Sertindole in schizophrenia: efficacy and safety issues.

Drug Evaluation

Sertindole in schizophrenia: efficacy and safety issues Maria Rosaria Anna Muscatello, Antonio Bruno†, Paolo Micali Bellinghieri, Gianluca Pandolfo & Rocco Antonio Zoccali

1.

Introduction

2.

Sertindole

3.

Pharmacodynamics

4.

Pharmacokinetics and

†

University of Messina, Department of Neurosciences, Section of Psychiatry, Messina, Italy

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Melbourne on 09/14/14 For personal use only.

metabolism 5.

Clinical efficacy

6.

Safety and tolerability

7.

Cost-effectiveness studies

8.

Dosage and administration

9.

Conclusion

10.

Expert opinion

Introduction: Despite substantial progress in the pharmacological treatment of schizophrenia, antipsychotic drugs are associated with insufficient effects on negative and cognitive symptoms, adverse events, poor compliance and drug discontinuation. Sertindole, first withdrawn from the market for cardiovascular safety concerns, is currently available in many countries. It has high affinity for dopamine D2, serotonin 5-HT2A, 5-HT2C and a1-adrenergic receptors, and a low potential for extrapyramidal symptoms. Areas covered: The pharmacodynamics, pharmacokinetics, clinical efficacy, safety and tolerability, and cost-effectiveness of sertindole are covered in this article, based on a literature review (PubMed) from 1990 to 2014. Expert opinion: The reviewed studies suggest a beneficial effect of sertindole on positive, negative and cognitive symptoms, and on relapse prevention. Although generally well tolerated, sertindole is associated with a doserelated QT-interval prolongation; thus, its administration requires electrocardiogram screening and monitoring. The presence of congenital long QT syndrome, prolongated QTc at baseline, cardiac disease and drug interactions should be carefully considered before prescribing sertindole. Further direct ‘head-to-head’ comparisons with other second-generation antipsychotics (SGAs), trials on special populations and further clarification on cardiac safety are needed to better define the role of sertindole in the treatment of schizophrenia. Keywords: atypical antipsychotic, efficacy, safety, schizophrenia, sertindole Expert Opin. Pharmacother. (2014) 15(13):1943-1953

1.

Introduction

Antipsychotic drugs (APs) have substantially modified the natural course and the outcome of schizophrenia. First-generation antipsychotics (FGAs), although effective in treating psychotic symptoms, show an unfavorable side effects profile that mainly includes extrapyramidal symptoms (EPS): Moreover, they are scarcely effective on negative and cognitive symptoms [1]. Second-generation antipsychotics (SGAs) have become the treatment of choice for schizophrenia, as recommended by current guidelines [2], because of a more favorable tolerability profile. Nevertheless, their use is associated with differential risk of metabolic syndrome [3]. It has been estimated that only a subset of patients with schizophrenia show a good outcome; most of the patients exhibit a range of residual symptoms [4], which have a significant impact on community outcome and quality of life. Common residual symptoms, such as anhedonia, reduced drive, emotional blunting, cognitive dysfunctions, social cognition impairments, post-psychotic depression and dysphoria, are scarcely responsive to APs and require additional treatments, both psychosocial and pharmacological [5], such as augmentation strategies [6-11]. Thus, the treatment of schizophrenia is still marked by many unmet needs, and further research efforts for developing new treatment options are required.

10.1517/14656566.2014.947960 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

1943

M. R. A. Muscatello et al.

Box 1. Drug summary. Drug name Phase Indication Pharmacology description

Route of administration Chemical structure

Sertindole (2-imidazolidinone, 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl] ethyl]) Launched Schizophrenia 5-Hydroxytryptamine 2 receptor antagonist Dopamine D2 receptor antagonist a1-Adrenoreceptor antagonist a--Adrenoreceptor antagonist Dopamine receptor antagonist 5-Hydroxytryptamine receptor antagonist Oral NH


O N

N

CI

N

F

Pivotal trial(s)

Sertindole was superior to placebo in improving overall schizophrenic symptoms [37], and at least equally as effective as haloperidol, with indication of superiority in relapse prevention [38-40]. No marked differences were found in comparisons with risperidone [43,44], and olanzapine [45] on schizophrenia symptoms

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).

2.

Sertindole

Sertindole ([1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H indol3-y1]-1 piperidinyl] ethyl]-2-imidazolidinone]) (Box 1) was introduced in Europe in 1996 but was voluntarily withdrawn by the manufacturer after it was shown to increase cardiovascular mortality [12], effect ascribed to the QT prolongation. In 2006, after studies demonstrating that the overall mortality rates with sertindole were comparable to those with other antipsychotics [13], the drug was approved in European market with the stipulation of close electrocardiogram (ECG) screening and monitoring. Sertindole is currently available in over 54 countries around the world [14]. Several reviews and expert opinions on sertindole have been published [13-23]. The aim of the present review was to update available data on clinical efficacy, tolerability and safety profile of sertindole. Using the keywords ‘sertindole,’ ‘serdolect,’ ‘schizophrenia’ and ‘atypical antipsychotics,’ we performed a literature search using the international database PubMed to 1944

find all the studies published in English from 1990 to 2014. Additional references were identified from the bibliographies of published articles. Searches were last updated April 25, 2014. We selected articles for review if their content was informative to the topic. 3.

Pharmacodynamics

Sertindole exerts a potent antagonism at serotonin 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, dopamine D2 and a1-adrenergic receptors; its affinity for histamine H1, cholinergic muscarinic and a2-adrenergic receptors is low [24,25]. In preclinical studies, sertindole selectively inhibited mesolimbic dopaminergic activity with negligible effects on nigrostriatal dopaminergic trait [26-28]. In humans, positron emission tomography (PET) studies showed that sertindole induced a 5-HT2A receptor occupancy of ~ 100% and a relatively low striatal D2 receptor occupancy (52 -- 68%) [29,30]. Sertindole, compared to haloperidol, had an activating function in the

Expert Opin. Pharmacother. (2014) 15(13)

Sertindole

dorsolateral and anterior prefrontal cortex, and this effect suggests a potential impact on negative and cognitive symptoms [31].


4.

Pharmacokinetics and metabolism

The oral bioavailability of sertindole is about 75%; peak plasma levels are reached within 10 h after oral doses [32]. Sertindole passes both the blood-brain and placental barriers, and its plasma protein binding is 99.5%, mainly to albumin and a1-acid glycoprotein [33]. The drug is metabolized in the liver by the cytochrome P450 isoenzymes CYP2D6 and CYP3A4; its main metabolites, dehydrosertindole and norsertindole, have negligible pharmacological effects. Because of the genetic polymorphism of the CYP2D6 isoform, poor metabolizers show reduction in sertindole clearance up to 67% and plasma sertindole concentrations 2 -- 3 times higher than extensive metabolizers. The drug and its metabolites are excreted in the feces, with a minor amount (~ 4%) in the urine. Sertindole has a mean half-life of 53 -- 102 h, and the steady state is reached after 2 -- 3 weeks of daily assumption. In elderly subjects, slower titration and lower maintenance dose are suggested [34]. In hepatically impaired patients, a dose reduction is required, whereas it is not necessary in patients with renal impairment [35]. Concomitant treatment with CYP2D6 inhibitors or with CYP3A4 inhibitors may increase plasma sertindole concentrations up to two- to threefold [36]. 5.

Clinical efficacy

Positive and negative symptoms The efficacy of sertindole in schizophrenia has been evaluated in seven randomized, double-blind clinical trials, without considering results from smaller studies presented as case reports, posters and proceedings of congresses. These studies included one flexible-dose placebo-controlled trial [37], three comparisons with haloperidol [38-40], two with risperidone [41,42] and one with olanzapine [43]. Of the seven double-blind sertindole trials, only one evaluated the long-term outcome [40]. The efficacy and safety of sertindole in the longterm treatment of schizophrenia was further evaluated in an open-label study (Table 1) [44]. A 6-week, Phase II trial, evaluated the efficacy of three doses of sertindole (8, 12 and 20 mg/day) versus placebo on 205 schizophrenia patients. Only sertindole 20 mg/day resulted more effective than placebo in reducing Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) total scores. Neither of the two lower doses was associated with symptoms improvement [37]. In an 8-week Phase III study on 497 hospitalized patients both sertindole (12, 20 and 24 mg/day) and haloperidol (4, 8 and 16 mg/day) at all doses were equally more effective than placebo for reducing PANSS and BPRS total scores from baseline to the end of the trial, with the best results seen 5.1

with the 20 mg/day dose of sertindole and the 8 mg/day dose of haloperidol. Sertindole 24 mg/day was not more efficacious than 20 mg/day [38]. Another 8-week Phase III trial on 617 patients randomized to sertindole (8, 16, 20 and 24 mg/day) or haloperidol (10 mg/day) showed that sertindole 16 mg/day and haloperidol 10 mg/day were associated with a significant reduction in PANSS total score, as well as in PANSS negative subscale score [39]. Since sertindole 16 mg/day was as efficacious as 20 mg/day, the initial titration of 16 mg/day was suggested, whereas the dose of 8 mg/day should be considered suboptimal [37-39]. A 12-month randomized study on 282 schizophrenia outpatients assessed that time to treatment failure was numerically superior with 24 mg/day sertindole than with 10 mg/day haloperidol. Both treatment groups showed improvement in PANSS total score from baseline to end point, whereas sertindole was associated with a greater improvement in negative symptoms after 2 months of treatment; however, no significant difference between the two treatment groups was found after 12 months. At 1-year follow-up, sertindole-treated patients remained free of hospitalization for relapses and were medically compliant significantly longer than did haloperidoltreated patients [40]. An open-label, flexible-dose study assessed the safety and tolerability of sertindole in the long-term treatment of schizophrenia. Upon completion of an 8-week, randomized clinical trial with haloperidol versus sertindole, patients were offered sertindole maintenance treatment up to 18 months. Of a total sample of 294 patients, 237 (81%) had received sertindole at the dose of 16 mg/day and 57 (19%) had received haloperidol. Both treatments were effective in reducing PANSS and Clinical Global Impression (CGI) ‘severity-of-illness’ (CGI-S) scores [41]. Direct comparisons of sertindole with other SGAs are still limited. The retrospective, single-arm NICHE study on 344 patients showed that a subset of patients switched to sertindole had clinical improvement, as documented by the decrease in the number and duration of hospitalizations due to psychotic relapses, as well as suicide attempts [42]. A randomized, 12-week study compared the efficacy and tolerability of sertindole (12 -- 24 mg/day; n = 98) with risperidone (4 -- 10 mg/day; n = 89) in 187 schizophrenia out- and inpatients. Although the study power was reduced by the withdrawal of sertindole from the European market, positive and negative symptoms improved after 12 weeks of treatment with both drugs, with sertindole-treated patients showing a greater reduction in PANSS negative subscale scores. Data for leaving study early were available, but total was high (35.8%) [43]. A further randomized, Phase III study, compared sertindole (12 -- 24 mg/day) with risperidone (6 -- 12 mg/day) in 217 treatment-resistant patients. No significant difference was found between the two groups in efficacy measures (PANSS and BPRS total scores from baseline to end point) [44].


1945

1946 8 weeks

Multicenter, double-blind, placebocontrolled

Multicenter, randomized, double-blind

Multicenter, randomized, double-blind

Zimbroff et al. (1997) [38]

Daniel et al. (1998) [40]

Hale et al. (2000) [39]


Schizophrenia (n = 617; 39%)

Schizophrenia (n = 282; NA)


Schizophrenia (n = 205; NA)

Diagnosis (number of patients; % total discontinuation)

Total (n = 492; 27%) 8 mg/day (n = 120; 44%) 16 mg/day (n = 127; 37%) 20 mg/day (n = 128; 36%) 24 mg/day (n = 117; 38%)

24 mg/day (n = 141; 19%)

Total (n = 157; 33%) 8 mg/day (n = 52; 33%) 12 mg/day (n = 51; 31%) 20 mg/day (n = 54; 35%) Total (n = 216; NA) 12 mg/day (n = 76) 20 mg/day (n = 68) 24 mg/day (n = 72)

Sertindole regimen (number of patients; % discontinuation)

Haloperidol 10 mg/day (n = 125; 39%)

Haloperidol 10 mg/day (n = 141; 21%)

Haloperidol (n = 208; NA) 4 mg/day (n = 71) 8 mg/day (n = 67) 16 mg/day (n = 70)

NA

Active comparator regimen (number of patients; % discontinuation)

NA

NA

Placebo (n = 73; NA)

Placebo (n = 48; 39%)

Placebo (number of patients; % discontinuation)

PANSS CGI BAS SAS AIMS

PANSS SANS

PANSS BPRS SANS CGI BAS SAS AIMS

PANSS BPRS CGI BAS SAS AIMS

Outcome measures

PANSS- P: S 20 mg/day and 24 mg/day and each H dose range more effective than Pl; SANS: Only S 20 mg/day more effective than Pl PANSS- T: S more effective than H after 5 weeks; no statistically significant differences at 1-year follow-up PANSS- T: efficacy for S 16 and 24 mg/day and H 10 mg/day

PANSS, BPRS, CGI: S 20 mg/day more effective than Pl

Main efficacy results

AIMS: Abnormal involuntary movement scale; BAS: Barnes akathisia scale; BPRS: Brief psychiatric rating scale; CGI: Clinical global impression scale; H: Haloperidol; NA: Not available; O: Olanzapine; PANSS- T (N, P): Positive and negative syndrome scale-total (negative and positive subscales); Pl: Placebo; R: Risperidone; S: Sertindole; SANS: Scale for the assessment of negative symptoms; SAS: Simpson-angus scale.

8 weeks

5 weeks 1-year follow-up

8 weeks

Multicenter, randomized, placebocontrolled

Van Kammen et al. (1996) [37]

Trial duration

Study design

Authors/year of publication

Table 1. Published efficacy trials of sertindole in schizophrenia.




Multicenter, randomized, double-blind, flexible-dose

Multicenter, randomized, double-blind, parallel-group

Randomized, double-blind, parallel-group, flexible-dose

Azorin et al. (2006) [43]

Kane et al. (2011) [44]

Kwon et al. (2012) [45] 12 weeks

12 weeks

12 weeks

Trial duration

Schizophrenia (n = 389; 24.6%)

Schizophrenia Treatment-resistant patients (n = 321; 39%)


Diagnosis (number of patients; % total discontinuation)

Sertindole mean dose = 17 mg/day (n = 196; 32.1%)

Sertindole 12 -- 24 mg/day (n = 216; 34%)

Sertindole 12 -- 24 mg/day, mean dose = 16.2 mg/day (n = 97; 39%)

Sertindole regimen (number of patients; % discontinuation)

Olanzapine mean dose = 16 mg/day (n = 193; 17.1%)

Risperidone 6 -- 12 mg/day (n = 105; 29%)

Risperidone 4 -- 10 mg/day, mean dose = 6.6 mg/day (n = 89; 31%)

Active comparator regimen (number of patients; % discontinuation)

NA

NA

NA

Placebo (number of patients; % discontinuation)

PANSS

PANSS BPRS SANS CGI

PANSS CGI Drug attitude inventory Global assessment of functioning

Outcome measures

PANSS- T: no statistical differences between S and R; PANSS- N: greater reduction for S-treated patients PANSS, BPRS, SANS, CGI: no statistical differences between S and R S failed to prove non-inferiority to O in terms of reduction in PANSS total score


AIMS: Abnormal involuntary movement scale; BAS: Barnes akathisia scale; BPRS: Brief psychiatric rating scale; CGI: Clinical global impression scale; H: Haloperidol; NA: Not available; O: Olanzapine; PANSS- T (N, P): Positive and negative syndrome scale-total (negative and positive subscales); Pl: Placebo; R: Risperidone; S: Sertindole; SANS: Scale for the assessment of negative symptoms; SAS: Simpson-angus scale.

Study design

Authors/year of publication

Table 1. Published efficacy trials of sertindole in schizophrenia (continued).


Sertindole

1947


Table 2. Published efficacy trials of sertindole on cognitive symptoms in schizophrenia. Authors/year of publication

Study design


Gallhofer et al. Randomized, (2007) [55] double-blind

Trial Number of duration patients

12-week

40

Nielsen et al. (2012) [58]

Double-blinded, 12-week randomized, placebo-controlled, augmentation study (Clozapine)

50

Nielsen et al. (2014) [59]

Double-blind, randomized, head-to-head

9

12-week

Sertindole regimen

Active comparator regimen

10 -- 24 mg/day Haloperidol

Outcome measures


WCST Digit span Reaction time

S was more effective than H in improving cognitive performances at weeks 4 and 12 4 -- 16 mg/day NA EuroCog battery: Augmentation did Maze Exit not improve Finger tapping cognitive function test nor clinical K-test symptoms Reaction time/response readiness 16 -- 24 mg/day Olanzapine CANTAB No statistical 10 -- 20 mg/day differences between S and O

H: Haloperido; NA: Not available; O: Olanzapine; S: Sertindole; WCST: Wisconsin card sorting test.

In a 12-week, double-blind, flexible-dose study, 389 patients were randomized to receive sertindole (n = 196; mean dose = 17 mg/day) or olanzapine (n = 193; mean dose = 16 mg/day). Sertindole failed to prove non-inferiority to olanzapine in terms of reduction in PANSS total score; however, this can be ascribed to the higher withdrawal rate in the sertindole group, as documented by the last-observation-carried-forward analysis [45]. A 12-week, double-blind, placebo-controlled study evaluated the augmentation of clozapine (minimum dose 150 mg/day) with sertindole (16 mg/day) in a sample of partial-responder schizophrenia patients. Sertindole was not better than placebo in improving residual symptoms, as documented by PANSS and CGI total scores at end point [46]. A large meta-analysis of 212 trials on 15 antipsychotics confirmed the superiority of sertindole over placebo but did also demonstrate a small efficacy of sertindole compared with both FGAs and SGAs [47]. Cognitive symptoms In preclinical studies, SGAs were ineffective in normalizing set-shifting deficits [48,49], whereas sertindole has consistently been shown to reverse phencyclidine-induced cognitive deficits, impairment in attentional shifting, visual memory deficit induced by MK-801 and cognitive inflexibility [50-54]. A 12week, double-blind study compared the effect of sertindole (10 -- 24 mg/day) and haloperidol on cognitive functioning in 40 schizophrenia patients. Neuropsychological assessment included Wisconsin Card Sorting test, digit span and reaction time. Sertindole was more effective than haloperidol in improving cognitive performances [55]. In a PET (18F)fluorodeoxyglucose and MRI study on 15 patients receiving sertindole up to 24 mg/day or haloperidol up to 16 mg/day 5.2

1948

under a blind condition, higher metabolic rates in the dorsolateral and anterior prefrontal cortex were observed in sertindole group [56]. In healthy subjects (n = 30), the effect of sertindole on gating measures (prepulse inhibition -- PPI, and the P50 auditory event-related potential suppression) was dependent on baseline gating levels; sertindole increased PPI and P50 suppression in subjects exhibiting low baseline PPI or P50 suppression, whereas it attenuated PPI and P50 suppression in subjects with high levels of baseline gating [57]. In a 12-week, placebo-controlled, augmentation study on 50 patients receiving clozapine and randomized to sertindole (up to 16 mg) or placebo, adjunctive sertindole did not improve executive functions and motor speed nor clinical symptoms [58]. The SEROLA study compared the effect of sertindole (16 -- 24 mg/day) and olanzapine (10 -- 20 mg/day) on cognitive functions in nine schizophrenia patients who underwent the CANTAB cognitive battery and the PANSS. At end point, no significant differences were found on neurocognitive and clinical measures between groups (Table 2) [59]. 6.

Safety and tolerability

Adverse events Sertindole is commonly associated with headache (5.2 -33.8%), insomnia (9.3 -- 31.3%), rhinitis/nasal congestion (15.3 -- 28.5%), abnormal ejaculation (8.9 -- 21.8%) sedation (8.2 -- 18.1%) and vomiting (17.1%) [60]; these AEs are not dose-related. In Phase II/III trials [37-41], and in the meta-analysis by Lewis et al. [61], sertindole (8 -- 24 mg/day) was comparable to placebo regarding EPS. Studies comparing sertindole with 6.1



Sertindole

risperidone showed a significantly lower incidence of EPS among sertindole-treated patients [43,44]. Furthermore, the emergence of EPS during sertindole treatment does not seem to be dose-dependent [40]. The favorable profile of sertindole on EPS was confirmed by the meta-analysis of Leucht et al. [47]. Sertindole caused significant increases in prolactin in the short-, but not in the long-term trials [37,39,40], along with small increases in plasma glucose [17], total cholesterol [37,44] and triglycerides [17]. Sertindole induced a statistically significant greater mean weight gain versus placebo and haloperidol [39,40,61]; when compared with risperidone, both treatments were associated with a moderate weight gain and body mass index, but with no increased risk of metabolic syndrome [62]. QT prolongation and cardiac mortality FGAs and SGAs, as well as other drugs, are differentially associated with prolongation of QTc of the ECG [63], which is based on the capacity to inhibit the cardiac delayed potassium rectifier channel IKr, a channel expressed by the HERG gene [64]. During sertindole treatment, a dose-dependent increase (~ 22 ms) in the QTc interval was observed [65]. Preclinical data in animal models showed that, despite the QT prolongation, the torsadogenic potential of sertindole was remarkably low [66]. Sertindole was associated with drug-induced T-wave morphology changes [67], whereas it had no effect on the new arrhythmia markers, QT dispersion and Tpeak--Tend [68]. Data from previous studies showed that the cardiovascular mortality was almost 10 times greater in sertindole-treated patients compared with patients treated with other antipsychotics [12] and that the risk of sudden cardiac death was fivefold greater during sertindole treatment than during risperidone treatment (hazard ratio = 5.1, 95% CI: 1.5 -- 17.9) [69]. 6.2

Overall mortality and suicide The safety profile of sertindole and mortality rates during treatment have been assessed by postmarketing surveillance studies: a Prescription Event Monitoring (PEM) study [70], the sertindole European Safety and Exposure Survey (ESES) [71], the European Post-marketing Observational Sertindole (EPOS) study [72], the Sertindole Safety Survey (SSS) [73], the Sertindole Cohort Prospective (SCoP) [74] and cohort studies [75]. Overall results have shown that death rates among sertindole-treated patients were similar to that of other SGAs, varying from 0.79 deaths/100 patient-years exposure (PYE) to 2.34 deaths/100 PYE [12]. Concerning suicide, lower mortality rates (0.21 -- 0.37/100 PYE) [71] and lower incidence of suicide attempts (p = 0.037) [76] were found for sertindole compared with other SGAs. 6.3

7.

Cost-effectiveness studies

Markov model for cost-effectiveness analysis in European cohorts showed that sertindole represents a suitable alternative to current treatment options for its low direct and indirect

medical costs, mainly due to relapse prevention, decreased hospitalizations and compliance [77,78]. A similar trend was confirmed by a systematic review of full economic evaluations and cost-utility analyses within the field of mental disorders [79]. A recent meta-analysis showed that several individual SGAs were associated with significantly lower relapse rates at specific time points and, specifically, clozapine at 3 months (p = 0.03) and 6 months (p = 0.006), olanzapine at 6 months (p = 0.0003) and sertindole (p = 0.02) as well as ziprasidone (p = 0.01) at 12 months [80]. 8.

Dosage and administration

Sertindole is prescribed to patients who are intolerant to at least one other AP at the initial dose of 4 mg/day, which can be titrated by increments of 4 mg after 4 -- 5 days until the effective dose range of 12 -- 20 mg/day (maximum dose: 24 mg/day) is reached. ECG screening at baseline and monitoring during treatment are required. Sertindole is contraindicated in patients with a history of clinically significant cardiovascular disease, with congenital long QT syndrome or a family history of this disease, as well as in patients treated with drugs known to prolong the QT interval [81]. 9.

Conclusion

Sertindole is currently available for the treatment of schizophrenia in many countries under special safety conditions. Due to its pharmacological profile (high affinity for serotonin 5-HT2A and 5-HT2C and a1 adrenergic receptors, mesolimbic and mesocortical selectivity) [24-31], sertindole demonstrated efficacy in treating positive, negative and cognitive symptoms [37-44,55-58], a low potential to cause sedation and EPS [47], and an acceptable metabolic profile [62]. Sertindole appears to have a slightly favorable profile than other APs on relapse rates and quality of life [22,23]. However, except for haloperidol, risperidone and olanzapine, no randomized trials have compared sertindole with other APs. 10.

Expert opinion

The suspension of sertindole from the market led to the need to evaluate safety issues more than clinical efficacy; as a consequence, mainly short-term efficacy studies have been conducted, resulting in limited evidence and a still incomplete external validity [21]. Given current available findings, sertindole is at least equally as effective as haloperidol [38-40], risperidone [43,44] and olanzapine [45] on schizophrenia symptoms. Its effect on cognitive symptoms is supported by both preclinical [48-54] and clinical studies versus haloperidol [55] and olanzapine [59]. However, the role of sertindole on cognition needs further clarification, since haloperidol is not effective in cognitive impairment, and it could even worsen cognitive functions [82,83], whereas the olanzapine study [59] has included only nine patients (four completers).


1949



Concerning safety, although the high proportion of fatal arrhythmias and sudden deaths associated with sertindole treatment was not confirmed [12], cardiac safety remains a major concern when considering sertindole for the treatment of schizophrenia. The potential cardiovascular toxicity of sertindole cannot be completely ruled out because of its effects on QT-interval and on T-wave morphology, which are considered reliable predictors of torsades de pointe [67,84]. Although schizophrenia patients are considered a high-risk population for sudden death independent of drug treatment, cardiovascular risk is also associated with drug interaction, and coadministration of psychotropic drugs is common in clinical practice. Sertindole will be most likely prescribed in combination with other psychotropics, such as APs [46], antidepressants and mood stabilizers. Beyond the risk of synergistic effects with other drugs inducing QTc prolongation, whose concurrent use is contraindicate, the drug interaction profile of sertindole has not yet been fully understood. Thus, subjects requiring co-prescription, those with preexisting cardiovascular disease, and elderly patients, need careful monitoring. On the other hand, the awareness of cardiac risk is not enough balanced by the clear knowledge that sertindole is superior to currently available APs. ‘Head-to-head’ comparisons with other SGAs designed as independent double-blind, randomized clinical trials are necessary to better Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

2.

..

3.

4.

..

1950

Kane J, Mayerhoff D. Do negative symptoms respond to pharmacologic treatment? Br J Psychiatry 1989;55(Suppl 7):115-18 Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373:31-41 An important meta-analysis of Antipsychotic drugs (APs) which clearly demonstrated that second-generation antipsychotics (SGAs) are not an homogeneous class of compounds. Meyer JM, Davis VG, Goff DC, et al. Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: prospective data from phase 1. Schizophr Res 2008;101(1-3):273-86 Tamminga CA, Holcomb HH. Phenotype of schizophrenia: a review and formulation. Mol Psychiatry 2005;10(1):27-39 An outstanding review on schizophrenia.

5.

understand the therapeutic potential of sertindole. Sertindole should also be tested in refractory patients in comparison with clozapine, in special populations (children and adolescents, female patients and elderly subjects), in patients with primary negative or deficit symptoms, and in first-episode or prodromic patients. Furthermore, effects on neuroplasticity and brain morphology should also be evaluated. Given available data, it is uneasy to define the place of sertindole in the management of schizophrenia in the next 5 years. Sertindole is available as a second-line choice for the treatment of schizophrenia; although it appears to have an equivalent profile or slightly favorable to other APs on relapse rate, quality of life and all-cause mortality rate, its full effectiveness in schizophrenia treatment remains to be more firmly established, as the total amount of available information has not substantially changed in the recent years.

Declaration of interest The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Bell MD, Corbera S, Johannesen JK, et al. Social cognitive impairments and negative symptoms in schizophrenia: are there subtypes with distinct functional correlates? Schizophr Bull 2013;39(1):186-96

6.

Tiihonen J, Leucht S. Clozapine resistance-augmentation strategies. Eur Neuropsychopharmacol 2013;23:338

7.

Muscatello MR, Pandolfo G, Mico` U, et al. Augmentation of clozapine with ziprasidone in refractory schizophrenia: a double-blind, placebo-controlled study. J Clin Psychopharmacol 2014;34:129-33

8.

9.

10.

Muscatello MR, Bruno A, Pandolfo G, et al. Effect of aripiprazole augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. Schizophr Res 2011;127:93-9 Zoccali R, Muscatello MR, Bruno A, et al. The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study. Schizophr Res 2007;93:109-16 Muscatello M, Bruno A, Pandolfo G, et al. Topiramate augmentation of clozapine in schizophrenia:


a double-blind, placebo-controlled study. J Psychopharmacol 2011;25:667-74 11.

Mico’ U, Bruno A, Pandolfo G, et al. Duloxetine as adjunctive treatment to clozapine in patients with schizophrenia: a randomized, placebo-controlled trial. Int Clin Psychopharmacol 2011;26:303-10

12.

Moore N. Higher cardiovascular mortality with sertindole in ADROIT: a signal not confirmed. Int J Psychiatry Clin Pract 2002;6:S3-9 An excellent review of postmarketing surveillance studies and mortality issues on sertindole.

..

13.

Lindstrom E, Levander S. Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother 2006;7:1825-34

14.

Pae CU. Sertindole: dilemmas for its use in clinical practice. Expert Opin Drug Saf 2013;12(3):321-6

15.

Tamminga CA, Mack RJ, Granneman R, et al. Sertindole in the treatment of psychosis in schizophrenia: efficacy and safety. Int Clin Psychopharmacol 1997;12(Suppl 1):S29-35

16.

Hale AS. A review of the safety and tolerability of sertindole.

Sertindole


17.

Kasper S. Sertindole: safety and tolerability profile. Int J Psychiatry Clin Pract 2002;6(Suppl 1):S27-32

18.

Perquin L, Steinert T. A review of the efficacy, tolerability and safety of sertindole in clinical trials. CNS Drugs 2004;18(Suppl 2):19-30

19.

Cincotta SL, Rodefer JS. Emerging role of sertindole in the management of schizophrenia. Neuropsychiatr Dis Treat 2010;6:429-41

20.

..

21.

22.

..

23.

..

24.

25.

26.

Spina E, Zoccali R. Sertindole: pharmacological and clinical profile and role in the treatment of schizophrenia. Expert Opin Drug Metab Toxicol 2008;4:629-38 An informative review on pharmacology and efficacy of sertindole.

27.

28.

29.

Skarsfeldt T. Electrophysiological profile of the new atypical neuroleptic, sertindole, on midbrain dopamine neurons in rats: acute and repeated treatment. Synapse 1992;10:25-32 Hietala J, Kuoppamaki M, Majasuo H, et al. Sertindole is a serotonin 5-HT2C inverse agonist and decreases agonist but not antagonist binding to 5-HT2C receptors after chronic treatment. Psychopharmacology (Berl) 2001;157:180-7 Petit-Taboue MC, Landeau B, Barre L, et al. Parametric PET imaging of 5-HT2A receptor distribution with 18F-setoperone in the normal human cortex. J Nucl Med 1999;40:25-32

30.

Nyberg S, Olsson H, Nilsson U, et al. Low striatal and extra-striatal D2 receptor occupancy during treatment with the atypical antipsychotic sertindole. Psychopharmacology (Berl) 2002;162:37-41

Azorin JM, Kaladjian A, Fakra E, Adida M. Sertindole for the treatment of schizophrenia. Expert Opin Pharmacother 2010;11(18):3053-64 A comprehensive expert review on sertindole.

31.

Buchsbaum MS, Haznedar M, Newmark RE, et al. FDG-PET and MRI imaging of the effects of sertindole and haloperidol in the prefrontal lobe in schizophrenia. Schizophr Res 2009;114:161-71

Karamatskos E, Lambert M, Mulert C, Naber D. Drug safety and efficacy evaluation of sertindole for schizophrenia. Expert Opin Drug Saf 2012;11(6):1047-62 One of the most complete expert review which provides valuable information on efficacy and safety of sertindole in the treatment of schizophrenia.

32.

Muscatello MRA, Bruno A, Pandolfo G, et al. Emerging treatments in the management of schizophrenia. Focus on sertindole. Drug Des Devel Ther 2010;4:187-201

Arnt J, Skarsfeldt T. Do novel antipsychotics have similar pharmachological characteristics? A review of the evidence. Neuropsychopharmacology 1998;18:63-101 Hyttel L, Nielsen JB, Nowak G. The acute effect of sertindole on brain 5-HT2, D2 and alpha one receptors. J Neural Transm 1992;89:61-9 Mørk A, Witten LM, Arnt J. Effect of sertindole on extracellular dopamine, acetylcholine, and glutamate in the medial prefrontal cortex of conscious rats: a comparison with risperidone and

erythromycin on the CYP3A component of sertindole clearance in healthy volunteers. J Clin Pharmacol 1997;37(11):1056-61

exploration of mechanisms involved. Psychopharmacology (Berl) 2009;206:39-49

Int Clin Psychopharmacol 1998;13(Suppl 3):S65-70

33.

34.

35.

36.

Wong SL, Linen P, Mack RJ, Granneman GR. Effects of food, antacid, and dosage form on the pharmacokinetics and relative bioavailability of sertindole in healthy volunteers. Biopharm Drug Dispos 1997;18:533-41 Wang JS, Zhu HJ, Markowitz JS, et al. Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein. Psychopharmacology (Berl) 2006;187:415-23 Wong SL, Cao G, Mack RJ, Granneman GR. Pharmacokinetics of sertindole in healthy young and elderly male and female subjects. Clin Pharmacol Ther 1997;62:157-64 Wong SL, Menacherry S, Mulford D, et al. Parmacokinetics of sertindole and dehydrosertindole in volunteers with normal or impaired renal function. Eur J Clin Pharmacol 1997;52:223-7 Wong SL, Cao G, Mack RJ, Granneman GR. The effect of


37.

.

38.

.

Van Kammen DP, McEvoy JP, Targum SD, et al. A randomized, controlled, dose-ranging trial of sertindole in patients with schizophrenia. Psychopharmacology (Berl) 1996;124:168-75 An important dose-ranging trial on sertindole. Zimbroff DL, Kane JM, Tamminga CA, et al. Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Sertindole Study Group. Am J Psychiatry 1997;154:782-91 An important comparison of sertindole and haloperidol.

39.

Hale A, Azorin JM, Kasper S, et al. Sertindole improves both the positive and negative symptoms of schizophrenia: results of a phase III trial. Int J Psychiatry Clin Pract 2000;4:55-62

40.

Daniel DG, Wozniak P, Mack RJ, et al. Long-term efficacy and safety comparison of sertindole and haloperidol in the treatment of schizophrenia. Psychopharmacol Bull 1998;34:61-9 The first long-term comparison of sertindole and haloperidol.

..

41.

Hale AS, Azorin JM, Lemming OM, Mæhlum E. Sertindole in the long-term treatment of schizophrenia. Int Clin Psychopharmacol 2012;27(4):231-7

42.

Azorin JM, Murteira S, Hansen K, Toumi M. Evaluation of patients on sertindole treatment after failure of other antipsychotics: a retrospective analysis. BMC Psychiatry 2008;8:16

43.

Azorin JM, Strub N, Loft H. A doubleblind, controlled study of sertindole versus risperidone in the treatment of moderate-to-severe schizophrenia. Int Clin Psychopharmacol 2006;21:49-56

44.

Kane JM, Potkin SG, Daniel DG, Buckley PF. A double-blind, randomized study comparing the efficacy and safety of sertindole and risperidone in patients with treatment-resistant schizophrenia. J Clin Psychiatry 2011;72(2):194-204

45.

Kwon JS, Mittoux A, Hwang JY, et al. 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

1951


.

46.


.

47.

..

48.

49.

50.

51.

52.

53.

1952

previous treatments: a randomized, double-blind, parallel-group, flexible-dose study. Int Clin Psychopharmacol 2012;27(6):326-35 The first comparison of sertindole with olanzapine.

clozapine on MK-801 induced visual memory deficits in mice. Pharmacol Biochem Behav 2011;99(4):557-65 54.

Nielsen J, Emborg C, Gydesen S, et al. Augmenting clozapine with sertindole: a double-blind, randomized, placebocontrolled study. J Clin Psychopharmacol 2012;32:173-8 The first augmentation study of sertindole added to clozapine.

55.

Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;382(9896):951-62 An excellent, out-standing meta-analysis of SGAs.

56.

Rodefer JS, Nguyen TN, Karlsson JJ, Arnt J. Reversal of subchronic PCPinduced deficits in attentional set shifting in rats by sertindole and a 5-HT(6) receptor antagonist: comparison among antipsychotics. Neuropsychopharmacology 2008;33:2657-66 Goetghebeur P, Dias R. Comparison of haloperidol, risperidone, sertindole, and modafinil to reverse an attentional setshifting impairment following subchronic PCP administration in the rat-a back translational study. Psychopharmacology (Berl) 2009;202:287-93 Didriksen M, Skarsfeldt T, Arnt J. Reversal of PCP-induced learning and memory deficits in the Morris’ water maze by sertindole and other antipsychotics. Psychopharmacology (Berl) 2007;193:225-33 Broberg BV, Glenthøj BY, Dias R, et al. Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia-subchronic and early postnatal PCP treatment in attentional set-shifting. Psychopharmacology (Berl) 2009;206(4):631-40 Idris N, Neill J, Grayson B, et al. Sertindole improves sub-chronic PCPinduced reversal learning and episodic memory deficits in rodents: involvement of 5-HT(6) and 5-HT (2A) receptor mechanisms. Psychopharmacology (Berl) 2010;208:23-36 Mutlu O, Ulak G, Celikyurt IK, et al. Effects of olanzapine, sertindole and

57.

..

58.

59.

Nikiforuk A, Popik P. Effects of quetiapine and sertindole on subchronic ketamine-induced deficits in attentional set-shifting in rats. Psychopharmacology (Berl) 2012;220(1):65-74 Gallhofer B, Jaanson P, Mittoux A, et al. Course of recovery of cognitive impairment in patients with schizophrenia: a randomised double-blind study comparing sertindole and haloperidol. Pharmacopsychiatry 2007;40:275-86 Buchsbaum MS, Haznedar M, Newmark RE, et al. FDG-PET and MRI imaging of the effects of sertindole and haloperidol in the prefrontal lobe in schizophrenia. Schizophr Res 2009;114:161-71 Holstein DH, Csomor PA, Geyer MA, et al. The effects of sertindole on sensory gating, sensorimotor gating, and cognition in healthy volunteers. J Psychopharmacol 2011;25(12):1600-13 The first study on the effect of sertindole on sensory gating and cognition in healthy people. Nielsen RE, Levander S, Thode D, Nielsen J. Effects of sertindole on cognition in clozapine-treated schizophrenia patients. Acta Psychiatr Scand 2012;126(1):31-9 Nielsen RE, Odur F, Ostergaard T, et al. Comparison of the effects of Sertindole and Olanzapine on Cognition (SEROLA): a double-blind randomized 12-week study of patients diagnosed with schizophrenia. Ther Adv Psychopharmacol 2014;4(1):4-14

60.

Perquin LN, Steinert T. A review of the efficacy, tolerability and safety of sertindole in clinical trials. CNS Drugs 2004;18(Suppl 2):19-30

61.

Lewis R, Bagnall AM, Leitner M. Sertindole for schizophrenia. Cochrane Database Syst Rev 2005(3):CD001715 An excellent Cochrane review of sertindole for the treatment of schizophrenia.

..

62.

De Hert M, Mittoux A, He Y, Peuskens J. Metabolic parameters in the short- and long-term treatment of schizophrenia with sertindole or


risperidone. Eur Arch Psychiatry Clin Neurosci 2011;261:231-9 63.

..

Beach SR, Celano CM, Noseworthy PA, et al. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics 2013;54(1):1-13 Up-to-date and comprehensive review on recent literature regarding risk factors for QTc prolongation with antidepressants and antipsychotics.

64.

Witchel HJ, Hancox JC. Familial and acquired long QT syndrome and the cardiac rapid delayed rectifier potassium current. Clin Exp Pharmacol Physiol 2000;27:753-66

65.

Haverkamp W, Eckhardt L, Matz J, Frederiksen K. Sertindole: cardiac electrophysiological profile. Int J Psychiatry Clin Pract 2002;6:11-20

66.

Eckardt L, Breithardt G, Haverkamp W. Electrophysiologic characterization of the antipsychotic drug sertindole in a rabbit heart model of torsades de pointes: low torsadogenic potential despite QT prolongation. J Pharmacol Exp Ther 2002;300:64-71

67.

Nielsen J, Graff C, Hardahl T, et al. Sertindole causes distinct electrocardiographic T-wave morphology changes. Eur Neuropsychopharmacol 2009;19:702-7

68.

Nielsen J, Andersen MP, Graff C, et al. The effect of sertindole on QTD and TPTE. Acta Psychiatr Scand 2010;121:385-8

69.

Hertz S. NDA file. 2010. Available from: http://www.fda.gov/downloads/Drugs/ DrugSafety/PostmarketDrug Safety Information for Patients and Providers/ UCM234349.pdf

70.

Wilton LV, Heeley EL, Pickering RM, Shakir SA. Comparative study of mortality rates and cardiac dysrhythmias in postmarketing surveillance studies of sertindole and two other atypical antipsychotic drugs, risperidone and olanzapine. J Psychopharmacol 2001;15:120-6

71.

Peuskens J, Moore N, Azorin JM, et al. The European sertindole safety and exposure survey: a follow-up study of 8600 patients. Pharmacoepidemiol Drug Saf 2007;16:804-11

72.

Kasper S, M€oller H-J, Hale A. The European post-marketing observational sertindole study: an investigation of the safety of antipsychotic drug treatment.

Sertindole

a comprehensive model. Int J Psychiatry Clin Pract 1998;2(Suppl 2):S79-86


Eur Arch Psychiatry Clin Neurosci 2010;260:59-68 73.

Lanc¸on C, Toumi M, Sapin C, Hansen K. The Sertindole Safety Survey: a retrospective analysis under a named patient use programme in Europe. BMC Psychiatry 2008;8:57

78.

Lindstr€om E, Eberhard J, Fors BM, et al. A pharmacoeconomic analysis of sertindole in the treatment of schizophrenia in Sweden. Nord J Psychiatry 2011;65:403-13

74.

Thomas SHL, Drici MD, Hall GC, et al. Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP). Acta Psychiatr Scand 2010;122:345-55 An important postmarketing surveillance study on sertindole.

79.

Sonntag M, K€onig HH, Konnopka A. The estimation of utility weights in cost-utility analysis for mental disorders: a systematic review. Pharmacoeconomics 2013;31:1131-54

..

75.

76.

..

77.

Muldoon C, Cochran J. Mortality rates in three comparative cohorts of patients who received sertindole, olanzapine or risperidone: a hospital-based, retrospective study. J Outcomes Res 2006;10:47-55 Crocq MA, Naber D, Lader MH, et al. Suicide attempts in a prospective cohort of patients with schizophrenia treated with sertindole or risperidone. Eur Neuropsychopharmacol 2010;20:829-38 An important prospective study on suicide mortality during sertindole or risperidone treatment. Launois R, Graf von der Schulenburg MG, Knapp M, Toumi M. Cost-effectiveness of sertindole versus olanzapine or haloperidol:

80.

..

Kishimoto T, Agarwal V, Kishi T, et al. Relapse prevention in schizophrenia: a systematic review and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics. Mol Psychiatry 2013;18:53-66 An excellent review and meta-analysis on the effect of first-generation antipsychotics and SGAs on relapse prevention in schizophrenia.

81.

H. Lundbeck A/S. Sertindole: summary of product characteristics. H. Lundbeck A/S, Copenhagen; 2005

82.

Cleghorn JM, Kaplan RD, Szechtman B, et al. Neuroleptic drug effects on cognitive function in schizophrenia. Schizophr Res 1990;3:211-19

83.

Iasevoli F, Tomasetti C, Marmo F, et al. Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole.


..

84.

..

Psychopharmacology (Berl) 2010;212:329-44 An interesting preclinical study which demonstrated that sertindole and haloperidol differentially modulate proteins and signaling pathways of the glutamatergic postsynaptic density. Glassman AH, Bigger JT. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001;158:1774-82 A comprehensive review of the cardiac risk associated with AP treatment.

Affiliation Maria Rosaria Anna Muscatello1 MD PhD, Antonio Bruno†1 MD PhD, Paolo Micali Bellinghieri1,2 MD, Gianluca Pandolfo1 MD PhD & Rocco Antonio Zoccali3 MD † Author for correspondence 1 University of Messina, Department of Neurosciences, Section of Psychiatry, Policlinico Universitario, Via Consolare Valeria -- Messina 98125, Italy Tel: +39 090 22212092; Fax: +39 090 695136; E-mail: [email protected] 2 University of Messina, Department of Experimental and Clinical Medicine, Messina, Italy 3 Professor, University of Messina, Department of Neurosciences, Section of Psychiatry, Messina, Italy

1953

Efficacy and safety of sertindole in schizophrenia: a clinical review.

Sertindole: safety and tolerability profile.

Sertindole: a clinical efficacy profile.

Safety, efficacy and ethical issues regarding weight-loss medications.

Ophthalmology issues in schizophrenia.

Neurology issues in schizophrenia.

Cytokines in schizophrenia: methodological issues.

Sertindole improves both the positive and negative symptoms of schizophrenia: Results of a phase III trial.

IVF for fertility preservation in breast cancer patients--efficacy and safety issues.

Food Safety Issues in China.

Schizophrenia and substance abuse: prevalence issues.

Vitamin B6 safety issues.

Contemporary professional issues in research on schizophrenia.

Efficacy, safety, and impact on hospitalizations of paliperidone palmitate in recent-onset schizophrenia.

Sleep polygraphy in schizophrenia: methodological issues.

Long-term efficacy and safety of quetiapine in treatment-refractory schizophrenia: A case report.

Sertindole: cardiac electrophysiological profile.

Safety Issues Regarding Prescription Opioids.

Memory self-efficacy in schizophrenia.

Post-marketing surveillance of sertindole.

Sugammadex: A Scientific Review Including Safety and Efficacy, Update on Regulatory Issues, and Clinical Use in Europe.

Issues in treatment efficacy research with alcoholics.

Smoking ban in psychiatric wards raises safety and ethical issues.

Editorial: emerging issues in sociotechnical systems thinking and workplace safety.