Showing papers by "Robin M. Murray published in 2012"

Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population

Abstract: Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.

Incidence of Schizophrenia and Other Psychoses in England, 1950–2009: A Systematic Review and Meta-Analyses

Abstract: Background We conducted a systematic review of incidence rates in England over a sixty-year period to determine the extent to which rates varied along accepted (age, sex) and less-accepted epidemiological gradients (ethnicity, migration and place of birth and upbringing, time) Objectives To determine variation in incidence of several psychotic disorders as above Data Sources Published and grey literature searches (MEDLINE, PSycINFO, EMBASE, CINAHL, ASSIA, HMIC), and identification of unpublished data through bibliographic searches and author communication Study Eligibility Criteria Published 1950–2009; conducted wholly or partially in England; original data on incidence of non-organic adult-onset psychosis or one or more factor(s) pertaining to incidence Participants People, 16–64 years, with first -onset psychosis, including non-affective psychoses, schizophrenia, bipolar disorder, psychotic depression and substance-induced psychosis Study Appraisal and Synthesis Methods Title, abstract and full-text review by two independent raters to identify suitable citations Data were extracted to a standardized extraction form Descriptive appraisals of variation in rates, including tables and forest plots, and where suitable, random-effects meta-analyses and meta-regressions to test specific hypotheses; rate heterogeneity was assessed by the I2-statistic Results 83 citations met inclusion Pooled incidence of all psychoses (N = 9) was 317 per 100,000 person-years (95%CI: 246–409), 232 (95%CI: 183–295) for non-affective psychoses (N = 8), 152 (95%CI: 119–195) for schizophrenia (N = 15) and 124 (95%CI: 90–171) for affective psychoses (N = 7) This masked rate heterogeneity (I2: 054–097), possibly explained by socio-environmental factors; our review confirmed (via meta-regression) the typical age-sex interaction in psychosis risk, including secondary peak onset in women after 45 years Rates of most disorders were elevated in several ethnic minority groups compared with the white (British) population For example, for schizophrenia: black Caribbean (pooled RR: 56; 95%CI: 34–92; N = 5), black African (pooled RR: 47; 95%CI: 33–68; N = 5) and South Asian groups in England (pooled RR: 24; 95%CI: 13–45; N = 3) We found no evidence to support an overall change in the incidence of psychotic disorder over time, though diagnostic shifts (away from schizophrenia) were reported Limitations Incidence studies were predominantly cross-sectional, limiting causal inference Heterogeneity, while evidencing important variation, suggested pooled estimates require interpretation alongside our descriptive systematic results Conclusions and Implications of Key Findings Incidence of psychotic disorders varied markedly by age, sex, place and migration status/ethnicity Stable incidence over time, together with a robust socio-environmental epidemiology, provides a platform for developing prediction models for health service planning

Preterm Birth and Psychiatric Disorders in Young Adult Life

Abstract: Context: Preterm birth, intrauterine growth restriction, and delivery-related hypoxia have been associated with schizophrenia. It is unclear whether these associations pertain to other adult-onset psychiatric disorders and whether these perinatal events are independent. Objective: To investigate the relationships among gestational age, nonoptimal fetal growth, Apgar score, and various psychiatric disorders in young adult life. Design: Historical population-based cohort study. Setting: Identification of adult-onset psychiatric admissions using data from the National Board of Health and Welfare, Stockholm, Sweden. Participants: All live-born individuals registered in the nationwide Swedish Medical Birth Register between 1973 and 1985 and living in Sweden at age 16 years by December 2002 (n=1 301 522). Main Outcome Measures: Psychiatric hospitalization with nonaffective psychosis, bipolar affective disorder, depressive disorder, eating disorder, drug dependency, or alcohol dependency, diagnosed according to the International Classification of Diseases codes for 8 through 10. Cox proportional hazards regression models were used to estimate hazard ratios and 95% CIs. Results: Preterm birth was significantly associated with increased risk of psychiatric hospitalization in adulthood (defined as16 years of age) in a monotonic manner across a range of psychiatric disorders. Compared with term births (37-41 weeks), those born at 32 to 36 weeks’ gestation were 1.6 (95% CI, 1.1-2.3) times more likely to have nonaffective psychosis, 1.3 (95% CI, 1.1-1.7) times more likely to have depressive disorder, and 2.7 (95% CI, 1.6-4.5) times more likely to have bipolar affective disorder. Those born at less than 32 weeks’ gestation were 2.5 (95% CI, 1.0-6.0) times more likely to have nonaffective psychosis, 2.9 (95% CI, 1.8-4.6) times more likely to have depressive disorder, and 7.4 (95% CI, 2.7-20.6) times more likely to have bipolar affective disorder. Conclusions: The vulnerability for hospitalization with a range of psychiatric diagnoses may increase with younger gestational age. Similar associations were not observed for nonoptimal fetal growth and low Apgar score.

Meta-Analysis of the Association of Urbanicity With Schizophrenia

Abstract: The association between urbanicity and risk of schizophrenia is well established. The incidence of schizophrenia has been observed to increase in line with rising levels of urbanicity, as measured in terms of population size or density. This association is expressed as Incidence Rate Ratio (IRR), and the results are usually presented by comparing the most urban with the most rural environment. In this study, we undertook to express the effect of urbanicity on the risk of schizophrenia in a linear form and to perform a meta-analysis of all available evidence. We first employed a simple regression analysis of log (IRR) as given in each study on the urbanicity category, assuming a uniform distribution and a linear association. In order to obtain more accurate estimates, we developed a more sophisticated method that generates individual data points with simulation from the summary data presented in the original studies, and then fits a logistic regression model. The estimates from each study were combined with meta-analysis. Despite the challenges that arise from differences between studies as regards to the number and relative size of urbanicity levels, a linear association was observed between the logarithm of the odds of risk for schizophrenia and urbanicity. The risk for schizophrenia at the most urban environment was estimated to be 2.37 times higher than in the most rural environment. The same effect was found when studies measuring the risk for nonaffective psychosis were included.

Dopamine Synthesis Capacity in Patients With Treatment-Resistant Schizophrenia

Abstract: ObjectiveElevated presynaptic striatal dopaminergic function is a robust feature of schizophrenia. However, the relationship between this dopamine abnormality and the response to dopamine-blocking antipsychotic treatments is unclear. The authors tested the hypothesis that in patients with schizophrenia the response to antipsychotic treatment would be related to the severity of presynaptic dopamine dysfunction, as indexed using [18F]-DOPA uptake positron emission tomography (PET).MethodTwelve patients with treatment-resistant schizophrenia, twelve patients with schizophrenia who had responded to antipsychotics, and twelve healthy volunteers matched for gender, age, ethnicity, weight, and cigarette smoking underwent [18F]-DOPA PET scanning. [18F]-DOPA influx rate constants (Kicer values) were measured in the striatum and its functional subdivisions.ResultsPatients who had responded to antipsychotic treatment showed significantly higher Kicer striatal values than did patients with treatment-resistant illness...

How Genes and Environmental Factors Determine the Different Neurodevelopmental Trajectories of Schizophrenia and Bipolar Disorder

Abstract: More than a century after Kraepelin’s distinction between dementia praecox (schizophrenia) and manic depression (bipolar disorder), the major classification systems continue to categorize them separately. However, clinicians frequently encounter patients who do not fall neatly intoeither category. Furthermore, antipsychotic drugs, once thought only to be useful in schizophrenia, are also effective in bipolar disorder, which is not surprising given that dopamine dysregulation is implicated in both disorders. Conversely, mood stabilizers are useful in treating certain schizophrenic patients, and similarly, antidepressants have a role in treatment of negative symptoms in schizophrenia. In this article, we will argue that recent studies support a model 1,2 whereby, on a background of some shared genetic liability for both disorders, patients with schizophrenia have been subject to additional genetic and environmental risk factors that impair neurodevelopment.

Individualized prediction of illness course at the first psychotic episode: a support vector machine MRI study

Abstract: Background - To date, magnetic resonance imaging (MRI) has made little impact on the diagnosis and monitoring of psychoses in individual patients. In this study, we used a support vector machine (SVM) whole-brain classification approach to predict future illness course at the individual level from MRI data obtained at the first psychotic episode. Method - One hundred patients at their first psychotic episode and 91 healthy controls had an MRI scan. Patients were re-evaluated 6.2 years (s.d.=2.3) later, and were classified as having a continuous, episodic or intermediate illness course. Twenty-eight subjects with a continuous course were compared with 28 patients with an episodic course and with 28 healthy controls. We trained each SVM classifier independently for the following contrasts: continuous versus episodic, continuous versus healthy controls, and episodic versus healthy controls. Results - At baseline, patients with a continuous course were already distinguishable, with significance above chance level, from both patients with an episodic course (p=0.004, sensitivity=71, specificity=68) and healthy individuals (p=0.01, sensitivity=71, specificity=61). Patients with an episodic course could not be distinguished from healthy individuals. When patients with an intermediate outcome were classified according to the discriminating pattern episodic versus continuous, 74% of those who did not develop other episodes were classified as episodic, and 65% of those who did develop further episodes were classified as continuous (p=0.035). Conclusions - We provide preliminary evidence of MRI application in the individualized prediction of future illness course, using a simple and automated SVM pipeline. When replicated and validated in larger groups, this could enable targeted clinical decisions based on imaging data.

Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe

Abstract: Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n=11 540; P=3.89 × 10−9, odds ratio (OR)=1.25). This finding was replicated in 23 206 independent samples of European ancestry (P=0.0029, OR=1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder.

Childhood maltreatment is associated with increased body mass index and increased C-reactive protein levels in first-episode psychosis patients.

Abstract: Background The high incidence of the metabolic syndrome in patients with psychosis is mainly attributed to antipsychotic treatment. However, it is also possible that psychological stress plays a role, inducing a chronic inflammatory process that may predispose to the development of metabolic abnormalities. We investigated the association between childhood maltreatment and inflammatory and metabolic biomarkers in subjects with first-episode psychosis and healthy controls. Method Body mass index (BMI), weight and waist circumference were measured in 95 first-episode psychosis patients and 97 healthy controls. Inflammatory and metabolic markers were measured in a subsample of 28 patients and 45 controls. In all the subjects we collected information on childhood maltreatment and recent stressors. Results Patients with childhood maltreatment had higher BMI [25.0 (s.e.=0.6) kg/m2] and C-reactive protein (CRP) levels [1.1 (s.e.=0.6) mg/dl] when compared with healthy controls [23.4 (s.e.=0.4) kg/m2, p=0.030 and 0.2 (s.e.=0.1) mg/dl, p=0.009, respectively]. In contrast, patients without childhood maltreatment were not significantly different from healthy controls for either BMI [24.7 (s.e.=0.6) kg/m2, p=0.07] or CRP levels [0.5 (s.e.=0.2) mg/dl, p=0.25]. After controlling for the effect of BMI, the difference in CRP levels across the three groups remained significant (F 2,58=3.6, p=0.035), suggesting that the increase in inflammation was not driven by an increase in adipose tissue. Conclusions Childhood maltreatment is associated with higher BMI, and increased CRP levels, in patients with a first-episode psychosis. Further studies need to confirm the mechanisms underlying the putative causal relationship between childhood maltreatment and higher BMI, and whether this is indeed mediated by increased inflammation.

Volumetric Abnormalities Predating the Onset of Schizophrenia and Affective Psychoses: An MRI Study in Subjects at Ultrahigh Risk of Psychosis

Abstract: It remains unclear whether brain structural abnormalities observed before the onset of psychosis are specific to schizophrenia or are common to all psychotic disorders. This study aimed to measure regional gray matter volume prior to the onset of schizophreniform and of affective psychoses. We investigated 102 subjects at ultrahigh risk (UHR) of developing psychosis recruited from the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia. Twenty-eight of these subjects developed psychosis subsequent to scanning: 19 schizophrenia, 7 affective psychoses, and 2 other psychoses. We examined regional gray matter volume using 1.5 mm thick, coronal, 1.5 Tesla magnetic resonance imaging and voxel-based morphometry methods of image analysis. Subjects were scanned at presentation and were followed up clinically for a minimum of 12 months, to detect later transition to psychosis. We found that both groups of subjects who subsequently developed psychosis (schizophrenia and affective psychosis) showed reductions in the frontal cortex relative to UHR subjects who did not develop psychosis. The subgroup that subsequently developed schizophrenia also showed smaller volumes in the parietal cortex and, at trend level, in the temporal cortex, whereas those who developed an affective psychosis had significantly smaller subgenual cingulate volumes. These preliminary findings suggest that volumetric abnormalities in UHR individuals developing schizophrenia vs affective psychoses comprise a combination of features that predate both disorders and others that may be specific to the nature of the subsequent disorder.

Post-traumatic stress disorder, depression and suicidality in inpatients with substance use disorders.

Abstract: Introduction and Aims. The international literature suggests that traumatic events are common for patients with substance use disorders (SUDs), and are often associated with the development of post-traumatic stress disorder (PTSD) and other psychiatric comorbidities. However, limited research has been conducted among Australian SUD patients. The aim of the present study was to examine the prevalence of these disorders in a group of Australian patients admitted for detoxification. Design and Methods. Data were collected from 253 inpatients using a modified version of the Composite International Diagnostic Interview, the 10-item Trauma Screening Questionnaire, the Zung Self-rating Depression Scale and questions from the PsyCheck. Results. Approximately 20% of inpatients experienced moderate to severe depressive symptoms, and 37% had a lifetime history of self-harm or attempted suicide. Approximately 80% of patients had experienced at least one traumatic event, most experiencing multiple traumas. The mean age of first trauma was 14 years. Almost 45% of patients screened positive for current PTSD symptoms. Women were nine times more likely to have been raped and five times more likely to have been sexually molested than men. PTSD symptoms were associated with greater trauma exposure, younger age of first trauma, specific trauma types, moderate to severe depressive symptoms and a history of self-harm or attempted suicide. Despite their difficulties, patients with PTSD symptoms had high rates of retention in treatment. Discussion and Conclusions. Patients entering treatment for SUDs should be assessed for PTSD, depression and suicidality. These conditions impact significantly on treatment outcomes, and require the development of appropriate treatment strategies.[Dore G, Mills K, Murray R, Teesson M, Farrugia P. Post-traumatic stress disorder, depression and suicidality in inpatients with substance use disorders. Drug Alcohol Rev 2011]. Language: en

Do child abuse and maltreatment increase risk of schizophrenia

Abstract: INTRODUCTION: IntroductionaaAlthough childhood abuse is a recognised risk factor for depression, post-traumatic stress disorder, and substance misuse, its role in the aetiology of psychotic disorder remained controversial. This is in part because the putative effect of childhood trauma on psychosis has been mostly evaluated by small, cross sectional, uncontrolled studies that raised methodological issues. METHODS: Papers concerning the association between childhood trauma and psychotic disorders (to November, 2011) were identified using a comprehensive search of PubMed, Psychinfo, and Scopus and analysing reference list of relevant papers. A narrative synthesis was used to summarise results. RESULTS: An association between childhood abuse and psychotic symptoms was consistently reported by large cross sectional surveys with an effect ranging from 1.7 to 15. However, we cannot conclude that the relationship is causal as lack of longitudinal studies prevent us from fully excluding alternative explanations such as reverse causality. Gender, cannabis use, and depressive and post-traumatic stress disorder symptoms appear to moderate the effect of childhood trauma on psychotic disorders. However, specificity of childhood abuse in psychotic disorders and, particularly, in schizophrenia has not been demonstrated. CONCLUSION: Although the association between childhood abuse and psychosis has been replicated, the etiological role of such early adversity has yet to be fully clarified. So far none of the studies reported support the hypothesis that childhood abuse is either sufficient or necessary to develop a psychotic disorder. It seems likely that any effect of childhood abuse on schizophrenia needs to be understood in terms of genetic susceptibility and interaction with other environmental risk factors. Language: en

Superior intellectual ability in schizophrenia: neuropsychological characteristics.

Abstract: OBJECTIVE: It has been suggested that neurocognitive impairment is a core deficit in schizophrenia. However, it appears that some patients with schizophrenia have intelligence quotients (IQs) in the superior range. In this study, we sought out schizophrenia patients with an estimated premorbid Intelligence Quotient (IQ) of at least 115 and studied their neuropsychological profile. METHOD: Thirty-four patients meeting diagnostic criteria for schizophrenia or schizoaffective disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV), with mean estimated premorbid IQ of 120, were recruited and divided into two subgroups, according to whether or not their IQ had declined by at least 10 points from their premorbid estimate. Their performance on an extensive neuropsychological battery was compared with that of 19 IQ-matched healthy controls and a group of 16 "typical" schizophrenia patients with estimated premorbid IQ <110, using one way ANOVAs and profile analysis using MANOVAs. RESULTS: Schizophrenia patients whose estimated premorbid and current IQ both lay in the superior range were statistically indistinguishable from IQ-matched healthy controls on all neurocognitive tests. However, their profile of relative performance in subtests was similar to that of typical schizophrenia patients. Patients with superior premorbid IQ and evidence of intellectual deterioration had intermediate scores. CONCLUSIONS: Our results confirm the existence of patients meeting DSM-IV diagnostic criteria for schizophrenia who have markedly superior premorbid intellectual level and appear to be free of gross neuropsychological deficits. We discuss the implications of these findings for the primacy of cognitive deficits in schizophrenia.

Mortality in first-contact psychosis patients in the UK: a cohort study

Abstract: BACKGROUND The excess mortality following first-contact psychosis is well recognized. However, the causes of death in a complete incidence cohort and mortality patterns over time compared with the general population are unknown. METHOD All 2723 patients who presented for the first time with psychosis in three defined catchment areas of the U.K. in London (1965-2004, n=2056), Nottingham (1997-1999, n=203) and Dumfries and Galloway (1979-1998, n=464) were traced after a mean of 11.5 years follow-up and death certificates were obtained. Data analysis was by indirect standardization. RESULTS The overall standardized mortality ratio (SMR) for first-contact psychosis was 184 [95% confidence interval (CI) 167-202]. Most deaths (84.2%, 374/444) were from natural causes, although suicide had the highest SMR (1165, 95% CI 873-1524). Diseases of the respiratory system and infectious diseases had the highest SMR of the natural causes of death (232, 95% CI 183-291). The risk of death from diseases of the circulatory system was also elevated compared with the general population (SMR 139, 95% CI 117-164) whereas there was no such difference for neoplasms (SMR 111, 95% CI 86-141). There was strong evidence that the mortality gap compared with the general population for all causes of death (p<0.001) and all natural causes (p=0.01) increased over the four decades of the study. There was weak evidence that cardiovascular deaths may be increasing relative to the general population (p=0.07). CONCLUSIONS People with first-contact psychosis have an overall mortality risk that is nearly double that of the general population. Most excess deaths are from natural causes. The widening of the mortality gap over the last four decades should be of concern to all clinicians involved in delivering healthcare.

The association of white matter volume in psychotic disorders with genotypic variation in NRG1 , MOG and CNP : a voxel-based analysis in affected individuals and their unaffected relatives

Abstract: We investigated the role of variation in putative psychosis genes coding for elements of the white matter system by examining the contribution of genotypic variation in three single-nucleotide polymorphisms (SNPs) neuregulin 1 (NRG1) SNP8NRG221533, myelin oligodendrocytes glycoprotein (MOG) rs2857766 and CNP (rs2070106) and one haplotype HAP(ICE) (deCODE) to white matter volume in patients with psychotic disorder and their unaffected relatives. Structural magnetic resonance imaging and blood samples for genotyping were collected on 189 participants including patients with schizophrenia (SZ) or bipolar I disorder (BDI), unaffected first-degree relatives of these patients and healthy volunteers. The association of genotypic variation with white matter volume was assessed using voxel-based morphometry in SPM5. The NRG1 SNP and the HAP(ICE) haplotype were associated with abnormal white matter volume in the BDI group in the fornix, cingulum and parahippocampal gyrus circuit. In SZ the NRG1 SNP risk allele was associated with lower white matter volume in the uncinate fasciculus (UF), right inferior longitudinal fasciculus and the anterior limb of the internal capsule. Healthy G-homozygotes of the MOG SNP had greater white matter volume in areas of the brainstem and cerebellum; this relationship was absent in those with a psychotic disorder and the unaffected relatives groups. The CNP SNP did not contribute to white matter volume variation in the diagnostic groups studied. Variation in the genes coding for structural and protective components of myelin are implicated in abnormal white matter volume in the emotion circuitry of the cingulum, fornix, parahippocampal gyrus and UF in psychotic disorders.

Sexual dysfunction in people with prodromal or first-episode psychosis

Abstract: Background Sexual dysfunction is common in psychotic disorder but it is not clear whether it is intrinsic to the development of the illness or secondary to other factors. Aims To compare sexual function in people at ultra-high risk (UHR) of a psychotic disorder, patients with first-episode psychosis predominantly taking antipsychotic drugs and healthy volunteers. Method Sexual function was assessed in a UHR group ( n = 31), a group with first-episode psychosis ( n = 37) and a matched control group of healthy volunteers ( n = 56) using the Sexual Function Questionnaire. Results There was a significant effect of group on sexual function ( P <0.001). Sexual dysfunction was evident in 50% of the UHR group, 65% of first-episode patients and 21% of controls. Within the UHR group, sexual dysfunction was more marked in those who subsequently developed psychosis than in those who did not. Across all groups the severity of sexual dysfunction was correlated with the severity of psychotic symptoms ( P <0.001). Within the first-episode group there was no significant difference in sexual dysfunction between patients taking prolactin-raising v. prolactin-sparing antipsychotics. Conclusions Sexual dysfunction is present prior to onset of psychosis, suggesting it is intrinsic to the development of illness unlikely to be related to the prolactin-raising properties of antipsychotic medication.

Prefrontal and Striatal Volumes in Monozygotic Twins Concordant and Discordant for Schizophrenia

Abstract: dle, inferior, and orbital frontal cortices (SFC, MFC, IFC, and OFC, respectively); the caudate; and putamen. Covarying for whole-brain volume, age, and gender, we found that concordant but not discordant twins with schizophrenia had significantly lower volumes of MFC and OFC than control twins. In contrast, both patient groups had significantly lower SFC volumes than both groups of nonschizophrenic twins. There were no significant group differences in IFC and the striatum. We conclude that the prefrontal cortex shows a heterogeneous pattern of genetic influences on volumetric reductions in schizophrenia.

A twin study of schizoaffective-mania, schizoaffective-depression and other psychotic syndromes

Abstract: The nosological status of schizoaffective disorders remains controversial. Twin studies are potentially valuable for investigating relationships between schizoaffective-mania, schizoaffective-depression, and other psychotic syndromes, but no such study has yet been reported. We ascertained 224 probandwise twin pairs [106 monozygotic (MZ), 118 same-sex dizygotic (DZ)], where probands had psychotic or manic symptoms, from the Maudsley Twin Register in London (1948–1993). We investigated Research Diagnostic Criteria schizoaffective-mania, schizoaffective-depression, schizophrenia, mania and depressive psychosis primarily using a non-hierarchical classification, and additionally using hierarchical and data-derived classifications, and a classification featuring broad schizophrenic and manic syndromes without separate schizoaffective syndromes. We investigated inter-rater reliability and co-occurrence of syndromes within twin probands and twin pairs. The schizoaffective syndromes showed only moderate inter-rater reliability. There was general significant co-occurrence between syndromes within twin probands and MZ pairs, and a trend for schizoaffective-mania and mania to have the greatest co-occurrence. Schizoaffective syndromes in MZ probands were associated with relatively high risk of a psychotic syndrome occurring in their co-twins. The classification of broad schizophrenic and manic syndromes without separate schizoaffective syndromes showed improved inter-rater reliability, but high genetic and environmental correlations between the two broad syndromes. The results are consistent with regarding schizoaffective-mania as due to co-occurring elevated liability to schizophrenia, mania, and depression; and schizoaffective-depression as due to co-occurring elevated liability to schizophrenia and depression, but with less elevation of liability to mania. If in due course schizoaffective syndromes show satisfactory inter-rater reliability and some specific etiological factors they could alternatively be regarded as partly independent disorders

Systematic Review of the Incidence and Prevalence of Schizophrenia and Other Psychoses in England, 1950-2009

Abstract: The Department of Health commissioned this series of systematic reviews on the incidence and prevalence of schizophrenia and other psychotic disorders in England. Incidencei is the number of people who develop an illness for the first time, per year, in a given place; prevalence is the proportion of a defined community who already have or develop an illness at a particular time or during a specified period. Psychotic disorders are a group of mental illnesses characterised by delusions, hallucinations and other problems of thought and emotion. Schizophrenia is a particular type of psychotic disorder, as are affective psychoses that can include psychotic depression and bipolar disorder. In this summary we concentrate on all psychoses as a broad group, and on schizophrenia and affective psychoses as two main sub‐types of psychotic disorders; the full report contains a more detailed breakdown.

Is earlier intervention for schizophrenia possible?: Identifying antecedents of schizophrenia in children aged 9-12 years

Abstract: More recently, clinicians have recognized that attenuated symptoms and significant disability precede the onset of frank psychosis in the majority of patients. This awareness has led to even earlier intervention strategies, targeting help-seeking individuals in the prodromal phase of schizophrenia. These individuals have been identified clinically, using a combination of attenuated psychotic symptoms (Yung et al., 2003) or subtle self-experienced basic symptoms in a range of domains (Klosterkotter, Hellmich, Steinmeyer, & Schultze-Lutter, 2001) and a positive family history of schizophrenia. Results obtained to date suggest that these innovative services have successfully delayed, but not averted, transition to psychosis (Yung et al., 2007).

Patterns of deficits in brain function in bipolar disorder and schizophrenia: a cluster analytic study.

Abstract: Historically, bipolar disorder and schizophrenia have been considered distinct disorders with different etiologies. Growing evidence suggests that overlapping genetic influences contribute to risk for these disorders and that each disease is genetically heterogeneous. Using cluster analytic methods, we empirically identified homogeneous subgroups of patients, their relatives, and controls based on distinct neurophysiologic profiles. Seven phenotypes were collected from two independent cohorts at two institutions. K-means clustering was used to identify neurophysiologic profiles. In the analysis of all participants, three distinct profiles emerged: "globally impaired", "sensory processing", and "high cognitive". In a secondary analysis, restricted to patients only, we observed a similar clustering into three profiles. The neurophysiological profiles of the Schizophrenia (SZ) and Bipolar Disorder (BPD) patients did not support the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic distinction between these two disorders. Smokers in the globally impaired group smoked significantly more cigarettes than those in the sensory processing or high cognitive groups. Our results suggest that empirical analyses of neurophysiological phenotypes can identify potentially biologically relevant homogenous subgroups independent of diagnostic boundaries. We hypothesize that each neurophysiology subgroup may share similar genotypic profiles, which may increase statistical power to detect genetic risk factors.

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

Abstract: 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

Longitudinal follow-up of cavum septum pellucidum and adhesio interthalamica alterations in first-episode psychosis: a population-based MRI study

Abstract: Background Neurodevelopmental alterations have been described inconsistently in psychosis probably because of lack of standardization among studies. The aim of this study was to conduct the first longitudinal and population-based magnetic resonance imaging (MRI) evaluation of the presence and size of the cavum septum pellucidum (CSP) and adhesio interthalamica (AI) in a large sample of patients with first-episode psychosis (FEP). Method FEP patients (n=122) were subdivided into schizophrenia (n=62), mood disorders (n=46) and other psychosis (n=14) groups and compared to 94 healthy next-door neighbour controls. After 13 months, 80 FEP patients and 52 controls underwent a second MRI examination. Results We found significant reductions in the AI length in schizophrenia FEP in comparison with the mood disorders and control subgroups (longer length) at the baseline assessment, and no differences in any measure of the CSP. By contrast, there was a diagnosis×time interaction for the CSP length, with a more prominent increase for this measure in the psychosis group. There was an involution of the AI length over time for all groups but no diagnosis×time interaction. Conclusions Our findings suggest that the CSP per se may not be linked to the neurobiology of emerging psychotic disorders, although it might be related to the progression of the disease. However, the fact that the AI length was shown to be shorter at the onset of the disorder supports the neurodevelopmental model of schizophrenia and indicates that an alteration in this grey matter junction may be a risk factor for developing psychosis.

Theory of Mind as a potential trait marker of schizophrenia: a family study.

Abstract: Introduction Although there is some evidence that Theory of Mind (ToM) deficits may be trait markers of schizophrenia it is not clear yet if ToM deficits are primary deficits, that is, to be independent of deficits in general intellectual abilities and executive function The aim was to examine if ToM deficits may be trait markers of the illness and the effect of cognitive inhibition, general intellectual abilities and depression on ToM abilities of patients with schizophrenia and their unaffected parents Methods We assessed ToM abilities (first-order and second-order ToM stories, The Revised Eyes Test), cognitive inhibition (Stroop Task), general intellectual ability (Standard Progressive Matrices Test Plus) in patients with schizophrenia (N=21) and their unaffected fathers (N=21) and mothers (N=21) in comparison with healthy control families (healthy control males, N=21, healthy control fathers, N=21, healthy control mothers, N=21) Results Patients showed deficits in first-order ToM tasks but some o

Mismatch negativity (mmn) and sensory auditory processing in children aged 9-12 years presenting with putative antecedents of schizophrenia

Abstract: Identification of markers of abnormal brain function in children at-risk of schizophrenia may inform early intervention and prevention programs. Individuals with schizophrenia are characterized by attenuation of MMN amplitude, which indexes automatic auditory sensory processing. The current aim was to examine whether children who may be at increased risk of schizophrenia due to their presenting multiple putative antecedents of schizophrenia (ASz) are similarly characterized by MMN abnormalities, relative to typically developing (TD) children. EEG was recorded from 22 ASz and 24 TD children aged 9 to 12 years (matched on age, sex, and IQ) during a passive auditory oddball task (15% duration deviant). ASz children were those presenting: (1) speech and/or motor development lags/problems; (2) internalizing, externalizing, and/or peer-relationship problems in the clinical range; and (3) psychotic-like experiences. TD children presented no antecedents. MMN amplitude, but not latency, was signifi cantly greater frontally in the ASz group than in the TD group. While MMN abnormalities were present in children at risk of schizophrenia, the nature of this abnormality differed from that observed in adults with schizophrenia. This may reflect developmental and disease effects in a pre-prodromal phase of psychosis onset. Longitudinal follow-up is necessary to establish the developmental trajectory of MMN in at-risk children.