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Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

Treatment-resistant symptoms occur in about a third of patients with schizophrenia and are associated with a substantial reduction in their quality of life. The development of new treatment options for clozapine-resistant schizophrenia constitutes a crucial, unmet need in psychiatry. Additionally, an overview of past and possible future research avenues to optimise the early detection, diagnosis, and management of clozapine-resistant schizophrenia is unavailable. In this Health Policy, we discuss the ongoing challenges associated with clozapine-resistant schizophrenia faced by patients and health-care providers worldwide to improve the understanding of this condition. We then revisit several clozapine guidelines, the diagnostic tests and treatment options for clozapine-resistant schizophrenia, and currently applied research approaches in clozapine-resistant schizophrenia. We also suggest methodologies and targets for future research, divided into innovative nosology-oriented field trials (eg, examining dimensional symptom staging), translational approaches (eg, genetics), epidemiological research (eg, real-world studies), and interventional studies (eg, non-traditional trial designs incorporating lived experiences and caregivers' perspectives). Finally, we note that low-income and middle-income countries are under-represented in studies on clozapine-resistant schizophrenia and propose an agenda to guide multinational research on the cause and treatment of clozapine-resistant schizophrenia. We hope that this research agenda will empower better global representation of patients living with clozapine-resistant schizophrenia and ultimately improve their functional outcomes and quality of life.

Objective: This study examined the prevalence of psychiatric symptoms among residents/workers in Manhattan 3-6 months after the Sept. 11, 2001, terrorist attacks. Method: A total of 1,009 adults (516 men and 493 women) were interviewed in person throughout Manhattan. All answered questions about themselves before and after September 11 that included their emotional status. Results: A total of 56.3% had at least one severe or two or more mild to moderate symptoms. Women reported significantly more symptoms than men. Loss of employment, residence, or family/friends correlated with greater and more severe symptoms. The most distressing experiences appeared to be painful memories and reminders; dissociation was rare. Only 26.7% of individuals with severe symptoms were obtaining treatment. Conclusions: Over half of the individuals had some emotional sequelae 3-6 months after September 11, but the percent was decreasing. Only a small portion of those with severe responses was seeking treatment.

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2Aand transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

Objective: Some genome-wide scans and association studies for schizophrenia susceptibility genes have yielded significant positive findings, but there is disagreement between studies on their locations, and no mutation has yet been found in any gene. Since schizophrenia is a complex disorder, a study with sufficient power to detect a locus with a small or moderate gene effect is necessary. Method: In a genome-wide scan of 382 sibling pairs with a diagnosis of schizophrenia or schizoaffective disorder, 396 highly polymorphic markers spaced approximately 10 centimorgans apart throughout the genome were genotyped in all individuals. Multipoint nonparametric linkage analysis was performed to evaluate regions of the genome demonstrating increased allele sharing, as measured by a lod score. Results: Two regions with multipoint maximum lod scores suggesting linkage were found. The highest lod scores occurred on chromosome 10p15-p13 (peak lod score of 3.60 at marker D10S189) and the centromeric region of chromosome 2 (peak lod score of 2.99 at marker D2S139). In addition, a maximum lod score of 2.00 was observed with marker D22S283 on chromosome 22q12, which showed evidence of an imprinting effect, whereby an excess sharing of maternal, but not paternal, alleles was present. No evidence of linkage was obtained at several locations identified in previous studies, including chromosomes 1q, 4p, 5p-q, 6p, 8p, 13q, 15p, and 18p. Conclusions: The findings of this large genome-wide scan emphasize the weakness and fragility of linkage reports on schizophrenia. No linkage appears to be consistently replicable across large studies. Thus, it has to be questioned whether the genetic contribution to this disorder is detectable by these strategies and the possibility raised that it may be epigenetic, i.e., related to gene expression rather than sequence variation. Nevertheless, the positive findings on chromosome 2, 10, and 22 should be pursued further.

Objective: The primary purpose of this article was to determine if cognitive abilities decline, remain unchanged, or modestly improve throughout the course of schizophrenic illness. Method: Forty-two patients with a first hospitalization for schizophrenia or schizophreniform disorder and 16 normal comparison subjects had a battery of neuropsychological tests and a magnetic resonance imaging (MRI) brain scan at approximate yearly intervals for the first 2 to 5 years of illness. Summary rating scales for language, executive, memory, processing speed, and sensory-perceptual functions were constructed. Results: Patients with schizophrenia scored 1 to 2 standard deviations below normal comparison subjects on neuropsychological test measures during the course of the study. Patients exhibited less improvement than comparison subjects on measures of verbal memory. In general, improvement in positive symptoms over the time interval was associated with improvement in cognition. No changes in regional brain measurements were correlated with cognitive change in the patient group. Conclusions: Patients with schizophrenia have considerable cognitive dysfunction in the first 4 to 5 years of illness, which is stable at a level of 1 to 2 standard deviations below that of comparison subjects. There is little evidence for deterioration of cognitive abilities over the first few years of illness, with the exception of verbal memory, which shows significantly less improvement in patients over time relative to that of comparison subjects.

Objective: A cortical gray matter deficit has been found in cross-sectional studies of patients with chronic schizophrenia. The purpose of this study was to examine whether this deficit is present early in the course of illness. Method: The authors measured cortical gray matter volume on magnetic resonance images acquired within 6 months of onset of illness from 22 patients with first-episode schizophrenia and 51 age-matched comparison subjects from the Stony Brook First Episode Study. Results: A significant cortical gray matter deficit and lateral ventricular enlargement were found in schizophrenic patients relative to the comparison group. Conclusions: The presence of the cortical gray matter deficit close to onset of illness supports the role of preexisting structural brain deficits in the genesis of schizophrenia.

This study compared 32 consecutively admitted first-episode schizophreniform patients, 26 patients with chronic schizophrenia according to the DSM-III-R criteria, and 25 normal comparison subjects on a comprehensive battery of neuropsychological tests to determine the degree of cognitive impairment existing at the onset of schizophrenic illness. Patients were tested within 2 weeks of admission to the hospital, after their medication had been stabilized. Results: With age and education controlled, the first-episode and chronic patients performed significantly worse than the normal subjects on neuropsychological summary measures of executive function, verbal memory, spatial memory, concentration/speed, and global cognitive function and on left and right hemisphere function scales. The first-episode patients were as cognitively impaired as the chronic patients on all summary scales and many of the individual tests. Both groups showed relatively greater left than right hemisphere dysfunction. Conclusions: These findings suggest that substantial cognitive deficits, comparable to those of chronic patients, are present early in the course of psychotic illness. (Am J Psychiatry 1992; 149:898-903)

Objective: The purpose of this study was to determine whether men and women with schizophrenia demonstrate differences in cognitive abilities. Method: Two cohorts of patients with schizophrenia, an acute first-episode and a chronically hospitalized group, were evaluated with a neuropsychological battery and compared with a normal group of subjects. Results: After adjustment for age, age at onset, and premorbid IQ, male chronic patients performed worse than female chronic patients on measures of visual memory. These differences were eliminated after control for symptom severity. No other differences were found in cognitive function between men and women in either cohort. Conclusions: Sex differences in cognitive function in schizophrenic patients are not robust findings.

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2= 0.032; liability R2= 0.017; P< 10−52), Latino (Nagelkerke’s R2= 0.089; liability R2= 0.021; P< 10−58), and European individuals (Nagelkerke’s R2= 0.089; liability R2= 0.037; P< 10−113), further highlighting the advantages of incorporating data from diverse human populations.

Objective: The purpose of the study was to determine whether the duration of illness before antipsychotic drug treatment for schizophrenia was associated with the severity of cognitive deficits and volumetric brain structure anomalies observed in some patients with a first episode of schizophrenia. Method: Duration of psychotic symptoms and of other symptoms marking a behavioral change was estimated from structured interviews with 50 patients who had a first episode of schizophrenia and their family members. Interviews were conducted within a month of the patients' hospitalization. Duration of untreated psychotic symptoms and of behavioral change was correlated with neuropsychological summary scores from a comprehensive cognitive battery and with measurements of lateral ventricular, temporal lobe, and cerebral hemispheric volumes. Results: No significant correlations were observed between measures of untreated illness and the severity of either cognitive or structural brain deficits at baseline. Conclusions: The duration of untreated symptoms of schizophrenia, for which an association with an uncontrolled toxic brain process has been proposed, is unlikely to explain why first-episode patients with schizophrenia have widespread deficits in cognitive functioning and have detectable ventricular enlargement and some loss of cortical mass.

The X chromosome has long been an intriguing site for harboring genes that have importance in brain development and function. It has received the most attention for having specific genes underlying the X-linked inherited intellectual disabilities, but has also been associated with schizophrenia in a number of early studies. An X chromosome hypothesis for a genetic predisposition for schizophrenia initially came from the X chromosome anomaly population data showing an excess of schizophrenia in Klinefelter’s (XXY) males and triple X (XXX) females. Crow and colleagues later expanded the X chromosome hypothesis to include the possibility of a locus on the Y chromosome and, specifically, genes on X that escaped inactivation and are X-Y homologous loci. Some new information about possible risk loci on these chromosomes has come from the current large genetic consortia genome-wide association studies, suggesting that perhaps this hypothesis needs to be revisited for some schizophrenias. The following commentary reviews the early and more recent literature supporting or refuting this dormant hypothesis and emphasizes the possible candidate genes still of interest that could be explored in further studies.

The genetic mechanism for schizophrenia still remains unknown despite decades of research. A tremendous amount of investigator time and effort has gone into ascertainment of clinical samples for genetic studies over the years. Most recently, a large international effort of unprecedented collaboration has occurred to combine data worldwide in pursuit of uncovering the relevant genetic risk factors. However, in the process, the use of multiplex families to understand the genetics has waned, and it has been presumed that large resources of unrelated patients and controls are more efficient to find risk alleles than families. This commentary is a call to return to the use of this largely abandoned resource for further understanding the underlying biological mechanism of this serious mental illness.

Co-occurrence of psychotic symptoms with symptoms typically thought of as posttraumatic stress disorder (PTSD) is well known, and there has been considerable debate whether this represents a psychotic subtype or a comorbid psychotic disorder.

Technology in genetics and brain imaging has advanced so rapidly that it is difficult to be knowledgeable about all the new tools being used in the pursuit of progress toward understanding and treating mental illness. While findings from new studies remain promising, caution is needed with regard to their current applicability to clinical use, both to predict who is likely to become ill and who is likely to respond to medication. A perspective on the past, using schizophrenia as an example, illustrates important findings that were published, had much visibility, and caused a flurry of new related studies, but then slowly disappeared, either to be abandoned as an artifact of the assay or study design, an epiphenomenon, or as simply nonreplicated findings not leading to further progress. Remembering that good science is “the pursuit of the truth” and not joining the latest “bandwagon fad” of “believers” is an important principle to adhere to when participating in the politics of science.

The XXI World Congress of Psychiatric Genetics (WCPG), sponsored by the International Society of Psychiatric Genetics (ISPG), took place in Boston, Massachusetts, on 17–21 October 2013. Approximately 900 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported.

This review outlines the positive and negative aspects of DNA testing and provides an account of the issues particularly relevant to schizophrenia.

The XXth World Congress of Psychiatric Genetics(WCPG), sponsored by The International Society of Psychiatric Genetics(ISPG) took place in Hamburg, Germany on October 14–18, 2012. Approximately 600 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned sessions as rapporteurs. This manuscript represents topics covered in most, but not all, oral presentations during the conference, and some of the major notable new findings reported at this 2012 WCPG. © 2013 Wiley Periodicals, Inc.

The purpose of this article is to review major findings in event related potential (ERP) research in schizophrenia patients, specifically focusing on the N400 component.

The XVIIIth World Congress of Psychiatric Genetics, sponsored by The International Society of Psychiatric Genetics took place in Athens, Greece on October 3–7, 2010. Approximately 950 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by junior travel awardees, as well as others who were volunteers from student meeting attendees. Each was assigned sessions as rapporteurs. This report represents some of the areas covered in oral presentation during the conference, and reports on some of the notable major new findings described at this 2010 World Congress of Psychiatric Genetics.

The XVII World Congress of Psychiatric Genetics, sponsored by The International Society of Psychiatric Genetics (ISPG) took place in San Diego, California from 4 to 8 November 2009. Approximately 550 participants gathered to discuss the latest molecular genetic findings relevant to serious mental illness, including schizophrenia, mood disorders, substance abuse, autism, and attention deficit disorder. Recent advances in the field were discussed, including the genome-wide association studies results, copy number variation (CNV) in the genome, genomic imaging, and large multicenter collaborations. The following report, written by junior travel awardees who were assigned sessions as rapporteurs represents some of the areas covered in oral presentation during the conference, and reports on some of the notable major new findings described at this 2009 World Congress of Psychiatric Genetics.

Recent genetics research focusing on schizophrenia has led to candidate cognitive and neuroimaging variables as intermediate phenotypes or “endophenotype” markers for the illness. Among other stringent criteria, to be an endophenotype, a marker must demonstrate heritability. In an effort to explore the validity of a selection of cognitive and neuroimaging endophenotypes, the present study was designed to determine estimates of their heritability. One hundred fourteen subjects, including 27 with schizophrenia and 39 unaffected relatives from 23 multiplex schizophrenia families, participated in a comprehensive neuropsychological test battery and structural brain imaging with diffusion tensor imaging DTI. Variables were selected if they previously have been demonstrated to show differences between people with schizophrenia and normal controls. Significant evidence of heritability was confirmed for overall cognitive function “g”, as well as expressive and receptive language, verbal and visual memory, processing speed and cognitive inhibition. In addition, significant heritability estimates were determined for specific regions in the frontal, central, parietal, and occipital areas. These results suggest that the variables chosen may be useful endophenotypes for genetic and early detection studies, although further work with larger cohorts should be conducted to show that deficits in these functions and structures also segregate with schizophrenia within families and thus fully satisfy the definition of an endophenotype. In addition, other cognitive and neuroimaging variables that were not studied here may be candidates for schizophrenia endophenotypes. © 2010 WileyLiss, Inc.

The XVI World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics took place in Osaka, Japan, October 2008. Approximately 600 participants gathered to discuss the latest molecular genetic findings relevant to serious mental illnesses, including schizophrenia, bipolar disorder, major depression, alcohol and drug abuse, autism, and attention-deficit disorder. Recently, the field has advanced considerably and includes new genome-wide association studies with the largest numbers of individuals screened and density of markers to date, as well as newly uncovered genetic phenomena, such as copy number variation that may prove to be relevant for specific brain disorders. The following report represents some of the areas covered during this conference and some of the major new findings presented.

Genomic copy number variations (CNVs) are a major form of variation in the human genome and play an etiologic role in several neuropsychiatric diseases. Tandem repeats, particularly with long (>50 bp) repeat units, are a relatively common yet underexplored type of CNV that may significantly contribute to human genomic variation and disease risk. We therefore carried out a pilot experiment to explore the potential role of long tandem repeats as risk factors in psychiatric disorders.

Schizophrenia is a severe mental disorder with substantial genetic vulnerability. This review discusses recent neuroimaging studies reporting on impairment in brain functioning relevant to language processing in individuals with schizophrenia and those who are at a genetic risk for its development.

The understanding of complex heritable psychiatric disorders such as schizophrenia could be clarified by examining endophenotypes within genetically isolated populations, such as the one found in the Central Valley of Costa Rica. The reduction of familial variability within a sample could allow the relationship between the cognitive and symptomatic manifestations of the illness and the genetic underpinnings to become more observable. This study investigates the neuropsychological test performances of 41 family members from four extended multiplex families within the Spanish origin population of the Central Valley of Costa Rica as potential endophenotypes for genetic studies.

The cognitive deficits present in individuals with sex chromosome aneuploidies suggest that hemispheric differentiation of function is determined by an X–Y homologous gene Crow 1993; Lancet 342:594–598. In particular, females with Turners syndrome TS who have only one Xchromosome exhibit deficits of spatial ability whereas males with Klinefelters syndrome KS who possess a supernumerary Xchromosome are delayed in acquiring words. Since spatial and verbal abilities are generally associated with right and left hemispheric function, such deficits may relate to anomalies of cerebral asymmetry. We therefore applied a novel image analysis technique to investigate the relationship between sex chromosome dosage and structural brain asymmetry. Specifically, we tested Crows prediction that the magnitude of the brain torque i.e., a combination of rightward frontal and leftward occipital asymmetry would, as a function of sex chromosome dosage, be respectively decreased in TS women and increased in KS men, relative to genotypically normal controls. We found that brain torque was not significantly different in TS women and KS men, in comparison to controls. However, TS women exhibited significantly increased leftward brain asymmetry, restricted to the posterior of the brain and focused on the superior temporal and parietal–occipital association cortex, while KS men showed a trend for decreased brain asymmetry throughout the frontal lobes. The findings suggest that the number of sex chromosomes influences the development of brain asymmetry not simply to modify the torque but in a complex pattern along the anteroposterior axis. © 2008 WileyLiss, Inc.

The World Congress of Psychiatric Genetics (WCPG) has become an annual event since the early 1990's sponsored by the International Society of Psychiatric Genetics (ISPG). Each year the latest published and unpublished findings are aired for discussion by representatives of the majority of research programs on this topic world‐wide. The 2007 congress was held in New York City and attracted over 1000 researchers. The topics emphasized included results from whole genome association studies, the significance of copy number variation and the important contributions of epigenetic events to psychiatric disorders. There were over 20 oral sessions devoted to these and other topics of interest. Young investigator recipients of travel awards served as rapporteurs to summarize sessions and these summaries follow.

This review explores what is known about the association of cannabis with schizophrenia, its effects on the brain, and whether the brain changes known to be present in schizophrenia could be caused by cannabis and thus lead to a psychosis.

Klinefelter's Syndrome (KS) is a chromosomal karyotype with one or more extra X chromosomes. KS individuals often show language impairment and the phenotype might be due to overexpression of genes on the extra X chromosome(s). We profiled mRNA derived from lymphoblastoid cell lines from males with documented KS and control males using the Affymetrix U133P microarray platform. There were 129 differentially expressed genes (DEGs) in KS group compared with controls after Benjamini–Hochberg false discovery adjustment. The DEGs included 14 X chromosome genes which were significantly over‐represented. The Y chromosome had zero DEGs. In exploratory analysis of gene expression–cognition relationships, 12 DEGs showed significant correlation of expression with measures of verbal cognition in KS. Overexpression of one pseudoautosomal gene, GTPBP6 (GTP binding protein 6, putative) was inversely correlated with verbal IQ (r = −0.86, P < 0.001) and four other measures of verbal ability. Overexpression of XIST was found in KS compared to XY controls suggesting that silencing of many genes on the X chromosome might occur in KS similar to XX females. The microarray findings for eight DEGs were validated by quantitative PCR. The 14 X chromosome DEGs were not differentially expressed in prior studies comparing female and male brains suggesting a dysregulation profile unique to KS. Examination of X‐linked DEGs, such as GTPBP6, TAF9L, and CXORF21, that show verbal cognition–gene expression correlations may establish a causal link between these genes, neurodevelopment, and language function. A screen of candidate genes may serve as biomarkers of KS for early diagnosis. © 2007 Wiley‐Liss, Inc.

An increased incidence of psychiatric and structural brain abnormalities in individuals with Klinefelter syndrome (KS, 47 XXY) could be due to the presence of extra copies of X‐Y homologous genes that escape X inactivation. Of particular interest are the two brain‐expressed genes Protocadherin11XY (PCDH11XY) and the Synaptobrevin‐like gene (SYBL1) which have been duplicated from the X chromosome to the Y chromosome to give X‐Y homologous gene pairs that are specific to modern humans. We examined the DNA of KS individuals reported recently by DeLisi et al. 2005 and determined the parental origin of the X alleles, the degree of skewed X inactivation and investigated the CpG island methylation status of PCDH11XY and SYBL1 by bisulphite sequencing and quantification of methylated HpaII sites. We used a novel method for quantification of unmethylated CpGs with the restriction enzyme McrBC which cuts methylated but not unmethylated CpGs. The results showed that KS individuals have two methylated and one unmethylated SYBL1 allele whereas PCDH11XY is unmethylated and escapes X inactivation on the extra X chromosome. Overexpression of PCDH11XY in KS is probable and variable escape from inactivation of this Homo sapiens‐specific gene could account for some abnormalities in KS. The origin of the parental alleles or their preferential X inactivation was not associated with psychotic symptoms. © 2006 Wiley‐Liss, Inc.

The accumulated literature on candidate gene findings in psychiatric genetics is extensive. There is concern that many of the published findings to data are false positives. At the October 2005 World Congress of Psychiatric Genetics this issue was discussed by a panel of experts. This manuscript describes the panel discussion, its implications for the reporting of association studies of psychiatric disorders and suggestions for when to decide that a positive finding is truly positive. © 2006 Wiley‐Liss, Inc.

Schizophrenia is a chronic progressive disorder that has at its origin structural brain changes in both white and gray matter. It is likely that these changes begin prior to the onset of clinical symptoms in cortical regions, particularly those concerned with language processing. Later, they can be detected by progressive ventricular enlargement. Current magnetic resonance imaging (MRI) technology can provide a valuable tool for detecting early changes in cortical atrophy and anomalous language processing, which may be predictive of who will develop schizophrenia.

A written questionnaire about genetic testing was distributed to all registrants at The 2004 World Congress of Psychiatric Genetics, mailed to clinical psychiatrists obtained from a directory of clinicians practicing in New York City, and mailed to members of families who have multiple affected family members with schizophrenia. A total of 274 individuals responded (162 researchers, 64 clinicians, and 48 family members). This survey shows that the majority of family members who completed the questionnaire (83.3%) would want to be tested if a genetic test were to become available. Over half of the family members (56.2%) would want prenatal testing. Similarly, over half of the clinicians (56.3%) would recommend it, despite only 25% of the researchers reporting that it would be a future useful tool. All of the clinicians surveyed thought adoption agencies should inform families about a family history of schizophrenia, while only half of the researchers thought this should be done (51.9%). These differences in opinions between consumers, their clinicians, and researchers could be based on a lack of understanding of the amount of risk conferred to family members by reported gene variants. Providing public discussions for placing these risks in perspective should be the responsibility of researchers. Open public discussion of the ethical and social uses of the information gained from psychiatric genetic research and its limitations is encouraged. © 2005 Wiley‐Liss, Inc.

Males with an extra‐X chromosome (Klinefelter's syndrome) frequently, although not always, have an increased prevalence of psychiatric disturbances that range from attention deficit disorder in childhood to schizophrenia or severe affective disorders during adulthood. In addition, they frequently have characteristic verbal deficits. Thus, examining brain magnetic resonance imaging (MRI) scans of these individuals may yield clues to the influence of X chromosome genes on brain structural variation corresponding to psychiatric and cognitive disorders. Eleven adult XXY and 11 age matched XY male controls were examined with a structured psychiatric interview, battery of cognitive tests, and an MRI scan. Ten of eleven of the XXY men had some form of psychiatric disturbance, four of whom had auditory hallucinations compared with none of the XY controls. Significantly smaller frontal lobe, temporal lobe, and superior temporal gyrus (STG) cortical volumes were observed bilaterally in the XXY men. In addition, diffusion tensor imaging (DTI) of white matter integrity resulted in four regions of reduced fractional anisotropy (FA) in XXY men compared with controls, three in the left hemisphere, and one on the right. These correspond to the left posterior limb of the internal capsule, bilateral anterior cingulate, and left arcuate bundle. Specific cognitive deficits in executive functioning attributable to frontal lobe integrity and verbal comprehension were noted. Thus, excess expression of one or more X chromosome genes influences both gray and white matter development in frontal and temporal lobes, as well as white matter tracts leading to them, and may in this way contribute to the executive and language deficits observed in these adults. Future prospective studies are needed to determine which gene or genes are involved and whether their expression could be modified with appropriate treatments early in life. Brain expressed genes that are known to escape inactivation on extra‐X chromosomes would be prime candidates. © 2005 Wiley‐Liss, Inc.

Protocadherin X and Protocadherin Y (PCDHX and PCDHY) are cell‐surface adhesion molecules expressed predominantly in the brain. The PCDHX/Y gene‐pair was generated by an X–Y translocation approximately 3 million years ago (MYA) that gave rise to the Homo sapiens‐specific region of Xq21.3 and Yp11.2 homology. Genes within this region are expected to code for sexually dimorphic human characteristics, including, for example, cerebral asymmetry a dimension of variation that has been suggested is relevant to psychosis. We examined differences in patients with schizophrenic or schizoaffective psychosis in the genomic sequence of PCDHX and PCDHY in coding and adjacent intronic sequences using denaturing high performance liquid chromatography (DHPLC). Three coding variants were detected in PCDHX and two in PCDHY. However, neither the coding variants nor the intronic polymorphisms could be related to psychosis within families. Low sequence variation suggests selective pressure against sequence change in modern humans in contrast to the structural chromosomal and sequence changes including fixed X–Y differences that occurred in this region earlier in hominid evolution. Our findings exclude sequence variation in PCDHX/Y as relevant to the aetiology of psychosis. However, we note the unusual status of this region with respect to X‐inactivation. Further investigation of the epigenetic control of PCDHX/Y in relation to psychosis is warranted. © 2004 Wiley‐Liss, Inc.