Antisaccade performance is related to genetic loading for schizophrenia

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JOURNAL OF PSYCHIATRIC RESEARCH

Journal of Psychiatric Research 43 (2009) 291–297

www.elsevier.com/locate/jpsychires

Antisaccade performance is related to genetic loading for schizophrenia Nadine Petrovsky a,*, Frank Weiss-Motz a, Svenja Schulze-Rauschenbach a, Matthias Lemke b, Peter Hornung b, Stephan Ruhrmann c, Joachim Klosterko¨tter c, Wolfgang Maier a, Ulrich Ettinger d, Michael Wagner a a

Department of Psychiatry and Psychotherapy, Rheinische Friedrich–Wilhelms-University of Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany b Rheinische Kliniken Bonn, Germany c Department of Psychiatry and Psychotherapy, University of Cologne, Germany d Centre for Neuroimaging Sciences, Institute of Psychiatry, King’s College London, UK Received 14 December 2007; received in revised form 17 April 2008; accepted 15 May 2008

Abstract Disturbances of the oculomotor system are promising endophenotypes for schizophrenia. Increased error rates in the antisaccade task and prolonged antisaccade latencies have been found in patients with schizophrenia and their first degree relatives. We investigated oculomotor performance in 41 parents of schizophrenia patients and 22 controls with a prosaccade task and an antisaccade task. Parents were grouped into parents with a positive family history for schizophrenia (N = 9) and parents with a negative family history for schizophrenia (N = 32). An overlap-paradigm was applied; eye movements were recorded using infrared oculography. The combined group of parents made more antisaccade direction errors than controls (p = 0.005) and there was a linear increase in direction errors from controls via negative family history parents to positive family history parents (p = 0.008). Antisaccade latencies were prolonged in the combined parent group (p = 0.057) compared to controls and there was a linear increase in latency with genetic loading (p = 0.018). No group differences were found for prosaccade parameters. These results support the hypothesis that antisaccade impairment is associated with genetic loading for schizophrenia. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Schizophrenia; Endophenotype; Antisaccade; Genetics

1. Introduction Schizophrenia has a strong genetic component, as shown by family, twin and adoption studies (Gottesman and Shields, 1967; Cardno and Gottesman, 2000; Sullivan et al., 2003; Harrison and Weinberger, 2005). Given the phenotypic complexity of schizophrenia, researchers have turned to study intermediate phenotypes, or endophenotypes. These are markers of risk for the illness thought to have a simpler genetic architecture than the disorder itself and may be useful in identifying risk genes or characteris-

*

Corresponding author. Tel.: +49 228 287 16946; fax: +49 228 287 16371. E-mail address: [email protected] (N. Petrovsky). 0022-3956/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2008.05.005

ing their cognitive or neurophysiological mechanisms (Weinberger, 2002). Antisaccade deficits constitute a widely studied schizophrenia endophenotype (Turetsky et al., 2007). The task demands the inhibition of a reflexive saccade; instead, the participant has to initiate a voluntary eye movement from a central stimulus to the mirror image location of a peripheral stimulus. Since the late 1980s, more than 50 studies have consistently reported that schizophrenia patients display a greater number of antisaccade errors than non-psychiatric controls (Turetsky et al., 2007). In addition, a number of studies have reported antisaccade deficits in biological first-degree relatives of schizophrenia patients (Clementz et al., 1994; Ross et al., 1998; McDowell et al., 1999; Curtis et al., 2001; Ettinger et al., 2004; Ettinger et al., 2006) and recent evidence suggests substantial heritability

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(Greenwood et al., 2007). Moreover, studies suggest that antisaccade deficits are stable over time in schizophrenia patients (Gooding et al., 2004) and their relatives (Calkins et al., 2003). Thus, deficiencies in the antisaccade task may be regarded as a viable schizophrenia endophenotype as they meet important criteria for an endophenotype including association with illness, heritability, and temporal stability (Gottesman and Gould, 2003; Braff et al., 2007). Within the domain of family studies it may be particularly advantageous to study parents of schizophrenia patients. First, the healthy parents of schizophrenia patients have passed the age of risk for developing schizophrenia. Therefore, possible deficits in parents cannot be attributed to a prodromal stage of schizophrenia. Second, given the genetic transmission of schizophrenia it can be assumed that at least one parent is a carrier of schizophrenia susceptibility genes. By assessing the family history of each parent of a schizophrenia patient, one can classify parents into parents with and without further familial loading for schizophrenia. A parent with a family history for schizophrenia is thought to be more likely to carry specific, transmittable genetic risk factors for schizophrenia. This positive family history parent is also called ‘‘obligate carrier” or ‘‘more likely carrier” (MLC) and is an unaffected parent with another psychotic relative in addition to the affected child. In contrast, a parent of a schizophrenia patient who does not have an additional affected relative is called a negative family history parent. Therefore, any phenotypic deficit hypothesized to be associated with specific genetic vulnerability for schizophrenia should occur more frequently in the positive family history parent. So far, only two studies have specifically addressed antisaccade performance in parents of schizophrenia patients; however, these remain inconsistent. The study by Ross et al. (1998) investigated oculomotor responses with an antisaccade gap paradigm (including a brief temporal gap between the central and peripheral stimuli) in 32 parents of schizophrenia patients who were divided into three groups: more likely carriers (MLC), less likely carriers (LLC) and indeterminate risk carriers. Ross and coworkers (1998) identified eight MLC and eight LLC who formed eight parent dyads (that is the LLC was the spouse of the MLC). The remaining eight parent pairs were classified as indeterminate risk carriers. This group consisted of seven parent dyads for which the ancestral family history could not be ascertained for either parent and one parent dyad for which both parents had a positive family history for schizophrenia. Ross et al. (1998) found that LLC were impaired on antisaccade spatial accuracy, whereas MLC made more antisaccade errors than LLC and controls. A more recent study by MacCabe and coworkers (2005) studied antisaccade performance in first degree relatives of schizophrenia patients with a step paradigm (no temporal gap between central and peripheral stimuli). The eighty relatives in this study were subdivided into relatives from singly affected families (n = 49) and multiply affected families (n = 31). In addition, in multiply affected families, 10 par-

ents of schizophrenia patients who had a parent or sibling affected and a unilineal transmission of liability within that family, were identified as so called presumed obligate carriers. MacCabe and coworkers (2005) did not find differences in latency or error rate between relatives from singly and multiply affected families. There was also no significant difference between obligate carriers and other relatives from multiply affected families (MacCabe et al., 2005). The present study aimed to clarify inconsistencies in the previous literature concerning antisaccades in parents of schizophrenia patients (Ross et al., 1998; MacCabe et al., 2005). Advancing on previous research we employed an antisaccade paradigm thought to be particularly sensitive to genetic loading for schizophrenia. McDowell and Clementz (1997) found that an overlap paradigm (brief temporal overlap of central and peripheral stimuli) better separates between first-degree relatives of schizophrenia patients and controls. Therefore, we employed an overlap antisaccade task known to maximise group differences between relatives and controls (McDowell and Clementz, 1997) and recruited parents of schizophrenia patients and age-matched controls using identical inclusion/exclusion criteria, in order to avoid bias due to asymmetrical inclusion criteria (Levy et al., 2004). We hypothesised that parents would show worse performance than healthy controls. Based on a genetic loading hypothesis for schizophrenia, we hypothesised that parents with a positive family history for schizophrenia would exhibit greater deficits than negative family history parents. 2. Methods and materials 2.1. Participants Forty-one biological parents (16 males, 25 females, mean age 57.8 ± 10.0 years) of schizophrenic patients with a DSM-IV diagnosis of schizophrenia were recruited at two psychiatric hospitals in Bonn (University Hospital Bonn and Rheinische Kliniken Bonn). All parents were interviewed employing the Structured Clinical Interview for DSM-IV, SCID-IV (First et al., 1995). Exclusion criteria were a diagnosis of a lifetime psychotic disorder, a history of neurological illness or another severe medical condition, head injury with loss of consciousness for more than 5 min, lifetime history of alcohol or substance abuse. In addition, parents were excluded if they were taking psychiatric medications or other medications which act on the CNS. Parents were interviewed by a trained clinical psychologist using an in-depth-interview, the SCID-IV and the Family Informant Schedule and Criteria (FISC), Mannuzza and Fyer, 1990), to obtain family histories and to construct genograms. If available, medical records were obtained additionally. All collected information about the parents’ families was evaluated by a senior psychiatrist and the interviewer to establish best-estimate diagnoses. Family histories were considered positive if a parent had

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a first or second degree relative (excluding direct descendants) with evidence of fulfilling DSM-IV criterion A for schizophrenia for more than one month and no other psychotic disorder. Nine of the parents were identified as ‘‘positive family history” parents (PFH) or ‘‘more likely carriers”. Of this positive family history parent group, seven PFH parents were based on first degree relatives, two PFH parents were based on second degree relatives. For 32 of the parents no family history of schizophrenia could be identified as the information provided during the interviews indicated no additional case of schizophrenia in their family. That is, these parents did not describe any symptoms for their relatives or the described symptoms did not meet DSM-IV Axis I criteria. These parents were classified as ‘‘negative family history” parents (NFH). Twenty-two control subjects (9 males, 13 females, mean age 56.9 ± 9.1 years) were recruited from the local community by contacting a random sample of the inhabitants of Bonn based on a list from the city registry. Controls were screened according to the same criteria as the parents, with the only additional requirement that they did not have a relative with a history of psychosis (up to the third degree of kinship). Controls were closely matched to parents in demographic variables (Table 1). Verbal IQ of all participants was estimated with a standardised German vocabulary test, the MWT-B (Mehrfachwahl–Wortschatz-Intelligenztest, Lehrl, 1989). Ethical approval of the local ethics committee and participants’ informed consent were obtained.

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for 200 ms after the appearance of the peripheral target (overlap condition). Altogether, there were 120 trials (60 prosaccade and 60 antisaccade trials). The first five trials of each block were practice trials and were not included in the analysis. The prosaccade instruction was to look toward the peripheral target as quickly and as accurately as possible. In the antisaccade task, subjects were instructed not to look toward the target but to look away from the peripheral target to the mirror position on the opposite side of the computer screen as quickly and as accurately as possible. 2.3. Eye movement recording and analysis Eye movement data were obtained using infrared oculography (IRIS 6500, Skalar Medical BV, Delft, The Netherlands) with a 500 Hz sampling rate. At the beginning of each prosaccade or antisaccade block, eye movements were calibrated for each eye. Eye movements were parsed quantitatively using a semiautomated custom analysis software package, and were visually inspected by a rater (F.W.M.) blind to group status. Blinks and other artefacts were identified by inspection of the trace and were removed from the analysis. Saccades were detected using minimum amplitude (1°), velocity (30°/s), and latency (100 ms) criteria and individually confirmed by the rater. Saccades were classified as prosaccades, antisaccades, prosaccade direction errors or antisaccade direction errors. A correct prosaccade was scored when the direction of gaze was shifted to the peripheral target; dependent measure was latency, that is the time (ms) between target presentation and saccade initiation. A prosaccade direction error was counted when the first saccade was made away from the target. Antisaccade latency was the time (ms) between peripheral target appearance and the initiation of the antisaccade in the opposite direction. An antisaccade direction error was counted when the first saccade was made towards the target. The rates of direction errors were calculated as the percentage of error trials over the total number of valid trials for prosaccade and antisaccade trials separately.

2.2. Saccadic tasks Participants were seated comfortably 41 cm from a 17in. monitor, head movements were minimized using a chinrest. The testing room was quiet and dimly lit. Experimental stimuli were presented using ERTSÒ (BeriSoft Corporation, Frankfurt, Germany). Participants performed two blocks of prosaccade trials and two blocks of antisaccade trials. The order was fixed, alternating proand antisaccade blocks, beginning with the prosaccade trials. For both tasks, subjects fixated a white central fixation cross on a black background. The fixation cross appeared for 1500, 2000, 2500 or 3000 ms at random. A peripheral target (a white cross) then appeared at 16° either to the left or to the right of the central fixation cross for a duration of 1000 ms. The central fixation cross remained on the screen

2.4. Statistical analyses Statistical analyses were conducted using SPSS 14.0 (SPSS Inc., Chicago, IL USA). The Kolmogorov–Smirnov-Test was used to check for normal distribution of the performance measures. All dependent variables except the antisaccade errors were normally distributed (all

Table 1 Demographic information

Controls Negative family history Positive family history

N

Age

Males/females (N)

Education in years

Verbal IQ

22 32 9

56.9 (9.1) 56.8 (10.2) 61.6 (8.9)

9:13 13:19 3:6

14.7 (3.3) 14.4 (3.3) 15.7 (3.4)

113.6 (9.4) 111.2 (11.5) 115.8 (16.3)

Legend: Data indicate means (standard deviation) unless indicated otherwise.

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p > 0.2). Antisaccade error distribution was positively skewed (p < 0.001; skewness = 2.03, standard error = 0.30). Therefore, we used the square root transformation which successfully normalized error rates (Kolmogorov–Smirnov-Test: p = 0.200). Table 2 displays the raw antisaccade error percentages, all calculations were performed with the transformed values. We first compared groups (PFH, NFH, controls) on age, years of education, and verbal IQ using univariate analysis of variance (ANOVA). We investigated the gender distribution across groups using v2 test. To investigate whether parents as a whole show worse performance than healthy controls we calculated Student’s t tests for independent samples. The two comparison groups were all parents (N = 41) versus controls (N = 22), the test variables were the saccadic variables (error rates and latencies). Further group differences in performance measures were analyzed using ANOVA with Group (PFH, NFH, controls) as between-subjects factor and saccadic variables as dependent variables; post hoc testing was carried out according to the LSD (least significant difference) method. Additionally, if antisaccade performance reflects an endophenotype sensitive to genetic loading we may expect a linear relationship between performance (direction errors, latency) and genetic load (PFH > NFH > controls). This hypothesis was tested using contrasts weighted to account for unequal sample sizes. Effect sizes were calculated with Cohen’s d and Glass’s delta, where d is defined as the difference between two means divided by the pooled standard deviation (Cohen, 1988) and delta (D) is defined as the difference between two means divided by the standard deviation of the control group (Glass, 1976). The effect size d assumes equal variances in the groups being compared (Cohen, 1988); if variances are not equal then the value of d is under- or overestimated. Glass’s D, which takes into account unequal variances, tends to be larger than d, especially when the groups being compared differ in variance (Levy et al., 2004). 3. Results 3.1. Demographic variables Groups (PFH, NFH, controls) did not differ on age (F[2, 60] = 0.93, p = 0.40), years of education (F = [2, 60]

= 1.27, p = 0.29), verbal IQ (F[2, 60] = 0.64, p = 0.53), or gender (Pearson v2 = 0.18, df = 2, p = 0.92) (Table 1). 3.2. Saccadic measures: effects of genetic loading The results of the saccadic measures are shown in Table 2. The Student’s t tests showed that parents as a group made significantly more antisaccade errors than controls T(61) = 2.90, p = 0.005. Mean antisaccade error rate for the parents group was 15.76% (SD = 15.34), for the controls mean error rate was 6.71% (SD = 6.57). There was also a strong trend that parents as a group showed longer antisaccade latencies T(61) = 1.94, p = 0.057. The mean antisaccade latency was 328.44 ms (SD = 57.27) for parents and 300.68 ms (SD = 47.57) for controls. Parents did not differ from controls regarding the prosaccade variables (prosaccade error rate and prosaccade latency) (both p > 0.15). The ANOVA with the between-subjects factor Group (PFH, NFH, controls) for investigation of further group effects showed that in the prosaccade task, there was no effect of group on either variable (both p > 0.28). In the antisaccade task, there was a significant effect of group on antisaccade direction errors (F[2, 60] = 4.28; p = 0.02). Post-hoc tests showed that NFH parents made significantly more errors than controls (p = 0.01) (effect sizes d = 0.74, D = 1.19). Likewise, PFH parents displayed higher error rates than controls (p = 0.03) (effect sizes d = 1.01, D = 2.05), but the two parent groups did not differ from each other (p = 0.61) (effect sizes d = 0.37, D = 0.25). Our initial hypothesis of a gradual increase in error rate from control to NFH and PFH was confirmed by a significant linear (p = 0.008) but not quadratic (p = 0.33) contrast (see Fig. 1). A strong trend towards a significant effect of group was found for antisaccade latency (F[2, 60] = 3.02; p = 0.056). Post-hoc tests revealed that PFH parents were significantly slower than controls (p = 0.02) (effect sizes d = 0.92, D = 1.08). NFH parents did not differ from either group (both p > 0.14). We found the same pattern for antisaccade latency as for the antisaccade error rate: the controls displayed the shortest latencies, followed by the NFH parents, followed by the PFH group which had the longest latencies. This pattern was supported by a significant linear

Table 2 Saccadic performance in parents of schizophrenia patients and in controls Controls

Prosaccade latency (ms) Antisaccade latency (ms) Prosaccade direction errors (%) Antisaccade direction errors (%)

258.66 300.68 0.10 6.71

(42.41) (47.57) (0.45) (6.57)

Negative family history

247.99 321.85 0.49 14.52

(43.51) (51.66) (1.13) (12.55)

Postive family history

274.40 351.88 0.48 20.20

(55.38) (72.54) (1.45) (23.18)

ANOVA F (degrees of freedom)

p

1.30 3.02 1.07 4.28

0.28 0.056a 0.35 0.02b

[2, 60] [2, 60] [2, 60] [2, 60]

Legend: Data indicate means (standard deviation) unless indicated otherwise. Post-hoc tests are considered significant at p 6 0.05. a Positive family history > controls (p = 0.02). b Negative family history > controls (p = 0.01); positive family history > controls (p = 0.03).

N. Petrovsky et al. / Journal of Psychiatric Research 43 (2009) 291–297 30.00

Antisaccade Errors (%)

25.00

20.00

15.00

10.00

5.00

0.00 Controls

Negative Family History

Positive Family History

Fig. 1. Antisaccade error rate in parents and controls (linear trend p = 0.008). Legend: Data indicate means ± SEM (standard error of the mean).

400

Antisaccade Latency (ms)

380 360 340 320 300 280 260 240 Controls

Negative Family History

Positive Family History

Fig. 2. Antisaccade latency in parents and controls (linear trend p = 0.018). Legend: Data indicate means ± SEM (standard error of the mean).

(p = 0.018) but not quadratic (p = 0.76) trend (see Fig. 2). 4. Discussion This study aimed to investigate whether antisaccade performance is impaired in parents of schizophrenia patients as a function of genetic load. We found that parents as a whole made significantly more antisaccade errors and showed non-significantly longer antisaccade latencies than controls. However, parents did not differ from controls concerning prosaccade measures. The present study extends the findings of previous studies which examined antisaccade performance in biological first-degree relatives and in particular, in parents of schizophrenia patients. PFH parents showed deficits in two aspects of the antisaccade task, i.e. the suppression of reflexive errors and the generation of volitional antisaccades. NFH parents also showed a significant impairment for antisaccade direction errors though to a lesser extent than PFH parents. Concerning antisaccade latency, the difference between PFH parents and controls was significant

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but NFH parents’ scores were in between and did not differ significantly from either group. For both variables there was a significant linear contrast, suggesting an effect of genetic load (control < NFH < PFH). Groups did not differ in prosaccade performance. This indicates that parents of schizophrenia patients neither demonstrated a general oculomotor deficit nor did they exhibit fundamental motivational problems. Instead, the results point to a specific impairment in the complex neural processes required to perform the antisaccade task. Our findings support the idea of a genetic loading for schizophrenia as the positive family history parents (PFH) (who are likely to carry transmittable genetic risk factors due to their familial position) differed from controls more strongly than did the parents with a negative family history for schizophrenia (NFH). Therefore, deficits in antisaccade performance appear to be associated with genetic vulnerability for schizophrenia. The present findings are also in line with the study by Ross and coworkers (1998) who found increased error rates in more likely carrier parents when compared to controls. Moreover, our NFH parent group differed from controls in antisaccade direction error rate. A study by MacCabe et al. (2005) did not find antisaccade latency or direction error rate impairments in parents of schizophrenia patients. The reason for this inconsistency is unclear but could be related to differences in methodology, for example the use of an overlap task in our study and a step task in MacCabe et al. (2005). McDowell and Clementz (1997) showed that overlap antisaccade tasks may best differentiate relatives from controls. In terms of antisaccade latencies, the present study showed that PFH parents exhibited impaired performance when compared to controls whereas the NFH parents did not differ from either group. Neither Ross and coworkers (1998) nor MacCabe et al. (2005) found latency deficits in the relatives. However, McDowell and colleagues (1999) found prolonged antisaccade latencies in relatives of schizophrenia patients. Furthermore, Ettinger and coworkers (2006) assessed performance on an antisaccade task in monozygotic twin pairs discordant for schizophrenia and in matched monozygotic healthy control twins. Results showed that non-schizophrenic co-twins displayed increased antisaccade latencies when compared to controls. Given that antisaccade deficits likely constitute an endophenotype for schizophrenia it is also important to investigate the underlying brain structures which are involved in the generation and suppression of saccadic eye movements. Neurophysiological findings in monkeys as well as brain imaging studies in humans showed that amongst other brain structures, the dorsolateral prefrontal cortex (DLPFC), the posterior parietal cortex, the supplementary eye fields (SEF), the frontal eye fields (FEF), and the superior colliculus (SC) play a decisive role in saccadic behaviour (Munoz and Everling, 2004). Knowledge of the neural correlates underlying the behavioural deficit might advance the search for (and characterisation of)

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illness-relevant genes. Recently, Raemaekers and colleagues (2006) found that unaffected siblings of schizophrenia patients showed reduced activation in the caudate nucleus during antisaccades, indicating a striatal deficit as a potential genetic risk factor for schizophrenia. Further work should address which structures and neurotransmitter systems are responsible for the varying deficits in firstdegree relatives of schizophrenia patients. A limitation of this study refers to the sample size. The studied groups were relatively small given the known difficulties in recruiting large numbers of parents of schizophrenia patients who meet none of the exclusion criteria, such as psychiatric symptoms. Furthermore, we specifically looked for the more likely carrier parents who represent a rare group of parents. Another limitation concerns the fact that we did not test patients with schizophrenia with our antisaccade paradigm. However, antisaccade deficits in patients with schizophrenia are well established (Hutton and Ettinger, 2006); in fact, since Fukushima et al. (1988) first report of increased direction errors on the antisaccade task there has to our knowledge not been a failure to replicate this finding. Finally, spatial accuracy data from this study could not be used due to calibration problems. Other studies on antisaccades in first-degree relatives of schizophrenia patients have reported on antisaccade spatial accuracy (e.g. Clementz et al., 1994; Karoumi et al., 2001; Ettinger et al., 2006; Ross et al., 1998). Antisaccade spatial accuracy might be another important potential endophenotype of schizophrenia as illustrated by the interesting findings by Ross et al. (1998) and Ettinger et al. (2006). Ettinger and colleagues (2006) showed that the non-schizophrenic co-twins of monozygotic twin pairs discordant for schizophrenia made less accurate antisaccades than comparison twins. Ross and coworkers (1998) demonstrated that negative family history parents had deficits in spatial accuracy of antisaccades whereas positive family history parents did not show this deficit. Possibly, problems with the accuracy of antisaccadic eye movements reflect problems with or sensorimotor transformations which might be an independent vulnerability factor for schizophrenia. Thus, in combination with other risk factors, these deficits may contribute to the genetic risk for developing psychotic disorders. To conclude, antisaccade performance was shown in this study to be impaired as a function of genetic loading for schizophrenia. This finding strongly supports the use of antisaccade deficits as an endophenotype for schizophrenia. Given the positive findings from this as well as previous (Clementz et al., 1994; Curtis et al., 2001; Ettinger et al., 2006; Ross et al., 1998) studies, future research should investigate the specific molecular genetic factors underlying the antisaccade deficit in schizophrenia. Conflict of interest All authors declare that they have no conflicts of interest.

Contributors J.K., W.M., and M.W. designed the study and wrote the protocol. S.S.-R. recruited subjects and performed the clinical interviews. S.R. evaluated the clinical interviews and co-wrote the manuscript. M.L. and P.H. contributed in designing the study and supervised subject recruitment. F.W.-M. carried out testing of the subjects and performed preprocessing of the data. N.P. analysed the data and wrote the manuscript. U.E. supervised the data analysis and co-wrote the manuscript. All authors contributed to and have approved the final manuscript. Role of funding source This study was supported by the German Research Foundation (DFG Wa 731/6), the German Ministry of Education and Research BMBF (German Research Network on Schizophrenia) and the German Academic Exchange Service DAAD. The DFG, BMBF and the DAAD had no further role in 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. Acknowledgements The authors thank the participants in this study for their contribution. Furthermore, the authors thank Corinna Weiler and Gabriele Herrmann for their help with recruitment and technical assistance. Ulrich Ettinger is funded by a NIHR (National Institute for Health Research) Personal Award. The views expressed in this publication are those of the authors and not necessarily those of the NHS, NIHR or Department of Health. References Braff DL, Freedman R, Schork NJ, Gottesman II. Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophrenia Bulletin 2007;33: 21–32. Calkins ME, Iacono WG, Curtis CE. Smooth pursuit and antisaccade performance evidence trait stability in schizophrenia patients and their relatives. International Journal of Psychophysiology 2003;49: 139–46. Cardno AG, Gottesman II. Twin studies of schizophrenia: from bow-andarrow concordances to star wars Mx and functional genomics. American Journal of Medical Genetics 2000;97:12–7. Clementz BA, McDowell JE, Zisook S. Saccadic system functioning among schizophrenia patients and their first-degree biological relatives. Journal of Abnormal Psychology 1994;103:277–87. Cohen J. Statistical power analysis for the behavioral sciences, vol. 2. Hillsdale: Lawrence Erlbaum Associates; 1988.

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