attentional performance and measures of schizotypy in patients with schizophrenia and in their nonpsychotic first-degree relatives

Schizophrenia Research 46 (2000) 269–283 www.elsevier.com/locate/schres

Executive/attentional performance and measures of schizotypy in patients with schizophrenia and in their nonpsychotic first-degree relatives Annie Laurent a, *, Michel Biloa-Tang b, Thierry Bougerol a, Dominique Duly a, Anne-Marie Anchisi a, Jean-Luc Bosson c, Jacques Pellat d, Thierry d’Amato e, Jean Dalery e a Department of Psychiatry, University Hospital of Grenoble, BP 217 38043 Grenoble, France b Clinique Georges Dumas, 38700 La Tronche, France c Department of Statistics, University Hospital of Grenoble, BP 217 38043 Grenoble, France d Department of Neuropsychology, University Hospital of Grenoble, BP 217 38043 Grenoble, France e Institut de Psychopathologie Cognitive et Neurobiologique, Hoˆpital du Vinatier, 95, Boulevard Pinel, 69677 BronCedex, France Received 21 April 1999; accepted 18 November 1999

Abstract Previous studies of executive/attentional functions have found impairments in nonpsychotic first-degree relatives of patients with schizophrenia. The aims of this study were: (1) to replicate these findings by three laboratory measures of attention/information processing — a continuous performance test (DS-CPT ), a forced-choice span of apprehension task (SPAN ), and a digit symbol substitution test (DSST ), and by a series of neuropsychological tests sensitive to prefrontal cortical damage — Trail Making A and B, verbal fluency ( VFT ), Stroop Color and Word Test (Stroop), and Wisconsin Card Sorting Test ( WCST ); (2) to investigate whether such executive/attentional deficits are associated with schizotypal traits assessed using the social anhedonia, physical anhedonia, perceptual aberration and magical ideation scales (Chapman, L.J., Chapman, J.P., Raulin, M.L. 1976. Scales for physical and social anhedonia. J. Abnorm. Psychol. 85, 374–382; Chapman, L.J., Chapman, J.P., Raulin, M.L., 1978. Body-image aberration in schizophrenia. J. Abnorm. Psychol. 87, 399–407; Eckblad, M., Chapman, L.J., 1983. Magical ideation as an indicator of schizotypy. J. Consult. Clin. Psychol. 51, 215–225). In both patient and relative groups, performance was significantly poorer on the DSST, VFT and Trail B, and the reaction time on the SPAN was significantly longer. These neuropsychological impairments were present as much in siblings as in parents of schizophrenic patients; age did not appear to cancel differences between the relative and control groups. In the relative group, the four scores of schizotypy were at an intermediate level between those of patient and control groups, and the social anhedonia and perceptual aberration scores tended to be significantly different between the relative and the control groups. Only two significant correlations were found between the neuropsychological performance and the measures of schizotypy. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Executive/attentional functioning; Risk factors; Schizophrenia; Schizotypy

* Corresponding author. Present address: Service de Psychologie Me´dicale Infantile, BP 217 38043 Grenoble, France. Tel.: +33476765419; fax: +33476765830. E-mail address: [email protected] (A. Laurent) 0920-9964/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII: S0 9 2 0 -9 9 6 4 ( 9 9 ) 0 0 23 2 - 7

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1. Introduction Family, twin and adoption studies have unequivocally demonstrated that genetic factors play a substantial role in the etiology of the schizophrenic disorder, but the nature of the genetic diathesis and the mode of inheritance remain to be identified. Since offspring of psychiatrically normal monozygotic co-twins of patients with schizophrenia are about as likely to be schizophrenic as are the offspring of the schizophrenic twin (Gottesman and Bertelsen, 1989), the absence of a diagnosable psychiatric illness is therefore perfectly compatible with being a carrier of a predisposing gene or genes. A biological or behavioral marker more frequently present in patients with schizophrenia and in a proportion of their clinical healthy relatives than in the general population could assist in identifying individuals at increased risk for the development of schizophrenia. Evidence has been accumulated in recent years which suggests that certain executive/attentional measures could be phenotypic markers of predisposition to schizophrenia. Firstly, executive/ attentional impairments have been observed in both acutely psychotic and relatively remitted schizophrenic patients, suggesting that impaired performance represents a trait rather than a state characteristic (Asarnow and MacCrimmon, 1978; Nuechterlein and Dawson, 1984; Sweeney et al., 1991; Saykin et al., 1991; Cannon et al., 1994; Shedlack et al., 1997). Secondly, impaired executive/attention has also been found in subjects with schizotypal features (Lenzenweger et al., 1991, Lenzenweger and Korfine, 1994; Obiols et al., 1993; Trestman et al., 1995; Harvey et al., 1996) and in children of schizophrenic subjects (Rutschmann et al., 1977; Asarnow and MacCrimmon, 1978; Nuechterlein, 1983; Cornblatt and Erlenmeyer-Kimling, 1985), raising the possibility that this deficit may represent a marker of vulnerability to the development of schizophrenia-related disorders. However, studies in adult first-degree relatives of patients with schizophrenia are still relatively rare and some of the results are conflicting. For example, studies employing the Wisconsin Card Sorting Test in unaffected relatives of schizophrenic patients have

provided both positive (Pogue-Geile et al., 1991; Mirsky et al., 1992; Franke et al., 1993, Faraone et al., 1995; Toomey et al., 1998) and negative (Goldberg et al., 1990; Scarone et al., 1993; Keefe et al., 1994) results. Moreover, some areas of neuropsychological functioning selectively impaired in schizophrenia, such as verbal fluency (Saykin et al., 1991), have been little studied in first-degree relatives and require additional research ( Franke et al., 1993; Roxborough et al., 1993; Keefe et al., 1994). Previous data from family and adoption studies have indicated a significant increase in the prevalence of schizotypal and, to a smaller degree, paranoid and schizoid personality disorders in the families of patients with schizophrenia compared with normal families (Lowing et al., 1983; Baron et al., 1985; Frangos et al., 1985; Kendler, 1985; Tsuang et al., 1991). Furthermore, results from family studies suggest that schizotypal personality disorder, the prototype for the milder schizophrenia-spectrum personality disorders (SSPD), may be a more common phenotypic expression of the schizophrenia-related genotype than chronic schizophrenia ( Kendler et al., 1981; Baron et al., 1983; Siever et al., 1990). Thus, the usefulness of performance on executive/attentional tests as a vulnerability marker for schizophrenia would be enhanced if such deficits among nonpsychotic relatives of schizophrenic patients could be shown to be associated with schizotypal factors. There have been, as yet, few studies addressing whether executive/attentional deficits found in the relatives of patients with schizophrenia are associated with measures of schizotypy, and their results are conflicting: a dependence between executive/ attentional deficits and schizotypal features has been found in some studies (Grove et al., 1991; Franke et al., 1993; Chen et al., 1998) but not in others (Franke et al., 1994). The purposes of the present study were as follows. (1) To confirm that clinically stabilized schizophrenics and their adult nonschizophrenic siblings and parents share, when compared with healthy controls, similar deficits in executive/ attentional abilities evaluated by, on the one hand, three laboratory measures of attention/ information processing: a continuous performance

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test (a measure of sustained attention), a forcedchoice span of apprehension task (a measure of the number of stimuli that can be attended to, apprehended, and reported in a single brief exposure), and a digit symbol substitution test (a measure of the capacity to focus on stimuli and execute responses briskly) and, on the other hand, a series of neuropsychological tests known to be sensitive to prefrontal cortical damage: the Trail Making Part A and B, a verbal fluency test, the Stroop Color and Word Test, and the Wisconsin Card Sorting Test. Because parents and siblings share, on average, 50% of their genes with the schizophrenic proband, we predicted that the first-degree relatives’ performance would be at an intermediate level between that of patients and control subjects. (2) To determine whether executive/attentional disturbances and schizotypy assessed by four psychosis proneness scales developed by Chapman and associates (Chapman and Chapman, 1987; Chapman et al., 1994) reflect independent or correlated areas of dysfunction in the relatives of patients with schizophrenia. Furthermore, the present study expanded on prior work by including a high number of parents of schizophrenic patients; it was then possible to estimate whether this respective family status or age could modify potential differences between relatives and controls. This is of special interest, since most previous studies have included only relatives younger than age 50 in order to avoid neuropsychological confounds associated with sequelae of aging, and therefore little is known about neuropsychological functioning of elderly relatives of schizophrenic patients.

2. Methods 2.1. Participants Twenty-three schizophrenic outpatients were screened from a register from two Grenoble area public hospitals. All were chronic patients living in the community. Inclusion criteria were a DSMIII-R (American Psychiatric Association, 1987) diagnosis of schizophrenia, a stabilized clinical state (no current exacerbation of psychotic symptoms and no change in general clinical state for

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6 months prior to testing), and knowledge of the identity of living biological first-degree relatives. Seven patients were classified as paranoid, four as undifferentiated, six as disorganized and six as residual type. The mean duration of illness was 9.7±7 years (range: 1–25). None of the probands underwent a change in medication less than 1 month prior to the investigations. For each consenting proband, a list of all liveborn first-degree relatives was compiled. With the proband’s permission, a relative was contacted to ensure complete and correct information on the study. Only first-degree relatives without a history of psychiatric hospitalization, and with no current mental health treatment (including medication and/or psychotherapy) were invited to participate. The at-risk group comprised 25 parents and 22 siblings. The control group consisted of 34 subjects recruited from hospital staff and from the community. Exclusion criteria were: (1) a personal history of psychosis and/or psychiatric hospitalization, (2) current mental health treatment, and (3) a history of schizophrenia or unipolar depression or bipolar disorder in their first-degree relatives. All subjects underwent screening for psychiatric diagnoses, using the Structured Clinical Interview for DSM-III-R (Spitzer et al., 1988); furthermore, the relative and control subjects, except one relative, were screened for a SSPD using the Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II; Spitzer and Williams, 1986). According to Thaker et al.’s (1993) methodology, the thresholds required by DSM-III-R for personality disorders were lowered by one criterion point. Controls were included in the study only if they had no DSM-III-R Axis I or II diagnosis. Relatives were included in the study only if they had no DSM-III-R Axis I diagnosis. Fourteen relatives (30.4%) had at least one personality disorder which belongs to the ‘odd’ personality disorder cluster: three had a schizotypal, four a schizoid, five a paranoid personality disorder, one displayed a schizoid and a paranoid personality disorder and, finally, one displayed all three types of personality disorders. This percentage is in agreement with the study of Thaker et al. (1993), who found 37% of relatives with one or more cluster A diagnoses.

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Three controls were excluded from the study because they presented a SSPD. For the three groups, inclusion criteria were: (1) to be at least 18 years old, (2) to have at least an eight-grade education, and (3) to be native speakers of French. Exclusion criteria were: (1) history of head injury with loss of consciousness for longer than 5 min; (2) substance abuse within the past 6 months, and (3) medical illness with central nervous system effects. The experimental procedure of this study has been approved by the responsible Ethical Committee of Grenoble, France, and each subject has given written informed consent. 2.2. Clinical evaluation Patients were administered Kay’s Positive And Negative Syndrome Scale (PANSS; Kay et al., 1988). The 23 patients’ mean scores were 14.7±5.7, 23.9±7.3 and 39.2±9.6 for, respectively, the positive syndrome score, negative syndrome score and general psychopathology score of the PANSS. Four scales developed by Chapman and colleagues to assess schizotypy were used: (1) the Physical Anhedonia Scale (PhyAnhS; Chapman et al., 1976), consisting of 61 true–false items that measure a deficit in the ability to experience pleasure; (2) the Social Anhedonia Scale (SocAnhS; Chapman et al., 1976), 40 items, which taps social withdrawal, indifference to people and social reticence; (3) the Perceptual Aberration Scale (PAS; Chapman et al., 1978), which consists of 28 items designed to tap grossly schizophrenic-like distortions in the perception of one’s body and seven items for other perceptual distortions; and (4) the Magic Ideation Scale (MIS; Eckblad and Chapman, 1983), 30 items, which measures belief in forms of causation that, by conventional standards of the dominant culture, are regarded as invalid and magical. The subjects were asked to complete a self-report questionnaire containing items from the four scales (these items were intermixed with each other and with items from other scales, in order to avoid placing obvious emphasis on particular content areas) and to return it during the week after testing. For both anhedo-

nia scales, we obtained completed questionnaires from 23 patients, 46 relatives and 27 controls; because the French versions of the PAS and the MIS were not available when the study began, PAS and MIS scores were obtained for only 18 patients, 43 relatives and 27 controls.

2.3. Neuropsychological assessment 2.3.1. The Degraded Stimulus-Continuous Performance Test (DS-CPT) An IBM-compatible personal computer was used to administer the computerized version of a Degraded Stimulus-Continuous Performance Test (DS-CPT; UCLA CPT version 7.10, Nuechterlein and Asarnow, 1997) and a Span of Apprehension Task (SPAN; UCLA SPAN version 4, Nuechterlein and Asarnow, 1994). Both tests were administered in a darkened room, free from distractions. Subjects were seated directly in front of the monitor at a distance of 1 m. The DS-CPT consists of rapidly changing (one per second) and briefly presented (29 ms) digits from 0 to 9. The stimuli were degraded by randomly reversing 40% of the pixels. Subjects were instructed to press a button whenever a 0 appeared (25% of the trials). One-hundred and sixty trials were provided as practice; the test itself consisted of 480 stimuli presented immediately after the practice. The DS-CPT performance was evaluated with two indices derived from signal detection theory: d∞, a measure of perceptual sensitivity, referring to an individual’s ability to discriminate target stimuli from nontarget stimuli; and b (or ln b), a response criterion, measuring the amount of perceptual evidence a person requires to decide that a stimulus is a target (Swets, 1973). The higher d∞, the better the attentional performance; the higher b, the more conservative the response style. Both indices were estimated from a joint consideration of both the hit rate and the falsealarm rate. Sensitivity is relatively free from motivational effects (Swets and Sewall, 1963), which would be reflected in the response criterion instead. Mean reaction times for the DS-CPT were calculated by using the reaction time for all correct responses.

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2.3.2. The Span of Apprehension (SPAN) The SPAN consists of arrays of either 3 or 12 upper-case letters briefly (80 ms) presented, one of them being either a T or an F. A series of practice trials was presented and followed by 128 individual test trials (16 3-letter arrays, followed by 32 12-letter, 16 3-letter, 16 12-letter, thirty-two 3-letter, and then sixteen 12-letter arrays). Subjects were instructed to identify which of the two target letters ( T or F ) appeared on the screen, and to guess if in doubt, by pressing one of two buttons (marked T or F, respectively) with the index finger of the dominant hand placed equidistant between the two response buttons. The location of the target letters on the screen was randomly distributed among the 16 possible target locations. The SPAN performance was evaluated by examining the percentage of correct responses over the 3- and the 12-letter arrays. Mean reaction times were calculated by using the reaction time for all correct responses on each array size, separately. 2.3.3. The Digit Symbol Substitution Test (DSST) The DSST of the Wechsler Adult Intelligence Scale — Revised ( WAIS-R; Wechsler, 1981) was used. The score was the number of correct substitutions obtained during 90 s. 2.3.4. The Trail Making Test, parts A and B (Trail A, Trail B) The Trail B was chosen as a measure of executive function and set alternation ( Reitan, 1958, 1978). Its complement ( Trail A) makes all of the same cognitive demands except set alternation; thus, with the use of Trail A as a covariate for Trail B, it is possible to assess frontal functions by eliminating factors such as psychomotor speed and ability (Jarvis and Barth, 1986). The outcome variable was time to completion (Reitan, 1958). 2.3.5. The Wisconsin Card Sorting Test (WCST) The WCST (Heaton, 1981) was chosen to assess concept formation and abstraction. While the performance decrement may be associated with frontal cortical function ( Weinberger et al., 1986), inferences about specific structural or functional impairment may not be warranted (Hermann et al., 1988). Variables were the numbers of persev-

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erative errors ( WCST PE ) and of categories achieved ( WCST CA). 2.3.6. A Verbal Fluency Test (VFT) This test has been associated with frontal lobe damage, particularly the left frontal lobe (Milner, 1975). Subjects were given five trials, each lasting 2 min. To assess letter fluency, they were asked to generate as many words as possible beginning with the letters ‘p’, ‘r’ and ‘v’. To assess category fluency, they were asked to generate words from the ‘animal’ and ‘fruit’ categories. The sum of words produced in the three-letter and the twocategory trials were averaged separately to determine, respectively, an overall letter and category verbal fluency. 2.3.7. Stroop Color and Word Test (Stroop; Golden, 1978) The Stroop measures the ability to inhibit a response and to focus attention (Lezak, 1995). This test has been found impairment in patients with left frontal lobe lesions (Perret, 1974). The variable of analysis chosen was the interference score (Levin et al., 1989). 2.3.8. Estimated Full Scale IQ score (Brooker and Cyr, 1986) This was assessed by the Vocabulary and the Block Design subtests of the WAIS-R ( Wechsler, 1981). All tests were administered individually, in a counterbalanced order, in a small room with minimal extraneous stimulations. Standard instructions and scoring methods for each test were used. All tests were administered by the same author, who was unaware of the subjects’ status at the time of administration and scoring. A second examiner independently rescored each protocol in order to eliminate potential errors. Total time for the test battery was approximately 80 min. All subjects showed good motivation during testing. 2.4. Data analysis To determine the appropriateness of parametric statistics for each variable, the distributions of all variables were examined within each group. If distributions were non-normal, standard trans-

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formations were applied. Trail A and B were transformed to logarithm values. Since transformation procedures failed to normalize the WCST (PE and CA) and the four scores of schizotypy distribution, a nonparametric statistic was used in those cases ( Kruskal–Wallis H-test, followed when indicated by a Mann–Whitney test to establish which of the comparisons accounted for the significance of a given effect). Comparisons among the three study groups were conducted by one-way analyses of variance (ANOVAs) for the other measures, followed when indicated by post hoc analyses (PLSD Fisher’s test). Since our main hypotheses focused on the comparisons between the patients’ relatives and the control subjects and, since deficits in nonpsychotic individuals at-risk for schizophrenia are expected to be subtle, the level of significance was set at alpha<0.05 (i.e. no Bonferroni was made). Mean attentional performance of the firstdegree relatives, with vs without a SSPD, was compared using a Mann–Whitney test. In the relative and in the control groups, the effect of age (below or above age 50) was assessed through two-way ANOVAs, using groups and age as independent measures and neuropsychological measures as covariates. For comparisons between dichotomous variables, Fisher’s exact tests were

used. Spearman rank order correlations were used to evaluate the relationship between executive/ attentional performance and scores of schizotypy; the level of significance was set at alpha<0.01.

3. Results 3.1. Sociodemographic characteristics The demographic characteristics of the three groups (S=schizophrenics, R=relatives, C=controls) are presented in Table 1. There were no significant differences between the relatives of patients with schizophrenia and the comparison group in age, sex, handedness, IQ and years of education. The patients were significantly younger than their relatives and the controls (F=10.2, df= 2,101, P<0.0001; S vs R: P<0.0001, S vs C: P<0.001) and schizophrenics had significantly lower IQ than controls (F=4.9, df=2,101, P<0.01; S vs C: P<0.005). In the patient group, the proportion of men was significantly higher than in both other groups (P<0.0001). 3.2. Executive/attentional performance The neuropsychological performance in the three groups is presented in Table 2. One of the

Table 1 Demographic characteristics of patients with schizophrenia (S), their first-degree relatives (R) and control subjects (C ) Variable

Age (years)a IQb Education (years)

Genderc Male Female Handedness Right Left

Schizophrenic patients (n=23)

First-degree relatives (n=47)

Control subjects (n=34)

ANOVA

Mean±S.D.

Mean±S.D.

Mean±S.D.

F

31.6±7.1 89.0±12.8 11.0±3.0 n (%)

46.3±14.4 94.5±11.0 11.8±3.5 n (%)

43.8±13.6 98.4±9.7 12.2±3.3 n (%)

10.2 <0.0001 4.9 <0.01 0.9 NS Fisher’s exact P-value

21 (91) 2 (9)

17 (36) 30 (64)

23 (68) 11 (32)

20 (87) 3 (13)

46 (98) 1 (2)

32 (94) 2 (6)

<0.0001

a S vs R: P<0.0001; S vs C: P<0.001. b S vs R: P<0.05; S vs C: P<0.005. c S vs R: P<0.0001; S vs C: P<0.0001.

NS

P

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A. Laurent et al. / Schizophrenia Research 46 (2000) 269–283 Table 2 Neuropsychological performance scores in the schizophrenic (S), first-degree relative (R) and control (C ) groupsa Test

DSSTb DS-CPT d∞c ln b d RT (ms)e SPAN 3-letter (% correct) 12-letter (% correct) 3-letter RT (ms)f 12-letter RT (ms)g VFLh VFCi ln Trail A (s) ln Trail B (s)j Stroop (Interference) WCST (PE ) WCST (CA)k

Schizophrenic patients (n=23) Mean±S.D.

First-degree relatives (n=47) Mean±S.D.

Control subjects (n=34) Mean±S.D.

ANOVA or Kruskal–Wallis F/H

P

42.7±11.1

49.2±12.4

57.7±11.1

11.4

<0.0001

3.11±0.83 1.15±1.13 557±82

3.43±0.88 1.33±1.03 502±63

3.80±0.91 0.72±1.00 477±60

4.2 3.3 9.9

<0.05 <0.05 =0.0001

96.6±4.8 78.8±8.4 786±165 1101±266 54.3±17.6 40.6±10.1 3.62±0.38 4.63±0.49 1.98±6.50 27.3±26.0 3.13±2.34

97.2±3.3 78.5±9.1 752±138 1032±183 72.5±16.8 55.9±9.7 3.54±0.40 4.22±0.36 5.2±7.3 11.3±11.2 4.77±1.58

96.5±3.5 81.7±7.4 655±89 887±171 72.5±16.8 55.9±9.7 3.54±0.40 4.22±0.36 5.2±7.3 17.0±1.8 4.63±1.67

0.3 1.5 8.2 8.8 10.5 16.7 0.9 7.2 1.4 3.6 8.2

NS NS =0.0005 <0.0005 <0.0001 <0.0001 NS <0.005 NS NS =0.01

a DSST: Digit Symbol Substitution Test; DS-CPT: Degraded Stimulus-Continuous Performance Test; SPAN: Span of Apprehension; VFL: Verbal Fluency for letters; VFC: Verbal Fluency for categories; WCST (PE ): Wisconsin Card Sorting Test (perseverative errors); WCST (CA): Wisconsin Card Sorting Test (categories achieved). b S vs C: P<0.0001; S vs R: P<0.05; R vs C: P<0.005. c S vs C: P=0.005; R vs C: P=0.07. d R vs C: P=0.01. e S vs C: P<0.0001; S vs R: P<0.005; R vs C: P=0.09. f S vs C: P<0.0005; R vs C: P<0.005. g S vs C: P<0.0005; R vs C: P<0.005. h S vs C: P=0.0001; R vs C: P<0.0005. i S vs C: P<0.0001; S vs R: P=0.0001; R vs C: P<0.05 j S vs C: P<0.0005; S vs R: P<0.05; R vs C: P<0.05 k S vs C: P<0.05; S vs R: P<0.005

relatives was unable to complete the DS-CPT and the SPAN due to equipment malfunctions. One control and one relative did not perform the Stroop and the WCST due to color blindness. The ANOVA for the DS-CPT d∞ demonstrated a significant group effect (F=4.22, df=2,99, P<0.05) and post hoc analyses revealed that d∞ was significantly lower in the patient group (P= 0.005) and tended to be lower in the relative group (P=0.07) than in the control group. The ANOVA for the DS-CPT ln b demonstrated a significant group effect (F=3.33, df=2,99, P<0.05) and post hoc analyses revealed that ln b was smaller in the relative than in the control group (P=0.01). The ANOVA for the DS-CPT reaction time showed a

significant group effect (F=9.96, df=2,99, P= 0.0001), and the schizophrenic group had significantly longer time reaction than the control (P<0.0001) and the relative (P<0.005) groups. For the SPAN, the three groups did not differ significantly from one another on the percentage of accuracy for the 3- and 12-letter arrays. However, the ANOVA for the SPAN reaction time demonstrated a significant group effect for the 3-letter arrays (F=8.23, df=2,99, P=0.0005; S vs C: P<0.0005; R vs C: P<0.005) and for the 12-letter arrays (F=8.81, df=2,99, P<0.0005; S vs C: P<0.0005; R vs C: P<0.005). The ANOVA for the DSST showed a significant group effect (F=11.4, df=2,100, P<0.0001), with

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lower performance in the schizophrenic and the relative groups than in the control group (S vs C: P<0.0001; R vs C: P<0.005). The patient group performed more poorly than the relative group on the DSST (P<0.05). Significant group differences were observed for the VFT ( letters: F=10.58, df=2,100, P<0.0001; categories: F=16.7, df=2,100, P<0.0001), for the ln Trail B (F=7.20, df=2,99, P<0.005) and the WCST CA (H=8.23, df=2, P=0.01). Patients’ performance was lower than controls’ performance on the VFT ( letters: P=0.0001; categories: P<0.0001), ln Trail B (P<0.0005) and WCST CA (U=237, P<0.05). Relatives performed more poorly as a group than controls on the VFT ( letters: P<0.0005; categories: P<0.05) and ln Trail B (P<0.05). To examine the contribution of the general psychomotor speed and ability to performance on the Trail B, a logistic regression was used. When the Trail B was entered in the model in a first step, there

was a significant difference between relative and control groups (correlation coefficient=−0.15; P=0.03). When the Trail A was added in the model in a second step, the difference between groups was still significant (partial correlation coefficient=−0.13; P=0.05). The neuropsychological scores of the subgroup of 14 first-degree relatives with a SSPD did not differ significantly from those of the subgroup of 32 relatives without a SSPD (P>0.05) ( Table 3). To take into account the differences on age and IQ between the patient and the control groups, a logistical regression with an adjustment on these two variables was performed to predict group (patient versus control ) from each neuropsychological score. The P-value was still significant for the DSST (P<0.005), d∞ (P=0.01), DS-CPT reaction time (P<0.005), SPAN 3-letter arrays reaction time (P<0.05), SPAN 12-letter arrays reaction time (P<0.05), VFT for categories (P=0.005), Trail B (P<0.05) and WCST CA (P<0.05).

Table 3 Neuropsychological performance in the subgroups of relatives with (SSPD+) and without (SSPD−) schizophrenia spectrum personality disordersa Variable

DSST DS-CPT d∞ ln b RT (ms) SPAN 3-letter (% correct) 12-letter (% correct) 3-letter RT (ms) 12-letter RT (ms) VFL VFC ln Trail A (s) ln Trail B (s) Stroop (Interference) WCST (PE ) WCST (CA)

SSPD+ (n=14)

SSPD− (n=32)

Mann–Whitney

Mean±S.D.

Mean±S.D.

U

P

49.3±12.1

48.9±12.8

220

NS

3.37±0.99 1.3±1.0 504±65

3.45±0.86 1.3±1.0 501±64

201 198 185

NS NS NS

97.3±2.3 77.8±8.1 793±155 1056±187 54.7±14.9 50.2±11.2 43.8±17.2 89.0±25.8 4.8±11.3 18.8±9.7 4.8±1.2

97.2±3.8 79.0±9.7 742±127 1034±175 59.2±16.4 51.1±8.14 41.9±17.6 90.7±38.2 1.3±7.6 15.3±12.0 4.7±1.7

181 177 236 183 190 207 209 214 186 153 208

NS NS NS NS NS NS NS NS NS NS NS

a DSST: Digit Symbol Substitution Test; DS-CPT: Degraded Stimulus-Continuous Performance Test; SPAN: Span of Apprehension; VFL: Verbal Fluency for letters; VFC: Verbal Fluency for categories; WCST (PE ): Wisconsin Card Sorting Test (perseverative errors); WCST (CA): Wisconsin Card Sorting Test (categories achieved).

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3.3. Effect of age in the relative and control groups To assess the effect of age on neuropsychological differences between the relative and control groups, each group was divided according to a criterion of age (below or above age 50). The age of 50 was chosen since all siblings were younger than 50 (100%) and all parents, except four, were older than 50 (85%). The mean age was 59.6±6.3 years and 58.3±6.9 years for subjects older than 50 (U= 117, P>0.05), and 35.5±8.9 years and 34.8±7.6 years for subjects younger than 50 (U= 260, P>0.05) in the relative and the control groups, respectively. For the 81 subjects included in those analyses, the ANOVAs showed a significant impairment with age on all tests except the DS-CPT reaction time, the SPAN 12-letter reaction time, the VFT for letters and the Stroop. However, there was no age×group interaction for any of the neuropsychological measures (P>0.05), e.g., neuropsychological differences between relatives and controls older than 50 were the same as the differences between relatives and controls younger

than 50. The data broken by age and group are presented on Table 4. 3.4. Relationship between attentional performance and measures of schizotypy The scores of the four self-report scales are presented in Table 5. The ANOVAs for the SocAnhS, PhyAnhS, PAS and MIS showed a significant group effect (H=17.92, df=2, P= 0.0001; H=13.84, df=2, P=0.001; H=10.45, df= 2, P<0.005; H=7.25, df=2, P<0.05, respectively). Post hoc analyses revealed that the schizophrenic group had significantly higher scores on these four scales than the control group (U=87, P<0.0001; U=132.5, P=0.0005; U=111.5, P<0.005; U=131, P<0.01, respectively) and than the relative group (U=296.5, P<0.005; U=278.0, P<0.005; U=252.5, P<0.05; U=238.5, P<0.05, respectively). Although the relative group’s scores were for each of the four scales at an intermediate level between those of the patient and control groups, only the SocAnhS (U=490.5, P=0.13)

Table 4 Group mean scores of variables broken by age and group (relative and control groups) and statistical analysis of group differencesa Test

<50 years old Relatives

DSST DS-CPT d∞ ln b RT (ms) SPAN 3-letter (% correct) 12-letter (% correct) 3-letter RT (ms) 12-letter RT (ms) VFL VFC ln Trail A (s) ln Trail B (s) Stroop (Interference) WCST (PE ) WCST (CA)

>50 years old Controls

Relatives

ANOVA (age×group) Relatives

F

P

54.4±9.8

63.0±10.3

42.8±12.3

49.5±6.5

0.16

0.69

3.71±0.84 1.52±1.07 503±57

4.06±0.84 0.93±0.87 480±54

3.11±0.83 1.12±0.97 501±71

3.38±0.88 0.39±1.14 471±70

0.04 0.08 0.05

0.84 0.76 0.81

98.1±1.7 81.3±8.5 700±91 1019±193 56.4±12.6 52.2±8.4 3.57±0.35 4.29±0.30 2.16±9.07 12.4±6.9 5.4±1.0

98.3±1.5 84.2±6.2 633±89 886±189 73.3±17.2 58.0±8.7 3.35±0.29 4.11±0.39 4.24±8.05 14.8±10.8 4.7±1.7

96.2±4.4 75.4±9.0 812±159 1048±176 59.5±19.2 48.8±9.7 3.79±0.40 4.60±0.34 2.46±8.91 20.7±13.5 4.0±1.8

93.6±3.7 77.7±7.5 691±80 888±146 71.3±16.7 52.8±10.5 3.83±0.39 4.40±0.37 6.86±6.02 20.5±13.0 4.4±1.6

4.11 0.02 1.04 0.10 0.44 0.17 2.40 0.02 0.32 0.25 2.24

0.04 0.87 0.30 0.74 0.50 0.67 0.12 0.88 0.57 0.61 0.13

a DSST: Digit Symbol Substitution Test; DS-CPT: Degraded Stimulus-Continuous Performance Test; SPAN: Span of Apprehension; VFL: Verbal Fluency for letters; VFC: Verbal Fluency for categories; WCST (PE ): Wisconsin Card Sorting Test (perseverative errors); WCST (CA): Wisconsin Card Sorting Test (categories achieved).

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Table 5 Scores of schizotypy in the schizophrenic (S ), first-degree relative (R) and control (C ) groups Scale

Social anhedonia scalea Physical anhedonia scaleb Perceptual aberration scalec Magical ideation scaled aS bS cS dS

vs vs vs vs

R: R: R: R:

Schizophrenic patients

First-degree relatives

Control subjects

Kruskall–Wallis

Mean±S.D.

Mean±S.D.

Mean±S.D.

H

n=23 13.7±5.3 20.5±8.7 n=18 7.9±8.7 7.8±6.9

n=46 9.3±5.0 13.1±8.1 n=43 2.8±3.2 4.0±4.3

n=27 6.5±3.2 11.8±6.3 n=27 1.4±1.5 3.3±2.8

P

17.9 13.8 10.4 7.2

0.0001 0.001 <0.005 <0.05

P<0.005; S vs C: P<0.0001; R vs C: P=0.13. P<0.005; S vs C: P=0.0005. P<0.05; S vs C: P<0.005; R vs C: P=0.06. P<0.05; S vs C: P<0.01.

−0.70, P<0.0005). In the relative group, a significant correlation was found between the PhysAnhS scores and the WCST (PE) (rho=0.42, P<0.01).

and PAS (U=432.5, P=0.06) scores tended to be higher in the relative than in the control group. In each of the three groups, correlations were calculated between DS-CPT d∞, percentage of accuracy for the 12-letter arrays (SPAN ), DSST, VFT, Trail A, Trail B, Stroop, WCST (PE and CA), and the four self-report scales’ scores. The results are presented in Table 6. In the schizophrenic group, a significant correlation was found between the MIS scores and the DSST performance (rho=

4. Discussion The comparison of the first-degree relatives of patients with schizophrenia and of healthy controls

Table 6 Correlations between neuropsychological performance and the schizotypy scores in the schizophrenic (S), relative (R) and control (C ) groupsa Test

DSST DS-CPT:d∞ SPAN 12 VFL VFC Trail A Trail B Stroop WCST (PE ) WCST (CA)

Social anhedonia

Physical anhedonia

PAS

MIS

S

R

C

S

R

C

S

R

C

S

R

C

−0.19 −0.18 −0.07 0.12 0.20 0.03 0.003 −0.06 0.19 −0.16

−0.19 −0.24 −0.12 −0.22 −0.21 0.07 0.19 0.35 0.31 −0.28

−0.16 −0.36 −0.04 −0.14 0.04 0.02 0.23 0.22 0.24 −0.41

−0.27 −0.11 −0.36 −0.16 −0.23 −0.07 0.22 0.33 0.40 −0.41

−0.10 −0.15 −0.12 −0.23 −0.24 0.04 0.03 0.12 0.42b −0.30

0.00 −0.13 0.13 −0.10 −0.02 −0.23 0.26 −0.04 0.07 −0.18

−0.43 −0.55 −0.005 −0.23 −0.12 0.24 0.16 0.31 0.003 −0.07

−0.12 −0.08 0.26 −0.02 −0.19 0.31 0.18 0.01 −0.08 0.13

−0.26 −0.01 −0.15 0.22 −0.31 0.04 0.44 −0.02 0.08 −0.12

−0.70c −0.21 −0.31 −0.42 −0.23 0.38 0.35 0.31 0.40 −0.39

−0.06 −0.05 0.29 0.006 −0.05 0.18 −0.002 0.12 −0.01 0.05

−0.42 −0.12 0.12 0.21 −0.09 0.02 0.46 0.11 0.20 −0.09

a DSST: Digit Symbol Substitution Test; DS-CPT: Degraded Stimulus-Continuous Performance Test; SPAN 3: Span of Apprehension 3-letter (% correct responses); SPAN 12: Span of Apprehension 12-letter (% correct responses); VFL: Verbal Fluency for letters; VFC: Verbal Fluency for categories; WCST (PE ): Wisconsin Card Sorting Test (perseverative errors); WCST (CA): Wisconsin Card Sorting Test (categories achieved); PAS: Perceptual Aberration Scale; MIS: Magical Ideation Scale. b P<0.01. c P<0.005.

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on executive/attentional test scores and the question of a potential link between executive/ attentional deficits (i.e., putative behavioral phenotypic markers of vulnerability to schizophrenia) and measures of schizotypy (i.e., clinical markers of psychosis proneness) were the two major focuses of this study. In contrast with previous studies (Grove et al., 1991; Condray and Steinhauer, 1992; Maier et al., 1992; Chen et al., 1998), first-degree relatives of patients with schizophrenia only tended to show a poorer discrimination ability ( lower DS-CPT d∞ scores) than controls. This result could be explained by the fact that, in the present study, the relative group had a more conservative response style than the control group, whereas in most studies, controls and first-degree relatives do not differ in ln b (Grove et al., 1991; Maier et al., 1992). Thus, it seems that the relatives were especially motivated and hard working. Concerning the SPAN 3-letter arrays, the high frequency of correct responses, the similarity of means between all groups and the relatively low variances in all groups indicated the presence of a ceiling effect. The percentage of correct responses for the 12-letter arrays did not differ significantly between the three groups. Since the SPAN is thought to involve serial scanning processes (Asarnow et al., 1991), the significantly longer reaction time in the patient and relative groups could be related to impairments in the speed of these serial scanning processes. SPAN performance has been less studied in first-degree relatives than the CPT performance. Asarnow et al. (1977) found impaired performance in foster children whose biological mothers were schizophrenic, but Harvey et al. (1985) failed to replicate this finding. Differences found by Maier et al. (1992) between the adult relative and the control groups only reached the level of significance (P=0.05) for the percentage of accuracy for 8-letter arrays; moreover, it must be noted that in their study, IQ or education level were not assessed. In Wagener et al. (1986), the number of mothers of schizophrenic patients classified as poor attenders was greater on a 10-letter version of the SPAN than the number found in normative samples; however, the comparison was made using normative samples of control

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subjects of considerably younger age than the mothers of the patients. The DSST was impaired in the patient and in the relative groups. This test requires focusing on a particular stimulus set, avoiding distraction, and performing a skilled motor task. It involves visual search combined with motor speed and is referred to as a test of selective attention in the informationprocessing paradigm ( Kremen et al., 1994). Compared with normal controls, this deficit on perceptual–motor speed has already been found in children of patients with schizophrenia (Mednick and Schulsinger, 1968; Landau et al., 1972), and in adult relatives (Mirsky et al., 1992, 1995). In their study, Mirsky et al. (1995) were unable to rule out the fact that low DSST scores in relatives of patients with schizophrenia may be due to alcohol abuse. The present study indicates that low scores on the DSST exist also in relatives without alcohol abuse, since relatives with an Axis I diagnosis were not included. Patients demonstrated deviant patterns of neuropsychological performance on the Trail B, on the WCST (CA), and on the VFT (categories) as compared to controls. These findings are in line with previous reports in literature of frontal lobe deficiencies in schizophrenia ( Kolb and Whishaw, 1983; Marrison-Stewart et al., 1992). The relative group was impaired on the VFT for letters and categories. Impaired verbal fluency has previously been found in some studies (PogueGeile et al., 1991; Franke et al., 1993; Roxborough et al., 1993; Keefe et al., 1994); however, Goldberg et al. (1990) did not find altered verbal fluency in unaffected co-twins. A possible explanation for Goldberg et al.’s results could be a selection bias: because a much larger percentage of the siblings of schizophrenic probands than of co-twins are expected not to be schizophrenic (i.e., 90% vs 40%), selection on the basis of discordance in twins may bias the sample composition toward a less genetic form of the disorder. Contrarily to the performance on the Trail A, the performance on the Trail B was significantly lower in the relative than in the control group; in taking into account the Trail A, the logistic regression showed that relatives had a specific deficit in set alternation when compared with controls.

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Several studies (Pogue-Geile et al., 1991; Franke et al., 1993; Harris et al., 1996) have found that the performance on the Trail B was worse in schizophrenics’ relatives than in normal controls. However, only Keefe et al. (1994) took into account the contribution to the general psychomotor speed (i.e. the scores on the Trail A) to show that set alternation was specifically disturbed in these subjects. The lack of difference between relative and control groups on the WCST performance is in accordance with some studies (Goldberg et al., 1990; Condray and Steinhauer, 1992; Scarone et al., 1993; Keefe et al., 1994) but not with others (Pogue-Geile et al., 1991; Mirsky et al., 1992; Franke et al., 1993; Faraone et al., 1995, Toomey et al., 1998). Some of the differences in findings among the various studies could stem from criteria used for the evaluation. For instance, for Mirsky et al. (1992), the score used was the mean of three scores (number of categories attained, percentage of correct responses and number of errors). Neuropsychological differences between the subgroups of relatives and controls older than 50 were the same as differences between the subgroups of relatives and controls younger than 50. Thus, aging does not seem to be a confounding variable in this kind of study. Since the subgroup of subjects older than age 50 comprised exclusively parents of schizophrenic patients, it appears that impairments especially described in siblings do exist in schizophrenics’ parents too. Although three controls were excluded from the study because they presented a SSPD, it seems unlikely that their inclusion in the control group would have changed the results of the statistical analyses, since there were no differences on the neuropsychological performance between relatives with and without such a diagnosis. Among the four self-report questionnaire scores, only the SocAnhS and the PAS scores tended to be different between the relative and the control groups. In previous studies, the SocAnhS scores were significantly higher in relatives of patients with schizophrenia ( Katsanis et al., 1990; Kendler et al., 1996), the PhyAnhS scores were higher too ( Katsanis et al., 1990; Clementz et al., 1991; Grove et al., 1991), the MIS scores were

similar ( Kendler et al., 1996) and the PAS scores similar ( Franke et al., 1994) or lower ( Katsanis et al., 1990; Clementz et al., 1991; Grove et al., 1991) than in controls. In the relative group, a significant correlation was found between the negative dimension of schizophrenia assessed by the PhysAnhS and the number of perseverative errors in the WCST. This result is in line with a previous study in healthy siblings of schizophrenic inpatients (Franke et al., 1993); however, contrarily to these authors, we did not find a significant correlation between the PhyAnhS scores and the VFT or Trail performance. In the relative group, we did not find significant correlations between the DS-CPT and the measures of schizotypy: this finding is not concordant with the study of Grove et al. (1991), who found a significant correlation between d∞, and on one hand the PhysAnhS scores, and on the other hand the PAS scores. However, although Chen et al. (1998) found, in their relative group, a significant correlation between performance on the CPT and two factors of schizotypy, these authors suggested that CPT deficit and schizotypy may be distinct traits since the schizophrenic probands’ CPT deficit predict poorer attentional performance but failed to predict more schizotypal features in their relatives. In conclusion, this study demonstrated that first-degree relatives of patients with schizophrenia share some of the executive/attentional deficits observed in schizophrenia. These deficits could be phenotypic markers of predisposition to schizophrenia. Further studies are required to replicate these results and to investigate whether these deficits in relatives are mediated by structural and/or metabolic disturbance in the frontal brain region. It would also be of interest to study families with multiply affected individuals (Shedlack et al., 1997) to clarify whether there is co-inheritance of cognitive deficits with schizophrenia within these families. Furthermore, in the first-degree relative group, a link existed between the WCST PE and the negative dimension of schizotypy. However, most of the neuropsychological performance did not correlate with the measures of schizotypy. This absence of correlation could result from the

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heterogeneity of schizophrenia: although both personality and cognitive dysfunctions represent potential indicators of an elevated risk for schizophrenia, these indicators need not necessarily be correlated. Tsuang et al. (1990) have argued that the symptoms of schizophrenia represent the final common pathway of a diversity of etiologies in different subsamples of subjects at risk. According to this concept, a variety of risk factors for schizophrenia may reflect diverse etiologies in different samples and might therefore be uncorrelated. Consequently, these indicators could be used independently in the identification of affected patients in genetic linkage and aggregation studies of schizophrenia.

Acknowledgements The authors are grateful to the schizophrenic patients, their relatives and the controls for participating in this study. Furthermore, they thank Dr Nuechterlein and Dr Asarnow for their computerized version of the DS-CPT and SPAN.

References American Psychiatric Association, 1987. Diagnostic and Statistical Manual of Mental Disorders. third ed., revised, American Psychiatric Press, Washington, DC. Asarnow, R.F., Steffy, R.A., MacCrimmon, D.J., Cleghorn, J.M., 1977. An attentional assessment of foster children at risk for schizophrenia. J. Abnorm. Psychol. 86, 267–275. Asarnow, R.F., Granholm, E., Sherman, T., 1991. Span of apprehension in schizophrenia. In: Steinhauer, S.R., Gruzelier, J.H., Zubin, J. (Eds.), Neuropsychology, psychophysiology and information processing. In: Handbook of Schizophrenia vol. 5. Elsevier, Amsterdam, pp. 335–370. Asarnow, R.F., MacCrimmon, D.J., 1978. Residual performance deficit in clinically remitted schizophrenics: a marker of schizophrenia? J. Abnorm. Psychol. 87, 597–608. Baron, M., Gruen, R., Asnis, L., Kane, J., 1983. Familial relatedness of schizophrenia and schizotypal states. Am. J. Psychiatry 140, 1437–1442. Baron, M., Gruen, R., Rainer, J.D., Kane, J., Asnis, L., Lord, S., 1985. A family study of schizophrenic and normal control probands: implications for the spectrum concept of schizophrenia. Am. J. Psychiatry 142, 447–454. Brooker, B.H., Cyr, J.J., 1986. Tables for clinicians to use to convert WAIS-R short forms. J. Clin. Psychol. 42, 982–986. Cannon, T.D., Zorrilla, L.E., Shtasel, D., Gur, R.E., Gur, R.C., Marco, E.J., Moberg, P., Price, R.A., 1994. Neuropsycho-

281

logical functioning in siblings discordant for schizophrenia and healthy volunteers. Arch. Gen. Psychiatry 51, 651–661. Chapman, L.J., Chapman, J.P., 1987. The search for symptoms predictive of schizophrenia. Schizophr. Bull. 13, 497–503. Chapman, L.J., Chapman, J.P., Kwapil, T.R., Eckblad, M., Zinser, M.C., 1994. Putatively psychosis-prone subjects 10 years later. J. Abnorm. Psychol. 103, 171–183. Chapman, L.J., Chapman, J.P., Raulin, M.L., 1976. Scales for physical and social anhedonia. J. Abnorm. Psychol. 85, 374–382. Chapman, L.J., Chapman, J.P., Raulin, M.L., 1978. Bodyimage aberration in schizophrenia. J. Abnorm. Psychol. 87, 399–407. Chen, W.J., Liu, S.K., Chang, C.-J., Lien, Y.-J., Chang, Y.-H., Hwu, H.-G., 1998. Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients. Am. J. Psychiatry 155, 1214–1220. Clementz, B.A., Grove, W.M., Katsanis, J., Iacono, W.G., 1991. Psychometric detection of schizotypy: perceptual aberration and physical anhedonia in relatives of schizophrenics. J. Abnorm. Psychol. 100, 607–612. Condray, R., Steinhauer, S.R., 1992. Schizotypal personality disorder in individuals with and without schizophrenic relatives: similarities and contrasts in neurocognitive and clinical functioning. Schizophr. Res. 7, 33–41. Cornblatt, B.A., Erlenmeyer-Kimling, E., 1985. Global attentional deviance as a marker of risk for schizophrenia: specificity and predictive validity. J. Abnorm. Psychol. 94, 470–486. Eckblad, M., Chapman, L.J., 1983. Magical ideation as an indicator of schizotypy. J. Consult. Clin. Psychol. 51, 215–225. Faraone, S.V., Seidman, L.J., Kremen, W.S., Pepple, J.R., Lyons, M.J., Tsuang, M.T., 1995. Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a diagnostic efficiency analysis. J. Abnorm. Psychol. 104, 286–304. Frangos, E., Athanassena, G., Tsitourides Katsanou, H., Alexandralsu, P., 1985. Prevalence of DSM-III schizophrenia among the first-degree relatives of schizophrenic probands. Acta Psychiatr. Scand. 72, 382–386. Franke, P., Maier, W., Hardt, J., Hain, C., 1993. Cognitive functioning and anhedonia in subjects at risk for schizophrenia. Schizophr. Res. 10, 77–84. Franke, P., Maier, W., Hardt, J., Hain, C., Cornblatt, B.A., 1994. Attentional abilities and measures of schizotypy: their variation and covariation in schizophrenic patients, their siblings, and normal control subjects. Psychiatry Res. 54, 259–272. Goldberg, T.E., Ragland, J.D., Torrey, E.F., Gold, J.M., Bigelow, L.B., Weinberger, D.R., 1990. Neuropsychological assessment of monozygotic twins discordant for schizophrenia. Arch. Gen. Psychiatry 47, 1066–1072. Golden, C.J., 1978. Stroop Color and Word Test. Stoelting, Chicago, IL. Gottesman, I.I., Bertelsen, A., 1989. Confirming unexpressed genotypes for schizophrenia: risks in the offspring of

282

A. Laurent et al. / Schizophrenia Research 46 (2000) 269–283

Fischer’s Danish identical and fraternal discordant twins. Arch. Gen. Psychiatry 46, 867–872. Grove, W.M., Lebow, B.S., Clementz, B.A., Cerri, A., Medus, C., Iacono, W.G., 1991. Familial prevalence and coaggregation of schizotypy indicators: a multitrait family study. J. Abnorm. Psychol. 100, 115–121. Harris, J.G., Adler, L.E., Young, D.A., Cullum, C.M., Rilling, L.M., Cicerello, A., Intemann, P.M., Freedman, R., 1996. Neuropsychological dysfunction in parents of schizophrenics. Schizophr. Res. 20, 253–260. Harvey, P.D., Keefe, R.S.E., Mitroupolou, V., DuPre, R., Lees Roitman, S., Mohs, R.C., Siever, L.J., 1996. Informationprocessing markers of vulnerability to schizophrenia: performance of patients with schizotypal and nonschizotypal personality disorders. Psychiatry Res. 60, 49–56. Harvey, P.D., Weintraub, S., Neale, J.M., 1985. Span of apprehension deficits in children vulnerable to psychopathology: a failure to replicate. J. Abnorm. Psychol. 94, 410–413. Heaton, R., 1981. The Wisconsin Card Sorting Test Manual. Psychological Assessment Resources, Odessa, FL. Hermann, B.P., Wyler, A.R., Richey, E.T., 1988. Wisconsin Card Sorting Test performance in patients with complex partial seizures of temporal lobe origin. J. Clin. Exp. Neuropsychol. 10, 467–476. Jarvis, P.E., Barth, J.T., 1986. Halstead–Reitan Test Battery: An Interpretative Guide. Psychological Assessment Resources, Odessa, FL. Katsanis, J., Iacono, W.G., Beiser, M., 1990. Anhedonia and perceptual aberration in first-episode psychotic patients and their relatives. J. Abnorm. Psychol. 99, 202–206. Kay, S.R., Opler, L.A., Lindenmayer, J.P., 1988. Reliability and validity of the positive and negative syndrome scale for schizophrenics. Psychiatry Res. 23, 99–110. Keefe, R.S.E., Silverman, J.M., Lees Roitman, S.E., Harvey, P.D., Duncan, M.A., Alroy, D., Siever, L.J., Davis, K.L., Mohs, R.C., 1994. Performance of nonpsychotic relatives of schizophrenic patients on cognitive tests. Psychiatry Res. 53, 1–12. Kendler, K.S., 1985. Diagnostic approaches to schizotypal personality disorder: a historical perspective. Schizophr. Bull. 11, 538–553. Kendler, K.S., Gruenberg, A.M., Strauss, J.S., 1981. An independent analysis of the Copenhagen sample of the Danish adoption study of schizophrenia. Arch. Gen. Psychiatry 38, 982–987. Kendler, K.S., Thacker, L., Walsh, D., 1996. Self-report measures of schizotypy as indices of familial vulnerability to schizophrenia. Schizophr. Bull. 22, 511–520. Kolb, B., Whishaw, I.Q., 1983. Performance of schizophrenic patients on tests sensitive to left and right frontal, temporal or parietal function in neurological patients. J. Nerv. Ment. Dis. 171, 435–443. Kremen, W.S., Seidman, L.J., Pepple, J.R., Lyons, M.J., Tsuang, M.T., Faraone, S.V., 1994. Neuropsychological risk indicators for schizophrenia: a review of family studies. Schizophr. Bull. 20, 103–119. Landau, R., Harth, P., Othnay, N., Scharfhertz, C., 1972. The

influence of psychotic parents on their children’s development. Am. J. Psychiatry 129, 70–75. Lenzenweger, M.F., Cornblatt, B.A., Putnick, M., 1991. Schizotypy and sustained attention. J. Abnorm. Psychol. 100, 84–89. Lenzenweger, M.F., Korfine, L., 1994. Perceptual aberrations, schizotypy, and the Wisconsin Card Sorting Test. Schizophr. Bull. 20, 345–357. Levin, S., Yurgelun-Todd, D., Craft, S., 1989. Contribution of clinical neuropsychology to the study of schizophrenia. J. Abnorm. Psychol. 98, 341–356. Lezak, M.D., 1995. Neuropsychological Assessment. third ed., Oxford University Press, Oxford. Lowing, P.A., Mirsky, A.F., Pereira, R., 1983. The inheritance of schizophrenia spectrum disorders: a reanalysis of the Danish adoptee study data. Am. J. Psychiatry 140, 1167–1171. Maier, W., Franke, P., Hain, C., Kopp, B., Rist, F., 1992. Neuropsychological indicators of the vulnerability to schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 16, 703–715. Marrison-Stewart, S.L., Williamson, P.C., Corning, W.C., Kutcher, S.P., Snow, W.G., Merskey, H., 1992. Frontal and non-frontal lobe neuropsychological lobe performance and clinical symptomatology in schizophrenia. Psychol. Med. 22, 353–359. Mednick, S.A., Schulsinger, F., 1968. Some premorbid characteristics relating to breakdown in children with schizophrenic mothers. In: Rosenthal, D., Kety, S.S. (Eds.), The Transmission of Schizophrenia. Pergamon Press, Oxford. Milner, B., 1975. Psychological aspects of focal epilepsy and its neurological management. Purpura, D.P., Penry, J.K., Walter, R.D. ( Eds.), Advances in Neurology vol. 8. Raven Press, New York. !Mirsky, A.F., Lochhead, S.J., Jones, B.P., Kugelmass, S., Walsh, D., Kendler, K.S., 1992. On familial factors in the attentional deficit in schizophrenia: a review and report of two new subject samples. J. Psychol.. Res. 26, 383–403. Mirsky, A.F., Yardley, S.L., Jones, B.P., Walsh, D., Kendler, K.S., 1995. Analysis of the attention deficit in schizophrenia: a study of patients and their relatives in Ireland. J. Psychiatr. Res. 29, 23–42. Nuechterlein, K.H., 1983. Signal detection in vigilance tasks and behavioral attributes among offspring of schizophrenic mothers and among hyperactive children. J. Abnorm. Psychol. 92, 4–28. Nuechterlein, K.H., Asarnow, R.F., 1994. Direction for the Use of the UCLA Span of Apprehension Program, Version 4.0 for Arrays of 3 and 12 Letters on IBM AT and Fully Compatible Microcomputers. Department of Psychiatry and Behavioral Sciences, UCLA, Los Angeles, CA. Nuechterlein, K.H., Asarnow, R.F., 1997. Direction for the Use of the UCLA Continuous Performance Test (CPT ) Program for IBM AT and Fully Compatible Microcomputers, Version 7.10 for Degraded Stimulus CPT and Conventional ‘‘0’’ CPT. Department of Psychiatry and Behavioral Sciences, UCLA, Los Angeles, CA.

A. Laurent et al. / Schizophrenia Research 46 (2000) 269–283 Nuechterlein, K.H., Dawson, M.E., 1984. Information processing and attentional functioning in the developmental course of schizophrenic disorders. Schizophr. Bull. 10, 160–203. Obiols, J.E., Garcia-Domingo, M., de Trincheria, I., Domenech, E., 1993. Psychometric schizotypy and sustained attention in young males. Personal. Individ. Diff. 14, 381–384. Perret, E., 1974. The left frontal lobe of man and the suppression of habitual responses in verbal categorical behaviour. Neuropsychologia 12, 323–330. Pogue-Geile, M.F., Garrett, A.H., Brunke, J.J., Hall, J.K., 1991. Neuropsychological impairments are increased in siblings of schizophrenic patients. Schizophr. Res. 4, 390. Reitan, R.M., 1958. Validity of the Trail Making Test as an indicator of organic brain damage. Percept. Motor Skills 8, 271–276. Reitan, R.M., 1978. Manual for Administration of N0europsychological Test Batteries for Adults and Children. Reitan Neuropsychology Laboratories, Tucson, AZ. Roxborough, H., Muir, W.J., Blackwood, D.H.R., Walker, M.T., Blackburn, I.M., 1993. Neuropsychological and P300 abnormalities in schizophrenics and their relatives. Psychol. Med. 23, 305–314. Rutschmann, J., Cornblatt, B., Erlenmeyer-Kimling, L., 1977. Sustained attention in children at risk for schizophrenia: report on a continuous performance test. Arch. Gen. Psychiatry 34, 571–575. Saykin, A.J., Gur, R.C., Gur, R.E., Molzey, P.D., Mozley, L.H., Resnick, S.M., Kester, D.B., Stafiniak, P., 1991. Neuropsychological function in schizophrenia. Selective impairment in memory and learning. Arch. Gen. Psychiatry 48, 618–624. Scarone, S., Abbruzzese, M., Gambini, O., 1993. The Wisconsin Card Sorting Test discriminates schizophrenic patients and their siblings. Schizophr. Res. 10, 103–107. Shedlack, K., Lee, G., Sakuma, M., Xie, S-H., Kushner, M., Pepple, J., Finer, D.L., Hoff, A.L., DeLisi, L.E., 1997. Language processing and memory in ill and well siblings from multiplex families affected with schizophrenia. Schizophr. Res. 25, 43–52. Siever, L.J., Silverman, J.M., Horvath, T.B., Klar, H., Coccaro, E.F., Keefe, R.S.E., Pinkham, L., Rinaldi, P., Mohs, R.C., Davis, K.L., 1990. Increased morbid risk for schizophreniarelated disorders in relatives of schizotypal personality disordered patients. Arch. Gen. Psychiatry 47, 634–640. Spitzer, R.L., Williams, J.B., 1986. Structured Clinical Interview for DSM-III-R Personality Disorders (SCID II ). Bio-

283

metric Research Department, New York State Psychiatric Institute, New York. Spitzer, R.L., Williams, J.B., Gibbon, M., First, M.B., 1988. Structured Clinical Interview for DSM III-R. New York State Psychiatric Institute, New York. Sweeney, J.A., Haas, G.L., Keilp, J.G., Long, M., 1991. Evaluation of the stability of neuropsychological functioning after acute episodes of schizophrenia: one-year follow-up study. Psychiatry Res. 38, 63–76. Swets, J.A., 1973. The relative operating characteristic in psychology: a technique for isoloating effects of response bias finds wide use in study of perception and cognition. Science 182, 990–1001. Swets, J.A., Sewall, S.T., 1963. Invariance of signal detectability over stages of practice and levels of motivation. J. Exp. Psychol. 66, 120–126. Thaker, G., Moran, M., Adami, H., Cassady, S., 1993. Psychosis proneness scales in schizophrenia spectrum personality disorders: familial vs. nonfamilial samples. Psychiatry Res. 46, 47–57. Toomey, R., Faraone, S.V., Seidman, L.J., Kremen, W.S., Pepple, J.R., Tsuang, M.T., 1998. Association of neuropsychological vulnerability markers in relatives of schizophrenic patients. Schizophr. Res. 31, 89–98. Trestman, R.L., Keefe, R.S.E., Mitropoulou, V., Harvey, P.D., de Vegvar, M.L., Lees-Roitman, S., Davidson, M., Aronson, A., Silverman, J., Siever, L.J., 1995. Cognitive function and biological correlates of cognitive performance in schizotypal personality disorder. Psychiatry Res. 59, 127–136. Tsuang, M.T., Gilbertson, M.W., Faraone, S.V., 1991. Genetic transmission of negative and positive symptoms in the biological relatives of schizophrenic. In: Maneros, A., Andreasen, N., Tsuang, M. ( Eds.), Negative versus Positive Schizophrenia. Springer, Berlin, pp. 265–291. Tsuang, M.T., Lyons, M.J., Faraone, S.V., 1990. Heterogeneity of schizophrenia: conceptual models and analytic strategies. Br. J. Psychiatry 156, 17–26. Wagener, D.K., Hogarty, G.E., Goldstein, M.J., Asarnow, R.F., Browne, A., 1986. Information processing and communication deviance in schizophrenic patients and their mothers. Psychiatry Res. 18, 365–377. Wechsler, D., 1981. Wechsler Adult Intelligence Scale — Revised. Harcourt Brace Jovanovich, New York, NY. Weinberger, D.R., Berman, K.F., Zec, R.F., 1986. Psysiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia: I. Regional cerebral blood flow evidence. Arch. Gen. Psychiatry 43, 114–125.