齐拉西酮注射剂与氟哌啶醇注射剂治疗精神分裂症急性期患者的对照研究

目的比较齐拉西酮注射剂与氟哌啶醇注射剂治疗精神分裂症急性期的疗效与副作用。方法选用齐拉西酮注射剂与氟哌啶醇注射剂,将75例患者分至齐拉西酮组（n=38）和氟哌啶醇组（n=37）,进行为期5天的治疗。两组分别完成34例和33例。在治疗前及治疗后采用阳性与阴性综合征量表（PANSS）、修改版外显攻击行为量表（MOAS）、临床总体印度量表（CG I）、不良反应量表（TESS）评定疗效及药物不良反应。治疗前进行基线心电图测定,与治疗后QTc间期比较。结果齐拉西酮组和氟哌啶醇组治疗前后PANSS阳性症状量表因子分、MOAS加权总分减分率相当;CG I评分达到好转与以上者分别为25例（73.5%）、26例（78.8%）;齐拉西酮组不良反应主要为失眠10例（29.4%）,QTc间期延长3例（7.9%）,心律失常2例（5.3%）。氟哌啶醇组不良反应主要为锥体外系反应16例（48.5%）,无QTc间期延长者。结论齐拉西酮注射剂与氟哌啶醇注射剂对治疗精神分裂症急性期患者的疗效相当,但应高度重视齐拉西酮对心脏不良反应,特别是心律失常及QTc间期的延长。     

Electrocardiographic changes in children and adolescents treated with ziprasidone: a prospective study

OBJECTIVE: To assess the electrocardiographic safety profile of low-dose ziprasidone (< or =40 mg/day) among pediatric outpatients treated for up to 6 months. METHOD: This was a prospective, open-label trial involving 20 subjects with a mean age of 13.2 +/- 3.0 years. Subjects received a mean ziprasidone dose of 30 +/- 13 mg/day and were followed for 4.6 +/- 2.0 months, receiving a median of nine electrocardiograms each (range 2-11; total, 176). RESULTS: There were statistically significant changes from baseline to peak values in heart rate, PR, and QTc intervals, but not in QRS complex width. The mean QTc prolongation was 28 +/- 26 milliseconds and not related to dose (r = 0.16, p = .07). The peak QTc of three subjects reached or exceeded 450 milliseconds; one subject experienced a 114-millisecond prolongation. There was poor agreement (kappa = 0.25) between automated and manual identification of long QTc intervals (> or =440 milliseconds). CONCLUSIONS: These preliminary findings, occurring at doses low by current treatment standards, suggest that close electrocardiographic monitoring is warranted when prescribing ziprasidone to children, particularly at higher doses or when combined with other QTc-prolonging agents.     

Pediatric case report of quetiapine overdose and QTc prolongation.

BACKGROUND: Consideration of the risk of QTc interval prolongation associated with atypical antipsychotic administration is mounting, as this can lead to sudden cardiac death. METHODS: This is a case report of a 14-year-old boy with a history of major depressive disorder with psychotic features, post-traumatic stress disorder, oppositional defiant disorder, and polysubstance abuse who ingested 1900 mg of quetiapine. RESULTS: One and one half hours after ingestion, the QTc interval lengthened from 453 msec to 618 msec on the printout (manual calculation was 444 msec to 500 msec, respectively). On the baseline EKG, the QTc interval was 411 msec (manual calculation of 416 msec). CONCLUSION: This report presents an association between higher doses of quetiapine, resulting in higher serum levels and QTc interval prolongation. Also, this report demonstrates the importance of manually calculating the QTc interval to ensure accuracy of the measurement. A review of the literature revealed two case reports and a study where quetiapine was associated with an increase in QTc interval. Further studies are necessary to understand the relationship between higher doses of quetiapine, resulting in higher serum levels, and the propensity for QTc interval prolongation to ensure safe clinical use of this medication.     

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.     

High-dose ziprasidone-induced acute dystonia

There are few clinical data describing the relative risks of extrapyramidal symptoms (EPS) at higher doses of ziprasidone (i.e., greater than 160 mg/day) when compared to lower doses. We report on a patient who displayed no EPS with ziprasidone 160 mg/day for several months, but did display marked, acute dystonic reactions on ziprasidone 240 mg/day. The observations from the present case indicate that high-dose, ziprasidone-induced acute dystonia may occur even if no such side effects have been experienced at doses up to and including 160 mg/day.     

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.     

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.     

Effectiveness, tolerability, and safety of ziprasidone in patients with schizophrenia or schizoaffective disorder: results of a multi-centre observational trial.

PURPOSE: The ZEISIG study (Ziprasidone Experience in Schizophrenia in Germany/Austria) investigated the effectiveness of ziprasidone as measured by discontinuation rates and mean changes of the BPRS total. Secondary objectives included quality of life, subjective well-being, tolerability, and safety. SUBJECTS AND METHODS: Two hundred and seventy-six subjects with schizophrenia and schizoaffective disorder were treated within an open-label, 12-week, prospective, flexible-dose observational trial of ziprasidone (40-160 mg/day). Baseline and outcome assessments mainly included Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions Scale (CGI), Short-Form 12 (SF-12), and Subjective Well-being under Neuroleptic treatment (SWN-K). RESULTS: Study discontinuation due to any cause was evident in 58% of subjects, most of them within the first 4 weeks after study initiation. In study completers, ziprasidone was associated with improvements in BPRS total (44.8 to 33.6; p<0.001), CGI, SF-12, and SWN-K total scores (80.5 to 89.5). Ziprasidone was related to reduction of weight, fasting glucose, and serum lipids. No cardiovascular adverse event or significant increase of the QTc interval was observed. DISCUSSION AND CONCLUSION: Approximately 60% of subjects discontinued ziprasidone prematurely, probably related to an initial and overall underdose. The present study confirmed previous tolerability and safety data of ziprasidone as well as results of its effectiveness. Independent from reason to switch, previous antipsychotic class, and severity of illness at baseline, the recommended starting dose of 80 mg/day as well as the maximum treatment dose of 160 mg/day may not be sufficient for a selected subgroup of patients.     

Practical aspects of the use of ziprasidone in schizophrenia

Ziprasidone is an atypical antipsychotic with affinity to the D2, 5HT2A, 5HT2C, 5HT1A, 5HT1B/1D receptors. It is available in both oral and intramuscular forms. It is well absorbed from the digestive tract and its absorption increases after the meal. Ziprasidone is used for the treatment of schizophrenia and bipolar manic states in doses 40-80 mg administered twice a day. The i.m. form should be given 40 mg/day only during three days. Ziprasidone shows similar an efficacy toward the positive symptoms as olanzapine. The i.m. form of ziprasidone showed better efficacy toward psychotic symptoms and lower risk for extrapyramidal symptoms than haloperidol. It is well tolerated. The most frequent side-effects are somnolence, nausea, and dyspepsia. The risk for metabolic side-effects was low. In some patients treated with ziprasidone, the prolongation of the QTc was noted.     

Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death.

OBJECTIVE: The authors review the mechanisms and establish the risk of torsade de pointes and sudden death with antipsychotic drugs. METHOD: They present a review of original concepts, the distinction between familial and drug-induced cases of torsade de pointes, and the recognition of the role of noncardiac drugs in torsade de pointes and sudden death. They review the evidence linking QTc interval prolongation, potassium channels, and torsade de pointes from both the long QT syndrome and drugs. They examine the risk for torsade de pointes from antipsychotic drugs and estimate the frequency of sudden death on the basis of epidemiological data in normal and schizophrenic populations. RESULTS: All drugs that cause torsade de pointes prolong the QTc interval and bind to the potassium rectifier channel, but the relationships are not precise. Prediction of torsade de pointes and sudden death can be improved by examining dose dependency, the percent of QTc intervals higher than 500 msec, and the risk of drug-drug interactions. Although sudden unexpected death occurs almost twice as often in populations treated with antipsychotics as in normal populations, there are still only 10-15 such events in 10,000 person-years of observation. CONCLUSIONS: Although pimozide, sertindole, droperidol, and haloperidol have been documented to cause torsade de pointes and sudden death, the most marked risk is with thioridazine. There is no association with olanzapine, quetiapine, or risperidone. Ziprasidone does prolong the QT interval, but there is no evidence to suggest that this leads to torsade de pointes or sudden death. Only widespread use will prove if ziprasidone is entirely safe. To date, all antipsychotic drugs have the potential for serious adverse events. Balancing these risks with the positive effects of treatment poses a challenge for psychiatry.     

Ziprasidone in adolescents with autism: an open-label pilot study

INTRODUCTION: The antipsychotic drugs are the best-studied agents shown to reduce symptoms in autism, including hyperactivity, aggression, self-abusive behavior, temper tantrums, lability, irritability, social withdrawal, and stereotypical behaviors. However, significant weight gain has been associated with use of many atypical agents. Ziprasidone has been weight neutral in adult populations, but data from adolescents and patients with autism are sparse. However, ziprasidone administration has been associated with increases in the QTc. The purpose of this study was to collect pilot data on the efficacy and safety of ziprasidone in adolescents with autism, focusing on safety issues of weight gain and QTc. METHODS: Twelve adolescents with autism (mean age 14.5 +/- 1.8 years) were treated in a 6-week open pilot study. Ziprasidone dosage ranged from 20 to 160 mg/day (mean, 98.3 +/- 40.4 mg/day). The primary efficacy measure was the Clinical Global Impressions-Improvement item (CGI-I); other efficacy measures included the Aberrant Behavior Checklist and the Children's Psychiatric Rating Scale. RESULTS: Based on the CGI-I, 9 of 12 (75%) patients were treatment responders. Ziprasidone was weight neutral, and the QTc increased by a mean of 14.7 msec. Two subjects had acute dystonic reactions. Cholesterol decreased and prolactin remained the same. CONCLUSIONS: Ziprasidone shows promise as a treatment for adolescents with autism. More definitive trials are needed.     

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.     

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.     

QTc prolongation due to propranolol overdose

Prolongation of the QTc interval (a QT interval that has been corrected for heart rate) increases the risk of cardiac arrhythmias, and is an important topic with regard to psychotropic medication. Several typical (e.g., pimozide, thioridazine, haloperidol) and atypical (e.g., sertindole, ziprasidone) antipsychotics may cause QTc prolongation as well as some antidepressants in overdose (e.g., citalopram). We wish to present a case of QTc prolongation that was due to an overdose of propranolol (used in psychiatry for the treatment of akathisia, lithium-induced tremor, and performance anxiety; used in medicine for hypertension and congestive heart failure).     

Absence of cardiovascular adverse effects of sertraline in children and adolescents

OBJECTIVE: In a 12 week, placebo-controlled, parallel-design, multicenter study of sertraline for obsessive-compulsive disorder in 107 children and 80 adolescents, the authors prospectively assessed cardiovascular effects to doses of sertraline of < or = 200 mg/day. METHOD: Vital signs (blood pressure and heart rate) and electrocardiograph parameters (ECGs) were systematically evaluated at baseline and again throughout treatment. RESULTS: There were no clinically significant cardiovascular adverse events in any of the subjects enrolled in the study. Moreover, compared with baseline and placebo, sertraline treatment at an average dose of 167 mg did not result in any clinically meaningful changes in any ECG indices (PR, QRS, and QTc intervals), cardiac rhythm, blood pressure, or heart rate. CONCLUSIONS: These prospectively derived results support the cardiovascular safety of sertraline at doses up to 200 mg in children and adolescents.     

Correlation of QTc interval prolongation and serum level of citalopram after intoxication--a case report

Citalopram (CIT) is a widely used antidepressant which acts by a selective serotonin reuptake inhibition. It is considered to be safer than tricyclic antidepressants at therapeutic levels, but also with respect to intoxications. We report the case of a 46-year-old woman, who ingested in suicidal intention 1400?mg CIT. During the following inpatient treatment repeatedly ECGs and determinations of the serum level of CIT were performed. Initially the patient's serum level of CIT was 1231?ng/mL and QTc interval was 541.60?ms. It took 12 days until the serum level of CIT fell below the upper threshold of the recommended therapeutic range (130?ng/mL). The QTc interval on the sixth day after the intoxication for the first time was below 500?ms. The QTc interval correlated significantly with the serum level of CIT after intoxication (r=0.943; p<0.005). Although CIT is estimated as a safe antidepressant regarding serious adverse effects, toxic doses can lead to potentially hazardous ECG changes which according to our findings correlate strongly with the serum level of the drug.     

Effect of initial ziprasidone dose on length of therapy in schizophrenia

OBJECTIVE: To examine the effects of initial ziprasidone dose on discontinuation rates, using retrospective integrated medical and pharmacy claims data. METHODS: Patients > or = 18 years with a diagnosis of schizophrenia or schizoaffective disorder and a ziprasidone claim between March 2001 and February 2003 who were continuously enrolled for at least six months before and three months after initiation of ziprasidone were included. They were stratified by initial daily dose (> or = 40 and < 80 mg [low] vs. > or = 80 and < 120 mg [medium] vs. 120-160 mg [high]). The six-month risk of discontinuation was examined using Cox proportional hazards models controlling for gender, psychiatric comorbidities, and pre-ziprasidone utilization of antipsychotics (atypical, conventional, none). RESULTS: The mean age of the sample (n=1058) was 38 years; 42% were male. The six-month risk of discontinuation was significantly lower in patients in the high-dose group as compared to the low-dose group (HR=0.737 for high-dose vs. low-dose, 95% CI=0.581, 0.935; P=0.012) and trended towards significance when comparing high-dose and medium-dose groups (HR=0.857 for high-dose vs. medium-dose, 95% CI=0.694, 1.059; P=0.153). CONCLUSIONS: Patients initiating ziprasidone therapy with an initial dose of at least 120 mg/day had better medication adherence compared to those initiating at lower doses. These findings confirm results seen in clinical trials suggesting improved efficacy and tolerability at higher ziprasidone doses.