Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A case is presented of Torsade de Pointes (TDP) with T wave alternans in a 31-year-old female receiving a moderate dose of chlorpromazine. She was treated in an another hospital for schizophrenia with chlorpromazine (100 mg daily) for several years and admitted to Fujisawa city hospital for numerous episodes of syncope. The electrocardiogram immediately after admission revealed a marked QTc prolongation to 0.81 seconds, T wave alternation without any obvious change in morphology of the QRS complex, and recurrent ventricular tachycardia called TDP. The T wave alternans and TDP were easily abolished by intravenous administration of a bolus of 50 mg lidocaine infusion. The QT interval however, remained prolonged. Physical examination, including cardiac examination, was normal. Serum potassium was 3.6/mEq. Chlorpromazine was discontinued immediately after admission and no further episodes of TDP were seen after the first day. After the QT interval returned to almost normal, chlorpromazine (50 mg daily) was re-administered. Two days after the re-administration, the electrocardiogram revealed marked QT interval prolongation with prominent T waves. Psychotropic drugs, such as chlorpromazine, prolong the QT interval and cause TDP. Chlorpromazine appears to have been responsible for TDP and the T wave alternans in this case. TDP caused by a moderate dose of chlorpromazine has not been previously reported. Lone T wave alternans unaccompanied by changes in the QRS complex is a rare phenomenon and the mechanism underlying T wave alternans remains unknown.
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PMID:[Torsade de Pointes with T wave alternans in a patient receiving moderate dose of chlorpromazine: report of a case]. 221 93

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.
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PMID:Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. 1123 51

Many antipsychotics are used to treat disorders other than schizophrenia, such as bipolar disorder. However, some of these agents are associated with cardiovascular side effects that can have serious or fatal implications for the patient. One dangerous side effect is QT prolongation, which can lead to torsades de pointes and ventricular arrhythmia. The group of drugs labeled as antipsychotics is diverse, making it challenging for the clinician to keep track of which agents cause which effects and important for the clinician to learn to identify signs of cardiovascular side effects and manage those events when they occur.
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PMID:Cardiovascular effects of antipsychotics used in bipolar illness. 1191 71

Many psychotropic medications might cause prolongation of the QTc interval; however, antipsychotics have recently come under increasing scrutiny in this regard. Ziprasidone, a newly marketed second-generation antipsychotic, was initially delayed in approval by the FDA due to its propensity to prolong the QTc interval in patients with schizophrenia. While ziprasidone does prolong the QTc interval, safety, concomitant medication, and overdose data present little reason to consider ziprasidone a major risk factor for Torsades de Pointes thus far. The paucity of data regarding this agent, however, and its use in those with additional risk factors for QTc-interval prolongation are striking. The risk for this phenomenon has not been studied in patients with concomitant disease states that might be associated with QTc-interval prolongation or in those taking metabolic inhibitors which might inhibit aldehyde oxidase. Little is known about a major metabolic route of ziprasidone, oxidation by aldehyde oxidase. Finally, experience with other agents associated with QTc-interval prolongation raises the possibility that both the type and number of individuals studied to date might not be sufficient to reveal problems with ziprasidone. This paper will review the literature concerning real and theoretical implications of pharmacokinetic and pharmacodynamic interactions with ziprasidone, particularly with regard to these effects on the QTc interval.
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PMID:Ziprasidone and the QTc interval: pharmacokinetic and pharmacodynamic considerations. 1239 57

Schizophrenia is one of the most debilitating mental illnesses, complicated by an increased incidence of suicide amongst patients compared with the general population. A recent report has also demonstrated a 33% increase in -relative risk of death associated with circulatory disease, indicating that the latter may be a more critical factor than either suicide or accidental death in this population. Indeed, the average life expectancy of a person with schizophrenia is currently approximately a decade less than that of the general population. Additionally, it has been shown that in over 50% of people with schizophrenia, there is a reduction in their chance of reaching psychosocial goals. Since the arrival of the first antipsychotic drugs in the middle of the last century, the outlook for patients with schizophrenia has improved markedly. In particular, the introduction of the new generation (atypical) class of antipsychotic agents in the 1980s and 90s has resulted in a significant reduction in the incidence of violent and aggressive episodes in treated patients. A better side-effect profile of these drugs, especially reduced extra pyramidal symptoms (EPS), has resulted in improved patient outcomes and the possibility of good long-term control of the disorder. However, while the introduction of antipsychotic agents has undoubtedly revolutionised the prognosis for patients with schizophrenia, these medications are not without their own problems. One of the concerns to emerge over the last fifteen years is unpredictable, sudden and unexplained death in patients taking antipsychotic drugs. The cause of sudden death in this population is controversial and the role of drugs is not clear. People with schizophrenia also appear to be at higher risk of cardiovascular disease compared with the general population. Many factors may play a role in this including a higher prevalence of smoking, poorer diet, more sedentary lifestyle and a greater likelihood of alcoholism and substance abuse. However, it is possible that the impact of adverse effects on the cardiovascular system related to certain antipsychotic drug use may well increase the prevalence of mortality and morbidity due to cardiovascular events and may also play a significant role in the reduced life expectancy of the patient with schizophrenia. The range of mechanisms whereby antipsychotic drugs can influence cardiovascular function is very broad and includes: receptor blockade; conduction disturbance (eg bundle branch block); delayed ventricular repolarisation (prolonged QTc interval); left ventricular dysfunction; sinus node abnormalities; myocarditis; postural hypotension; polydipsia-hyponatremia syndrome; weight gain; glucose intolerance. Of these, QTc interval prolongation, with the risk of progression to the potentially fatal ventricular tachyarrhythmia Torsades de Pointes (TdP), is of particular concern as this arrhythmia is unpredictable and difficult to manage. Coupled with these clinical concerns are regulatory issues regarding several compounds that have received warnings or been withdrawn from the market. Recently, there has been no clear guidance for psychiatrists regarding QTc interval prolongation and TdP. This document seeks: 1) to explore drug-induced ventricular arrhythmias with particular emphasis on QTc interval prolongation as a warning of increased vulnerability, 2) to provide guidelines on the therapeutic management of the patient with schizophrenia to minimize the risk of iatrogenic cardiotoxicity. Several guidance documents have previously been published in this area including the report published by the UK Working Group of the Royal College of Psychiatrists' Psychopharmacology Sub-Group in 1997, and the policy document on the potential for QTc prolongation and proarrhythmia by non-antiarrhythmic drugs published in June 1999 under the auspices of the European Society of Cardiology. This document seeks to supplement currently published guidelines.
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PMID:[Minimizing the risks associated with QTc prolongation in people with schizophrenia. A consensus statement by the Cardiac Safety in Schizophrenia Group]. 1250 68

Ziprasidone is a second-generation antipsychotic that received Food and Drug Administration approval in February 2001. It has a unique receptor profile that includes high-affinity antagonist activity at dopamine D2 receptors, inverse agonist activity at serotonin (5-HT)2A receptors, agonist activity at 5-HTlA receptors, and a relatively high affinity for the serotonin and norepinephrine transporters. The 5-HTIA affinity, together with the inhibitory effect on mono-amine reuptake, may underlie the hypothesized beneficial effects on comorbid affective and cognitive abnormalities in schizophrenia and schizoaffective disorder. The short-term efficacy of ziprasidone for core positive symptoms of schizophrenia appears to be comparable to other conventional and atypical antipsychotics. The short-term efficacy of ziprasidone in acute mania has been established based on two 3-week, double-blind, placebo-controlled trials.Open-label treatment for up to 52 weeks confirms the sustained efficacy and safety of ziprasidone in bipolar disorder. Maintenance studies in schizophrenia and schizoaffective disorder indicate that long-term ziprasidone therapy is effective in preventing relapse, while maintaining cognitive and psychosocial benefits. The safety database suggests that the overall cardiovascular and cerebrovascular risk associated with ziprasidone is lower than with other atypicals, with notably lower risk of drug-related increases in weight, glucose, or lipids. The data also suggest a modestly increased risk of QTc prolongation that is not dose related or linked to torsades de pointes. Switching to ziprasidone from other atypicals appears to improve both clinical symptoms and metabolic parameters, though more studies are needed to fully characterize these benefits. This monograph summarizes the efficacy, tolerability, and safety of oral ziprasidone in the treatment of schizophrenia, schizoaffective disorder, and bipolar mania.
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PMID:From clinical research to clinical practice: a 4-year review of ziprasidone. 1638 Oct 88

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.
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PMID:Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia. 1852 Oct 91

Amisulpride is an atypical antipsychotic agent effective in the treatment of schizophrenia. There are few cases in the literature relating to the toxicity of this agent and reported fatalities are rare. Drug induced prolongation of the QT interval of the electrocardiograph (ECG) is increasingly recognised with various classes of drugs and in particular with antipsychotics. Cardiotoxicity can manifest as ventricular tachyarrhythmia, including torsades de pointes (TdP), complicating QT prolongation. We report a case of fatal amisulpride toxicity where the post-mortem blood concentration was 48 mg/L. Hitherto under-recognised toxic effects of novel chemotherapeutic agents can pose challenges for the forensic pathologist charged with performing medico-legal autopsies in cases of sudden unexpected death in young adults and particularly in those with schizophrenia. A knowledge of the ability of antipsychotic agents to induce fatal cardiac arrhythmias should inform the approach to the autopsy (including determination of the cause and mechanism of death) in such cases, as should an appreciation of the dangers inherent in the interpretation of post-mortem toxicology.
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PMID:Fatality due to amisulpride toxicity: a case report. 1853 80

Medical illnesses are particularly common in patients who have schizophrenia and one of the major tasks for consultation-liaison psychiatrists, and others, is to determine which medications are safest in which co-morbid condition. The authors review the relative risks for various antipsychotics, especially focusing on cardiovascular, pulmonary, and gastrointestinal co-morbid illnesses. The authors further review the atypical antipsychotics' cardiovascular risks, especially for prolonging QT intervals, in trying to avoid the risk for torsades de pointes. The relative risk for anticholinergic actions for these medicines is also reviewed, as this is especially important in the medically ill or elderly. The authors also review the relative safety of antipsychotics in patients who have liver disease and pulmonary disease. Finally, the authors review specific drug interactions that may be problematic when treating the medically ill with atypical antipsychotics.
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PMID:Management of schizophrenia with medical disorders: cardiovascular, pulmonary, and gastrointestinal. 1994 82

Drug safety of atypical antipsychotics is important due to the increasing mortality gap between patients with schizophrenia and the general population. This editorial discusses the safety evaluation of ziprasidone with a focus on the risk of the potentially fatal cardiac arrhythmia, torsades de pointes (TdP). The exact incidence of antipsychotic-induced TdP remains unknown because capturing TdP warrants continuous monitoring and tens of thousands of patient-years due to the rarity of TdP. For this reason, surrogate markers such as the QTc interval are used despite their limitations. New surrogate markers Tpeak-Tend and T-wave morphology have seen the light of day but their validity remain unknown. Large pragmatic trials have been conducted, but their contributions to drug safety evaluations are controversial. Finally, psychiatrists should have in mind that safety evaluation should include more than the risk of TdP. Some atypical antipsychotics are associated with life-shortening side effects, such as severe weight gain and type 2 diabetes, which may contribute more to the overall mortality than TdP. In addition to this, suboptimal treatment may result in life-shortening behaviors such as suicide. A shared decision including a thorough discussion of risks and benefits with the patients is essential.
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PMID:The safety of atypical antipsychotics: does QTc provide all the answers? 2150 86


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