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Hiroaki Okayasu,1 Takahiro Shinozaki,1 Yumiko Takano,1 Norio Sugawara,1 Kumiko Fujii,2 Norio Yasui-Furukori,1 Yuji Ozeki,2 Kazutaka Shimoda1 1Department of Psychiatry, Dokkyo Medical University, Tochigi, Japan; 2Department of Psychiatry, Shiga University of Medical Science, Shiga, JapanCorrespondence: Hiroaki Okayasu Tel +81 282-86-1111Email hokayasu@dokkyomed.ac.jpPurpose: Antipsychotic drugs have been implicated as risk factors for QT prolongation, which is a predictor of sudden cardiac death. However, the QT interval is considered an imperfect marker for proarrhythmic risk. Recently, improved methods, namely, QT dispersion (QTD), QTD ratio (QTDR), T wave peak-to-end interval (Tp-e), Tp-e/QT ratio and Tp-e/QTc ratio, have been regarded as proarrhythmic risk markers. We attempted to reevaluate the risk of sudden cardiac death due to antipsychotics use by measuring these improved evaluation methods.Patients and Methods: We retrospectively evaluated QTc, QTD, QTDR, Tp-e, Tp-e/QT ratio and Tp-e/QTc ratio from the medical records of 410 patients with schizophrenia diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, or 5th Edition. Information on drugs administered was obtained from medical records. We investigated the correlation between each index on ECG and medication, such as antipsychotics, prescribed to participants with linear regression analysis. We also compared each index between 235 healthy controls and 235 patients matched for age and sex.Results: Positive correlations between QTc and levomepromazine and brexpiprazole were identified. Levomepromazine and lithium were positively correlated with QTD. Levomepromazine, quetiapine, asenapine, clozapine and carbamazepine were positively correlated with QTDR. Levomepromazine, olanzapine, brexpiprazole and lithium were positively correlated with Tp-e. Olanzapine, brexpiprazole and lithium were positively correlated with the Tp-e/QT ratio. Olanzapine, brexpiprazole and lithium were positively correlated with Tp-e/QTc ratio. Significant differences in all indexes were noted between the patients and healthy controls.Conclusion: According to our results, the prediction of the risk of sudden cardiac death by each index was inconsistent. We should evaluate the predictive factor of ventricular arrhythmia according to various electrocardiogram indexes because QTc alone could not identify the risk of sudden cardiac death.Keywords: antipsychotic drugs, sudden cardiac death, electrocardiogram, QT prolongation, QT dispersion, T peak-to-end interval

Background: Patients with genetic evidence of long QT syndromes type 1 and 2 (LQT1, associated with impaired outward potassium current IKs; and LQT2, associated with impaired outward potassium current IKr) may have normal baseline QT intervals (phenotype/genotype discordance) and elude clinical detection. Beta-adrenergic stimulation may unmask occult LQT1, but no maneuver has consistently unmasked the LQT2 phenotype. Objective: The purpose of this study was to test the repolarization reserve hypothesis (multiple challenges to repolarization are required to produce an abnormal phenotype), using subjects with LQT1 and LQT2 mutations but normal QT interval. We hypothesized that IKr channel blockade would prolong the QT interval excessively in subjects with LQTS compared with controls and that IKr channel blockade could unmask the abnormal LQTS phenotype in subjects with LQTS versus controls, as measured by the T peak-to-end interval (Tpe), a sensitive measure of abnormal repolarization. Methods: Subjects with known LQT1 (n = 5) and LQT2 (n = 6) mutations but baseline QTc ≤450 ms and age- and gender-matched controls (n = 22) received intravenous erythromycin (an IKr blocker). RR, QRS, QT, and Tpe intervals were measured at baseline and after drug infusion. Results: Erythromycin caused only modest QT prolongation in all groups. In contrast, Tpe was specifically prolonged by IKr channel blockade in LQT2 subjects but not in LQT1 subjects or controls. Conclusion: Short-acting IKr channel blockade, together with the sensitive repolarization measure Tpe, can unmask abnormal repolarization in LQT2. Our finding of abnormal repolarization in LQT2 subjects exposed to IKr channel blockade supports the repolarization reserve hypothesis. [Copyright &y& Elsevier]