International Journal of Psychiatry in Clinical Practice

ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20

Sertindole: a clinical efficacy profile A Hale To cite this article: A Hale (2002) Sertindole: a clinical efficacy profile, International Journal of Psychiatry in Clinical Practice, 6:1, 21-26 To link to this article: http://dx.doi.org/10.1080/13651500215966

Published online: 12 Jul 2009.

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2002 Martin Dunitz Ltd International Journal of Psychiatry in Clinical Practice 2002 Volume 6 (Suppl 1) Pages S21 ± S26

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Sertindole: a clinical efficacy profile ANTHONY HALE

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University of Kent at Canterbury, Kent, UK

Correspondence Address Anthony Hale, PhD FRCPsych, Professor of Mental Illness, Kent Institute of Medicine and Health Sciences, University of Kent at Canterbury, UK Tel: +44-1227-459-371 Fax: +44-1227-812-26 8 E-mail: [email protected]

Sertindole is an effective atypical antipsychotic drug that is associated with significant improvements in the symptoms of schizophrenia. It is at least as efficacious as haloperidol and risperidone in treating the overall and positive symptoms of schizophrenia and has been shown to have advantages over these two drugs with respect to the treatment of the negative symptoms of schizophrenia. In clinical trials, notable improvements in patients’ quality of life were observed, which suggest that patients prescribed sertindole would be more likely to adhere to treatment and continue taking the drug as part of their long-term treatment regimen. Continued treatment gives patients the best chance of avoiding relapse. Indeed, other benefits of sertindole demonstrated in clinical trials include relatively low relapse and re-admission rates. Sertindole could theoretically reduce the financial burden of schizophrenia on health- and social-care systems by reducing the need for re-hospitalization and by enabling patients to manage their illness and to live as normal a life as possible. (Int J Psych Clin Pract 2002; 6 (Suppl 1): S21 ± S26) Keywords sertindole negative symptoms hospitalization

INTRODUCTION

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ntipsychotic drug therapy has progressed considerably since the advent of chlorpromazine in the 1950s, which at the time represented a significant step 1 forward in psychiatric treatment. While conventional antipsychotics like chlorpromazine provide effective relief from the positive symptoms of schizophrenia ± hallucinations, delusions and disordered thinking1 ± they do so at a price. That price is a poor side-effect profile that includes, among others, the extremely unpleasant extrapyramidal symptoms (EPS) of parkinsonism, dystonia, akathisia and tardive dyskinesia.2 Moreover, the conventional antipsychotics have little effect on the negative symptoms of schizophrenia and can also 3 adversely affect cognitive function. Side effects can be treated with other drugs but this is rarely a satisfactory solution. Such treatments not only add to the drug burden on patients but also can themselves cause 4 additional side effects. Not surprisingly, patients have trouble complying with treatments that cause unpleasant side effects and poor compliance is a major factor in relapse and re-admission to hospital.5 Relapses or exacerbations of psychotic symptoms give rise to a high psychological, social and financial

schizophrenia quality of life

burden that affects patients, their friends, their relatives, and health- and social-care systems.6 While the conventional antipsychotics were useful, their adverse effects on patients’ quality of life and ability to function, and the availability of better-tolerated alternative 7 treatments, has led to these drugs being superseded. The development of the so-called atypical antipsychotic drugs, that began with clozapine, heralded a new era of antipsychotic therapy and one in which the focus of research shifted to the development of drugs with receptor binding profiles that would provide high levels of antipsychotic efficacy in combination with low levels of side effects.8 ,9 Such drugs would enable patients to control their symptoms and give them the best possible chance of living a normal life. The atypical antipsychotics are now accepted as firstline treatment for schizophrenia and, as a result, treatment goals have altered.1 0 No longer is the goal just to reduce psychotic symptoms. Instead, treatment is now expected to decrease the number of relapses and re-admissions to hospital by enabling patients to remain on a long-term therapy that enhances their quality of life and enables them to function normally.6 Ideally, antipsychotic treatments should also address the negative symptoms of schizophrenia, such as under-activity, low drive, social with-

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drawal and emotional apathy, improve impaired cognitive functioning, and reduce depression and the risk of suicide.1 1 ,1 2 Moreover, new treatments must also provide pharmacoeconomic benefits over the older, cheaper con6 ventional antipsychotics. Sertindole (Serdolect1) is a phenyl indole derivative that has been shown to be an effective atypical antipsychotic therapy in randomized clinical trials.1 3 Currently available data from the large-scale trials conducted in North America and Europe, which are briefly reviewed below, suggest that sertindole is a potentially more effective allround antipsychotic treatment than either haloperidol or risperidone.

SERTINDOLE

HALOPERIDOL

THE LANDMARK STUDY A complex but groundbreaking North American study ± the Landmark Study ± demonstrated the clinical efficacy of sertindole in 497 patients.1 4 This study was unusual in that it was not only placebo-controlled but it also included an active comparator drug ± haloperidol ± at three fixed dosages. This study defined the optimum dose range for haloperidol. This randomized, double-blind, multicentre study included seven treatment arms: sertindole at three dosages (12, 20 and 24 mg/day), haloperidol at three dosages (4, 8 and 16 mg/day) and placebo. Inpatients with at least moderately severe schizophrenia were included in the study. All patients were therefore required to have total scores of 8 or more points for any two of the Brief Psychiatric Rating Scale (BPRS) positive-symptom items (hallucinatory behaviour, conceptual disorganization, unu8 ,1 4 sual thought content or suspiciousness). To avoid the inclusion of treatment-refractory patients, only those patients who had either not been treated within the past 5 years or who were known to have responded to antipsychotic drug treatment were included in the study.1 4 Following a single-blind placebo lead-in period of up to 1 week’s duration, patients were randomized to one of the treatment groups, but only if their BPRS scores had not improved by 20% or more during the lead-in period. Patients received double-blind treatment for 8 weeks in total. Both sertindole and haloperidol were significantly more effective than placebo in reducing the severity of patients’ symptoms as measured by the Positive and Negative Symptom Scale (PANSS) total score (Figure 1A), BPRS scores and Clinical Global Impression of Improvement (CGI-I) scores (data not shown). Only haloperidol at a dose of 4 mg/day failed to produce significant improvements in 14 CGI scores at the end of treatment (data not shown). When compared to placebo, all dosages of sertindole significantly reduced PANSS positive symptom scores, as did haloperidol at all three dosages (P40.05) (data not shown).15 Scores on the positive subscale of the BPRS were also significantly reduced by all active treatments (data not shown).

While few differences were observed between sertindole and haloperidol with respect to total and positive symptoms, the two drugs differed in their effect on the negative symptoms of schizophrenia. Both drugs improved negative symptoms, as measured by the PANSS negative subscale score, but only sertindole at a dose of 20 mg/day produced a statistically significant change from baseline (P40.05) (Figure 1B).1 4 ,1 6

STUDY M93-098 Like the Landmark Study, study M93-098 compared sertindole (20 and 24 mg/day) with both haloperidol (16 mg/day) and placebo.1 6 This randomized, double-blind study took place in 30 centres and recruited 462 patients with schizophrenia. In this study, all three active treatments significantly improved PANSS total, PANSS positive and general

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Figure 1 ( A ) M e a n c h a n g e fro m b a se lin e to fin a l e v a lu a tio n in P A N S S to ta l s c o r e in 4 77 p a tie n ts w ith s ch iz o p h r e n ia tre a te d w ith se rtin d o le , h a lo p e r id o l o r p la c e bo IT T 14 p o p ula tio n . * P 40 .0 5 v s p la c e bo ; L O C F , a n a ly sis o f v a ria n c e ( A N O V A ) . ; ( B ) M e a n ch a ng e fro m b a s e lin e to fin a l e v a lu a tio n in P A N S S n eg a tiv e s y m p to m su b sc a le sc o re in p a tien ts w ith s c h iz o p h re n ia tre a te d w ith e ith e r se rtin d o le o r h a lo p e rid o l fo r 8 w e e k s ( IT T ) * P 40 .0 5 v s p la c e b o , L O C F , w e ig h te d c o m p a r is o n 1 4 ,1 6 fro m th e A N O V A

Sertindole ± clinical efficacy profile

psychopathology subscales, BPRS total, and CGI improvement scores compared with placebo (P40.05). However, sertindole (24 mg/day) also significantly reduced PANSS negative subscale scores compared with placebo (P40.05) (data not shown).

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THE EUROPEAN STUDY In a multicentre study conducted in 89 centres in 11 European countries, 617 inpatients with schizophrenia of similar severity to that in patients included in the Landmark Study were enrolled.1 3 ,1 7 Patients were required to score more than 2 points on two of the following four PANSS items and score a sum of 8 or more points for any two of the four items: conceptual disorganization, hallucinatory behaviour, suspiciousness and unusual thought content. As in the Landmark Study, patients, while acutely ill, had previously benefited from antipsychotic medication or had not received previous treatment. Patients received one of four dosages of sertindole (8, 16, 20 or 24 mg/day) or a reference dose of haloperidol (10 mg/day). Treatment continued for 8 weeks after a placebo run-in period of up to 1 week. Sertindole at a dose of 8 mg/day has been shown to have an efficacy similar to placebo,1 8 and in this study, sertindole 8 mg/day acted as a lower reference dose for a dose ± effect evaluation. Of the 617 patients enrolled, 595 were included in the intent-to-treat (ITT) population. Sertindole (16 and 24 mg/ day) and haloperidol (10 mg/day) provided significant symptomatic improvement on the PANSS total score compared with sertindole at a dose of 8 mg/day (Figure 2A). Sertindole (16 mg/day) was significantly more effective than haloperidol (10 mg/day) in improving patients’ negative symptoms, as measured by the PANSS negative subscale score (Figure 2B). It is not clear why in this study sertindole 20 and 24 mg/day dosages should not have provided significant improvements in the negative symptoms compared with haloperidol. These dosages have been shown to be effective in relieving the patients’ negative symptoms in the Landmark Study and the M93-098 Study.

SERTINDOLE

RISPERIDONE

Sertindole was also compared with risperidone in a multicentre, randomized, double-blind, flexible-dose study conducted in France. The study was planned to include 400 patients but discontinued early as a result of the suspension of the marketing authorizations of sertindole. The data have 15 not previously been published. Data are available for 186 patients who were treated with either 12 ± 24 mg sertindole administered once daily (n=89) or 4 ± 10 mg risperidone administered twice daily (n=97) for 12 weeks after a placebo washout period. During an initial 16-day titration period, sertindole was started at 4 mg/day and was increased by 4 mg every fourth day up to 16 mg/day, whilst risperidone was initially dosed at 2 mg daily, increasing every fourth

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Figure 2 ( A ) M e a n c h a n g e fro m b a s e lin e to fin a l e v a lu a tio n in P A N S S to ta l s co re in 59 5 p a tie n ts w ith s c h iz o p h re n ia tre a te d w ith e ith e r s er tin d o le o r h a lo p e rid o l fo r 8 17 w e e k s ( IT T ) . * P 40 .0 5 c o m p a re d w ith se rtin d o le ( 8 m g /d a y ) , L O C F , A N O V A . (B) Mean change from baseline to final evaluation in PANSS negative symptom subscale score in patients with schizophrenia treated with either sertindole or 15 haloperidol for 8 weeks (ITT). *P40.05 vs haloperidol, OC, ANOVA

day to 6 mg/day. The investigator was free to adjust the dose according to the patient’s response to treatment between days 17 and 84 (dose range 12 ± 24 mg/day for sertindole and 4 ± 10 mg/day for risperidone). At the end of the study, the mean modal dosages were 16.4 and 6.7 mg/day for sertindole and risperidone, respectively. Both these dosages approximated the optimal clinically relevant dosages and were therefore appropriate to compare. Moreover, the risperidone dose was not sufficiently high to give rise to a high risk of EPS. Sertindole and risperidone were similarly effective in improving CGI (severity and improvement), Drug Attitude Inventory and Global Assessment of Functioning scores. Both treatment groups showed improvement in total PANSS score from baseline to endpoint (mean change: sertindole 29.3; risperidone 25.8 points; LOCF). Repeated measurements analysis of PANSS total scores showed a

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highly statistically significant difference in favour of sertindole when compared to risperidone (P=0.0006). Moreover, the sertindole-treated patients had statistically significantly greater improvement than the risperidonetreated patients on the PANSS negative subscale scores from baseline to endpoint (Figure 3).

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LONG-TERM TREATMENT WITH SERTINDOLE In a North American randomized, double-blind clinical trial, 282 patients with schizophrenia were treated with either sertindole (24 mg/day) or haloperidol (10 mg/day) 19 for 12 months. Patients in both the sertindole and haloperidol groups had improved total PANSS scores from baseline to Month 12. There were no statistically significant differences between the two treatments in terms of the reduction in PANSS total scores although mean scores were consistently lower in the sertindole group throughout the study. In addition, while haloperidol had little effect on patients’ negative symptoms, sertindole reduced scores on the Scale for the Assessment of Negative Symptoms (SANS). However, the difference was statistically significant at only one time point (Month 2) of the study (P40.05 vs 19 haloperidol; Figure 4). Most importantly, this study also showed that patients treated with sertindole were significantly less likely to experience an exacerbation of schizophrenic symptoms resulting in re-hospitalization and were less likely to discontinue their medication than were patients treated

Figure 3 M e a n c h a n g e fro m b a s e lin e to fin a l e v a lu a tio n in P A N S S ne g a tiv e sy m p to m s u bs c a le sc o re in p a tie n ts w ith s c h iz o p h re n ia tre a te d w ith eith e r s e rtin d o le o r ris p e rid o n e fo r 8 w e e k s ( IT T , L O C F ) , * P 40 .0 5 vs risp e rid o n e , fro m c o m p a ris o n 15 of AN COVA

with haloperidol (P40.05), ITT population. After 12 months of treatment, only two out of 94 patients in the sertindole group had been re-admitted to hospital, compared with 12 of the 109 patients assigned to the haloperidol group. Similarly, only two patients on sertindole were withdrawn from the study due to noncompliance compared with 13 in the haloperidol group. The mirror study, a classic open-label study, followed 38 patients who took part in sertindole clinical trials and continued to take the drug for 1 year after the trials were 1 9 ,2 0 completed. The number of days spent in hospital by this group was retrospectively compared to that of a similar cohort of 42 patients who underwent psychiatric treatment for the same period. The mean number of days spent in hospital prior to treatment with sertindole was 28 days, which was similar to that in the usual-treatment group (Figure 5). However, when looking at re-hospitalization during treatment with sertindole, patients spent significantly fewer days in hospital (a mean of 4), compared with 18 days in the usual-treatment group (P40.05). Moreover, no corresponding increase in the use of outpatient care facilities was observed, which suggests that sertindole reduces the financial burden of schizophrenia on healthcare resources.

SERTINDOLE AND NEGATIVE SYMPTOMS The clinical trials suggest that sertindole is effective against the negative symptoms of schizophrenia. However, the dose ± response relationship does not appear to be straightforward. Though all dosages of sertindole reduced the patients’ negative symptoms, there was no consistent statistically significant optimal dose ± response relationship for therapeutic effect against the negative symptoms (the

Figure 4 M e a n c h a n g e fr o m ba s e lin e in to ta l S A N S s co re s in 1 9 9 p a tie n ts w h o r e ce iv e d eith e r s e rtin d o le ( 2 4 m g /d a y ) o r h a lo p e rid o l ( 1 0 m g /d a y ) fo r 1 2 m o n th s ( IT T , 19 O C ) . * P 40 .0 5 vs h a lo p e rid o l, w e ig h ted c o m p a ris o n o f th e A N O V A

Sertindole ± clinical efficacy profile

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in patients with schizophrenia. Only the European study 17 has attempted to assess these effects. This study, however, did provide promising results. Sertindole, at a dose of 16 mg/day, significantly improved the PANSS cognitive component score compared with the 8 mg/day reference dose. Haloperidol (10 mg/day) did not significantly improve cognition in this study (Figure 6).1 5

SERTINDOLE AND QUALITY OF LIFE

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Figure 5 N u m b e r o f d a y s s p e n t in h o s p ita l in th e y e a r p r io r to tre a tm e n t w ith e ith e r s er tin d o le o r us u a l tre a tm e n t ( P e rio d 1 ) a n d th e n u m be r o f d a y s s p e n t in h o sp ita l d u e to re -h o s p ita liz a tio n /re a d m iss io n d u rin g th e fo llo w in g 1 2 m o n th s o f 20 tre a tm e nt ( P er io d 2 ) . * P 40.0 5 v s `u su a l c a r e’ g r o u p

Using Heinrich’s Quality of Life Scale in a long-term clinical trial, it was observed that patients receiving sertindole experienced a numerically larger improvement in their quality of life (mean change 10.32; n=45), as compared with haloperidol (mean change 3.28; n=54). The sertindole dose in this study (24 mg/day) was higher than that which would now be considered appropriate, as it is more likely to be associated with side effects. Although the between-groups difference was not statistically significant, 15 it revealed a trend that needs to be further elucidated.

CONCLUSION

Figure 6 M e a n c h a n g e fro m b a se lin e to fin a l e va lu a tio n in P A N S S c o g n itiv e c o m p o n e n t s co re in 5 95 p a tie n ts ( IT T , O C ) tre a te d w ith e ith er s e rtin d o le ( 8 ± 2 4 m g /d a y ) o r 15 h a lo p e rid o l ( 1 0 m g /d a y ) . * P 40 .0 5 v s s e rtin d o le 8 m g , 1 7 A N O V A

16-mg dose level in the European study, the 20-mg dose level in the Landmark Study, and the 24-mg dose level in Study M93-098 were statistically significantly different from comparator). Furthermore, the direct comparison of sertindole to risperidone showed a statistically significantly greater improvement with sertindole (12 ± 24 mg) on the PANSS negative subscale score change from baseline when compared to risperidone (4 ± 10 mg).

SERTINDOLE AND COGNITION Animal models predict that sertindole does not impair cognitive function in patients2 1 ,2 2 but, as yet, few data are available on the effects of sertindole on cognitive function

In conclusion, sertindole has clearly been shown to be an effective antipsychotic drug in several randomized, double-blind clinical trials. It is at least as efficacious as haloperidol and risperidone, and could offer greater benefits in terms of its effect on the negative symptoms of schizophrenia, even when compared to some other atypical antipsychotics. An explorative study also suggests that sertindole improves patients’ cognitive abilities, although this and the drug’s effect on negative symptoms must be confirmed in future clinical trials. A study has also shown a trend of patients’ quality of life improving more during sertindole treatment than during haloperidol treatment. In combination with the relatively low relapse rates observed during long-term sertindole treatment, these benefits confirm that it is effective in the treatment of patients with schizophrenia.

KEY POINTS . Sertindole is at least as efficacious as haloperidol and risperidone . Sertindole is superior to haloperidol and risperidone in relieving patients’ negative symptoms of schizophrenia . Sertindole has the potential to increase patients’ quality of life . Animal models predict that sertindole does not impair cognitive function of patients

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14. Zimbroff DL, Kane JM, Tamminga CA, et al (1997) Controlled, dose ± response study of sertindole and haloperidol in the treatment of schizophrenia. Am J Psychiatry 154: 782 ± 91. 15. H. Lundbeck A/S. Data on file. 16. Kane JM (1998) Sertindole: a review of clinical efficacy. Int Clin Psychopharmacol 13 (suppl. 3): S59 ± 64. 17. Hale AS (1998) A review of the safety and tolerability of sertindole. Int Clin Psychopharmacol 13 (suppl. 3): S65 ± 70. 18. van Kammen DP, McEvoy JP, Targum SD, et al (1996) A randomized, controlled, dose-ranging trial of sertindole in patients with schizophrenia. Psychopharmacol (Berlin) 124: 168 ± 75. 19. Daniel DG, Wozniak P, Mack RJ, et al (1998) Long-term efficacy and safety comparison of sertindole and haloperidol in the treatment of schizophrenia. Psychopharmacol Bull 34: 61 ± 9. 20. Nabulsi AA, Braus AJ, Mack RJ, et al (1996) Reduction of hospital days in sertindole treated patients ± one year findings. Poster presented at 149th Annual Meeting of the American Psychiatric Association (APA), New York, USA. 21. Didriksen M (1995) Effects of antipsychotics on cognitive behaviour in rats using the delayed non-match to position paradigm. Eur J Pharmacol 281: 241 ± 50. 22. Skarsfeldt T (1996) Differential effect of antipsychotics on place navigation of rats in the Morris water maze. A comparative study between novel and reference antipsychotics. Psychopharmacology 124: 126 ± 33. 23. Heinrichs DW, Hanlon TE, Carpenter WT (1984) The quality of life scale: an instrument for rating the schizophrenic deficit syndrome. Schizophr Bull 10: 388 ± 98.

Sertindole: a clinical efficacy profile.

Sertindole is an effective atypical antipsychotic drug that is associated with significant improvements in the symptoms of schizophrenia. It is at lea...
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