Antisaccade task performance in patients at ultra high risk for developing psychosis

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1 Schizophrenia Research 95 (2007) Antisaccade task performance in patients at ultra high risk for developing psychosis Dorien Nieman a,b,, Hiske Becker a, Reinaud van de Fliert a, Niels Plat a,b, Lo Bour b, Hans Koelman b, Maria Klaassen a, Peter Dingemans a, Maurice Niessen a, Don Linszen a a Department of Psychiatry, Academic Medical Center, Meibergdreef 5, 1105 AZ Amsterdam, Netherlands b Department of Neurology, Clinical Neurophysiology Unit, Academic Medical Center, Amsterdam, Netherlands Received 19 July 2006; received in revised form 20 June 2007; accepted 25 June 2007 Available online 26 July 2007 Abstract Patients with schizophrenia consistently perform worse than healthy controls on the antisaccade task in which the subject is required to inhibit a reflexive saccade to a suddenly appearing visual target and look in the opposite direction. To our knowledge there is no research yet showing how patients at ultra high risk (UHR) for developing psychosis perform on the antisaccade task. The aim of the present study was to investigate antisaccade task performance in UHR patients. Patients were eligible for the study when they met criteria for one or more of the following groups: Attenuated symptoms or brief limited intermitted psychotic symptoms or a first-degree family member with a psychotic disorder and reduced functioning or basic symptoms. In 35 UHR patients we assessed antisaccades, neuropsychological test performance and symptomatology. Antisaccade task results were compared with those obtained in 42 age- and intelligence-matched patients with recentonset schizophrenia and 28 matched healthy controls. Antisaccade error rate was significantly higher in the UHR patients than in the controls. Schizophrenia patients performed worse than the UHR patients and the control subjects. We found a trend towards higher antisaccade error rate at baseline in the UHR patients who later made the transition to psychosis compared to the UHR patients who did not make the transition to psychosis. Poor spatial working memory function was related to increased antisaccade errors in the UHR group. Abnormal antisaccade task performance is also present in patients at UHR for developing psychosis. Subsequent research needs to clarify if increased antisaccade error rate is predictive of a psychotic episode. In UHR patients, poor antisaccade performance may reflect working memory dysfunction Elsevier B.V. All rights reserved. Keywords: Utlra high risk patients; Psychosis; Eye movements; Antisaccade task; Neuropsychology; Transition to psychosis 1. Introduction Corresponding author. Department of Psychiatry, Academic Medical Center, Meibergdreef 5, 1105 AZ Amsterdam, Netherlands. Tel.: ; fax: address: d.h.nieman@amc.uva.nl (D. Nieman). The antisaccade task generates the most frequently observed volitional saccade abnormality in schizophrenia (Crawford et al., 1996; Fukushima et al., 1990). In the antisaccade task, subjects are asked not to look at a suddenly appearing visual target but to make a saccade in the opposite direction at a similar distance from the central fixation point. It has been suggested that the dorsolateral prefrontal cortex is involved in suppressing reflexive saccades, and that the frontal eye fields trigger the correct saccade to the opposite side (Muri et al., 1998). It is unknown how patients at ultra high risk /$ - see front matter 2007 Elsevier B.V. All rights reserved. doi: /j.schres

2 D. Nieman et al. / Schizophrenia Research 95 (2007) (UHR) for developing psychosis perform on the antisaccade test. The development of schizophrenia is generally preceded by a prodromal phase in which there is a clear deterioration from a previous level in functioning. The length of this prodromal phase is extremely variable and varies from weeks to years. The mechanism by which this prodromal state evolves into psychosis is not really understood (Hodges et al., 1999). Additionally, to predict whether the symptoms of a prodromal state evolve in a psychosis or not, is also not yet possible. The retrospective term prodrome therefore cannot appropriately be applied to prospective investigations (Yung et al., 2003). The term ultra high risk has been used to indicate a subthreshold syndrome that can be regarded as a risk factor for subsequent psychosis within the next year, but that psychosis is not inevitable (Yung et al., 2003). McGorry et al. (1995) were able to define three groups thought to be at ultra high risk of developing a psychotic disorder. Group 1: Attenuated psychotic symptoms defines a group of people who have symptoms that deviate from normal phenomena but which are not frankly psychotic e.g. ideas of reference, odd beliefs and paranoid ideation. Group 2: Brief Limited Intermittent Psychotic Symptoms (BLIPS), defines a group that has symptoms of psychotic intensity but which are very infrequent, or which have a total duration of less than 7 days before resolving spontaneously. Group 3: Trait and state risk factors, defines a group who have nonspecific symptoms such as lowered mood or anxiety symptoms plus some trait-risk factors for psychotic disorder, either a schizotypical personality disorder or a family history of a psychotic disorder in a first-degree relative. The non-specific symptoms must have a duration of at least 1 month and must be associated with marked disability or decrease in functioning. 20 of 49 subjects considered as belonging to an ultra high risk group as mentioned above (40.8%) developed a psychotic disorder within 12 months (Yung et al., 2003). Thus 59% did not. If UHR patients would be treated with antipsychotic medication, 59% would receive medication that was not indicated. Therefore, it is important that the percentage correct prediction of psychosis is increased. Cognitive abnormalities have been reported in UHR subjects. Hawkins et al. (2004) found that UHR patients performed at levels intermediate to population norms and data reported for schizophrenia samples on a comprehensive neuropsychological exam. In the context of normal intelligence, this intermediate status suggests that, as a group, these subjects are not fully normal in neuropsychological functioning. Wood et al. (2003) found spatial working memory disorders in UHR patients. Working memory is fundamental to the human ability to reason and make judgments that rely on remembered contextual information and is thought to be mediated mainly by the dorsolateral prefrontal cortex (Beardsley, 1997). The relationship between antisaccade errors and neuropsychological test performance in UHR subjects is yet unexplored. The first aim of the present study was to investigate antisaccade task performance in patients at UHR for developing psychosis. If antisaccade task performance is reduced in UHR patients, further research is warranted to elucidate if this test could enhance the percentage correct prediction of psychosis. The second aim was to investigate the relationship between neuropsychological tests and antisaccade task performance to gain insight into underlying pathological mechanisms of antisaccade task performance in UHR patients. 2. Materials and methods 2.1. Subjects Thirty-five patients (five women) with a UHR of developing psychosis were assessed with the antisaccade test. Mean age was 20.1 years±3.7, SD. The UHR patients were referred to the Academic Medical Center, Amsterdam, Netherlands by psychiatrists and psychologists for a second opinion with the question whether a psychotic development was taking place. The exclusion criteria were: previous psychotic episode for more than one week (as assessed with the Structured Clinical Interview for Diagnosis, sections B and C; Spitzer et al., 1992), symptoms due to substance abuse (as assessed with the Comprehensive International Diagnostic Interview, sections J and L; WHO, 1993),symptomsduetoanorganic mental disorder, IQ below 85 (as assessed Dutch National Adult Reading Test; Schmand et al., 1991), vision disorders, endocrine disease and known neuropsychological impairment (e.g., closed head injury). The inclusion criteria were: age between 16 and 35 years, belong to one of the following four groups (see Introduction): 1) Familial risk plus reduced functioning (drop of 30% in GAF score in the last year), 2) attenuated psychotic symptoms, 3) BLIPS and 4) at least two basic symptoms. All UHR patients were assessed at intake with the Structured Interview for Prodromal Syndromes (SIPS; Miller et al., 2003), Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) and Scale for the Assessment of Basic Symptoms-Prediction List (BSABS-P, Klosterkötter et al., 2001). The SIPS is a comprehensive diagnostic tool

3 56 D. Nieman et al. / Schizophrenia Research 95 (2007) designed specifically for the assessment of the whole spectrum of prodromal signs and symptoms. The scale is composed of 19 items (5 positive, 6 negative, 4 disorganisation, 4 general symptoms) each of which is given a score of one to six according to defined criteria. A score between 3 and 5 on the positive symptoms indicates attenuated psychotic symptoms and a score of 6 indicates a psychotic state. The PANSS is composed of 30 items, each of which is given a score of one to seven according to defined criteria. The BSABS-P assesses 17 selected selfperceived disturbances in cognition and perception that were found to be predictive for a transition to psychosis. Each basic symptom is given a score of zero to six according to frequency of occurrence. Twenty-two patients used no medication, 8 patients used antipsychotic medication, 3 patients were using antidepressive medication (paroxetine). Two patients used both antipsychotic and antidepressive medication. No patients used benzodiazepines or lithium. Mean PANSS score was 48 ± 9. Mean Global Assessment of Functioning Scale (GAF) score was 49±12. Forty-two patients with schizophrenia performed the antisaccade task (six women), mean age was 21 years±3.1, range years (Nieman et al., 2000). All patients attended the adolescent psychiatric clinic of the Academic Medical Center for inpatient and outpatient treatments and they all satisfied the Diagnostic and Statistical Manual (DSM IV) of mental disorders (APA, 1994) criteria for the diagnosis of schizophrenia or schizoaffective disorder (n = 5). Three of the five patients with schizoaffective disorder were diagnosed with schizophrenia at 2 year follow up. Diagnosis was confirmed with the CIDI (WHO, 1993). Exclusion criteria were diagnosis of a primary alcohol- or drug-related psychosis, vision disorders, endocrine disease and known neuropsychological impairment due to factors other than schizophrenia (e.g., closed head injury and mental retardation) and IQ below 85 (as assessed with subtests of the Wechsler Adult Intelligence Scale). All 42 patients were assessed at intake and at the moment of eye movement recording with the PANSS. Schizophrenia patients were semi-randomized for medication; if patients were admitted with olanzapine or risperidone and responded well, then medication was continued. Otherwise, patients were randomly allocated to olanzapine or risperidone. Nineteen patients were treated with olanzapine (mean dosage 15.8 mg ± 4.9) and 19 patients with risperidone (mean dosage 3.9 mg ± 1.5). One patient had pimozide and one sertindole. Two patients were not compliant for their prescribed medication at the time of testing. Three patients with olanzapine and two with risperidone used an antidepressant (paroxetine) and one patient with olanzapine and two patients with risperidone used antiparkinsonian medication. No patients used benzodiazepines or lithium. Mean number of previous psychotic episodes was 0.2 ± Mean illness duration was 19.3 months±15.1. Mean PANSS score at the moment of intake was 82±21 and at the moment of eye movement recording 59 ± 18. The investigation was carried out in accordance with the latest version of the Declaration of Helsinki. The study design was approved by the Medical Ethical Committee of the Academic Medical Center. Informed consent of the participants was obtained after the nature of the procedures had been fully explained at a time when patients were no longer in a psychotic phase of the illness. Twenty-eight healthy controls (eleven women) with a mean age of 22.5 years±4.2 (range years) served as control group for antisaccade task performance. All control subjects were interviewed with the SIPS and BSABS. When their scores were in the UHR range, subjects were excluded from the study. Other exclusion criteria were vision disorders, endocrine disease, psychiatric illness present or in the past, familial history of psychiatric illness, known neuropsychological impairment (e.g., closed head injury) and IQ below 85 (as assessed Dutch National Adult Reading Test). They were matched as a group on age and estimated premorbid IQ. The control subjects received a fee for their participation of 40 euros. Demographics of the three groups are listed in Table 1. Premorbid IQ was estimated with the highest level of education ever reached. In the UHR and schizophrenia group, patients may drift downwards in their educational level. If a downward drift occurs, this premorbid IQ estimate is not influenced. The three groups did not significantly differ in: age and level of education. Gender was significantly different between the control group and the schizophrenia and UHR patients (Chi 2 =9.4, p = 0.009). There were no significant differences in antisaccade error rate between men and women in any of the Table 1 Demographics in the three groups. UHR patients n=35 Schizophrenia patients n=42 Control subjects n=28 Mean age (SD) 20.1 (3.7) 21 (3.1) 22.5 (4.2) Gender (%) 5 women (14) 6 women (14) 11 women (39) a Highest 1 3 (7) 8 (19) 4 (14) education 2 10 (30) 10 (24) 7 (25) level (%) 3 14 (40) 18 (43) 8 (29) 4 8 (23) 6 (14) 9 (32) Education level: 1. lower vocational training, 2. lower general secondary education/intermediate vocational training, 3. higher general secondary education/higher vocational training, 4. pre-university education/university. a Chi 2 =9.4, p=0.009.

4 D. Nieman et al. / Schizophrenia Research 95 (2007) Fig. 1. Number of UHR patients in the four inclusion groups. three groups. Therefore, sex ratio was not included in the antisaccade error rate analyses Neuropsychological test battery A neuropsychological test battery was administered to all subjects that included a test to assess verbal learning and memory: The Dutch translation of the California Verbal Learning Test (CVLT, Lezak, 1995). Psychomotor speed: Finger Tapping. Semantic memory: Verbal Fluency Test (VF, Lezak, 1995). Spatial working memory: Spatial WorkingMemoryTest(SWMT,Keefe et al., 1995). In most subjects, the neuropsychological test session was completed in 1.5 to 2 h. Subjects were tested within a week before or after the eye movement assessment Eye movement recording In the present study reflexive and antisaccades were recorded using the double magnetic induction (DMI) method (Bour et al., 1984) with a high spatial and temporal resolution. The DMI method has been described in detail elsewhere (Nieman et al., 2000). In the antisaccade task, subjects were told not to look at the appearing target but to look immediately in the opposite direction at an equal distance of the central fixation point. The target, a red spot of 0.5 diameter, and 20 cd/ m 2 luminance was first projected on the back of a screen at gaze straight-ahead position (central fixation point). Then, after a random period between 600 and 1200 ms the laser-spot was abruptly moved, to an eccentric position, located 5 randomly left or right of the fixation point. After 2 s the spot was projected to the correct antisaccadic eye location (feedback signal). After 300 ms the spot was again projected to gaze straightahead position. All subjects practiced the antisaccade task in four practice trials. If the subject made wrong antisaccades, corrective instructions were given. Only after subjects had made two correct antisaccades, the antisaccade task was started. Following the practice trials, 20 trials were presented to each subject. Antisaccade task variables were error rate, mean latency of the correct and wrong antisaccades and mean antisaccade gain. All variables were calculated with an interactive computer program written in Labview. Antisaccade error rate comprises the percentage of wrong antisaccades. Only first responses and responses with a latency longer than 100 ms were included. Saccade detection velocity was 50 /s. The gain is always positive for the wrong antisaccades, i.e., towards the visual target, and negative for the correct antisaccades, i.e., away from the target. Schizophrenia patients were tested when they had been on the same medication for six weeks, when they were no longer in an acute, positive phase of the disease. UHR patients were tested at intake. Fig. 2. Antisaccades in a control subject and UHR patient. The black, bold lines represent the laser-target (fixation, appearance, feedback) and the red, thin lines represent the eye movements. The UHR patient looks in each trial directly at the target, whereas the control subject inhibits this reflexive response.

5 58 D. Nieman et al. / Schizophrenia Research 95 (2007) Table 2 Mean (±SD) of the antisaccade and neuropsychological outcome variables in the UHR and schizophrenia patients and control subjects UHR patients n=35 Schizophrenia patients n=42 Control subjects n=28 Effect size UHR vs controls Effect size UHR vs schizophrenia Error rate (%) 29 (21) 52 (30) 19 (13) Latency correct antisaccades (ms) (72.5) (75.1) (60.8) Latency wrong antisaccades (ms) (63.3) (66.4) (42.6) Gain correct antisaccades.82 (.26).86 (.41) 1.03 (.41) Gain wrong antisaccades.72 (.16).73 (.14).69 (.14) SWMT mean distance series (8.7) (21.5) (8.28) VF Category animals (5.1) (4.4) (7.4)# CVLT (9.5) (7.4) (7.4) FT left 51.8 (5.3) 45.1 (7.7) 50.7 (7.1) FT right 58.5 (6.3) 49.4 (10.4) 57.7 (5.3) pb0.0001;+pb0.004; #pb SWMT = Spatial Working Memory Test, VF = Verbal Fluency, CVLT = California Verbal Learning Test, FT = Finger Tapping. The last three columns show the effect sizes (Cohen's d 0.2 small effect; 0.5 moderate effect; 0.8 large effect). Effect size schizophrenia vs controls 2.4. Statistical analysis Antisaccade and neuropsychological variables in the UHR and schizophrenia patient and control group were compared using analysis of variance (ANOVA) with post hoc two-tailed t-tests. For the antisaccade error rate, a t- test with pooled variance was used because the standard deviation was significantly unequal between the groups. Antisaccade error rate in the UHR group that made the transition to psychosis and the UHR group that did not make the transition to psychosis was compared with the Mann Whitney U test. Effect sizes were calculated, using Cohen's d. Correlations between the antisaccade task and the neuropsychological test battery were examined with Pearson correlation coefficients. Using a Bonferroni correction, only two-tailed p-values below 0.02 were considered significant for correlation coefficients. The data were analyzed with a statistical computer program (SPSS 11.0). 3. Results Fig. 1 depicts the number of UHR patients falling into the four inclusion groups. Most patients fell in more than one inclusion category. Examples of antisaccades in an UHR patient and a control are shown in Fig. 2. Three wrong antisaccades are depicted in the registration of the UHR patient and three correct antisaccades in the control subject. Mean and standard deviation of the antisaccade and neuropsychological outcome variables in the UHR and schizophrenia patients and control subjects are listed in Table 2. Four schizophrenia patients had none of the antisaccades correct (error rate 100%). Four controls had all of the antisaccades correct (error rate 0%). None of the UHR patients had either an error rate of 100 % nor 0%. Analysis of variance indicated differences in antisaccade error rate between the UHR, schizophrenia patient and control group (F = 18.7, pb ). Antisaccade error rate was significantly higher in the UHR patient group, than seen in the control group (t[61]= 2.30; pb0.03). Antisaccade error rate was significantly lower in the UHR group, than seen in the schizophrenia patient group (t[75] = 3.94; p b ). The schizophrenia patient group had a significantly higher antisaccade error rate than the control group (t[61]=6.45; pb0.0001). In the UHR group, high percentage of wrong antisaccades (high error rate) was related with poor working memory function (SWMT, r= 0.43; pb 0.02) and not with other neuropsychological tests. There was no significant relationship between antisaccade error rate and symptomatology as assessed with the SIPS, PANSS and BSABS-P. Ten UHR patients who were assessed with the antisaccade task at baseline made the transition to psychosis (29%). Mean time to transition was 10.8 months (SD 6.2). Mean error rate in the UHR group that made the transition to psychosis was 35 (SD 17). Mean error rate in the UHR group that has not made the transition to psychosis was 25 (SD 22). The difference was marginally significant (z = 1.8, p=0.09) but the effect size was moderate (.51). 4. Discussion We found antisaccade error rate in a group of UHR patients to be significantly higher than in controls but not as high as in a matched schizophrenia sample. Furthermore,

6 D. Nieman et al. / Schizophrenia Research 95 (2007) our results showed a trend towards higher antisaccade error rate at baseline in the UHR patients who later made the transition to psychosis compared to the UHR patients who did not make the transition to psychosis. The percentage of errors in the antisaccade task increased with decreased working memory function (SWMT) in the UHR group. Thus, the UHR patients hold an intermediate position between schizophrenia patients and controls. Our findings indicate that neurophysiological abnormalities found in schizophrenia are already present in the UHR phase. Results of the analysis comparing antisaccade error rate of the transition UHR group with the no transition UHR group are preliminary because the transition group was relatively small and the follow up period is not yet concluded. Findings of the ongoing follow-up period will be reported subsequently. The present study suggests that working memory is the cognitive function that possibly mediates the suppression of unwanted reflexive saccades in young patients with UHR symptoms. Other cognitive functions, e.g., semantic memory retrieval and motor speed were not related to reflexive saccade suppression. In a previous study, increased antisaccade error rate was related to decreased working memory function in a group of recent-onset schizophrenia patients (Nieman et al., 2000). Hutton et al. (2004) found in a large sample of schizophrenia patients that increased antisaccade error rate was related to decreased spatial working memory function. From several neuropsychological studies using functional magnetic resonance imaging, performed in healthy subjects, it has been postulated that cognitive tests of working memory are associated with the dorsolateral prefrontal cortex (Kammer et al., 1997; Callicott et al., 1999). In addition, a study of patients with cerebral lesions has indicated that only lesions restricted to the dorsolateral prefrontal cortex resulted in increased error rate whereas lesions to other prefrontal areas did not affect error rate (Pierrot- Deseilligny et al., 1991). These data and our findings may, therefore, indicate that high antisaccade error rate in UHR patients may, at least in part, be due to dorsolateral prefrontal cortex dysfunctioning. It is unlikely that one assessment could predict psychosis in a UHR group with a certainty of 100%. Several biological assessments combined with psychopathological assessments could lead to a profile that may predict psychosis with a higher percentage of accuracy than 40%. However, more research is needed in this direction. Most of the schizophrenia patients and some of the UHR patients used antipsychotic medication. Two studies reported increased error rate in small groups of relatively young schizophrenia patients without previous antipsychotic medication (Crawford et al., 1995; Hutton et al., 1998). Thus, medication is most likely not the mediating factor in increased antisaccade error rate in the UHR and schizophrenia group. In conclusion, abnormal antisaccade task performance relates to poor working memory function in UHR patients. The abnormalities in the antisaccade task may reflect an inability to suppress reflexive processes that may start in the stage before a psychotic episode or may be an underlying vulnerability trait for schizophrenia. More longitudinal research is needed to gain insight in the development of these deficits. The predictive power of antisaccade error rate for transition to psychosis will be discussed in a subsequent paper. Role of the funding source This study was funded by grant QLGU-CT from the European Commission in Brussels, Belgium. The European Commission had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors Author Hiske Becker included patients in the study and was involved in clinical assessments concerning transition to psychosis. Reinaud van de Fliert was involved in recruiting patients into the study and clinical assessments. Niels Plat assessed patients neurophysiologically and contributed to the statistical analysis of these data. Lo Bour wrote the eye movement recording protocol and supervised eye movement recording and analysis. Hans Koelman was involved in the design of the study. Maria Klaassen included patients in the study and did clinical assessments. Peter Dingemans was involved in management of the Ultra High Risk project. Maurice Niessen assessed and analysed neuropsychological and demographic data. 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