International Journal of Psychiatry in Clinical Practice
ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20
Sertindole: safety and tolerability profile S Kasper To cite this article: S Kasper (2002) Sertindole: safety and tolerability profile, International Journal of Psychiatry in Clinical Practice, 6:1, 27-32 To link to this article: http://dx.doi.org/10.1080/13651500215967
Published online: 12 Jul 2009.
Submit your article to this journal
Article views: 8
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijpc20 Download by: [Washington University in St Louis]
Date: 06 November 2015, At: 16:39
#
2002 Martin Dunitz Ltd International Journal of Psychiatry in Clinical Practice 2002 Volume 6 (Suppl 1) Pages S27 ± S32
S27
Sertindole: safety and tolerability profile SIEGFRIED KASPER
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
Department of General Psychiatry, University of Vienna, Austria
Correspondence Address Siegfried Kasper, Professor, MD, UniversitaÈtsklinik fuÈr Psychiatrie, Klinische Abteilung fuÈr allgemeine Psychiatrie, WaÈhringer GuÈ rtel 18±20, A-1090 Vienna, Austria Tel: +43 1 40 400 3538 Fax: +43 1 40 400 3099 E-mail: [email protected]
Sertindole is a novel generation or atypical antipsychotic drug that has recently been re-introduced to the market. The safety and tolerability profile of sertindole have demonstrated a positive benefit/risk ratio in clinical trials and post-marketing studies. The number of patients who experienced extrapyramidal symptoms (EPS) while taking sertindole in clinical trials was similar to that of patients on placebo, and significantly less than that of patients on haloperidol. The relative lack of EPS is probably the result of the drug’s highly selective blockade of limbic dopamine D2 receptors and its lack of effect on other dopamine D2 receptors, but may be due to low occupancy at dopamine D2 striatal receptors. Sertindole also has a high affinity for serotonin 5-HT2 and a1 receptors. It has been shown not to cause sedation and its propensity to cause anticholinergic side effects is low, probably due to its lack of antihistamine and antimuscarinic activity. Sertindole does not cause any clinically significant changes in serum prolactin levels. QT interval prolongation does occur in some patients. The sertindole mortality rate is comparable to that of both risperidone and olanzapine (1.46, 1.75 and 1.20, respectively). Overall, sertindole is a well-tolerated drug that does not cause EPS, sedation or hyperprolactinaemia. (Int J Psych Clin Pract 2002; 6 (Suppl 1): S27 ± S32) Keywords sertindole tolerability
INTRODUCTION
T
he long list of non-arrhythmic compounds associated with QT interval prolongation has generated much concern for regulatory bodies and clinicians. In some cases, this has led to the withdrawal of a drug from the market. In the case of sertindole, the compound was suspended for 4 years while additional data were collected and analysed. The data allowed the CPMP to lift the suspension on the basis of a positive benefit/risk profile. The circumstances of the suspension and the data supporting the re-introduction 1 ,2 are presented. The most unpleasant and severe side effects associated with conventional antipsychotic drugs are extrapyramidal symptoms (EPS), which require concomitant anti3 ,4 cholinergic drug therapy. These drugs offer control of the positive symptoms of schizophrenia ± hallucinations, delusions, and disordered thinking ± and were a significant step forward in the treatment of schizophrenia. The atypical or novel generation antipsychotics not only offer relief of the positive symptoms of schizophrenia, but
safety schizophrenia
are also better than the old drugs at relieving the negative symptoms, such as blunted affect, withdrawal and anergia, 5 ,6 while causing lower levels of EPS. However, while the atypical antipsychotics are less likely to cause EPS than the older drugs, they can induce sexual dysfunction, weight gain and diabetes, and these side effects are gaining importance as more and more patients are prescribed 7 atypical antipsychotic drug therapy. Schizophrenia is often a chronic disorder that requires long-term drug treatment to enable patients to function and lead normal daily lives without frequent admissions to hospital. Patients must therefore be comfortable taking, in many cases, lifelong medication. Patients with schizophrenia are therefore no different from other patients with chronic diseases in that they need drugs to control their symptoms, that are easy to take and that do not adversely affect their lives. In the case of antipsychotic drug therapy, this means treatments that do not cause EPS, sedation, cognitive impairment, weight gain or sexual dysfunction, and, obviously, drugs that do not shorten patients’ lives.8 Sertindole, as an atypical antipsychotic, is one option open to patients with schizophrenia. It is effective against
S28
S Kasper
the positive symptoms of the illness and also has been 9 shown to reduce the negative symptoms. The purpose of this paper is to review certain aspects of the drug’s tolerability profile that could influence both the decision to prescribe sertindole and the patient’s decision to continue taking it as part of a long-term treatment plan.
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
QT INTERVAL PROLONGATION The QT interval corrected for heart rate (QTC interval) is affected by several factors, including time of day, gender and age, as well as some drugs. QTC prolongation is often considered associated with the development of serious ventricular arrhythmias, one of the most severe forms of which is torsades de pointes, which can lead to sudden cardiac death. Sertindole, like e.g., haloperidol and ziprasidone, is known to cause a degree of QTC prolongation. However, based on pharmacological and clinical properties, important counter-regulatory mechanisms limit 1 ,2 the arrhythmogenic potential of sertindole. An absolute value in the QTC interval in excess of 10 500 ms is considered clinically significant. In clinical trials, prolonged QTC interval was observed in 3 ± 5% of patients and 2% had a QTC F (Fredericia correction) interval in excess of 500 ms at any time during the 1 1 ,1 2 studies. These percentages should be viewed in the light of the fact that a standard lead on the ECG was not predefined but rather the maximum value from any lead was recorded. The effect of sertindole on the QT interval 13 appears to be dose-related but, in the clinical trials, there have been no documented cases of ventricular arrhythmias or torsades de pointes identified in any patient treated with 11 the prescribed dosages of sertindole. In all but one study in the clinical development programme, the selection criteria did not exclude patients with cardiovascular history. All patients were monitored electrocardiographically before the start of treatment, during dose titration, and during treatment, resulting in 11 000 ECG recordings. Safeguards in the product’s summary of product characteristics will avoid the drug being prescribed to high-risk patients. In most patients, sertindole is unlikely to cause ventricular arrhythmias and the low risk of such events is outweighed by the benefits of the drug.
MORTALITY In contrast to clinical trials of drugs, such as risperidone and olanzapine, the sertindole clinical trial programme did not exclude patients with cardiovascular risk factors. Despite this, the mortality rates recorded in clinical trials were comparable to those of olanzapine and risperidone 12 (Table 1). Moreover, post-marketing surveillance studies have shown that, as patient exposure to sertindole rose after the drug was launched, the mortality rate did not change.1 1
Most importantly, with regard to concerns over the drug’s cardiac safety, sertindole is not associated with a cardiac death rate that is significantly different from either risperidone or olanzapine. In fact, in clinical trials, the cardiac mortality rate per 100 patient-years exposure (PYE) was 0.31 deaths/100 PYE for sertindole compared with 0.23/100 PYE for risperidone and 0.53/100 PYE for olanzapine.1 1 Moreover, suicide rates were lowest among patients treated with sertindole (Table 1).1 2
EPS Not surprisingly, patients often discontinue treatment when they experience EPS. This unpleasant side effect may be associated with social stigma and suicide among 14 patients with schizophrenia. In a large German drug surveillance study, Grohmann et al (1994) found that the two most common reasons for discontinuing drug treatment among 7877 patients were parkinsonian symptoms and akathisia, two of the most common symptoms 15 associated with EPS. Almost 250 patients discontinued treatment due to parkinsonian symptoms and almost 200 because of akathisia. Sertindole, like other atypical antipsychotics, does not burden patients with EPS and this fact is exemplified by the results of a large North American study in which 497 patients received sertindole, haloperidol or placebo for 8 weeks. 9 In this study, EPS experienced by patients treated with sertindole were not significantly different than EPS reported by patients treated with placebo (Figure 1). However, the proportion of patients receiving placebo who experienced EPS was relatively high, probably as a result of patients stopping conventional antipsychotic treatment to take part in the study or as a result of schizophrenia itself. Nonetheless, the incidence of EPS among patients treated with sertindole was low and patients did not develop these symptoms as the study continued. This is in marked contrast to the group of patients treated with haloperidol, whose risk of developing EPS increased as the study progressed. Likewise, the difference between the number of patients treated with sertindole or placebo using anti-EPS
Table 1 All-cause mortality and suicide rates (per 100 patient-years) during clinical trials of sertindole, haloperidol, risperidone, and olanzapine 12 (mean and 95% Poisson’s confidence interval).
Antipsychotic
All-cause mortality mean (95% CI)
Sertindole Haloperidol Risperidone Olanzapine
1.46 1.78 1.75 1.20
(0.96 ± 2.14) (1.09 ± 2.75) (0.98 ± 2.88) (0.4 ± 2.90)
Suicide rate, mean (95% CI) 0.45 0.98 1.05 0.51
(0.19 ± 0.89) (0.49 ± 1.75) (0.47 ± 2.00) (0.06 ± 1.84)
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
Sertindole: safety and tolerability profile
Figure 1 P e rc e n ta g e o f p a tie n ts w h o e xp e rie n c e d E P S d u rin g 8 w e e k s o f tre a tm e n t w ith e ith er se r tin d o le ( 1 2 , 20 o r 2 4 m g /d a y ) , h a lo p e r id o l ( 4 , 8 o r 1 6 m g /d a y ) , o r p la c e b o ( * P = 0 .0 0 1 v s p la c e bo ; {P 40 .0 5 v s a n y se rtind o le d o s e ; F is ch e r ’s e xa ct 9 te s t, n = 49 7 p a tie n ts) .
medication during the study was not statistically significant. Again, significantly more patients treated with haloperidol used anti-EPS medication (Figure 2). Similarly, in the European study,1 6 ,1 7 scores on three movement rating scales [Barnes Akathisia Scale (BAS), Simpson Angus Rating Scale (SAS) and Abnormal Involuntary Movement Scale (AIMS)] either improved (8, 16 and 20 mg/day) or were unchanged (24 mg/day) during treatment with sertindole (Figure 3). In the haloperidol group, mean SAS, BAS, and AIMS scores were statistically significantly worse relative to 8 mg/day sertindole. As in the North American study, the highest dose of sertindole (24 mg/day) was associated with higher levels of EPS than the lower, recommended doses of the drug (12 ± 20 mg/ day). The lack of EPS observed during treatment with sertindole could be due to the result of the drug’s ability to block serotonin (5-hydroxytryptamine) 5-HT2 receptors as well as its relatively lower affinity for striatal dopamine D2 receptors, a feature characteristic of several atypical antipsychotics.1 8 ,1 9 ,2 0 The propensity of haloperidol to cause EPS is lowest using a dose of 4 mg/day ± 21 it possesses a much lower affinity for 5-HT2 receptors and therefore most likely cannot attenuate these symptoms to the same extent as an atypical antipsychotic (Figure 1). High D2 receptor occupancy is often associated with antipsychotic effectiveness against the positive symptoms 22 of schizophrenia. However, clozapine is known to have a low affinity for these receptors but is a highly effective antipsychotic drug. Indeed, sertindole, risperidone and quetiapine all have relatively low D2 occupancy values (Figure 4). The link between EPS and D2 receptor occupancy is more certain: sertindole, clozapine and quetiapine at commonly employed therapeutic doses fail to reach the receptor occupancy threshold of approximately 70%
S29
Figure 2 P e r ce n ta g e o f p a tie nts w h o to o k a n ti-E P S m e d ic a tio n d ur ing 8 w e e k s o f tre a tm e n t w ith e ith e r s e rtind o le ( 1 2 , 2 0 o r 2 4 m g /d a y ) , h a lo p e rid o l ( 4 , 8 o r 16 m g /d a y ) , o r p la c e b o ( * P 40 .0 5 v s a ll th r e e s e rtin d o le g ro up s a n d p la c e bo ; 9 F isc h e r’s ex a c t tes t, n = 4 9 7 p a tie n ts ) .
Figure 3 C h a n g e fro m ba se lin e to fin a l e v a lu a tio n in m o v e m e n t ra tin g s c a le s c o re s fo r 61 7 p a tie n ts ( IT T p o p u la tio n ) tre a te d w ith e ith e r se rtin d o le ( 8, 1 6 , 2 0 o r 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 8 w e e k s ( * P 40 .0 5 vs se r tin d o le 8 m g g ro u p ) , n= 6 1 7 p a tie nts . S A S , S im p s o n A n g u s R a tin g S c a le ; B A S , B a rn e s A k a th isia S ca le; 17 A IM S , A bn o rm a l In v o lu n ta ry M o v e m e n t S c a le . T h e m e a n s c o r e fo r 2 4 m g /d a y se rtin d o le w a s 0 .0 fo r a ll m o v e m e n t r a ting s ca le s .
required to trigger EPS, which helps explain the low level 2 3 ,2 4 of EPS associated with these drugs. At a low dose (4±6 mg/day), risperidone also fails to reach the EPS D2 receptor occupancy threshold but does so at higher doses (48 mg/day); olanzapine reaches the threshold even at a 25 dose of 10 mg. The relative lack of EPS with these drugs 18 might be explained by their activity at 5-HT2 receptors 24 and, in the case of olanzapine, its anticholinergic activity. The conventional antipsychotic haloperidol occupies 88% of receptors, which, as expected, is well in excess of the EPS threshold. If the risk of EPS increases as the dose of some antipsychotics rises, it may be reasonable to presume that patients with refractory schizophrenia are more likely to experience EPS, as they are given higher drug doses than
S30
S Kasper
events that were reported by 510% of sertindole-treated 11 patients.
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
COGNITION
Figure 4 39 D 2 re c ep to r o c c u p a n c y ( % ) o f va rio u s a n tip s y c h o tic d ru g s.
other patients. However, even patients with refractory schizophrenia are less likely to experience EPS while taking sertindole compared to patients taking risperidone. In a 12week multi-centre, double-blind, randomized study with centres in USA and Canada, including 321 treatmentresistant schizophrenic patients, 21% of patients treated with sertindole (12 ± 24 mg/day) experienced EPS-related treatment-emergent adverse events, compared with 36% of those treated with risperidone (6 ± 12 mg/day), P50.01 11 chi-square test. In a 12-week, multi-centre, double-blind, randomized, flexible dose study conducted in France in 186 schizophrenic patients, similar results were obtained: only 19% of patients treated with sertindole (12 ± 24 mg/ day) experienced EPS, compared with 28% of those treated 11 with risperidone (4 ± 10 mg/day). In the latter study the difference between sertindole and risperidone was reduced, possibly because the risperidone dose was slightly lower than in the former study.
SEDATION The study by Grohmann et al (1994) revealed that, after EPS, sedation was the next most common reason for 15 patients discontinuing their antipsychotic medication. Sedation is a serious and common side effect that reduces patients’ quality of life and prevents them from being effectively rehabilitated. Sertindole, however, does not cause sedation,1 6 probably because it has a very low affinity 26 for histamine H1 receptors.
ANTICHOLINERGIC SIDE EFFECTS The propensity of sertindole to cause anticholinergic effects is small, probably due to its low affinity for muscarinic 21 cholinergic receptors. Adverse events that could be attributed to anticholinergic effects were infrequent in sertindole trials. Constipation and dry mouth were the only potentially anticholinergic treatment-emergent adverse
Animal models predict that sertindole does not impair cognitive function in patients.2 7 The Morris water maze is a widely used animal model for both spatial learning and 28 memory. As the task is easy for control rats, no improvement in spatial learning is expected, and so the model can be regarded as a test for side effects (e.g. memory or learning impairment).2 9 Sertindole, at clinically equivalent dose levels, did not affect spatial learning in this 29 model. As yet, few data are available on the effects of sertindole on cognitive function in patients with schizophrenia. Only one study has attempted to assess these 17 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 inactive comparator dose. Haloperidol (10 mg/day) did not significantly improve cognition in this 30 study.
WEIGHT GAIN Weight gain can be a significant problem for people with schizophrenia and, in conjunction with other risk factors, such as poor diet, little exercise and smoking, it can raise patients’ risk of cardiovascular disease and diabetes. In addition to the health risk of weight gain, there is also the added psychological and social burden of weight gain. Since the atypical antipsychotics are now accepted as firstline treatment for schizophrenia, side effects such as weight gain are increasingly mentioned by patients, who previously would have complained that EPS was the most 31 worrying side effect of their treatment. It is unclear which mechanism causes weight gain during treatment with antipsychotic drugs.3 2 Indeed, in some patients, weight gain is simply the result of regaining weight lost in the period immediately prior to admission to hospital, when they experienced acute psychosis. Sertindole, like other antipsychotics, does cause a degree of weight gain. In the short-term studies (n=684), a significantly greater increase from baseline in mean weight was observed for sertindole-treated patients (2.8 kg) compared to that observed for placebo-treated patients (0.2 kg). In long-term uncontrolled studies (n=1445), the mean increase in weight from baseline to final evaluation was 5 kg in sertindole-treated patients.1 1 Since weight gain itself, and possibly as yet unknown drug effects, can also lead to impaired glucose tolerance, diabetes and impaired lipid profiles, this side effect must be taken seriously. Moreover, the cosmetic effects of weight gain can also lead patients to discontinue their medication and could increase the risk of an exacerbation of
Sertindole: safety and tolerability profile
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
33
symptoms. If possible, therefore, patients’ weight should be monitored and they should be given advice on how to prevent weight gain and how to follow a healthy lifestyle. Blood glucose and lipid levels should also, ideally, be checked regularly. Sertindole has no consistent effect on blood lipids. In both short-term and long-term trials, the mean cholesterol concentrations at endpoint were similar to those at baseline. A small, but statistically significant increase in triglycerides was seen in short-term trials. However, as this was not observed in a long-term trial, where triglycerides decreased from baseline, it is not considered clinically relevant. A small increase in mean serum glucose has been observed in sertindole-treated patients and 4% of sertindole-treated patients in the shortterm studies had potentially clinically significant glucose values (5175 mg/dl) compared to 2% among placebotreated patients.
PROLACTIN LEVELS Elevated prolactin levels are thought to be associated with the non-selective D2 -receptor blocking activity of some antipsychotics. Blockade of these receptors in the tuberofundibular region of the brain is thought to cause raised prolactin levels and consequent galactorrhoea and lactation ± a particularly upsetting side effect for both men and women. Hyperprolactinaemia also causes menstrual disturbances in women. A significant increase in mean prolactin levels was observed in short-term clinical trials of sertindole (+4.6 ng/ml), but all values remained within the reference range. In the long-term clinical trials, no mean change from baseline in serum prolactin levels was observed, indicating that the increase observed in short-term trials is not sustained during long1 1 ,1 2 term treatment.
S31
the a1 -mediated side effects of postural hypotension, dizziness, and syncope when sertindole was administered in a single dose of 8 mg. Three dose titration studies were performed from which it was established that in healthy subjects, sertindole should be initiated at 4 mg/day and increased by 4 mg every fourth day to minimise the possibility of side effects. A more rapid titration regimen increased the possibility of a1 -mediated side effects.1 1
DISCUSSION Sertindole was a promising atypical antipsychotic drug prior to its temporary withdrawal in 1998. It had been shown to be effective in the treatment of the positive symptoms of schizophrenia, to possess activity against the 9 negative symptoms of the illness, and to be well 9 ,3 5 ,3 6 tolerated. Concerns over the drug’s cardiac safety led to the temporary withdrawal of sertindole, but a thorough analysis of post-marketing surveillance data together with the clinical trial data has revealed that the drug presents no greater risk to patients than other atypical antipsycho3 7 ,3 8 tics. Nonetheless, since sertindole does cause QT interval prolongation, psychiatrists are advised to monitor patients electrocardiographically prior to and during treatment to ensure that patients at risk of cardiac adverse events are not given the drug. Due to its a1 receptor activity, sertindole has to be titrated up to maintenance dosage, but overall, sertindole is considered to be a well-tolerated drug. Long-term, often lifelong, antipsychotic therapy is increasingly being recognized as the key to episode-free schizophrenia. Provided possible side effects are explained to patients and they are helped to cope with them when they do occur, such side effects need not deter patients from continuing with long-term treatment.
REDUCED EJACULATORY VOLUME Reduced ejaculatory volume, which occurred in 13% of men treated with sertindole in placebo-controlled trials, but in only 2% of the men in the placebo group, is also 11 associated with sertindole treatment. This side effect is probably related to the drug’s a1 -receptor antagonist activity.
POSTURAL HYPOTENSION Sertindole has a1 -adrenergic activity and the first study of sertindole in man showed that healthy subjects experienced
KEY POINTS . Sertindole does not cause sedation . Sertindole is associated with only placebo-level EPS . Sertindole is associated with an increased QT interval . The mortality rate on sertindole is comparable to those on other antipsychotic treatments . Sertindole has a favourable safety and tolerability profile
S32
S Kasper
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
REFERENCES 1. Moore N (2002) Higher cardiovascular mortality with sertindole in ADROIT: a signal not confirmed. Int J Psych Clin Pract 6 (suppl 1): S3 ± S9 2. Haverkamp W, Eckardt L, Frederiksen K, Matz J (2002) Sertindole: cardiac electrophysiological profile. Int J Psych Clin Pract 6 (suppl 1): S11 ± S20 3. Fleishhacker WW (1995) New drugs for the treatment of schizophrenic patients. Acta Psychiatr Scand 91 (suppl 388): 24 ± 30. 4. Goff DC, Baldessarini RJ (1993) Drug interactions with antipsychotic agents. J Clin Psychopharmacol 13 (1): 57 ± 67. 5. Kane JM, Honigfeld G, Singer J, et al (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45: 789 ± 96. 6. Tamminga CA (1997) The promise of new drugs for schizophrenia treatment. Can J Psychiatry 42: 265 ± 73. 7. Hummer M, Fleischhacker W (2000) Non-motor side effects of novel antipsychotics. Curr Opin CPNS Invest Drugs 2: 45 ± 51. 8. Kane JM (1999) Management strategies for the treatment of schizophrenia.J Clin Psychiatry 60 (suppl 12:) 13 ± 17. 9. 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. 10. CPMP/986/96 (1997) Points to consider, the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. 11. H. Lundbeck A/S. Data on file. 12. Kasper S, Quiner S, Pezawas L (1998) A review of the benefit:risk profile of sertindole. Int J Psych Clin Pract 2 (suppl 2:) S59 ± 64. 13. Agelink MW, Zeit T, Baumann B, et al (2001) In vivo cardiovascular effects of the new atypical neuroleptic sertindole. Int J Psych Clin Pract 5: 33 ± 40. 14. Casey DE (1998) Effects of clozapine therapy in schizophrenia individuals at risk for tardive dyskinesia. J Clin Psychiatry 59 (suppl 3:) 31 ± 7. 15. Grohmann R, Ruther E, Schmidt LG (1994) UnerwuÈnschte Wirkungen von Psychopharmaka. Ergebnisse de AMUÈP-Studie. Berlin: Springer. 16. Hale AS (1998) A review of the safety and tolerability of sertindole. Int Clin Psychopharmacol 13 (suppl 3:) S65 ± 70. 17. Hale AS, Azorin J-M, Kasper S, et al (2000) Sertindole is associated with a low level of extrapyramidal symptoms in schizophrenic patients: results of a Phase III trial. Int J Psych Clin Pract 4: 47 ± 54. 18. Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacol 21:106 ± 15S. 19. Hyttel J, Nielsen JB, Nowak G (1992) The acute effect of sertindole on brain 5-HT2, D2 and a1 receptors (ex vivo radioreceptor binding studies). J Neural Transm [GenSect] 89: 61 ± 9. 20. Kasper S, Tauscher J, KuÈfferle B, et al (1998) Sertindole and dopamine D2 receptor occupancy in comparison to risperidone, clozapine and haloperidol ± a123I-IBZM SPECT study. Psychopharmacology 136: 367 ± 373. 21. Richelson E, Souder T (2000) Binding of antipsychotic drugs to human brain receptors. Focus on newer generation compounds. Life Sciences 68: 29 ± 39.
22. Nyberg S, Dencker S-J, Malm U, et al (1998) D2- and 5-HT2 receptor occupancy in high-dose neuroleptic-treated patients. Int J Neuropsychopharmcol 1: 95 ± 101. 23. Nyberg S, Olsson H, Nilsson U, et al (2002) Low striatal and extra-striatal D2 receptor occupancy during treatment with the atypical antipsychotic sertindole. Psychopharmacology. Online publication 14 May. 24. Bymaster FP, Perry KW, Nelson DL, et al (1999) Olanzapine: a basic science update. Br J Psychiatry 174 (suppl 37:) 36 ± 40. 25. Farde L, Hall H, Ehrin E, Sedvall GC (1996) Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 231: 258 ± 261. 26. Sanchez C, Arnt J, Dragsted N (1991) Neurochemical and in vivo pharmacological profile of sertindole, a limbic-selective compound. Drug Dev Res 22: 239 ± 50. 27. Arnt J, Skarsfelt T (1998) Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 18: 63 ± 101. 28. Morris RGM (1984) Development of water maze procedure for studying spatial learning in the rat. J Neurosci Methods 11: 47 ± 60. 29. 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. 30. Hale A (2002) Sertindole ± clinical efficacy profile. Int J Psch Clin Pract 6 (suppl 1): S21 ± S26. 31. Taylor DM, McAskill R (2000) Atypical antipsychotics and weight gain ± a systematic review. Acta Psychiatr Scand 101: 416 ± 32. 32. Casey DE, Zorn SH (2001) The pharmacology of weight gain with antipsychotics. J Clin Psychiatry 62 (suppl 7:) 4 ± 10. 33. HaÈgg S, Joelsson L, MjoÈrndal T, et al (1998) Prevalence of diabetes and impaired glucose tolerance in patients treated with clozapine compared with patients treated with conventional depot neuroleptic medications. J Clin Psychiatry 59: 294 ± 9. 34. Sadock VA (2000) Normal human sexuality and sexual and gender identity disorders. In: Sadock BJ, Sadock VA (eds) Comprehensive textbook of psychiatry, 7th edition. Philadelphia: Lipincott Williams & Wilkins: 1577 ± 662. 35. 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. 36. Kane JM (1997) Sertindole: a review of clinical efficacy. Int Clin Psychopharmacology 13 (suppl 3:) S59 ± 64. 37. Branford D, Thomson B, Muldoon C (2002) Mortality in three comparative cohorts of patients who received sertindole, risperidone and olanazapine: a hospital-based, retrospective study. Poster presented at 18th International Conference on Pharmacoepidemiology (ICPE), Edinburgh, 18 ± 21 August. 38. Sturkenboom MCJM, Picelli G, Moore N (2001) Mortality during use of sertindole and other anti-psychotics in The Netherlands and Belgium. Pharmacoepidemiol & Drug Safety 10: S1 ± 164. 39. Kasper S, Tauscher J, Willeit M, et al (2002) Receptor and transporter imaging-studies in schizophrenia, depression, bulimia, and Tourette’s disorder. Implications for psychopharmacology. World J Biol Psychiatry 3: 133 ± 46.
ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20
Sertindole: safety and tolerability profile S Kasper To cite this article: S Kasper (2002) Sertindole: safety and tolerability profile, International Journal of Psychiatry in Clinical Practice, 6:1, 27-32 To link to this article: http://dx.doi.org/10.1080/13651500215967
Published online: 12 Jul 2009.
Submit your article to this journal
Article views: 8
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijpc20 Download by: [Washington University in St Louis]
Date: 06 November 2015, At: 16:39
#
2002 Martin Dunitz Ltd International Journal of Psychiatry in Clinical Practice 2002 Volume 6 (Suppl 1) Pages S27 ± S32
S27
Sertindole: safety and tolerability profile SIEGFRIED KASPER
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
Department of General Psychiatry, University of Vienna, Austria
Correspondence Address Siegfried Kasper, Professor, MD, UniversitaÈtsklinik fuÈr Psychiatrie, Klinische Abteilung fuÈr allgemeine Psychiatrie, WaÈhringer GuÈ rtel 18±20, A-1090 Vienna, Austria Tel: +43 1 40 400 3538 Fax: +43 1 40 400 3099 E-mail: [email protected]
Sertindole is a novel generation or atypical antipsychotic drug that has recently been re-introduced to the market. The safety and tolerability profile of sertindole have demonstrated a positive benefit/risk ratio in clinical trials and post-marketing studies. The number of patients who experienced extrapyramidal symptoms (EPS) while taking sertindole in clinical trials was similar to that of patients on placebo, and significantly less than that of patients on haloperidol. The relative lack of EPS is probably the result of the drug’s highly selective blockade of limbic dopamine D2 receptors and its lack of effect on other dopamine D2 receptors, but may be due to low occupancy at dopamine D2 striatal receptors. Sertindole also has a high affinity for serotonin 5-HT2 and a1 receptors. It has been shown not to cause sedation and its propensity to cause anticholinergic side effects is low, probably due to its lack of antihistamine and antimuscarinic activity. Sertindole does not cause any clinically significant changes in serum prolactin levels. QT interval prolongation does occur in some patients. The sertindole mortality rate is comparable to that of both risperidone and olanzapine (1.46, 1.75 and 1.20, respectively). Overall, sertindole is a well-tolerated drug that does not cause EPS, sedation or hyperprolactinaemia. (Int J Psych Clin Pract 2002; 6 (Suppl 1): S27 ± S32) Keywords sertindole tolerability
INTRODUCTION
T
he long list of non-arrhythmic compounds associated with QT interval prolongation has generated much concern for regulatory bodies and clinicians. In some cases, this has led to the withdrawal of a drug from the market. In the case of sertindole, the compound was suspended for 4 years while additional data were collected and analysed. The data allowed the CPMP to lift the suspension on the basis of a positive benefit/risk profile. The circumstances of the suspension and the data supporting the re-introduction 1 ,2 are presented. The most unpleasant and severe side effects associated with conventional antipsychotic drugs are extrapyramidal symptoms (EPS), which require concomitant anti3 ,4 cholinergic drug therapy. These drugs offer control of the positive symptoms of schizophrenia ± hallucinations, delusions, and disordered thinking ± and were a significant step forward in the treatment of schizophrenia. The atypical or novel generation antipsychotics not only offer relief of the positive symptoms of schizophrenia, but
safety schizophrenia
are also better than the old drugs at relieving the negative symptoms, such as blunted affect, withdrawal and anergia, 5 ,6 while causing lower levels of EPS. However, while the atypical antipsychotics are less likely to cause EPS than the older drugs, they can induce sexual dysfunction, weight gain and diabetes, and these side effects are gaining importance as more and more patients are prescribed 7 atypical antipsychotic drug therapy. Schizophrenia is often a chronic disorder that requires long-term drug treatment to enable patients to function and lead normal daily lives without frequent admissions to hospital. Patients must therefore be comfortable taking, in many cases, lifelong medication. Patients with schizophrenia are therefore no different from other patients with chronic diseases in that they need drugs to control their symptoms, that are easy to take and that do not adversely affect their lives. In the case of antipsychotic drug therapy, this means treatments that do not cause EPS, sedation, cognitive impairment, weight gain or sexual dysfunction, and, obviously, drugs that do not shorten patients’ lives.8 Sertindole, as an atypical antipsychotic, is one option open to patients with schizophrenia. It is effective against
S28
S Kasper
the positive symptoms of the illness and also has been 9 shown to reduce the negative symptoms. The purpose of this paper is to review certain aspects of the drug’s tolerability profile that could influence both the decision to prescribe sertindole and the patient’s decision to continue taking it as part of a long-term treatment plan.
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
QT INTERVAL PROLONGATION The QT interval corrected for heart rate (QTC interval) is affected by several factors, including time of day, gender and age, as well as some drugs. QTC prolongation is often considered associated with the development of serious ventricular arrhythmias, one of the most severe forms of which is torsades de pointes, which can lead to sudden cardiac death. Sertindole, like e.g., haloperidol and ziprasidone, is known to cause a degree of QTC prolongation. However, based on pharmacological and clinical properties, important counter-regulatory mechanisms limit 1 ,2 the arrhythmogenic potential of sertindole. An absolute value in the QTC interval in excess of 10 500 ms is considered clinically significant. In clinical trials, prolonged QTC interval was observed in 3 ± 5% of patients and 2% had a QTC F (Fredericia correction) interval in excess of 500 ms at any time during the 1 1 ,1 2 studies. These percentages should be viewed in the light of the fact that a standard lead on the ECG was not predefined but rather the maximum value from any lead was recorded. The effect of sertindole on the QT interval 13 appears to be dose-related but, in the clinical trials, there have been no documented cases of ventricular arrhythmias or torsades de pointes identified in any patient treated with 11 the prescribed dosages of sertindole. In all but one study in the clinical development programme, the selection criteria did not exclude patients with cardiovascular history. All patients were monitored electrocardiographically before the start of treatment, during dose titration, and during treatment, resulting in 11 000 ECG recordings. Safeguards in the product’s summary of product characteristics will avoid the drug being prescribed to high-risk patients. In most patients, sertindole is unlikely to cause ventricular arrhythmias and the low risk of such events is outweighed by the benefits of the drug.
MORTALITY In contrast to clinical trials of drugs, such as risperidone and olanzapine, the sertindole clinical trial programme did not exclude patients with cardiovascular risk factors. Despite this, the mortality rates recorded in clinical trials were comparable to those of olanzapine and risperidone 12 (Table 1). Moreover, post-marketing surveillance studies have shown that, as patient exposure to sertindole rose after the drug was launched, the mortality rate did not change.1 1
Most importantly, with regard to concerns over the drug’s cardiac safety, sertindole is not associated with a cardiac death rate that is significantly different from either risperidone or olanzapine. In fact, in clinical trials, the cardiac mortality rate per 100 patient-years exposure (PYE) was 0.31 deaths/100 PYE for sertindole compared with 0.23/100 PYE for risperidone and 0.53/100 PYE for olanzapine.1 1 Moreover, suicide rates were lowest among patients treated with sertindole (Table 1).1 2
EPS Not surprisingly, patients often discontinue treatment when they experience EPS. This unpleasant side effect may be associated with social stigma and suicide among 14 patients with schizophrenia. In a large German drug surveillance study, Grohmann et al (1994) found that the two most common reasons for discontinuing drug treatment among 7877 patients were parkinsonian symptoms and akathisia, two of the most common symptoms 15 associated with EPS. Almost 250 patients discontinued treatment due to parkinsonian symptoms and almost 200 because of akathisia. Sertindole, like other atypical antipsychotics, does not burden patients with EPS and this fact is exemplified by the results of a large North American study in which 497 patients received sertindole, haloperidol or placebo for 8 weeks. 9 In this study, EPS experienced by patients treated with sertindole were not significantly different than EPS reported by patients treated with placebo (Figure 1). However, the proportion of patients receiving placebo who experienced EPS was relatively high, probably as a result of patients stopping conventional antipsychotic treatment to take part in the study or as a result of schizophrenia itself. Nonetheless, the incidence of EPS among patients treated with sertindole was low and patients did not develop these symptoms as the study continued. This is in marked contrast to the group of patients treated with haloperidol, whose risk of developing EPS increased as the study progressed. Likewise, the difference between the number of patients treated with sertindole or placebo using anti-EPS
Table 1 All-cause mortality and suicide rates (per 100 patient-years) during clinical trials of sertindole, haloperidol, risperidone, and olanzapine 12 (mean and 95% Poisson’s confidence interval).
Antipsychotic
All-cause mortality mean (95% CI)
Sertindole Haloperidol Risperidone Olanzapine
1.46 1.78 1.75 1.20
(0.96 ± 2.14) (1.09 ± 2.75) (0.98 ± 2.88) (0.4 ± 2.90)
Suicide rate, mean (95% CI) 0.45 0.98 1.05 0.51
(0.19 ± 0.89) (0.49 ± 1.75) (0.47 ± 2.00) (0.06 ± 1.84)
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
Sertindole: safety and tolerability profile
Figure 1 P e rc e n ta g e o f p a tie n ts w h o e xp e rie n c e d E P S d u rin g 8 w e e k s o f tre a tm e n t w ith e ith er se r tin d o le ( 1 2 , 20 o r 2 4 m g /d a y ) , h a lo p e r id o l ( 4 , 8 o r 1 6 m g /d a y ) , o r p la c e b o ( * P = 0 .0 0 1 v s p la c e bo ; {P 40 .0 5 v s a n y se rtind o le d o s e ; F is ch e r ’s e xa ct 9 te s t, n = 49 7 p a tie n ts) .
medication during the study was not statistically significant. Again, significantly more patients treated with haloperidol used anti-EPS medication (Figure 2). Similarly, in the European study,1 6 ,1 7 scores on three movement rating scales [Barnes Akathisia Scale (BAS), Simpson Angus Rating Scale (SAS) and Abnormal Involuntary Movement Scale (AIMS)] either improved (8, 16 and 20 mg/day) or were unchanged (24 mg/day) during treatment with sertindole (Figure 3). In the haloperidol group, mean SAS, BAS, and AIMS scores were statistically significantly worse relative to 8 mg/day sertindole. As in the North American study, the highest dose of sertindole (24 mg/day) was associated with higher levels of EPS than the lower, recommended doses of the drug (12 ± 20 mg/ day). The lack of EPS observed during treatment with sertindole could be due to the result of the drug’s ability to block serotonin (5-hydroxytryptamine) 5-HT2 receptors as well as its relatively lower affinity for striatal dopamine D2 receptors, a feature characteristic of several atypical antipsychotics.1 8 ,1 9 ,2 0 The propensity of haloperidol to cause EPS is lowest using a dose of 4 mg/day ± 21 it possesses a much lower affinity for 5-HT2 receptors and therefore most likely cannot attenuate these symptoms to the same extent as an atypical antipsychotic (Figure 1). High D2 receptor occupancy is often associated with antipsychotic effectiveness against the positive symptoms 22 of schizophrenia. However, clozapine is known to have a low affinity for these receptors but is a highly effective antipsychotic drug. Indeed, sertindole, risperidone and quetiapine all have relatively low D2 occupancy values (Figure 4). The link between EPS and D2 receptor occupancy is more certain: sertindole, clozapine and quetiapine at commonly employed therapeutic doses fail to reach the receptor occupancy threshold of approximately 70%
S29
Figure 2 P e r ce n ta g e o f p a tie nts w h o to o k a n ti-E P S m e d ic a tio n d ur ing 8 w e e k s o f tre a tm e n t w ith e ith e r s e rtind o le ( 1 2 , 2 0 o r 2 4 m g /d a y ) , h a lo p e rid o l ( 4 , 8 o r 16 m g /d a y ) , o r p la c e b o ( * P 40 .0 5 v s a ll th r e e s e rtin d o le g ro up s a n d p la c e bo ; 9 F isc h e r’s ex a c t tes t, n = 4 9 7 p a tie n ts ) .
Figure 3 C h a n g e fro m ba se lin e to fin a l e v a lu a tio n in m o v e m e n t ra tin g s c a le s c o re s fo r 61 7 p a tie n ts ( IT T p o p u la tio n ) tre a te d w ith e ith e r se rtin d o le ( 8, 1 6 , 2 0 o r 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 8 w e e k s ( * P 40 .0 5 vs se r tin d o le 8 m g g ro u p ) , n= 6 1 7 p a tie nts . S A S , S im p s o n A n g u s R a tin g S c a le ; B A S , B a rn e s A k a th isia S ca le; 17 A IM S , A bn o rm a l In v o lu n ta ry M o v e m e n t S c a le . T h e m e a n s c o r e fo r 2 4 m g /d a y se rtin d o le w a s 0 .0 fo r a ll m o v e m e n t r a ting s ca le s .
required to trigger EPS, which helps explain the low level 2 3 ,2 4 of EPS associated with these drugs. At a low dose (4±6 mg/day), risperidone also fails to reach the EPS D2 receptor occupancy threshold but does so at higher doses (48 mg/day); olanzapine reaches the threshold even at a 25 dose of 10 mg. The relative lack of EPS with these drugs 18 might be explained by their activity at 5-HT2 receptors 24 and, in the case of olanzapine, its anticholinergic activity. The conventional antipsychotic haloperidol occupies 88% of receptors, which, as expected, is well in excess of the EPS threshold. If the risk of EPS increases as the dose of some antipsychotics rises, it may be reasonable to presume that patients with refractory schizophrenia are more likely to experience EPS, as they are given higher drug doses than
S30
S Kasper
events that were reported by 510% of sertindole-treated 11 patients.
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
COGNITION
Figure 4 39 D 2 re c ep to r o c c u p a n c y ( % ) o f va rio u s a n tip s y c h o tic d ru g s.
other patients. However, even patients with refractory schizophrenia are less likely to experience EPS while taking sertindole compared to patients taking risperidone. In a 12week multi-centre, double-blind, randomized study with centres in USA and Canada, including 321 treatmentresistant schizophrenic patients, 21% of patients treated with sertindole (12 ± 24 mg/day) experienced EPS-related treatment-emergent adverse events, compared with 36% of those treated with risperidone (6 ± 12 mg/day), P50.01 11 chi-square test. In a 12-week, multi-centre, double-blind, randomized, flexible dose study conducted in France in 186 schizophrenic patients, similar results were obtained: only 19% of patients treated with sertindole (12 ± 24 mg/ day) experienced EPS, compared with 28% of those treated 11 with risperidone (4 ± 10 mg/day). In the latter study the difference between sertindole and risperidone was reduced, possibly because the risperidone dose was slightly lower than in the former study.
SEDATION The study by Grohmann et al (1994) revealed that, after EPS, sedation was the next most common reason for 15 patients discontinuing their antipsychotic medication. Sedation is a serious and common side effect that reduces patients’ quality of life and prevents them from being effectively rehabilitated. Sertindole, however, does not cause sedation,1 6 probably because it has a very low affinity 26 for histamine H1 receptors.
ANTICHOLINERGIC SIDE EFFECTS The propensity of sertindole to cause anticholinergic effects is small, probably due to its low affinity for muscarinic 21 cholinergic receptors. Adverse events that could be attributed to anticholinergic effects were infrequent in sertindole trials. Constipation and dry mouth were the only potentially anticholinergic treatment-emergent adverse
Animal models predict that sertindole does not impair cognitive function in patients.2 7 The Morris water maze is a widely used animal model for both spatial learning and 28 memory. As the task is easy for control rats, no improvement in spatial learning is expected, and so the model can be regarded as a test for side effects (e.g. memory or learning impairment).2 9 Sertindole, at clinically equivalent dose levels, did not affect spatial learning in this 29 model. As yet, few data are available on the effects of sertindole on cognitive function in patients with schizophrenia. Only one study has attempted to assess these 17 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 inactive comparator dose. Haloperidol (10 mg/day) did not significantly improve cognition in this 30 study.
WEIGHT GAIN Weight gain can be a significant problem for people with schizophrenia and, in conjunction with other risk factors, such as poor diet, little exercise and smoking, it can raise patients’ risk of cardiovascular disease and diabetes. In addition to the health risk of weight gain, there is also the added psychological and social burden of weight gain. Since the atypical antipsychotics are now accepted as firstline treatment for schizophrenia, side effects such as weight gain are increasingly mentioned by patients, who previously would have complained that EPS was the most 31 worrying side effect of their treatment. It is unclear which mechanism causes weight gain during treatment with antipsychotic drugs.3 2 Indeed, in some patients, weight gain is simply the result of regaining weight lost in the period immediately prior to admission to hospital, when they experienced acute psychosis. Sertindole, like other antipsychotics, does cause a degree of weight gain. In the short-term studies (n=684), a significantly greater increase from baseline in mean weight was observed for sertindole-treated patients (2.8 kg) compared to that observed for placebo-treated patients (0.2 kg). In long-term uncontrolled studies (n=1445), the mean increase in weight from baseline to final evaluation was 5 kg in sertindole-treated patients.1 1 Since weight gain itself, and possibly as yet unknown drug effects, can also lead to impaired glucose tolerance, diabetes and impaired lipid profiles, this side effect must be taken seriously. Moreover, the cosmetic effects of weight gain can also lead patients to discontinue their medication and could increase the risk of an exacerbation of
Sertindole: safety and tolerability profile
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
33
symptoms. If possible, therefore, patients’ weight should be monitored and they should be given advice on how to prevent weight gain and how to follow a healthy lifestyle. Blood glucose and lipid levels should also, ideally, be checked regularly. Sertindole has no consistent effect on blood lipids. In both short-term and long-term trials, the mean cholesterol concentrations at endpoint were similar to those at baseline. A small, but statistically significant increase in triglycerides was seen in short-term trials. However, as this was not observed in a long-term trial, where triglycerides decreased from baseline, it is not considered clinically relevant. A small increase in mean serum glucose has been observed in sertindole-treated patients and 4% of sertindole-treated patients in the shortterm studies had potentially clinically significant glucose values (5175 mg/dl) compared to 2% among placebotreated patients.
PROLACTIN LEVELS Elevated prolactin levels are thought to be associated with the non-selective D2 -receptor blocking activity of some antipsychotics. Blockade of these receptors in the tuberofundibular region of the brain is thought to cause raised prolactin levels and consequent galactorrhoea and lactation ± a particularly upsetting side effect for both men and women. Hyperprolactinaemia also causes menstrual disturbances in women. A significant increase in mean prolactin levels was observed in short-term clinical trials of sertindole (+4.6 ng/ml), but all values remained within the reference range. In the long-term clinical trials, no mean change from baseline in serum prolactin levels was observed, indicating that the increase observed in short-term trials is not sustained during long1 1 ,1 2 term treatment.
S31
the a1 -mediated side effects of postural hypotension, dizziness, and syncope when sertindole was administered in a single dose of 8 mg. Three dose titration studies were performed from which it was established that in healthy subjects, sertindole should be initiated at 4 mg/day and increased by 4 mg every fourth day to minimise the possibility of side effects. A more rapid titration regimen increased the possibility of a1 -mediated side effects.1 1
DISCUSSION Sertindole was a promising atypical antipsychotic drug prior to its temporary withdrawal in 1998. It had been shown to be effective in the treatment of the positive symptoms of schizophrenia, to possess activity against the 9 negative symptoms of the illness, and to be well 9 ,3 5 ,3 6 tolerated. Concerns over the drug’s cardiac safety led to the temporary withdrawal of sertindole, but a thorough analysis of post-marketing surveillance data together with the clinical trial data has revealed that the drug presents no greater risk to patients than other atypical antipsycho3 7 ,3 8 tics. Nonetheless, since sertindole does cause QT interval prolongation, psychiatrists are advised to monitor patients electrocardiographically prior to and during treatment to ensure that patients at risk of cardiac adverse events are not given the drug. Due to its a1 receptor activity, sertindole has to be titrated up to maintenance dosage, but overall, sertindole is considered to be a well-tolerated drug. Long-term, often lifelong, antipsychotic therapy is increasingly being recognized as the key to episode-free schizophrenia. Provided possible side effects are explained to patients and they are helped to cope with them when they do occur, such side effects need not deter patients from continuing with long-term treatment.
REDUCED EJACULATORY VOLUME Reduced ejaculatory volume, which occurred in 13% of men treated with sertindole in placebo-controlled trials, but in only 2% of the men in the placebo group, is also 11 associated with sertindole treatment. This side effect is probably related to the drug’s a1 -receptor antagonist activity.
POSTURAL HYPOTENSION Sertindole has a1 -adrenergic activity and the first study of sertindole in man showed that healthy subjects experienced
KEY POINTS . Sertindole does not cause sedation . Sertindole is associated with only placebo-level EPS . Sertindole is associated with an increased QT interval . The mortality rate on sertindole is comparable to those on other antipsychotic treatments . Sertindole has a favourable safety and tolerability profile
S32
S Kasper
Downloaded by [Washington University in St Louis] at 16:39 06 November 2015
REFERENCES 1. Moore N (2002) Higher cardiovascular mortality with sertindole in ADROIT: a signal not confirmed. Int J Psych Clin Pract 6 (suppl 1): S3 ± S9 2. Haverkamp W, Eckardt L, Frederiksen K, Matz J (2002) Sertindole: cardiac electrophysiological profile. Int J Psych Clin Pract 6 (suppl 1): S11 ± S20 3. Fleishhacker WW (1995) New drugs for the treatment of schizophrenic patients. Acta Psychiatr Scand 91 (suppl 388): 24 ± 30. 4. Goff DC, Baldessarini RJ (1993) Drug interactions with antipsychotic agents. J Clin Psychopharmacol 13 (1): 57 ± 67. 5. Kane JM, Honigfeld G, Singer J, et al (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45: 789 ± 96. 6. Tamminga CA (1997) The promise of new drugs for schizophrenia treatment. Can J Psychiatry 42: 265 ± 73. 7. Hummer M, Fleischhacker W (2000) Non-motor side effects of novel antipsychotics. Curr Opin CPNS Invest Drugs 2: 45 ± 51. 8. Kane JM (1999) Management strategies for the treatment of schizophrenia.J Clin Psychiatry 60 (suppl 12:) 13 ± 17. 9. 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. 10. CPMP/986/96 (1997) Points to consider, the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. 11. H. Lundbeck A/S. Data on file. 12. Kasper S, Quiner S, Pezawas L (1998) A review of the benefit:risk profile of sertindole. Int J Psych Clin Pract 2 (suppl 2:) S59 ± 64. 13. Agelink MW, Zeit T, Baumann B, et al (2001) In vivo cardiovascular effects of the new atypical neuroleptic sertindole. Int J Psych Clin Pract 5: 33 ± 40. 14. Casey DE (1998) Effects of clozapine therapy in schizophrenia individuals at risk for tardive dyskinesia. J Clin Psychiatry 59 (suppl 3:) 31 ± 7. 15. Grohmann R, Ruther E, Schmidt LG (1994) UnerwuÈnschte Wirkungen von Psychopharmaka. Ergebnisse de AMUÈP-Studie. Berlin: Springer. 16. Hale AS (1998) A review of the safety and tolerability of sertindole. Int Clin Psychopharmacol 13 (suppl 3:) S65 ± 70. 17. Hale AS, Azorin J-M, Kasper S, et al (2000) Sertindole is associated with a low level of extrapyramidal symptoms in schizophrenic patients: results of a Phase III trial. Int J Psych Clin Pract 4: 47 ± 54. 18. Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacol 21:106 ± 15S. 19. Hyttel J, Nielsen JB, Nowak G (1992) The acute effect of sertindole on brain 5-HT2, D2 and a1 receptors (ex vivo radioreceptor binding studies). J Neural Transm [GenSect] 89: 61 ± 9. 20. Kasper S, Tauscher J, KuÈfferle B, et al (1998) Sertindole and dopamine D2 receptor occupancy in comparison to risperidone, clozapine and haloperidol ± a123I-IBZM SPECT study. Psychopharmacology 136: 367 ± 373. 21. Richelson E, Souder T (2000) Binding of antipsychotic drugs to human brain receptors. Focus on newer generation compounds. Life Sciences 68: 29 ± 39.
22. Nyberg S, Dencker S-J, Malm U, et al (1998) D2- and 5-HT2 receptor occupancy in high-dose neuroleptic-treated patients. Int J Neuropsychopharmcol 1: 95 ± 101. 23. Nyberg S, Olsson H, Nilsson U, et al (2002) Low striatal and extra-striatal D2 receptor occupancy during treatment with the atypical antipsychotic sertindole. Psychopharmacology. Online publication 14 May. 24. Bymaster FP, Perry KW, Nelson DL, et al (1999) Olanzapine: a basic science update. Br J Psychiatry 174 (suppl 37:) 36 ± 40. 25. Farde L, Hall H, Ehrin E, Sedvall GC (1996) Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 231: 258 ± 261. 26. Sanchez C, Arnt J, Dragsted N (1991) Neurochemical and in vivo pharmacological profile of sertindole, a limbic-selective compound. Drug Dev Res 22: 239 ± 50. 27. Arnt J, Skarsfelt T (1998) Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 18: 63 ± 101. 28. Morris RGM (1984) Development of water maze procedure for studying spatial learning in the rat. J Neurosci Methods 11: 47 ± 60. 29. 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. 30. Hale A (2002) Sertindole ± clinical efficacy profile. Int J Psch Clin Pract 6 (suppl 1): S21 ± S26. 31. Taylor DM, McAskill R (2000) Atypical antipsychotics and weight gain ± a systematic review. Acta Psychiatr Scand 101: 416 ± 32. 32. Casey DE, Zorn SH (2001) The pharmacology of weight gain with antipsychotics. J Clin Psychiatry 62 (suppl 7:) 4 ± 10. 33. HaÈgg S, Joelsson L, MjoÈrndal T, et al (1998) Prevalence of diabetes and impaired glucose tolerance in patients treated with clozapine compared with patients treated with conventional depot neuroleptic medications. J Clin Psychiatry 59: 294 ± 9. 34. Sadock VA (2000) Normal human sexuality and sexual and gender identity disorders. In: Sadock BJ, Sadock VA (eds) Comprehensive textbook of psychiatry, 7th edition. Philadelphia: Lipincott Williams & Wilkins: 1577 ± 662. 35. 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. 36. Kane JM (1997) Sertindole: a review of clinical efficacy. Int Clin Psychopharmacology 13 (suppl 3:) S59 ± 64. 37. Branford D, Thomson B, Muldoon C (2002) Mortality in three comparative cohorts of patients who received sertindole, risperidone and olanazapine: a hospital-based, retrospective study. Poster presented at 18th International Conference on Pharmacoepidemiology (ICPE), Edinburgh, 18 ± 21 August. 38. Sturkenboom MCJM, Picelli G, Moore N (2001) Mortality during use of sertindole and other anti-psychotics in The Netherlands and Belgium. Pharmacoepidemiol & Drug Safety 10: S1 ± 164. 39. Kasper S, Tauscher J, Willeit M, et al (2002) Receptor and transporter imaging-studies in schizophrenia, depression, bulimia, and Tourette’s disorder. Implications for psychopharmacology. World J Biol Psychiatry 3: 133 ± 46.
