抗精神病药物与QT间期延长和尖端扭转型室速

QT间期是心室除极和复极在心电图上的表现，根据专家调查，认为最有可能延长QT间药的药物依次为抗心律失常药、抗精神病药；在高危患者有可能为抗感染药、抗精神病药及抗抑郁药。QT间期延长可引起一种称为“尖端扭转型室速（Torsade Pointes，TdP）”的潜在致命性心律失常，故而QT间期延长对药物选择具有重要的临床意义。     

精神分裂症患者QTc问期延长的影响因素

目的 调查精神分裂症患者心电图QTc间期延长及相关影响因素。方法 对服用稳定剂量抗精神病药的522例住院精神分裂症患者进行横断面调查,收集人口学资料,测定空腹血糖等生化指标,并进行心电图检查,以QTc≥440ms作为QTc间期延长标准,分析QTc间期延长状况及其相关因素。结果 QTc间期延长发生率12．8％,女性（22．7％）高于男性（7．8％）,差异有统计学意义（P〈0．01）,心电图窦性心动过速和传导阻滞患者QTc间期延长风险分别是心电图正常患者的2．6和3．1倍（P〈0．05）。结论 抗精神病药治疗期间QTc间期延长发生率存在性别差异,女性QTc间期延长的风险可能更高。     

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.     

抗精神病药物导致QTc间期延长影响因素的研究 进展

精神分裂症患者与一般人群相比,心血管疾病死亡风险明显升高,这与抗精神病药物的 使用有一定的关系。抗精神病药物导致 QTc 间期延长,增加了室性快速心律失常或尖端扭转型室性心 动过速（TdP）的发生风险,严重者可恶化为致命的心室颤动,甚至心脏性猝死（SCD）。性别、年龄和电解 质紊乱对 QTc 间期延长均有影响;不同抗精神病药物对 QTc 间期的影响不同;单一抗精神病药物治疗和 多种抗精神病药物联合治疗对 QTc 间期的影响也不同;抗精神病药物导致的 QTc 间期延长也受到遗传 因素的影响,随着药物遗传学的发展,许多与抗精神病药物导致 QT 间期延长的相关基因被鉴定出来。 现就抗精神病药物导致 QTc 间期延长影响因素的研究进展予以综述,以期为临床诊疗提供参考。     

抗精神病药对QTc间期的影响

目的探讨研究抗精神病药对心脏的安全性.方法对服用单一抗精神病药治疗的精神分裂症病人检测心电图(ECG),观察比较其QTc间期.结果服奥氮平患者QTc间期延长的百分比显著低于服其他典型与非典型抗精神病药患者.结论在治疗精神分裂症及相关疾病时,只有奥氮平最少可能出现导致恶性心律异常的QTc间期延长.     

四种抗精神病药对女性精神分裂症患者心电图QT间期的影响

目的探讨抗精神病药物对精神分裂症患者QT间期的影响。方法将92例住院的女性精神分裂症患者随机分配四种药物进行治疗,每组随时间的延长增加剂量,并于入组前及治疗后第4一周末进行心电图检测,对QT间期结果进行比较。结果氨磺必利组、齐拉西酮组、奥氮平组、氯氮平组在治疗后第4、8周末,QT间期存在显著性差异（P〈0．01）,经组内两两比较在治疗后第4、8周末氨磺必利组分别与奥氮平组、氯氮平组,齐拉西酮组与奥氮平组、氯氮平QT间期比较有显著性差异（P〈0．05,P〈0．01）。通过四组药物自身配对治疗前与第4周末,治疗前与第8周末,第4周末与第8周末比较发现氨磺必利组、齐拉西酮组内QT间期存在显著性差异（P〈0．01）。结论氨磺必利、齐拉西酮对QT间期的影响应受到关注,注意心电图的监测,奥氮平对QT间期的影响相对较小。     

抗精神病药对精神分裂症首次发病患者听感觉门控P50的影响

目的探讨抗精神病药对精神分裂症首次发病患者听感觉门控电位P50的影响。方法采用配对听觉条件（S1）、测试（S2）刺激范式，对33例未经抗精神病药治疗的精神分裂症首次发病患者（患者组），给予第一代和第二代抗精神病药治疗，分别于治疗前、治疗6周后进行听觉诱发电位P50检测，并与30名健康成年人（对照组）对照。结果（1）治疗前，患者组S1波幅[（1．86±0．90）μV]低于对照组[（2．79±1．70）μV]，波幅比值S2／S1（1．03±0．61）高于对照组（0．46±0．26），差异均有统计意义（P〈0．05～0．01）；两组s2波幅及潜伏期的差异均无统计意义。（2）治疗6周后，患者组P50检测结果与治疗前相比，差异均无统计意义。（3）与第一代抗精神病药相比，第二代抗精神病药能提高S1波幅（P〈0．05）。结论精神分裂症患者治疗前已存在P50抑制异常，经两类抗精神病药治疗6周仍未能明显改善；与第一代抗精神病药相比，第二代抗精神病药治疗可提高S1波幅。     

精神药物的不良反应（三） 长期住院精神分裂症患者伴发代谢综合征情况

目的：了解长期住院精神分裂症患者伴发代谢综合征（MS）的情况。方法：抽样调查住院至少2年以上的长期住院精神分裂症患者,测定患者身高、腰围、体质量及代谢指标,依据世界糖尿病联盟（IDF）规定的诊断标准甄别出MS患者;同时调查与之相关的抗精神病药使用情况。结果：MS发生率为43.4%,女性52.0%高于男性34.9%（χ2=7.420,P〈0.01）;Logistic回归分析发现MS与性别、体质量指数有关;抗精神病药种类与MS发生无显著相关。结论：长期住院接受抗精神病药治疗的精神分裂症患者伴发MS较高。     

精神分裂症与糖尿病关系的探讨

目的：了解住院精神分裂症患者中糖尿病的发病情况及其与抗精神病药等因素的关系。方法：回顾性调查符合CCMD－2－R诊断标准的住院精神分裂症患者中的糖尿病发病情况以及抗精神病药的使用情况等相关因素,观察体重、血糖和血脂的变化。糖尿病的诊断按照 WHO关于糖尿病的诊断标准（1980年）作出。将精神分裂症患者中的糖尿病发生率与一般人群中的患病率进行比较,并分析影响糖尿病发生的相关因素。结果：在503例精神分裂症住院患者中,糖尿病的发生率为15．1％,为普通人群（2．5％）的6倍（x^2＝18．10,P＜0．01）。抗精神病药物可引起体重的显著增加(t＝5．45,P＜0．01）。糖尿病的发生与精神分裂症的持续病程、长期住院、患者的年龄以及阳性糖尿病家族史等因素有关。氯氮平对糖尿病的影响与其他抗精神药物无显著差异（x^2＝0．38,P＞0．05）。结论：精神分裂症患者中糖尿病的发生率远高于普通人群,抗精神病药物引起的体重增加可能与此有关,临床上应予以关注。     

精神疾病患者孕产期治疗探讨

目的：探讨精神疾病患者孕产期治疗方法。方法：回顾性分析1999年1月至2007年4月期间足月妊娠分娩的192例精神疾病患者的临床资料。结果：68例发作期的患者分娩时，剖宫产38例（56、7％），其中无产科原因而因精神症状剖宫产20例（29.9％）；稳定期患者124例，剖宫产38例（30．6％），99例妊娠中晚期坚持服抗精神病药，新生儿出生情况良好，未见畸形。结论：精神疾病患者孕中晚期抗精神病药维持治疗很有必要，对发作期的患者分娩时适当放宽剖宫产指征，以保障母婴安全；产后及时、足量恢复抗精神病药使用。     

Functional polymorphisms of the cytochrome P450 1A2 (CYP1A2) gene and prolonged QTc interval in schizophrenia

CYP1A2 is an important inducible enzyme involved in the metabolism of antipsychotics. This study examined two functional polymorphisms in the gene as potential markers in predicting prolongation of QTc interval in patients treated with antipsychotics. QT intervals were measured by 12-lead electrocardiography (ECG) for patients with a DSM-IV diagnosis of schizophrenia. Genomic DNA extracted from venous blood were genotyped for the two polymorphisms by PCR-RFLP. Statistically significant result for CYP1A2(*)1F was noted for all patients receiving chlorpromazine equivalent doses of above 300 mg and also for a further subgroup on antipsychotics known to be CYP1A2 substrates (p=0.007, mean QTc in ms for A/A: 395.5+/-15.1, A/C: 425.7+/-25.1, C/C: 427.3+/-20.7). For CYP1A2(*)1C, there was no statistically significant association between genotypes and mean QTc interval. Overall, there was a trend of those with the C allele of the CYP1A2(*)1F polymorphism having longer QTc intervals. The results of this study suggest that the CYP1A2(*)1F polymorphism may contribute to the risk of developing prolonged QT-interval in patients who are treated with higher doses of antipsychotics.     

Antipsychotics and QT prolongation

OBJECTIVE: To evaluate literature relating to cardiac QT prolongation and the use of antipsychotic drugs. METHOD: Literature searches of EMBASE, Medline, PsychLIT were performed in December 2001 and reference sections of retrieved papers scrutinized for further relevant reports. RESULTS: The Cardiac QTc interval is difficult to measure precisely or accurately but appears to be a useful predictor of risk of dysrhythmia (specifically torsade de pointes) and sudden death. It is less clear that drug-induced QTc prolongation gives rise to similar risks but data are emerging, linking antipsychotic use to increased cardiac mortality. Many antipsychotics have been clearly associated with QTc prolongation. Methodological considerations arguably preclude assuming that any antipsychotic is free of the risk of QTc prolongation and dysrhythmia. CONCLUSION: Available data do not allow assessment of relative or absolute risk of dysrhythmia or sudden death engendered by antipsychotics but caution is advised. Risk of dysrhythmia can very probably be reduced by careful prescribing of antipsychotics in low doses in simple drug regimens which avoid metabolic interactions. Electrocardiographic monitoring may also help to reduce risk but review by specialist cardiologist may be necessary.     

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.     

QTc-interval abnormalities in a forensic population

Background Antipsychotic drugs have been linked to sudden death among psychiatric patients, with a suggestion that prolongation of the QT‐interval detectable on a standard electrocardiogram may be linked to fatal cardiac arrhythmias in these circumstances. Patients in secure forensic psychiatric facilities may be particularly likely to be on high‐dose antipsychotic medication, and yet, as far as the authors are aware, no study of QT‐intervals among such patients has been reported. Aim To investigate the prevalence of QT‐interval abnormalities and associated known risk factors for fatal cardiac arrhythmias in a sample of forensic patients. Method Participants had a 12‐lead electrocardiogram taken at 50 mm/s. Information was collected on their age, gender, psychiatric diagnosis, history of cardiovascular, liver and kidney diseases, and smoking, on all medications and on history of seclusion over the previous 12 months. Analysis was carried out using binary logistic regression. Results Lower rates of QT‐interval abnormalities than might be expected for this population were found. It was also found that a high dose of antipsychotics was associated with QTc prolongation (Adjusted OR = 9.5, 95% CI 2.6–34.2), a result consistent with previous literature. Conclusion Forensic patients need not be at increased risk of QTc abnormality provided risk factors are properly managed. A high dose of antipsychotic medication increases the risk of QTc prolongation. Copyright © 2007 John Wiley & Sons, Ltd.     

Analysis of the QTc interval during olanzapine treatment of patients with schizophrenia and related psychosis

BACKGROUND: There may be a temporal association between some antipsychotics and prolongation of the heart-rate-corrected QT interval (QTc) representing a delay in ventricular repolarization. QTc prolongation significantly exceeding normal intra-individual and interindividual variation may increase the risk of ventricular tachydysrhythmias, especially torsade de pointes, and therefore, sudden cardiac death. METHOD: Electrocardiogram recordings obtained as part of the safety assessment of olanzapine in 4 controlled, randomized clinical trials (N = 2,700) were analyzed. These analyses were conducted to characterize any change in QTc temporally associated with olanzapine, compared with placebo, haloperidol, and risperidone, in acutely psychotic patients (DSM-III-R and DSM-IV) and to characterize variability and temporal course of the QTc in this patient population. Changes from baseline to minimum and maximum QTc were tested for significance, and baseline to acute-phase endpoint change in mean QTc was tested for significance within treatments and for differences between olanzapine and comparators. The possibility of a linear relationship between dose of olanzapine and mean change in QTc, as well as incidence of treatment-emergent prolongation of QTc (change from < 430 msec at baseline to > or =430 msec at endpoint), was tested. RESULTS: The incidence of maximum QTc > or = 450 msec during treatment was approximately equal to the incidence of QTc > or =450 msec at baseline. CONCLUSION: Results of these analyses suggest that olanzapine, as therapeutically administered to patients with schizophrenia and related psychoses, does not contribute to QTc prolongation resulting in potentially fatal ventricular arrhythmias.     

The QTc interval and its dispersion in patients receiving two atypical antipsychotics

Objective  Treatment with atypical antipsychotics may prolong the rate-corrected Q–T interval (QTc) on electrocardiogram and increase the risk of dangerous ventricular arrhythmias. Polytherapy with atypical antipsychotics is becoming common, but the effect of this practice on the QTc has not been explored in detail. Methods  Among 364 adults treated with atypical antipsychotics randomly selected from consecutive admissions to a single hospital, electrocardiograms with measurable Q–T intervals in at least six leads were available for 38 of 49 patients receiving polytherapy with two atypical antipsychotics. Daily chlorpromazine equivalent, QTc duration and QTc dispersion were assessed in this group and in 73 closely matched patients receiving atypical antipsychotic monotherapy. Results  The daily chlorpromazine equivalent of atypical antipsychotics was significantly greater in the polytherapy group (525.2 vs. 244.7 mg, P = 0.0003). Polytherapy and monotherapy patients were similar with regard to QTc duration, QTc dispersion and proportion of patients with gender-adjusted QTc prolongation (7.9% vs. 9.6%). The QTc duration had only a modest correlation with the total antipsychotic dose (P = 0.064). The presence of hypokalemia (3.0–3.5 mEq/l) was not associated with longer QTc intervals. Conclusions  The common practice of polytherapy with two atypical antipsychotics does not seem to lead to significant QTc prolongation compared to monotherapy. Grant Support: The Zucker Hillside Hospital Advanced Center for Intervention and Services Research for the Study of Schizophrenia (MH074543-01) from the National Institute of Mental Health, Bethesda, Maryland.     

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.     

Autonomic neuropathy and prolongation of QT interval in human immunodeficiency virus infection

Autonomic neuropathy has been reported in human immunodeficiency virus positive (HIV+) patients. Since alterations in cardiac innervation may determine QT interval prolongation, this interval was studied in a group of HIV+ subjects to evaluate if it is prolonged and to compare this measurement with other diagnostic tests for autonomic neuropathy. Fifty-seven HIV+ and 23 human immunodeficiency virus negative (HIV–) subjects were studied. Autonomic function was tested by noninvasive cardiovascular reflex tests, and the QT interval on the electrocardiogram was measured at rest, at maximum tachycardia during Valsalva manoeuvre, and afterwards at maximum bradycardia. QT intervals were corrected for heart rate according to Bazzett's formula (QTc). Autonomic neuropathy was found in 37 HIV+ subjects: 25 had moderate autonomic neuropathy (HIV+/mAN) and twelve had severe autonomic neuropathy (HIV+/sAN). The 23 HIV– and 20 HIV+ (HIV+/AN–) patients did not have autonomic neuropathy. QTc intervals were significantly longer in HIV+/sAN and HIV+/mAN than in HIV– at rest; in HIV+/sAN than in HIV– at maximum tachycardia; in HIV+/sAN and HIV+/mAN than in HIV+, in HIV+/sAN and HIV+/mAN than in HIV+/AN– and in HIV+/sAN than in HIV+/mAN at maximum bradycardia. QTc was 440 ms in 24 out of 37 (64.8%) patients with autonomic neuropathy and in five out of 20 (25%) HIV+/AN– patients (sensitivity 65%, specificity 75%). A significant correlation was observed between scores of autonomic involvement and QTc interval prolongation. This study confirms that the QTc measurement is a reliable parameter indicating the presence of autonomic neuropathy. Since QT prolongation may determine ventricular arrhythmias, such patients must be followed because they may be at increased risk of sudden death.