Perseveration in schizophrenia: failure to generate a plan and relationship with the psychomotor poverty subsyndrome

Psychiatry Research 112 (2002) 13–26

Perseveration in schizophrenia: failure to generate a plan and relationship with the psychomotor poverty subsyndrome Marja G. Lansera,b, Hans J.C. Bergerc, Bart A. Ellenbroeka,*, Alexander R. Coolsa, Frans G. Zitmanb,1 a

Department of Psychoneuropharmacology, University Medical Centre St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands b Department of Psychiatry, University Medical Centre St. Radboud, Nijmegen, The Netherlands c Department of Medical Psychology, University Medical Centre St. Radboud, Nijmegen, The Netherlands Received 13 July 2001; received in revised form 23 May 2002; accepted 21 July 2002

Abstract Although perseveration in the Wisconsin Card Sorting Test (WCST) has been studied extensively in schizophrenia, the underlying cognitive dysfunctions are not yet clear. In schizophrenia, perseveration has been found to relate to frontal and striatal abnormalities. Therefore, both a failure to generate a plan as seen in patients with frontal abnormalities, or a failure to execute a plan as observed in Parkinson patients, who suffer primarily from striatal abnormalities, could explain perseveration in schizophrenia. The aim of the present study was to distinguish between these two cognitive dysfunctions, which are described by Frith in his routes-to-action model. The main difference between these dysfunctions is the ability to use external guidance. In the present study, 39 schizophrenic patients and 36 healthy controls were assessed with the California Verbal Learning Test (CVLT) and the WCST, in which use of external guidance can be measured, and with the Positive and Negative Syndrome Scale (PANSS) to determine the relationship with symptomatology. The results showed that half of the schizophrenic patients showed perseveration, which could be explained by a failure to generate a plan and was related to the psychomotor poverty subsyndrome. No evidence was found for a failure to execute a plan. Type of antipsychotic medication used (atypical vs. typical) proved not relevant. The results are discussed in the light of evidence for involvement of the dorsolateral prefrontal cortex in perseveration in schizophrenia. 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Schizophrenia; Perseveration; Prefrontal cortex; Striatum; Cues; Wisconsin Card Sorting Test; California Verbal Learning Test

*Corresponding author. Tel.: q31-24-3616479; fax: q31-24-3540044. E-mail address: [email protected] (B.A. Ellenbroek). 1 Present address: Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands. 0165-1781/02/$ - see front matter 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 1 7 8 1 Ž 0 2 . 0 0 1 7 8 - 6

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1. Introduction Schizophrenic patients have been found to show perseveration on the Wisconsin Card Sorting Test (WCST) (Butler et al., 1992; Franke et al., 1992; Cuesta et al., 1995; Haut et al., 1996), a test developed to measure the ability to sort stimuli into abstract categories and shift cognitive set (Berg, 1948). Although the WCST has been used with schizophrenic patients extensively, the cognitive dysfunctions underlying perseveration in these patients are not yet clear. Several neuropsychological studies have provided evidence for an important role for the frontostriatal loops in shifting cognitive sets in patients with schizophrenia (Robbins, 1991; Elliott et al., 1995; Pantelis et al., 1997, 1999). In imaging studies, correlations have been found between WCST performance and both striatal (Rossi et al., 1996; Stratta et al., 1997) and frontal abnormalities (Berman et al., 1986; Weinberger and Berman, 1988; Paulman et al., 1990; Kahn and Davidson, 1995; Okubo et al., 1997). These abnormalities in striatum and frontal cortex of schizophrenic patients have been observed in patients using medication as well as in neuroleptic-naive patients (Wong et al., 1986; Weinberger and Berman, 1988; Andreasen et al., 1992; Buchsbaum et al., 1992; Siegel et al., 1993; Andreasen et al., 1997). Since there are close connections between the prefrontal cortex (PFC) and striatum within the fronto-striatal loops (Alexander et al., 1986), both PFC and striatal abnormalities may lead to the same behavioural deficits. It has been shown that both patients with frontal lesions and patients with Parkinson’s disease (PD), who suffer from degeneration of the nigro-striatal pathway, have problems in shifting cognitive set. However, subtle differences can be detected. It has been found that PD patients are able to benefit from cues to shift set (Fimm et al., 1994; Hsieh et al., 1995), even when these cues do not convey information about the correct solution to a problem (van-Spaendonck et al., 1995). Patients with lesions of the PFC have been found to benefit only from cues that are explicitly related to the content of the solution, like explanation of the

possible categories (Delis et al., 1992; Dimitrov et al., 1999; Stuss et al., 2000). Cues that do not convey information about the solution are, for instance, present in the acquisition phase of the WCST, during which the first category has to be found (van-Spaendonck et al., 1996). In the acquisition phase, problem solving is much more externally guided than in the phase after the first shift. Instructions and feedback can be unequivocally used in the acquisition, whereas after the unannounced shift, internally guided problem solving is required. The subject has to discover that the former solution is no longer correct and has to find alternatives without the help of further instructions or other external guidance (van-Spaendonck et al., 1996). Indeed, it has been frequently found that PD patients show normal performance when no shifting is required (Beatty et al., 1989; Richards et al., 1993; Hsieh et al., 1995; vanSpaendonck et al., 1995). External guidance is also present after the second shift, because then alternative solutions have been generated and the set-up of the test has become clearer. PD patients have been found to improve after the second shift (van-Spaendonck et al., 1995). In contrast with PD patients, frontal patients have problems in all phases of the WCST (Heaton et al., 1993). These differential performances presumably reflect dysfunctions at different information processing levels. This has clearly been illustrated by Frith et al. (Frith and Done, 1988; Frith, 1992; Cahill and Frith, 1996; Frith and Dolan, 1996). In their model, two routes-to-action: the willed route and the stimulus-driven route are distinguished (Fig. 1). In the willed route a self-generated plan is turned into action or, worded differently, behaviour is internally guided. In the stimulus-driven route, the action is externally guided. A disturbance in the willed route-to-action can lead to perseveration but might also lead to stimulus-bound behaviour or lack of action, depending on the given task. This willed route could be dysfunctional because of a failure to generate a plan or a failure to execute a plan. Frith (1992) proposed a role for the PFC in the generation of a plan and a role for the striatum in the execution of a plan. This model makes clear why PD patients benefit from cues that give no

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Fig. 1. The model proposed by Frith with two routes-to-action: the willed route and the stimulus-driven route (Frith, 1992). In the present article, we distinguished between failure to generate a plan (1) and failure to execute a plan (2). The results showed that WCST perseveration in schizophrenia can be explained by a failure to generate a plan, which is related to frontal lobe functioning. Perseveration could not be explained by a failure to execute a plan, which is related to striatal functioning.

information about the correct solution. They are able to generate plans, but are in need of an external trigger to execute these plans. Frontal patients only take advantage of cues that convey clear information about the solution, because these cues can compensate for the inability to generate a plan. The goal of the present study was to investigate whether perseveration in schizophrenia can be explained by a failure to generate a plan or a failure to execute a plan. We used a battery of neuropsychological tests including the WCST, the California Verbal Learning Test (CVLT), and memory and intelligence tests to control for confounding factors. The potentially confounding factors emotional discomfort and hostility (Bell et al., 1994) were taken into account because they might affect motivation. Motivational problems are a major concern in schizophrenia research (Elliott and Sahakian, 1995). The WCST was used to measure perseveration, and was analysed in phases, as was introduced by van-Spaendonck et al. (1995). To test whether a

failure to generate a plan can explain perseveration, patients were selected who showed perseveration in all phases of the WCST. Without a plan, one cannot benefit from the external guidance in the test. To test whether a failure to execute a plan can explain perseveration, patients were selected who showed perseveration only in the shift 1 phase, because then no external guidance is present. After selection of patients on WCST perseveration, the subgroups were tested on performance pattern on the CVLT to confirm the presence of a failure to generate or execute a plan. In the CVLT, the subject can use externally guided serial ordering of the words or internally generated semantic ordering. When a plan cannot be executed, semantic ordering will be decreased, because this requires execution of an internally generated plan. Serial ordering will be increased, because this strategy is externally guided. Without a plan, there will be only a decrease in semantic ordering, because there is no benefit from the subtle cue provided by the serial ordering of the words. It has been found that

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frontal patients (Freedman and Cermak, 1986) and PD patients (Buytenhuijs et al., 1994) tend not to use semantic strategies to encode the words, and that PD patients instead rely increasingly on serial clustering (Buytenhuijs et al., 1994). We preselected patients on the use of classical and atypical antipsychotics to detect effects on cognitive performance. Moreover, we wished to distinguish between a failure to execute a plan due to striatal abnormalities related to the disease and a failure to execute a plan caused by the side effects of the classical antipsychotics. It has been found that classical antipsychotics affect set-shifting without cues (Berger et al., 1989), most likely due to their effects at the level of the striatum (Ellenbroek and Cools, 2000). For the atypical antipsychotics, most studies show either no effect on cognition or an improvement (Keefe et al., 1999). We considered failure to execute a plan a side effect of the classical antipsychotics only if it occurred in patients using classical antipsychotics and not in patients using atypical antipsychotics. Failure to execute a plan was considered to be due to the disease schizophrenia, if it occurred irrespective of the antipsychotic used. Since heterogeneous neuropsychological test performance in schizophrenia is a consistent finding (Crow, 1985; Braff et al., 1991; Heinrichs and Awad, 1993; Elliott and Sahakian, 1995) and the relationship between perseveration and symptomatology is not yet clear, we tested the relationship between symptomatology and failure to generate or execute a plan. We used the three syndromes as distinguished by Liddle: psychomotor poverty, disorganisation, and reality distortion (Liddle, 1987a,b; Malla et al., 1993; Cuesta et al., 1995; Gureje et al., 1995). 2. Methods 2.1. Subjects The schizophrenic patient group consisted of 39 patients from various institutes: the Vincent van Gogh Institute in Venray, ‘De Gelderse Roos’ in Wolfheze, Tiel, Zaltbommel and Geldermalsen, Psychiatric Centre Nijmegen, and the Department of Psychiatry at the University Medical Centre St.

Radboud. There were 17 inpatients and 22 outpatients. All subjects met DSM-III-R criteria for schizophrenia (American Psychiatric Association, 1987), and had been diagnosed by their treating clinicians. Selected were 17 patients using classical antipsychotics, and 22 patients using atypical antipsychotics. They used their antipsychotic medication for at least 4 weeks. The group of patients using classical antipsychotics were treated with haloperidol (ns6), perphenazine (ns2), zuclopenthixol (ns1), penfluridol (ns3), fluphenazine (ns1), flupenthixol (ns1), pimozide (ns2), or bromperidol (ns1). The atypical antipsychotics that were used, were olanzapine (ns 10), risperidone (ns4), clozapine (ns4), sertindole (ns3), or quetiapine (ns1). The mean duration of illness was 83.3 months (S.D.s103.7) since first hospitalisation (ns36) or, for patients that have never been hospitalised, since first contact with a psychiatrist for schizophrenic symptoms (ns3). The mean number of hospitalisations was 2.47 (S.D.s2.53). Eighteen patients used comedication, which might have affected test performance. It is known that benzodiazepines affect memory (Curran, 1991; Gorissen et al., 1995), which is required for normal performance on the criterion tests. Furthermore, there is evidence that anticholinergics affect shifting performance (vanSpaendonck et al., 1993). The control group consisted of 36 subjects, who did not have any psychiatric disorder. The majority was recruited from the employees of the University Medical Centre St. Radboud; a minority of the subjects came from outside the medical centre. The control group was matched with the patient group for age, sex and highest education followed. Highest education followed was used to estimate intellectual ability of the subjects. This was considered a more reliable estimate than highest education finished or years of education. Years of education give no information on the educational level. Highest education finished might underestimate the abilities of the schizophrenic patients, since the illness is often a limiting factor in further achievement (Stratta et al., 1993). The same education groups were used as in the manual of the WAIS-R: 0sprimary school; 1slower secondary

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school; 2shigher secondary school; 3sschool of higher vocational education; 4suniversity (Wechsler, 1955). Participants with a neurological disease were not included in this study. All participants gave their informed consent. 2.2. Cognitive assessment A battery of 15 tests was administered. The results of seven tests were used for the current study; the results of the other tests will be published elsewhere. The tests were given in a fixed order to every participant. To prevent weariness, the tests were divided over 3 separate days and after approximately every hour a 15-min break was taken. All testing was done by the same neuropsychologist (ML). 2.2.1. Reference tests It is known that WCST performance is related to intelligence (Gambini et al., 1992; Boone et al., 1993) and some studies have ascribed WCST problems in schizophrenia to intellectual deficits (Dieci et al., 1997; Laws, 1999). To assess verbal intelligence, the Vocabulary and Similarities subtests of the WAIS-R were used (Wechsler, 1955); to assess visuo-perceptual intelligence, Jigsaw and Sorting of a Dutch intelligence test, the Groninger Intelligence Test (GIT), were used. For Jigsaw, a relationship has been found with general spatial ability (Luteijn and van der Ploeg, 1983). In this test, the subject is asked to fit imaginary pieces into an outline. The subtest Sorting measures the ability to sort visual stimuli into categories; 20=8 cards, with different figures, have to be sorted into two categories. In psychiatric patients, correlations between GIT and WAIS IQ are high (0.70–0.90). The WCST also has a memory component. For instance, it is important to remember what solutions have been correct. Therefore, visuo-perceptual memory was assessed with two subtests of the Wechsler Memory Scale Revised (WMS-R): Figural Memory and Visual Paired Associates (Wechsler, 1987). Verbal memory was estimated by using the variable ‘speed of forgetting’ of the CVLT. This variable was chosen because it did not correlate with the amount of semantic ordering, being a criterion variable.

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2.2.2. Criterion tests The WCST was presented in its original form, with ambiguous cards (Heaton et al., 1993). For this study, a pack of 64 response cards was used, instead of 128 cards. To distinguish between a failure to generate and execute a plan, three phases were needed. Therefore, the test was completed when three categories (color, form and number) had been completed (10 successive correct responses), or when all 64 cards had been sorted. This method is comparable to that of van-Spaendonck et al., who introduced phase-analysis (vanSpaendonck et al., 1995). Contrary to van-Spaendonck et al., who scored the number of trials, we used the Heaton method in order to specifically study perseveration. The following variables were used: perseverative errors (PE), perseverative responses (PR) and perseveration, being the addition of PE and PR (Heaton et al., 1993). The Dutch version of the CVLT was administered to study the use of internally and externally guided strategies in learning items from a shopping list. This list can be categorised into four semantic categories of four items. The categories are clothes, fruit, tools, and herbs. The experimenter did not indicate that the items could be grouped. Scores for semantic and serial clustering were used, in which the total number of semantic or serial clusters was divided by the expected number of clusters based on chance (Mulder et al., 1996). To calculate these scores, the IBM-PC CVLT scoring program was used (Fridlund and Delis, 1987). 2.3. Psychiatric assessment On the third day of testing, the patients completed a 1-h psychiatric evaluation, for which the Positive and Negative Syndrome Scale (PANSS) was used (Kay et al., 1987). The interviewer had received PANSS training. The PANSS items for the three syndromes of Liddle were selected, using the extensive description of the syndromes was presented by Malla et al. (1993). The psychomotor syndrome consisted of the negative symptoms blunted affect, emotional withdrawal, poor rapport, passiveyapathetic social withdrawal, lack of spontaneity in conversation, and motor retardation. The

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disorganisation syndrome consisted of conceptual disorganisation, excitement, suspiciousness, hostility, stereotyped thinking, and active social avoidance. The reality distortion syndrome comprised: delusions, hallucinatory behaviour, and grandiosity. The PANSS items included all items used by Bassett et al., who selected PANSS items to test Liddle’s three-syndrome model (Bassett et al., 1994). To calculate the potentially confounding factors emotional discomfort and hostility, we used Bell’s method (Bell et al., 1994). Emotional discomfort included the items depression, anxiety, guilt and active social avoidance. Hostility included the items excitement, hostility, impaired impulse control and uncooperativeness. 2.4. Statistical analysis Statistical analyses were performed with the computerised Statistical Package for Social Sciences (SPSS), version 9.0 for Windows. As mentioned in the Introduction, we twice selected schizophrenic patients based on their pattern of perseveration on the WCST, to study whether perseveration is due to a failure to generate or a failure to execute a plan. First, a group of patients was selected that showed a z-score)1 for PE, PR or total perseveration for all three phases: the expected pattern in case of a failure to generate a plan. The z-scores were calculated using the performance of the control group as a reference. This group split at criterion resulted in a High Perseverating group (HP, ns20) and a Low Perseverating group (LP, ns19). Secondly, the patients were selected on perseveration in the shift 1 phase, while having a normal acquisition and second phase: the pattern expected for a failure to execute a plan. This selection process revealed that none of the patients showed this pattern. This finding indicates that perseveration cannot be explained by a failure to execute a plan. Therefore, only the HP group, which showed perseveration in all phases of the WCST (z)1), and the LP group, which showed low perseveration in the WCST (z/1), were used for further analysis. In order to test whether perseveration could be explained by

a failure to generate a plan, the HP, LP, and control groups were compared. To test for differences between the HP, LP, and control groups in demographic and illness-related variables, one-way ANOVA was used. Pearson x2 was used to test whether the groups differed in sex distribution and in the use of classical and atypical antipsychotics, anticholinergics and benzodiazepines. Group differences for the four reference variables were tested with a MANOVA, with all missing values being replaced by the schizophrenia or control group mean, whichever was appropriate. For the pairwise group comparisons, post hoc Bonferroni tests were used. Differences in the reference variables emotional discomfort and hostility were tested separately, using the non-parametric Mann–Whitney test, because of the non-ratio scaling of the PANSS variables. After testing for group differences in reference variables, correlations were calculated between the criterion variables and reference variables for which significant group differences had been found. Pearson correlations were used for the neuropsychological reference tests, and Spearman correlations were used for the symptoms emotional discomfort and hostility. In case of significant correlations, the reference variables were used as covariates in the comparison of the groups on the criterion tests. For WCST perseveration, extra analyses were performed to control for the reference variables intelligence and memory, by using these as covariates. The different phases were tested in different univariate analyses to be able to detect specific performance patterns on these phases. As was done for the reference variables, all missing values for perseveration were replaced with the schizophrenic or control group mean. This reduced the chance of finding significant differences between the two patient groups. Differences in the CVLT variables were tested with a multivariate analysis because serial and semantic clustering are interrelated. Since multiple comparisons were made for the criterion tests, a Bonferroni correction was used, which set the significance level at 0.0125. The relationship between perseveration and symptoms was determined by comparing the

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Table 1 Subject characteristics (M"S.D.)

Age Men:women Education Illness duration (in months) Number of hospitalisations Classical:atypical antipsychotics Anticholinergics:no anticholinergics Benzodiazepines:no benzodiazepines

LPa, ns19

HPa, ns20

Control group, ns36

31.4 (8.1) 15:4 2.3 (1.0) 96.4 (109.1) 2.7 (2.8) 6:13 5:14 4:15

31.9 (8.8) 12:8 2.1 (0.9) 71.6 (99.8) 2.3 (2.3) 11:9 7:13 4:16

32.4 (8.4) 25:11 2.4 (1.1) – – – – –

a

To test whether a failure to generate a plan could explain perseveration, patients were selected who showed perseveration in all phases of the WCST. This resulted in an HP and a rest group, the LP group. To test whether failure to execute a plan can explain perseveration, patients were selected who showed perseveration only in the shift 1 phase. None of the patients showed this pattern. Therefore, analyses were done for the HP and LP groups only.

patient subgroups on the three syndromes, using a Mann–Whitney test. Furthermore, Spearman correlations were calculated between syndromes and perseveration, both within the total patient group and within the HP group. The effects of type of antipsychotic were studied by comparing the performance on the criterion tests of the group of patients using classical antipsychotics with that of the group of patients using atypical antipsychotics. Group differences were tested in the same way as for the comparisons of the HP, LP and control groups. The effects of use of benzodiazepines and anticholinergics were studied with the same methods. 3. Results 3.1. Subject characteristics The subject characteristics of the HP, LP and control group are presented in Table 1. No differences were found in the demographic and illnessrelated variables. 3.2. Reference variables MANOVA yielded group differences for the reference tests (F(8, 140)s6.048, P-0.001, Pillai’s test), due to differences in visuo-perceptual intelligence and visuo-perceptual memory (Table 2). The HP group had a lower visuo-perceptual intelligence than the LP and control groups, and

both patient groups had visuo-perceptual memory problems. Pearson correlations revealed that visuoperceptual intelligence correlated significantly with perseveration in the acquisition (rsy0.430, Ps 0.006) and shift 2 phases of the WCST (rs y0.436, Ps0.006). The HP and LP group also differed on the hostility component (Mann–Whitney Us118.000, zsy2.062, Ps0.039), but not on emotional discomfort. Means revealed that the HP group scored higher on hostility (Ms7.65, S.D.s3.90), than the LP group (Ms5.42, S.D.s 1.57). Within the total patient group, the hostility component correlated significantly with perseverations in both shift 1 (Spearman, rs0.374, Ps 0.019) and shift 2 (Spearman, rs0.363, Ps 0.023). 3.3. Criterion variables After covariation for visuo-perceptual intelligence in the acquisition and shift 2 phases, the HP group still showed significantly more perseveration in all three phases than the LP and control groups (Table 2). After correction for differences in hostility between the HP and LP group, the differences between these patient groups in perseverations in shift 1 (F(1, 36)s9.737, Ps0.004) and shift 2 (F(1, 36)s6.375, Ps0.016) remained significant. The patients who showed the pattern of a failure to generate a plan on the WCST also showed evidence for this pattern in the CVLT. MANOVA yielded significant group differences (F(4, 144)s 5.496, P-0.001), with univariate F-tests revealing

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Table 2 Means and standard deviations of neuropsychological test performance of the LP, HP and control (C) groups LP, ns19 M (S.D.) Reference variablesc Verbal intelligence Visuo-perceptual intelligence Verbal memory (speed of forgetting) Visuo-perceptual memory

Criterion variables (1) WCST perseveration Acquisitiond Shift 1 Shift 2d (2) CVLTc,e Semantic clustering Serial clustering

57.95 28.03 y0.04 20.21

(13.50) (4.96) (0.48) (4.12)

HP, ns20 M (S.D.) 51.06 22.54 0.12 17.90

(14.20) (5.36) (0.12) (3.61)

C, ns36 M (S.D.) 55.14 29.32 0.05 23.44

(11.77) (4.32) (0.06) (3.20)

Fa

P

Comparison between groupsb

1.420 13.323 1.834 16.457

0.248 0.000 0.167 0.000

– HP-LP, C – HP, LP-C

0.26 (0.56) 1.74 (1.48) 1.65 (0.99)

4.05 (4.85) 9.77 (10.57) 5.65 (4.96)

0.53 (1.11) 3.67 (5.04) 2.09 (2.49)

7.380 8.481 4.819

0.001e 0.000e 0.011e

HP)LP, C HP)LP, C HP)LP, C

1.38 (0.48) 2.11 (1.27)

1.62 (0.80) 1.78 (1.03)

2.39 (0.88) 1.36 (1.00)

12.474 3.178

0.000 0.048

HP, LP-C –

a

Univariate F-tests with d.f.s2, 72 for reference variables, CVLT and WCST perseveration in shift 1; d.f.s2, 71 for WCST perseveration in acquisition and shift 2. b Post hoc Bonferroni tests (P-0.05). c Multivariate analysis of variance. d Univariate analysis using visuo-perceptual intelligence as covariate. e The level of significance was set at 0.0125 following Bonferroni correction.

differences for semantic and serial clustering (Table 2). Post hoc Bonferroni tests showed that the HP group structured less semantically than controls, but had a normal serial structuring, whereas the LP group showed decreased semantic and increased serial structuring. After Bonferroni correction for multiple comparisons, which set the significance level at 0.0125, the group differences

for both WCST and CVLT remained significant, except for the difference found for serial clustering. The CVLT performance pattern of the HP group confirmed the presence of a failure to generate a plan as an explanation for perseveration (Table 3). Since the selection procedure revealed that none of the schizophrenic patients showed the WCST performance pattern as expected in case of a failure

Table 3 Pattern of test performance in HP group HP

Expected pattern in case of Failure to generate a plan

Failure to execute a plan

WCST perseveration

Acquisition Shift 1 Shift 2

y y y

y y y

0 y 0

CVLT

Semantic clustering Serial clustering

y 0

y 0

y q

(y) Abnormal performance; (0) normal performance; (q) increased performance. The CVLT performance pattern of the HP group, which was preselected on perseveration in all three phases of the WCST, confirmed the presence of a failure to generate a plan.

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to execute a plan, we can conclude that failure to execute a plan cannot explain perseveration. 3.4. Effects of medication In the HP and LP groups, the distributions of patients using classical and atypical antipsychotics were not different, according to the chi-square test. However, to make sure that minor differences in distribution (Table 1) did not play a role in the differences in test performance found between the HP and LP groups, patients using classical and patients using atypical antipsychotics were compared. The classical and atypical groups did not differ from each other on performance on the criterion tests, nor were there any differences in demographic or illness-related variables. In addition, no differences were found between patients using benzodiazepines and patients not using benzodiazepines. The same held true for anticholinergics. In sum, differences between the HP and LP groups cannot be ascribed to the type of antipsychotic used, nor were they due to the use of comedication. 3.5. Relationship with the three subsyndromes of Liddle A significant positive correlation was found between perseveration in shift 1 and psychomotor poverty (rs0.590, Ps0.006), when correlations were calculated for the HP group. No significant correlations were found for the total patient group. The HP and LP groups did not differ on the syndromes, so no evidence was found for the subsyndromes matching with the differences in WCST perseveration. The mean scores on the PANSS items were between absent and mild for both the HP and LP groups. 4. Discussion The results provided evidence for a failure to generate a plan as an explanation for perseveration in schizophrenia. A failure to execute a plan could not explain perseveration because no patients showed the performance pattern indicative of this failure.

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Not all schizophrenic patients showed perseveration in the WCST. This is in correspondence with several other studies, which also found relatively intact WCST functioning in some of the schizophrenic patients tested (Braff et al., 1991; Goldstein et al., 1996; Weickert et al., 2000). For the patients of the HP group, we found evidence for a failure to generate a plan. This group had difficulties using internally generated strategies in the WCST and in the CVLT, while not being able to take advantage of external guidance present in these tests. The group of patients that did not perseverate in the WCST, the LP group, did not show the pattern of a failure to generate a plan. Thus, this failure was specifically related to perseverating schizophrenic patients. The failure to generate a plan in the HP group cannot be ascribed to confounding factors like intellectual deficits, memory problems, hostility, emotional discomfort, use of classical or atypical antipsychotics, or use of comedication, because the evidence for a failure to generate a plan was found after adjustment for differences in these variables. The findings are in agreement with remediation studies, in which a decrease of perseveration was found after full explanation of categories (Goldman et al., 1992; Vollema et al., 1995; Young and Freyslinger, 1995). Explanation of the categories might compensate for the lack of a plan or strategy (Bellack et al., 1990). Remediation studies using verbalisation also can be viewed as supportive for our findings (Rossell and David, 1997; Stratta et al., 1997). Stratta et al. found that schizophrenic patients with high perseveration and negative symptoms improved with verbalisation, which was explained by bypassing a plan for action (Stratta et al., 1997). Moreover, our results are consistent with the conclusions of Iddon et al., who found evidence for impaired strategy generation in schizophrenic patients in both visuo-spatial and verbal tasks (Iddon et al., 1998). The present results are also in accordance with the study of Pantelis et al., in which schizophrenic patients needed less initial thinking time, more subsequent thinking time, and showed lower accuracy than controls (Pantelis et al., 1997). This performance pattern has also been found for patients with frontal lobe lesions (Owen et al., 1990; Pantelis et al., 1997).

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In case of a failure to generate a plan, it is expected that initial thinking time is short, but more subsequent time is needed to compensate for the lack of a plan. For patients with PD a prolonged initial thinking time has been found (Owen et al., 1992).

Despite the correlations that were found, there was no evidence for the subsyndromes matching the differences in perseveration. Therefore, severity of symptomatology cannot explain a large part of the variance in perseveration. This is in line with the finding of Nieuwenstein et al. (2001).

4.1. Perseveration-symptomatology relationships In the current study, evidence was found for a relationship between negative symptoms and perseveration due to a failure to generate a plan. No significant correlations were found for the total patient group, probably due to the lack of (variation in) perseveration in the LP group. Within the HP group a positive correlation was found between perseverations in the shift 1 phase of the WCST and the psychomotor poverty syndrome of Liddle. No correlations were found for the acquisition and the shift 2 phases, due to absence of perseveration in the acquisition phase (perseveration scores0) and the many missing values in the shift 2 phase. Relevant to note is that the missing values of the HP group were replaced by the mean of the total patient group, thereby reducing the chance of finding significant differences between the two patient groups (see statistical analysis). The correlation found between perseveration in shift 1 and psychomotor poverty (which comprises mostly negative symptoms) is in line with other studies (Cuesta et al., 1995; Berman et al., 1997, 1997; Basso et al., 1998). In some studies, however, correlations have been found between WCST perseveration and the disorganisation syndrome (Liddle and Morris, 1991; Rowe and Shean, 1997). These seemingly contradictory findings are probably due to differences in duration of hospitalisation. Our HP group consisted of 40% inpatients, 87.5% of which had an illness duration of less than 2 years. The patients of Basso et al. were also not severely disabled (Basso et al., 1998), in contrast with the patients from the studies of Liddle and Morris (1991) and Rowe and Shean (1997). Presumably, patients needing a long period of institutionalisation are more severely affected at onset of the disease than patients that do not need long hospitalisation, possibly due to the extended pathology in the former group (Pantelis et al., 1999).

4.2. Failure to generate a plan and the dorsolateral PFC On the involvement of the dorsolateral PFC (DLPFC) in a failure to generate a plan, we can only speculate, since imaging has not been done in the current neuropsychological study. We found that perseveration in schizophrenic patients could be explained by a failure to generate a plan, as seen in frontal patients. Moreover, we found a correlation between perseveration and psychomotor poverty, which is associated with dysfunction of the DLPFC (Liddle et al., 1992). These findings converge with brain imaging studies showing that perseveration is associated with decreased activity in the DLPFC (Weinberger et al., 1986, 1988). 4.3. Limitations and clinical implications of the present study We only used schizophrenic patients with mild symptomatology that were not chronically institutionalised. This is due to the preselection of patients on their ability to complete a quite extensive test battery. It may limit the extrapolation of the results to more severely disturbed patients. Another limitation concerns the study of effects of antipsychotic medication. Since we selected patients that were already using either a classical or an atypical antipsychotic drug, we may have induced a confounding factor, related to differences in (the severity of) the disease prior to medication. It would therefore be interesting to repeat the present study, using a random assignment of patients to either a classical or an atypical antipsychotic. In the current study, we distinguished between a failure to generate and a failure to execute a plan. However, Frith (1992) explained the negative

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symptoms of schizophrenia as a failure to turn a plan into intentions (Fig. 1). This is in line with the disconnection hypothesis (McGuire and Frith, 1996; Friston, 1998), which is more adequate for explaining neuropsychological dysfunction in schizophrenia than focal frontal lesions (Rushe et al., 1999). Since we chose to distinguish between a failure to generate and execute a plan, however, with the present results it is not possible to differentiate between a lack of a plan and failure to turn a plan into intentions. Another limitation of our study is that we cannot completely rule out other explanations for our results. The WCST is a complex test involving, amongst others, concept formation, memory, working memory, context memory, inhibition, and planning. Moreover, it has been found that the WCST performance depends on age, education and intelligence. In our study, we controlled for many of these factors, but alternative explanations remain possible. The context information theory, for instance, states that a deficit in processing context information underlies various cognitive impairments in schizophrenia (Servan-Schreiber et al., 1996). In the WCST, context information about instructions has to be used for behavioural inhibition. Problems using this context information could therefore lead to perseveration. However, as far as we know, no evidence has been found of a relationship between WCST perseveration and context memory. Stratta et al. did find a relationship with unique errors (Stratta et al., 2000). Our study has shown a way of studying cognitive dysfunction underlying perseveration in schizophrenia. More research on alternative explanations for WCST perseveration in schizophrenia is required for a better understanding of the cognitive processes that are involved in perseveration in the WCST. This knowledge is important because it provides cues for the remediation of perseveration in schizophrenic patients. 4.4. Conclusion To conclude, the present study demonstrated that part of a group of schizophrenic patients with mild symptomatology showed perseveration in the WCST. For this subgroup, it was found that per-

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severation could be explained by a failure to generate a plan and correlates with the psychomotor poverty syndrome of Liddle. These results fit in with the evidence for involvement of the DLPFC in perseveration in schizophrenia. No evidence was found for a failure to execute a plan, a deficit found in patients with PD, who show primarily abnormalities in the striatum. Acknowledgments We are grateful to the 75 participants for taking part in our study, and to the Vincent van Gogh Institute in Venray, the psychiatric hospital Wolfheze, the PDT and RIAGG Tiel of ‘De Gelderse Roos Rivierenland’, the Psychiatric Centre Nijmegen, and the Department of Psychiatry of the University Medical Centre St. Radboud, for referring patients with schizophrenia and for their kind cooperation. References Alexander, G.E., DeLong, M.R., Strick, P.L., 1986. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience 9, 357–381. American Psychiatric Association, 1987. DSM-III-R: Diagnostic and Statistical Manual of Metal Disorders, 3rd edition, revised. American Psychiatric Press, Washington, DC. Andreasen, N.C., O’Leary, D.S., Flaum, M., Nopoulos, P., Watkins, G.L., Boles, G.L., Hichwa, R.D., 1997. Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naive patients. Lancet 349, 1730–1734. Andreasen, N.C., Rezai, K., Alliger, R., Swayze, V.W., Flaum, M., Kirchner, P., Cohen, G., O’Leary, D.S., 1992. Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 singlephoton emission computed tomography and the Tower of London. Archives of General Psychiatry 49, 943–958. Bassett, A.S., Bury, A., Honer, W.G., 1994. Testing Liddle’s three-syndrome model in families with schizophrenia. Schizophrenia Research 12, 213–221. Basso, M.R., Nasrallah, H.A., Olson, S.C., Bornstein, R.A., 1998. Neuropsychological correlates of negative, disorganized and psychotic symptoms in schizophrenia. Schizophrenia Research 31, 99–111. Beatty, W.W., Staton, R.D., Weir, W.S., Monson, N., Whitaker, H.A., 1989. Cognitive disturbances in Parkinson’s disease. Journal of Geriatric Psychiatry and Neurology 2, 22–33. Bell, M.D., Lysaker, P.H., Beam, G.J., Milstein, R.M., Lindenmayer, J.P., 1994. Five-component model of schizophrenia: assessing the factorial invariance of the Positive and Negative Syndrome Scale. Psychiatry Research 52, 295–303.

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