A Randomised Double-blind Study Comparing Sertindole

Original Paper 1

Phpsy/550/13.9.2007/Macmillan

Course of Recovery of Cognitive Impairment in Patients with Schizophrenia: A Randomised Double-blind Study Comparing Sertindole and Haloperidol

Author

B. Gallhofer1, P. Jaanson2, A. Mittoux3, P. Tanghøj3, S. Lis1, S. Krieger1

Affiliation

1

Cognitive Neuroscience Laboratory and Department of Psychiatry, Centre for Psychiatry, Justus-Liebig University, Giessen, Germany 2 Psychiatric Clinic, Department of Psychiatry, University of Tartu, Tartu, Estonia 3 H. Lundbeck A/S, Ottiliavej 9, Valby, Copenhagen, Denmark

Abstract & Objective: To compare the impact of sertindole and haloperidol on cognitive function in patients suffering from schizophrenia. Methods: In a 12 week trial, of the 40 patients randomised to treatment, 34 (17 sertindole and 17 haloperidol) were included in the analysis set. Cognitive sub-processes were investigated with the Reaction Time Decomposition (RTD) method and the Wisconsin Card Sorting Test (WCST), at baseline, Week 4 and Week 12. Results: In executive function, i.e. set shifting tasks, sertindole reversed cognitive deficits significantly more than haloperidol. It was

Introduction &

received revised accepted

12.02.2007 17.08.2007 24.08.2007

Bibliography DOI 10.1055/s-2007-990291 Pharmacopsychiatry 2007; 40: 1–12 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0176-3679 Correspondence B. Gallhofer Cognitive Neuroscience Laboratory Centre for Psychiatry Justus-Liebig University Am Steg 22 35385 Giessen Germany Tel.: + 49/641/994 57 01 Fax: + 49/641/994 57 09 [email protected]. uni-giessen.de

Cognitive impairment associated with schizophrenia has a great impact on quality of life and functional outcome [8, 23]. Even though improvement in cognition is a vital factor in recovery [37] the treatment of schizophrenia has traditionally focused on the reduction of positive symptoms, such as hallucinations, thought disorder, and delusions. Despite the advancement of the concept of negative symptoms, it was found that improving negative symptoms and reducing positive symptoms could not fully return patients to everyday life. Consequently, the existence of a dyscognitive subsyndrome was presumed. Early attempts to characterise the specific cognitive deficits in schizophrenia, which went beyond unspecific neuropsychological tests, were the Stroop test (ST), the Digit Span (DS), and the Wisconsin Card Sorting Test (WCST), maze tasks, and verbal memory tasks. Results from the early papers suggested that cognitive deficits in schizophrenia arose from a systemic failure, mostly in the executive compartment of the cognitive system of the brain [51, 19, 68, 10, 34, 43]. However,

demonstrated that this atypical drug improved cognitive processing independently of motor function. Patients receiving sertindole markedly improved on the RTD task at Week 4 and continued to improve (although at a slower rate) at Week 12, those patients receiving haloperidol showed marked impairment at Week 4 with partial recovery by Week 12. Conclusion: The study demonstrated two distinct processes of action on cognition between sertindole and haloperidol and the marked beneficial effects of sertindole, particularly in parameters that are regarded as schizophrenia-related cognitive disturbances.

despite these studies, it has remained difficult to trace and understand the underlying compartments that are involved in the failure of overall cognitive function. Various authors have therefore proposed possible candidate circuits of the brain [29, 9, 46, 54]. Posner proposed a stepwise modular approach to the measurement of cognitive dysfunction [58]. The WCST has been used to distinguish executive function in the dorso-lateral prefrontal cortex. However, the WCST cannot systematically distinguish between the various aspects of neuronal circuitry needed to bring about executive function. Since the mid 1990s, focus on cognitive dysfunction has increased considerably. The cognitive domains that describe the disease process in patients with schizophrenia are attention, memory, executive functioning, and verbal fluency, as well as information processing speed [50, 40]. Recent reports confirm that conventional antipsychotic treatment does not produce significant positive effects on cognitive dysfunction in schizophrenia, and the reported cognitive effects of atypical antipsychotics have been controversial

Gallhofer B et al. Course of Recovery of Cognitive Impairment … Pharmacopsychiatry 2007; 40: 1–12

2 Original Paper


Sertindole First-episode patients Haloperidol Screening Sertindole

Chronically ill patients

and behavioural planning capabilities. It was assumed that differences between the two treatment groups would contribute to the understanding of the roles of different antipsychotic treatment strategies in relation to cognitive strain in schizophrenia. The aim of the study therefore is to compare the treatment groups with respect to the most salient cognitive tasks suitable to reveal the differences outlined above.

Haloperidol Run-in period (3-7 days)

Fig. 1

Dosing phase (12 weeks)

Study design.

[66, 48, 6, 22, 20, 45]. Potential mechanisms for the lack of positive overall effects on cognition are extrapyramidal side effects (EPS) associated with antipsychotic drugs, anticholinergic properties of drugs that are applied to improve EPS, and the high anti-dopaminergic activity seen with conventional antipsychotic therapies. The therapeutic effect of typical antipsychotics has been attributed largely to their antagonism of dopamine D2 receptors [11]. However, the multiple neurotransmitter interaction of atypical antipsychotics suggest that, while D2 occupancy is important for antipsychotic action, effects on other neurotransmitter receptors may also be involved [21]. As atypical antipsychotics affect a wide range of neurotransmitter receptors [38], a variety of side effects, that are commonly neglected, such as antihistaminergic properties, may also contribute to impairment of cognition. Nevertheless, the predominant factor likely to have a significant impact on cognitive function is EPS [70]. Some reports show evidence of improvement of cognitive function with atypical antipsychotics [20]. Generally, atypical antipsychotics are less likely to produce EPS than conventional drugs [16, 27]. The reason for their superiority in this field is probably a result of their lower D2 occupancy. For example, clozapine has D2 occupancy of 20–67 % [49, 53] whilst typical antipsychotics have occupancies of 70–89 % [18]. Positron emission tomography (PET) studies have found that EPS are more likely to occur when D2 occupancy is over 80 % [52]. The lower likelihood of EPS, and resulting reduced need for concomitant anticholinergic therapy, means that atypical antipsychotic therapy has the potential to enhance cognitive function in schizophrenia. Sertindole, an atypical substance with a low risk of EPS, is known to be effective [30, 73] at a D2 occupancy of 52–68 % [53] and is, therefore, a good example for the paradigms of both Farde (margin between onset of antipsychotic effect and onset of EPS) and Kapur (the priniple of salience) [18, 31]. Another critical aspect is sedation caused by some atypical substances and the possible impact of this side effect on cognition. In this context, it is worth noting that sertindole has neither antihistaminergic- nor anticholinergic receptor occupancy [4], and is, therefore, expected to differ from the group of more sedative antipsychotic drugs. The aim of the present study was to compare the impact of sertindole and haloperidol on the course of cognitive functions in patients suffering from schizophrenia. A set of computerised tasks was designed to explore cognitive function. Reaction-time tasks were used to measure information processing, speed and attention. The Wisconsin Card Sorting Task measures executive functions, a construct that comprises abstraction, problem solving,

Patients and Methods & Patients Patients were recruited from three study centres in Estonia. They were included if they: (i) were men or non-pregnant, non-lactating women aged 18–45 years who met DSM-IV criteria for schizophreniform disorder or acute schizophrenia or schizophrenia; (ii) had not taken benzodiazepine and/or anticholinergic medication for at least 48 hours prior to baseline cognitive testing; and (iii) had a score >2 on at least two of the following four PANSS items [32] conceptual disorganisation (P2); hallucinatory behaviour (P3); suspiciousness (P6); and unusual thought content (G9), with the sum of any two of these four items being ≥ 8. Patients were excluded if their ECG QTC interval was ≥ 430 ms for men or ≥ 450 ms for women at the screening visit. Patients were to be withdrawn during the study if an ECG showed a QTC interval ≥ 470 msec to avoid the threat of a torsade des pointes effect. The study was conducted according to previous labels of sertindole, was approved by the local ethics committees and national regulatory authorities in accordance with local requirements, and was conducted in accordance with Good Clinical Practice guidelines [28] and the [72] and subsequent revisions. All patients (or their legal representative) gave written informed consent before the start of the study.

Design This multicentre, randomised, double-blind, four-armed, study was designed to compare the effect of sertindole (10–24 mg once daily) to that of haloperidol (5–15 mg once daily) on cognition in schizophreniform disorder/schizophrenia patients. The patients were grouped into first-episode or chronic patients (䊉䉴 Fig. 1). The intended duration of treatment was 12 weeks. The study was prematurely terminated because sertindole was temporarily withdrawn from the EU market. Sertindole is associated with a dose-dependent increase in the QT interval which gave rise to a cardiac safety concern of an excess mortality associated with the use of sertindole. Therefore the European Commission temporarily withdrew sertindole from the EU market until non-clinical and epidemiological studies had indicated that the known QT prolongation induced by sertindole did not translate into increased mortality. First-episode patients did not require a run-in period. Thus, upon screening and stratification, these patients were immediately randomised to sertindole or haloperidol in a ratio of 1:1. First-episode patients were titrated over 3 weeks (21 days) to 12 mg/day of sertindole or 6 mg/day of haloperidol (䊉䉴 Fig. 1). For chronically ill patients, the study consisted of a 3–7 day single-blind placebo run-in period after which the patients were randomised to sertindole or haloperidol in a ratio of 1:1. Chronically ill patients were titrated over 13 days to 16 mg/day of sertindole or 11 mg/day of haloperidol.


Original Paper 3


A

Simple Reaction Task

‘react to all stimuli’ stimuli

Stimulus Disc rimination Task

‘ react to triangles only ’

Choice Reaction Task

Fig. 2 Diagram illustrating the principle of (A) Reaction Time Decomposition and (B) Wisconsin Card Sorting.

‘react to triangles with and squares with ’

B

Wrong

After the titration periods, the investigator was free to adapt the dose according to the patient’s response to treatment (dose ranges 10–16 mg/day and 12–24 mg/day sertindole, and 5–8 mg/ day and 9–15 mg/day haloperidol, for first-episode and chronically ill patients, respectively). Concomitant treatment with lorazepam to control states of anxiety and agitation, up to a dose of 10 mg/day, was permitted throughout the study. In addition, biperidene, up to a dose of 12 mg/day, could be used to relieve EPS. However, the patients had to be free of benzodiazepine and anticholinergic medication for 48 hours prior to cognitive assessment.

Cognitive tasks A battery of computerised cognitive tasks (䊉䉴 Fig. 2) was performed at baseline (Week 0), and at treatment Weeks 4 and 12. The tasks examined elementary cognitive sub-processes, such as information processing, speed and attention (Reaction Time Decomposition (RTD)), and executive functioning (Wisconsin Card Sorting Test (WCST)).

Reaction Time Decomposition Tasks A simple reaction time task was used to calculate the overall reaction time. The main feature of this test is that each additional task requires a cognitive sub-process that was not stressed by the task presented before. In addition, a stimulus discrimination task and a choice reaction task were used to measure reaction time for two sub-processes of information processing: stimulus identification and response selection. Tasks were presented on the computer screen. For the simple reaction task patients were instructed to move a cursor as quickly as possible from a resting circle to a target array whenever a visual stimulus (stimulus presentation time: 100 ms) was presented on a computer screen. In the stimulus discrimination task, two kinds of stimuli were presented (a square and a triangle). The patients were instructed to move a cursor from a resting circle to a target whenever a stimulus of a specified kind (the square) was presented on a computer screen (䊉䉴 Fig. 2). The

other kind of stimuli (the triangle) was to be ignored. For the choice reaction task, two kinds of stimuli were presented (a square and a triangle) and two different target areas were shown. Patients were instructed to move a cursor according to the kind of stimulus presented, to the corresponding target array (the square to target 1, the triangle to target 2). Stimulus reset. A new stimulus was automatically presented, if there was no reaction after three seconds. Each task was performed and measured 40 times at each assessment visit. The Total Reaction Time (ToT-RT), i.e. the time between presentation of the stimulus and reaching the target, was measured for each of the three tasks. Each task was performed and measured 40 times at each visit. For each patient, a median ToT-RT for each task was calculated because averages of patients’ reaction times were often biased by outliers.

Wisconsin Card Sorting Test The WCST measures executive function, a system that comprises abstraction, problem solving, and behavioural planning capabilities. The test was carried out by displaying a row of four “cards” on a computer screen, each one displayed a designated number of components of a certain shape and colour. The patient was presented with a card that appeared at the bottom of the computer screen. This card matched one of the cards in the row according to colour, shape, or number of components. The patient had to match the bottom card with one of the cards above according to colour, shape or number of components. Following feedback a second card was presented on the bottom row, and the task repeated. The patient was expected to use the feedback to learn to which criterion (colour shape or number) the cards should be matched. Patients had to find out as quickly as possible when the matching category had changed. Stimulus reset. A new card would not be presented until the patient responded. If necessary, the examiner instructed the patient to guess. After three such instructions to guess, the task was ended.


4 Original Paper


Fig. 3 Flow chart summarizing the disposition of patients. Randomised n=40

BASELINE

SERTINDOLE n = 20 First episode n = 13 Chronically ill n=7

WEEK 4

HALOPERIDOL n=20 First episode n = 13 Chronically ill n=7

Cognitive Data Set (CDS )* n = 17

Cognitive Data Set* n = 17

First episode n = 12 Chronically ill n =5

First episode n = 12 Chronically ill n= 5

First Chronically ill episode

First Chronically ill episode

Total withdrawn

n== 4 n

n=3

Total withdrawn

n== 3 n

n== 4 n

-Adverse events -Consent withdrawn -Non-compliance -Lost to follow-up

n=3 n= n== 0 n n== 0 n n== 1 n

n =1 n= n== 1 n n== 1 n n== 0 n

-Adverse events -Consent withdrawn -Non-compliance -Lost to follow-up

n=2 n= n== 1 n n== 0 n n== 0 n

n=3 n= n== 1 n n== 0 n n== 0 n

WEEK 12

Completers

CDS analysis n = 16

CDS analysis n = 16

First episode n = 11 Chronically ill n=5

First episode n = 11 Chronically ill n =5

n =13

First episode n = 9 Chronically ill n = 4

Completers

n = 13

First episode n = 10 Chronically ill n = 3

*Cognitive Data Set (CDS) = patients who had valid cognitive assessments at baseline and at week 4

Reaction times were measured as well as number of categories achieved, cards presented, total errors, perseverative errors, non-perseverative errors, and perseverative responses were recorded. It is assumed that non-perseverative errors signify mainly a lack of concentration, while perseverative errors point to a more specific working memory deficit as found in patients suffering from schizophrenia.

Statistical methods All randomised patients with at least one post-baseline cognitive assessment were included in the Cognitive Data Set (CDS); the CDS was used for the analysis of all cognitive parameters. Each cognitive parameter was analysed using the same likelihood-based Mixed-effects Model Repeated Measures (MMRM) analysis of variance. Research has shown that the MMRM approach is more robust towards drop-out biases from missing data than is the more traditional Last Observation Carried Forward (LOCF) analysis of variance [41, 42]. The repeated measurement factor consisted of the visit at baseline, at 4 weeks and at 12 weeks. The dependent variable was the change from baseline to both post-baseline visits (week 4 and week 12) in the cognitive parameter being analysed. Independent variables included the fixed, categorical effects of the visit and the treatment-byvisit interaction, along with the fixed, continuous covariate of the baseline-by-visit interaction of the cognitive parameter being analysed. In order to adjust for the potential impact of EPS on the cognitive outcome, the model included further fixed,

continuous covariates of the interactions with visit of baseline and post-baseline scores of the Simpson and Angus Scale (SAS) [65]. For comparison, an initial analysis using the MMRM model without EPS as a covariate will also be reported. The analyses were performed separately for all patients in the CDS and for the subgroup of first-episode patients. (The number of chronic patients was too small for a separate analysis) Baseline patient characteristics were compared between treatment groups using t-tests for continuous parameter scores and Fisher’s exact test for categorical variables. For baseline comparisons t-tests were performed separately for first episode and chronic patients as well as for the total group. All statistical tests were two-sided and statistical significance was set at the 5 % level. All statistical analyses were performed using SAS version 9.1 (statistical software package from SAS® Institute).

Results & Baseline characteristics and patient disposition A flow-chart summarising the disposition of patients is shown in 䊉䉴 Fig. 3. There were 20 patients in each group randomised to receive a double blind treatment. In each group 13 were firstepisode patients and 7 were chronically ill. Six patients did not meet the criteria of having a valid cognitive assessment at least at baseline and at Week 4 and were not included in the Cognitive


Original Paper 5


Table 1

Baseline characteristics, Cognitive Data Set (CDS)

Characteristic patients in CDS§ sex, n male female age (years) mean (SD) median min, max weight (kg) mean (SD) median min, max body mass index (BMI) mean (SD) median min, max age when first diagnosed (years) mean (SD) median min, max duration of illness (years) mean (SD) median min, max duration of current episode (weeks) mean (SD) median min, max drug naive, n yes no

First-episode patients SER†

HAL‡

12 2 10


All patients

SER

HAL

SER

HAL

12

5

5

17

17

4 8

1 4

0 5

3 14

4 13

25.9 (6.7) 25 18, 38

30.3 (8.9) 31 18, 46

33.2 (6.6) 33 25, 42

30.8 (5.3) 29 27, 40

28.1 (7.3) 28 18, 42

30.4 (7.8) 29 18, 46

60.5 (8.0) 61 47, 75

60.2 (11.9) 59 45, 89

68.8 (10.6) 72 56, 82

61.6 (4.7) 63 56, 68

62.9 (9.4) 61 47, 82

60.6 (10.2) 60 45, 89

20.7 (1.9) 21 17, 23

20.9 (3.0) 20 17, 29

24.9 (6.1) 23 21, 36

21.9 (2.5) 21 19, 26

22.0 (3.9) 22 17, 36

21.2 (2.8) 21 17, 29

25.8 (6.6) 25 18, 38

30.2 (8.7) 31 18, 45

24.4 (7.4) 23 19, 37

20.4 (3.5) 19 16, 24

25.4 (6.6) 23 18, 38

27.3 (8.7) 24 16, 45

8.7 (4.2) 6.0 5.3, 13.6

10.7 (6.4) 8.0 5.5, 21.2

2.6 (4.6) 0.03 0.01, 13.6

43.1 (91.2) 2.6 1.1, 206.3

2.5 (1.8) 1.7 1.1, 5.6

13.5 (49.7) 1.1 0.1, 206.3

0.11 (0.30) 0.02 0.01, 1.07

0.02 (0.01) 0.02 0.01, 1.04

1.2 (0.5) 1.1 0.1, 2.1

1.1 (0.4) 1.1 0.7, 2.3

9 3

9 3

0 5

0 5

9 8

3.2 (6.0) 0.02 0.01, 21.2 1.5 (1.2) 1.1 0.7, 5.6 9 8

No statistically significant differences found between treatment groups †

SER: sertindole

‡

HAL: haloperidol

§

CDS: Cognitive Data Set

Data Set (CDS). Six patients (2 first-episode and 1 chronically ill patients on sertindole, and 1 first-episode and 2 chronically ill patients on haloperidol) were late drop outs and had valid cognitive assessments at drop out 9–12 weeks after start of doubleblind treatment; for the analysis, the cognitive data from these patients were included in the last visit at Week 12. The most common reason for premature discontinuation was adverse events followed by premature discontinuation, withdrawal of consent lost to follow up, and non-compliance to study drug (䊉䉴 Fig. 3). All patients were Caucasian and there were no significant between-group differences with regard to diagnostic composition, sex, age, education, and duration of illness or age at onset. Amongst the 40 recruited patients, in each group, there were 13 first-episode and 7 chronically ill patients. The average age of the patients was 28.8 (SD = 7.2) years. The ratio of men to women was 1:3, which is an unusual ratio among patients with schizophrenia enrolled in clinical trials. However, the gender distribution between the two groups was equal (䊉䉴 Table 1). In the CDS, 12 of the patients were first-episode and five were chronically ill. The median duration of the current episode of schizophrenia was approximately 1–2.5 weeks. In each group of the first-episode patients, 9 out of the 12 first-episode patients were drug naïve. Patient severity of illness is summarised in 䊉䉴 Table 2. Using PANSS or SAS there was no significant difference between

the scores at base line in the degree of severity of illness. However, with the PANSS negative score, sertindole treated chronically ill patients showed significantly higher scores. An overview of the cognitive parameter scores at baseline for the CDS is presented in 䊉䉴 Table 3. Cognitive parameter scores at baseline were similar between the two treatment groups. The mean time used to solve the RTD tasks for all patients was 678 ms for the simple reaction task, 815 ms for the stimulus discrimination task, and 866 ms for the choice reaction task. The mean number of total errors in the WCST for all patients was 36, of which 18 were non-perseverative errors.

Applied doses of medications Patients in the CDS received an average dose of 13.7 mg/day sertindole (95 % CI = 12.0, 15.3) or 6.9 mg/day haloperidol (95 % CI = 5.7, 8.0) at Week 4, and 11.8 mg/day sertindole (95 % CI = 9.8, 13.7) or 5.8 mg/day haloperidol (95 % CI = 4.3, 7.2) at Week 12. The median dose was 12 mg/day sertindole and 6 mg/day haloperidol at both assessment weeks.

Changes in Cognitive Tests Initial analysis All reaction times are covariate adjusted differences in change from baseline between treatment groups. In the initial MMRM model, excluding the EPS covariates and adjusting only for cog-


6 Original Paper

Table 2


Baseline severity of illness, Cognitive Data Set (CDS)

Scale

First-episode patients

patients in CDS§ PANSS total score mean (SD) median min, max PANSS positive score mean (SD) median min, max PANSS negative score mean (SD) median min, max SAS total score mean (SD) median min, max


SER†

HAL‡

12

12

72.9 (21.7) 67 41, 109

64.7 (20.6) 61 32, 99

70.6 (9.4) 70 58, 84

20.2 (4.2) 21 15, 27

18.0 (4.1) 19 11, 24

14.8 (11.1) 16 0, 33 0.8 (1.5) 0 0, 4

All patients

SER

HAL

SER

HAL

5

5

17

17

66.0 (6.2) 68 57, 73

72.2 (18.6) 68 41, 109

65.1 (17.3) 63 32, 99

16.6 (2.6) 15 15, 21

20.4 (4.3) 18 16, 26

19.1 (4.1) 18 15, 27

18.7 (4.2) 18 11, 26

14.0 (9.8) 16 1, 30

19.0 (3.1)* 20 15, 23

13.6 (1.7) 14 11, 15

16.1 (9.6) 17 0, 33

13.9 (8.2) 15 1, 30

0.1 (0.3) 0 0, 1

2.4 (2.7) 2 0, 7

1.8 (2.5) 0 0, 5

1.2 (2.0) 0 0, 7

0.6 (1.5) 0 0, 5

*significant difference, p < 0.01, between treatment groups using t-test †

SER: sertindole

‡

HAL: haloperidol

§


Table 3

Baseline cognitive parameter scores, Cognitive Data Set (CDS)

Scale

First-episode patients §

patients in CDS reaction time decomposition reaction time (ms) simple reaction task mean (SD) median min, max stimulus discrimination task mean (SD) median min, max choice reaction task mean (SD) median min, max Wisconsin Card Sorting Test number of errors total errors mean (SD) median min, max perseverative errors mean (SD) median min, max non-perseverative errors mean (SD) median min, max

SER†

HAL‡

12

12

Chronically ill patients SER 5

HAL 5

All patients SER

HAL

17

17

677 (362) 525 322, 1310

586 (203) 585 310, 1025

752 (378) 772 384, 1306

829 (512) 611 452, 1716

699 (356) 584 322, 1310

657 (327) 605 310, 1716

811 (285) 705 472, 1458

764 (188) 741 491, 1173

723 (180) 657 512, 918

1038 (358) 1036 651, 1545

785 (256) 698 472, 1458

845 (270) 759 491, 1545

828 (258) 766 600, 1523

873 (196) 893 554, 1238

838 (206) 781 557, 1084

971 (316) 963 582, 1329

831 (238) 781 557, 1523

902 (231) 895 554, 1329

35.5 (22.3) 32.0 11, 88

31.8 (21.0) 30.5 9, 74

50.2 (33.4) 42.0 13, 92

33.2 (26.0) 31.0 10, 76

39.8 (25.8) 33.0 11, 92

32.2 (21.8) 31.0 9, 76

17.4 (11.5) 18.0 5, 43

16.8 (11.7) 13.5 4, 41

24.0 (19.3) 20.0 4, 55

14.8 (13.6) 8.0 6, 38

19.4 (13.9) 18.0 4, 55

16.2 (11.9) 12.0 4, 41

18.1 (13.6) 13.0 6, 45

15.0 (12.2) 14.0 4, 46

26.2 (17.1) 22.0 9, 50

18.4 (13.8) 18.0 4, 38

20.5 (14.7) 15.0 6, 50

16.0 (12.3) 15.0 4, 46

No statistically significant differences found between treatment groups †

SER: sertindole

‡

HAL: haloperidol

§



Original Paper 7


Table 4

Baseline-adjusted mean changes from baseline in SAS total scores at weeks 4 and 12, Cognitive Data Set (CDS), Analysis of covariance (ANCOVA) All patients

SAS score

Wk

n

Mean

Std. error

First-episode patients p value§

n

change SER† HAL SER HAL

4 4 12 12

17 17 16 16

0.67 2.98 − 0.69 1.64

Mean

Std.error

p value

1.31 1.31 0.85 0.85

0.2898

change 1.26 1.26 0.68 0.68

0.2084 0.0230

12 12 11 11

0.51 2.57 − 0.20 1.75

0.1291

§

Null hypothesis of no difference between treatment groups tested using t-test

†

SER: sertindole

‡

HAL: haloperidol

nitive baseline score, according to the statistical methods described earlier, sertindole treatment was statistically significantly superior to haloperidol on all three RTD tasks at Week 4 and at Week 12. At week 4, the sertindole patients were faster than haloperidol patients at the simple reaction task (272 ms; p < 0.01), the stimulus discrimination task (225 ms, p < 0.01), and the choice reaction task (254 ms; p < 0.01) in the all patients group. For first-episode patients the corresponding times were 284, 290, and 266 ms faster (p < 0.01 for all tests) versus haloperidol treated patients. At week 12, the sertindole (all-patients) group was faster in the simple reaction task (183 ms; p < 0.01), the stimulus discrimination task (162 ms; p < 0.01), and the choice reaction task (210 ms; p < 0.01) than the haloperidol group. The corresponding times for first-episode patients were 202, 221, and 226 ms faster, (p < 0.01 for all tests), versus haloperidol treated patients. Sertindole was also statistically significantly superior to haloperidol on the perseverative errors parameter at Week 12, with 11.0 fewer perseverative errors than for haloperidol both in the all patients group and the group of first-episode patients (p = 0.0111 and p = 0.0231, respectively). At this time point sertindole treated patients had 3.6 and 4.7 fewer non-perseverative errors for all patients and first-episode patients, respectively, although the difference was only statistically significant for first-episode patients (p = 0.0888 and p = 0.0340, respectively). There was no difference between treatment groups in the change of either perseverative or non-perseverative errors at Week 4 in the group of all patients, except for the sertindole treated first-episode patients who had 7.6 fewer nonperseverate errors (p = 0.0307).

EPS-adjusted analysis Potentially, an effect of EPS induced by haloperidol could account for the overall lack of a positive effect on cognition following treatment with haloperidol. On the SAS, the baseline adjusted mean change for the haloperidol-treated patients was 2.3 points larger than that for the sertindole-treated patients at both Week 4 and Week 12 in the all patients group and 2.1 and 1.9 points larger at Week 4 and Week 12, respectively, for first-episode patients (䊉䉴 Table 4). There was a high variation in the change scores at Week 4, and the difference between treatment groups in SAS score only reached statistical significance at Week 12 (p = 0.0230 for all patients, but not quite for first-episode patients (p = 0.1291); (traditional ANCOVA with baseline SAS score as covariate). Overall, the results from the EPS-adjusted analysis resembled those from the initial analysis. In the all patients group, sertindole remained statistically significantly superior to haloperidol on all three RTD tasks at Week 4 and Week 12, and sertindole remained statistically significantly superior to haloperidol on

the perseverative errors parameter at Week 12. Similar results were seen for the subgroup of first-episode patients although the differences for the simple reaction task and the choice reaction task were only marginally statistically significant at Week 4, due to lack of statistical power from the lower number of patients in this group. The differences in the number of non-perseverative errors made by patients receiving sertindole was numerically superior to haloperidol but did not reach statistical significance. The EPS-adjusted results are shown in 䊉䉴 Table 5 and details from the analysis are described below.

Changes in Reaction Time Decomposition Tasks In general, sertindole-treated patients needed less time than haloperidol-treated patients to solve each of the RTD tasks. At the early treatment assessment time point (Week 4), the sertindole group were 158, 75 and 92 ms faster than at baseline for the simple reaction task, stimulus discrimination task and choice reaction task, respectively, in all patients, and 113, 80 and 71 ms faster in the first-episode patients. Patients in the haloperidol group were 82, 107 and 119 ms slower than at baseline for the simple reaction task, stimulus discrimination task and choice reaction task, respectively, in all patients and 80 ms, 155 ms and 119 ms slower in the first-episode patients (䊉䉴 Table 5). The differences in mean change in reaction time between the improvement in the sertindole group and the impairment in the haloperidol group were all statistically significant: 240 ms (all patients) and 193 ms (first-episode patients) for the simple reaction task (p = 0.0034 and p = 0.0543, respectively), 181 ms (all patients) and 235 ms (first-episode patients) for the stimulus discrimination task (p = 0.0111 and p = 0.0141, respectively), and 211 ms (all patients) and 190 ms (first-episode patients) for the choice reaction task (p = 0.0091 and p = 0.0630, respectively) (䊉䉴 Table 5). At the second treatment assessment time point (Week 12), the sertindole group continued to improve for all RTD tasks, although at a rate that was less marked than at the early assessment, whereas in the haloperidol group the initial early impairment was found to be reversed to a mild improvement (䊉䉴 Fig. 4A, B, C). At the 12 week assessment, the sertindole group were 184, 141 and 130 ms faster than at baseline for the simple reaction task, stimulus discrimination task and choice reaction task, respectively, in all patients, and 115, 128, 102 ms faster in the first-episode patients (䊉䉴 Table 5). At week 12, the haloperidol (all-patients) group had a shorter reaction time (19 ms) than at baseline for the simple reaction task; for the stimulus discrimination task and the choice reaction task the haloperidol group was 18 and 67 ms slower, respectively, than at baseline. The firstepisode patients were 39, 67 and 70 ms slower than at baseline for the simple reaction task, stimulus discrimination task and


8 Original Paper


Table 5 EPS-adjusted mean changes from baseline in RTD and WCST tasks at weeks 4 and 12, Cognitive Data Set (CDS), Mixed-effects Model Repeated Measures (MMRM) All patients Assessment

Wk

n

Mean change

Std. error

First-episode patients p value†

n

Mean change

Std. error

p value†

RTD simple reaction task SER HAL SER HAL stimulus discrimination task SER HAL SER HAL choice reaction task SER HAL SER HAL WCST total errors SER HAL SER HAL perseverative errors SER HAL SER HAL non-perseverative errors SER HAL SER HAL

4 4 12 12

17 17 16 16

− 158.1 81.7 − 184.4 − 19.0

52.3 53.5 40.1 37.7

4 4 12 12

17 17 16 16

− 74.6 106.8 − 140.6 17.8

46.3 47.2 37.8 35.6

4 4 12 12

17 17 16 16

− 91.9 119.1 − 129.9 67.3

52.0 53.4 40.4 37.8

4 4 12 12

17 17 16 16

− 3.9 − 5.6 − 16.8 − 3.8

3.6 3.7 4.3 3.8

4 4 12 12

17 17 16 16

− 1.7 − 3.7 − 9.6 2.0

2.5 2.6 3.2 2.9

4 4 12 12

17 17 16 16

− 1.7 − 2.4 − 7.2 − 5.8

2.2 2.2 1.6 1.5

0.0034 0.0061

0.0111 0.0057

0.0091 0.0016

0.7556 0.0387

0.5860 0.0144

0.8344 0.5547

12 12 11 11

− 112.7 79.8 − 115.3 38.9

64.4 65.6 49.7 48.5

12 12 11 11

− 80.0 154.7 − 128.3 56.5

60.1 61.1 41.7 40.2

12 12 11 11

− 71.1 119.0 − 101.6 69.7

65.7 67.0 34.9 34.1

12 12 11 11

− 5.0 − 1.3 − 19.8 − 4.1

4.7 4.8 4.6 4.4

12 12 11 11

− 0.9 − 2.6 − 12.2 1.0

3.5 3.5 3.5 3.3

12 12 11 11

− 4.1 1.6 − 8.0 − 5.2

2.2 2.2 1.6 1.5

0.0543 0.0435

0.0141 0.0055

0.0630 0.0026

0.5985 0.0287

0.7387 0.0158

0.0887 0.2443

†

Null hypothesis of no difference between treatment groups tested using t-test

the choice reaction task, respectively (䊉䉴 Table 5). At Week 12, the differences in the change in reaction time between the two treatment groups were statistically significant in favour of the sertindole group: 165 ms (all patients) and 154 ms (first-episode patients) for the simple reaction task (p = 0.0061 and p = 0.0435, respectively), 158 ms (all patients) and 185 ms (first-episode patients) for the stimulus discrimination task (p = 0.0057 and p = 0.0055, respectively), and 197 ms (all patients) and 171 ms (first-episode patients) for the choice reaction task (p = 0.0016 and p = 0.0026, respectively) (䊉䉴 Table 5).

Changes in the Wisconsin Card Sorting Test Total errors, perseverative and non-perseverative errors On average, sertindole-treated patients made slightly more errors than haloperidol-treated patients in the WCST at baseline (䊉䉴 Table 3). After the initial treatment period from baseline to Week 4, the patients in both treatment groups improved to a similar extent. Later in the study, sertindole-treated patients continued to improve, whereas haloperidol-treated patients deteriorated. Results of the statistical analysis of change from baseline in the number of total errors are presented in 䊉䉴 Table 5. At Week 12, patients receiving sertindole performed statistically significantly better than those receiving haloperidol; sertindole patients had 13 (all patients) and 16 (first-episode patients)

fewer errors than that for haloperidol (p = 0.0387 and p = 0.0287, respectively). Although there was a difference in the number of total errors between the two treatment groups, splitting the numbers into perseverative and non-perseverative errors, showed a more differentiated result. No differences were found for non-perseverative errors, while a significant difference was found for perseverative errors. It could be seen that the number of perseverative errors was influenced by treatment in different ways (䊉䉴 Table 5; 䊉䉴 Fig. 5A). This was particularly apparent at the second treatment assessment (Week 12). In the sertindole group, the number of perseverative errors was seen to have markedly decreased over the entire study period, with a mean change from baseline to Week 12 of 9.6 errors (all patients) and 12.2 errors (first-episode patients). In contrast, while patients in the haloperidol group improved at Week 4 similar to the sertindole treated patients, they later deteriorated; with an increase of 2.0 errors (all patients) and 1.0 error (firstepisode patients) at week 12. Comparing the sertindole and haloperidol treatments, the sertindole group had 11.6 (all patients) and 13.2 (first-episode patients) fewer perseverative errors (p = 0.0144 and p = 0.0158, respectively) than the haloperidol group. The number of non-perseverative errors decreased in both treatment groups during the whole study period (䊉䉴 Table 5; 䉴 Fig. 5B). For sertindole-treated patients, the mean decrease 䊉


Original Paper 9


A

Sertindole 100 0 -100 -200 -300

0

2

4

6

8

10 0

12

300

Mean Change +/- SEM (ms)

Haloperidol Sertindole

5 0 -5 -10 -15 -20 2

4

6

8

10

12

B

B Haloperidol 200

Sertindole

100 0 -100 -200 -300

0

2

4

6

8

10

12

C Mean Change +/- SEM (ms)

10

0 Mean Change +/- SEM (errors)

Mean Change +/- SEM (ms)

Haloperidol

200

Mean Change +/- SEM (errors)

A 300

10 5

Haloperidol Sertindole

0 -5 -10 -15 -20 0

2

4

6

8

10

12

Treatment Week 300

Haloperidol 200

Fig. 5 EPS-adjusted mean change from baseline in Wisconsin Card Sorting Test, for A. Perseverative Errors and B. Non-perseverative Errors, Cognitive Data Set (CDS).

Sertindole

100 0 -100 -200 -300

0

2

4

6

8

10

12

Treatment Week Fig. 4 EPS-adjusted mean change from baseline in Reaction Time Decomposition Tasks for A. Simple Reaction Task, B Stimulus Discrimination Task, and C. Choice Reaction Task Cognitive Data Set (CDS).

from baseline to Week 12 was 7.2 errors (all patients) and 8.0 errors (first-episode patients) and for haloperidol-treated patients it was 5.8 errors (all patients) and 5.2 errors (first-episode patients). The estimated difference between treatment groups was 1.4 errors (all patients) and 2.7 errors (first-episode patients) (p = 0.5547 and p = 0.2443, respectively) in favour of sertindole.

Discussion & In this study we compared the impact of sertindole and haloperidol on cognitive function in patients suffering from schizophrenia. A set of computerised tasks was designed to explore various compartments of the visuo-motor circuitry of the brain. Differences between the two treatment groups could contribute to the understanding of the cognitive strain in schizophrenia. The

present study underlines the importance of the use of experimental cognitive paradigms for the investigation of cognitive failure in schizophrenia. At the same time, it adds evidence to the importance of time course observations on drug effects on cognition.

Cognitive deficits and the visuo-spatial pathway in schizophrenia Earlier studies have already pointed out that the cognitive deficit in schizophrenia is distinct from alterations found in patients with other mental disorders [47], and that functions of the visuo-spatial pathway of the brain may be crucial for cognitive functioning [5, 2, 62, 15]. Deficits have been described most extensively in the dorsolateral prefrontal cortex [10, 14, 57, 67]. However, neuropsychologists and other neuroscientists have maintained that failure of cognition, like most other symptoms in schizophrenia, must involve a complex and interacting multitude of functional systems, and that failure of a certain morphological entity in the brain cannot be regarded as an isolated phenomenon, but that its failure should be studied in the context of its impact on the whole brain [5, 1, 46, 13, 29]. More recently, this view has been elaborated by Carlsson [12] who, by merely describing the complexity of interactions between various neurotransmitters and functional circuits of the brain in the origin of schizophrenic symptomatology, maintained that ‘…thinking in loops might be an efficient strategy for obtaining a functional understanding of the neuronal circuitry involved in the complex symptomatology of schizophrenia.’


10 Original Paper fMRI studies using the connectivity paradigm have confirmed the systemic nature of the visuo-spatial system [46, 44]. Posner and others have therefore proposed that cognitive investigations should aim to define the relevant compartments involved in the tested process. They have suggested a modular approach to the understanding of the observed phenomena [58, 3]. Previous studies from our own group have confirmed that distinct qualitative and quantitative changes in cognition can be demonstrated when comparing first-episode patients from their healthy controls [34]. Following this line of thought, in the present study, the digital version of the WCST [25], and of a reconceptualised RTD task [35], were applied on both first-episode and chronic schizophrenic patients. Results support the idea that both the use of such tasks and the observation at various points in time reveal specific phenomena.

Specificity of drugs and impact of the course of time First, it was confirmed that haloperidol, the substance with high D2 dopaminergic receptor affinity has an immediate negative effect on all components of the RTD task, i.e. from simple reaction to choice reaction. This suggests that the whole visuospatial pathway is negatively affected by haloperidol in a systemic manner. In contrast, patients on sertindole, the atypical substance, showed significant improvement in every component of the described task set, indicating the reverse effect. Despite of the small number of patients, results from the whole group could be maintained in the subsample of first-episode patients. The latter suggests that the found difference between the two substances represents a contextual phenomenon of the illness rather than a contamination artefact. Sertindole’s 5-HT2A and 5-HT6 antagonistic properties are believed to improve cognition. In animal studies, 5-HT2A antagonists increase extracellular dopamine in rat prefrontal cortex which could have a procognitive effect [63, 39]. The 5-HT6 receptor is a candidate for cognition-enhancing effects based on studies of selective 5-HT6 antagonists [71, 24, 61, 36, 17, 26]. Another crucial aspect is the observation of changes in cognition over time. Again, looking at the three measured points, a marked difference was found between the two substances. While patients on haloperidol showed a significant impairment after 4 weeks, the sertindole patients demonstrated significant improvement after 4weeks. At 12 weeks, however, both groups of patients showed improvement. When both improvement periods are combined, the best overall values were observed in the sertindole group, furthermore, secondary improvement in the haloperidol group could hardly level previous impairment. The latter result may contribute to the discussion about necessary compensation mechanisms for the haloperidol group that are not required when sertindole is applied. It could be argued that patients impaired on haloperidol during the first 4 weeks need their remaining mental resources to overcome the negative effects of haloperidol while patients on sertindole do not suffer from such impairment during the first treatment period and, therefore, show immediate improvement. During the second observation period, patients can further build on their previously achieved level of higher function.

Brain plasticity and experience from animal models An alternative explanation could be found in the effects of both substances on brain plasticity. Recent concepts regarding brain plasticity point to a loss of a specific fraction of brain plasticity, i.e., ‘fast stabilising plasticity’, which is related to neural com-


plexity as a measure of neural network integration in the brain [33]. It is a prerequisite to extract important features from different sensory inputs and to simultaneously generate coherent perceptual and cognitive states in order to integrate specific segregated brain processes into global brain activity [56]. This concept postulates that mental disorder is associated with disturbed brain plasticity resulting in an imbalance of state–space brain configurations. In an animal experiment, Rodefer and coworkers [59] used PCP-induced deficits in extradimensional shift learning to model cognitive changes in schizophrenia. They demonstrated that subchronic PCP administration induced such changes in brain plasticity in rats. In a second experiment, they exposed PCP-pre-treated animals to haloperidol, clozapine, risperidone, and sertindole. The results demonstrated that, while haloperidol could not reverse PCP-induced deficits, clozapine and risperidone showed weak but positive effects, while sertindole significantly reversed the deficits [60]. These results from an animal research model are consistent with other animal models referring to brain plasticity [64] and the clinical findings from the present study and they have been taken up by a variety of authors in concepts attempting to explain specific effects seen both with haloperidol and clozapine [33]. WCST is regarded as a tool to investigate executive function in terms of dorsolateral prefontal function [7]. Our results demonstrate a significant difference only for the perseverative errors and in favour of sertindole. As this part of the task is known as having some specificity in patients with schizophrenia [55], it could be argued that a schizophrenia-specific process is being addressed by one of the investigated substances. However, as no differences could be found after four weeks, again, longer term processes, such as brain plasticity phenomena may be an alternative explanation.

Exclusion of EPS as the cause of distinction Finally, in the past, there has been the point made that EPS may be the main cause for the differences seen between conventional and atypical substances. However, in a previous study, our group [45] demonstrated that motor impairment remained stable over time in a maze paradigm, where a tracking sequence was used to test the difference between zotepine and clozapine. As in this study, these two substances represent different dopamine affinities. In the present study the differences could be maintained using a statistical model that adjusted for a potential EPS effect by inclusion of the SAS scale as a covariate. In addition, in order to distinguish between sensory and motor processes, the RTD paradigm offers the option to calculate movement latency (the time consumed during the sensory processing period), and movement time (the time component covering the motor execution of a given task). Hence, EPS will be contained in this parameter. For both the movement latency time and the movement time, patients in the sertindole group performed significantly better than patients in the haloperidol group. It must, therefore be concluded that, at least in the present study, other effects than EPS are causative for the observed cognitive impairment on haloperidol. This is in good keeping with the findings of Weiser and colleagues [69] who reported that patients receiving risperidone suffered from EPS similar in severity to the EPS of the patients receiving haloperidol. However, their performance on a task involving visuo-motor and attentional skills was similar to that of patients receiving another atypical antipsychotic drug with a significantly lower affinity to the D2 receptor system, i.e. olanzapine.


Original Paper 11


Limitations of the study & The scientific standard of the this work is limited by the fact that the study was stopped prematurely thus leading to the inclusion of fewer patients than planned and therefore less study power than anticipated. The inclusion of both first-episode patients and chronically ill patients induced some heterogeneity in the study. Since all chronically ill patients had previously received treatment to stabilise their illness, whereas most of the first-episode patients (75 % in both treatment groups) were drug naive, the SD of the baseline PANSS total scores were lower in the chronically ill patients (9.4 for sertindole treated patients and 6.2 for haloperidol patients) than in the first-episode patients (21.7 in the sertindole group and 20.6 in the haloperidol group). This inequality of variance between the two populations was caused mainly by a difference in the PANSS negative scores: in the first-episode patients SD was 11.1 for sertindole and 9.8 for haloperidol and in the chronically ill patients SD equal to 3.1 for sertindole and 1.7 for haloperidol. As regards the cognitive tests at baseline, however, there were no such distinctive differences in the variance between the two populations. Another drawback of the small sample sizes is that no direct comparison between first episode and chronic patients could be drawn. Moreover, the repeated application of the same tests implies improvement due to practice that may be different for the two treatment groups, because the two drugs may affect learning differently, but also this would contribute to the overall superiority of sertindole. The present study confirms the existence of two distinct processes of action of sertindole and haloperidol on cognition and the marked beneficial effects of sertindole, particularly in parameters that are regarded as schizophrenia-related cognitive disturbances. Furthermore, it stresses the need of time course observations in order to track specific effects of substances on the brain for the better understanding of brain function.

Acknowledgments & This study was conducted at three sites in Estonia (Dr. Peeter Jaanson in Tartu, Dr. Erika Saluveer in Tallinn, Dr. Ljudmila Väre in Pärsti Vald), and was supported by an unrestricted grant from H. Lundbeck A/S. Presented in part at 16th European College of Neuropsychopharmacology (ECNP) Congress, Prague, The Czech Republic, 20–24 September, 2003; and at Cognition and Schizophrenia, Institute of Psychiatry, London, United Kingdom, 16–17 September, 2004.

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