Stanley AJ, et al. The use of selective serotonin receptor inhibitors (SSRIs) is not associated with increased risk of endoscopy-refractory bleeding, rebleeding or mortality in peptic ulcer bleeding. Aliment Pharmacol Ther, 2017, 46(3): 355-363.
20.	Hou Y, Ye X, Wu G, et al. A comparison of disproportionality analysis methods in national adverse drug reaction databases of China. Expert Opin Drug Saf, 2014, 13(7): 853-857.
21.	張震坡, 鄭靖萍, 梁燕坤, 等. 基于FAERS數據庫的阿基侖賽相關血液及淋巴系統不良事件信號挖掘與分析. 中國循證醫學雜志, 2025, 25(7): 838-842.
22.	關瑜, 李雷, 朱旭, 等. 基于自發呈報系統的聯合用藥不良反應信號檢測方法研究進展. 中國藥物評價, 2022, 39(6): 489-495.
23.	Laporte S, Chapelle C, Caillet P, et al. Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: a meta-analysis of observational studies. Pharmacol Res, 2017, 118: 19-32.
24.	Pothen N, Patel P, Jafri A. Selective serotonin reuptake inhibitors and bleeding risk in the geriatric population. Innov Clin Neurosci, 2024, 21(10): 34-37.
25.	Andrade C, Sharma E. Serotonin reuptake inhibitors and risk of abnormal bleeding. Psychiatr Clin North Am, 2016, 39(3): 413-426.
26.	McFarland D, Merchant D, Khandai A, et al. Selective serotonin reuptake inhibitor (ssri) bleeding risk: considerations for the consult-liaison psychiatrist. Curr Psychiatry Rep, 2023, 25(3): 113-124.
27.	Leong C, Alessi-Severini S, Enns MW, et al. Cerebrovascular, cardiovascular, and mortality events in new users of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors: a propensity score-matched population-based study. J Clin Psychopharmacol, 2017, 37(3): 332-340.
28.	Perahia DG, Bangs ME, Zhang Q, et al. The risk of bleeding with duloxetine treatment in patients who use nonsteroidal anti-inflammatory drugs (NSAIDs): analysis of placebo-controlled trials and post-marketing adverse event reports. Drug Healthc Patient Saf, 2013, 5: 211-219.
29.	Woroń J, Siwek M, Gorostowicz A. Adverse effects of interactions between antidepressants and medications used in treatment of cardiovascular disorders. Psychiatr Pol, 2019, 53(5): 977-995.

1. World Health Organization. World mental health report: transforming mental health for all. 2022.
2. Institute for Health Mmetrics and Evaluation. Mental health. 2021.
3. 中華醫學會, 中華醫學會雜志社, 中華醫學會全科醫學分會, 等. 抑郁癥基層診療指南(2021年). 中華全科醫師雜志, 2021, 20(12): 1249-1260.
4. 中華醫學會神經病學分會, 中華醫學會神經病學分會腦血管病學組. 中國急性缺血性卒中診治指南2023. 中華神經科雜志, 2024, 57(6): 523-559.
5. 中華醫學會行為醫學分會, 中華醫學會行為醫學分會認知應對治療學組. 抑郁癥治療與管理的專家推薦意見(2022年). 中華行為醫學與腦科學雜志, 2023, 32(3): 193-202.
6. Zhao Y, Zhang Y, Yang L, et al. Safety profile of selective serotonin reuptake inhibitors in real-world settings: a pharmacovigilance study based on FDA adverse event reporting system. Ann Pharmacother, 2024, 58(11): 1105-1116.
7. Bixby AL, VandenBerg A, Bostwick JR. Clinical management of bleeding risk with antidepressants. Ann Pharmacother, 2019, 53(2): 186-194.
8. Jiang HY, Chen HZ, Hu XJ, et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis. Clin Gastroenterol Hepatol, 2015, 13(1): 42-50.
9. Anglin R, Yuan Y, Moayyedi P, et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol, 2014, 109(6): 811-819.
10. Hackam DG, Mrkobrada M. Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis. Neurology, 2012, 79(18): 1862-1865.
11. Renoux C, Vahey S, Dell'Aniello S, et al. Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage. JAMA Neurol, 2017, 74(2): 173-180.
12. Sch?fer W, Princk C, Kollhorst B, et al. Antidepressants and the risk of hemorrhagic stroke in the elderly: a nested case-control study. Drug Saf, 2019, 42(9): 1081-1089.
13. Shin JY, Park MJ, Lee SH, et al. Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study. BMJ, 2015, 351: h3517.
14. Bobo WV, Moore KM, Betcher HK, et al. The association of antidepressants in late pregnancy with postpartum hemorrhage: systematic review of controlled observational studies. J Child Adolesc Psychopharmacol, 2024, 34(10): 428-446.
15. Singh I, Achuthan S, Chakrabarti A, et al. Influence of pre-operative use of serotonergic antidepressants (SADs) on the risk of bleeding in patients undergoing different surgical interventions: a meta-analysis. Pharmacoepidemiol Drug Saf, 2015, 24(3): 237-245.
16. Lee MT, Park KY, Kim MS, et al. Concomitant use of NSAIDs or SSRIs with NOACs requires monitoring for bleeding. Yonsei Med J, 2020, 61(9): 741-749.
17. 《口服抗凝藥物治療管理路徑專家共識》編寫組. 口服抗凝藥物治療管理路徑專家共識. 臨床藥物治療雜志, 2024, 22(9): 1-23.
18. Smith MM, Smith BB, Lahr BD, et al. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are not associated with bleeding or transfusion in cardiac surgical patients. Anesth Analg, 2018, 126(6): 1859-1866.
19. Laursen SB, Leontiadis GI, Stanley AJ, et al. The use of selective serotonin receptor inhibitors (SSRIs) is not associated with increased risk of endoscopy-refractory bleeding, rebleeding or mortality in peptic ulcer bleeding. Aliment Pharmacol Ther, 2017, 46(3): 355-363.
20. Hou Y, Ye X, Wu G, et al. A comparison of disproportionality analysis methods in national adverse drug reaction databases of China. Expert Opin Drug Saf, 2014, 13(7): 853-857.
21. 張震坡, 鄭靖萍, 梁燕坤, 等. 基于FAERS數據庫的阿基侖賽相關血液及淋巴系統不良事件信號挖掘與分析. 中國循證醫學雜志, 2025, 25(7): 838-842.
22. 關瑜, 李雷, 朱旭, 等. 基于自發呈報系統的聯合用藥不良反應信號檢測方法研究進展. 中國藥物評價, 2022, 39(6): 489-495.
23. Laporte S, Chapelle C, Caillet P, et al. Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: a meta-analysis of observational studies. Pharmacol Res, 2017, 118: 19-32.
24. Pothen N, Patel P, Jafri A. Selective serotonin reuptake inhibitors and bleeding risk in the geriatric population. Innov Clin Neurosci, 2024, 21(10): 34-37.
25. Andrade C, Sharma E. Serotonin reuptake inhibitors and risk of abnormal bleeding. Psychiatr Clin North Am, 2016, 39(3): 413-426.
26. McFarland D, Merchant D, Khandai A, et al. Selective serotonin reuptake inhibitor (ssri) bleeding risk: considerations for the consult-liaison psychiatrist. Curr Psychiatry Rep, 2023, 25(3): 113-124.
27. Leong C, Alessi-Severini S, Enns MW, et al. Cerebrovascular, cardiovascular, and mortality events in new users of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors: a propensity score-matched population-based study. J Clin Psychopharmacol, 2017, 37(3): 332-340.
28. Perahia DG, Bangs ME, Zhang Q, et al. The risk of bleeding with duloxetine treatment in patients who use nonsteroidal anti-inflammatory drugs (NSAIDs): analysis of placebo-controlled trials and post-marketing adverse event reports. Drug Healthc Patient Saf, 2013, 5: 211-219.
29. Woroń J, Siwek M, Gorostowicz A. Adverse effects of interactions between antidepressants and medications used in treatment of cardiovascular disorders. Psychiatr Pol, 2019, 53(5): 977-995.

Chinese Journal of Evidence-Based Medicine

Mining and analysis of hemorrhagic adverse events signals of SSRIs and SNRIs based on the FAERS database

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