Sertindole Treatment Research Articles

Recognition of high-specificity hERG K+ channel inhibitor-induced arrhythmia in cardiomyocytes by automated template matching

Cardiovascular disease (CVD) is the number one cause of death in humans. Arrhythmia induced by gene mutations, heart disease, or hERG K+ channel inhibitors is a serious CVD that can lead to sudden death or heart failure. Conventional cardiomyocyte-based biosensors can record extracellular potentials and mechanical beating signals. However, parameter extraction and examination by the naked eye are the traditional methods for analyzing arrhythmic beats, and it is difficult to achieve automated and efficient arrhythmic recognition with these methods. In this work, we developed a unique automated template matching (ATM) cardiomyocyte beating model to achieve arrhythmic recognition at the single beat level with an interdigitated electrode impedance detection system. The ATM model was established based on a rhythmic template with a data length that was dynamically adjusted to match the data length of the target beat by spline interpolation. The performance of the ATM model under long-term astemizole, droperidol, and sertindole treatment at different doses was determined. The results indicated that the ATM model based on a random rhythmic template of a signal segment obtained after astemizole treatment presented a higher recognition accuracy (100% for astemizole treatment and 99.14% for droperidol and sertindole treatment) than the ATM model based on arrhythmic multitemplates. We believe this highly specific ATM method based on a cardiomyocyte beating model has the potential to be used for arrhythmia screening in the fields of cardiology and pharmacology.

Sertindole in the long-term treatment of schizophrenia

This study assessed the safety and tolerability of sertindole in the long-term treatment of schizophrenia. An open-label, noncomparative, flexible-dose study was carried out in 11 European countries. Upon completion of an 8-week, haloperidol-referenced randomized clinical trial with sertindole, patients were offered sertindole maintenance treatment up to 18 months. In total, 294 patients were enrolled, of whom 237 (81%) had received sertindole and 57 (19%) had received haloperidol in the lead-in trial. The modal dose during the maintenance period was 16 mg/day. Patients showed therapeutic improvement indicated by significant decreases in the Positive And Negative Syndrome Scale and Clinical Global Impression 'severity-of-illness' scores. An adverse event was the primary reason for withdrawal in 13% of patients. The most common adverse events were fatigue and weight gain, both with incidences of 14%. The incidence of extrapyramidal symptoms was 18%, and 11% of the patients required anticholinergic medication. No statistically significant changes were observed in laboratory values or vital signs, but the mean serum prolactin levels decreased. The mean change in weight from baseline to the last assessment was 2.7 kg. The largest weight increase was observed in patients who were underweight at baseline. Long-term treatment with sertindole was safe and well tolerated, and patients showed clinical improvement beyond acute treatment.

The efficacy and safety of 12 weeks of treatment with sertindole or olanzapine in patients with chronic schizophrenia who did not respond successfully to their previous treatments

The aim of this study was to evaluate the efficacy, safety, and tolerability of sertindole in comparison with olanzapine in patients with chronic schizophrenia who did not respond successfully to their previous treatments. Patients with schizophrenia who were at least moderately ill and had failed to respond to previous antipsychotic treatment were randomized to double-blind sertindole or olanzapine treatment. A total of 389 patients were treated, 196 with sertindole (mean dose=17 mg/day) and 193 with olanzapine (mean dose=16 mg/day). Both drugs improved all the efficacy scale scores including the Positive and Negative Syndrome Scale total score. Although sertindole failed to prove noninferiority to olanzapine in terms of reduction in PANSS total score with the last-observation-carried-forward analysis, this can be attributed to the higher withdrawal rate in the sertindole group by day 16 by which sertindole was up-titrated to the effective dose. On excluding early withdrawals, the noninferiority criterion was fulfilled, as also in the observed-case analysis. They had similar safety profiles with respect to the total incidence of adverse events. The incidence of asymptomatic QT prolongation was higher in the sertindole group. Sertindole has an efficacy and safety profile that is comparable to that of olanzapine. The slow titration schedule and lack of sedating effect of sertindole should be considered when initiating treatment with this drug.

Sertindole, a Potent Antagonist at Dopamine D<sub>2</sub> Receptors, Induces Autophagy by Increasing Reactive Oxygen Species in SH-SY5Y Neuroblastoma Cells

Autophagy is associated with cell survival and cell death. Autophagy is implicated in the pathophysiology of various human diseases. In order to identify autophagy regulatory molecules, we screened a chemical drug library in SH-SY5Y cells and selected Sertindole as a potent autophagy inducer. Sertindole was developed as an antipsychotic drug for Schizophrenia. Sertindole treatment highly induced the formation of autophagosomes as well as LC3 conversion. Subsequently, Sertindole-induced autophagy was efficiently suppressed by down regulation of ATG5. Sertindole also increased reactive oxygen species (ROS) production, which contributes to autophagy-associated cell death in neuroblastoma cells. ROS scavengers such as N-acetylcysteine and Trolox suppressed not only ROS generation but also autophagy activation by Sertindole. These results suggest Sertindole induces autophagy and autophagy-associated cell death by ROS production in neuroblastoma cells.

Sertindole and impaired atrioventricular function, in the absence of Q–T prolongation: A case report

SERTINDOLE IS AN atypical antipsychotic agent with high-affinity and concomitant moderate-potency blocking effect to the rapid component of the human cardiac delayed rectifier potassium current (IKr),1 encoded by the human Ether-à-go-go-related (hERG) gene. This property underlies the prolongation of the Q–T interval observed during sertindole administration and may cause life-threatening ventricular arrhythmias. We report the case of a 52-year-old male patient who was diagnosed with schizophrenia and was treated with antipsychotic medication from the age of approximately 40 years old, and who was recently started on sertindole. Sertindole was initiated following serious tardive dyskinesia (TD) caused by his previous medication (quetiapine). After 6 weeks of sertindole treatment (16 mg/day), TD remitted and improvement in his psychotic symptoms was observed. The electrocardiograms (ECG) showed normal Q–T intervals (baseline ECG, QTc = 400 msec; heart rate [HR], 70/min; PR, 180 msec; second ECG [2 weeks later following 8 mg/day of sertindole], QTc = 424 msec; HR, 105/min; PR, 180 msec; third ECG [3 weeks later following 16 mg/day of sertindole], QTc = 413 msec; HR, 100/min; PR, 180 msec; and fourth ECG without further changes). Six months following the initiation of sertindole the patient reported five syncopal episodes without clear prodromal symptoms. The patient recalled two sporadic syncopal episodes in his mid 20s. Electroencephalography (EEG) and brain computed tomography were carried out and were within normal limits. Non-interventional cardiological investigation (echocardiography, stress-test, Holter ECG and head-up tilting test) were normal. During the tilting test, blood pressure changed from 135/75 mmHg (baseline) to 130/68 mmHg immediately after tilting, ruling out orthostatic hypotension. Throughout the test, blood pressure and HR range were 15 mmHg and 10 beats per minute, respectively, ruling out vasovagal syncope. Electrophysiological study was negative for sinus node dysfunction and ventricular arrhythmogenesis, but documented an abnormal atrioventricular conduction: (i) H–V interval of 72 (normal values: 35–55 msec); and (ii) Wenckebach point of atrioventricular conduction at an atrial pacing cycle length of 490 msec. Two weeks after the discontinuation of sertindole, H–V was not shortened (70 msec) and based on the current indications for pacemaker implantation and considering the co-morbid psychiatric disease, a pacemaker was implanted and the patient has remained free of symptoms. Since the recurrent syncopal episodes coincided with sertindole administration, sertindole was implicated as a possible triggering factor, unmasking a subclinical defect in the conduction system. This may be attributed to the effect of sertindole on (i) the IKr current and its predominance in the atrioventricular conduction;2 and (ii) the Purkinje fibers.3 Clinicians should be aware of this possible effect of the drug.

The effect of sertindole on QTD and TPTE

Recent research suggests that other surrogate markers than QTc, including QTc dispersion and Tpeak-Tend, may better correlate with cardiac arrhythmia risk. While sertindole significantly prolongs the QTc interval, the effects on other markers of arrhythmia risk, such as QTc dispersion and Tpeak-Tend are unknown. Digital 12-lead ECG was recorded at baseline and at steady-state in 37 patients switched to sertindole. ECG was analysed for Fridericia-corrected QT duration (QTcF), QT dispersion and Tpeak-Tend. From a baseline QTcF of 407 +/- 22 ms, mean QTcF prolongation during sertindole treatment was 20 +/- 23 ms, P < 0.01. No effect on QTc dispersion was found (-1 +/- 11 ms; P = 0.41). No increased duration of the Tpeak-Tend interval from baseline was found (+7 +/- 21 ms; P = 0.05). These findings might be related to the absence of confirmed Torsade de Pointes (TdP) cases related to sertindole exposure, despite sertindole's QTc prolonging effects.

Sertindole causes distinct electrocardiographic T-wave morphology changes

Sertindole's propensity to prolong the QT interval relates to blockade of the KCNH2 (HERG) encoded Ikr potassium channel, but there has been limited detailed data on T-wave morphology changes. Digital 12-lead ECG was recorded at baseline and at steady-state in 37 patients switched to sertindole. ECG was analyzed for quantitative T-wave morphology changes and Fridericia-corrected QT duration (QTcF). Prominent T-wave morphology changes occurred during sertindole treatment and in some cases without concomitant prolongation of the QTcF interval. Four patients developed notched T-waves during sertindole treatment. Mean QTc prolongation was 19 ms. The mean effect size was higher for T-wave morphology combination score (MCS) (ES=1.92; 95% CI: 1.35-2.49) compared to the mean effect size for QTcF (ES=0.88; 95% CI: 0.52-1.24). The use of T-wave morphology analysis may become clinically relevant, particularly if shown to be associated with drug-induced arrhythmia risk.

P.8.a.032 ECG changes during sertindole treatment

P.8.a.032 ECG changes during sertindole treatment

The Sertindole Cohort Prospective (SCoP) study: rationale, design and methodology

To describe the rationale and methodology of the Sertindole Cohort Prospective (SCoP) study. The SCoP study was a prospective, randomized, partially blinded, active-controlled, multinational trial. It was designed to assess the safety of the antipsychotic sertindole in the treatment of schizophrenia under normal conditions of use. Risperidone, a widely used antipsychotic, not associated with major safety concerns, served as comparator drug. Inclusion criteria were deliberately broad in order to ensure high external validity, but patients had to be eligible for treatment with both drugs. The first primary endpoint was all-cause mortality, a measure highly resistant to bias, and the second was hospitalization with arrhythmia. Secondary endpoints comprised cause-specific fatal events, hospitalizations, suicide attempts and treatment duration. An Independent Safety Committee (ISC) classified the events using blinded data and provided advice to an Independent Management Committee (IMC) that was overseeing the trial. It was calculated that 3800 person years of exposure were needed in each treatment arm to obtain a power of 80%. This makes the SCoP study one of the largest post-authorization trials ever conducted in schizophrenia research. This report describes the design of the study, its rationale and the methods used. Naturalistic estimates of drug safety constitute essential information when prescribing antipsychotic medication. In the SCoP study, data were collected prospectively in a randomized, controlled manner and under normal conditions of use. Such a design ensured the high quality of data needed to adequately evaluate the 'real-world' safety of sertindole treatment.

Evaluation of patients on sertindole treatment after failure of other antipsychotics: A retrospective analysis

BackgroundUse of the atypical antipsychotic sertindole was suspended for four years due to safety concerns. During the suspension, the regulatory authorities required further studies, including this one, to be conducted. The purpose of this study was to determine if a subset of patients with psychotic illness exists which particularly benefits from sertindole treatment after failure of other antipsychotic drugs, including atypical antipsychotics.MethodsThis was a retrospective single-arm observational crossover study of 344 patients, who served as their own controls. Patients mainly from the Sertindole Safety Study who had shown good response to sertindole, and who had followed up to four alternating six month periods of treatment with sertindole and other antipsychotics, were included. (In Period 1 patients took non-sertindole treatment, in Period 2, sertindole was taken, in Period 3, patients reverted to non-sertindole treatment, and in Period 4, sertindole was taken again.) Patient records for each period of treatment were assessed for objective data: number and duration of hospitalizations due to worsening of psychotic symptoms; the amount of self-harming behaviour; indicators of social status. Retrospective evaluation of changes in clinical symptoms from the patients' records was also conducted. Dates and reasons for stopping and/or switching medication were also recorded.ResultsThere was improvement in all objective measured parameters during the periods of sertindole treatment. In particular, the average number of hospitalizations per year due to worsening of psychotic symptoms was reduced in the following way in the group studied over four treatment periods: Period 1 (non-sertindole treatment) 3.4; Period 2 (sertindole treatment) 1.0; Period 3 (non-sertindole treatment) 2.0; Period 4 (sertindole treatment) 1.8. The duration of hospitalizations also decreased significantly during the periods of sertindole treatment. Results showed that patients improved in objective social parameters when switched to sertindole treatment; assessment of the patients' affective lives showed a significant increase in the number of patients having a stable relationship during sertindole treatment; and assessment of the number of patients employed showed an increase after the first and second switch to sertindole treatment (from Period 1 to Period 2 and from Period 3 to Period 4, respectively).Adverse events and lack of efficacy were the main reasons for switching to sertindole.ConclusionA group of patients benefited from sertindole after other antipsychotic treatments, including that with atypical antipsychotics, had failed. Further studies are needed to investigate if there is a specific patient profile that corresponds to these responders.

Biases affecting the proportional reporting ratio (PRR) in spontaneous reports pharmacovigilance databases: the example of sertindole

Automated measures of reporting disproportionality in databases of spontaneous reports of adverse drug reactions are an emerging tool to identify drug-related alerts. Sertindole, a new atypical neuroleptic known to prolong the QT interval, was suspended in November 1998 because the proportion of reports of fatal reactions suggesting arrhythmia among all reports with sertindole was almost ten times higher than that for other atypical neuroleptics in the UK. This excess risk was not predicted in preclinical data and had not been found in premarketing trials. Reporting patterns over time were analysed. Prescription Event Monitoring (PEM) studies and a large retrospective cohort allowed for the comparison of actual death rates with atypical neuroleptics, and to assess which proportion of the deaths that occurred were reported. There were indications of possible skewing of reporting related to notoriety, surveillance and market size effects. Death rates in PEM studies were essentially similar between sertindole and other neuroleptics. Cardiac deaths had been two to three times more often reported than other causes of death. Proportional reporting ratios indicate differential reporting of possible reactions, not necessarily differential occurrence. There was no indication of an actual increase of risk of all causes or cardiac deaths during sertindole treatment, but only an increased risk of its being reported. The suspension of sertindole was rescinded by Committee on Proprietary Medicinal Products (CPMP) in October 2001.

Sertindole treatment does not increase mortality in schizophrenics-marketing suspension lifted

Sertindole treatment does not increase mortality in schizophrenics-marketing suspension lifted

Efficacy, cardiac safety and tolerability of sertindole: a drug surveillance.

Sertindole is a novel atypical antipsychotic, which has shown efficacy in the treatment of positive and negative symptoms of schizophrenia in phase II and III studies. Furthermore, these studies have demonstrated tolerability and a favourable side-effect profile. In contrast to classical antipsychotics, sertindole was not associated with extrapyramidal symptoms (EPS). We report drug surveillance data in 34 comorbid and comedicated sertindole treated patients suffering from different psychotic disorders. The drug surveillance consisted of two distinct phases: inpatient treatment and outpatient follow-up. Clinical global impression (severity and improvement of illness), psychotic symptoms, side-effects, and blood parameters have been carefully documented. With special respect to cardiac safety electrocardiograms (ECGs) have been recorded twice (during sertindole treatment and during treatment with an antipsychotic different from sertindole). Recommended ECG-parameters for assessment of the proarrhythmic risk of a drug have been calculated (QTc-, QTc2-interval; QT-, QTc-dispersion). The majority of patients (n = 29) have been treated previously with several typical and/or atypical antipsychotics. We observed a clinical response to sertindole treatment in 29 patients (85%). Both positive and negative symptoms improved with sertindole and no severe side-effects have been documented. EPS occurred at placebo level. A mean QTc-interval prolongation of 19.7 ms (4.7%) has been detected. None of the patients developed clinical or electrocardiographic evidence of cardiac dysrhythmia during sertindole treatment, or other clinical evidence of cardiac abnormalities. In summary, sertindole did show efficacy for positive and negative symptoms together with a favourable side-effect profile. No evidence for an increased proarrhythmic risk has been found.

Chronic Olanzapine or Sertindole Treatment Results in Reduced Oral Chewing Movements in Rats Compared to Haloperidol

Chronic haloperidol treatment typically produces late-onset, purposeless oral chewing movements in laboratory rats with a prevalence of 40 to 60%. Chronic clozapine does not produce these movements. Based on the phenomenologic and pharmacologic similarities between these rat chewing movements and human tardive dyskinesia (TD), the animal movements are often used as a model of tardive dyskinesia (TD). Here we report results of the association of oral chewing movements in rats with chronic administration of two new antipsychotic drugs, olanzapine and sertindole. Because each of these antipsychotic drugs has a very low incidence of acute Parkinsonism in human studies, they are candidates for showing a low tardive dyskinesia risk. Neither new drug produced a significant incidence of haloperidol-like chewing in rats, nor did movement ratings after their chronic administration differ from placebo; whereas, haloperidol produced a 60% prevalence of purposeless chewing and a prevalence significantly increased from placebo. This low rate of oral dyskinesias in rats is consistent with several of the preclinical characteristics of the drugs and correlates with their low acute motor side effects in clinical trials. We propose, although have not yet tested in humans, that these animal results will predict low TD liability of these drugs.

EPOS: Increasing our understanding of the treatment of schizophrenia; Start of a prospective referenced cohort study of sertindole in clinical practice

Sertindole is a new limbic-selective antipsychotic agent which has recently received marketing authorization in several countries across Europe for the treatment of schizophrenia. The experience gained in around 2200 patients treated with sertindole in controlled clinical trials has enabled optimal targeting of sertindole to those patient groups who will benefit most and who are least likely to experience adverse effects. Ultimately, it is how a new medicinal product is used in clinical practice, how it performs in everyday life, and how the patient who takes it feels and functions that determine the real benefit/risk ratio of a new medicinal product. The European Post-marketing Observational Serdolect® project (EPOS) is a post-marketing, referenced, observational, cohort, safety study in the treatment of schizophrenic patients initiated earlier this year. It is planned to recruit over 12 000 patients in two cohorts in centres throughout Europe. The aims are to provide a full safety evaluation of sertindole under marketed conditions at the relevant clinical dosage, and further, to provide epidemiological data on schizophrenic patients receiving sertindole or other treatment under the usual clinical conditions in Europe. At the moment, the study is the only one of its kind to be undertaken in schizophrenia and will provide important new data for psychiatrists around the world.