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Meta-Analysis of Selective Serotonin Reuptake Inhibitor–Associated QTc Prolongation
Abstract
OBJECTIVE: To evaluate the association between selective serotonin reuptake inhibitors (SSRIs) and corrected QT interval (QTc) prolongation via meta-analysis of prospective studies. DATA SOURCES: PubMed/MEDLINE database (January 1, 1975-August 15, 2012), with additional reports identified using hand searches of reference lists of relevant articles. Key words searched were QT, torsades de pointes, and sudden cardiac death, combined with antidepressants, citalopram, escitalopram, fluoxetine, sertraline, paroxetine, and fluvoxamine. English-, Spanish-, and German-language articles were included. STUDY SELECTION: Two reviewers independently identified prospective controlled studies in adults that reported data related to QTc intervals prior to and following treatment with SSRIs. DATA EXTRACTION AND SYNTHESIS: Three reviewers independently extracted study-level data including population characteristics, method of QTc measurement and treatment and outcome data. Two independent reviewers critiqued study quality. Publication bias was assessed visually using a funnel plot and quantitatively. Heterogeneity was measured using Cochran Q statistic. RESULTS: Sixteen articles (with 25 distinct data subsets) involving 4,292 patients were included. SSRIs were associated with a dose-dependent increase in QTc interval compared to placebo (+6.10 milliseconds; 95% CI, 3.47-8.73; P < .001). Tricyclic antidepressants (TCAs) were associated with a significantly greater QTc increase than SSRIs (TCA prolongation, 7.05 milliseconds; 95% CI, 3.84-10.27 greater than SSRIs; P < .001). With respect to specific SSRI agents, citalopram was associated with significantly greater QTc prolongation than sertraline, paroxetine, and fluvoxamine. CONCLUSIONS: SSRIs were associated with a modest but statistically significant increase in the QTc interval, although to a lesser extent than TCAs; this finding was not limited to any single study. Citalopram was associated with more QTc prolongation than most other SSRIs.
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“The QTc prolongation was also dose dependent.”
From Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review (2018) · cites this paper as [24]
In the citing paper
“Among SSRIs, citalopram prolonged the QTc to the greatest extent.”
From Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review (2018) · cites this paper as [24]
In the citing paper
“A meta-analysis, which included 16 prospective controlled studies, showed that SSRIs caused significantly greater QTc interval prolongation than did placebo by 6 milliseconds.24”
From Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review (2018) · cites this paper as [24]
In the citing paper
“Moreover, the study further showed that TCAs prolong the QTc to a greater extent than SSRIs.”
From Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review (2018) · cites this paper as [24]
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“line with a previous study that investigated the effects of antidepressants on QT interval in which was reported that QT prolongation among SSRIs were largely caused by citalopram and escitalopram (the effects of mirtazapine was not studied).(19) The individual antidepressants differ substantially between each other i…”
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Bandt, D. D., Haile, S. R., Devillers, L., Bourrion, B., & Menges, D. (2024) · BMJ Mental Health · doi:10.1136/bmjment-2024-301026 · Cited by 17
“38 Anxiolytic sales demonstrated a declining trend from 2012 to 2019 in line with other studies, as their utilisation—especially the prescription of benzodiazepines—was increasingly discour-aged in clinical practice guidelines due to their risk for adverse effects and dependence.”
ResultAssimon, M. M., Pun, P. H., Al‐Khatib, S. M., Brookhart, M. A., Gaynes, B. N., Winkelmayer, W. C., & Flythe, J. E. (2022) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.5428 · Cited by 15
“to follow-up, (6) index SSRI discontinuation (using a 7-day grace period), (7) switch to a non-index SSRI, (8) PPI discontinuation (using a 7-day grace period) among those using a PPI on the SSRI index date, (9) PPI initiation among those not using a PPI on the index date, (10) completion of 1-year of follow-up, and (…”
MethodYamazaki-Hashimoto, Y., Nakamura, Y., Ohara, H., Cao, X., Kitahara, K., Izumi‐Nakaseko, H., Ando, K., Yamazaki, H., Ikeda, T., Yamazaki, J., et al. (2014) · The Journal of Toxicological Sciences · doi:10.2131/jts.40.33 · Cited by 15
Criticisms of drugs in early development for the treatment of depression: what can be improved?
Wang, S., Han, C., & Pae, C. (2014) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2014.985784 · Cited by 15
“Moreover, recent studies suggest that conventional antidepressants, selective serotonin reuptake inhibitors (SSRIs), are also associated with a significant increase in the QTc interval [2].”
BackgroundPromising new pharmacological targets for depression: The search for efficacy
Tsugiyama, L. E., de Moraes, R. C. M., Moraes, Y. A. C., & de Oliveira, J. F. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103804 · Cited by 14
The effectiveness and limitations of regulatory warnings for the safe prescribing of citalopram
Bugden, S., & Friesen, K. J. (2015) · Drug Healthcare and Patient Safety · doi:10.2147/dhps.s91046 · Cited by 14
Wu, C., Tsai, Y.-T., Hsiung, C. A., & Tsai, H. (2016) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000000631 · Cited by 14
“Among SSRIs, previous reports indicated that citalopram was associated with the greatest QTc prolongation; however, there was no statistically significant difference between fluoxetine, paroxetine, and placebo.(6) Besides SSRIs, overdose of venlafaxine might also be associated with QTc prolongation.”
Behlke, L. M., Lenze, E. J., Pham, V., Miller, J. P., Smith, T. W., Saade, Y., Karp, J. F., Reynolds, C. F., Blumberger, D. M., Stefan, C., et al. (2020) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000001287 · Cited by 16
“Increased QTc interval has become a proxy marker for drug-induced risk of sudden cardiac death,(10) and several studies have demonstrated that some specific antidepressants prolong the QTc.(11,12) Although some studies have raised concern regarding selective serotonin reuptake inhibitors such as citalopram and QTc pro…”
BackgroundInfluentialChang, L., & Liu, N. (2017) · Heart and Mind · doi:10.4103/hm.hm_6_16 · Cited by 14
“significantly greater than increases found in sertraline, paroxetine, or fluvoxamine.[45] This ultimately prompted the”
BackgroundSerial follow‐up of corrected QT interval in Rett syndrome
Clark, B. C., Kopp, A. R., Morey, W., & Djukic, A. (2019) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.14419 · Cited by 12
“Certain medications, including selective serotonin reuptake inhibitors (SSRIs), are known to cause prolongation of the QT interval.(14) These medications and other agents with effects on serotonin have been shown to have a positive impact on behaviour, sleep, and respiratory patterns in patients with RTT.”
BackgroundAntidepressants and the Risk of Cardiovascular Events in Elderly Affected by Cardiovascular Disease
Biffi, A., Rea, F., Scotti, L., Lucenteforte, E., Vannacci, A., Lombardi, N., Chinellato, A., Onder, G., Vitale, C., Cascini, S., et al. (2020) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000001189 · Cited by 14
Hines, L. J., Wilke, R. A., Myers, R. A., Mathews, C. A., Liu, M., Baye, J. F., Petry, N., Cicali, E. J., Duong, B. Q., Elwood, E. N., et al. (2024) · Clinical and Translational Science · doi:10.1111/cts.13822 · Cited by 15
“14,16,18,19 For CYP2C19 rapid and ultrara-pid metabolizers (carrying one or two increased function alleles), more rapid metabolism increases risk of therapeutic failure due to inadequate plasma drug concentrations of the active parent drug.”
BackgroundBehandlung der Depression bei koronarer Herzerkrankung
Agorastos, A., Lederbogen, F., & Otte, C. (2015) · Der Nervenarzt · doi:10.1007/s00115-014-4162-z · Cited by 12
“Während Citalopram mit der größten QTc-ZeitVerlängerung assoziiert ist, zeigen Substanzen wie Sertralin, Paroxetin und Fluoxetin im Vergleich ein niedrigeres Risiko [52, 53].”
BackgroundRisk of Cardiac Events Associated with Antidepressant Therapy in Patients with Long QT Syndrome
Weng, M., Szepietowska, B., Polonsky, B., McNitt, S., Moss, A., Zaręba, W., & Auerbach, D. S. (2017) · American Journal of Cardiology · doi:10.1016/j.amjcard.2017.10.010 · Cited by 10
Mortality among psychiatric inpatients in China: A national survey
Wu, X., Xia, L., Yang, Y., Zhang, L., Li, M., Liu, T., Liu, Y., Cotes, R. O., Jiang, F., Tang, Y., et al. (2022) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2022.103262 · Cited by 13
Guo, S., Chen, L., Cheng, S., & Xu, H. (2019) · Medicine · doi:10.1097/md.0000000000015786 · Cited by 12
“However, Beach et al[14] have conducted a meta-analysis to evaluate the association between SSRIs and correlated QT interval prolongation, and concluded that SSRIs were associated with a modest but statistically significant increase in the QTc interval.”
BackgroundMenchón, J. M., Bobes, J., Álamo, C., Alonso, P., García‐Portilla, M. P., Ibáñez, Á., Real, E., Bousoño, M., Sáiz-González, M. D., & Sáiz-Ruiz, J. (2019) · Revista de Psiquiatría y Salud Mental · doi:10.1016/j.rpsm.2019.01.003 · Cited by 11
Fung, K. W., Baye, F. M., Kapusnik-Uner, J., & McDonald, C. J. (2021) · Drugs - Real World Outcomes · doi:10.1007/s40801-021-00230-1 · Cited by 14
Lack of relationship between plasma levels of escitalopram and QTc-interval length
Carceller‐Sindreu, M., de Diego-Adeliño, J., Portella, M. J., García–Moll, X., Figueras, M., Fernández-Vidal, A., Queraltó, J. M., Puigdemont, D., & Álvarez, E. (2017) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-016-0758-6 · Cited by 11
Wei, A., Peng, J., Gu, Z., & Li, J. (2017) · Medicine · doi:10.1097/md.0000000000009071 · Cited by 12
“Compared with TCAs, SSRIs have shown significant antidepressant activity and good tolerability.([4]) When taken alone, fluoxetine was associated with a low risk of cardiac adverse effects.”
BackgroundAntidepressants: Indications, Contraindications, Interactions, and Side Effects
Corponi, F., Fabbri, C., & Serretti, A. (2020) · Springer eBooks · doi:10.1007/978-3-319-56015-1_29-1 · Cited by 13
Fabbri, C., Boriani, G., Diemberger, I., Filippi, M. G., Ravegnini, G., Hrelia, P., Minarini, A., Albani, D., Forloni, G., Angelini, S., et al. (2016) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.12720 · Cited by 11
Acquired drug-induced long QTc: new insights coming from a retrospective study
Vecchis, R. D., Ariano, C., Biase, G. D., & Noutsias, M. (2018) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-018-2537-y · Cited by 14
Campbell, K. S. J., Collier, A. C., Irvine, M. A., Brain, U. M., Rurak, D. W., Oberlander, T. F., & Lim, K. I. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.680177 · Cited by 9
“Additionally, higher SRI doses may have cardiac side effects in adults, such as QT interval prolongation (93).”
BackgroundAnxiety Predicts Poor Prognosis in Patients With Hypertrophic Cardiomyopathy
He, C., Zhai, C., Huang, S.-D., Fan, H., Qian, Y., Zhu, C.-Y., & Hu, H. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.890506 · Cited by 10
“Finally, antidepressant medications including selective serotonin reuptake inhibitors have been associated with a modest effect on the QT interval, with citalopram appearing to cause the greatest QTc prolongation (36, 37).”
Background
Metadata
- Authors
- Beach, S. R., Kostis, W. J., Celano, C. M., Januzzi, J. L., Ruskin, J. N., Noseworthy, P. A., & Huffman, J. C.
- Affiliations
- Massachusetts General Hospital (US)
- Harvard University (US)
- ORCID
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2014-05-15
- Volume
- 75
- Issue
- 05
- Pages
- e441-e449
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W2092475629
- Cited by
- 253
- References
- 0
- Citations by year
- 2026: 23 · 2025: 18 · 2024: 18 · 2023: 17 · 2022: 30 · 2021: 20 · 2020: 18 · 2019: 19 · 2018: 22 · 2017: 17 · 2016: 22 · 2015: 21 · 2014: 7
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Health and Mental Health
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- selective serotonin reuptake inhibitors, QTc prolongation, torsades de pointes, sudden cardiac death, citalopram, tricyclic antidepressants, antidepressant side effects, sertraline, paroxetine, fluvoxamine, fluoxetine
- MeSH terms
- Antidepressive Agents, Tricyclic, Humans, Long QT Syndrome, Selective Serotonin Reuptake Inhibitors
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