Personalized approach to prediction and prevention of haloperidol-induced QT interval prolongation: brief review

Relevance. Antipsychotics are widely used in psychiatry. Haloperidol remains one of the most commonly used antipsychotics because of its effectiveness. However, it has various adverse reactions, including an increased risk of QT prolongation, a potentially fatal complication that can lead to Torsade de Pointes and sudden cardiac death.

Objective. To systematize information for practicing psychiatrists and clinical pharmacologists regarding a personalized approach to the prevention of QT interval prolongation in patients with mental disorders who are taking haloperidol.

Methods. A search for full-text articles published from 02/01/2013 to 02/01/2024 was conducted using PubMed, eLIBRARY.RU, and Google Scholar.

Results. This short review analyzes and summarizes the results of foreign and domestic studies on the effect of haloperidol on the QT interval, the role of risk factors and hereditary predisposition in the development of haloperidol-induced prolongation of the QT interval, and Torsade de Pointes in patients with mental disorders. The main mechanism of the cardiotoxic effect of haloperidol is the dose-dependent inhibition of potassium channels in the cardiomyocyte membrane. Haloperidol is extensively metabolized in the liver, which may cause significant interindividual variability in its pharmacokinetics. A decrease in the metabolism rate of haloperidol may lead to an increase in its concentration in the blood, thereby increasing the risk of developing cardiotoxic adverse reactions. To reduce the risk of developing haloperidol-induced prolongation of the QT interval, it is advisable to use predictive pharmacogenetic testing.

Conclusion. Generalized data on the effect of haloperidol on the duration of the QT interval and the risk of developing TdP in patients with mental disorders may be required by psychiatrists and clinical pharmacologists when selecting the dose and duration of haloperidol administration. Predictive pharmacogenetic testing can help reduce the incidence of potentially fatal cardiotoxic adverse reactions.

1. Rahman S, Marwaha R. Haloperidol. In: StatPearls. Treasure Island (FL): StatPearls Publishing; September 1, 2023.

2. Tavares J. Haloperidol's introduction in the United States: A tale of a failed trial and its consequences. J Hist Neurosci. 2024 Apr-Jun;33(2):169-179. doi: 10.1080/0964704X.2023.2283463.

3. Rognoni C, Bertolani A, Jommi C. Second-generation antipsychotic drugs for patients with schizophrenia: systematic literature review and metaanalysis of metabolic and cardiovascular side effects. Clin Drug Investig. 2021;41(4):303-319. doi: 10.1007/s40261-021-01000-1

4. Seeman MV. History of the dopamine hypothesis of antipsychotic action. World J Psychiatry. 2021 Jul 19;11(7):355-364. doi: 10.5498/wjp.v11.i7.355.

5. Alamri AS, Alhomrani M, Alsanie WF, et al. Enhancement of Haloperidol Binding Affinity to Dopamine Receptor via Forming a ChargeTransfer Complex with Picric Acid and 7,7,8,8-Tetracyanoquinodimethane for Improvement of the Antipsychotic Efficacy. Molecules. 2022 May 20;27(10):3295. doi: 10.3390/molecules27103295.

6. Государственный реестр лекарственных средств [Accessed January 30, 2024]. Available at: https://grls.rosminzdrav.ru/Default.aspx

7. Fda.gov [Internet]. What is a Serious Adverse Event? [Accessed January 30, 2024]. Available from: https://www.fda.gov/safety/reporting-seriousproblems-fda/what-serious-adverse-event

8. Burbuqe I, Boettger S, Schubert M, et al. QTc prolongation after haloperidol administration in critically ill patients post cardiovascular surgery: A cohort study and review of the literature. Palliat Support Care. 2020 Aug;18(4):447-459. doi: 10.1017/S1478951520000231. Erratum in: Palliat Support Care. 2022 Feb;20(1):149.

9. Ostroumova OD, Goloborodova IV. Drug-induced long QT interval: prevalence, risk factors, treatment and prevention. Consilium Medicum. 2019;21(5):62-67. (In Russ.). doi: 10.26442/20751753.2019.5.190415.

10. Iribarren C, Round AD, Peng JA, et al. Validation of a populationbased method to assess drug-induced alterations in the QT interval: a selfcontrolled crossover study. Pharmacoepidemiol Drug Saf. 2013;22(11):1222-1232. doi:10.1002/pds.3479/

11. Wu CS, Tsai YT, Tsai HJ. Antipsychotic drugs and the risk of ventricular arrhythmia and/or sudden cardiac death: a nation-wide case-crossover study. J Am Heart Assoc. 2015;4(2):e001568. doi: 10.1161/JAHA.114.001568.

12. Campleman SL, Brent J, Pizon AF, et al. Drug-specific risk of severe QT prolongation following acute drug overdose. Clin Toxicol (Phila). 2020 Dec;58(12):1326-1334. doi: 10.1080/15563650.2020.1746330.

13. Raschi E, Poluzzi E, Salvo F, et al. The contribution of national spontaneous reporting systems to detect signals of torsadogenicity: issues emerging from the ARITMO project. Drug Saf. 2016;39(1):59-68. doi: 10.1007/s40264-015-0353-1/

14. Friedrich ME, Winkler D, Konstantinidis A, et al. Cardiovascular Adverse Reactions During Antipsychotic Treatment: Results of AMSP, A Drug Surveillance Program Between 1993 and 2013. Int J Neuropsychopharmacol. 2020 Feb 1;23(2):67-75. doi: 10.1093/ijnp/pyz046.

15. Berling I, Isbister GK. Prolonged QT Risk Assessment in Antipsychotic Overdose Using the QT Nomogram. Ann Emerg Med. 2015 Aug;66(2):154-64. doi: 10.1016/j.annemergmed.2014.12.005.

16. Xiang YT, Chiu HF, Ungvari GS, et al. QTc prolongation in schizophrenia patients in Asia: clinical correlates and trends between 2004 and 2008/2009. Hum Psychopharmacol. 2015 Mar;30(2):94-9. doi: 10.1002/hup.2458.

17. Naksuk N, Thongprayoon C, Park JY, et al. Editor's Choice-Clinical impact of delirium and antipsychotic therapy: 10-Year experience from a referral coronary care unit. Eur Heart J Acute Cardiovasc Care. 2017 Sep;6(6):560-568. doi: 10.1177/2048872615592232.

18. Salvati B, Miola A, Toffanin T, et al. Prevalence and Risk Factors for QTc Prolongation in Acute Psychiatric Hospitalization. Prim Care Companion CNS Disord. 2022 Feb 17;24(1):21m02915. doi: 10.4088/PCC.21m02915.

19. Bohny P, Boettger S, Jenewein J. Dose-dependent QTc interval prolongation under haloperidol and pipamperone in the management of delirium in a naturalistic setting. Front Psychiatry. 2023 Oct 3;14:1257755. doi: 10.3389/fpsyt.2023.1257755.

20. Ozeki Y, Fujii K, Kurimoto N, et al. QTc prolongation and antipsychotic medications in a sample of 1017 patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Mar 17;34(2):401-5. doi: 10.1016/j.pnpbp.2010.01.008.

21. Sicouri S, Antzelevitch C. Sudden cardiac death secondary to antidepressant and antipsychotic drugs. Expert Opinion on Drug Safety, 2008; 7(2):181–194. doi: 10.1517/14740338.7.2.181.

22. Beach SR, Celano CM, Noseworthy PA, et al. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics. 2013 Jan-Feb;54(1):1-13. doi: 10.1016/j.psym.2012.11.001.

23. Beach SR, Gross AF, Hartney KE, et al. Intravenous haloperidol: A systematic review of side effects and recommendations for clinical use. Gen Hosp Psychiatry. 2020;67:42-50. doi: 10.1016/j.genhosppsych.2020.08.008.

24. CredibleMeds [Accessed January 31, 2024]. Available from: www.CredibleMeds.org

25. Sicouri S, Antzelevitch C. Mechanisms underlying the actions of antidepressant and antipsychotic drugs that cause sudden cardiac arrest. Arrhythm Electrophysiol Rev. 2018;7(3):199-209. doi: 10.15420/aer.2018.29.2.

26. Champéroux P, Fares R, Bastogne T, et al. Contribution of haemodynamic side effects and associated autonomic reflexes to ventricular arrhythmias triggering by torsadogenic hERG blocking drugs. Br J Pharmacol. 2022;179(18):4549-4562. doi: 10.1111/bph.15905.

27. Volkov V. Cardiotoxicity of antipsychotic drugs. Tver: Triada Publishing House LLC, 2018. (In Russ.). ISBN 978-5-94789-855-2.

28. Shnayder NA, Kidyaeva AV, Vaiman EE, et al. Role of Pharmacokinetics and Pharmacogenetics of Antidepressant-Induced Prolongation of the QT Interval and Torsade de Pointes in Patients with Mental Disorders. Personalized Psychiatry and Neurology. 2023;3(2):72-119. doi: 10.52667/2712-9179-2023-3-2-72-119

29. Busse D, Leandersson S, Amberntsson S, et al. Industrial Approach to Determine the Relative Contribution of Seven Major UGT Isoforms to Hepatic Glucuronidation. J Pharm Sci. 2020;109(7):2309-2320. doi: 10.1016/j.xphs.2020.03.013

30. Clinical psychopharmacogenetics ed by. R.F. Nasyrova, N.G. Neznanova. SPb: DEAN Publishing House, 2019. (In Russ.). ISBN 978-5-6043573-7-8.

31. Zhuravlev NM, Otmachov AP, Bartasinskaya AE. Clinical Case of a 36-year-old Patient with Paranoid Schizophrenia and Drug-Induced QT Prolongation. Personalized Psychiatry and Neurology. 2022;2(2):78-83. doi: 10.52667/2712-9179-2022-2-2-78-83.

32. Shnayder NA, Abdyrakhmanova AK, Nasyrova R.F. Phase I of Antipsychotics Metabolism and its Pharmacogenetic Testing. Personalized Psychiatry and Neurology. 2022;2(1):4-21. doi: 10.52667/2712-9179-2022-2-1-4-21.

33. Shnayder NA, Abdyrakhmanova AK, Nasyrova RF. Oxidation of antipsychotics. Encyclopedia 2022;2:974-989. doi: 10.3390/encyclopedia2020064

34. DrugBank [Internet]. Haloperidol. Available at: https://go.drugbank. com/drugs/DB00502. Accessed: 2024 January 25.

35. OMIM [Updated February 2, 2024] [Accessed February 4, 2024]. Available at: https://www.omim.org/