Revisiting the suitability of antisaccade performance as an endophenotype in schizophrenia
Highlights
► We examined antisaccade performance in SZ patients with and without cognitive deficits. ► We also examined deficits in the relatives of patients on this task. ► Error rate was the best predictor for classifying patients with cognitive deficits. ► Relatives of poor performers showed higher error rates than other relatives. ► Error rate is a useful cognitive endophenotype to identify subtypes of the disorder.
Introduction
One strategy applied to the understanding of complex psychiatric disorders is the identification of brain dysfunctions that may be related to genetic variation. Endophenotypes are quantitative, heritable, and trait-related features that refer to genetically influenced phenotypes which may be part of a complex illness (Braff et al., 2006, Gottesman and Gould, 2003, Risch, 1990). They co-segregate with a disease, and are associated with a significantly increased prevalence in unaffected relatives of patients, as compared with the general population.
A number of putative physiological endophenotype markers have been proposed for schizophrenia (Allen et al., 2009, Turetsky et al., 2007). Several studies have pointed to antisaccade eye movement abnormalities as a biologically plausible and statistically robust trait marker (Hutton and Ettinger, 2006, Kallimani et al., 2009, Turetsky et al., 2007), based on findings of performance impairments in both patients and their biological relatives (Clementz et al., 1994, Fukushima et al., 1988). Antisaccadic eye movements are also related to well-established neural control circuits, and the availability of experimental manipulations for saccadic tasks (for review, see Everling & Fischer, 1998) provides appropriate analytic tools for experimental studies. Such characteristics suggest that the study of antisaccadic eye movements in schizophrenia is potentially useful for exploring the pathophysiology and, tentatively, the genetic basis of this disorder.
Yet, there are several caveats to the proposal of poor antisaccade performance as a candidate endophenotype in schizophrenia. One is the inconsistent finding of deficits in first-degree relatives of individuals with schizophrenia, challenging one basic criterion of endophenotypes which posits that the deficits must be present in unaffected relatives of patients (co-familiarity criterion) (for reviews, see Calkins et al., 2008, Levy et al., 2008). Another, and potentially more serious one, is the substantial heterogeneity in individuals with the disorder. While an endophenotype should provide a method for identifying more homogenous subtypes of the disorder (Berrettini, 2005, Braff et al., 2006, Gottesman and Gould, 2003, Risch, 1990), few studies have unequivocally mapped poor antisaccade performance on etiologically distinct and homogeneous entities. The present study was designed to re-examine the performance of relatives of patients with schizophrenia, and to investigate whether antisaccade measures were correlated with a prior distinction between a schizophrenia subtype characterized by pervasive cognitive deficit (CD), and another subtype with minor or patchy deficits that was labeled as cognitively spared (CS) (Hallmayer et al., 2005).
In the standard antisaccade task, subjects visually fixate a central cue which is suddenly replaced by the onset of a peripheral target. Rather than reflexively shifting gaze to that stimulus, subjects are instructed to look at its opposite mirror location (Hallett, 1978). The task thus requires inhibiting the reflexive saccade and generating a voluntary antisaccade. Since Fukushima et al. (1988) reported an excessive antisaccade error rate in individuals with chronic schizophrenia, every study has replicated this finding regardless of variation in the paradigm (Calkins et al., 2004, De Wilde et al., 2008, Haraldsson et al., 2008, Harris et al., 2006, Hutton et al., 2002, Hutton et al., 1998, Nieman et al., 2000, Radant et al., 2007, Radant et al., 2010, Reuter et al., 2005). By contrast, studies examining reaction time of correct trials have reported mixed results, with either increases in latencies (Brownstein et al., 2003, Curtis et al., 2001, McDowell and Clementz, 1997), or no increases (Clementz et al., 1994, Crawford et al., 1995, Fukushima et al., 1988). McDowell and Clementz (1997) found longer latency of self-correction saccades in schizophrenia patients, although this measure has been overlooked by other studies.
Findings in unaffected first-degree relatives who share part of the genetic vulnerability for schizophrenia have been mixed. Typically, reaction times on correct response are unimpaired compared to healthy controls (Boudet et al., 2005, Crawford et al., 1995, Karoumi et al., 2001, MacCabe et al., 2005). Several studies have reported elevated error rates (Clementz et al., 1994, Curtis et al., 2001, Karoumi et al., 2001, Katsanis et al., 1997, McDowell and Clementz, 1997), although these results have not always been replicated (Brownstein et al., 2003, Thaker et al., 2000; Boudet et al., 2005, De Wilde et al., 2008, Ettinger et al., 2006, MacCabe et al., 2005, Radant et al., 2010). It has been suggested that mixed findings might be due to differences in inclusion and exclusion criteria of relatives and controls (Levy et al., 2004). Other explanations propose that inconsistent results in first-degree relatives may be due to individual differences in genetic liability, on the basis of findings showing that relatives of schizophrenia patients who performed poorly on the antisaccade task had worse performance on the antisaccade task than the relatives of patients who had normal performance on this task (Curtis et al., 2001). These findings highlight the need to consider genetic heterogeneity in relatives, and to identify more sensitive measures of antisaccade performance. Notably, almost all studies of relatives of schizophrenia patients have focused on error rate and latency of correct response, while the latency of self-correction saccade is one measure that has largely been overlooked in the search for potential endophenotypes. In the current study, we sought to maintain close correspondence in the inclusion/exclusion criteria for relatives and controls to avoid biases (Levy et al., 2004), to examine family correspondence in antisaccade performance, and to examine the latency of the self-correction saccade in addition to the usual antisaccade measures.
The second aim was to examine the heterogeneity in performance within the patient group. Since Bleuler (1911), schizophrenia has been considered a collection of syndromes rather than a single disease entity. So far, various methods have been applied to delineate schizophrenia subtypes (Jablensky, 2006). The Western Australian Family Study of Schizophrenia (WAFSS) was designed to explore heterogeneity and identify subtypes in schizophrenia by using composite multivariate neurocognitive endophenotypes (Hallmayer et al., 2005, Jablensky, 2006, Jablensky, 2009). The WAFSS integrated by latent structure analysis several neurocognitive endophenotypes indexing general cognitive ability, sustained attention, executive functioning, verbal memory, and speed of information processing. The majority (∼90%) of schizophrenia patients in the sample were classified into two distinct, only partially overlapping subtypes: a cognitive deficit subtype (CD) with generalized cognitive deficit and a cognitively spared subtype (CS) with mild or ‘patchy’ deficits. The whole-genome linkage screen of the cohort indicated a distinct genetic basis for the CD subtype, due to significant linkage to chromosome 6p25-22, from which the CS patients were definitively excluded (Hallmayer et al., 2005). The research question in the present study was whether antisaccade performance as a putative endophenotype marker could differentiate between these two subtypes of schizophrenia.
In summary, the aims of present study included: (i) a detailed comparison of saccadic performance in schizophrenia patients, unaffected first-degree relatives and healthy controls, and (ii) testing whether the two genetically underpinned subtypes of schizophrenia, namely CD and CS, differ on antisaccade performance.
Section snippets
Participants
This study comprised a total of 254 participants (156 males) from the Western Australian Family Study of Schizophrenia (WAFSS) (Hallmayer et al., 2005, Jablensky, 2009). All participants underwent a standardized diagnostic and clinical assessment protocol. A subsample of 93 patients (79 males) recruited from consecutive admissions to a major psychiatric hospital in Perth, Western Australia, provided the data for the current study. Patients were examined using a semi-structured clinical
Comparisons of schizophrenia patients, relatives and controls
Table 1 presents the demographic characteristics of the total study sample. First-degree relatives of schizophrenia patients were significantly older than patients and controls. There was also a significant between-group difference in education, with patients having significantly fewer years of education compared to both relatives and controls. Table 1 also shows a larger number of males in the patient group compared to the groups of relatives and controls who had a similar distribution of sex.
Discussion
The present study aimed to investigate the proposal of poor antisaccade performance as a candidate endophenotype in schizophrenia with the examination of: (i) the performance of first-degree relatives of schizophrenia and (ii) whether antisaccade measures can aid in the discrimination of more homogeneous and genetically underpinned subtypes of the disorder, namely CD and CS case clusters.
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2017, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Studies with significant results had small to large effect sizes. Twelve studies have compared error rates, with eleven studies finding patients made more antisaccade errors than first-degree relatives (Brownstein et al., 2003; Clementz et al., 1994; Crawford et al., 1998; Ettinger et al., 2004, 2006; Kang et al., 2011; Katsanis et al., 1997; Louchart-de la Chapelle et al., 2005; Mazhari et al., 2011; Radant et al., 2010; Reilly et al., 2013), and one study failing to find group differences (Karoumi et al., 2001). Error rates ranged between 23.5% and 58.3% for patients and 10.3% and 68.0% for relatives.