Abnormalities of rate-corrected QT intervals in Parkinson's disease-a comparison with multiple system atrophy and progressive supranuclear palsy

A number of patients with Parkinson's disease (PD) and multiple system atrophy (MSA), in whom sudden death does occur occasionally, have QT or rate-corrected QT (QTc) interval prolongation on electrocardiogram (ECG). Although these QT or QTc interval abnormalities are likely related to autonomic dysfunction, the pathophysiology remains unknown. The aim of this study was to compare the degree of QTc interval prolongation among akinetic-rigid syndromes, namely PD and related disorders, and to evaluate the relationship between QTc prolongation and severity of autonomic dysfunction. Thirty-four patients with PD, 22 with MSA, 11 with progressive supranuclear palsy (PSP) and 30 healthy controls underwent standard autonomic function tests, and electrocardiography variables (RR, QT and QTc intervals) were measured by an ECG recorder with an automated analyzer. The relationship between QTc interval and cardiovascular reflex tests were also analyzed. Orthostatic hypotension and decreased heart rate in response to respiratory stimuli were prominent in MSA, while these were relatively mild in PD. Unlike the RR and QT intervals, the QTc interval significantly differed among all groups (p<0.01). The QTc interval was significantly prolonged in PD (409+/-17 ms; p<0.001) and MSA (404+/-14 ms; p<0.05) compared with healthy controls (394+/-19 ms). Neither autonomic dysfunction nor QTc interval prolongation was evident in PSP. QTc intervals and cardiovascular reflexes did not correlate, except for Valsalva ratio. The QTc interval was obviously prolonged in PD patients to an extent that could not be accounted for simply by autonomic dysfunction levels. MSA patients showed slightly prolonged QTc intervals in spite of marked cardiovascular autonomic dysfunction. Abnormalities of the QTc may reflect the degeneration of cardioselective sympathetic and parasympathetic neurons that cannot be fully captured by cardiovascular autonomic function tests.     

Antipsychotic drugs and QT interval prolongation

The QTc prolongation by antipsychotic drugs is of major concern, especially in light of the data indicating an increased risk of sudden death in psychiatric patients taking these drugs. Sudden death in psychiatric patients could be partially attributed to drug-induced torsades de pointes and for this reason careful evaluation of QTc prolonging properties of antipsychotic drugs is needed. Antipsychotic drugs prolong QT interval usually by blocking the potassium I_Kr current. Improved understanding of ion channel structure and kinetics and its role in repolarization has tremendous impact on understanding of the mechanisms of drug-induced QT prolongation and torsades de pointes. Proarrhythmia caused by a QT-prolonging drug occurs infrequently, and usually multiple factors need to operate to precipitate such an event including a combination of two or more drugs affecting the same pathway, hypokalemia, and possibly genetic predisposition. Currently prescribed antipsychotics might cause QT prolongation ranging from 4–6 ms for haloperidol and olanzapine to 35 ms for thioridazine. The response of a patient to a drug is very individual and therefore an individualized system of drug administration and monitoring needs to be developed which takes into account baseline QTc duration and its changes after a drug was introduced. A systematic approach while stratifying psychiatric patients as those with short QTc (QTc 0.41 sec), borderline QTc (QTC = 0.42–0.44 sec), and prolonged QTc ( 0.45 sec) is being proposed to improve the safety of administering antipsychotic drugs and to decrease the risk of drug-related sudden death in psychiatric patients.     

The effect of sertindole on QTD and TPTE

Nielsen J, Andersen MP, Graff C, Kanters JK, Hardahl T, Dybbro J, Struijk JJ, Meyer JM, Toft E. The effect of sertindole on QTD and TPTE. Objective: Recent research suggests that other surrogate markers than QTc, including QTc dispersion and Tpeak‐Tend, may better correlate with cardiac arrhythmia risk. While sertindole significantly prolongs the QTc interval, the effects on other markers of arrhythmia risk, such as QTc dispersion and Tpeak‐Tend are unknown. Method: Digital 12‐lead ECG was recorded at baseline and at steady‐state in 37 patients switched to sertindole. ECG was analysed for Fridericia‐corrected QT duration (QTcF), QT dispersion and Tpeak‐Tend. Results: From a baseline QTcF of 407 ± 22 ms, mean QTcF prolongation during sertindole treatment was 20 ± 23 ms, P < 0.01. No effect on QTc dispersion was found (?1 ± 11 ms; P = 0.41). No increased duration of the Tpeak‐Tend interval from baseline was found (+7 ± 21 ms; P = 0.05). Conclusion: These findings might be related to the absence of confirmed Torsade de Pointes (TdP) cases related to sertindole exposure, despite sertindole’s QTc prolonging effects.     

Electrocardiographic abnormalities in patients treated with clozapine

BACKGROUND: Cardiovascular side effects of clozapine are not uncommon, but few systematic studies of these effects have been performed. In this study, we reviewed data on the electrocardiographic (ECG) abnormalities in patients treated with clozapine. METHOD: Sixty-one patients treated with clozapine were selected from the Seoul National University Hospital Treatment-Resistant Schizophrenia Clinic. A retrospective chart review was conducted to identify ECG abnormalities and cardiovascular side effects. RESULTS: The prevalence of ECG abnormalities in patients who had been using antipsychotics other than clozapine was 13.6% at baseline, which increased significantly to 31.1% after commencement of clozapine treatment. Among the 53 patients without baseline ECG abnormalities, 13 showed new-onset ECG abnormalities after using clozapine. Normal ECG under previous antipsychotic medication reduced the risk of new-onset ECG abnormalities, whereas increased age was found to increase the risk. The occurrence of orthostatic hypotension or tachycardia was not related to the development of ECG abnormalities. Most of the newly developed abnormalities had little clinical significance, and they tended to occur during the initial phase of treatment. In 10 patients, ECGs normalized despite the continued use of clozapine. Clozapine increased corrected QT interval (QTc) in a dose-dependent fashion; however, the clinical significance of this observation is uncertain. Pathologic prolongation of QTc was found to be rare. CONCLUSION: Although a substantial portion of patients treated with clozapine developed ECG abnormalities, most of the abnormalities were benign and did not hinder further treatment.     

A retrospective study of the safety of intramuscular ziprasidone in agitated elderly patients

OBJECTIVE: Authors evaluated the safety of intramuscular ziprasidone for use in acute agitation in an elderly population. METHOD: Medical records were reviewed retrospectively to identify consecutive patients who were admitted to our neuropsychiatry service with the presenting complaint of dementia (DSM-IV) with agitation and who were given intramuscular ziprasidone and then administered an electrocardiogram (ECG) (N = 23). Some patients also had a baseline ECG (N = 14). QTc intervals were recorded, and significance was defined as a QTc of > or =450 ms or a 10% prolongation from baseline. A paired-samples t test was performed to compare the baseline and postmedication QTc intervals. Confounding factors were examined, and cardiac events (torsades de pointes, cardiac arrest) were recorded. RESULTS: There was no significant difference in the QTc interval between the baseline and the post-ziprasidone values. One patient had a QTc greater than 500 ms and 25% over baseline, and therefore the medication was discontinued. The mean prolongation of the QTc interval was only 0.5 ms. There were no episodes of torsades de pointes. Other medications that the patients were taking did not appear to affect the QTc interval in an expected manner. CONCLUSION: Larger studies need to be done to evaluate the safety of intramuscular ziprasidone in agitated elderly patients, a population with an increased risk of QT prolongation and torsades de pointes because of their age, comorbid conditions, and concomitant use of multiple medications.     

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

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) = 1.14 to 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, benzodiazepines, 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 produce QTc interval prolongation, which may be of use in clinical decision making concerning the choice of antipsychotic medication.     

Antipsychotic Polypharmacy and Corrected QT Interval: A Systematic Review

Objective:

It remains unclear whether antipsychotic polypharmacy, a common clinical practice, is related to an increased risk of corrected time between start of Q wave and end of T wave (QTc) interval prolongation. We conducted a systematic review of the literature to address this important issue.

Method:

A systematic literature search was conducted in October 2014, using MEDLINE, Embase, and PsycINFO. Studies and case reports were included if they reported QTc intervals or QTc interval changes before and after antipsychotic polypharmacy or QTc intervals in both antipsychotic polypharmacy and monotherapy groups.

Results:

A total of 21 articles (10 clinical trials, 4 observational studies, and 7 case reports) met inclusion criteria. The clinical trials have shown that a combination treatment with risperidone or pimozide is not obviously related to an increase in QTc interval, whereas ziprasidone or sertindole combined with clozapine may prolong QTc interval. Among the 4 observational studies, antipsychotic polypharmacy was not clearly associated with QTc prolongation in 3 studies, each cross-sectional. In contrast, one prospective study showed a significant increase in QTc interval following antipsychotic coadministration. The case reports indicated an increased risk of QTc prolongation in at least some patients receiving antipsychotic polypharmacy.

Conclusions:

Currently available evidence fails to confirm that antipsychotic polypharmacy worsens QTc prolongation in general, although the evidence is scarce and inconsistent. Clinicians are advised to remain conservative in resorting to antipsychotic polypharmacy, as a combination of some QTc-prolongation liable antipsychotics may further prolong QTc interval, and efficacy supporting the clinical benefits of antipsychotic polypharmacy is equivocal, at best.     

Assessment of appropriate medication administration for hospitalized patients with Parkinson's disease

BackgroundFor Parkinson’s disease (PD) patients, adherence to a regular PD medication schedule is important in achieving optimal symptom control. There are few published studies quantifying PD medication administrations in hospitalized PD patients.MethodsHospitalization records for 100 veterans with idiopathic PD and admitted to our center were reviewed to determine the on time rate and contraindicated medication doses. A barcode based computerized medication administration system within the electronic medical record provided information of the exact time the medication was given to a patient.ResultsEighty-nine idiopathic PD patients met study inclusion criteria. Among them, 87 were on levodopa monotherapy or in combination with other PD medications. Two patients were on dopamine agonists only. A total of 3873 doses of PD medications were prescribed during hospitalization. Among 675 incorrect medication administrations, 322 doses were omitted, 300 doses late by ≥30 min, and 53 doses given early by ≥30 min. Contraindicated medications were prescribed for 19 patients. The correct administration percentage was lower during the first 2 days post-admission compared to subsequent days (mean 74.6% vs. 82.8%) and higher for patients who had neurological consultations (mean 85.5% vs. 76.5%). Correct administration rates were better for patient-based medication schedules (85.6%) than with hospital-based schedules (77.5%), but did not achieve statistical significance.ConclusionAdherence to regular PD medication dosing schedules during hospitalization is problematic, but improves with specialist consultation. Staff involved in the admission process for PD patients should work to safeguard against disruption of the prescribed home dosing schedule.     

Autonomic neuropathy and QT interval in hemodialysed patients

Abstract. Background QT interval prolongation increases the risk of ventricular arrhythmias and sudden death in diabetic autonomic neuropathy and ischemic heart disease. In end–stage renal disease (ESRD), the effects of hemodialysis on QT interval are diverse and the influence of autonomic neuropathy has yet to be clearly defined. Methods Sixty–nine ERSD patients (age 64 ± 14) were studied. Prior to the dialysis session, patients underwent four standard autonomic cardiovascular tests; before and after the dialysis session, a 12–lead ECG was recorded. Corrected QT intervals (QTc) were measured and QT dispersion (QTd) was calculated. Twelve subjects (age 59 ± 6) with normal renal function served as control group. Results Compared to controls, ESRD patients showed a longer QTc (434 ± 26 vs 414 ± 28ms; p = 0.016) and a similar QTd (35 ± 13 vs 37 ± 14ms; p = 0.54).QTc was > 440ms in 33.3% of the patients. No difference in the prevalence or score of autonomic neuropathy was observed between the subgroups with and without a prolonged QTc. After the hemodialysis session, QTc increased in 56% and decreased in 43% of the patients, and QTd increased in 45 % and decreased in 55% of the patients. QTc and QTd changes were not related to the presence of autonomic neuropathy. Conclusions A large variability in QTc and QTd response was observed after hemodialysis. Autonomic neuropathy did not contribute to QTc and QTd length, nor to QTc and QTd change after dialysis.     

No significant QTc interval changes with high-dose ziprasidone: a case series

This study examined the effects of high-dose ziprasidone on the electrocardiograms (ECGs) of adult inpatients. This was done in an effort to assess the incremental risk of QTc interval prolongation when using ziprasidone in doses above the maximum dose of 160 mg/day approved by the Food and Drug Administration. We retrospectively examined pre- and post-treatment QTc intervals in 15 subjects at the James A. Haley Veterans Affairs Medical Center who had received high doses of ziprasidone, ranging from 240 to 320 mg/day, due to intractable psychotic symptoms. Pure baseline ECGs were not always attainable, since the majority of the subjects were taking concomitant medications at the time that ziprasidone was initiated. Analysis yielded an average increase of 3.4 msec from pre- to post-treatment, with a maximum post-treatment interval of 452 msec and no cases having a pre- to post- treatment QTc interval increase > 20 msec. These findings are statistically insignificant and do not approach the 500 msec threshold of concern. This study suggests that high-dose ziprasidone does not have a significant incremental effect on QTc interval prolongation in certain subsets of patients. However, it does not rule out the possibility that ziprasidone could have deleterious effects in higher risk populations or that ziprasidone could have rare, idiosyncratic cardiogenic effects. Limitations of the study are identified and recommendations for future research are presented.     

Impact of Age and Sex on QT Prolongation in Patients Receiving Psychotropics

Objective:

To assess older age and female sex, 2 of the major risk factors for potentially fatal cardiac arrhythmias or sudden cardiac death in patients prescribed psychotropics, within the context of electrocardiographic evidence of time between start of Q wave and end of T wave (QT) interval prolongation, which is an indicator of an increased risk for potentially fatal cardiac arrhythmias.

Method:

The literature on the relation between age, sex, and QT interval with respect to psychotropic drugs was reviewed.

Results:

The QT interval must be corrected (QTc) for heart rate. Because slower heart rates prolong and faster heart rates shorten the QT interval, people with faster heart rates may have a prolonged QT interval that is not apparent until the correction is performed. QTc values for apparently healthy post-pubertal people are less than 450 ms for males and less than 470 ms for females. The longer QT intervals in women may account for their increased risk of potentially fatal cardiac arrhythmias on psychotropics. QTc increases with increasing age. Assessment of QTc in older people is especially important to identify people with a longer QTc who are more likely to attain a serious QT level with drugs that prolong QTc. The age-related increase in QTc is more evident in men than women, suggesting that male sex does not afford protection against potentially fatal arrhythmias at older age.

Conclusion:

The association of increasing age and female sex with greater QT intervals indicates the need to have an increased awareness of the QTc prior to use of these psychotropics and to evaluate the QTc after initiation of therapy.     

Electrocardiographic changes in patients receiving neuroleptic medication

Warner JP, Barnes TRE, Henry JA. Electrocardiographic changes in patients receiving neuroleptic medication. Acta Psychiatr Scand 1996: 93: 311–313. © Munksgaard 1996. The precise aetiology of sudden death in patients receiving neuroleptic medication is uncertain, but cardiac arrhythmias are a possible cause. We investigated the link between neuroleptic medication and electrocardiographic changes predictive of malignant cardiac arrhythmias. Electrocardiographs were performed on 111 patients receiving neuroleptic medication and on 42 unmedicated controls. Prolonged QTc intervals were more common in the patient sample, but QTc dispersion was not significantly increased. QTc interval prolongation was more likely in patients on doses above 2000 mg chlorpromazine equivalents daily (odds ratio 4.28, P<0.02). Neuroleptic medication, especially at high doses, is associated with ECG changes that may herald more serious cardiac problems.     

Electrocardiographic safety profile and monitoring guidelines in pediatric psychopharmacology

Summary. A number of medications commonly used in pediatric psychopharmacology can prolong the QTc interval of the electrocardiogram. QTc prolongation can in turn predispose to torsades de pointes, a sometimes deadly arrhythmia. These considerations are clinically relevant given documented, if still controversial, reports of sudden deaths associated with the use of the tricyclic antidepressant (TCA) desipramine in children. While most reports of QTc prolongation have involved adult patients, this adverse effect can occur in children. After discussing the QTc parameters derivation, accuracy, and limitations, this article reviews current knowledge about the propensity of the antipsychotics (both atypical and traditional), TCAs, and alpha agonists to prolong the QTc interval in young patients. Based on the literature reviewed, guidelines are provided for clinical and electrocardiographic monitoring in pediatric psychopharmacology.     

QTc interval measurement and metabolic parameters in psychiatric patients taking typical or atypical antipsychotic drugs: a preliminary study

BACKGROUND: Antipsychotic drugs have been associated with prolongation of the QTc interval on the electrocardiogram, and QTc prolongation is, in turn, associated with an increased risk of cardiac arrhythmias and sudden death. Antipsychotic polypharmacy has been implicated in reduced survival, possibly secondary to cardiotoxic effects of antipsychotic medication. Abnormalities of glucose homeostasis, which may be more common in individuals with major mood disorders and schizophrenia, also affect the QTc interval. METHOD: We performed detailed assessment of metabolic parameters in 103 psychiatric out-patients, from across the diagnostic spectrum, who had been taking antipsychotic medication (typical, atypical, or a combination thereof) for a minimum of 6 months. We measured the QTc interval in a subset of these patients (N = 65). RESULTS: Only 2 patients (3%) had a prolonged QTc interval. There was a statistical trend (p = .08) toward a lower QTc interval in patients receiving antipsychotic polypharmacy. QTc interval was associated with age (p = .04) but not with any metabolic parameter. CONCLUSION: QTc prolongation in this population is uncommon. There was a significant association between increasing age and QTc interval, but cardiac repolarization was not related to any metabolic parameter. Further large prospective studies of similar patients are needed to confirm these findings.     

抗精神病药致首发精神疾病QTc 间期变化的相关 因素分析

目的 调查抗精神病药致首发精神疾病QTc间期延长的影响因素.方法 对服用稳定剂量抗精神病药治疗1月的309例首发精神疾病患者进行回顾性调查,收集人口学资料、空腹血糖、血压、血脂等生化指标、心电图资料,以QTc≥440ms作为QTc间期延长的标准,分析QTc间期延长的状况及其相关因素.结果 QTc间期延长的发生率为10.6%.药物治疗组QTc间期均值大于基线期,差异有统计学意义(P<0.05);药物联合电休克治疗组以及药物联合脑电治疗组QTc间期与基线期相比,差异无统计学意义(P>0.05).单一抗精神病药治疗组QTc间期与基线期差异无统计学意义(P>0.05);而抗精神病药联用以及抗精神病药联用抗抑郁药/心境稳定剂组QTc间期均值大于基线期,差异有统计学意义(P<0.05).抗精神病药等效氯丙嗪剂量<1000mg/d组别QTc间期与基线期相比差异有统计学意义(P<0.05).抗精神病药剂量与QTc间期没有相关性.女性是QTc间期延长的风险因素(OR=3.26,95%CI=1.050~10.094),其他因素未进入回归方程.结论 首发精神疾病患者抗精神病药治疗期间QTc间期延长存在性别差异,女性发生QTc间期延长的风险是男性的3.26倍.药物联用延长的QTc间期并未达到异常值.抗精神病药剂量与QTc间期没有相关性.除了性别因素外,其他指标不是QTc间期延长的风险因素.     

精神病患者猝死的相关因素分析

目的　探讨精神病患者猝死的相关因素。方法　选取 1997年 1月至 2 0 0 1年 12月在北京回龙观医院住院治疗中发生猝死的 6 5例精神病患者作为猝死组 ,以 2 0 0 2年 2月 2 0日所有在院的 110 7例精神病患者作为对照组。收集两组病例的主要人口学资料 (年龄、性别、精神障碍种类和病程 )和主要临床资料 (如合并躯体疾病种类、心电图特征、QTc间期、抗精神病药种类及剂量、合并其他精神药物的种类及剂量 ,主要不良反应等 ) ;对猝死组收集死因的临床判断及任何可能与猝死有关的资料。结果　 (1)猝死组与对照组患者在抗精神病药剂量及QTc间期 (总体 )的差异均无显著性 (均P >0 0 5 )。 (2 )两组中接受氯氮平治疗者的QTc间期 [(0 36± 2 5 4 )ms]均长于非氯氮平治疗者 [(0 35±3 2 3)ms],差异有非常显著性意义 (P =0 0 0 ) ;其中 ,猝死组和对照组用氯氮平治疗者的QTc间期分别为 [(0 39± 1 31)ms和 (0 36± 2 4 6 )ms],未用氯氮平治疗者的QTc间期分别为 [(0 33± 3 2 3)ms和(0 35± 3 2 1)ms]。 (3)猝死组慢性起病者 (96 9% )多于对照组 (87 7% ;P =0 0 3) ,合并躯体疾病的比例 (89 2 % )高于对照组 (39 1% ;P =0 0 0 ) ,心电图异常率 (5 8 5 % )也高于对照组 (2 5 8% ;P =0 0 0 )。经非参数检     

蛛网膜下腔出血患者并发长QT间期综合征的危险因素探讨

目的：分析哪些因素与蛛网膜下腔出血患者伴发长QT间期综合征有关。方法：对98例发病2小时内人住我院的蛛网膜下腔出血患者分别记录了年龄、性别以及是否有糖尿病史,测定了每一例的心电图QT间期,用Bazettformula方法计算了经心率校正后的QT间期即QTc,并测定了每一例患者的血钠、血钾、血钙、血镁浓度和血糖水平。用多元线性回归方法分析了蛛网膜下腔出血患者的校正后QT间期即QTc与年龄、性别、血钠、血钾、血钙、血镁浓度及血糖水平的关系。结果：平均QTc间期为469．80±24．19ms。多元线性回归分析表明女性、低血钾及血糖为QTc间期延长的独立危险因素。女性相对于男性的相对危险度为4．23,低血钾(＜3．5mmol/L)者与正常血钾者比较相对危险度为2．86,高血糖(＞7．4mmol/L)患者相对于非高血糖患者(≤7．4mmol/L)的相对危险度为1．10。结论：女性、低血钾浓度及高血糖水平是蛛网膜下腔出血患者QTc延长的独立危险因素。