Clinical Observations of Sertindole in 53 Hospitalised Patients with Psychotic Disorders 1

Transcription

1 Clin Drug Invest 2005; 25 (1): SHORT COMMUNICATION /05/ /$34.95/ Adis Data Information BV. All rights reserved. Clinical Observations of Sertindole in 53 Hospitalised Patients with Psychotic Disorders 1 Tilman Steinert, Barbara Hauger, Jürgen Eckardt and Peter Schmid Department of Psychiatry I, Weissenau, Ulm University, Ulm, Germany Sertindole (Serdolect, Lundbeck A/S, Copenhagen) 2 is an atypical antipsychotic characterised by predominantly mesolimbic (dopamine D2-blocking) activity, and some inhibition of serotonin 5-HT2 and α 1 -adrenergic receptors. Sertindole has no effect on muscarinic or histaminergic H1 receptors, as con- firmed by anticholinergic and sedative properties similar to placebo. [1-5] Like some other atypical antipsychotics, it is efficacious against the negative symptoms of schizophrenia. [6-8] The most frequent side effect observed with sertindole is nasal congestion. Other common adverse effects are dizziness, paraesthesia, peripheral oedema, weight gain, postu- ral hypotension, dyspnoea, dry mouth, prolongation of the QTc interval, and, in men, reduced ejaculatory volume. [7,9-14] At the start of the clinical develop- ment of sertindole, it was known that the QTc prolongation that occurs with other antipsychotics and that is associated with the occurrence of malignant arrhythmia could occur with sertindole. After its introduction in 1996, sertindole was the subject of criticism in 1998 due to the deaths of a number of patients. A re-analysis of the deaths during clinical trials revealed that among 2750 patients treated with sertindole there were seven deaths for which investigators could not exclude the possibility of a connection with sertindole. [9,15] After that, as a consequence of the Adverse Drug Reaction On-line Information Tracking (ADROIT) signal in the UK, the manufacturer removed the drug from the market at the end of Following a decision by the European Agency for the Evaluation of Medicinal Products, marketing authorisation for sertindole was suspended in the European Union from January to December 2000 due to its uncertain risk-benefit ratio, then extended by a further year. However, based on further clinical and non-clinical evidence suggesting that there is no link between sertindole-induced QTc prolongation and fatal arrhythmias and in conjunction with suit- able restrictions on its use in patients with underly- ing cardiac problems, the European Commission issued a decision on 26 June 2002 to lift the suspen- sion of marketing authorisation for medicinal products for human use that contain the active substance sertindole. Use of sertindole will initially be re- stricted to patients enrolled in large post-marketing surveillance studies. These studies were initiated in 2002 and are currently taking place worldwide. Between 1996 and 1998, we performed clinical observations of patients treated with sertindole in the Lake Constance branch of the Weissenau De- partment of Psychiatry, Germany. The study was discontinued when the drug was removed from the market. Because of the suspension of the marketing authorisation, we refrained from evaluating and publishing the data. When the suspension was lifted, the study was originally published in German in However, now that sertindole is being reintroduced to clinical practice, and due to the fact that clinical experience with the substance dates back 1 Reproduced with permission from Psychopharmakotherapie 2003; 10: Some data have been expanded since the original article was published and the reference list has been expanded. 2 The use of trade names is for product identification purposes only and does not imply endorsement.

2 80 Steinert et al. switch to another antipsychotic was required. Inves- tigators had been trained in the use of the GAF and CGI prior to study commencement. We also asked physicians for their subjective impression with regard to efficacy and side effects compared with the previous medication. The clinicians responsible for each of the three participating wards collected the data reported. The statistical evaluation was performed using the Statistica program (StatSoft, Tulsa, OK, USA). Categorical differences were calculated using the chi-squared (χ 2 ) test. The t-test was used to compare continuous normally distributed variables and the Wilcoxon matched-pairs test for non-normally dis- tributed data. The Mann Whitney U-test was used for variables on ordinal-scale level. several years, it is likely that the observations gained then will be of current interest to an international audience. So far, the only reports on clinical administration of sertindole in Germany are case studies. [1] 1. Patients and Methods Shortly after the market introduction of sertindole, we decided to perform this clinical observation study in view of the medical interest in the new antipsychotic. Neither the data collection nor its evaluation was in any way connected with the manufacturing company. Sertindole was prescribed only for medical reasons as part of normal care. Following the first positive observations at the time, there was a relatively high willingness to prescribe sertindole as a first-line treatment or at least as an early alternative. We report on all patients who received sertindole in our department until it was withdrawn from the market in Patients with mania were not treated with sertindole at that time. All patients who received treatment with sertindole were aged >18 years and <65 years and were in generally good physical condition. No patient had a previously known heart disease or cardiac arrhythmia. In addition to clinical and demographic data, we recorded: the reasons given for switching to or starting sertindole treatment; previous medications; side effects during treatment; reasons for discontinuing the treatment (where appropriate); maximum dose of sertindole taken; dose at the time of discharge; and any concomitant medications. The objective ratings used were the Global Assessment of Functioning scale (GAF) [16] and the Clinical Global Impression scale (CGI). [17] The GAF quantifies psychological, social and occupational functioning on a scale of mental health, whereas the CGI measures treatment response through three items: severity of illness (7-point scale), global improvement (7-point scale) and efficacy (4-point scale). Both physician-reported rating scales were administered on starting treatment with sertindole and at the time of discharge or discontinuation. CGI subscales of dyskinesia, parkinsonism and dystonia were also administered on commencement and at the time of discharge or at the time of discontinuation, if a 2. Results Clinical observations were recorded for 53 male and female patients. Table I shows characteristics of Table I. Characteristics of subjects at baseline (n = 53) [18] Characteristic Frequency Sex [no. (%)] female 26 (49) male 27 (51) Age (range) [y] 36.7 (18 68) Diagnosis [no. of patients (%)] paranoid schizophrenia (F 20.0) 41 (77.4) delusional disorder (F 22.0) 2 (3.8) transient psychotic disorder (F 23) 2 (3.8) disorganised schizophrenia (F 20.1) 1 (1.9) undifferentiated schizophrenia (F20.3) 1 (1.9) residual schizophrenia (F 20.5) 1 (1.9) simple schizophrenia (F 20.6) 1 (1.9) other schizophrenia (F 20.8) 1 (1.9) schizotypal disorder (F 21) 1 (1.9) schizoaffective disorder (F 25) 1 (1.9) moderate mental retardation (F 71) 1 (1.9) Duration of stay (range) [days] 84.2 (15 353) No. of previous hospital admissions (range) 3.9 (1 18) Previous treatment with [no. of pts (%)] butyrophenones 36 (68) tricyclic antidepressants 35 (66) risperidone 9 (17) olanzapine 9 (17) clozapine 8 (15)

3 Sertindole in Patients with Psychotic Disorders 81 Table II. Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) scale values [mean values (standard deviation)] Scale Completers (n = 43) Dropouts (n = 10) on admission on discharge on admission on discontinuation (medication switch) GAF 39.9 (14.8) 63.0 (14.4) a 33.9 (17.1) 43.3 (18.8) b CGI severity 3.8 (1.1) 1.7 (1.3) a 4.2 (1.2) 3.6 (1.5) b CGI dyskinesia 0.9 (1.7) 0.3 (0.8) c 1.3 (2.3) 0.9 (2.0) b CGI parkinsonism 1.6 (2.3) 0.3 (1.0) a 2.9 (1.9) 1 (1.5) b CGI dystonia 0.9 (1.7) 0.1 (0.4) c 1 (1.9) 0.5 (1.6) b a p < versus admission. b p-values not calculated due to small sample size. c p < 0.01 versus admission. the patients at the start of the study. The reason for the prescription of sertindole was specified as intolerable extrapyramidal side effects of conventional antipsychotics in 20 participants (38%) [the most frequently cited reason] and insufficient efficacy of conventional antipsychotics in six patients (11.3%). Seven patients (13%) were switched to sertindole because they were unable to tolerate the adverse effects of previously prescribed atypical antipsychotics, and seven patients (13%) were switched from atypical antipsychotics to sertindole because of insufficient efficacy. Eight patients (15%) were treated with first-line sertindole on admission, and in five of the 53 patients (9.4%) the prescription was changed during long-term treatment with the aim of minimising side effects. In one case, the drug was prescribed with the intention of achieving a selective influence on negative symptoms. Treatment with sertindole had to be discontinued in ten patients (18.9%) after an average of 47 days (range days) [referred to as dropouts ]. Forty-three patients (75%) were discharged while receiving sertindole (referred to as completers ). Satisfactory response to treatment on the GAF and CGI scales, and satisfactory regression of extrapyramidal side effects as measured by the CGI subscales of dyskinesia, parkinsonism and dystonia, was found in all patients during the course of the study (table II). The change in GAF and CGI scores between admission and discontinuation or discharge was highly significant in the total sample (p < 0.001). For all scales, the dropouts tended to have more pathological symptoms than the completers at the admission stage, but this did not reach statistical significance because of the low number of dropouts. The dropouts also had more severe pathological symptoms at the end of observation. This was to be expected as these patients were still undergoing hospital treatment at the time of switching from sertindole to another medication. The reasons for discontinuation of sertindole were: insufficient efficacy in four cases; complete absence of ejaculation in two cases; nasal conges- tion up to the formation of necroses in three cases; and one case each due to dizziness and hyperkinesia (in one case, both loss of ejaculation and persistent nasal congestion were the reason for discontinua- tion). Adverse events reported by the 43 completers are shown in table III. Subjectively, both the doctors in Table III. Adverse events reported by the 43 completers Adverse event No. (%) of patients Nasal congestion 7 (16) Increased thirst 7 (16) Absence of ejaculation a 6 (14) Constipation 3 (7) Akathisia 3 (7) Increased relative QTc interval 3 (7) Weight gain of >5kg within observational period 2 (5) Dizziness 1 (2) Parkinsonism 1 (2) Difficulty in initiating and maintaining sleep 1 (2) Drowsiness 1 (2) a Absence of ejaculation (rather than a quantitative reduction) was reported by eight of the 27 (30%) male patients treated in total.

4 82 Steinert et al. charge and the patients were relatively satisfied with QTc prolongation (investigators prespecified that the therapy. Prescribing doctors assessed treatment patients with an absolute QTc time of 500ms were efficacy as superior to that of the previous med- to be withdrawn). Prolongations above 450ms but ication in 28 (53%) of the total sample (including below 500ms that were defined as requiring subsedropouts), in 19 (36%) cases as the same, and in quent ECG controls were recorded in a few cases. only one (3%) case as worse than previous med- This is consistent with the findings of a previous ication (in other cases there had been no previous study, in which sertindole was associated with a medication or assessments were not available). small increase in QTc interval, but there was no Compared with the previous medication, the side- significant difference in the number of subjects with effect profile of sertindole was assessed as better in a QTc of 500ms between sertindole and placebo. [14] 32 (71%) cases, comparable in eight (18%) cases No fatal arrhythmias occurred during the present and worse in only three (7%) cases. study, supporting the findings of Zimbroff and co- The doses of sertindole taken varied between 8 workers. [14] and 24mg, with an average maximum dose during It has to be emphasised that the patients investiinpatient treatment of 17.6mg (range 12 24mg) and gated in this study were generally in good physical an average dose on discharge of 16.8mg (range condition and did not experience heart disease. Al mg). though this population is not representative of the Of the 43 completers, 19 (44%) patients were general public, it does reflect a typical sample of discharged with sertindole as monotherapy; 17 patients with psychotic disorders aged <65 years. (39.5%) patients were receiving concomitant treat- Nevertheless, caution must be used when applying ment with other antipsychotics (flupentixol, halothe results of this study to older patients who are peridol, clozapine and zotepine); six (14.0%) pamore likely to have co-existing cardiac conditions. tients were receiving antidepressive agents; five Precautionary ECG monitoring is necessary in all (11.6%) patients were on mood stabilisers; one patients prior to commencing treatment with ser- (2.3%) patient was on a benzodiazepine; two (4.7%) tindole, when the maximum daily dose of sertindole patients were taking antiparkinsonian drugs (biperis administered, or when concomitant drugs with iden); and nine (20.9%) patients were receiving nonpotential pharmacokinetic interactions are taken psychotropic drugs. with sertindole. 3. Discussion In the current study, only nine patients received non-psychotropic drugs. A clinically significant Sertindole was found to be efficacious in a samportion weight gain only occurred in a relatively small prople of patients in the routine care of a public hospital of cases, although it should be noted that no representing a range of psychotic disorders. In this precise data were collected. A reliable evaluation of study, the discontinuation rate of <25% suggests weight gain under clinical conditions was not feasi- that sertindole was well accepted by doctors and ble because of the short duration of hospital stays patients. Almost half of the completers were diswith and the changes to regular eating habits associated charged with sertindole as monotherapy. When paulation hospitalisation. The definitive absence of ejac- tients were discharged with sertindole, there was (rather than a reduction in ejaculatory voltients virtually no need for antiparkinsonian drugs, alby ume) was a significant side effect and was reported though extrapyramidal symptoms with other antitent nearly a third of the male patients treated, consis- psychotics were the most common reason for changfrequent with the rate found in previous studies. [14] This ing to sertindole. With an overall perception of the side effect suggests that sertindole could be efficacy as satisfactory, the range of side effects problematical for some male patients. Also frequent observed was different to that expected from the was nasal congestion, which in individual cases literature. No patients discontinued treatment due to resulted in a clinically relevant breathing disorder

5 Sertindole in Patients with Psychotic Disorders Domeney AM, Arnt J, Costall B, et al. Effect of sertindole on raised mesolimbic dopaminergic activity in the rat. Drug Dev that did not subside if the therapy was continued and made discontinuation necessary. Res 1994; 31: Although this observational study was not ran- 6. Daniel DG, Wozniak P, Mack RJ, et al. Long term efficacy and domised or controlled, the efficacy of sertindole safety comparison of sertindole and haloperidol in the treat- ment of schizophrenia. Psychopharmacol Bull 1998; 34: 61-9 reported in this study was consistent with that reported in previous placebo-controlled and activetindole: a case series. J Clin Psychiatry 1997; 58: Lee AM, Knoll JL, Suppes T. The atypical antipsychotic ser- comparator trials. [14,19,20] A third of patients were 8. Brown LA, Levin GM. Sertindole, a new atypical antipsychotic receiving other antipsychotic drugs at the end of the for the treatment of schizophrenia. Pharmacotherapy 1998; 18: study, which may confound the results presented However, the use of drug combinations reflects the usual clinical practice for such patients. 4. Conclusion 9. Fritze J, Bandelow B. QT-Verlängerung und das neue, atypische Neuroleptikum Sertindol. Psychopharmakotherapie 1998; 5: Lundbeck A/S, Sertindole: Product Monograph. Copenhagen: H. Lundbeck A/S, 1997: Lundbeck A/S. Sertindole: summary of product characteristics. Copenhagen: H. Lundbeck A/S, 1996: Tamminga CA, Mack RJ, Granneman GR, et al. Sertindole in the treatment of psychosis in schizophrenia: efficacy and safe- Treatment with sertindole was efficacious and well tolerated, and would therefore appear to be a ty. Int Clin Psychopharmacol 1997; 12 Suppl. 1: practicable addition to the range of second-generation (atypical) antipsychotics. However, particular attention should be paid to side effects, which, al- with schizophrenia. Psychopharmacology 1996; 124: though not dangerous, may subjectively be very distressing, such as the absence of ejaculation, nasal congestion and increased feeling of thirst due to dry mouth. Acknowledgements There was no funding for this study, and the authors have no conflicts of interest directly relevant to the content of this study. 13. Van Kammen DP, McEvoy JP, Targum SD, et al. A random- ised, controlled, dose-ranging trial of sertindole in patients 14. Zimbroff DL, Kane JM, Tamminga CA, et al. A controlled, dose-response study of sertindole and haloperidol in schizophrenia. Am J Psychiatry 1997; 154: Editorial. Zum Risikoprofil von Sertindol (Serdolect). Arzneitelegramm 1997; 12: American Psychiatric Association (APA), DSM-III-R. Diagnostic and statistical manual of mental disorders. 3rd rev. ed. Washington: APA, CIPS. Internationale Skalen für Psychiatrie. Weinheim: Beliz, International statistical classification of diseases and related health problems, tenth revision. Geneva: World Health Organization, Hale A, Azorin JM, Kasper S, et al. Sertindole improves both the positive and negative symptoms of schizophrenia: results References of a phase III trial. Int J Psychiat Clin Pract 2000; 4 (1): Bickmann E, Groβe K, Laux G. Klinische Beobachtungen an schizophrenen Patienten unter Behandlung mit Sertindol. 20. Azorin JM, Toumi M, Sloth-Nielsen M. Sertindole is well Psychopharmakotherapie 2001; 8: tolerated and demonstrates efficacy advantages over risperidone in the treatment of moderate to severe schizophrenia 2. Hyttel J, Arnt J, Costall B, et al. Pharmacological profile of the [abstract]. Eur Neuropsychopharmacol 2002; 12 Suppl. 3: atypical neuroleptic sertindole. Clin Neuropharmacol 1992; 15 S300 Suppl. 1: 267A-8 3. Hyttel J, Nielsen JB, Nowak G. The acute effect of sertindole on brain 5-HT2, D2 and alpha1 receptors (ex vivo radio receptor binding studies). J Neural Transm Gen Sect 1992; 89: 61-9 Correspondence and offprints: Prof. Tilman Steinert, Zen- trum für Psychiatrie Weissenau, D Ravensburg, 4. Sanchez C, Arnt J, Costall B, et al. Sertindole: a limbicselective neuroleptic with potent anxiolytic effects. Drug Dev Germany. Res 1995; 34: tilman.steinert@zfp-weissenau.de