Qtc prolongation and antipsychotic medications in a sample of 1017 patients with schizophrenia

Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) 401–405 Progress in Neuro-Psychopharmacology & Biological j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p QTc prolongation and antipsychotic medications in a sample of 1017 patientswith schizophrenia Yuji Ozeki ,, Kumiko Fujii , Naoki Kurimoto , Naoto Yamada Masako Okawa , Takesuke Aoki Jun Takahashi Nobuya Ishida , Minoru Horie Hiroshi Kunugi a Department of Psychiatry, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, 321-0293, Japanb Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashimachi, Kodaira, Tokyo, 187-8502, Japanc Department of Psychiatry, Shiga University of Medical Science, Setatsukinowacyo, Otsu, 520-2121, Japand Department of Sleep Medicine, Shiga University of Medical Science, Setatsukinowacyo, Otsu, 520-2121, Japane Minakuchi Hospital, 2-2-43, Minakuchihonnmachi, Kouka, 528-0031, Japanf Biwako Hospital, 1-8-5, Sakamoto, Otsu, 520-0113, Japang Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Setatsukinowacyo, Otsu, 520-2121, Japan Many antipsychotic drugs cause QT prolongation, although the effect differs based on the particular drug. We sought to determine the potential for antipsychotic drugs to prolong the QTc interval (>470 ms in men and > 480 ms in women) using the Bazett formula in a “real-world” setting by analyzing the electrocardiograms of 1017 patients suffering from schizophrenia. Using logistic regression analysis to calculate the adjusted relative risk (RR), we found that chlorpromazine (RR for 100 mg = 1.37, 95% confidence interval (CI) = 1.14to 1.64; p < .005), intravenous haloperidol (RR for 2 mg = 1.29, 95% CI = 1.18 to 1.43; p < .001), and sultopride (RR for 200 mg = 1.45, 95% CI = 1.28 to 1.63; p < .001) were associated with an increased risk of QTc prolongation. Levomepromazine also significantly lengthened the QTc interval. The second-generation antipsychotic drugs (i.e., olanzapine, quetiapine, risperidone, and zotepine), mood stabilizers, benzodiaze- pines, and antiparkinsonian drugs did not prolong the QTc interval. Our results suggest that second-generation antipsychotic drugs are generally less likely than first-generation antipsychotic drugs to produceQTc interval prolongation, which may be of use in clinical decision making concerning the choice ofantipsychotic medication.
2010 Elsevier Inc. All rights reserved.
A cohort study of three U.S. medical programs foundthat patients with treated schizophrenia had higher rates of cardiac QTc interval prolongation is associated with presyncope, syncope, arrest and ventricular arrhythmia than did controls (patients with polymorphic ventricular tachycardia, the subtype torsade de pointes, glaucoma and those with psoriasis), with risk ratios ranging from 1.7 to and sudden cardiac death (Previous studies have 3.2 . A study of 554 sudden cardiac death subjects indicated an increased risk of sudden cardiac death in patients treated reported that the current use of antipsychotics was associated with a three-fold increased risk of cardiac death A retrospective cohort study of 481,744 Tennessee Medicaid Although torsade de pointes and sudden death are rare, rate- enrollees, of whom 1487 died from sudden cardiac death, found that corrected QT (QTc) prolongation serves as a risk factor for these current moderate-dose antipsychotic use (>100 mg of thioridazine conditions. In a study of 495 psychiatric patients receiving various equivalents) increased the rate of sudden cardiac death (multivariate psychotropic drugs and 101 healthy reference individuals, 8% of risk ratio of 2.39), when compared with the nonuse of antipsychotics patients showed QTc prolongation (>456 ms) ).
Advanced age (>65 years), as well as the use of tricyclic antidepres-sants, thioridazine, and droperidol were indicated as robust predictors Abbreviations: QTc, rate-corrected QT; 95% CI, 95% confidence interval; HPD, of QTc lengthening (). High antipsychotic doses were haloperidol; HPDiv, intravenous injection of haloperidol; RR, relative risk; ECG,electrocardiogram; SGAs, second-generation antipsychotics; FGAs, also associated with QTc prolongation (). In a sample antipsychotics; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th ed.; of 111 psychiatric inpatients receiving a median daily dose of more CP, chlorpromazine; LP, levomepromazine; OR, odds ratio.
than 600 mg [chlorpromazine (CP) equivalent] of antipsychotics, 90% ⁎ Corresponding author. Department of Psychiatry, Dokkyo University School of had schizophrenia or related psychoses, and 23% showed QTc interval Medicine, 880 Kitakobayashi, Mibu, 321-0293, Japan. Tel.: +81 282 86 1111; fax: +81 of >420 ms, whereas only 2% of unmedicated controls did ( However, there is little clinical data to aid in assessing the 0278-5846/$ – see front matter 2010 Elsevier Inc. All rights reserved.
doi: Y. Ozeki et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) 401–405 risk of QTc prolongation for an individual antipsychotic in a dose- dependent manner, particularly for second-generation antipsychotics Medication and rate of QTc prolongation in 1017 patients. Drugs which were administrated tomore than 3% of patients are shown.
(SGAs). Some case reports have indicated that SGAs can induce QTcprolongation However, such anecdotal reports do not provide clear evidence of whether SGAs increase the risk of QTc prolongation, as in first-generation anti- psychotics (FGAs), in a real-world setting. This study examined the risk of QTc prolongation of antipsychotic drugs in a large clinical sample from Japan. Japan is known to use higher doses of antipsychotics (), providing a unique opportunity to investigate the risk of QTc prolongation in a wide range of Clinical information, including data on QTc intervals, was collected from inpatients with schizophrenia who were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed.
(DSM-IV) in four independent hospitals. Approval from the ethics committee of each hospital was obtained. Data collection on all inpatients with schizophrenia was begun on the following dates in Abbreviations: eq = equivalent; HPD = haloperidol, CP = chlorpromazine; LP = three psychiatric hospitals Biwako Hospital, Toyosato Hospital, and levomepromazine, CBZ = carbamazepine, VPA = sodium valproate; No. = Number, SD =standard deviation.
Minakuchi Hospital: February 2, 2007; February 3, 2007; and July 29,2007, respectively. In the fourth hospital, the National Center ofNeurology and Psychiatry Hospital, clinical records were collected for sonian drugs, and benzodiazepines were converted into those of CP, all patients who were admitted to its psychiatric wards between 1998 biperiden, and diazepam equivalents, respectively ( and 2007. A total of 1065 inpatients were included from the four Subjects who were coadministered medical drugs (i.e., non hospitals, and all of them underwent ECG screening. Among them, 37 psychotropic drugs) with an increased risk of producing torsade de patients were excluded due to hypokalemia (serum potassium <3.5 mEq/L), which can induce QTc interval prolongation (). Two were excluded because of hypothy- roidism, and nine because of cardiac disease (four patients with rightbundle branch block, two with post-acute myocardial infarction, one First, logistic regression analysis was applied to examine risk with WPW syndrome, one with atrial–ventricular block, and one who factors for QTc prolongation. Age, sex, antipsychotic dose (CP underwent surgery for atrial septal defect). The remaining 1017 equivalent), benzodiazepine dose (diazepam equivalent), and anti- patients had a mean age of 42.6 years (S.D., 18.2) and were included in parkinsonian drug dose (biperiden equivalent) were included in the backward stepwise regression model. In the second analysis, age, sex,and individual antipsychotic doses were entered as independent variables in the logistic regression analysis. Then, the adjusted relativerisks of important explanatory variables were calculated via the A standard 12-lead ECG was recorded at 25 mm/s. Because the QTc backward stepwise regression analysis. Drugs that were administrat- interval is influenced by heart rate, it was corrected by Bazett's ed in more than 3% of the patients were analyzed.
formula (QTc: QTc = QT/RR1/2) (An ECG recording Linear regression analysis was used to determine which anti- showing the longest QTc interval was selected for each patient whose psychotics lengthened the QTc interval in a dose-dependent manner, ECG was recorded two or more times. The QTc was measured as the antipsychotic dose was entered as a continuous variable. Then, automatically by a program on the ECG apparatus (MAC 5500 with the adjusted coefficients were calculated using the stepwise selection 12SL algorithm by GE health care [Amersham Place, Little Chalfont, model. Age, sex, and individual antipsychotic doses were entered as Buckinghamshire, UK]). For patients with a QTc > 430 ms, QTc and RR intervals were measured manually for the chest lead with the The χ2 test was used to examine the risk-increasing effect of maximal T-wave amplitude, according to The excessive use of antipsychotics (cut-off points of 1000 or 1500 mg/day end of the T-wave was determined as the intersection between the of CP equivalent). All statistical analyses were performed using the tangent to the steepest downslope of the T-wave and the isoelectric SPSS, version 13.0 (SPSS Japan, Inc., Tokyo, Japan). All p-values line. QTc prolongation was defined as a QTc length of more than reported are two tailed. Statistical significance was considered when 470 ms in males and more than 480 ms in females, as 99% of “healthy” people can be excluded by this cut-off value Oneof the coauthors (M.H.), a cardiologist who specializes in arrhythmias, trained the authors on how to evaluate an ECG recording. Informationon drugs administered within 24 h of the ECG recording was obtained.
The prevalence of QTc prolongation (> 470 ms in male and shows the distribution of drugs that were administered in >480 ms in female) was 2.5% (male: 3.7%; female: 1.0%). Logistic more than 3% of the patients and the prevalence of QTc prolongation regression analysis showed that the antipsychotic dose was a for each medication. One hundred forty-two patients were drug free significant risk factor for QTc prolongation whereas when the ECG was recorded, because they were given the test at antiparkinsonian drugs, benzodiazepines, and mood stabilizers were admission before they had taken any drugs. Two hundred sixty-five not risk factors for QTc prolongation. Administration of antipsychotic patients were on monotherapy. Doses of antipsychotics, antiparkin- doses greater than 1000 and 1500 mg/day of CP equivalent was found Y. Ozeki et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) 401–405 Result of logistic regression analysis on the risk of QTc prolongation for standardizeddoses.
In a large clinical sample, we confirmed that a daily dose of antipsychotics (CP equivalents) was associated with a dose-dependentincreased risk of QTc prolongation; however, the use of antiparkinso- nian drugs, benzodiazepines, and mood stabilizers did not significantly increase this risk. With regard to individual antipsychotics, CP, HPDiv, and sultopride were shown to significantly increase the risk of QTc prolongation. CP, HPDiv, LP, and sultopride were found to significantly lengthen the QTc interval, whereas HPD, bromperidol, olanzapine, quetiapine, risperidone, and zotepine were not.
Our observation that a daily dose of antipsychotics was associated with a risk of QTc prolongation is consistent with previous studies doses of more than 1000 and 1500 mg/day of CP equivalents were found to increase the risk of QTc prolongation by approximately 2.0 and 3.0 fold, respectively, when compared to their counterparts. Reilly et al. also reported that a high dose (1000 to 2000 mg/day) and a very high dose (>2000 mg/day) predicted QTc prolongation [odds ratio(OR), 5.3 and 8.2, respectively] ). Warner et al.
reported an OR of 4.3 for doses higher than 2000 mg/day ( Abbreviations: eq = equivalent, CP = chlorpromazine, CBZ = carbamazepine; VPA =sodium valproate, CI = confidence interval.
In contrast to antipsychotics, mood stabilizers showed nosignificant risk-increasing effect. This is consistent with a previousfinding, which showed that lithium or carbamazepine did not to increase the risk of QTc prolongation 1.97 fold (95% CI, 1.48–2.59, significantly increase the risk of QTc prolongation ( p < 0.001) and 2.76 fold (95% CI, 1.80–4.18, p < 0.001), respectively, ). However, a recent study suggested that lithium increases the when compared to their counterparts. On examination of individual QTc interval significantly (18.6 ms; 95% CI, 4.8–32.4 ms) ( antipsychotics, haloperidol intravenous injection (HPDiv), CP, and ). Furthermore, lithium is known to cause T-wave changes sultopride were found to increase the risk of QTc prolongation torsade de pointes when combined with a QTc-lengthening antipsy- In the stepwise selection model of the multiple linear regression analysis, CP, HPDiv, levomepromazine (LP), and sultopride were requires careful ECG monitoring. With respect to valproate, our study found to lengthen the QTc interval. Age was also indicated as a risk may be the first to investigate the risk of QTc prolongation for this factor for QTc lengthening. Adjusted coefficients for CP, HPDiv, LP, drug in a clinical setting. With regard to coadministered benzodiaz- sultopride, and sex are shown in . Adding 100 mg of LP, for epine and antiparkinsonian drugs, our results suggest no significant example, extended the QTc interval by 4.65 ms. Bromperidol, effect on QTc prolongation. Although some patients taking diazepam olanzapine, quetiapine, risperidone, and zotepine had no significant and biperiden equivalent showed QTc interval prolongation (), lengthening effect on the QTc interval.
the results of logistic regression analysis showed no significant risk-increasing effect of these drugs (Therefore, these patients were also taking chlorpromazine equivalent and it was the chlor- Result of logistic regression analysis on the risk of QTc prolongation for each promazine equivalent that explained the QTc interval prolongation.
Indeed, to our knowledge, there has been no study reporting that these drugs cause QTc prolongation or torsade de pointes.
With respect to individual antipsychotics, previous studies have reported that thioridazine, intravenous droperidol, sertindole, and ziprasidone are associated with a strong risk-increasing effect on QTc QTc prolongation effect of each antipsychotic by linear regression model.
Abbreviations: HPD = haloperidol, CP = chlorpromazine, LP = levomepromazine, iv = Abbreviations: HPD = haloperidol, CP = chlorpromazine, LP = levomepromazine; iv = intravenous injection, CI = confidence interval.
intravenous injection, CI = confidence interval.
Y. Ozeki et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) 401–405 In Japan, commercial use of thioridazine ended in 2005; than that of thioridazine and chlorpromazine. Olanzapine, in intravenous droperidol has not been used in psychiatric treatment; particular, was reported to have little effect on the QTc-interval and sertindole and ziprasidone have not been introduced. Thus, we could not confirm the effect of these drugs. However, our results of a patient who was treated with olanzapine and showed an provide robust evidence that HPDiv increases the risk of QTc abnormal QTc interval. reviewed the literature and prolongation. This concurs with Hatta et al. who compared the found nine cases in which QTc prolongation was associated with SGA differences in QTc length among psychiatric emergency patients who administration (four cases of risperidone [one case was his original received intravenous flunitrazepam alone and those who received case], three cases of quetiapine, and two cases of ziprasidone). Taken intravenous flunitrazepam and haloperidol and found that the latter together, although our results suggest that the SGAs (olanzapine, group showed significantly longer QTc intervals than the former quetiapine, risperidone, and zotepine) are less likely to produce QTc interval prolongation than the FGAs examined herein, the SGAs can identified cases of patients aged ≥60 years who developed QTc also cause QTc prolongation. Thus, further investigations with a more interval prolongation, polymorphic ventricular tachycardia/torsade refined methodology are warranted. In particular, the current group- de pointes and/or sudden cardiac death while taking antipsychotic or derived formula for correcting QT interval measurements to a heart antidepressant drugs or a combination of these medications. Among rate of 60 beats per/min (QTc) are unsatisfactory ), and, such cases, most frequently reported medication was HPDiv (14 out of as pointed out by , determining the effect of drug- 37 cases). These findings and ours support the recent alert of the U.S.
induced change amid the noise of random variation (regression to the Food and Drug Administration warning that HPDiv increases the risk mean) will require a new technology.
of QTc prolongation and torsade de pointes based on at least 28 cases Female gender is known to be a risk factor for QTc prolongation Oral HPD, in contrast, was found to have no statistically female gender as a significant risk factor in our sample. Moreover, QTc significant risk-increasing effect on QTc prolongation, although it had prolongation was found more commonly in male patients than in a significant QTc-lengthening effect. Previous findings have suggested female patients. One reason for these results was that the antipsy- that oral HPD at low or moderate doses had no clear effect on QTc, but chotic dose was substantially lower in female patients than in male that it is associated with QTc prolongation and torsade de pointes at patients (mean CP equivalent dose: 841 vs. 1066 mg/day; frequency of > 1500 mg/day: 13.9% vs. 20.8%). In addition, because some Taken together, excessively high blood levels of the drug after previous studies in psychotic patients did not detect the gender an intravenous injection or oral intake of high doses may be critical for the effect of HPD. Regarding bromperidol (oral use only), a chemically may have other factors that attenuate the gender difference.
similar butyrophenone to HPD, we obtained no evidence for its effect There are several limitations to the study. First, we did not include on QTc prolongation or lengthening. To our knowledge, this is the first medications other than psychotropic drugs in the analysis; however, study to examine bromperidol for such effects. Further studies are the subjects included in the analysis were not coadministered other warranted to confirm our results. With respect to CP, we detected medical drugs that increased the risk for torsade de pointes ( significant effects on both QTc prolongation and QTc lengthening, We also excluded patients suffering from cardiac which is consistent with previous findings, suggesting an intermedi- diseases. Furthermore, psychotropic drugs that were administrated ate effect of CP on QTc (i.e., a weaker effect than that of thioridazine, to 3% or fewer of the patients in the sample were not included in the analysis. The fact that nearly all patients received multiple drugs and a substantial proportion of participants (69%) were treated with no significant risk-increasing effect of CP ( antipsychotic polypharmacy may have made it difficult to obtain a LP, another phenothiazine, was also found to lengthen clear result for each drug. However, there is great value in assessing the QTc interval in the multiple regression analysis. In the logistic the increased risk of QTc prolongation in such a practical setting. Our regression, statistical significance was nearly achieved (p = 0.06, participants were all inpatients, and therefore individuals with severe ). These results suggest that LP is likely to increase the risk of symptomatology and those patients on high doses of antipsychotics QTc prolongation. Although there have been little data on LP in were likely to be overrepresented. A recent study reported the relation to QTc in the literature, an association between sudden death possibility that an acute psychotic state itself may be a risk factor for and the use of phenothiazines is prominent, and LP might have been QTc prolongation ). Severe symptomatology might involved in such deaths (). Finally, sultopride, a have biased the results toward an increased prevalence of the QTc benzamide derivative, was found to significantly increase the risk of QTc prolongation and QTc lengthening. To our knowledge, this is the To screen QTc interval, we used an automated program, which first time that such evidence has been obtained for sultopride. Further may be fraught with errors. However, , for studies are warranted to confirm our results.
example, reported that patients with automatic QTc of <430 ms were Our results provide no evidence for the possible risk-increasing at very low risk of having a prolonged QT interval where their effect of the examined SGAs (olanzapine, quetiapine, risperidone, and definition of prolonged QTc interval was >450 ms in women and zotepine) on QTc prolongation. Recently, reported >440 ms in men. We measured QTc interval manually for patients that atypical antipsychotics double the risk of sudden cardiac death with an automated QTc of >430 ms, although our definition of QTc when compared with nonusers of antipsychotic drugs, a finding that prolongation was > 480 ms in women and >470 ms in men. Thus, it contradicts our data. However, SGAs can induce weight gain, insulin was unlikely that we missed patients with QTc prolongation in our resistance, and dyslipidemia ), all of which are study. Furthermore, the reliability of the measurement algorithm of risk factors for ischemic heart diseases. Therefore, the increased the ECG equipment (MAC 5500 with 12SL algorithm by GE health care sudden death observed by could be attributable to [Amersham Place, Little Chalfont, Buckinghamshire, UK]) that we the increased risk of ischemic heart diseases rather than torsade de used was reported to be high. The data obtained by this algorithm was pointes due to QTc prolongation. reported within 10 ms of the manual measurement in 95.9% of ECGs and within that SGAs, such as risperidone, quetiapine, ziprasidone, and olanza- 15 ms in 99.3% of ECGs (). Thus, the possible pine, induced QTc interval prolongation. In the review of effect of the use of the automated program is likely minimal. Another it was suggested that risperidone and quetiapine could limitation might be that we used the chest lead with the maximal T- lengthen the QTc interval, although the effect observed was smaller wave amplitude because clear T-wave leads are needed for precise Y. Ozeki et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) 401–405 manual measurement. However, Bazett generally used limb lead II to Elming H, Sonne J, Lublin HK. The importance of the QT interval: a review of the literature.
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