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article i nfo Background: Structural alterations of the lateral temporal cortex (LTC) in association with memory impairments have been reported in schizophrenia. This study investigated whether alterations of LTC structure were linked with impaired facial and/or verbal memory in young first-degree relatives of people with schizophrenia and, thus, may be indicators of vulnerability to the illness. Methods: Subjects included 27 non-psychotic, first-degree relatives of schizophrenia patients, and 48 healthy controls, between the ages of 13 and 28. Participants underwent high-resolution magnetic resonance imaging (MRI) at 1.5 Tesla. The LTC was parcellated into superior temporal gyrus, middle temporal gyrus, inferior tempo- ral gyrus, and temporal pole. Total cerebral and LTC volumes were measured using semi-automated morphom- etry. The Wechsler Memory Scale — Third Edition and the Children's Memory Scale — Third Edition assessed facial and verbal memory. General linear models tested for associations among LTC subregion volumes, familial risk and memory. Results: Compared with controls, relatives had significantly smaller bilateral middle temporal gyri. Moreover, right middle temporal gyral volume showed a significant positive association with delayed facial memory in rel- atives. Conclusion: These results support the hypothesis that smaller middle temporal gyri are related to the genetic li- ability to schizophrenia and may be linked with reduced facial memory in persons at genetic risk for the illness. The findings add to the growing evidence that children at risk for schizophrenia on the basis of positive family history have cortical and subcortical structural brain abnormalities well before psychotic illness occurs.

Background The Harvard Adolescent Family High Risk (FHR) Study examined multiple domains of function in young relatives of individuals diagnosed with schizophrenia to identify precursors of the illness. One such area is motor performance, which is deviant in people with schizophrenia and in children at risk for schizophrenia, usually offspring. The present study assessed accuracy of motor performance and degree of lateralization in FHR adolescents and young adults. Methods Subjects were 33 non-psychotic, first-degree relatives of individuals diagnosed with schizophrenia, and 30 non-psychotic comparison subjects (NpC), ranging in age from 13 to 25 who were compared using a line-drawing task. Results FHR individuals exhibited less precise and coordinated line drawing but greater degree of lateralization than controls. Performance on the linedrawing task was correlated with degree of genetic loading, a possible predictor of higher risk for schizophrenia in the pedigree. Conclusions The observation of increased motor deviance and increased lateralization in FHR can be utilized in identification and initiation of the treatment in those at high risk in order to prevent or delay the full manifestation of this devastating condition. The use of a rigorously quantified measure is likely to add to the sensitivity of measuring motor performance, especially when impairments may be subtle.

Recently, numerous genome-wide association studies (GWASs) have identified numerous risk loci for schizophrenia, but follow-up studies are still essential to confirm those results. Therefore, we followed up on top GWAS hits by genotyping implicated loci in additional schizophrenia family samples from our own collection. Five-hundred thirty-six Asian families (comprising 1633 members including 698 schizophrenics) were genotyped in this study. We analyzed 12 single nucleotide polymorphisms (SNPs) in strongly implicated candidate genes revealed by GWASs and their follow-up studies. We then used meta-analysis to combine our results with those of the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). In our newly genotyped samples, there were no significant associations of any of the 12 candidate SNPs with schizophrenia; however, all genome-wide significant results from the schizophrenia PGC analysis were maintained after combination with our new data by meta-analysis. One SNP (rs4765905 in CACNA1C) showed a stronger effect and decreased p-value (5.14e-17) after meta-analysis relative to the original PGC results, with no significant between-study heterogeneity. The findings of this study support the significant results in the PGC, especially for CACNA1C. The sample size in our study was considerably smaller than that in the PGC-SCZ study; thus, the weights carried by our samples in the meta-analysis were small. Therefore, our data could not vastly reduce PGC association signals. However, we considered that the well replicated results from the PGC hold up in our new samples, and may suggest that the top hits from the PGC are generalizable, even to other ancestral groups.

Background Clues to the etiology and pathophysiology of schizophrenia can be examined in their first-degree relatives because they are genetically related to an ill family member, and have few confounds like medications. Brain abnormalities observed in young relatives are neurobiological indicators of vulnerability to illness. We examined the hypothesis that the hippocampus and parahippocampus are structurally abnormal and are related to default mode network (DMN) function and cognitive abnormalities in relatives of probands. Methods Subjects were 27 non-psychotic, first-degree relatives of individuals diagnosed with schizophrenia, and 48 normal controls, ages 13 to 28, undergoing high-resolution magnetic resonance imaging (MRI) at 1.5 T. After structural scan acquisition a subset of subjects performed 2-back working memory (WM) and 0-back tasks during functional MRI (fMRI) alternating with rest. fMRI data were analyzed using SPM-8. Volumes of total cerebrum, hippocampus, and parahippocampal gyrus were measured using semi-automated morphometry. Results Compared to controls, relatives had significantly smaller left hippocampi, without volumetric reduction in the parahippocampus. Relatives showed significantly less suppression of DMN activity in the left parahippocampal gyrus. Left hippocampal and posterior parahippocampal volumes were inversely and significantly associated with DMN processing (smaller volumes, less suppression) in relatives. Task suppression in parahippocampal gyrus significantly correlated with WM performance within the relatives. Conclusion Results support the hypothesis that the vulnerability to schizophrenia includes smaller hippocampi and DMN suppression deficits, and these are associated with poorer WM. Findings suggest a primary structural, neurodevelopmental, medial temporal lobe abnormality associated with altered DMN function independent of psychosis.

Objectives The familial (“genetic”) high-risk (FHR) paradigm enables assessment of individuals at risk for schizophrenia based on a positive family history of schizophrenia in first-degree, biological relatives. This strategy presumes genetic transmission of abnormal traits given high heritability of the illness. It is plausible, however, that adverse environmental factors are also transmitted in these families. Few studies have evaluated both biological and environmental factors within a FHR study of adolescents. Methods We conceptualize four precursors to psychosis pathogenesis: two biological (genetic predisposition, prenatal health issues (PHIs)) and two environmental (family environment, stressful life events (SLEs)). Participants assessed between 1998 and 2007 (ages 13–25) included 40 (20F/20M) adolescents at FHR for schizophrenia (FHRs) and 55 (31F/24M) community controls. ‘Genetic load’ indexed number of affected family members relative to pedigree size. Results PHI was significantly greater among FHRs, and family cohesion and expressiveness were less (and family conflict was higher) among FHRs; however, groups did not significantly differ in SLE indices. Among FHRs, genetic liability was significantly associated with PHI and family expressiveness. Conclusions Prenatal and family environmental disruptions are elevated in families with a first-degree relative with schizophrenia. Findings support our proposed ‘polygenic neurodevelopmental diathesis–stress model’ whereby psychosis susceptibility (and resilience) involves the independent and synergistic confluence of (temporally-sensitive) biological and environmental factors across development. Recognition of biological and social environmental influences across critical developmental periods points to key issues relevant for enhanced identification of psychosis susceptibility, facilitation of more precise models of illness risk, and development of novel prevention strategies.

Background Schizophrenia and affective psychoses share several common biological origins, particularly genetic susceptibility. Kraepelin posited that differing clinical expressions in these disorders reflect different etiopathologies. We tested a neuropsychological component of this hypothesis by evaluating verbal memory and visual memory performance in nonpsychotic youth at familial risk for psychosis, taking into account contributions to memory dysfunction including executive processing and psychopathology. Methods Teenage and young adults (ages 13–25) at familial high-risk (FHR) for schizophrenia (HR-SCZ, n = 41) or affective psychosis (HR-AFF, n = 24) were compared to community controls (CC, n = 54) on verbal (Miller–Selfridge Context Memory) and visual (Rey–Osterrieth Complex Figure) memory tests in which the roles of strategy and contextual processing on distinct recall domains could be assessed. Effects of psychopathology, vigilance and working memory were investigated to determine their influence on memory performance. Results HR-AFF and HR-SCZ exhibited similarly impaired memory profiles and elevated levels of psychopathology compared to CC. HR-SCZ were significantly impaired on both verbal memory and visual–spatial memory, while HR-AFF in verbal memory only. However, effect sizes, in the medium range, were largely comparable between the two HR groups. Deficits in verbal recall and in visual memory organization remained significant after adjustment for confounders. Conclusions Youth at FHR for psychosis present relatively common memory deficits across both visual–spatial and verbal modalities that are not explained by current psychopathology, vigilance or working memory deficits. Deficits in organizing information to be recalled represent a promising trait of psychosis vulnerability.

The diverse spatial and temporal expression of alternatively spliced transcript isoforms shapes neurodevelopment and plays a major role in neuronal adaptability. Although alternative splicing is extremely common in the brain, its role in mental illnesses such as schizophrenia has received little attention. To examine this relationship, postmortem brain tissue was obtained from 20 individuals with schizophrenia (SZ) and 20 neuropsychiatrically normal comparison subjects. Gray matter samples were extracted from two brain regions implicated in the disorder: Brodmann Area 10 and caudate. Affymetrix Human Gene 1.0 ST arrays were used on four subjects per group to attain an initial profile of differential expression of transcribed elements within and across brain regions in SZ. Numerous genes of interest with altered mRNA transcripts were identified by microarray through the differential expression of particular exons and 3′ untranslated regions (UTRs) between diagnostic groups. Select microarray results—including dysregulation of ENAH exon 11a and CPNE3 3′UTR—were verified by qRTPCR and replicated in the remaining independent sample of 16 SZ patients and 16 normal comparison subjects. These results, if further replicated, clearly illustrate the importance of Identifying transcriptomic variants in expression studies, and implicate novel candidate genes in the disorder.

Genetic studies of schizophrenia focus increasingly on putative endophenotypes because their genetic etiology may be simpler than clinical diagnosis. The Consortium on the Genetics of Schizophrenia (COGS), a multisite family study, aims to identify the genetic basis of several endophenotypes including verbal declarative memory (VDM), a neurocognitive function that shows robust impairment in schizophrenia. We present data on one type of measure of VDM, the California Verbal Learning Test, Second Edition (CVLT-II), in schizophrenia probands (n=305), their full biological siblings (n=449) and parents (n=232), and in community comparison subjects (CCS; n=509) across seven sites. Probands performed more poorly on each of five CVLT-II measures compared to related sibling and parent groups and CCS. Siblings and parents performed significantly worse than CCS on one measure (Discriminability), but with smaller effect sizes and less impairment than observed previously. The results raise questions about the homogeneity of VDM as an endophenotype, about methodological issues related to sampling, and about psychometric issues that impact the utility of the CVLT for detecting VDM deficits in nonpsychotic relatives of persons with schizophrenia.

Background: Regional prefrontal cortex gray matter reductions have been identified in schizophrenia, likely reflecting a combination of genetic vulnerability and disease effects. Few morphometric studies to date have examined regional prefrontal abnormalities in non-psychotic biological relatives who have not passed through the age range of peak risk for onset of psychosis. We conducted a region-of-interest morphometric study of prefrontal subregions in adolescent and young adult relatives of schizophrenia patients. Methods: Twenty-seven familial high-risk (FHR) first-degree relatives of schizophrenia patients and forty-eight control subjects without a family history of psychosis (ages 13–28) underwent high-resolution magnetic resonance imaging at 1.5 Tesla. The prefrontal cortex was parcellated into polar, dorsolateral, ventrolateral, ventromedial and orbital subregions. The Chapman scales measured subpsychotic symptoms. General linear models examined associations of prefrontal subregion volumes with familial risk and subpsychotic symptoms. Results: FHR subjects had significantly reduced bilateral ventromedial prefrontal and frontal pole gray matter volumes compared with controls. Ventromedial volume was significantly negatively correlated with magical ideation and anhedonia scores in FHR subjects. Conclusions: Selective, regional prefrontal gray matter reductions may differentially mark genetic vulnerability and early symptom processes among non-psychotic young adults at familial risk for schizophrenia.

Several linkage studies have shown significant linkage of schizophrenia to chromosome 6p region, which includes the positional candidate genes, Dystrobrevin-binding protein 1 (DTNBP1). The aim was to examine the association evidence of the candidate gene in 693 Taiwanese families with at least two affected siblings of schizophrenia. We genotyped nine SNPs of this gene with average intermarker distance of 17 kb. Intermarker linkage disequilibrium was calculated with GOLD. Single locus and haplotype association analyses were performed with TRANSMIT program. We found no significant association between schizophrenia and DTNBP1 either through single locus or haplotype analyses. We failed to replicate the association evidence between DTNBP1 and schizophrenia and this gene may not play a major role in the etiology of schizophrenia in this Taiwanese family sample.

Objective The purpose of the present study was to evaluate both the independent and joint effects of genetic risk and clinical status on neurocognitive functioning in adolescents from a population isolate with an elevated risk for schizophrenia and strong familial aggregation of cases. Method The subjects were 310 non-help seeking, drug-naive adolescents 14–19 years of age from the Republic of Palau. The sample comprised 98 Genetically High Risk (GHR) adolescents, 54 of whom were symptomatic, and 212 Genetically Low Risk (GLR) adolescents, including 113 Clinically High Risk (CHR) subjects who were symptomatic and 99 normal controls who were non-symptomatic. Neurocognitive testing was conducted after the clinical assessment and included Wechsler Memory Scale tests of logical, visual and working memory, the perceptual organization and processing speed subtests of the WISC-III, CPT-IP measures of sustained attention, and tests of fine and gross neuromotor function. Results GHR adolescents showed impairments in immediate logical memory, verbal working memory, CPT-IP performance, and fine motor skills. The only two cognitive components influenced by the presence of early psychosis symptoms were WISC-III perceptual organization and spatial working memory. Neurocognitive deficits did not increase with increasing levels of psychopathology. We found no significant interactive effects of genetic risk and clinical status on neurocognitive functioning. Conclusions Genetic risk and clinical status exert independent effects on neurocognitive function in HR adolescents, and genetic risk has a broader impact than clinical status. Our results suggest that many of the neurocognitive impairments associated with early psychosis are genetically mediated and can occur in genetically vulnerable individuals regardless of their clinical status. However, visuospatial processing appears to be uniquely disrupted by emerging symptomatology.

The genes of D-amino acid oxidase (DAAO) activator (DAOA or G72; 13q34) and DAAO (12q24) have been suggested as candidate genes and involved in the N-methyl-D-aspartate receptor regulation pathway for schizophrenia. In order to evaluate the potential association of these two genes with schizophrenia in a Taiwanese sample, three single nucleotide polymorphisms (SNPs) for DAAO (rs2111902, rs3918346, rs3741775) and eleven SNPs for G72 (rs3916965, rs3916966, rs3916967, rs2391191, rs3916968, rs947267, rs778294, rs3916970, rs3916971, rs778293, rs3918342) were genotyped by the MALDI-TOF mass spectrometry method in 218 families (864 individuals) containing at least two siblings affected with schizophrenia. In SNP-based single locus association analyses, neither G72 nor DAAO showed significant association with schizophrenia. Additionally, a three-SNP haplotype in DAAO, and a four-SNP as well as a two-SNP haplotype in G72, showed no significant associations with schizophrenia. These results suggest that the DAAO and G72 genes are not susceptibility genes for schizophrenia in a Taiwanese sample.

The insula is anatomically situated to be critically involved in many bio-behavioral functions impaired in schizophrenia. Furthermore, its total volume has been shown to be reduced in schizophrenia. In the present study, we tested the hypothesis that in schizophrenia it is the anterior insular lobule (aINS(lbl)) rather than the posterior insular lobule (pINS(lbl)) that is smaller, given that limbic system abnormalities are central in schizophrenia and that the affiliations of the limbic system are principally with the anterior insular lobule. We used T1-weighted high resolution magnetic resonance imaging (MRI) to measure the cortical volume of the left and right anterior and posterior insular subdivisions. The subjects included a sample of healthy community controls (N=40) and chronic patients with DSM-III-R schizophrenia (N=41). We correlated insula volumes with positive and negative symptoms. We found that the total aINS(lbl), and the left aINS(lbl) in particular, were significantly volumetrically smaller in schizophrenia compared to controls, and significantly correlated with bizarre behavior. Given that the anterior insular lobule offers anatomic features that allow for MRI-based morphometric analysis, namely its central and circular sulci, this brain structure provides a useful model to test hypotheses regarding genotype-phenotype relationships in schizophrenia using the anterior insular lobule as a candidate endophenotype.

Based on a strategy developed by Seidman et al. (Seidman, L.J., Faraone, S.V., Kremen, W.S., Pepple, J.R., Lyons, M.J., Tsuang, M.T., 1993. Neuropsychological dysfunctions in the non-psychotic first-degree relatives of schizophrenic patients, Poster presented at the annual meeting of the Society for Research and Psychopathology. Chicago, IL) we examined neuropsychological heterogeneity in schizophrenia using clinical neuropsychological descriptions of individual cases as the starting point. We blindly rated neuropsychological profiles of 74 schizophrenia patients and 91 normal controls based primarily on prototypes from the clinical literature in neuropsychology. Patients were classified as having the following profile types: within normal limits (WNL) (23%, n=17), frontal/abstraction (46%, n=34), widespread/diffuse (14%, n=10), left temporal/verbal memory (8%, n=6) and other (9%, n=7). As expected based on our classification scheme, the groups had different profile shapes (group x function interactions). They were also significantly different from one another in terms of overall severity (main effects); however, severity differences were not inherent in the definition of all groups. Longer duration of illness and greater overall cognitive impairment were observed as one went from the left temporal to the frontal to the widespread groups. Longitudinal studies are needed to determine whether the different neuropsychological profiles reflect true subgroup differences or within-person change over time. Further research-probably including neuroimaging and genetic studies-will also be needed to determine the validity and the utility of this strategy for identifying neuropsychological profile types.

A meta-analysis of whole-genome linkage scans confirmed linkage between schizophrenia and markers on the long arm of chromosome 13. The gene HTR2A, which codes for the 5HT2a receptor, is located in this area. The T102C single nucleotide polymorphism of HTR2A has been the subject of much research. The production of the C-allele form of HTR2A is significantly less than that of the T-allele form in normal controls and schizophrenic patients. Although the association of schizophrenia with the C allele of HTR2A was confirmed by a meta-analysis 5 years ago, there was a continuous debate because negative findings were also considerable, which may have been due to ethnic differences in association. We performed another meta-analysis, since the number of available studies of this association has recently doubled. In the meta-analysis of 31 case-control association studies, we found a significant association between the C allele of the T102C polymorphism and schizophrenia, which was more pronounced in European samples than in the entire sample. We found significant heterogeneity in the allele-wise analysis (C vs. T) and homozygous genotype-wise analysis (CC vs. TT), both of which were at least partially explained by differences between samples from Asian and European countries. In East Asian countries, there was not a significant association with the C allele or CC homozygosity, indicating strong genetic differences and noncombinability of data between European and East Asian populations. Interestingly, the frequency of the T allele was much higher in East Asian patients and controls (59.5% and 57.5%, respectively) than in European patients and controls (40% and 43.5%, respectively). In five family-based association studies, we did not find significant evidence for association of the C allele with schizophrenia; yet, the pooled OR was 1.3 (95% CI=0.9-1.8, z=1.47, p=0.14), which is consistent with the results of the case-control studies. The effects of other genes, environmental effects on DNA methylation, or different methods of classification may be the causes for such heterogeneity, but more study in this area is needed.

Several studies suggest that the nonschizophrenic relatives of schizophrenic patients exhibit structural brain abnormalities that may be manifestations of genes that predispose to schizophrenia. In this work, we examine the utility of such measures for linkage analyses. Subjects were 45 nonpsychotic first-degree adult relatives of schizophrenic patients and 48 normal controls. Sixty contiguous 3-mm coronal, T1-weighted 3D magnetic resonance images of the entire brain were acquired on a 1.5-T magnet. We used factor analysis to derive MRI-based phenotypes for analysis. The factor analyses produced three factors that significantly discriminated relatives from controls. We used a linear combination of the three factor scores to derive an MRI phenotype. A receiver operating characteristic (ROC) analysis of this phenotype estimated an area under the curve (AUC) statistic of 0.85. The phenotype also discriminated nonpsychotic relatives having two schizophrenic relatives from those having only one. The nonpsychotic relatives of schizophrenic patients show deviant values on MRI measures of brain structure and the distribution of these deviations among relatives and controls suggests that if these results can be replicated, an MRI-derived phenotype could be useful for genetic linkage and association analyses.

Evidence for neuropsychological deficits in schizophrenia is substantial whereas evidence for the specificity of dysfunction is relatively sparse. To assess specificity, we compared neuropsychological function in patients with chronic schizophrenia, patients with chronic psychotic bipolar disorder and normal controls. Groups were comparable on age, ethnicity and expected intellectual ability (based on single word reading). Patients with schizophrenia and bipolar psychoses were also relatively similar on age at onset and number of hospitalizations. Using multivariate analyses of variance with sex and parental SES as covariates (our primary analyses), patients with schizophrenia were significantly more impaired than controls on seven of eight neuropsychological functions (all but verbal ability), and were significantly more impaired than bipolar patients on abstraction, perceptual-motor speed and vigilance. Bipolar patients were significantly impaired compared to controls on declarative verbal memory, and showed moderate-to-large effect size decrements on abstraction, perceptual-motor speed and vigilance. Results were not attenuated when IQ was controlled, which was significantly lower in patients with schizophrenia. Analyses indicated that the two psychiatric groups had similar profile patterns, but that patients with schizophrenia had a more severe impairment than patients with bipolar psychoses. Further research is required to determine whether similar mechanisms underly the neurocognitive deficits in these disorders.

We used the Schizotypal Personality Questionnaire to evaluate schizotypal traits in 44 normal volunteers and 40 non-psychotic, biological relatives of schizophrenic probands. Relatives endorsed more cognitive-perceptual traits than did controls; a group-by-sex interaction indicated that male relatives accounted for this difference. Although not statistically significant, a similar pattern was observed for interpersonal traits. Thus, elevated rates of some schizotypal traits appear to be more prominent in male than in female relatives of schizophrenic probands, at least when assessed by self-report. Subscale analysis indicated that differences were accounted for primarily by suspiciousness and ideas of reference, suggesting that paranoid-like phenomena from both the cognitive-perceptual and interpersonal factors may constitute an important dimension of schizotypy in relatives. Unlike previous studies, we did not find any differences in constricted affect or disorganization signs. Interviews and other non-self-report techniques are probably best suited for an assessment of these features, although the question remains as to whether the combination of both approaches might provide some incremental discriminatory power.

We investigated the association of neuropsychological risk indicators in a matched sample of first-degree relatives of schizophrenic patients ( n =54) and normal controls ( n =72). We focussed on three functions previously identified in a smaller, initial sample as putative risk indicators of the schizophrenia genotype: abstraction, verbal memory and auditory attention. The expanded sample of relatives displayed significantly lower scores than controls on abstraction, verbal memory and auditory attention. The relatives demonstrated significant intercorrelations among these three functions. The significant correlations among relatives between attention and verbal memory and between attention and abstraction differed significantly from these correlations among controls. We discuss how the use of multiple risk indicators may help us better identify those relatives that carry the schizophrenia genotype.

In our prior work with a young sample (age < 60), we showed that three neuropsychological functions were impaired among relatives of schizophrenic patients: abstraction, verbal memory, and auditory attention. In the present work we show that these results do not generalize to an older sample aged 60 years and greater. Thus, although we and others have put forth measures of neuropsychological function as indicators of the schizophrenia genotype, the present study suggests that conclusions may be limited to non-elderly samples. Further work is needed to address this issue definitively.

To confirm etiological heterogeneity, it is required that schizophrenic patients may be separated into at least two classes having different known etiologies and, perhaps, different pathophysiological signatures. In contrast, the homogeneity hypothesis asserts that there is a single necessary and sufficient cause or configuration of causes of schizophrenia. Because the link between phenotypic heterogeneity and etiological heterogeneity is tenuous, attempts to use purely phenotypic data to infer etiologic heterogeneity must be viewed cautiously. We examined three candidate causes for schizophrenia: genes, obstetric complications and viral infection. Cytogenetic studies show that some rare cases of schizophrenia are due to gross abnormalities of chromosomes. As for the large majority of schizophrenic patients, the candidate cause data most certainly reject the most parsimonious version of the hypothesis of etiological homogeneity: that all schizophrenia is caused by exactly the same pattern of genetic mutations, birth related complications and exposure to the same viral infections. We conclude that the heterogeneity debate should consider the possibility of rewording the question: 'Heterogeneity: yes or no?' to 'Heterogeneity: how much?'

We extended research originating with the Tsuang-Winokur criteria for paranoid and nonparanoid schizophrenia. To partially resolve problems of subtype instability, 41 consecutive admissions meeting DSM-III-R criteria for schizophrenia were subdivided according to whether they ever experienced prominent systematized delusions. Neuropsychological profiles for paranoid patients and nonparanoids with a history of systematized delusions were extremely similar. When combined, this 'systematized' group had significantly better general verbal ability and verbal memory than patients who never manifested systematized delusions. There was also a significant neuropsychological function-by-group interaction. The neuropsychological data suggested that systematized patients had better premorbid cognitive functioning as well as a greater discrepancy between premorbid verbal ability and current attentional functioning. No between-group differences were found on a measure of prefrontal-executive function, nor were there any neuropsychological differences between traditionally defined (DSM-III-R) paranoid and nonparanoid subgroups. This study suggests a possible shift in the dividing line between paranoid and nonparanoid subtypes and illustrates the potential value of neuropsychological data for refining psychiatric nosologies.

Recent studies of the effect of gender on the familial risk for schizophrenia have shown that relatives of females have a higher risk for schizophrenia than relatives of males. This study attempts to explain the effect by examining factors found to differentiate schizophrenic men and women and found to be related to the familial risk for schizophrenia. Cox proportional hazard regression model was used to examine the simultaneous effects of age at onset, season of birth, and premorbid history, controlled for symptoms that have been found to differ by gender (dysphoria, paranoia, and flat affect). Results showed that the effect of gender on the transmission of schizophrenia could not be explained by gender differences in age at onset, symptom expression, premorbid history, and winter birth. However, premorbid history had an effect on familial risk independent of gender, indicating that probands with a poor premorbid history had a lower familial risk for schizophrenia than those with a good premorbid history. Implications of the findings are discussed.

The SELENBP1 gene previously was found to be up-regulated in microarray analysis of both peripheral blood cell and brain tissue samples from schizophrenia patients. Quantitative PCR analysis subsequently corroborated the altered expression of SELENBP1 in schizophrenia brain tissue samples from the Stanley Array Correction. The aim of this study was to extend those findings by employing family-based association methods to a sample of over 2400 individuals (including 1214 individuals affected by schizophrenia) of Han Chinese descent living in Taiwan. One of four haplotype-tagging SNPs and two different two-marker haplotypes showed nominally significant evidence for association with schizophrenia under an additive model, suggesting that genetic variation in SELENBP1 may influence risk for the disorder, while this significance did not remain when other inheritance models were considered. Further comprehensive analysis with other SNPs and haplotypes is needed and warranted.

Schizophrenic patients and normal control subjects took the University of Pennsylvania Smell Identification Test (UPSIT) and Wisconsin Card Sorting Test (WCST) as dual neuropsychological 'probes' of orbitofrontal (OF) and dorsolateral (DL) prefrontal function respectively. Patients were significantly impaired on both tasks compared to controls. UPSIT and WCST performance were uncorrelated in patients but were positively correlated in controls. The lack of correlation found in the patients suggests that the tasks may be tapping independent dysfunctions in schizophrenia reflecting differential impairment in fronto-limbic brain systems. Individual profiles of preserved and impaired performance on the UPSIT and WCST suggested that three schizophrenic patients had OF dysfunction, five had DL dysfunction and seven had a generalized (OF and DL) frontal system dysfunction. The reduced ability of schizophrenic patients to identify odors was largely independent of many deficits or confounds typically associated with schizophrenia and did not appear to be simply a function of generalized deficit. These data are preliminary and require replication with larger samples and validation with other measures of fronto-limbic system dysfunction.

Two groups of schizophrenic patients took the Wisconsin Card Sorting Test (WCST) in separate follow-up studies; a naturalistic clinical follow-up (n = 12, study 1) and a neuroleptic reduction study (n = 10, study 2). 11 of 22 subjects (50%) performed well on the task at one or both time points. In each study no group differences were found between time 1 and time 2 performance on three WCST variables. However, correlational analyses revealed considerable within-subject variation on the WCST in the study 1 sample, which was composed of younger and more acute patients than those in study 2. This variation was present despite within-subject stability on the WAIS-R Vocabulary and Block Design subtests. For the sample combined, a trend was found (p = 0.12) linking better WCST performance at either time period with higher WAIS-R Vocabulary scores. This intra-subject variability may reflect fluctuations in neuropsychological performance in schizophrenics who maintain the residual capacity to do the task. These findings highlight the importance of longitudinal studies of neuropsychological functioning in schizophrenia. Studies of larger samples are needed to confirm these initial results.

Objective Adult first-degree relatives of persons with schizophrenia carry elevated genetic risk for the illness, demonstrate working memory (WM) impairments, and manifest alterations in dorsolateral prefrontal cortical (DLPFC) function during WM. Because substantially less is known about these phenotypes in adolescent subjects we sought to demonstrate that young relatives of persons with schizophrenia manifest impaired WM and altered prefrontal activation. Methods Participants were 21 non-psychotic, unmedicated first-degree relatives of persons with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, depressed type and 24 unmedicated controls, recruited from the community and hospitals in metropolitan Boston (ages 13–28). We compared groups on an auditory WM task with interference prior to scanning and used functional magnetic resonance imaging (fMRI) to compare groups while performing visual 2-back WM and control vigilance tasks. Blood oxygen level dependent signal change was measured using two whole-brain gradient echo EPI pulse acquisitions (21 contiguous, 5 mm axial slices), acquired on a Siemens 1.5 T MR scanner. Data were analyzed using Statistical Parametric Mapping-99. Results The high risk subjects were significantly impaired on the auditory WM task, had significantly greater Phobic Anxiety, and marginally greater Psychoticism than controls on the Symptom Checklist-90-Revised, and showed significantly greater task-elicited activation in the right DLPFC (BA 46). Psychopathology, IQ, and in-scanner WM performance did not account for group differences in brain activation. Conclusions Data support a physiological difference (an exaggerated fMRI response) in DLPFC in adolescents at genetic risk for schizophrenia, independent of psychosis. Future work can study the relationship of these measures to possible onset of schizophrenia.

Objective Several case-control studies examined an association between schizophrenia and the 40-bp variable number tandem repeat (VTNR) polymorphism in the 3′-UTR of the dopamine transporter gene (SLC6A3). The results of these studies have been equivocal due to small sample size and low power. This meta-analysis has the aim to evaluate the collective evidence for an association between the VTNR polymorphism and schizophrenia. Method Different meta-analyses were performed, sequentially considering the 9- and 10-repeat alleles and different genotypes (genotypes 9/9, 9/10, 10/10) as risk factors for schizophrenia. Analyses of the alleles included 659 cases and 563 controls from six case-control studies. Results The pooled OR from each analysis approximated 1.0, and none were significant. Lack of significance attributable to the negative effects of single large studies or to heterogeneity between the studies was excluded. Conclusion Despite over 90% power to detect a significant odds ratio as small as 1.3, no association was observed. Considering the cumulative evidence from six case-control studies and results from additional family-based studies, it seems unlikely that the 40-base-pair VTNR polymorphism of the SLC6A3 gene influences risk for schizophrenia.

NOTCH4 initially received consideration as a risk gene for schizophrenia based on its location within a region on chromosome 6p that had previously shown strong evidence for genetic linkage with the illness. The initial published test for allelic association found strong evidence for involvement of this gene in schizophrenia, but subsequent studies failed to confirm this finding. Presently, we have used meta-analysis to derive a best estimate of the nature and magnitude of the associations between schizophrenia and five polymorphisms in and around the NOTCH4 gene. No significant association was detected between schizophrenia and repeat length of alleles at the (TAA)n, (CTG)n, or (TTAT)n polymorphisms, or between the disease and specific risk alleles at these polymorphisms or at the SNP1 or SNP2 polymorphisms. Heterogeneity and stronger evidence of association with the putative risk alleles of the (TAA)n, (CTG)n, SNP1, and SNP2 polymorphisms was observed in family-based studies than in case-control studies, suggesting that these polymorphisms may reliably influence risk for schizophrenia under certain circumstances. Since more consistent and robust associations with schizophrenia risk have been observed for haplotypes of these polymorphisms [especially those containing SNP2 and (CTG)n], additional large family-based or genomic-controlled studies would be helpful for definitively specifying the role of NOTCH4 haplotypes in risk for schizophrenia.

The goal of this study was to assess whether degree of information processing load differentially affects vigilance performance in patients with schizophrenia as compared to normal controls or patients with other attentional disorders. We contrasted the performance of clinically stable outpatients with schizophrenia (n = 18), with that of normal controls (n = 17), and adults with developmental attentional/learning disorders (n = 13) on simple and demanding versions of a visual continuous performance test (CPT). Patients with schizophrenia were significantly impaired on both versions of the CPT compared to normal controls, and showed a significant decline in perceptual sensitivity and significantly more omission errors with increased processing demands. Compared to adults with developmental attentional/learning disorders, patients with schizophrenia manifested a tendency toward a decline in perceptual sensitivity. There were no significant differences between groups on a measure of response bias. The data support the hypothesis that patients with schizophrenia have insufficient information processing resources to cope with higher processing demands on effortful attention tasks. Further study comparing schizophrenic patients with patients who have other neuropsychiatric disorders, controlling for severity of illness, is required to determine the specificity of this deficit in schizophrenia.

Compromised neurocognition is a core feature of schizophrenia. Following Heinrichs and Zakzanis's (1998) seminal meta-analysis of middle-aged and predominantly chronic schizophrenia samples, the aim of this study is to provide a meta-analysis of neurocognitive findings from 47 studies of first-episode (FE) schizophrenia published through October 2007. The meta-analysis uses 43 separate samples of 2,204 FE patients with a mean age of 25.5 and 2,775 largely age- and gender-matched control participants. FE samples demonstrated medium-to-large impairments across 10 neurocognitive domains (mean effect sizes from -0.64 to -1.20). Findings indicate that impairments are reliably and broadly present by the FE, approach or match the degree of deficit shown in well-established illness, and are maximal in immediate verbal memory and processing speed. Larger IQ impairments in the FE compared to the premorbid period, but comparable to later phases of illness suggests deterioration between premorbid and FE phases followed by deficit stability at the group level. Considerable heterogeneity of effect sizes across studies, however, underscores variability in manifestations of the illness and a need for improved reporting of sample characteristics to support moderator variable analyses.