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Jørn Arnt - One of the best experts on this subject based on the ideXlab platform.
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Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and Sertindole
Psychopharmacology, 2010Co-Authors: Felice Iasevoli, Carmine Tomasetti, Federica Marmo, Daniele Bravi, Jørn Arnt, Andrea De BartolomeisAbstract:Rationale A pivotal role for glutamate in the pathophysiology and treatment of schizophrenia has been suggested. Few reports have investigated the impact of antipsychotics on postsynaptic density (PSD) molecules involved in glutamatergic transmission and synaptic remodeling. Homer is a key PSD molecule putatively implicated in schizophrenia. Objectives We studied the effect, in acute and chronic paradigms, of a first and a second generation antipsychotic (haloperidol and Sertindole, respectively) on the expression of Homer1a and Homer-interacting PSD molecules. Results In the acute paradigm, Homer1a expression was induced by haloperidol but not Sertindole in the striatum, consistent with the less propensity of Sertindole to affect nigrostriatal neurotransmission. The profile of expression of two other inducible genes, Ania3 and Arc , was highly similar to Homer1a . In the cortex, haloperidol reduced Homer1a and induced Ania3 . In the chronic paradigm, striatal expression of Homer1a and Ania3 resembled that observed in the acute paradigm. In the cortex, haloperidol induced Homer1a , while Sertindole did not. Homer1b expression was increased by haloperidol in the striatum and cortex whereas Sertindole selectively induced Homer1b in the cortex. The expression of mGluR5 was increased by both antipsychotics. A modulation by haloperidol was also seen for PSD-95 and αCaMKII . Conclusions These results suggest that haloperidol and Sertindole may significantly modulate glutamatergic transcripts of the postsynaptic density. Sertindole induces constitutive genes in the cortex predominantly, which may correlate with its propensity to improve cognitive functions. Haloperidol preferentially modulates gene expression in the striatum, consistent with its action at nigrostriatal projections and its propensity to give motor side effects.
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Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT_6 and 5-HT_2A receptor mechanisms
Psychopharmacology, 2009Co-Authors: Nagi Idris, Louise M. Witten, Jo Neill, Ben Grayson, Benny Bang-andersen, Lise Tøttrup Brennum, Jørn ArntAbstract:Aim This study examined the efficacy of Sertindole in comparison with a selective 5-HT_6 and a 5-HT_2A receptor antagonist to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats. Methods In the first test, adult female hooded Lister rats were trained to perform an operant reversal learning task to 90% criterion. After training, rats were treated with PCP at 2 mg/kg (i.p.) or vehicle twice daily for 7 days, followed by 7 days washout. For the second test, novel object recognition (NOR), a separate batch of rats, had the same sub-chronic PCP dosing regime and washout period. In reversal learning, rats were treated acutely with Sertindole, the selective 5-HT_2A receptor antagonist M100.907 or the selective 5-HT_6 receptor antagonist SB-742457. Results The PCP-induced selective reversal learning deficit was significantly improved by Sertindole, M100.907 and SB-742457. Sertindole also significantly improved the sub-chronic PCP-induced deficit in NOR, a test of episodic memory following a 1 min and 1 h inter-trial interval. In vivo binding studies showed that the dose–response relationship for Sertindole in this study most closely correlates with affinity for 5-HT_6 receptor in vivo binding in striatum, although contribution from binding to 5-HT_2A receptors in vivo in cortex may also provide an important mechanism. Conclusion The efficacies of selective 5-HT_2A and 5-HT_6 receptor antagonists suggest potential mechanisms mediating the effects of Sertindole, which has high affinity for these 5-HT receptor subtypes. The Sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.
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Effect of Sertindole on extracellular dopamine, acetylcholine, and glutamate in the medial prefrontal cortex of conscious rats: a comparison with risperidone and exploration of mechanisms involved
Psychopharmacology, 2009Co-Authors: Arne Mørk, Louise M. Witten, Jørn ArntAbstract:Rationale Second-generation antipsychotics have some beneficial effect on cognition. Recent studies, furthermore, indicate differential effects of second-generation antipsychotics on impairment in executive cognitive function. Objective We evaluated the effect of the second-generation antipsychotic drug, Sertindole, on extracellular levels of dopamine (DA), acetylcholine (ACh), and glutamate (Glu) in the rat medial prefrontal cortex (mPFC). Risperidone was studied for comparison. Moreover, selective serotonin 5-HT_2A, 5-HT_2C, and 5-HT_6 receptor antagonists were used, given alone and in combination with the preferential DA D_2 receptor antagonist, haloperidol, to further clarify the action of the two drugs. Materials and methods Rats were treated acutely with vehicle or drugs, and extracellular levels of neurotransmitters were assessed by microdialysis in freely moving animals. Results Sertindole and risperidone significantly increased extracellular levels of DA. Haloperidol; the 5-HT_2A receptor antagonist, M100907; the 5-HT_2C receptor antagonist, SB242084; and the 5-HT_6 receptor antagonist, GSK-742457, induced minor increases in levels of DA, but the three latter compounds raised the DA levels notably in combination with haloperidol. Sertindole and risperidone significantly increased the extracellular levels of ACh but only Sertindole raised the extracellular levels of Glu. The selective 5-HT_6 receptor antagonist, SB-271046, significantly increased the extracellular levels of Glu. Conclusion Sertindole and risperidone markedly increased extracellular levels of DA in mPFC. The built-in 5-HT_2A/5-HT_2C/D_2 receptor antagonism of the two drugs might be involved in this action. Both drugs increased the extracellular levels of ACh but only Sertindole enhanced Glu levels. The high affinity of Sertindole for the 5-HT_6 receptor compared to risperidone may differentiate Sertindole from risperidone.
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Sertindole: A limbic selective neuroleptic with potent anxiolytic effects
Drug Development Research, 1995Co-Authors: Connie Sanchez, Jørn Arnt, Brenda Costall, A.m. Domeney, Elisabeth Kelly, Robert J. NaylorAbstract:The anxiolytic potential of the putative neuroleptic Sertindole was assessed in various animal models of anxiety in rodents and in the marmoset human threat test. Sertindole facilitates the exploratory behaviour of mice and rats in the black and white two-compartment box over a large dose range. Sertindole is more potent than diazepam, i.e., minimal effective doses (MED) in the mouse are 0.00023 nmol (0.1 ng/kg) and 0.46 μmol/kg (0.13 mg/kg), respectively, and MED in the rat are 0.23 nmol/kg (0.10 μg/kg) and 35 nmol/kg (10 μg/kg), respectively. Sertindole increases the time that pairs of rats spend in active social interaction (unfamiliar high light conditions) at extremely low doses (MED = 0.000023 nmol/kg [0.01 ng/kg]) being some 19 million-fold more active than diazepam (MED = 0.44 μmol/kg; 0.13 mg/kg). Sertindole inhibits isolation-induced aggressive behaviour in the mouse, but only at high doses, and Sertindole does not inhibit shock-induced suppression of drinking or footschock-induced ultrasonic vocalization in rat. Sertindole similarly shows potent anxiolytic-like activity in the marmoset human threat test (MED = 23 nmol/kg; 10 μg/kg). The range between anxiolytic doses and sedative doses is very large for Sertindole, i.e., sedation is observed at 2,300 nmol/kg (1 mg/kg). © Wiley-Liss, Inc.
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Effect of Sertindole on raised mesolimbic dopaminergic activity in the rat
Drug Development Research, 1994Co-Authors: A.m. Domeney, Jørn Arnt, Connie Sanchez, Brenda Costall, Robert J. Naylor, Annie G. SmithAbstract:The effect of Sertindole in models of mesolimbic dopamine excess in the rat was evaluated. Sertindole (0.0057–0.011 μmol/kg = 2.5–5 μg/kg, sc) and haloperidol (0.13–0.27 μmol/kg = 50–100 μg/kg, ip) inhibited the hyperactivity caused by the acute intra-accumbens injection of amphetamine (20 μg). The administration of Sertindole (0.0057–2.8 μmol/kg = 2.5 μg–1.25 mg/kg, sc daily), haloperidol (0.027–0.40 μmol/kg = 10–150 μg/kg, ip bd) or clozapine (15–31 μmol/kg = 5–10 mg/kg, ip, bd) during a 13-day period of dopamine infusion (25 μg/24 h) into the nucleus accumbens reduced the dopamine-induced hyperactivity response to control levels, except at the highest dose which reduced activity to below control levels. Locomotor activity remained at control levels after discontinuing the dopamine/Sertindole treatment regimen, whereas discontinuation of the dopamine/haloperidol treatment regimen resulted in rebound hyperactivity. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc) given either once daily or once every 2 days prevented the development of hyperactivity in the intra-accumbens dopamine infusion model. One injection given every 4 days failed to modify the response to a dopamine infusion. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc daily) inhibited hyperactivity caused by unilateral infusion of dopamine (50 μg/24 h, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test). In contrast to haloperidol, Sertindole failed to initiate circling behaviour following unilateral, intrastriatal injection. In conclusion, Sertindole, like haloperidol and clozapine, can reduce raised mesolimbic dopaminergic activity in the rat. Sertindole differs from haloperidol by its ability to return the hyperactivity response to control levels. © 1994 Wiley-Liss, Inc.
Jean-michel Azorin - One of the best experts on this subject based on the ideXlab platform.
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Sertindole in the long-term treatment of schizophrenia.
International clinical psychopharmacology, 2012Co-Authors: Anthony S. Hale, Jean-michel Azorin, Ole M. Lemming, Eli MæhlumAbstract: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.
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Sertindole for the treatment of schizophrenia.
Expert opinion on pharmacotherapy, 2010Co-Authors: Jean-michel Azorin, Arthur Kaladjian, Eric Fakra, Marc AdidaAbstract:Importance of the field: Despite considerable progress in the pharmacological treatment of schizophrenia, unmet needs remain concerning refractory patients, as well as improvement of negative symptoms, cognition, quality of life, adherence and tolerability. Sertindole, a second-generation antipsychotic with high affinity for dopamine D2, serotonin 5-HT2A, 5-HT2C, and α1-adrenergic receptors, is the first phenylindole-derived antipsychotic agent. Areas covered in this review: Pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of Sertindole are covered based on a literature review (PubMed) from 1990 to 2010. Pivotal as well as supportive randomized controlled trials are reviewed along with observational and/or naturalistic safety studies. What the reader will gain: This review of Sertindole will allow the reader to determine the place for Sertindole in the schizophrenia treatment landscape. Take home message: Studies conducted so far suggest a beneficial effect of sertindol...
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Evaluation of patients on Sertindole treatment after failure of other antipsychotics: A retrospective analysis
BMC psychiatry, 2008Co-Authors: Jean-michel Azorin, Susana Murteira, K. Hansen, Mondher ToumiAbstract:Use 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. This 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. There 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. A 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.
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a double blind controlled study of Sertindole versus risperidone in the treatment of moderate to severe schizophrenia
International Clinical Psychopharmacology, 2006Co-Authors: Jean-michel Azorin, Nathalie Strub, Henrik LoftAbstract:Sertindole is a non-sedating atypical antipsychotic effective in the management of schizophrenia and is associated with placebo-level incidence of extrapyramidal symptoms (EPS). In this randomized, double-blind, parallel-group, flexible-dose, multi-centre study, the efficacy and tolerability of Sertindole was directly compared with another atypical antipsychotic in patients with schizophrenia. A total of 187 patients were randomly assigned to treatment with Sertindole (12-24 mg/day, n=98) or risperidone (4-10 mg/day, n=89) for 12 weeks. Although early termination reduced the power of the study, some significant between-group differences were evident. Sertindole reduced the mean Positive and Negative Syndrome Scale total scores to a greater extent than risperidone, and the difference reached statistical significance at endpoint for the Observed Cases (OC) dataset. Moreover, Sertindole was superior for the treatment of negative symptoms compared to risperidone (P<0.05, Last Observation Carried Forward and OC). Both treatment groups were similarly effective in improving Clinical Global Impression (Severity and Improvement), the Drug Attitude Inventory and Global Assessment of Functioning scores. Sertindole and risperidone were both well tolerated. Numerically, fewer patients in the Sertindole group (19%) reported EPS-related adverse events than in the risperidone group (28%), although significantly more Sertindole-treated patients reported QT prolongation and abnormal ejaculation volume (P<0.05). In conclusion, Sertindole was well tolerated and demonstrated clinically relevant efficacy advantages over risperidone.
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A double-blind, controlled study of Sertindole versus risperidone in the treatment of moderate-to-severe schizophrenia.
International clinical psychopharmacology, 2006Co-Authors: Jean-michel Azorin, Nathalie Strub, Henrik LoftAbstract:Sertindole is a non-sedating atypical antipsychotic effective in the management of schizophrenia and is associated with placebo-level incidence of extrapyramidal symptoms (EPS). In this randomized, double-blind, parallel-group, flexible-dose, multi-centre study, the efficacy and tolerability of Sertindole was directly compared with another atypical antipsychotic in patients with schizophrenia. A total of 187 patients were randomly assigned to treatment with Sertindole (12-24 mg/day, n=98) or risperidone (4-10 mg/day, n=89) for 12 weeks. Although early termination reduced the power of the study, some significant between-group differences were evident. Sertindole reduced the mean Positive and Negative Syndrome Scale total scores to a greater extent than risperidone, and the difference reached statistical significance at endpoint for the Observed Cases (OC) dataset. Moreover, Sertindole was superior for the treatment of negative symptoms compared to risperidone (P
Miriam C. J. M. Sturkenboom - One of the best experts on this subject based on the ideXlab platform.
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Safety of Sertindole versus risperidone in schizophrenia: principal results of the Sertindole cohort prospective study (SCoP).
Acta psychiatrica Scandinavica, 2010Co-Authors: Shl Thomas, M. D. Drici, Gillian C. Hall, Marc-antoine Crocq, Brian S. Everitt, Malcolm Lader, C. Le Jeunne, Dieter Naber, Silvia G. Priori, Miriam C. J. M. SturkenboomAbstract:Thomas SHL, Drici MD, Hall GC, Crocq MA, Everitt B, Lader MH, Le Jeunne C, Naber D, Priori S, Sturkenboom M, Thibaut F, Peuskens J, Mittoux A, Tanghoj P, Toumi M, Moore ND, Mann RD. Safety of Sertindole versus risperidone in schizophrenia: principal results of the Sertindole cohort prospective study (SCoP) Objective: To explore whether Sertindole increases all-cause mortality or cardiac events requiring hospitalization, compared with risperidone. Method: Multinational randomized, open-label, parallel-group study, with blinded classification of outcomes, in 9858 patients with schizophrenia. Results: After 14147 person-years, there was no effect of treatment on overall mortality (Sertindole 64, risperidone 61 deaths, Hazard Ratio (HR) = 1.12 (90% CI: 0.83, 1.50)) or cardiac events requiring hospitalization [Sertindole 10, risperidone 6, HR = 1.73 (95% CI: 0.63, 4.78)]: Of these, four were considered arrhythmia-related (three Sertindole, one risperidone). Cardiac mortality was higher with Sertindole (Independent Safety Committee (ISC): 31 vs. 12, HR=2.84 (95% CI: 1.45, 5.55), P = 0.0022; Investigators 17 vs. 8, HR=2.13 (95% CI: 0.91, 4.98), P = 0.081). There was no significant difference in completed suicide, but fewer Sertindole recipients attempted suicide (ISC: 68 vs. 78, HR=0.93 (95% CI: 0.66, 1.29), P = 0.65; Investigators: 43 vs. 65, HR=0.67 (95% CI: 0.45, 0.99), P = 0.044). Conclusion: Sertindole did not increase all-cause mortality, but cardiac mortality was higher and suicide attempts may be lower with Sertindole.
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Biases affecting the proportional reporting ratio (PRR) in spontaneous reports pharmacovigilance databases: the example of Sertindole
Pharmacoepidemiology and drug safety, 2003Co-Authors: Nicholas Moore, Gillian C. Hall, Miriam C. J. M. Sturkenboom, R. D. Mann, Rajaa Lagnaoui, Bernard BégaudAbstract:Background 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. Method 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. Results 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. Conclusion 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. Copyright © 2003 John Wiley & Sons, Ltd.
Marek Jarema - One of the best experts on this subject based on the ideXlab platform.
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P03-197 - Daytime sleepiness, executive functions and working memory in schizophrenia patients treated with Sertindole and olanzapine
European Psychiatry, 2011Co-Authors: Mirella Denisiuk, Adam Wichniak, Małgorzata Jędrasik-styła, I. Zdunek, E. Waliniowska, Aleksandra Wierzbicka, W. Jernajczyk, Marek JaremaAbstract:Objectives Sedation is a frequent side effect of antipsychotic drugs with a high impact on patients’ functioning. We investigated whether patients who were switched from sedative antipsychotics to Sertindole, an antipsychotic drug without sedative effect, showed better results in measures of sleepiness, executive functions and working memory than patients with a good tolerance to sedative effect of olanzapine. Methods 18 patients with schizophrenia treated with Sertindole (9 females, mean age 27.9 ± 4,1, mean dose 15.6 ± 3.0 mg/d) and 18 sex and age matched patients treated with olanzapine (15.3 ± 6.5 mg/d) underwent EEG recording, Wisconsin Card Sorting Test (WCST), psychomotor vigilance task, filled out Epworth Sleepiness Scale (ESS) and Athens insomnia scale (AIS). PANSS, UKU, BARS scales and DAI-30 were used to rate mental state, medication side effects and subjective attitude to treatment. Results At time of the assessment PANSS scores were similar in Sertindole (43.6 ± 7.1) and olanzapine (42.3 ± 12.2) groups. Increased slow wave activity (SWA) was found in EEG in 3 patients treated with Sertindole and in 10 with olanzapine (p Conclusions Although Sertindole does not induce SWA in EEG and prolong sleep, patients who were switched to Sertindole did not have improved executive functions, vigilance and working memory as compared to patients treated with olanzapine.
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P03-360 - Activity, duration of rest, daytime sleepiness and sleep quality in schizophrenia patients treated with Sertindole and olanzapine
European Psychiatry, 2011Co-Authors: Adam Wichniak, Aleksandra Wierzbicka, W. Jernajczyk, K. Czasak, I. Musinska, T. Jakubczyk, Marek JaremaAbstract:Objectives Low activity and long rest times are frequent in patients with schizophrenia and are related to increased risk for metabolic disorder. We investigated whether patients who were switched from sedative antipsychotics to Sertindole, an antipsychotic drug without sedative effect, were more active than patients with good tolerance to sedative effect of olanzapine. Methods 18 patients with schizophrenia treated with Sertindole (9 females, mean age 27.9 ± 4,1, mean dose 15.6 ± 3.0 mg/d) and 18 sex and age matched patients treated with olanzapine (mean dose 15.3 ± 6.5 mg/d) underwent actigraphy for seven days. Daytime sleepiness and sleep quality were evaluated with Epworth Sleepiness Scale (ESS), Athens insomnia scale (AIS) and sleep diaries. PANSS, UKU, BARS scales were used to rate mental state and medication side effects. Results At the time of the assessment PANNS score was similar in Sertindole (43.6 ± 7.1) and olanzapine (42.3 ± 12.2) groups. The difference in time in bed as measured by actigraphy was not significant between patients treated with Sertindole (572.7 ± 54.8 min.) and olanzapine (600.6 ± 53.6 min.). Also mean 24-h-activity was comparable in both groups (86.6 ± 29.6 and 81.6 ± 27.9 units, respectively). There were not any significant differences in AIS and ESS scales. Conclusions Although Sertindole does not induce sedation, patients who were switched from sedative antipsychotics to Sertindole were not more active than patients treated with olanzapine. Adjustment of pharmacological treatment has to be supplemented with non-pharmacological interventions to promote activity in patients with schizophrenia.
Jimmi Nielsen - One of the best experts on this subject based on the ideXlab platform.
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cardiac effects of Sertindole and quetiapine analysis of ecgs from a randomized double blind study in patients with schizophrenia
European Neuropsychopharmacology, 2015Co-Authors: Jimmi Nielsen, Aurelia Mittoux, Jørgen Matz, Jørgen K. Kanters, Johannes J. Struijk, Egon Toft, Christoffer Polcwiartek, Claus GraffAbstract:The QT interval is the most widely used surrogate marker for predicting TdP; however, several alternative surrogate markers, such as Tpeak–Tend (TpTe) and a quantitative T-wave morphology combination score (MCS) have emerged. This study investigated the cardiac effects of Sertindole and quetiapine using the QTc interval and newer surrogate markers. Data were derived from a 12 week randomized double-blind study comparing flexible dosage of Sertindole 12–20 mg and quetiapine 400–600 mg in patients with schizophrenia. ECGs were recorded digitally at baseline and after 3, 6 and 12 weeks. Between group effects were compared by using a mixed effect model, whereas assessment within group was compared by using a paired t-test. Treatment with Sertindole was associated with QTcF and QTcB interval prolongation and an increase in MCS, T-wave asymmetry, T-wave flatness and TpTe. The mean increase in QTcF from baseline to last observation was 12.1 ms for Sertindole (p<0.001) and −0.5 ms for quetiapine (p=0.8). Quetiapine caused no increase in MCS, T-wave asymmetry, T-wave flatness or TpTe compared to baseline. In the categorical analysis, there were 11 patients (9.6%) receiving quetiapine who experienced more than 20 ms QTcF prolongation compared with 36 patients (33.3%) in the Sertindole group. Sertindole (12–20 mg) was associated with moderate QTc prolongation and worsening of T-wave morphology in a study population of patients with schizophrenia. Although, quetiapine (400–600 mg) did not show worsening of repolarization measures some individual patients did experience significant worsening of repolarization. Clinical Trials NCT00654706.
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Cardiac effects of Sertindole and quetiapine: Analysis of ECGs from a randomized double-blind study in patients with schizophrenia
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2015Co-Authors: Jimmi Nielsen, Aurelia Mittoux, Jørgen Matz, Jørgen K. Kanters, Johannes J. Struijk, Egon Toft, Christoffer Polcwiartek, Claus GraffAbstract:The QT interval is the most widely used surrogate marker for predicting TdP; however, several alternative surrogate markers, such as Tpeak–Tend (TpTe) and a quantitative T-wave morphology combination score (MCS) have emerged. This study investigated the cardiac effects of Sertindole and quetiapine using the QTc interval and newer surrogate markers. Data were derived from a 12 week randomized double-blind study comparing flexible dosage of Sertindole 12–20 mg and quetiapine 400–600 mg in patients with schizophrenia. ECGs were recorded digitally at baseline and after 3, 6 and 12 weeks. Between group effects were compared by using a mixed effect model, whereas assessment within group was compared by using a paired t-test. Treatment with Sertindole was associated with QTcF and QTcB interval prolongation and an increase in MCS, T-wave asymmetry, T-wave flatness and TpTe. The mean increase in QTcF from baseline to last observation was 12.1 ms for Sertindole (p
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Effects of Sertindole on cognition in clozapine-treated schizophrenia patients
Acta psychiatrica Scandinavica, 2012Co-Authors: René Ernst Nielsen, Sten Levander, D Thode, Jimmi NielsenAbstract:Nielsen RE, Levander S, Thode D, Nielsen J. Effects of Sertindole on cognition in clozapine-treated schizophrenia patients. Objective: To assess the cognitive effects of Sertindole augmentation in clozapine-treated patients diagnosed with schizophrenia. Cognition is secondary outcome of the trial. Method: A 12-week, double-blinded, randomized, placebo-controlled, augmentation study of patients treated with clozapine. Participants were randomized 1:1 to receive 16 mg of Sertindole or placebo as adjunctive treatment to clozapine. Results: Participants displayed substantial cognitive deficits, ranging from 1.6 standard deviation below norms at baseline to more than three standard deviations on tests of response readiness and focused attention. There were no significant differences between Sertindole augmentation and placebo groups at study end. Correlation analysis of Positive and Negative Syndrome (PANSS) subscales, Global Assessment of Functioning subscale (GAF-F) and Clinical Global Impression (CGI) with 20 neurocognitive indices was conducted, but no significant correlations were found. Second, we tested change from baseline to endpoint for the PANSS, GAF-F, and CGI, vs. the concomitant changes in cognitive test performance, and found no significant correlations. Conclusion: The clozapine-treated patients displayed marked cognitive deficits at baseline. Adding Sertindole did not improve or worsen cognitive functioning, which is in line with previous negative studies of the effect on cognition of augmenting clozapine treatment with another antipsychotic drug.
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Augmenting Clozapine With Sertindole A Double-Blind, Randomized, Placebo-Controlled Study
Journal of clinical psychopharmacology, 2012Co-Authors: Jimmi Nielsen, Charlotte Emborg, Susanne Gydesen, Jesper Dybbro, Jørgen Aagaard, Karsten Haderup, Pia Glyngdal, Susanne Fabricius, Dorrit Thode, Henrik LublinAbstract:Clozapine augmentation with antipsychotic drugs is widely used despite sparse evidence supporting this strategy. Sertindole is a nonsedating atypical antipsychotic drug with low affinity for choliner- gic receptors, which makes it potentially suitable for augmentation of clozapine. The study design was a 12-week, double-blind, randomized, placebo-controlled study including patients with International Statistical Classification of Diseases, 10th Revision schizophrenia (F20.0YF20.3) and treated with clozapine for at least 6 months who had not achieved sufficient response. Patients were randomized 1:1 to either Sertindole 16 mg or placebo, and assessment was done at baseline and after 6 and 12 weeks. Assessment included the Positive and Negative Syndrome Scale, Clinical Global Impression, Udvalg for Kliniske UndersLgelser, World Health Organization Quality of Life Brief, Drug Attitude Inven- tory, fasting glucose, lipids, and electrocardiogram. Clozapine augmen- tation with Sertindole was not superior to placebo regarding total score or subscale score of the Positive and Negative Syndrome Scale, Clinical Global Impression, World Health Organization Quality of Life Brief, or Drug Attitude Inventory. No increased adverse effects compared with placebo were found. Four patients randomized to Sertindole experienced a significant worsening of psychosis, and 2 of them required psychiat- ric admission. Metabolic parameters were unchanged during the study, but augmentation of clozapine with Sertindole was associated with a 12-millisecond (SD, 20-millisecond) QTc prolongation compared with 0 millisecond (SD, 20 milliseconds) in the placebo group (P G 0.03). Augmentation with Sertindole showed no benefits compared with pla- cebo. Psychiatrists should be aware that augmentation might not add any benefits for the patients and in some cases worsen psychosis.
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the effect of Sertindole on qtd and tpte
Acta Psychiatrica Scandinavica, 2010Co-Authors: Jimmi Nielsen, Mads Peter Andersen, Claus Graff, Jørgen K. Kanters, Thomas Bork Hardahl, J. Dybbro, Johannes J. Struijk, Jonathan M. Meyer, Egon ToftAbstract:Nielsen J, Andersen MP, Graff C, Kanters JK, Hardahl T, Dybbro J, Struijk JJ, Meyer JM, Toft E. The effect of Sertindole on QTD and TPTE. Objective: 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. Method: 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. Results: 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). Conclusion: 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.
