Anti-Dementia Drugs and Long QT Syndrome

Aim. Analysis and systematization of the results of domestic and foreign studies of drug-induced QT prolongation and the risk of Torsade de Pointes (TdP) associated with the use of antidementia drugs to update the knowledge of practicing neurologists about the possibility of predicting and preventing life-threatening cardiac adverse drug reactions.

Key points. Dementia is a syndrome that accompanies various neurodegenerative diseases, which causes significant maladjustment and disability in the patient. Anti-dementia drugs are used to slow down the progression of dementia which require long-term (lifelong) appointment. Therefore, the safety profile of these drugs is important in practice, in particular such conditions as the long QT syndrome and the development of ventricular tachycardia (TdP). The authors searched for full-text domestic and foreign publications (full-text versions of original articles, clinical cases, systematic reviews, meta-analyses, Cochrane reviews) in Russian and English, available in knowledge-intensive bibliographic databases (eLIBRARY, PubMed, Scopus, Springer, ClinicalKeys, OxfordPress, Google Scholar, MedCredit, DrugBank, PharmGKB), by keywords and their combinations. The study was conducted in accordance with the requirements for the PRISMA 2022 systematic review. The search depth is 10 years (2013–2023).

Conclusion. The systematic review demonstrated the variable effect of antidementia drugs on the processes of repolarization and depolarization of the ventricular myocardium: shortening of the QT interval, no effect, borderline prolongation of the QT interval, prolongation of the QT interval. Donepezil has the lowest cardiac safety profile. Studies of galantamine have yielded conflicting results. The lowest risk of QT prolongation and TdP development was observed with rivastigmine and memantine. There is insufficient data on the cardiac safety of the new generation of antidementia drugs: aducanumab, lecanemab and donanemab.

1. Chowdhary N., Barbui C., Anstey K.J., Kivipelto M. et al. Reducing the risk of cognitive decline and dementia: WHO recommendations. Front. Neurol. 2022;12:765584. DOI: 10.3389/fneur.2021.765584

2. Nesterova M.V. Topical issues of diagnosis and treatment of Alzheimer’s disease based on modern foreign guidelines. Medical Council. 2018;6:33–7. (in Russian). DOI: 10.21518/2079-701X-2018-6-33-37

3. McShane R., Westby M.J., Roberts E., Minakaran N. et al. Memantine for dementia. Cochrane Database Syst. Rev. 2019;3(3):CD003154. DOI: 10.1002/14651858.CD003154.pub6

4. Page M.J., Moher D., Bossuyt P.M., Boutron I. et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021;372:n160. DOI: 10.1136/bmj.n160

5. Shnayder N.A., Kidyaeva A.V., Vaiman E.E., Asadullin A.R. et al. Role of pharmacokinetics and pharmacogenetics of antidepressantinduced prolongation of the QT interval and Torsade de Pointes in patients with mental disorders. Personalized Psychiatry and Neurology. 2023;3(2):72–119. DOI: 10.52667/2712-9179-2023-32-72-119

6. Ostroumova O.D., Goloborodova I.V. Druginduced long QT interval: prevalence, risk factors, treatment and prevention. Consilium Medicum. 2019;21(3):62–7. (in Russian). DOI: 10.26442/20751753.2019.5.190415

7. Wang G.K., Mitchell J., Wang S.Y. Block of persistent late Na+ currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 2008;222(2):79–90. DOI: 10.1007/s00232-008-9103-y

8. Pardo-Moreno T., González-Acedo A., Rivas-Domínguez A., GarcíaMorales V. et al. Therapeutic approach to Alzheimer's disease: current treatments and new perspectives. Pharmaceutics. 2022;14(6):1117. DOI: 10.3390/pharmaceutics14061117

9. Lane C.A., Hardy J., Schott J.M. Alzheimer's disease. Eur. J. Neurol. 2018;25(1):59–70. DOI: 10.1111/ene.13439

10. Malik B.H., Hamid P., Khan S., Gupta D. et al. Correlation between donepezil and QTc prolongation and Torsades de Pointes: a very rare phenomenon. Cureus. 2019;11(12):e6451. DOI: 10.7759/cureus.6451

11. Ruangritchankul S., Chantharit P., Srisuma S., Gray L.C. Adverse drug reactions of acetylcholinesterase inhibitors in older people living with dementia: a comprehensive literature review. Ther. Clin. Risk Manag. 2021;17:927–49. DOI: 10.2147/TCRM. S323387.

12. Singh S.K., Srivastav S., Castellani R.J., Plascencia-Villa G. et al. Neuroprotective and antioxidant effect of Ginkgo biloba extract against AD and other neurological disorders. Neurotherapeutics. 2019;16(3):666–74. DOI: 10.1007/s13311-019-00767-8

13. Liu L.W., Yue H.Y., Zou J., Tang M. et al. Comprehensive metabolomics and lipidomics profiling uncovering neuroprotective effects of Ginkgo biloba L. leaf extract on Alzheimer's disease. Front. Pharmacol. 2022;13:1076960. DOI: 10.3389/fphar.2022.1076960

14. Fernandes F., Barroso M.F., De Simone A., Emriková E. et al. Multitarget neuroprotective effects of herbal medicines for Alzheimer's disease. J. Ethnopharmacol. 2022;290:115107. DOI: 10.1016/j.jep.2022.115107

15. Peng Y., Jin H., Xue Y.H., Chen Q. et al. Current and future therapeutic strategies for Alzheimer's disease: an overview of drug development bottlenecks. Front. Aging Neurosci. 2023;15:1206572. DOI: 10.3389/fnagi.2023.1206572

16. Kobayashi S., Sugama N., Nagano H., Miyamori A. et al. Analysis of adverse events of cholinesterase inhibitors and NMDA receptor antagonists on arrhythmias using the Japanese adverse drug event report database. Drugs Real World Outcomes. 2023;10(2):321–9. DOI: 10.1007/s40801-023-00362-6

17. Chae Y.J., Lee H.J., Jeon J.H., Kim I.B. et al. Effects of donepezil on hERG potassium channels. Brain Res. 2015;1597:77–85. DOI: 10.1016/j.brainres.2014.11.057

18. Vigneault P., Bourgault S., Kaddar N., Caillier B. et al. Galantamine (Reminyl) delays cardiac ventricular repolarization and prolongs the QT interval by blocking the HERG current. Eur. J. Pharmacol. 2012;681(1–3):68–74. DOI: 10.1016/j.ejphar.2012.02.002

19. Malone K., Hancox J.C. QT interval prolongation and Torsades de Pointes with donepezil, rivastigmine and galantamine. Ther. Adv. Drug Saf. 2020;11:2042098620942416. DOI: 10.1177/2042098620942416

20. Huang Y., Alsabbagh M.W. Comparative risk of cardiac arrhythmias associated with acetylcholinesterase inhibitors used in treatment of dementias — a narrative review. Pharmacol. Res. Perspect. 2020;8(4):e00622. DOI: 10.1002/prp2.622

21. Kambayashi R., Goto A., Hagiwara-Nagasawa M., IzumiNakaseko H. et al. Analysis of clinically-reported, memantineinduced cardiovascular adverse responses using the halothaneanesthetized dogs: reverse translational study. J. Pharmacol. Sci. 2022;148(4):34–350. DOI: 10.1016/j.jphs.2022.01.011

22. Ellermann C., Coenen A., Niehues P., Leitz P. al. Proarrhythmic effect of acetylcholine-esterase inhibitors used in the treatment of Alzheimer's disease: benefit of rivastigmine in an experimental whole-heart model. Cardiovasc. Toxicol. 2020;20(2):168–75. DOI: 10.1007/s12012-019-09543-8

23. Riepe M.W. High-dose cholinergic therapy with rivastigmine patch does not prolong QTc time in patients with Alzheimer's disease. J. Clin. Psychiatry. 2014;75(3):288. DOI: 10.4088/JCP.13l08730

24. Hadano Y., Ogawa H., Wakeyama T., Iwami T. et al. Donepezilinduced Torsades de Pointes without QT prolongation. J. Cardiol. Cases. 2013;8(2):e69–71. DOI: 10.1016/j.jccase.2013.05.004

25. Cubeddu L.X. Drug-induced Inhibition and trafficking disruption of ion channels: pathogenesis of QT abnormalities and drug-induced fatal arrhythmias. Curr. Cardiol. Rev. 2016;12(2):141–54. DOI: 10.2174/1573403x12666160301120217

26. Igeta H., Suzuki Y., Tajiri M., Someya T. Cardiovascular pharmacodynamics of donepezil hydrochloride on the PR and QT intervals in patients with dementia. Hum. Psychopharmacol. 2014;29(3):292–4. DOI: 10.1002/hup.2398

27. Kitt J., Irons R., Al-Obaidi M., Missouris C. A case of donepezil-related Torsades de Pointes. BMJ Case Rep. 2015;2015:bcr2015211900. DOI: 10.1136/bcr-2015-211900

28. Wang D., Wu Y., Wang A., Chen Y. et al. Electrocardiogram changes of donepezil administration in elderly patients with ischemic heart disease. Cardiol. Res. Pract. 2018;2018:9141320. DOI: 10.1155/2018/9141320

29. Jackson E.G., Stowe S. Lesson of the month 1: prolonged QT syndrome due to donepezil: a reversible cause of falls? Clin. Med. (Lond). 2019;19(1):80–1. DOI: 10.7861/clinmedicine.19-1-80

30. Kuwahata S., Takenaka T., Motoya T., Masuda K. et al. Effect of QT prolongation in patients taking cholinesterase inhibitors (donepezil) for Alzheimer's disease. Circ. Rep. 2021;3(3):115–21. DOI: 10.1253/circrep.CR-20-0115

31. Kho J., Ioannou A., Mandal A.K.J., Cox A. et al. Long term use of donepezil and QTc prolongation. Clin. Toxicol. (Philadelphia). 2021;59(3):208–14. DOI: 10.1080/15563650.2020.1788054

32. Park J.W., Kim K.A., Park J.Y. Effect of memantine on QT/QTc interval in a healthy korean population. Clin. Pharmacol. Drug Dev. 2021;10(10):1209–15. DOI: 10.1002/cpdd.931

33. Takehara H., Suzuki Y., Someya T. QT prolongation associated with memantine in Alzheimer's disease. Psychiatry Clin. Neurosci. 2015;69(4):239–40. DOI: 10.1111/pcn.12236

34. Kajitani K., Yanagimoto K., Monji A., Maruyama T. Memantine exacerbates corrected QT interval prolongation in Alzheimer's disease: a case report from an unintentional rechallenge. J. Am. Geriatr. Soc. 2016;64(1):232–3. DOI: 10.1111/jgs.13897

35. Nasyrova R.F., Neznanov N.G., eds. Clinical psychopharmacogenetics. SPb.: DEAN; 2020. 408 p. (in Russian)

36. Neznanov N.G. A paradigm shift to treat psychoneurological disorders. Personalized Psychiatry and Neurology. 2021;1(1):1–2.