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attentional cognitive functions in schizophrenic patients and their parents: a preliminary study
Schizophrenia Research 53 (2002) 93±99
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Executive/attentional cognitive functions in schizophrenic patients and their parents: a preliminary study Sonia Dollfus a,b,*, Cyril Lombardo a, Karim BeÂnali a,c, Isabelle Halbecq a,b, Pascale Abadie a,b, Rose-Marie Marie c, Perrine Brazo a,b a
Groupe d'Imagerie Neurofonctionnelle (GIN), Unite Mixte de Recherche 6095, CNRS-CEAÐUniversite de CaenÐUniversite Paris V, Centre CyceÃronÐBoulevard Henri BecquerelÐ14000 Caen, France b Centre Esquirol, Centre Hospitalier Universitaire (CHU) de Nacre, 14033 CAEN Cedex, France c INSERM U320, CyceÂron, Bd Becquerel, 14000 Caen, France Received 19 February 2000; accepted 15 December 2000
Abstract The aim of this study was to determine whether executive/attentional cognitive performances could be considered as markers of vulnerability to schizophrenia. The Stroop Color Word and ¯uency tests were signi®cantly impaired in schizophrenic patients and their parents compared to controls matched on age and sex while performances on Nelson's Modi®ed Card Sorting Test and the Trail Making Test did not differ. The impairments on the Stroop and ¯uency could be considered as endophenotypic markers of schizophrenia. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Schizophrenia; Executive/attentional functions; Genetic; Relatives
1. Introduction Family studies indicate that de®cits in executive functions tested with the Wisconsin Card Sorting Test (WCST) could be genetically transmitted (Pogue-Geile et al., 1991; Franke et al., 1992; D'Amato et al., 1998). Attentional abilities were also impaired in the relatives of schizophrenic patients (Grove et al., 1991; Franke et al., 1994; Harris et al., 1996; Harvey et al., 1996; D'Amato et al., 1998; Chen et al., 1998). However, no agreement on executive performances can be found in studies of high risk* Corresponding author. Tel.: 133-231065018; fax: 133231064987. E-mail address: [email protected] (S. Dollfus).
groups for schizophrenia (Goldberg et al., 1990; Scarone et al., 1993; Stratta et al., 1997; Keefe et al., 1997) and some studies showed that relatives could perform differently depending on the cognitive tests, poorly on the verbal ¯uency or the Trail Making Part B but normally on the WCST or the Trail Making Part A (Roxborough et al., 1993; Laurent et al., 1999a; Keefe et al., 1994). The majority of these studies involved siblings and eliminated the parents to avoid age as a confounding factor. The aim of the present study was to examine the executive/attentional functions in schizophrenic patients and their parents matched on age and sex with two healthy control groups. There were several advantages of this. The differences observed in both schizophrenic patients and parents could not be
0920-9964/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S 0920-996 4(01)00156-6
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S. Dollfus et al. / Schizophrenia Research 53 (2002) 93±99
attributed to age and sex. Therefore, cognitive performances may be considered as a genetic marker. Studying parents rather than siblings decreases common environmental factors which are more present among siblings and which may be confused with heredity. 2. Methods 2.1. Subjects Seventeen stable and unrelated schizophrenic (DSMIV) outpatients and their 17 families constituted of both parents (N 6 £ 2) and one of either parents (N 11) were included. Probands without parents did not participate in the study. The parents were interviewed with the Schedule for Affective Disorder and Schizophrenia±Life time (Endicott and Spitzer, 1978) and the International Personality Disorder Examination (Loranger et al., 1994): They had no present or past psychotic illness, personality disorders (paranoid, schizoid or schizotypal) nor any ancestral history for schizophrenia. Two control groups were constituted, each one matched to the patient and parent groups. Each subject was matched one to one on age as well as sex to the patients for the ®rst control group and one to one to the parents for the second control group. No healthy subject had neurological disorders, psychotic disorders, drug abuse or familial history of schizophrenia. Written informed consent was obtained from all subjects after complete description of the study. 2.2. Cognitive tests Neuropsychological tests were administered by a psychologist who was unaware of the subjects classi®cation. Nelson's modi®ed Card Sorting Test (MCST; Nelson, 1973) is a modi®ed version of the Wisconsin Card Sorting Test (WCST) (Milner, 1963). Two criteria were used (Lezak, 1995): the achieved categories which re¯ect the global capacity to plan and to organize and the number of perseverative errors which re¯ects the subject's dif®culty in forming concepts or in shifting their strategies (inability to overcome the previously established response pattern).
The test of verbal ¯uency which investigates the ability to maintain a mental set, includes a formal criterion (words beginning with the letter P) and a categorical criterion (words belonging to an animal category). The number of valid words pronounced in 2 min were used. The Trail Making Test (TMT) (Reitan and Wolfson, 1993), originally part of the Army Individual Test battery (1944), is a test of complex visual scanning with a motor component which can evaluate the ¯exibility in shifting the course of an ongoing activity. The difference in score in seconds (time B± time A) was used. This score removes the motor speed element from the test evaluation (Part A) (Lezak, 1995). The Stroop test (Golden, 1975) is a test of selective attention. The scores were the number of items completed in 45 s during three trials, without age correction. The ®rst trial consists of reading the names of color. The second trial is color naming. The third trial tests the interference with the color± word score as suggested by Golden (1978). Global cognitive functioning was measured by the Wechsler Adult Intelligence Scale±Revised (WAIS± R) (Wechsler, 1981) in schizophrenic patients and matched healthy subjects. The relatives and controls were evaluated using the Raven Progressive Matrices (Raven, 1960) or Raven's coloured Progressives Matrices (Raven, 1965) for subjects under or above 65 respectively. The results of the Raven test and the WAIS±R are known to be highly correlated (Raven et al., 1998) so that the IQ levels they provide can be compared with con®dence. 2.3. Statistical analysis Each patient with schizophrenia (and each patient's relative) has been matched to his respective control for the same age and sex levels. The matching process has attempted to control for sex and age disparities. Moreover, since the IQ may affect the cognitive items values, the IQ variable has been taken as covariate to control for variation that was not attributable to the cognitive items under study. According to the experimental design, the covariance mixed model (ANCOVA) seems to be the most appropriate statistical procedure for data analysis (Winer, 1971). The ANCOVA has been performed for the cognitive tests
S. Dollfus et al. / Schizophrenia Research 53 (2002) 93±99
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Table 1 Characteristics of subject groups. M mean; SD standard deviation Subjects/Variables
Schizophrenic subjects (N 17)
Controls matched to the schizophrenics (N 17)
Parents of the schizophrenics (N 23)
Controls matched to the parents (N 23)
Age (M ^ SD) Sex (% males) IQ (m ^ SD) a
29.8 ^ 5.9 70 80.5 ^ 16.4
28.1 ^ 4.0 70 104.1 ^ 9.9
58.1 ^ 6.1 30 83.1 ^ 16.8
55.7 ^ 8.3 30 92.0 ^ 15.2
a
`Diagnosis' effect (patients or parents vs matched controls); p , 0.001.
using family membership (`patients or their controls' vs `relatives or their controls') and diagnosis (`patients or relatives' vs `their respective controls') as independent variables with IQ covariate changing across trials. Thus, controlling for age, sex and IQ levels, results of the family membership effect, the diagnosis effect and the interaction of both family membership and diagnosis effects have been reported for each cognitive test. Nevertheless, since most of the cognitive tests have shown skewed distributions, the analysis have been performed using the base-e log transformation data instead of the original values to ful®ll the ANCOVA assumptions. However, for more convenience results have been reported within the original scale after inverse transformation of the computed data. All p-values were two-tailed and considered signi®cant when probabilities were less than 0.05. All analyses were performed using the BMDP w 4V (Los Angeles, CA) program on a SUN SPARC w/UNIX workstation.
3. Results General characteristics of subjects are presented on Table 1. The schizophrenic patients and their parents had lower IQs than their matched controls (p , 0.001). As indicated in Table 2, there was a signi®cant `diagnosis' effect without interaction regarding the ¯uency and the Stroop test. These effects meant that schizophrenic patients and their parents performed signi®cantly worse on ¯uency and Stroop tests compared to the matched healthy subjects. These effects were observed independently of IQ since the same results were obtained with and without IQ
as covariate. In contrast, the performances on the MCST and TMT depended on the IQ: a signi®cant `diagnosis' effect was observed when the analyses were carried out without IQ as covariate while no signi®cant `diagnosis' effect was obtained in analyses with IQ as covariate (ANCOVA) (Table 2). 4. Discussion 4.1. Global cognitive functioning Even if the patients with schizophrenia and their parents had lower IQ than their matched controls (p , 0.001), it is dif®cult to conclude that low IQ is a genetic vulnerability factor to schizophrenia. At the present time, we do not know whether the IQ de®cit found in schizophrenic patients is considered as a `trait' (and thus genetically determined) or as a `state' of illness. Recently, Gilvarry et al. (2000) found that schizophrenic patients had signi®cantly lower premorbid IQs than their relatives. However, according to Offord and Cross (1974), IQ levels could act as a mediating factor in the overt expression of schizophrenia; the low-IQ families may lead to an increased vulnerability to schizophrenia. Some authors (Kremen et al., 1995, 1998) showed lower verbal or total IQ in the relatives of schizophrenic patients compared to controls and have raised the role of environmental as well as genetic factors. 4.2. Executive/attentional functions We did not observe any difference of performance on MCST in contrast to some studies (Franke et al., 1992; Pogue-Geile et al., 1991). This discrepancy could be due to age as a confounding factor as
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Table 2 Performances on executive/attentional function tests in schizophrenics, parents and healthy subjects (mean and standard deviation) Schizophrenics (N 17) M (SD) MCST Categories Perseverative errors Fluency Formal Categorical TMT TMT B±A (seconds) Stroop test Word score Color score Color word score a b
Controls matched to schizophrenics (N 17) M (SD)
Parents of the schizophrenics (N 23) M (SD)
Controls matched to parents (N 23) M (SD)
P values in ANCOVA Family membership effect a
Diagnosis effect b
Interaction
4.0 (1.5) 5.8 (4.4)
5.5 (1.0) 1.0 (2.1)
3.7 (1.6) 7.0 (5.2)
4.7 (1.1) 4.2 (4.6)
0.002 10 24
0.1 0.3
0.8 0.7
14.2 (5.1) 20.5 (8.0)
24.6 (8.2) 29.5 (9.9)
17.2 (11.8) 26.8 (10.0)
25.2 (10.8) 39 (10.4)
0.1 0.03
0.04 0.01
0.7 0.4
91.2 (52.5)
41.9 (11.9)
91.6 (49.0)
61.6 (51.0)
2.10 24
0.1
0.6
86.1 (20.4) 57.2 (12.8) 29.5 (9.5)
105.3 (16.0) 76.3 (7.7) 44.7 (10.2)
92.4 (25.7) 63.1 (16.0) 30.3 (9.6)
99.7 (15.8) 72.8 (12.1) 40.6 (11.7)
2.10 23 0.8 0.9
0.1 0.02 0.003
0.6 0.2 0.3
Patients plus controls vs parents plus matched controls. Patients plus parents vs two matched controls.
S. Dollfus et al. / Schizophrenia Research 53 (2002) 93±99
Subjects/Cognitive tests
S. Dollfus et al. / Schizophrenia Research 53 (2002) 93±99
previously suggested (Heinrichs, 1990). In our study, the perseverative errors observed in both control groups suggest an age effect and are consistent with results found by Goldberg et al. (1990) and Keefe et al. (1994). The use of a shortened WCST-version in our study may be associated with reduced sensitivity which also may account for the failure of differences observed. The verbalization in the MCST of `®nd another rule' did not make the test too easy for the parents since their performances compared to the patient groups were similar or worse (Table 2). In line with Stratta et al. (1997); Goldberg et al. (1990); Battaglia et al. (1994); Scarone et al. (1993), our results suggested that the MCST performance was more likely a feature inherent to the disease process than an index of the genetic susceptibility to the illness. Our results showed that the relatives did not perform worse on the TMT than the healthy subjects. Goldberg et al. (1990) had similar results. In contrast, several authors (Pogue-Geile et al., 1991; Franke et al., 1993; Keefe et al., 1994; Harris et al., 1996) found that the TMT was more impaired in relatives than in control subjects but except for Keefe et al. (1994), they did not take into account the Part A (the motor speed element) which could account for differences between groups. This could also account for the discrepancy between our results and those of other authors who used the TMT score B in schizophrenic patients (Braff et al., 1991; Goldberg et al., 1993). However, our sub-groups had scores on the TMT with large standard deviations which thus could explain the absence of signi®cant differences (Table 2). Our ®ndings were consistent with several authors (Roxborough et al., 1993; Keefe et al., 1994; Laurent et al., 1999a) who found that relatives performed signi®cantly worse than matched controls on tests of formal or categorical verbal ¯uency. As ¯uencies were impaired in both schizophrenics and parents, they could constitute a genetic vulnerability marker for schizophrenia. The Stroop Color Word score which evaluates selective attention, in particular the inhibitory process, was signi®cantly lower in both schizophrenic patients and parents than in controls. This de®cit may be due in part to the impairment in the color naming speed evaluated with the color score (Table 2). Our
97
results agreed with several studies which found an impairment of the inhibitory process in schizophrenics (for a review see: Marczewski and Van Der Linden, 1999) and in the relatives (Park et al., 1996). Our results reinforced those of Harris et al. (1996); Laurent et al. (1999b) who found that the heritable component of neuropsychological dysfunction lies in attention de®cit even if selective attention was not speci®cally tested in these studies. As a similar de®cit on the Stroop Color Word was present in both schizophrenic patients and their parents, this de®cit could re¯ect a behavioral `trait' rather than an effect of illness or its treatment and may be considered as a vulnerability marker for schizophrenia. 4.3. Limitations of the study The ®rst limitation was the small size of the samples which might have dismissed true differences between groups due to a Type II error. Therefore, the present results should be considered as preliminary and need to be con®rmed with larger samples. The second limitation was to select schizophrenic probands without an ancestral history of schizophrenia and to eliminate parents with personality disorders (paranoid, schizotypal, schizoid). Thus, the parents could be considered as `low-risk' to schizophrenia. The presence of negative ®ndings with some tests does not exclude the possibility that heritable cognitive dysfunctions related to schizophrenic patients might be expressed as a phenotype in a `high-risk' family for schizophrenia. On the other hand, the fact to ®nd some cognitive performances impaired in these `low-risk' genetic families suggests that these performances might be more sensitive endophenotypic markers than others, especially because differences may not be attributed to differences in intellectual abilities, age and sex. Acknowledgements The French Health Ministry sponsored this study as a Programme Hospitalier de Recherche Clinique. This research was presented at the Association FrancËaise de Psychiatrie Biologique (AFPB) in Paris on 23 November 1999, and at the 10th Biennial Winter Workshop on Schizophrenia (Davos, 5±11 February 2000) and received the prize of the best presentation
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in research in psychiatry (prize AFPB/OrganonÐ Riom 1999). We thank L. Petit and E. Caputo for their helpful comments on English language.
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Executive/attentional cognitive functions in schizophrenic patients and their parents: a preliminary study Sonia Dollfus a,b,*, Cyril Lombardo a, Karim BeÂnali a,c, Isabelle Halbecq a,b, Pascale Abadie a,b, Rose-Marie Marie c, Perrine Brazo a,b a
Groupe d'Imagerie Neurofonctionnelle (GIN), Unite Mixte de Recherche 6095, CNRS-CEAÐUniversite de CaenÐUniversite Paris V, Centre CyceÃronÐBoulevard Henri BecquerelÐ14000 Caen, France b Centre Esquirol, Centre Hospitalier Universitaire (CHU) de Nacre, 14033 CAEN Cedex, France c INSERM U320, CyceÂron, Bd Becquerel, 14000 Caen, France Received 19 February 2000; accepted 15 December 2000
Abstract The aim of this study was to determine whether executive/attentional cognitive performances could be considered as markers of vulnerability to schizophrenia. The Stroop Color Word and ¯uency tests were signi®cantly impaired in schizophrenic patients and their parents compared to controls matched on age and sex while performances on Nelson's Modi®ed Card Sorting Test and the Trail Making Test did not differ. The impairments on the Stroop and ¯uency could be considered as endophenotypic markers of schizophrenia. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Schizophrenia; Executive/attentional functions; Genetic; Relatives
1. Introduction Family studies indicate that de®cits in executive functions tested with the Wisconsin Card Sorting Test (WCST) could be genetically transmitted (Pogue-Geile et al., 1991; Franke et al., 1992; D'Amato et al., 1998). Attentional abilities were also impaired in the relatives of schizophrenic patients (Grove et al., 1991; Franke et al., 1994; Harris et al., 1996; Harvey et al., 1996; D'Amato et al., 1998; Chen et al., 1998). However, no agreement on executive performances can be found in studies of high risk* Corresponding author. Tel.: 133-231065018; fax: 133231064987. E-mail address: [email protected] (S. Dollfus).
groups for schizophrenia (Goldberg et al., 1990; Scarone et al., 1993; Stratta et al., 1997; Keefe et al., 1997) and some studies showed that relatives could perform differently depending on the cognitive tests, poorly on the verbal ¯uency or the Trail Making Part B but normally on the WCST or the Trail Making Part A (Roxborough et al., 1993; Laurent et al., 1999a; Keefe et al., 1994). The majority of these studies involved siblings and eliminated the parents to avoid age as a confounding factor. The aim of the present study was to examine the executive/attentional functions in schizophrenic patients and their parents matched on age and sex with two healthy control groups. There were several advantages of this. The differences observed in both schizophrenic patients and parents could not be
0920-9964/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S 0920-996 4(01)00156-6
94
S. Dollfus et al. / Schizophrenia Research 53 (2002) 93±99
attributed to age and sex. Therefore, cognitive performances may be considered as a genetic marker. Studying parents rather than siblings decreases common environmental factors which are more present among siblings and which may be confused with heredity. 2. Methods 2.1. Subjects Seventeen stable and unrelated schizophrenic (DSMIV) outpatients and their 17 families constituted of both parents (N 6 £ 2) and one of either parents (N 11) were included. Probands without parents did not participate in the study. The parents were interviewed with the Schedule for Affective Disorder and Schizophrenia±Life time (Endicott and Spitzer, 1978) and the International Personality Disorder Examination (Loranger et al., 1994): They had no present or past psychotic illness, personality disorders (paranoid, schizoid or schizotypal) nor any ancestral history for schizophrenia. Two control groups were constituted, each one matched to the patient and parent groups. Each subject was matched one to one on age as well as sex to the patients for the ®rst control group and one to one to the parents for the second control group. No healthy subject had neurological disorders, psychotic disorders, drug abuse or familial history of schizophrenia. Written informed consent was obtained from all subjects after complete description of the study. 2.2. Cognitive tests Neuropsychological tests were administered by a psychologist who was unaware of the subjects classi®cation. Nelson's modi®ed Card Sorting Test (MCST; Nelson, 1973) is a modi®ed version of the Wisconsin Card Sorting Test (WCST) (Milner, 1963). Two criteria were used (Lezak, 1995): the achieved categories which re¯ect the global capacity to plan and to organize and the number of perseverative errors which re¯ects the subject's dif®culty in forming concepts or in shifting their strategies (inability to overcome the previously established response pattern).
The test of verbal ¯uency which investigates the ability to maintain a mental set, includes a formal criterion (words beginning with the letter P) and a categorical criterion (words belonging to an animal category). The number of valid words pronounced in 2 min were used. The Trail Making Test (TMT) (Reitan and Wolfson, 1993), originally part of the Army Individual Test battery (1944), is a test of complex visual scanning with a motor component which can evaluate the ¯exibility in shifting the course of an ongoing activity. The difference in score in seconds (time B± time A) was used. This score removes the motor speed element from the test evaluation (Part A) (Lezak, 1995). The Stroop test (Golden, 1975) is a test of selective attention. The scores were the number of items completed in 45 s during three trials, without age correction. The ®rst trial consists of reading the names of color. The second trial is color naming. The third trial tests the interference with the color± word score as suggested by Golden (1978). Global cognitive functioning was measured by the Wechsler Adult Intelligence Scale±Revised (WAIS± R) (Wechsler, 1981) in schizophrenic patients and matched healthy subjects. The relatives and controls were evaluated using the Raven Progressive Matrices (Raven, 1960) or Raven's coloured Progressives Matrices (Raven, 1965) for subjects under or above 65 respectively. The results of the Raven test and the WAIS±R are known to be highly correlated (Raven et al., 1998) so that the IQ levels they provide can be compared with con®dence. 2.3. Statistical analysis Each patient with schizophrenia (and each patient's relative) has been matched to his respective control for the same age and sex levels. The matching process has attempted to control for sex and age disparities. Moreover, since the IQ may affect the cognitive items values, the IQ variable has been taken as covariate to control for variation that was not attributable to the cognitive items under study. According to the experimental design, the covariance mixed model (ANCOVA) seems to be the most appropriate statistical procedure for data analysis (Winer, 1971). The ANCOVA has been performed for the cognitive tests
S. Dollfus et al. / Schizophrenia Research 53 (2002) 93±99
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Table 1 Characteristics of subject groups. M mean; SD standard deviation Subjects/Variables
Schizophrenic subjects (N 17)
Controls matched to the schizophrenics (N 17)
Parents of the schizophrenics (N 23)
Controls matched to the parents (N 23)
Age (M ^ SD) Sex (% males) IQ (m ^ SD) a
29.8 ^ 5.9 70 80.5 ^ 16.4
28.1 ^ 4.0 70 104.1 ^ 9.9
58.1 ^ 6.1 30 83.1 ^ 16.8
55.7 ^ 8.3 30 92.0 ^ 15.2
a
`Diagnosis' effect (patients or parents vs matched controls); p , 0.001.
using family membership (`patients or their controls' vs `relatives or their controls') and diagnosis (`patients or relatives' vs `their respective controls') as independent variables with IQ covariate changing across trials. Thus, controlling for age, sex and IQ levels, results of the family membership effect, the diagnosis effect and the interaction of both family membership and diagnosis effects have been reported for each cognitive test. Nevertheless, since most of the cognitive tests have shown skewed distributions, the analysis have been performed using the base-e log transformation data instead of the original values to ful®ll the ANCOVA assumptions. However, for more convenience results have been reported within the original scale after inverse transformation of the computed data. All p-values were two-tailed and considered signi®cant when probabilities were less than 0.05. All analyses were performed using the BMDP w 4V (Los Angeles, CA) program on a SUN SPARC w/UNIX workstation.
3. Results General characteristics of subjects are presented on Table 1. The schizophrenic patients and their parents had lower IQs than their matched controls (p , 0.001). As indicated in Table 2, there was a signi®cant `diagnosis' effect without interaction regarding the ¯uency and the Stroop test. These effects meant that schizophrenic patients and their parents performed signi®cantly worse on ¯uency and Stroop tests compared to the matched healthy subjects. These effects were observed independently of IQ since the same results were obtained with and without IQ
as covariate. In contrast, the performances on the MCST and TMT depended on the IQ: a signi®cant `diagnosis' effect was observed when the analyses were carried out without IQ as covariate while no signi®cant `diagnosis' effect was obtained in analyses with IQ as covariate (ANCOVA) (Table 2). 4. Discussion 4.1. Global cognitive functioning Even if the patients with schizophrenia and their parents had lower IQ than their matched controls (p , 0.001), it is dif®cult to conclude that low IQ is a genetic vulnerability factor to schizophrenia. At the present time, we do not know whether the IQ de®cit found in schizophrenic patients is considered as a `trait' (and thus genetically determined) or as a `state' of illness. Recently, Gilvarry et al. (2000) found that schizophrenic patients had signi®cantly lower premorbid IQs than their relatives. However, according to Offord and Cross (1974), IQ levels could act as a mediating factor in the overt expression of schizophrenia; the low-IQ families may lead to an increased vulnerability to schizophrenia. Some authors (Kremen et al., 1995, 1998) showed lower verbal or total IQ in the relatives of schizophrenic patients compared to controls and have raised the role of environmental as well as genetic factors. 4.2. Executive/attentional functions We did not observe any difference of performance on MCST in contrast to some studies (Franke et al., 1992; Pogue-Geile et al., 1991). This discrepancy could be due to age as a confounding factor as
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Table 2 Performances on executive/attentional function tests in schizophrenics, parents and healthy subjects (mean and standard deviation) Schizophrenics (N 17) M (SD) MCST Categories Perseverative errors Fluency Formal Categorical TMT TMT B±A (seconds) Stroop test Word score Color score Color word score a b
Controls matched to schizophrenics (N 17) M (SD)
Parents of the schizophrenics (N 23) M (SD)
Controls matched to parents (N 23) M (SD)
P values in ANCOVA Family membership effect a
Diagnosis effect b
Interaction
4.0 (1.5) 5.8 (4.4)
5.5 (1.0) 1.0 (2.1)
3.7 (1.6) 7.0 (5.2)
4.7 (1.1) 4.2 (4.6)
0.002 10 24
0.1 0.3
0.8 0.7
14.2 (5.1) 20.5 (8.0)
24.6 (8.2) 29.5 (9.9)
17.2 (11.8) 26.8 (10.0)
25.2 (10.8) 39 (10.4)
0.1 0.03
0.04 0.01
0.7 0.4
91.2 (52.5)
41.9 (11.9)
91.6 (49.0)
61.6 (51.0)
2.10 24
0.1
0.6
86.1 (20.4) 57.2 (12.8) 29.5 (9.5)
105.3 (16.0) 76.3 (7.7) 44.7 (10.2)
92.4 (25.7) 63.1 (16.0) 30.3 (9.6)
99.7 (15.8) 72.8 (12.1) 40.6 (11.7)
2.10 23 0.8 0.9
0.1 0.02 0.003
0.6 0.2 0.3
Patients plus controls vs parents plus matched controls. Patients plus parents vs two matched controls.
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Subjects/Cognitive tests
S. Dollfus et al. / Schizophrenia Research 53 (2002) 93±99
previously suggested (Heinrichs, 1990). In our study, the perseverative errors observed in both control groups suggest an age effect and are consistent with results found by Goldberg et al. (1990) and Keefe et al. (1994). The use of a shortened WCST-version in our study may be associated with reduced sensitivity which also may account for the failure of differences observed. The verbalization in the MCST of `®nd another rule' did not make the test too easy for the parents since their performances compared to the patient groups were similar or worse (Table 2). In line with Stratta et al. (1997); Goldberg et al. (1990); Battaglia et al. (1994); Scarone et al. (1993), our results suggested that the MCST performance was more likely a feature inherent to the disease process than an index of the genetic susceptibility to the illness. Our results showed that the relatives did not perform worse on the TMT than the healthy subjects. Goldberg et al. (1990) had similar results. In contrast, several authors (Pogue-Geile et al., 1991; Franke et al., 1993; Keefe et al., 1994; Harris et al., 1996) found that the TMT was more impaired in relatives than in control subjects but except for Keefe et al. (1994), they did not take into account the Part A (the motor speed element) which could account for differences between groups. This could also account for the discrepancy between our results and those of other authors who used the TMT score B in schizophrenic patients (Braff et al., 1991; Goldberg et al., 1993). However, our sub-groups had scores on the TMT with large standard deviations which thus could explain the absence of signi®cant differences (Table 2). Our ®ndings were consistent with several authors (Roxborough et al., 1993; Keefe et al., 1994; Laurent et al., 1999a) who found that relatives performed signi®cantly worse than matched controls on tests of formal or categorical verbal ¯uency. As ¯uencies were impaired in both schizophrenics and parents, they could constitute a genetic vulnerability marker for schizophrenia. The Stroop Color Word score which evaluates selective attention, in particular the inhibitory process, was signi®cantly lower in both schizophrenic patients and parents than in controls. This de®cit may be due in part to the impairment in the color naming speed evaluated with the color score (Table 2). Our
97
results agreed with several studies which found an impairment of the inhibitory process in schizophrenics (for a review see: Marczewski and Van Der Linden, 1999) and in the relatives (Park et al., 1996). Our results reinforced those of Harris et al. (1996); Laurent et al. (1999b) who found that the heritable component of neuropsychological dysfunction lies in attention de®cit even if selective attention was not speci®cally tested in these studies. As a similar de®cit on the Stroop Color Word was present in both schizophrenic patients and their parents, this de®cit could re¯ect a behavioral `trait' rather than an effect of illness or its treatment and may be considered as a vulnerability marker for schizophrenia. 4.3. Limitations of the study The ®rst limitation was the small size of the samples which might have dismissed true differences between groups due to a Type II error. Therefore, the present results should be considered as preliminary and need to be con®rmed with larger samples. The second limitation was to select schizophrenic probands without an ancestral history of schizophrenia and to eliminate parents with personality disorders (paranoid, schizotypal, schizoid). Thus, the parents could be considered as `low-risk' to schizophrenia. The presence of negative ®ndings with some tests does not exclude the possibility that heritable cognitive dysfunctions related to schizophrenic patients might be expressed as a phenotype in a `high-risk' family for schizophrenia. On the other hand, the fact to ®nd some cognitive performances impaired in these `low-risk' genetic families suggests that these performances might be more sensitive endophenotypic markers than others, especially because differences may not be attributed to differences in intellectual abilities, age and sex. Acknowledgements The French Health Ministry sponsored this study as a Programme Hospitalier de Recherche Clinique. This research was presented at the Association FrancËaise de Psychiatrie Biologique (AFPB) in Paris on 23 November 1999, and at the 10th Biennial Winter Workshop on Schizophrenia (Davos, 5±11 February 2000) and received the prize of the best presentation
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in research in psychiatry (prize AFPB/OrganonÐ Riom 1999). We thank L. Petit and E. Caputo for their helpful comments on English language.
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