New Generation Antipsychotic Drugs and QTc Interval Prolongation

BACKGROUND: Recent regulatory and clinical concerns have brought into sharp focus antipsychotic drug-induced QTc interval prolongation, torsades de pointes, and sudden cardiac death. Several new generation (atypical) antipsychotic drugs have either been withdrawn from clinical use or delayed in reaching the marketplace due to these concerns. Because torsades de pointes is rarely found, QTc interval prolongation serves as a surrogate marker for this potentially life-threatening arrhythmia. Current methods of calculating this electrocardiographic parameter have limitations. The primary care physician is a key member of the team managing a patient who requires administration of antipsychotic drugs. This article focuses on new generation antipsychotic drugs and principles useful to both the primary care physician and the psychiatrist. METHOD: PubMed was searched in September 2002 using the terms antipsychotic drug and QT interval. References were examined from review articles describing antipsychotic drugs and the QT interval. The author's files gathered over the past 20 years on the QT interval were also reviewed. RESULTS: Nine cases were available in which drug-induced QTc interval prolongation was associated with new generation antipsychotic drug administration. Eight cases were taken from the literature, and the author added one additional report. The newer agents involved were risperidone, quetiapine, and ziprasidone. In at least 8 cases, there was evidence of other risk factors associated with QTc interval prolongation. In one case frequently referenced in the literature, the authors misunderstood their own data showing that QTc interval prolongation did not relate to delayed ventricular repolarization. In another instance, 2 authors reported on the same patient, with important information missing from both articles. No evidence of torsades de pointes appeared in any of the 9 cases. CONCLUSIONS: No evidence is currently available in the literature implicating new generation antipsychotic drugs in the production of torsades de pointes. However, the absence of such evidence does not prove that newer antipsychotic drugs do not cause torsades de pointes. Among patients free of risk factors for QTc interval prolongation and torsades de pointes, current literature does not dictate any specific consultative or laboratory intervention before administering new generation antipsychotic drugs. When risk factors are present, evaluation and intervention specific to those risk factors should dictate the clinician's course of action. More specific guidelines for monitoring the QT interval and risk of torsades de pointes await improved methods of measuring the QTc interval relevant to each patient.     

Torsade de pointes in a patient with complex medical and psychiatric conditions receiving low-dose quetiapine

OBJECTIVE: Describe potential cardiac complications of low-dose quetiapine and other atypical antipsychotic drugs. METHOD: We present a case report of a 45-year-old Black woman with multiple medical and psychiatric problems taking low-dose quetiapine. RESULTS: Coincident with a generalized seizure, the patient developed 'ventricular fibrillation'. She was countershocked with restoration of normal sinus rhythm. The initial electrocardiogram showed QT interval prolongation. Shortly thereafter, classical torsade de pointes appeared, lasted 10 min, and resolved spontaneously. Hypomagnesemia was present. A cardiac electrophysiologist was concerned that the very slow shortening of the prolonged QTc interval after magnesium replacement implicated quetiapine as a risk factor for QTc interval prolongation and torsade de pointes. A psychosomatic medicine consultant asserted that the fragmented medical and psychiatric care almost certainly contributed to the patient's medical problems. We discuss other cases of QT interval prolongation by newer antipsychotic drugs and previous reports by our group concerning the association of psychotropic drugs, QT interval prolongation, and torsade de pointes. CONCLUSION: Atypical antipsychotic drug administration, when accompanied by risk factors, may contribute to cardiac arrhythmias including torsade de pointes.     

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.     

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.     

Low-dose escitalopram for 2 days associated with corrected QT interval prolongation in a middle-aged woman: a case report and literature review

Prolongation of the corrected QT interval (QTc) on the electrocardiography is an important clinical condition because it increases the risk of torsade de pointes, a medical emergency that can cause sudden cardiac death. QTc prolongation can be induced by many drugs, including antipsychotics and tricyclic antidepressants (TCAs). Compared with TCAs, use of selective serotonin reuptake inhibitors (SSRIs) was less likely to cause severe cardiac adverse effects. Escitalopram, one of the SSRIs, has shown significant antidepressant efficacy and well tolerability. Here, we present one female patient showing QTc prolongation induced by low-dose (5 mg/day) treatment of escitalopram for 2 days. The QTc returned to normal soon after discontinuation of escitalopram. Clinicians should be cautious about cardiac effects when using a SSRI, even in a low dose.     

Antipsychotic drugs and cardiovascular safety: current studies of prolonged QT interval and risk of ventricular arrhythmia

Cardiovascular mortality is higher among schizophrenic patients than in the general population, and it is possible that most unexplained sudden deaths among these patients are due to ventricular arrhythmias for which antipsychotic drugs are either the cause or a predisposing factor. Most antipsychotic agents show electrophysiological effects resembling those of class 1a antiarrhythmic agents, and may be responsible for prolonging the QT interval, potentially going on to cause torsades de pointes. Some of the antipsychotic agents carry a high risk of arrhythmias, related to their effects on the QT interval. These include thioridazine, pimozide, sultopride, droperidol, and to a lesser extent haloperidol and chlorpromazine. In the case of the new atypical antipsychotic agents, it is possible to rank the risks of different drugs, with sertindole (now withdrawn from sale) having the highest risk, and ziprasidone somewhat lower, followed by risperidone and finally by quetiapine, clozapine and olanzapine which have negligible effects on the QT interval. A number of risk factors have been demonstrated, particularly: hypokalaemia and hypomagnesaemia, bradycardia, congenital long QT syndrome, and any underlying cardiac pathology. Lastly, the risk associated with any given antipsychotic agent is increased if it is combined either with any other drug known to prolong the QT interval and provoke torsades de pointes, or with any drug capable of inhibiting the hepatic metabolism of the antipsychotic agent. A list of such drugs is provided, together with advice on the action to be taken when prescribing an antipsychotic agent to a patient with a long QT interval.     

Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics

Alterations of electrocardiogram results and cases of sudden cardiac death have been reported since the beginning of neuroleptic treatment. In particular, a temporal association exists between some antipsychotics and prolongation of the heart rate-corrected QT interval (QTc), an event that may increase the risk for developing a potentially fatal ventricular tachycardia arrhythmia known as torsades de pointes if it significantly exceeds normal intraindividual and interindividual variation. Although the incidence of serious adverse cardiac events in response to antipsychotic medications is relatively low, any possibility for the occurrence of cardiotoxicity warrants continued study. The present article reviews important differences among antipsychotic drugs in the potential for, and occurrence of, serious adverse cardiac outcomes and suggests that olanzapine, as therapeutically administered to patients with schizophrenia and related psychoses, does not contribute significantly to a QTc prolongation that could result in potentially fatal ventricular arrhythmias.     

The importance of the QT interval: a review of the literature

OBJECTIVE: QT interval (QTi) prolongation is generally associated with increased risk of ventricular arrhythmias such as torsade de pointes (TdP) and death. METHOD: Literature review based on publications identified by means of electronic and manual search. RESULTS: It has recently become apparent that not only antiarrhythmic drugs such as sotalol and quinidine, but also a variety of non-antiarrhythmic drugs such as certain antihistamines, antimicrobial drugs, psychiatric drugs and cisapride, may have the ability to induce prolongation of the QTi and TdP. Special concern should be drawn to the coadministration of drugs that inhibit the metabolism of these drugs such as ketoconazole, itraconazol and erythomycin. Patients with congenital long QT syndrome, patients with heart disease, with hypokalemia or hypomagnesemia, and women have an increased risk. Every sign of dizziness or syncope should be regarded as a warning sign of possible arrhythmia in patients treated with drugs that potentially prolong the QTi. CONCLUSION: Measurement of the QTi before and during treatment is generally recommended in high-risk patients.     

Mort subite, antipsychotiques et schizophrénie

Sudden death is a multidimensional notion that can be defined in several ways. Epidemiologically, sudden death affects from 15 to 30% of the population and 30% of the schizophrenics. Since antipsychotic drugs appeared in 1954, the death rate of the schizophrenic population has decreased but has still remained higher than the death rate of the entire population (standardized mortality rate from 1 to 4). However, there is no proof of a decrease in the number of sudden deaths because of a lack of statistical data about the first period of time. Several factors may explain the excessively high death rate of the schizophrenics but mainly cardiovascular risk factors and an insufficient diagnosis of somatic comorbid conditions. Stress is also a well-known aetiology of sudden death: Ventricular tachycardia can occur in situations of anxiety; the Tako Tsubo syndrome is a coronarian syndrome occurring in a context of emotional stress. Death due to cardiovascular factors is probably the main aetiology of the schizophrenics’ sudden deaths, which are often associated with a prolonged QT interval (it is considered today that the QT interval is prolonged beyond 450 MS). Schizophrenia is partly the cause of these sudden deaths with regard to the stress generated by the disease. The influence of drugs on these deaths, and especially antipsychotic drugs, has also been considered. So, the use of thioridazine and sertindole was suspended after a dose-effect and sudden deaths were observed. Other antipsychotic drugs, such as haloperidol and risperidone are associated with some cases of a prolonged QT interval, with a high dosage. Another aetiology of sudden death is epilepsy: Before the rise of antipsychotic drugs, the comitial crises rate was already higher among the schizophrenics and crises occur today with or without a subjacent treatment; but antipsychotic drugs have also been incriminated in some sudden deaths. In the case of sudden deaths caused by pulmonary embolism, schizophrenia is a predisposition, especially catatonic schizophrenia. Obesity, physical restraints in case of agitated state are also the causes of a restrained mobility that can favour pulmonary embolism. As for antipsychotic drugs, and especially clozapine, they favour a gain of weight and a sedation with a high dosage, which result in a reduced mobility. As for sudden deaths caused by choking, schizophrenia contributes to these deaths through a poor mastication, a poor dentition or poor hygienic and dietetic habits. Phenothiazines can favour these deaths insofar as they favour deglutition impairment; the use of haloperidol can result in a respiratory dyskinesia that leads to asphyxia; the clozapine-benzodiazepine combination must be avoided. In the case of sudden deaths through intestinal obstruction, constipation is often poorly diagnosed for schizophrenics for whom the pain threshold is higher and because of their negative symptoms. These factors already explained the excessive death rate among the schizophrenics before the antipsychotic drugs era. But antipsychotic drugs have an analgesic effect that delays the diagnosis of constipation and an anticholinergic effect that favours constipation. The combination with a tricyclic antidepressant increases the risk. The incrimination of antipsychotic drugs in the sudden deaths of the schizophrenics remains debatable and epidemiology provides no conclusion. An autopsy is sometimes not enough to put the blame or not on antipsychotic drugs. Prevention measures about morbidity and mortality associated with antipsychotic drugs that prolonged QT, and with schizophrenia itself are proposed. The connection between sudden death and antipsychotic drugs remains poorly understood: in psychiatry, the high sudden deaths rate is due to several factors and antipsychotic drugs remain the most commonly used treatment for psychosis.     

QTc prolongation by antiepileptic drugs and the risk of torsade de pointes in patients with epilepsy

Sudden unexpected death in epilepsy (SUDEP) is the most common epilepsy-related cause of death. While the precise pathophysiological mechanisms underlying SUDEP are still uncertain, impaired cardiac function including seizure-induced arrhythmias has received increased attention. In addition, the potential role of antiepileptic drugs has been suggested. While the preponderance of clinical data would suggest that use of most antiepileptic drugs does not pose excessive additional risk of QT prolongation, available data also do not provide sufficient evidence that these drugs are entirely free of risk in all patients. In particular, the potential for these medications, either alone or in combination, to prolong the QT interval should be considered. This review will discuss mechanisms for drug-induced QT prolongation and its relationship to potentially fatal arrhythmias such as torsades de pointes.This article is part of a Special Issue entitled “Translational Epilepsy Research”.     

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.     

Possible association of QTc interval prolongation with co-administration of quetiapine and lovastatin.

BACKGROUND: QTc interval prolongation can occur as a result of treatment with both conventional and novel antipsychotic medications and is of clinical concern because of its association with the potentially fatal ventricular arrhythmia, torsade de pointes. METHODS: One case is described in which a patient with schizophrenia, who was being treated for dyslipidemia, developed a prolonged QTc interval while taking quetiapine and lovastatin. RESULTS: QTc returned to baseline when the lovastatin dose was reduced. CONCLUSIONS: QTc prolongation associated with antipsychotic medication occurs in a dose-dependent manner. We therefore hypothesize that the addition of lovastatin caused an increase in plasma quetiapine levels through competitive inhibition of the cytochrome P(450) (CYP) isoenzyme 3A4. Our case highlights the potential for a drug interaction between quetiapine and lovastatin leading to QTc prolongation during the management of dysipidemia in patients with schizophrenia.     

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.     

QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy

Background  

Several antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected QT interval (QTc) exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment.     

Psychotropic drugs and long QT syndromes: case reports

Two depressed patients with long QT syndrome who experienced torsade de pointes ventricular tachycardia when treated with psychotropic drugs are discussed. These cases emphasize the significance of electrocardiographic evaluation of depressed patients, particularly in patients who show evidence of a long QT interval.     

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.     

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.     

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.     

Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia

Administration of certain drugs (for example, antiarrhythmics, antihistamines, antibiotics, antipsychotics) may occasionally affect myocardial repolarization and cause prolongation of the QT interval. We performed a whole genome association study of drug-induced QT prolongation after 14 days of treatment in a phase 3 clinical trial evaluating the efficacy, safety and tolerability of a novel atypical antipsychotic, iloperidone, in patients with schizophrenia. We identified DNA polymorphisms associated with QT prolongation in six loci, including the CERKL and SLCO3A1 genes. Each single nucleotide polymorphism (SNP) defined two genotype groups associated with a low mean QT change (ranging from -0.69 to 5.67 ms depending on the SNP) or a higher mean QT prolongation (ranging from 14.16 to 17.81 ms). The CERKL protein is thought to be part of the ceramide pathway, which regulates currents conducted by various potassium channels, including the hERG channel. It is well established that inhibition of the hERG channel can prolong the QT interval. SLCO3A1 is thought to play a role in the translocation of prostaglandins, which have known cardioprotective properties, including the prevention of torsades de pointes. Our findings also point to genes involved in myocardial infarction (PALLD), cardiac structure and function (BRUNOL4) and cardiac development (NRG3). Results of this pharmacogenomic study provide new insight into the clinical response to iloperidone, developed with the goal of directing therapy to those patients with the optimal benefit/risk ratio.     

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