QTc prolongation in short-term treatment of schizophrenia patients: effects of different antipsychotics and genetic factors

  • Ilja Spellmann
  • Matthias A. Reinhard
  • Diana Veverka
  • Peter Zill
  • Michael Obermeier
  • Sandra Dehning
  • Rebecca Schennach
  • Norbert Müller
  • Hans-Jürgen Möller
  • Michael Riedel
  • Richard Musil
Original Paper
  • 199 Downloads

Abstract

Antipsychotics are effective in treating schizophrenia but may lead to a higher cardiovascular risk due to QTc prolongation. Besides drugs, genetic and clinical factors may contribute to QTc prolongation. The aim of this study is to examine the effect of candidate genes known for QTc prolongation and their interaction with common antipsychotics. Thus, 199 patients were genotyped for nine polymorphisms in KCNQ1, KCNH2, SCN5A, LOC10537879, LOC101927066, NOS1AP and NUBPL. QTc interval duration was measured before treatment and weekly for 5 weeks while being treated with risperidone, quetiapine, olanzapine, amisulpride, aripiprazole and haloperidol in monotherapy. Antipsychotics used in this study showed a different potential to affect the QTc interval. We found no association between KCNH2, KCNQ1, LOC10537879, LOC101927066, NOS1AP and NUBPL polymorphisms and QTc duration at baseline and during antipsychotic treatment. Mixed general models showed a significant overall influence of SCN5A (H558R) on QTc duration but no significant interaction with antipsychotic treatment. Our results do not provide evidence for an involvement of candidate genes for QTc duration in the pathophysiology of QTc prolongation by antipsychotics during short-term treatment. Further association studies are needed to confirm our findings. With a better understanding of these interactions the cardiovascular risk of patients may be decreased.

Keywords

QTc prolongation Atypical antipsychotics Schizophrenia Pharmacogenetics Short-term tolerability 

Notes

Acknowledgements

We thank Thelma Coutts for assistance with language.

Compliance with ethical standards

Conflict of interest

The authors declare that over the past three years Author Dr. R. Musil has received research support from Janssen-Cilag, Speaker Honoraria from Otsuka and has been on the advisory board of Roche Pharmaceuticals, author Prof. Dr. M. Riedel has received grants/research support from AstraZeneca and Pfizer and is speaker or in the advisory board of AstraZeneca, Pfizer, Bristol-Meyers-Squibb, Otsuka and Servier. These affiliations have no relevance to the work covered in the manuscript. On behalf of all authors, the corresponding author states that there is no conflict of interest.

References

  1. 1.
    Aberg K, Adkins DE, Liu Y, McClay JL, Bukszar J, Jia P, Zhao Z, Perkins D, Stroup TS, Lieberman JA, Sullivan PF, van den Oord EJ (2012) Genome-wide association study of antipsychotic-induced QTc interval prolongation. Pharmacogenomics J 12(2):165–172CrossRefPubMedGoogle Scholar
  2. 2.
    Barbui C, Nose M, Mazzi MA, Thornicroft G, Schene A, Becker T, Bindman J, Leese M, Helm H, Koeter M, Weinmann S, Tansella M (2006) Persistence with polypharmacy and excessive dosing in patients with schizophrenia treated in four European countries. Int Clin Psychopharmacol 21(6):355–362CrossRefPubMedGoogle Scholar
  3. 3.
    Bazett H (1920) An analysis of the time-relations of electrocardiograms. Heart 7:353–370Google Scholar
  4. 4.
    Biancosino B, Barbui C, Marmai L, Dona S, Grassi L (2005) Determinants of antipsychotic polypharmacy in psychiatric inpatients: a prospective study. Int Clin Psychopharmacol 20(6):305–309CrossRefPubMedGoogle Scholar
  5. 5.
    Bokil NJ, Baisden JM, Radford DJ, Summers KM (2010) Molecular genetics of long QT syndrome. Mol Genet Metab 101(1):1–8CrossRefPubMedGoogle Scholar
  6. 6.
    Chang KC, Barth AS, Sasano T, Kizana E, Kashiwakura Y, Zhang Y, Foster DB, Marban E (2008) CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart. Proc Natl Acad Sci USA 105(11):4477–4482CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chen L, Zhang W, Fang C, Jiang S, Shu C, Cheng H, Li F, Li H (2011) Polymorphism H558R in the human cardiac sodium channel SCN5A gene is associated with atrial fibrillation. J Int Med Res 39(5):1908–1916CrossRefPubMedGoogle Scholar
  8. 8.
    De Bruin ML, van Puijenbroek EP, Bracke M, Hoes AW, Leufkens HG (2006) Pharmacogenetics of drug-induced arrhythmias: a feasibility study using spontaneous adverse drug reactions reporting data. Pharmacoepidemiol Drug Saf 15(2):99–105CrossRefPubMedGoogle Scholar
  9. 9.
    Goldenberg I, Mathew J, Moss AJ, McNitt S, Peterson DR, Zareba W, Benhorin J, Zhang L, Vincent GM, Andrews ML, Robinson JL, Morray B (2006) Corrected QT variability in serial electrocardiograms in long QT syndrome: the importance of the maximum corrected QT for risk stratification. J Am Coll Cardiol 48(5):1047–1052CrossRefPubMedGoogle Scholar
  10. 10.
    Gouas L, Nicaud V, Berthet M, Forhan A, Tiret L, Balkau B, Guicheney P (2005) Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population. Eur J Hum Genet 13(11):1213–1222CrossRefPubMedGoogle Scholar
  11. 11.
    Gouas L, Nicaud V, Chaouch S, Berthet M, Forhan A, Tichet J, Tiret L, Balkau B, Guicheney P (2007) Confirmation of associations between ion channel gene SNPs and QTc interval duration in healthy subjects. Eur J Hum Genet 15(9):974–979CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Haddad PM, Anderson IM (2002) Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 62(11):1649–1671CrossRefPubMedGoogle Scholar
  13. 13.
    Hasnain M, Vieweg WV (2014) QTc interval prolongation and torsade de pointes associated with second-generation antipsychotics and antidepressants: a comprehensive review. CNS Drugs 28(10):887–920CrossRefPubMedGoogle Scholar
  14. 14.
    Haverkamp W, Deuschle M (2006) Lengthening of QT interval by antipsychotic drugs. Nervenarzt 77(3):276, 278–280, 282–274 passimCrossRefGoogle Scholar
  15. 15.
    Hobday P, Mahoney D, Urban L (2006) Influence of the common H558R-SCN5A sodium channel polymorphism on the electrocardiographic phenotype in a population-based study. Heart Rhythm 3:S279–S280CrossRefGoogle Scholar
  16. 16.
    Hong Y, Rautaharju PM, Hopkins PN, Arnett DK, Djousse L, Pankow JS, Sholinsky P, Rao DC, Province MA (2001) Familial aggregation of QT-interval variability in a general population: results from the NHLBI Family Heart Study. Clin Genet 59(3):171–177CrossRefPubMedGoogle Scholar
  17. 17.
    Kanki H, Yang P, Xie HG, Kim RB, George AL Jr, Roden DM (2002) Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome. J Cardiovasc Electrophysiol 13(3):252–256CrossRefPubMedGoogle Scholar
  18. 18.
    Koepsell H, Endou H (2004) The SLC22 drug transporter family. Pflugers Arch 447(5):666–676CrossRefPubMedGoogle Scholar
  19. 19.
    Laursen TM, Wahlbeck K, Hallgren J, Westman J, Osby U, Alinaghizadeh H, Gissler M, Nordentoft M, 2013. Life expectancy and death by diseases of the circulatory system in patients with bipolar disorder or schizophrenia in the Nordic countries. PLoS One 8(6):e67133CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lehtinen AB, Daniel KR, Shah SA, Nelson MR, Ziegler JT, Freedman BI, Carr JJ, Herrington DM, Langefeld CD, Bowden DW (2009) Relationship between genetic variants in myocardial sodium and potassium channel genes and QT interval duration in diabetics: the Diabetes Heart Study. Ann Noninvasive Electrocardiol 14(1):72–79CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lassig B, Salanti G, Davis JM (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382(9896):951–962CrossRefPubMedGoogle Scholar
  22. 22.
    Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353(12):1209–1223CrossRefPubMedGoogle Scholar
  23. 23.
    Marjamaa A, Newton-Cheh C, Porthan K, Reunanen A, Lahermo P, Vaananen H, Jula A, Karanko H, Swan H, Toivonen L, Nieminen MS, Viitasalo M, Peltonen L, Oikarinen L, Palotie A, Kontula K, Salomaa V (2009) Common candidate gene variants are associated with QT interval duration in the general population. J Intern Med 265(4):448–458CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Melada A, Krcmar T, Vidovic A (2016) A dose-dependent relationship between quetiapine and QTc interval. Int J Cardiol 222:893–894CrossRefPubMedGoogle Scholar
  25. 25.
    Newton-Cheh C, Guo CY, Larson MG, Musone SL, Surti A, Camargo AL, Drake JA, Benjamin EJ, Levy D, D’Agostino RB, Hirschhorn S, O’Donnell JN C, J (2007) Common genetic variation in KCNH2 is associated with QT interval duration: the Framingham Heart Study. Circulation 116(10):1128–1136CrossRefPubMedGoogle Scholar
  26. 26.
    Newton-Cheh C, Larson MG, Corey DC, Benjamin EJ, Herbert AG, Levy D, D’Agostino RB, O’Donnell CJ (2005) QT interval is a heritable quantitative trait with evidence of linkage to chromosome 3 in a genome-wide linkage analysis: The Framingham Heart Study. Heart Rhythm 2(3):277–284CrossRefPubMedGoogle Scholar
  27. 27.
    Ozeki Y, Fujii K, Kurimoto N, Yamada N, Okawa M, Aoki T, Takahashi J, Ishida N, Horie M, Kunugi H (2010) QTc prolongation and antipsychotic medications in a sample of 1017 patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 34(2):401–405CrossRefPubMedGoogle Scholar
  28. 28.
    Paulussen AD, Gilissen RA, Armstrong M, Doevendans PA, Verhasselt P, Smeets HJ, Schulze-Bahr E, Haverkamp W, Breithardt G, Cohen N, Aerssens J (2004) Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J Mol Med (Berl) 82(3):182–188CrossRefGoogle Scholar
  29. 29.
    Pfeufer A, Jalilzadeh S, Perz S, Mueller JC, Hinterseer M, Illig T, Akyol M, Huth C, Schopfer-Wendels A, Kuch B, Steinbeck G, Holle R, Nabauer M, Wichmann HE, Meitinger T, Kaab S (2005) Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study. Circ Res 96(6):693–701CrossRefPubMedGoogle Scholar
  30. 30.
    Pfeufer A, Sanna S, Arking DE, Muller M, Gateva V, Fuchsberger C, Ehret GB, Orru M, Pattaro C, Kottgen A, Perz S, Usala G, Barbalic M, Li M, Putz B, Scuteri A, Prineas RJ, Sinner MF, Gieger C, Najjar SS, Kao WH, Muhleisen TW, Dei M, Happle C, Mohlenkamp S, Crisponi L, Erbel R, Jockel KH, Naitza S, Steinbeck G, Marroni F, Hicks AA, Lakatta E, Muller-Myhsok B, Pramstaller PP, Wichmann HE, Schlessinger D, Boerwinkle E, Meitinger T, Uda M, Coresh J, Kaab S, Abecasis GR, Chakravarti A (2009) Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet 41(4):407–414CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Pfeufer A, van Noord C, Marciante KD, Arking DE, Larson MG, Smith AV, Tarasov KV, Muller M, Sotoodehnia N, Sinner MF, Verwoert GC, Li M, Kao WH, Kottgen A, Coresh J, Bis JC, Psaty BM, Rice K, Rotter JI, Rivadeneira F, Hofman A, Kors JA, Stricker BH, Uitterlinden AG, van Duijn CM, Beckmann BM, Sauter W, Gieger C, Lubitz SA, Newton-Cheh C, Wang TJ, Magnani JW, Schnabel RB, Chung MK, Barnard J, Smith JD, Van Wagoner DR, Vasan RS, Aspelund T, Eiriksdottir G, Harris TB, Launer LJ, Najjar SS, Lakatta E, Schlessinger D, Uda M, Abecasis GR, Muller-Myhsok B, Ehret GB, Boerwinkle E, Chakravarti A, Soliman EZ, Lunetta KL, Perz S, Wichmann HE, Meitinger T, Levy D, Gudnason V, Ellinor PT, Sanna S, Kaab S, Witteman JC, Alonso A, Benjamin, E.J., Heckbert SR, 2010. Genome-wide association study of PR interval. Nat Genet 42 (2), 153–159CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    RDC, 2008. A language and environment for statistical computing. R Development Core Team, Vienna, Foundation for Statistical ComputingGoogle Scholar
  33. 33.
    Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SH (2000) QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 355(9209):1048–1052CrossRefPubMedGoogle Scholar
  34. 34.
    Stollberger C, Huber JO, Finsterer J (2005) Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol 20(5):243–251CrossRefPubMedGoogle Scholar
  35. 35.
    Stroup TS, McEvoy JP, Swartz MS, Byerly MJ, Glick ID, Canive JM, McGee MF, Simpson GM, Stevens MC, Lieberman JA (2003) The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull 29(1):15–31CrossRefPubMedGoogle Scholar
  36. 36.
    Taylor DM (2003) Antipsychotics and QT prolongation. Acta Psychiatr Scand 107(2):85–95CrossRefPubMedGoogle Scholar
  37. 37.
    van Noord C, Straus SM, Sturkenboom MC, Hofman A, Aarnoudse AJ, Bagnardi V, Kors JA, Newton-Cheh C, Witteman JC, Stricker BH (2009) Psychotropic drugs associated with corrected QT interval prolongation. J Clin Psychopharmacol 29(1):9–15CrossRefPubMedGoogle Scholar
  38. 38.
    Volpi S, Heaton C, Mack K, Hamilton JB, Lannan R, Wolfgang CD, Licamele L, Polymeropoulos MH, Lavedan C (2009) Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia. Mol Psychiatry 14(11):1024–1031CrossRefPubMedGoogle Scholar
  39. 39.
    Wenzel-Seifert K, Wittmann M, Haen E (2011) QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Dtsch Arztebl Int 108(41):687–693PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ilja Spellmann
    • 1
    • 2
  • Matthias A. Reinhard
    • 1
  • Diana Veverka
    • 1
  • Peter Zill
    • 1
  • Michael Obermeier
    • 3
  • Sandra Dehning
    • 4
  • Rebecca Schennach
    • 1
    • 5
  • Norbert Müller
    • 1
    • 6
  • Hans-Jürgen Möller
    • 1
  • Michael Riedel
    • 1
    • 7
  • Richard Musil
    • 1
  1. 1.Department of Psychiatry and PsychotherapyLudwig-Maximilians-University MunichMunichGermany
  2. 2.Department of Special Psychiatry, Social Psychiatry and PsychotherapyKlinikum StuttgartStuttgartGermany
  3. 3.GKM Gesellschaft für Therapieforschung mbHMunichGermany
  4. 4.Department of Child and Adolescent Psychiatry and PsychotherapyLudwig-Maximilians-University MunichMunichGermany
  5. 5.Department of Psychosomatic MedicineSchön Klinik RoseneckPrien am ChiemseeGermany
  6. 6.Marion von Tessin Memory-Zentrum gGmbHMunichGermany
  7. 7.Department of Psychiatry and PsychotherapySächsisches Krankenhaus RodewischRodewischGermany

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