A multinational case-control study comparing forensic and non-forensic patients with schizophrenia spectrum disorders: the EU-VIORMED project.

BACKGROUND: The relationship between schizophrenia and violence is complex. The aim of this multicentre case-control study was to examine and compare the characteristics of a group of forensic psychiatric patients with a schizophrenia spectrum disorders and a history of significant interpersonal violence to a group of patients with the same diagnosis but no lifetime history of interpersonal violence. METHOD: Overall, 398 patients (221 forensic and 177 non-forensic patients) were recruited across five European Countries (Italy, Germany, Poland, Austria and the United Kingdom) and assessed using a multidimensional standardised process. RESULTS: The most common primary diagnosis in both groups was schizophrenia (76.4%), but forensic patients more often met criteria for a comorbid personality disorder, almost always antisocial personality disorder (49.1 v. 0%). The forensic patients reported lower levels of disability and better social functioning. Forensic patients were more likely to have been exposed to severe violence in childhood. Education was a protective factor against future violence as well as higher levels of disability, lower social functioning and poorer performances in cognitive processing speed tasks, perhaps as proxy markers of the negative syndrome of schizophrenia. Forensic patients were typically already known to services and in treatment at the time of their index offence, but often poorly compliant. CONCLUSIONS: This study highlights the need for general services to stratify patients under their care for established violence risk factors, to monitor patients for poor compliance and to intervene promptly in order to prevent severe violent incidents in the most clinically vulnerable.

Difference between forensic patients with schizophrenia spectrum disorders in Italy and other European countries: Results of the EU-VIORMED project.

BACKGROUND: There has been a substantial change in the law on the provision of secure health services for offender-patients in Italy, a country currently with the lowest general psychiatry bed availability per head of the population in Europe, raising questions about possible differences in offender-patient admissions between European countries. AIMS: In this multicentre case-control study, our aim was to compare the socio-demographic, clinical and criminological characteristics of a sample of Italian forensic in-patients with schizophrenia or similar psychosis with patients in a similar diagnostic range in specialist in-patient services elsewhere in Europe. METHODS: Secure hospital unit in-patients with psychosis were recruited across five European countries (Italy, Austria, Germany, Poland and England). Consenting patients were interviewed by researchers and assessed using a multidimensional standardised process. Within country similarities between Austria, Germany, Poland and England were confirmed. RESULTS: Overall, 39 Italian participants had had fewer years of education than the 182 patients in the other countries and were less likely to have ever had skilled or professional employment. The Italian patients had been older at first contact with any mental health services than the other Europeans. Diagnosed comorbidity rates were similar, but the Italian group reported higher levels of disability. Although the other European forensic patients were more likely to be undergoing treatment at the time of their index offence, they were also more likely to have been poorly compliant with treatment. The rate of suicide-related behaviours was significantly lower among the Italian patients than among the others. CONCLUSIONS: Notwithstanding similar diagnoses, important differences emerged between patients in Italian forensic mental health resident services and those in four other European countries, some possibly reflecting less access to earlier relevant services in Italy. Others, including lower disability ratings among the Italian patients and a lower rate of suicide-related behaviours, may indicate that the Italian reforms carry benefits. This is worthy of further evaluation.

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

Pharmacological interventions to reduce violence in patients with schizophrenia in forensic psychiatry.

BACKGROUND: The purpose was to systematically investigate which pharmacological strategies are effective to reduce the risk of violence among patients with Schizophrenia Spectrum Disorders (SSD) in forensic settings. METHODS: For this systematic review six electronic data bases were searched. Two researchers independently screened the 6,003 abstracts resulting in 143 potential papers. These were then analyzed in detail by two independent researchers. Of these, 133 were excluded for various reasons leaving 10 articles in the present review. RESULTS: Of the 10 articles included, five were merely observational, and three were pre-post studies without controls. One study applied a matched case-control design and one was a non-randomized controlled trial. Clozapine was investigated most frequently, followed by olanzapine and risperidone. Often, outcome measures were specific to the study and sample sizes were small. Frequently, relevant methodological information was missing. Due to heterogeneous study designs and outcomes meta-analytic methods could not be applied. CONCLUSION: Due to substantial methodological limitations it is difficult to draw any firm conclusions about the most effective pharmacological strategies to reduce the risk of violence in patents with SSD in forensic psychiatry settings. Studies applying more rigorous methods regarding case-definition, outcome measures, sample sizes, and study designs are urgently needed.

Facial emotion recognition in people with schizophrenia and a history of violence: a mediation analysis.

Evidence for an association between impaired facial emotion recognition and violence in people with schizophrenia is inconclusive. In particular, the role of misidentification patterns involving specific emotions such as anger and the influence of clinical characteristics on this association remain unclear. In this study, we compared facial emotion recognition performance in age- and gender-matched schizophrenia spectrum disorders subjects with (N = 52) and without (N = 52) a history of violence. Data on current symptom severity, Cluster B personality status, past victimization, and alcohol and substance misuse were also collected. Compared to those without, subjects with a history of violence showed worse facial emotion recognition performances, involving anger, fear, disgust, sadness, and happiness. When formally testing the reporting of angry faces, evidence of enhanced sensitivity to anger was not supported. Finally, when the impact of current symptoms was assessed, higher severity of activation symptoms, including motor hyperactivity, elevated mood, excitement and distractibility, mediated the relationship between history of violence and poor facial emotion recognition performance. As a whole, our findings seem to support the role of perceptual deficits involving different emotions as well as of a mediation played by activation symptoms. Facial emotion recognition deficits associated with the propensity to violence, as well certain symptoms mediating their relationship, should be targeted by specific treatment approaches.

European violence risk and mental disorders (EU-VIORMED): a multi-centre prospective cohort study protocol.

BACKGROUND: The link between schizophrenia spectrum disorders (SSD) and violence is a core issue for most forensic psychiatric services. However, the drivers of violence in this population remain unclear, and, to date tools to predict violence risk have a range of limitations. Perhaps because of this uncertainty about the nature of violence risk, treatment programmes and care pathways for mentally disordered offenders vary substantially across the European Union, and differences in legal and policy frameworks are highly relevant. METHODS: The three-year EU-VIORMED project (Grant Number PP-2-3-2016, November 2017-October 2020) involves forensic centres in Italy, Austria, Germany, Poland, and the U.K. It aims to: (a) identify and compare violence risk factors, clinical needs, and decision making capacity in violent (N = 200, "cases") and nonviolent patients with SSD (N = 200; "controls") using a case-control design; (b) test the predictive validity of the HCR-20v3, OxMIS and FoVOx among cases alone (N = 200), using a prospective cohort study; and (c) compare forensic-psychiatric care pathways across the EU, in a continent wide service mapping study. DISCUSSION: Data collection started in September 2018 and continues. By September 2019, 333 participants have been enrolled (201 cases and 132 controls were recruited). Experts from 23 countries provided data for the service mapping exercise. TRIAL REGISTRATION: Retrospectively registered on January 2, 2019 as researchregistry4604 January 2, 2019.

Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders.

BACKGROUND: There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.AimsTo investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls. METHOD: Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls. RESULTS: Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest. CONCLUSIONS: Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interestR.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.

A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains.

This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.

Familial and environmental influences on brain volumes in twins with schizophrenia.

BACKGROUND: Reductions in whole brain and grey matter volumes are robust features of schizophrenia, yet their etiological influences are unclear. METHODS: We investigated the association between the genetic and environmental risk for schizophrenia and brain volumes. Whole brain, grey matter and white matter volumes were established from structural MRIs from twins varying in their zygosity and concordance for schizophrenia. Hippocampal volumes were measured manually. We conducted between-group testing and full genetic modelling. RESULTS: We included 168 twins in our study. Whole brain, grey matter, white matter and right hippocampal volumes were smaller in twins with schizophrenia. Twin correlations were larger for whole brain, grey matter and white matter volumes in monozygotic than dizygotic twins and were significantly heritable, whereas hippocampal volume was the most environmentally sensitive. There was a significant phenotypic correlation between schizophrenia and reductions in all the brain volumes except for that of the left hippocampus. For whole brain, grey matter and the right hippocampus the etiological links with schizophrenia were principally associated with the shared familial environment. Lower birth weight and perinatal hypoxia were both associated with lower whole brain volume and with lower white matter and grey matter volumes, respectively. LIMITATIONS: Scan data were collected across 2 sites, and some groups were modest in size. CONCLUSION: Whole brain, grey matter and right hippocampal volume reductions are linked to schizophrenia through correlated familial risk (i.e., the shared familial environment). The degree of influence of etiological factors varies between brain structures, leading to the possibility of a neuroanatomically specific etiological imprint.

White matter deficits in schizophrenia are global and don't progress with age.

INTRODUCTION: Diffusion tensor imaging has revealed differences in all examined white matter tracts in schizophrenia, with a range of explanations for why this may be. The distribution and timing of differences may help explain their origin; however, results are usually dependent on the analytical method. We therefore sought to examine the extent of differences and their relationship with age using two different methods. METHODS: A combined voxel-based whole-brain study and a tract-based spatial-statistics study of 104 patients with schizophrenia and 200 matched healthy controls, aged between 17 and 63 years. RESULTS: Fractional anisotropy was reduced throughout the brain in both analyses. The relationship of fractional anisotropy with age differed between patients and controls, with controls showing the gentle fractional anisotropy decline widely noted but patients showing an essentially flat relationship: younger patients had lower fractional anisotropy than controls, but the difference disappeared with age. Mean diffusivity was widely increased in patients. CONCLUSION: Reduction in fractional anisotropy and increase in mean diffusivity would be consistent with global disruption in myelination; the relationship with age would suggest this is present already at the onset of their illness, but does not progress.

Age-Related Differences and Heritability of the Perisylvian Language Networks.

Acquisition of language skills depends on the progressive maturation of specialized brain networks that are usually lateralized in adult population. However, how genetic and environmental factors relate to the age-related differences in lateralization of these language pathways is still not known. We recruited 101 healthy right-handed subjects aged 9-40 years to investigate age-related differences in the anatomy of perisylvian language pathways and 86 adult twins (52 monozygotic and 34 dizygotic) to understand how heritability factors influence language anatomy. Diffusion tractography was used to dissect and extract indirect volume measures from the three segments of the arcuate fasciculus connecting Wernicke's to Broca's region (i.e., long segment), Broca's to Geschwind's region (i.e., anterior segment), and Wernicke's to Geschwind's region (i.e., posterior segment). We found that the long and anterior arcuate segments are lateralized before adolescence and their lateralization remains stable throughout adolescence and early adulthood. Conversely, the posterior segment shows right lateralization in childhood but becomes progressively bilateral during adolescence, driven by a reduction in volume in the right hemisphere. Analysis of the twin sample showed that genetic and shared environmental factors influence the anatomy of those segments that lateralize earlier, whereas specific environmental effects drive the variability in the volume of the posterior segment that continues to change in adolescence and adulthood. Our results suggest that the age-related differences in the lateralization of the language perisylvian pathways are related to the relative contribution of genetic and environmental effects specific to each segment. SIGNIFICANCE STATEMENT: Our study shows that, by early childhood, frontotemporal (long segment) and frontoparietal (anterior segment) connections of the arcuate fasciculus are left and right lateralized, respectively, and remain lateralized throughout adolescence and early adulthood. In contrast, temporoparietal (posterior segment) connections are right lateralized in childhood, but become progressively bilateral during adolescence. Preliminary twin analysis suggested that lateralization of the arcuate fasciculus is a heterogeneous process that depends on the interplay between genetic and environment factors specific to each segment. Tracts that exhibit higher age effects later in life (i.e., posterior segment) appear to be influenced more by specific environmental factors.

Predictive validity of the HCR-20 for violent and non-violent sexual behaviour in a secure mental health service.

BACKGROUND: Violent and non-violent sexual behaviour is a fairly common problem among secure mental health service patients, but specialist sexual violence risk assessment is time-consuming and so performed infrequently. AIMS: We aimed to establish whether a commonly used violence risk assessment tool, the Health Clinical Risk management 20(HCR-20), has predictive validity specifically for inappropriate sexual behaviour. METHODS: A pseudo-prospective cohort design was used for a study in the adult wards of a large provider of specialist secure mental health services. Routine clinical team HCR-20 assessments were extracted from records, and incidents involving inappropriate sexual behaviour were recorded for the 3 months following assessment. RESULTS: Of 613 patients, 104 (17%) had engaged in at least one inappropriate sexual behaviour; in 65 (10.6%), the sexual act was violent. HCR-20 total score, clinical and risk management subscales, predicted violent and non-violent sexual behaviour. The negative predictive value of the HCR-20 for inappropriate sexual behaviour was over 90%. CONCLUSIONS: Prediction of violent sexual behaviour may be regarded as well within the scope of the HCR-20 as a structured professional judgement tool to aid violence risk prediction, but we found that it also predicts behaviours that may be of concern but fall below the violence threshold. High negative predictive values suggest that HCR-20 scores may have some utility for screening out patients who do not require more specialist assessment for inappropriate sexual behaviour. Copyright © 2015 John Wiley & Sons, Ltd.

Facial emotion processing in borderline personality disorder: a systematic review and meta-analysis.

A body of work has developed over the last 20 years that explores facial emotion perception in Borderline Personality Disorder (BPD). We identified 25 behavioural and functional imaging studies that tested facial emotion processing differences between patients with BPD and healthy controls through a database literature search. Despite methodological differences there is consistent evidence supporting a negative response bias to neutral and ambiguous facial expressions in patients. Findings for negative emotions are mixed with evidence from individual studies of an enhanced sensitivity to fearful expressions and impaired facial emotion recognition of disgust, while meta-analysis revealed no significant recognition impairments between BPD and healthy controls for any negative emotion. Mentalizing studies indicate that BPD patients are accurate at attributing mental states to complex social stimuli. Functional neuroimaging data suggest that the underlying neural substrate involves hyperactivation in the amygdala to affective facial stimuli, and altered activation in the anterior cingulate, inferior frontal gyrus and the superior temporal sulcus particularly during social emotion processing tasks. Future studies must address methodological inconsistencies, particularly variations in patients' key clinical characteristics and in the testing paradigms deployed.

Predictive validity of the HCR-20 for inpatient self-harm.

BACKGROUND: Few instruments have been developed to assess the risk of self-harm by psychiatric patients and the evidence for their predictive validity is limited. Given that individuals who self-harm may also engage in other-directed aggression, and that the behaviour can be a precursor to violence, we tested whether, and for which groups, the commonly used violence risk assessment HCR-20 demonstrated predictive validity for self-harm. PROCEDURES: A pseudo-prospective cohort study (N=504) was conducted in a UK secure/forensic mental health setting using routinely collected data. HCR-20 assessments were completed by the clinical team and incidents of self-harm during the 3months following assessment were coded from patient records. FINDINGS: The HCR-20 total score, H10 and R5 subscales, and SJ for violence significantly predicted self-harm; however, AUC values did not demonstrate large effect sizes (range .345 to .749). Personality disorder and impulsivity were the strongest predictors of self-harm, but the R5 scale contained the greatest proportion of relevant items. Predictive efficacy was superior for women compared with men and for those with schizophrenia or personality disorder compared with organic and developmental disorders. CONCLUSIONS: The HCR-20 appears to be a significant predictor of self-harm. It may be possible to supplement HCR-20 ratings with case specific knowledge and additional known risk factors for self-harm to make a valuable summary judgement about the behaviour and thus minimise the need for multiple assessment tools.

Analysis of multiple phenotypes in genome-wide genetic mapping studies.

BACKGROUND: Complex traits may be defined by a range of different criteria. It would result in a loss of information to perform analyses simply on the basis of a final clinical dichotomized affected / unaffected variable. RESULTS: We assess the performance of four alternative approaches for the analysis of multiple phenotypes in genetic association studies. We describe the four methods in detail and discuss their relative theoretical merits and disadvantages. Using simulation we demonstrate that PCA provides the greatest power when applied to both correlated phenotypes and with large numbers of phenotypes. The multivariate approach had low type I error only with independent phenotypes or small numbers of phenotypes. In this study, our application of the four methods to schizophrenia data provides converging evidence of the relative performance of the methods. CONCLUSIONS: Via power analysis of simulated data and testing of experimental data, we conclude that PCA, creating one variable based on a linear combination of all the traits, performs optimally. We propose that our comparison will provide insight into the properties of the methods and help researchers to choose appropriate strategy in future experimental studies.

Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder.

Studies of the major psychoses, schizophrenia (SZ) and bipolar disorder (BD), have traditionally focused on genetic and environmental risk factors, although more recent work has highlighted an additional role for epigenetic processes in mediating susceptibility. Since monozygotic (MZ) twins share a common DNA sequence, their study represents an ideal design for investigating the contribution of epigenetic factors to disease etiology. We performed a genome-wide analysis of DNA methylation on peripheral blood DNA samples obtained from a unique sample of MZ twin pairs discordant for major psychosis. Numerous loci demonstrated disease-associated DNA methylation differences between twins discordant for SZ and BD individually, and together as a combined major psychosis group. Pathway analysis of our top loci highlighted a significant enrichment of epigenetic changes in biological networks and pathways directly relevant to psychiatric disorder and neurodevelopment. The top psychosis-associated, differentially methylated region, significantly hypomethylated in affected twins, was located in the promoter of ST6GALNAC1 overlapping a previously reported rare genomic duplication observed in SZ. The mean DNA methylation difference at this locus was 6%, but there was considerable heterogeneity between families, with some twin pairs showing a 20% difference in methylation. We subsequently assessed this region in an independent sample of postmortem brain tissue from affected individuals and controls, finding marked hypomethylation (>25%) in a subset of psychosis patients. Overall, our data provide further evidence to support a role for DNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD.

Risk variant of oligodendrocyte lineage transcription factor 2 is associated with reduced white matter integrity.

The oligodendrocyte lineage transcription factor 2 (OLIG2) regulates the genesis of oligodendrocytes, the brain cells responsible for axonal myelination. Although it has been associated with psychiatric and neurological disorders, the impact of this gene on white matter integrity has never been investigated in humans. Using diffusion tensor imaging, we examined the effect of a single nucleotide polymorphism (rs1059004) in OLIG2 previously associated with reduced gene expression, and with psychiatric disorders on fractional anisotropy in 78 healthy subjects. We found that the risk allele (A) was associated with reduced white matter integrity in the corona radiata bilaterally. This is consistent with evidence that it is a schizophrenia susceptibility gene, and suggests that it may confer increased risk through an effect on neuroanatomical connectivity.

Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function.

The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation.

A case series of clozapine for borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is a common, debilitating disorder for which the evidence base for treatment is modest. This case series aimed to explore preliminary evidence of clozapine's effectiveness for patients with severe BPD. METHODS: We examined the case notes of 22 female inpatients with a primary diagnosis of BPD who had started treatment with clozapine. Baseline routine clinical data were extracted from the records and at 6 monthly intervals thereafter, up to a maximum of 18 months after starting treatment. Patients also were interviewed about their experiences. RESULTS: We found evidence for a beneficial effect of clozapine across several clinical domains. Symptom severity, need for enhanced observations, use of additional medication, and the number of aggressive incidents all significantly improved after clozapine. The greatest improvements appeared within the first 6 months of initiating treatment. There also was a significant increase in weight. CONCLUSIONS: The results suggest that clozapine, with suitable health monitoring, may be beneficial for this clinical population. Larger, randomized, blinded, and controlled prospective studies are needed to confirm these findings.

Prefrontal deviations in function but not volume are putative endophenotypes for schizophrenia.

This study sought to systematically investigate whether prefrontal cortex grey matter volume reductions are valid endophenotypes for schizophrenia, specifically investigating their presence in unaffected relatives, heritability, genetic overlap with the disorder itself and finally to contrast their performance on these criteria with putative neuropsychological indices of prefrontal functioning. We used a combined twin and family design and examined four prefrontal cortical regions of interest. Superior and inferior regions were significantly smaller in patients. However, the volumes of these same regions were normal in unaffected relatives and therefore, we could confirm that such deficits were not due to familial effects. Volumes of the prefrontal and orbital cortices were, however, moderately heritable, but neither shared a genetic overlap with schizophrenia. Total prefrontal cortical volume reductions shared a significant unique environmental overlap with the disorder, suggesting that the reductions were not familial. In contrast, prefrontal (executive) functioning deficits were present in the unaffected relatives, were moderately heritable and shared a substantial genetic overlap with liability to schizophrenia. These results suggest that the well recognized prefrontal volume reductions are not related to the same familial influences that increase schizophrenia liability and instead may be attributable to illness related biological changes or indeed confounded by illness trajectory, chronicity, medication or substance abuse, or in fact a combination of some or all of them.