clozapine and Long-QT-Syndrome

Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel's recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings.. A consensus meeting including psychiatric and other medical experts assembled on October 17-18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached.. Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations.. The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants' belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Cataract; Clozapine; Diabetes Mellitus, Type 2; Health Status; Humans; Hyperlipidemias; Hyperprolactinemia; Long QT Syndrome; Monitoring, Physiologic; Myocarditis; Obesity; Practice Guidelines as Topic; Schizophrenia; Sexual Dysfunctions, Psychological; Weight Gain

The pharmacotherapy of schizophrenia remains an ongoing challenge for researchers and clinicians alike. Current medications remain suboptimal to effectively treat this illness despite the recent surge of what are considered to be better antipsychotics: the atypicals. The atypicals cause fewer extrapyramidal symptoms and tardive dyskinesia, but there is growing concern regarding the significant long-term metabolic and cardiac adverse effects of these novel antipsychotics. There are differences among the atypicals in their propensity to produce these adverse effects, and clinicians should weigh the risk-benefit ratio for each drug with each individual patient. Diabetes, heart disease, obesity, and unhealthy lifestyle choices are on the rise in the general population, and individuals with chronic schizophrenia are even more at risk. The dilemma clinicians face in trying to avoid the neurological morbidity of the typicals (extrapyramidal side effects and tardive dyskinesia) is the risk of consequently exposing patients to both the morbidity and potential mortality of the atypicals (cardiovascular, endocrine, and metabolic adverse effects). The importance of baseline investigations and monitoring at regular intervals as well as identification of patients at risk for obesity, diabetes, and cardiovascular morbidity has become crucial. Informed decision making is essential for successful antipsychotic pharmacotherapy. For a condition, which often necessitates long-term pharmacotherapy, the importance of prevention and (or) minimization of morbidity and mortality related to adverse effects of such pharmacotherapy cannot be understated.

Topics: Antipsychotic Agents; Chlorpromazine; Clozapine; Diabetes Mellitus; Humans; Hyperlipidemias; Long QT Syndrome; Myocarditis; Schizophrenia; Torsades de Pointes

Patients suffering from schizophrenic psychoses sometimes insufficiently respond to antipsychotic monotherapy and then combination approaches are preferred. We aimed in validating the add-on of ziprasidone and risperidone to clozapine, and we performed a randomised head-to-head trial. Patients with partial response to clozapine were randomly attributed to augmentation with ziprasidone (n = 12) or risperidone (n = 12). Efficacy assessments included the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), the Hamilton Depression Scale (HAMD), the Clinical Global Impression (CGI) and the Global Assessment of Functioning (GAF). Furthermore, several safety and tolerability measures were obtained. After six weeks, both groups showed significant reductions of positive and negative symptoms. In addition, affective state, psychosocial functioning and clozapine side effects improved without significant differences between the groups. Both approaches were well tolerated. However, the ziprasidone group experienced a small elongation of the QTc interval and a reduction of extrapyramidal symptoms. Patients under clozapine-risperidone therapy developed a rise of serum prolactin levels. The clozapine augmentation with ziprasidone or risperidone resulted in significant psychopathological improvements. The side effects differed between the treatment groups. Further head-to-head comparisons of atypical antipsychotics as add-on to clozapine are necessary.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Female; Humans; Long QT Syndrome; Male; Middle Aged; Piperazines; Prolactin; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Thiazoles; Treatment Outcome; Young Adult

Many drugs have been associated with QTc prolongation and, in some cases, this is augmented by concomitant administration with metabolic inhibitors. The effects of 6 antipsychotics on the QTc interval at and around the time of estimated peak plasma/serum concentrations in the absence and presence of metabolic inhibition were characterized in a prospective, randomized study in which patients with psychotic disorders reached steady-state on either haloperidol 15 mg/d (n = 27), thioridazine 300 mg/d (n = 30), ziprasidone 160 mg/d (n = 31), quetiapine 750 mg/d (n = 27), olanzapine 20 mg/d (n = 24), or risperidone 6-8 mg/d increased to 16 mg/d (n = 25/20). Electrocardiograms (ECGs) were done at estimated Cmax at steady-state on both antipsychotic monotherapy and after concomitant administration of appropriate cytochrome P-450 (CYP450) inhibitor(s). Mean QTc intervals did not exceed 500 milliseconds in any patient taking any of the antipsychotics studied, in the absence or presence of metabolic inhibition. The mean QTc interval change was greatest in the thioridazine group, both in the presence and absence of metabolic inhibition. The presence of metabolic inhibition did not significantly augment QTc prolongation associated with any agent. Each of the antipsychotics studied was associated with measurable QTc prolongation at steady-state peak plasma concentrations, which was not augmented by metabolic inhibition. The theoretical risk of cardiotoxicity associated with QTc prolongation should be balanced against the substantial clinical benefits associated with atypical antipsychotics and the likelihood of other toxicities.

Topics: Adolescent; Adult; Antipsychotic Agents; Aryl Hydrocarbon Hydroxylases; Benzodiazepines; Biotransformation; Clozapine; Dibenzothiazepines; Electrocardiography; Female; Haloperidol; Heart Conduction System; Humans; Long QT Syndrome; Male; Middle Aged; Olanzapine; Quetiapine Fumarate; Risperidone; Thioridazine

Topics: Clozapine; COVID-19 Drug Treatment; Humans; Hydroxychloroquine; Long QT Syndrome

Topics: Antidotes; Clozapine; Emulsions; Humans; Lipids; Long QT Syndrome

Topics: Antipsychotic Agents; Clozapine; Electrocardiography; Heart Rate; Humans; Long QT Syndrome; Male; Middle Aged; Schizophrenia

Topics: Clozapine; Drug Monitoring; Electrocardiography; Female; Heart Rate; Humans; Long QT Syndrome; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance; Electrocardiography; Heart Rate; Humans; Long QT Syndrome; Pharmacovigilance; Schizophrenia

Numerous structurally unrelated drugs, including antipsychotics, can prolong QT interval and trigger the acquired long QT syndrome (aLQTS). All of them are thought to act at the level of KCNH2, a subunit of the potassium channel. Although the QT-prolonging drugs are proscribed in the subjects with aLQTS, the individual response to diverse QT-prolonging drugs may vary substantially.. We report here a case of aLQTS in response to small doses of risperidone that was confirmed at three independent drug challenges in the absence of other QT-prolonging drugs. On the other hand, the patient did not respond with QT prolongation to some other antipsychotics. In particular, the administration of clozapine, known to be associated with higher QT-prolongation risk than risperidone, had no effect on QT-length. A detailed genetic analysis revealed no mutations or polymorphisms in KCNH2, KCNE1, KCNE2, SCN5A and KCNQ1 genes.. Our observation suggests that some patients may display a selective aLQTS to a single antipsychotic, without a potassium channel-related genetic substrate. Contrasting with the idea of a common target of the aLQTS-triggerring drugs, our data suggests existence of an alternative target protein, which unlike the KCNH2 would be drug-selective.

Topics: Adult; Antipsychotic Agents; Clozapine; Electrocardiography; Female; Humans; Long QT Syndrome; Potassium Channels; Risperidone; Schizophrenia

The most feared cardiological consequence of clozapine is sudden cardiac death. A potential marker of it is QTc interval (QTc) prolongation. This study aimed to determine the prevalence of QTc prolongation in patients before and after 18 weeks of clozapine treatment and to detect predictors of QTc prolongation.. Patients undergoing treatment with clozapine who had been given an electrocardiogram prior to the treatment and had their electrocardiogram, serum clozapine and norclozapine levels taken on the 18th week were selected. Exclusion criteria were thioridazine, pimozide, diuretics or beta-blocker treatment, electrolytic alteration, heart diseases and substance misuse diagnosis. Prolonged QTc was defined as >450 ms in men and >470 ms in women.. No significant differences were detected in prevalence of prolonged QTc or mean QTc before and after 18 weeks of clozapine treatment (p = 0.15, p = 0.32, respectively). Age, heart rate at 18th week and QTc prior to clozapine treatment had significant effects on QTc at follow-up. Prolonged QTc during previous treatment and heart rate >95 beats/min at 18 weeks were found to be predictors of QTc prolongation.. No significant differences were detected in prevalence of QTc prolongation or mean QTc among patients before and after 18 weeks on clozapine.

Topics: Adolescent; Adult; Age Factors; Antipsychotic Agents; Clozapine; Electrocardiography; Female; Follow-Up Studies; Heart Rate; Humans; Long QT Syndrome; Male; Middle Aged; Prevalence; Retrospective Studies; Risk Factors; Young Adult

Topics: Clozapine; Female; Humans; Long QT Syndrome; Middle Aged

Mortality in schizophrenic patients is clearly higher than in the general population. One of the reasons is the higher prevalence of the lethal side-effects of antipsychotics: diabetic ketoacidosis, prolonged qt-c time and gastro-intestinal hypomotility associated with clozapine are three serious side-effects which sometimes prove fatal. Systematic screening, however, means that sideeffects can be diagnosed at an earlier, less severe stage, leading to higher rates of survival and remission. This should contribute to a normalising of the mortality rate.

Topics: Antipsychotic Agents; Clozapine; Diabetic Ketoacidosis; Gastrointestinal Motility; Humans; Long QT Syndrome; Risk Assessment; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Humans; Long QT Syndrome; Male; Middle Aged; Schizophrenia, Paranoid

Topics: Aged; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Electrocardiography; Female; Humans; Long QT Syndrome; Psychotic Disorders; Quetiapine Fumarate; Ventricular Premature Complexes

In this paper, we present a pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K(+) channel blockers. The blockade of HERG K(+) channels is one of the most important molecular mechanisms through which QT-prolonging drugs increase cardiac action potential duration. Since QT prolongation is one of the most undesirable side effects of drugs, we first tried to identify the minimum set of molecular features responsible for this action and then we attempted to develop a quantitative model correlating the 3D stereoelectronic characteristics of the molecules with their HERG blocking potency. Having considered an initial set of 31 QT-prolonging drugs for which the HERG K(+) channel blocking activity was measured on mammalian transfected cells, we started the construction of a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. This in silico tool might be useful in the design of new drug candidates devoid of the physicochemical features likely to cause the above-mentioned side effect.

Topics: Anti-Arrhythmia Agents; Cation Transport Proteins; Cluster Analysis; Databases, Factual; Ether-A-Go-Go Potassium Channels; Long QT Syndrome; Models, Molecular; Molecular Conformation; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Quantitative Structure-Activity Relationship

Topics: Animals; Antipsychotic Agents; CHO Cells; Clozapine; Cricetinae; Death, Sudden, Cardiac; Humans; Long QT Syndrome