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Aim: Many psychophysiological tests have been widely researched in the search for a biological marker of schizophrenia. The exploratory eye movement (EEM) test involves the monitoring of eye movements while subjects freely view geometric figures. Suzuki et al. (2009) performed discriminant analysis between schizophrenia and non-schizophrenia subjects using EEM test data; consequently, clinically diagnosed schizophrenia patients were identified as having schizophrenia with high probability (73.3%). The aim of the present study was to investigate the characteristics of schizophrenia patients who were identified as having schizophrenia on EEM discriminant analysis (SPDSE) or schizophrenia patients who were identified as not having schizophrenia on EEM discriminant analysis (SPDNSE).
Methods: The data for the 251 schizophrenia subjects used in the previous discriminant-analytic study were analyzed, and the demographic or symptomatic characteristics of SPDSE and SPDNSE were investigated. As for the symptomatic features, a factor analysis of the Brief Psychiatric Rating Scale (BPRS) rating from the schizophrenia subjects was carried out.
Results: Five factors were found for schizophrenia symptoms: excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization. SPDSE had significantly higher factor scores for excitement/hostility, negative symptoms and disorganization than SPDNSE. Furthermore, the BPRS total score for the SPDSE was significantly higher than that for the SPDNSE.
Conclusion: SPDSE may be a disease subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization, and EEM parameters may detect this subtype. Therefore, the EEM test may be one of the contributors to the simplification of the heterogeneity of schizophrenia.
MANY PSYCHOPHYSIOLOGICAL TESTS have been performed in the search for a biological marker for schizophrenia.1,2 Event-related potentials (ERP), P300,3 P504 and mismatch negativity (MMN),5,6 prepulse inhibition (PPI),7,8 saccadic and smooth pursuit eye movements9–12 and working memory tasks13,14 have been widely researched. Moreover, many researchers have focused on abnormalities of working memory as an endophenotype for schizophrenia in molecular genetic studies.15,16
We have studied eye movements while subjects freely viewed geometric figures; this is called the exploratory eye movement (EEM) test. In most previous studies, only schizophrenia patients have consistently shown disturbances of EEM.17–25 Moreover, the parents and siblings of schizophrenia patients had EEM dysfunctions.26,27 In addition, EEM demonstrated a significant linkage to chromosome 22q11.28 Chromosome 22q11 is one of the most interesting regions in the genetic etiology of schizophrenia. Microdeletions at chromosome 22q11 cause velo-cardio-facial syndrome (VCFS/DiGeorage syndrome: DGS), and patients with VCFS have a high risk of schizophrenia.29,30 Furthermore, there is strong evidence that this deletion is a risk factor for schizophrenia in a genome-wide association study (GWAS) using copy number variants (CNV).31 Therefore, we believe that EEM disturbance may be a biological marker of schizophrenia, in addition to the aforementioned physiological defects.
On the basis of these findings, we considered that the EEM test might be useful for the clinical diagnosis of schizophrenia as well. Suzuki et al. carried out a discriminant analysis between schizophrenia patients and non-schizophrenia subjects in a large sample using EEM test data.32 EEM performance was recorded in 251 schizophrenia patients and 389 non-schizophrenia subjects (111 patients with mood disorder; 28 patients with neurotic disorder; 250 normal controls). As a result, 184 of the 251 clinically diagnosed schizophrenia patients were identified as having schizophrenia (sensitivity, 73.3%); and 308 of the 389 clinically diagnosed non-schizophrenia subjects were identified as non-schizophrenic (specificity, 79.2%). Based on this finding, we propose that the EEM test might be useful for the clinical diagnosis of schizophrenia.
In the discriminant-analytic study,32 we were interested in characteristics of the schizophrenia patients who were identified as having schizophrenia on EEM discriminant analysis (SPDSE), or those who were identified as not having schizophrenia on EEM discriminant analysis (SPDNSE). Many researchers have indicated the potential heterogeneity of schizophrenia.33–37 Hence, the EEM parameters may be able to detect different subtypes of schizophrenia. In the present study, to clarify the features of SPDSE and SPDNSE, we reanalyzed that data,32 and focused on the demographic or symptomatic characteristics. If the characteristics of SPDSE and SPDNSE are clarified, further knowledge regarding the heterogeneity of schizophrenia may be yielded. Therefore, in the present study we discuss the features of SPDSE and SPDNSE and a further application of EEM for scientific research into schizophrenia.
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Suzuki et al. performed discriminant analysis between schizophrenia patients and non-schizophrenia subjects using the EEM test data.32 As a result, 184 of the 251 clinically diagnosed schizophrenia patients were identified as having schizophrenia (sensitivity, 73.3%). In the present study, results of the factor analysis of BPRS ratings from the aforementioned 251 schizophrenia subjects produced five factors of symptoms (excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization). Excitement/hostility, negative symptoms and disorganization were more predominant in the 184 SPDSE subjects compared to the SPDNSE subjects. Furthermore, the BPRS total score of the SPDSE was significantly higher than that of the SPDNSE. Consequently, the SPDSE group may consist of patients with severe schizophrenia, and the severity of symptoms in SPDSE was found to be due mainly to excitement/hostility, negative symptoms and disorganization.
Evidence for five dimensions in schizophrenia symptoms was found in the present study. Many studies have proposed similar five-factor structures.41–47 In these studies, the Positive and Negative Syndrome Scale (PANSS) has been used as the symptom rating scale. In contrast, the present data were based on the BPRS. All items of the BPRS, however, are included in the PANSS.39,48 Therefore, it is possible that the present findings reflect the past studies of the factor analysis using PANSS items. Consequently, although items included for each factor in previous studies and the present study were not identical, the present findings of the factor analysis are distinctly similar to previous factor-analytic study results. Thus, we consider that the present five-factor structure may be meaningful for the symptomatology of schizophrenia. The PANSS, however, is more informative than the BPRS, therefore the present study may be limited by this issue.
In the present study, demographic data, age, sex, duration of illness and drug dosage for SPDSE and SPDNSE were not significantly different. But there were significant differences for symptom, excitement/hostility, negative symptoms and disorganization between SPDSE and SPDNSE. In our previous study, EEM parameters were not influenced by the demographic data.27,32 Moreover, one of the EEM parameter, RSS, which was principally used in the discriminant analysis of SPDSE, was associated with negative symptoms.17 Altogether, we believe that differences between SPDSE and SPDNSE in the EEM may relate to symptoms of schizophrenia, but not demographic data, sex, age, course of illness or medication.
With regard to the ICD-10 subtypes, we also did not find significant differences between SPDSE and SPDNSE. This finding seems to conflict with the significant differences of the BPRS scores between the two groups. Lykouras et al. investigated relationships between the DSM-III-R schizophrenia subtypes and the PANSS scores.49 As a result, paranoid type was associated with positive symptoms, and disorganized type linked to negative symptoms. In addition to disorganized type, however, catatonic type related to negative symptoms. Moreover, based on the DSM-IV-TR, the schizophrenia symptoms have been divided into three dimensions.50 However, past reports and the present study propose that schizophrenia may be symptomatically more complex.41–47 This has also been indicated by Wolthaus et al.47 In this way, subtypes and dimensions of the diagnostic criteria are often not consistent with those of the symptomatic rating scales. There is, however, a possible limitation to the present study. Although we discussed diagnoses using the ICD-10 criteria and the BPRS scores in detail, inter-rater and intra-rater reliabilities for those were not formally assigned. Consequently, if they were formally assigned, the ICD-10 subtypes might coincide with the BPRS scores.
Based on the present findings, SPDSE may be associated with excitement/hostility, negative symptoms and disorganization in the present five symptomatic dimensions. Accordingly, SPDSE may have three different dimensions; but it can also be said that SPDSE may be a schizophrenia subtype characterized by these three dimensions. The present findings may indicate that there is a putative subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization. Furthermore, the EEM abnormality may be a biological marker for this subtype of schizophrenia. There is another point worth making. As mentioned here, the EEM parameter, RSS was associated with negative symptoms.17 Thus, negative symptoms may be the most specific of the three dimensions to the subtype.
In addition to the schizophrenia patients, their parents and siblings also had EEM dysfunction.26,27 Therefore, we considered that the EEM abnormality may be an intermediate phenotype of schizophrenia, and may be useful for linkage studies of schizophrenia. Indeed, we found a significant linkage to chromosome 22q11.2–12.1 in our previous linkage study using EEM impairment as an endophenotype of schizophrenia.28 Chromosome 22q11 is one of the most interesting regions for the etiology of schizophrenia. Moreover, in this area, there are several candidate genes for schizophrenia, for example COMT, PRODH and ZDHHC8, and so on.29,30
Many researchers have presented positive linkage and association findings with schizophrenia, but initial findings have often not been replicated.30 One of the most significant causes of conflicting results in the present molecular genetic studies of schizophrenia may be the potential heterogeneity of schizophrenia. Several investigators have suggested that schizophrenia is not a single disease entity but may reflect common symptomatology caused by several distinct genetic abnormalities.33–37 As mentioned here, the EEM deficits are linked to chromosome 22q11. If the EEM parameters are associated with a schizophrenia subtype with severe symptoms related to excitement/hostility, negative symptoms and disorganization, chromosome 22q11 and genes of 22q11 may relate to this subtype. In this manner, if we are able to find a new subtype using the EEM disturbances, and clarify the heterogeneity of schizophrenia, then linkage or association studies for schizophrenia using the subtype may yield further knowledge regarding the genetic influences on schizophrenia.
In conclusion, we have found evidence for the existence of five dimensions of schizophrenia symptoms: excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization. Schizophrenia patients with EEM abnormalities (SPDSE) may have severe symptoms related to excitement/hostility, negative symptoms and disorganization. In light of the heterogeneity of schizophrenia, SPDSE may be a disease subtype of schizophrenia with the aforementioned symptomatic features; and the EEM parameters may detect this subtype. Therefore, EEM may be one of the contributors to the simplification of the heterogeneity of schizophrenia. Consequently, we may apply EEM to other scientific studies as an endophenotype for schizophrenia.