Back
 OJPsych  Vol.4 No.4 , October 2014
Antipsychotic Medication and Risk of QTc Prolongation: Focus on Multiple Medication and Role of Cytochrome P450 Isoforms
Abstract: Objective: To identify the effects of antipsychotics on QTc prolongation in light of age, gender, antipsychotic combination pattern, antipsychotic doses and cytochrome P450 (CYP) mediation, using large database describing the antipsychotic treatment of patients with schizophrenia in Japan. Methods: Using database of 4176 patients with schizophrenia discharged between April 2004 and March 2005 and receiving outpatient treatment from 526 psychiatric hospitals in Japan. Of the patients, 1437 were included for the analysis. These patients were classified into three groups according to the antipsychotic CPZ-equivalent doses that they received (low, 1 - 299 mg; middle, 300 - 999 mg; and high, ≥1000 mg). QTc intervals ≥ 440 msec were considered prolonged. We reviewed all the package inserts of the antipsychotics used from the website of Pharmaceuticals and Medical Devices Agency. Results: The mean QTc interval of the total patient group was 410.4 ± 23.3 msec. The females had significantly higher QTc values than the males (414.5 ± 24.0 vs. 406.8 ± 22.2 msec, respectively; p < 0.05). Logistic regression analysis revealed that female gender (odds ratio [OR] = 1.83; 95% CI: 1.28 - 2.56), CYP3A4-metabolized drugs (OR 1.56; 95% CI: 1.05 - 2.30) were associated with an increased risk of QTc prolongation. Conclusion: The co-prescription of CYP3A4-mediated antipsychotic drugs should be carefully considered in females due to potential risk of QTc prolongation. Further studies of the cardiovascular safety of antipsychotics are warranted in patients receiving multiple medications.
Cite this paper: Ikeno, T. , Kugiyama, K. and Ito, H. (2014) Antipsychotic Medication and Risk of QTc Prolongation: Focus on Multiple Medication and Role of Cytochrome P450 Isoforms. Open Journal of Psychiatry, 4, 381-389. doi: 10.4236/ojpsych.2014.44044.
References

[1]   ICH Harmonized Tripartite Guideline E14 (2005) E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129357.pdf

[2]   Roden, D.M. (2004) Drug-Induced Prolongation of the QT Interval. The New England Journal of Medicine, 350, 1013-1022. http://dx.doi.org/10.1056/NEJMra032426

[3]   Brown, C.S., Farmer, R.G., Soberman, J.E. and Eichner, S.F. (2004) Pharmacokinetic Factors in the Adverse Cardiovascular Effects of Antipsychotic Drugs. Clinical Pharmacokinetics, 43, 33-56.
http://dx.doi.org/10.2165/00003088-200443010-00003

[4]   Glassman, A.H. and Bigger Jr., J.T., (2001) Antipsychotic Drugs: Prolonged QTc Interval, Torsade de Pointes, and Sudden Death. American Journal of Psychiatry, 158, 1774-1782.
http://dx.doi.org/10.1176/appi.ajp.158.11.1774

[5]   Mackin, P. and Young, A.H. (2005) QTc Interval Measurement and Metabolic Parameters in Psychiatric Patients Taking Typical or Atypical Antipsychotic Drugs: A Preliminary Study. Journal of Clinical Psychiatry, 66, 1386-1391. http://dx.doi.org/10.4088/JCP.v66n1107

[6]   Montanez, A., Ruskin, J.N., Hebert, P.R., Lamas, G.A. and Hennekens, C.H. (2004) Prolonged QTc Interval and Risks of Total and Cardiovascular Mortality and Sudden Death in the General Population: A Review and Qualitative Overview of the Prospective Cohort Studies. Archives of Internal Medicine, 164, 943-948. http://dx.doi.org/10.1001/archinte.164.9.943

[7]   Reilly, J.G., Ayis, S.A., Ferrier, I.N., Jones, S.J. and Thomas, S.H. (2000) QTc-Interval Abnormalities and Psychotropic Drug Therapy in Psychiatric Patients. Lancet, 355, 1048-1052.
http://dx.doi.org/10.1016/S0140-6736(00)02035-3

[8]   Stollberger, C., Huber, J.O. and Finsterer, J. (2005) Antipsychotic Drugs and QT Prolongation. International Clinical Psychopharmacology, 20, 243-251.
http://dx.doi.org/10.1097/01.yic.0000166405.49473.70

[9]   Taylor, D.M. (2003) Antipsychotics and QT Prolongation. Acta Psychiatrica Scandinavica, 107, 85-95. http://dx.doi.org/10.1034/j.1600-0447.2003.02078.x

[10]   van Noord, C., Straus, S.M., Sturkenboom, M.C., Hofman, A., Aarnoudse, A.J., Bagnardi, V., et al. (2009) Psychotropic Drugs Associated with Corrected QT Interval Prolongation. Journal of Clinical Psychopharmacology, 29, 9-15. http://dx.doi.org/10.1097/JCP.0b013e318191c6a8

[11]   Warner, J.P., Barnes, T.R. and Henry, J.A. (1996) Electrocardiographic Changes in Patients Receiving Neuroleptic Medication. Acta Psychiatrica Scandinavica, 93, 311-313.
http://dx.doi.org/10.1111/j.1600-0447.1996.tb10653.x

[12]   Yang, F.D., Wang, X.Q., Liu, X.P., Zhao, K.X., Fu, W.H., Hao, X.R., et al. (2011) Sex Difference in QTc Prolongation in Chronic Institutionalized Patients with Schizophrenia on Long-Term Treatment with Typical and Atypical Antipsychotics. Psychopharmacology, 216, 9-16.
http://dx.doi.org/10.1007/s00213-011-2188-5

[13]   Zemrak, W.R. and Kenna, G.A. (2008) Association of Antipsychotic and Antidepressant Drugs with Q-T Interval Prolongation. American Journal of Health-System Pharmacy, 65, 1029-1038.
http://dx.doi.org/10.2146/ajhp070279

[14]   Haddad, P.M. and Anderson, I.M. (2002) Antipsychotic-Related QTc Prolongation, Torsade de Pointes and Sudden Death. Drugs, 62, 1649-1671. http://dx.doi.org/10.2165/00003495-200262110-00006

[15]   Khan, M.M., Logan, K.R., McComb, J.M. and Adgey, A.A. (1981) Management of Recurrent Ventricular Tachyarrhythmias Associated with Q-T Prolongation. American Journal of Cardiology, 47, 1301-1308. http://dx.doi.org/10.1016/0002-9149(81)90263-0

[16]   Leslie, D.L. and Rosenheck, R. (2012) Off-Label Use of Antipsychotic Medications in Medicaid. The American Journal of Managed Care, 18, e109-e117.

[17]   Wang, P.S., Schneeweiss, S., Avorn, J., Fischer, M.A., Mogun, H., Solomon, D.H., et al. (2005) Risk of Death in Elderly Users of Conventional vs. Atypical Antipsychotic Medications. The New England Journal of Medicine, 353, 2335-2341. http://dx.doi.org/10.1056/NEJMoa052827

[18]   Ito, H., Okumura, Y., Higuchi, T., Tan, C.H. and Shinfuku, N. (2012) International Variation in Antipsychotic Prescribing for Schizophrenia: Pooled Results from the Research on East Asia Psychotropic Prescription (Reap) Studies. Open Journal of Psychiatry, 2, 340-346.
http://dx.doi.org/10.4236/ojpsych.2012.224048

[19]   Lelliott, P., Paton, C., Harrington, M., Konsolaki, M., Sensky, T. and Okocha, C. (2002) The Influence of Patient Variables on Polypharmacy and Combined High Dose of Antipsychotic Drugs Prescribed for In-Patients. Psychiatric Bulletin, 26, 411-414. http://dx.doi.org/10.1192/pb.26.11.411

[20]   Sim, K., Su, H.C., Fujii, S., Yang, S.Y., Chong, M.Y., Ungvari, G., et al. (2009) High-Dose Antipsychotic Use in Schizophrenia: A Comparison between the 2001 and 2004 Research on East Asia Psychotropic Prescription (REAP) Studies. British Journal of Clinical Pharmacology, 67, 110-117. http://dx.doi.org/10.1111/j.1365-2125.2008.03304.x

[21]   Scott, R.P. (2010) Drug Interactions. NIH.
http://www.cc.nih.gov/training/training/principles/slides/DrugInteractions2010-2011_text.pdf

[22]   Rendic, S. (2002) Summary of Information on Human CYP Enzymes: Human P450 Metabolism Data. Drug Metabolism Reviews, 34, 83-448. http://dx.doi.org/10.1081/DMR-120001392

[23]   Ogu, C.C. and Maxa, J.L. (2000) Drug Interactions Due to Cytochrome P450. Baylor University Medical Center Proceedings, 13, 421-423.

[24]   Kobayashi, M., Ito, H., Okumura, Y., Mayahara, K., Matsumoto, Y. and Hirakawa, J. (2010) Hospital Readmission in First-Time Admitted Patients with Schizophrenia: Smoking Patients Had Higher Hospital Readmission Rate than Non-Smoking Patients. The International Journal of Psychiatry in Medicine, 40, 247-257. http://dx.doi.org/10.2190/PM.40.3.b

[25]   Okumura, Y., Ito, H., Kobayashi, M., Mayahara, K., Matsumoto, Y. and Hirakawa, J. (2010) Prevalence of Diabetes and Antipsychotic Prescription Patterns in Patients with Schizophrenia: A Nationwide Retrospective Cohort Study. Schizophrenia Research, 119, 145-152.
http://dx.doi.org/10.1016/j.schres.2010.02.1061

[26]   Christensen, P.K., Gall, M.A., Major-Pedersen, A., Sato, A., Rossing, P., Breum, L., et al. (2000) QTc Interval Length and QT Dispersion as Predictors of Mortality in Patients with Non-Insulin-Dependent Diabetes. Scandinavian Journal of Clinical & Laboratory Investigation, 60, 323-332.
http://dx.doi.org/10.1080/003655100750046486

[27]   Saarnivaara, L., Klemola, U.M., Lindgren, L., Rautiainen, P. and Suvanto, A. (1990) QT Interval of the ECG, Heart Rate and Arterial Pressure Using Propofol, Methohexital or Midazolam for Induction of Anaesthesia. Acta Anaesthesiologica Scandinavica, 34, 276-281. http://dx.doi.org/10.1111/j.1399-6576.1990.tb03085.x

[28]   Inagaki, A. and Inada, T. (2006) Dose Equivalence of Psychotropic Drugs. Part 18: Dose Equivalence of Psychotropic Drugs: 2006-Version. Japanese Journal of Clinical Psychopharmacology, 9, 1443-1447. (in Japanese)

[29]   Bazett, H.C. (1920) The Time Relations of the Blood-Pressure Changes after Excision of the Adrenal Glands, with Some Observations on Blood Volume Changes. The Journal of Physiology, 53, 320-339.

[30]   Caccia, S. (2000) Biotransformation of Post-Clozapine Antipsychotics: Pharmacological Implications. Clinical Pharmacokinetics, 38, 393-414. http://dx.doi.org/10.2165/00003088-200038050-00002

[31]   Crouch, M.A., Limon, L. and Cassano, A.T. (2003) Clinical Relevance and Management of Drug-Related QT Interval Prolongation. Pharmacotherapy, 23, 881-908.
http://dx.doi.org/10.1592/phco.23.7.881.32730

[32]   de Leon, J., Sandson, N.B. and Cozza, K.L. (2008) A Preliminary Attempt to Personalize Risperidone Dosing Using Drug-Drug Interactions and Genetics: Part II. Psychosomatics, 49, 347-361.
http://dx.doi.org/10.1176/appi.psy.49.4.347

[33]   Desta, Z., Kerbusch, T., Soukhova, N., Richard, E., Ko, J.W. and Flockhart, D.A. (1998) Identification and Characterization of Human Cytochrome P450 Isoforms Interacting with Pimozide. Journal of Pharmacology and Experimental Therapeutics, 285, 428-437.

[34]   Fang, J., Baker, G.B., Silverstone, P.H. and Coutts, R.T. (1997) Involvement of CYP3A4 and CYP2D6 in the Metabolism of Haloperidol. Cellular and Molecular Neurobiology, 17, 227-233.
http://dx.doi.org/10.1023/A:1026317929335

[35]   Grimm, S.W., Richtand, N.M., Winter, H.R., Stams, K.R. and Reele, S.B. (2006) Effects of Cytochrome P450 3A Modulators Ketoconazole and Carbamazepine on Quetiapine Pharmacokinetics. British Journal of Clinical Pharmacology, 61, 58-69. http://dx.doi.org/10.1111/j.1365-2125.2005.02507.x

[36]   Lazarus, G.M. (2001) Gender-Specific Medicine in Pediatrics. The Journal of Gender-Specific Medicine, 4, 50-53.

[37]   Mizuno, Y., Tani, N., Komuro, S., Kanamaru, H. and Nakatsuka, I. (2003) In Vitro Metabolism of Perospirone in Rat, Monkey and Human Liver Microsomes. European Journal of Drug Metabolism and Pharmacokinetics, 28, 59-65. http://dx.doi.org/10.1007/BF03190868

[38]   Muralidharan, G., Cooper, J.K., Hawes, E.M., Korchinski, E.D. and Midha, K.K. (1996) Quinidine Inhibits the 7-Hydroxylation of Chlorpromazine in Extensive Metabolisers of Debrisoquine. European Journal of Clinical Pharmacology, 50, 121-128. http://dx.doi.org/10.1007/s002280050079

[39]   Olesen, O.V. and Linnet, K. (2000) Identification of the Human Cytochrome P450 Isoforms Mediating in Vitro N-Dealkylation of Perphenazine. British Journal of Clinical Pharmacology, 50, 563-571. http://dx.doi.org/10.1046/j.1365-2125.2000.00298.x

[40]   Perphenazine Package Insert (2013) http://www.info.pmda.go.jp/go/pack/1172006F1030_1_07/

[41]   Pimozide Package Insert (2013) http://www.info.pmda.go.jp/go/pack/1179022C1034_1_07/

[42]   Quetiapine Package Insert (2013) http://www.info.pmda.go.jp/go/pack/1179042C1023_2_14/

[43]   Ray, W.A., Murray, K.T., Meredith, S., Narasimhulu, S.S., Hall, K. and Stein, C.M. (2004) Oral Erythromycin and the Risk of Sudden Death from Cardiac Causes. The New England Journal of Medicine, 351, 1089-1096. http://dx.doi.org/10.1056/NEJMoa040582

[44]   Semla, T.P., Beizer, J.L. and Higbee, M.D. (2005) Geriatric Dosage Handbook. 10th Edition, Lexi Comp Inc, Hudson, 1286-1290.

[45]   Sharif, Z.A. (2003) Pharmacokinetics, Metabolism and Drug-Drug Interactions of Atypical Antipsychotics in Special Populations. Journal of Clinical Psychiatry, 5, 22-25.

[46]   Shiraga, T., Kaneko, H., Iwasaki, K., Tozuka, Z., Suzuki, A. and Hata, T. (1999) Identification of Cytochrome P450 Enzymes Involved in the Metabolism of Zotepine, an Antipsychotic Drug, in Human Liver Microsomes. Xenobiotica, 29, 217-229. http://dx.doi.org/10.1080/004982599238623

[47]   Tateishi, T., Watanabe, M., Kumai, T., Tanaka, M., Moriya, H., Yamaguchi, S., et al. (2000) CYP3A Is Responsible for N-Dealkylation of Haloperidol and Bromperidol and Oxidation of Their Reduced Forms by Human Liver Microsomes. Life Sciences, 67, 2913-2920. http://dx.doi.org/10.1016/S0024-3205(00)00874-2

[48]   Tyndale, R.F., Kalow, W. and Inaba, T. (1991) Oxidation of Reduced Haloperidol to Haloperidol: Involvement of Human P450IID6 (Sparteine/Debrisoquine Monooxygenase). British Journal of Clinical Pharmacology, 31, 655-660. http://dx.doi.org/10.1111/j.1365-2125.1991.tb05588.x

[49]   Yukawa, E., Hokazono, T., Yukawa, M., Ichimaru, R., Maki, T., Matsunaga, K., et al. (2002) Population Pharmacokinetics of Haloperidol Using Routine Clinical Pharmacokinetic Data in Japanese Patients. Clinical Pharmacokinetics, 41, 153-159. http://dx.doi.org/10.2165/00003088-200241020-00006

[50]   Zhou, S.F. (2009) Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance: Part II. Clinical Pharmacokinetics, 48, 761-804. http://dx.doi.org/10.2165/11318070-000000000-00000

[51]   Bromperidol Package Insert (2013) http://www.info.pmda.go.jp/go/pack/1179028C1066_2_11/

[52]   Ozeki, Y., Fujii, K., Kurimoto, N., Yamada, N., Okawa, M., Aoki, T., et al. (2010) QTc Prolongation and Antipsychotic Medications in a Sample of 1017 Patients with Schizophrenia. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 34, 401-405.
http://dx.doi.org/10.1016/j.pnpbp.2010.01.008

[53]   Chong, S.A., Mythily, Lum, A., Goh, H.Y. and Chan, Y.H. (2003) Prolonged QTc Intervals in Medicated Patients with Schizophrenia. Human Psychopharmacology, 18, 647-649.
http://dx.doi.org/10.1002/hup.540

[54]   Fluphenazine Decanoate Package Insert (2013)
http://www.info.pmda.go.jp/go/pack/1172405A1031_2_07/

[55]   Beach, S.R., Celano, C.M., Noseworthy, P.A., Januzzi, J.L. and Huffman, J.C. (2013) QTc Prolongation, Torsades de Pointes and Psychotropic Medications. Psychosomatics, 54, 1-13.
http://dx.doi.org/10.1016/j.psym.2012.11.001

[56]   Haloperidol Package Insert (2013) http://www.info.pmda.go.jp/go/pack/1179020C1191_1_11/

[57]   Haloperidol Decanoate Package Insert (2013)
http://www.info.pmda.go.jp/go/pack/1179406A1037_2_09/

[58]   Levomepromazine Package Insert (2013)
http://www.info.pmda.go.jp/go/pack/1172014B2056_1_13/

[59]   Nemonapride Package Insert (2013) http://www.info.pmda.go.jp/go/pack/1179036F1024_1_01/

[60]   Harrigan, E.P., Miceli, J.J., Anziano, R., Watsky, E., Reeves, K.R., Cutler, N.R., et al. (2004) A Randomized Evaluation of the Effects of Six Antipsychotic Agents on QTc, in the Absence and Presence of Metabolic Inhibition. Journal of Clinical Psychopharmacology, 24, 62-69.
http://dx.doi.org/10.1097/01.jcp.0000104913.75206.62

[61]   Olanzapine Package Insert (2013) http://www.info.pmda.go.jp/go/pack/1179044F4028_1_18/

[62]   Desta, Z., Kerbusch, T. and Flockhart, D.A. (1999) Effect of Clarithromycin on the Pharmacokinetics and Pharmacodynamics of Pimozide in Healthy Poor and Extensive Metabolizers of Cytochrome P450 2D6 (CYP2D6). Clinical Pharmacology & Therapeutics, 65, 10-20. http://dx.doi.org/10.1016/S0009-9236(99)70117-7

[63]   Risperidone Package Insert (2013) http://www.info.pmda.go.jp/go/pack/1179038C1027_1_27/

[64]   Trifluoperazine Package Insert (2013) http://www.info.pmda.go.jp/go/pack/1172008F1021_2_07/

[65]   Bai, C.X., Kurokawa, J., Tamagawa, M., Nakaya, H. and Furukawa, T. (2005) Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone. Circulation, 112, 1701-1710.
http://dx.doi.org/10.1161/CIRCULATIONAHA.104.523217

[66]   Shuba, Y.M., Degtiar, V.E., Osipenko, V.N., Naidenov, V.G. and Woosley, R.L. (2001) Testosterone-Mediated Modulation of HERG Blockade by Proarrhythmic Agents. Biochemical Pharmacology, 62, 41-49. http://dx.doi.org/10.1016/S0006-2952(01)00611-6

[67]   Ramirez, A.H., Schildcrout, J.S., Blakemore, D.L., Masys, D.R., Pulley, J.M., Basford, M.A., et al. (2011) Modulators of Normal Electrocardiographic Intervals Identified in a Large Electronic Medical Record. Heart Rhythm, 8, 271-277. http://dx.doi.org/10.1016/j.hrthm.2010.10.034

 
 
Top