Showing papers by "Robin M. Murray published in 2004"

Causal association between cannabis and psychosis: examination of the evidence

Abstract: Background Controversy remains as to whether cannabis acts as a causal risk factor for schizophrenia or other functional psychotic illnesses. Aims To examine critically the evidence that cannabis causes psychosis using established criteria of causality. Method We identified five studies that included a well-defined sample drawn from population-based registers or cohorts and used prospective measures of cannabis use and adult psychosis. Results On an individual level, cannabis use confers an overall twofold increase in the relative risk for later schizophrenia. At the population level, elimination of cannabis use would reduce the incidence of schizophrenia by approximately 8%, assuming a causal relationship. Cannabis use appears to be neither a sufficient nor a necessary cause for psychosis. It is a component cause, part of a complex constellation of factors leading to psychosis. Conclusions Cases of psychotic disorder could be prevented by discouraging cannabis use among vulnerable youths. Research is needed to understand the mechanisms by which cannabis causes psychosis.

Prevalence and correlates of self-reported psychotic symptoms in the British population

Abstract: Background The psychosis phenotype is generally thought of as a categorical entity. However, there is increasing evidence that psychosis exists in the population as a continuum of severity rather than an all-or-none phenomenon. Aims To investigate the prevalence and correlates of self-reported psychotic symptoms using data from the 2000 British National Survey of Psychiatric Morbidity. Method A total of 8580 respondents aged 16–74 years were interviewed. Questions covered mental health, physical health, substance use, life events and socio-demographic variables. The Psychosis Screening Questionnaire (PSQ) was used to identify psychotic symptoms. Results Of the respondents, 5.5% endorsed one or more items on the PSQ. Factors independently associated with psychotic symptoms were cannabis dependence, alcohol dependence, victimisation, recent stressful life events, lower intellectual ability and neurotic symptoms. Male gender was associated with paranoid thoughts, whereas female gender predicted hallucinatory experiences. Conclusions Self-reported psychotic symptoms are less common in this study than reported elsewhere, because of the measure used. These symptoms have demographic and clinical correlates similar to clinical psychosis.

Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes

Abstract: Context For more than a century, it has been uncertain whether or not the major diagnostic categories of psychosis—schizophrenia and bipolar disorder—are distinct disease entities with specific genetic causes and neuroanatomical substrates. Objective To investigate the relationship between genetic risk and structural variation throughout the entire brain in patients and their unaffected relatives sampled from multiply affected families with schizophrenia or bipolar disorder. Design Analysis of the association between genetic risk and variation in tissue volume on magnetic resonance images. Setting Psychiatric research center. Participants Subjects comprised 25 patients with schizophrenia, 36 of their unaffected first-degree relatives, 37 patients with bipolar 1 disorder who experienced psychotic symptoms during illness exacerbation, and 50 of their unaffected first-degree relatives. Main Outcome Measures We used computational morphometric techniques to map significant associations between a continuous measure of genetic liability for each subject and variation in gray or white matter volume. Results Genetic risk for schizophrenia was specifically associated with distributed gray matter volume deficits in the bilateral fronto-striato-thalamic and left lateral temporal regions, whereas genetic risk for bipolar disorder was specifically associated with gray matter deficits only in the right anterior cingulate gyrus and ventral striatum. A generic association between genetic risk for both disorders and white matter volume reduction in the left frontal and temporoparietal regions was consistent with left frontotemporal disconnectivity as a genetically controlled brain structural abnormality common to both psychotic disorders. Conclusions Genetic risks for schizophrenia and bipolar disorder are associated with specific gray matter but generic white matter endophenotypes. Thus, Emil Kraepelin’s pivotal distinction was neither wholly right nor wholly wrong: the 2 major psychoses show both distinctive and similar patterns of brain structural abnormality related to variable genetic risk.

Predictors of antisocial personality. Continuities from childhood to adult life.

Abstract: Background Antisocial behaviour in adult life has its roots in childhood. Aims To explore the independent and joint effects of childhood characteristics on the persistence of antisocial behaviour into adult life. Method A clinical sample of twins who were systematically ascertained in childhood was followed up 10–25 years later. A total of 225 twins were interviewed regarding childhood and adult psychiatric disorder, psychosocial functioning, and psychosocial and cognitive risk factors. Results Inunivariate analyses, childhood hyperactivity and conduct disorder showed equally strong prediction of antisocial personality disorder (ASPD) and criminality in early and mid-adult life. Lower IQ and reading problems were most prominent in their relationships with childhood and adolescent antisocial behaviour. In multivariate modelling childhood conduct disorder and hyperactivity predicted adult ASPD even when intervening risk factors were accounted for. The number of hyperactive and conduct symptoms also predicted adult outcome. Conclusions Childhood disruptive behaviour has powerful long-term effects on adult antisocial outcomes, which continue into middle adulthood. The importance of number of symptoms, the presence of disruptive disorder, and intermediate experiences highlight three areas where interventions might be targeted.

Corpus callosum size and very preterm birth: relationship to neuropsychological outcome.

Abstract: Thinning of the corpus callosum (CC) is often observed in individuals who were born very preterm. Damage to the CC during neurodevelopment may be associated with poor neuropsychological performance. This study aimed to explore any evidence of CC pathology in adolescents aged 14-15 years who were born very preterm, and to investigate the relationship between CC areas and verbal skills. Seventy-two individuals born before 33 weeks of gestation and 51 age- and sex-matched full-term controls received structural MRI and neuropsychological assessment. Total CC area in very preterm adolescents was 7.5% smaller than in controls, after adjusting for total white matter volume (P = 0.015). The absolute size of callosal subregions differed between preterm and full-term adolescents: preterm individuals had a 14.7% decrease in posterior (P < 0.0001) and an 11.6% decrease in mid-posterior CC quarters (P = 0.029). Preterm individuals who had experienced periventricular haemorrhage and ventricular dilatation in the neonatal period showed the greatest decrease in CC area. In very preterm boys only, verbal IQ and verbal fluency scores were positively associated with total mid-sagittal CC size and mid-posterior surface area. These results suggest that very preterm birth adversely affects the development of the CC, particularly its posterior quarter, and this impairs verbal skills in boys.

The structural brain correlates of neurological soft signs in ÆSOP first-episode psychoses study

Abstract: Patients with schizophrenia and related psychoses have an excess of minor neurological abnormalities (neurological soft signs) of unclear neuropathological origin. These include poor motor coordination, sensory perceptual difficulties and difficulties in sequencing complex motor tasks. Neurological soft signs seem not to reflect primary tract or nuclear pathology. It still has to be established whether neurological soft signs result from specific or diffuse brain structural abnormalities. Studying their anatomical correlates can provide not only a better understanding of the aetiopathogenesis of soft signs, but also of the pathophysiology of schizophrenia. Surprisingly few studies have investigated the brain correlates of neurological soft signs. In the present study, we investigated the relationship between brain structure and neurological soft signs in an epidemiologically based sample of 77 first-episode psychosis patients. We used the Neurological Evaluation Scale for neurological assessment and high-resolution MRI and voxel-based methods of image analysis to investigate brain structure. Higher rates of soft neurological signs (both motor and sensory) were associated with a reduction of grey matter volume of subcortical structures (putamen, globus pallidus and thalamus). Signs of sensory integration deficits were additionally associated with volume reduction in the cerebral cortex, including the precentral, superior and middle temporal, and lingual gyri. Neurological soft signs and their associated brain changes were independent of antipsychotic exposure. We conclude that neurological soft signs are associated with regional grey matter volume changes and that they may represent a clinical sign of the perturbed cortical-subcortical connectivity that putatively underlies psychotic disorders.

Effects of long-term prolactin-raising antipsychotic medication on bone mineral density in patients with schizophrenia

Abstract: Background High rates of osteoporosis in schizophrenia may result from the prolactin-raising effects of some antipsychotic medication. Aims To examine bone mineral density in relation to relevant endocrine variables in patients with schizophrenia taking prolactin-raising antipsychotics. Method Fifty-five patients who had been receiving prolactin-raising antipsychotic medication for >10 years underwent dual-energy X-ray absorptiometry of their lumbar and hip bones. Among the endocrine variables assessed were plasma prolactin and sex hormones. Results Age-related reduced bone mineral density measures were found in 17 (57%) of the male and 8 (32%) of the female patients. Higher doses of the female patients. Higher doses of medication were associated with increased rates of both hyperprolactinaemia and bone mineral density loss. Bone loss for the whole group was correlated with medication dose, and for men was inversely correlated with testosterone values. Conclusions These results suggest that patients with schizophrenia on long-term prolactin-raising antipsychotic medication are at high risk of developing reduced bone mineral density as a consequence of hyperprolactinaemia-induced hypogonadism.

Pathways to schizophrenia: the impact of environmental factors.

Abstract: Schizophrenia is an aetiologically complex disorder arising from the interaction of a range of factors acting at various stages of life. Schizophrenic individuals inherit genes that cause structural brain deviations which may be compounded by early environmental insults. As a result some pre-schizophrenic children exhibit subtle developmental delays, cognitive problems, or poor interpersonal relationships. They are susceptible to dysregulation of dopamine, the final pathway leading to the onset of a psychotic illness. Dopamine dysregulation may arise through a process of sensitization, which, in animals, can be caused by repeated administration of dopamine-releasing drugs. It is clear that the same process occurs in humans, and that some individuals are particularly sensitive to the effects of such drugs for either genetic reasons or through early environmental damage. Stress has also been shown to induce dopamine release in animal studies, and epidemiological studies have demonstrated that social stresses can precipitate schizophrenia. Thus, stresses, such as drug use and social adversity, in adolescence or early adult life may propel the neurodevelopmentally impaired individual over a threshold into frank psychosis.

Pituitary volume in psychosis.

Abstract: Background Patients with psychosis have activation of the hypothalamic–pituitary–adrenal (HPA) axis during the acute phase of the psychosis. Whether this has any morphological consequences for the pituitary gland is currently unknown. Aims To examine pituitary volume variation in people at different stages of psychotic disorder. Method Pituitary volume was measured using 1.5 mm, coronal magnetic resonance images in 24 people with first-episode psychosis, 51 with established schizophrenia and 59 healthy controls. Results Compared with the control group, the people with first-episode psychosis had pituitary volumes that were 10% larger, whereas those with established schizophrenia had pituitary volumes that were 17% smaller. In both of the groups with psychosis, there was no difference in pituitary volume between those receiving typical antipsychotic drugs and those receiving atypical antipsychotics. Conclusions The first episode of a psychosis is associated with a larger pituitary volume, which we suggest is due to activation of the HPA axis. The smaller pituitary volume in the group with established schizophrenia could be the consequence of repeated episodes of HPA axis hyperactivity.

A functional MRI study of working memory task in euthymic bipolar disorder: evidence for task-specific dysfunction

Abstract: Objectives: Even when euthymic bipolar disorder patients can have persistent deficits in working memory, but the neural basis of this deficit remains unclear. We undertook an functional magnetic resonance imaging investigation of euthymic bipolar disorder patients performing two working memory paradigms; the two-back and Sternberg tasks, selected to examine the central executive and the phonological loop respectively. We hypothesized that neuronal dysfunction would be specific to the network underlying the executive rather than the phonological loop component of working memory. Methods: Twelve right-handed euthymic bipolar I males receiving lithium carbonate monotherapy were matched with 12 controls. The two-back task comprised a single working memory load contrasted with baseline vigilance condition. The Sternberg paradigm used a parametric design incorporating variable working memory load with fixed delay between presentation of an array of items to be remembered and a target item. Functional activation data were acquired during performance of the tasks and were analysed to produce brain activation maps representing significant group differences in activation (ANOVA). Load–response curves were derived from the Sternberg task data set. Results: There were no significant between-group differences (t-test) in performance of the two-back task, or in 2 × 5 group by memory load ANOVA for the performance data from Sternberg task. In the two-back task, compared with controls bipolar disorder patients showed reductions in bilateral frontal, temporal and parietal activation, and increased activations with the left precentral, right medial frontal and left supramarginal gyri. No between-group differences were observed in the Sternberg task at any working memory load. Conclusions: Our findings support the notion that, in euthymic bipolar disorder, failure to engage fronto-executive function underpins the core neuropsychological deficits.

Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype.

Abstract: To determine if neuregulin 1 (NRG1) is associated with schizophrenia in Asian populations, we investigated a Han Chinese population using both a family trio design and a case–control design. A total of 25 microsatellite markers and single nucleotide polymorphisms (SNPs) were genotyped spanning the 1.1 Mb NRG1 gene including markers of a seven-marker haplotype at the 5′end of the gene found to be in excess in Icelandic and Scottish schizophrenia patients. The alleles of the individual markers forming the seven marker at-risk haplotype are not likely to be causative as they are not in excess in patients in the Chinese population studied here. However using unrelated patients, we find a novel haplotype (HAPChina 1), immediately upstream of the Icelandic haplotype, in excess in patients (11.9% in patients vs 4.2% in controls; P=0.0000065, risk ratio (rr) 3.1), which was not significant when parental controls were used. Another haplotype (HAPChina 2) overlapping the Icelandic risk haplotype was found in excess in the Chinese (8.5% of patients vs 4.0% of unrelated controls; P=0.003, rr 2.2) and was also significant using parental controls only (P=0.0047, rr 2.1). A four-marker haplotype at the 3′ end of the NRG1 gene, HAPChina 3, was found at a frequency of 23.8% in patients and 13.7% in nontransmitted parental haplotypes (P=0.000042, rr=2.0) but was not significant in the case–control comparison. We conclude that different haplotypes within the boundaries of the NRG1 gene may be associated with schizophrenia in the Han Chinese.

Effect of symptoms on executive function in bipolar illness

Abstract: BACKGROUND The relationship between cognitive function and symptomatology in bipolar disorder is unclear. This study assessed executive function during the manic, depressed and remitted stages of bipolar I disorder. METHOD Tasks assessing phonological and semantic verbal fluency, the Hayling Sentence Completion Test, the Stroop Neuropsychological Screening Test and the Cognitive Estimates Test were administered to manic (n = 15), depressed (n = 15), and remitted (n = 15) bipolar I patients, and to healthy controls (n = 30). Multiple regression analyses and analyses of covariance were used to identify potential determinants of executive dysfunction in the three bipolar groups. RESULTS Executive function deficits were particularly associated with the manic state. In general, manic patients performed less accurately than the remitted and depressed groups, and their performance deficit was related to the severity of positive thought disorder. The depressed and remitted bipolar groups showed a less widespread pattern of impairment. Deficits in response initiation, strategic thinking and inhibitory control were evident in all the bipolar groups. CONCLUSIONS Executive function deficits in bipolar I disorder are most evident during mania, and are particularly associated with formal thought disorder. However, deficits in response initiation, strategic thinking and inhibitory control may be more related to the underlying disorder than a particular symptom profile.

Effects of very low birthweight on brain structure in adulthood.

Abstract: Very-low-birthweight (VLBW) individuals are at high risk of brain injury in the perinatal period We wished to determine how such early brain lesions affect brain structure in adulthood Thirty-two VLBW adults (20 female, 12 male) and 18 term, normal birthweight sibling control individuals (nine female, nine male) underwent structural MRI at a mean age of 23 years 4 months (range 17 to 33 years; SD 34) Images were analyzed using an automated tissue segmentation algorithm in order to estimate whole brain tissue class volumes in native space Images were then warped to a template image in standard space There was no significant between-group difference in whole brain, grey matter, white matter, or total cerebral spinal fluid (CSF) volumes However, lateral ventricular volume was significantly increased by 41% in those with VLBW The ratio of grey to white matter was also significantly increased (by 10%) in those with VLBW Group comparison maps showed widespread changes in the distribution of grey and white matter, and relative excess of ventricular CSF, in the brains of VLBW individuals Increased ventricular volume predicted decreased grey matter in subcortical nuclei and limbic cortical structures, and decreased periventricular white matter We conclude that these diffuse abnormalities of grey and white matter are a consequence of the interaction of perinatal brain injury and ongoing neurodevelopmental processes

Temporal course of auditory hallucinations.

Abstract: We used functional magnetic resonance imaging to examine how brain activity associated with auditory verbal hallucinations in schizophrenia changed during hallucinatory events. Activation in the left inferior frontal and right middle temporal gyri was evident 6-9 s before the person signalled the onset of the hallucination, whereas activation in the bilateral temporal gyri and the left insula coincided with the perception of the hallucination. This supports the hypothesis that during hallucinations activation in cortical regions mediating the generation of inner speech may precede the engagement of areas implicated in the perception of auditory verbal material.

Association analysis of the DRD4 and COMT genes in methamphetamine abuse.

Abstract: We analyzed two polymorphisms in genes encoding proteins of the dopamine system, the Val158Met polymorphism in the catechol-O-methyltransferase gene and the 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene for association with methamphetamine abuse. We used a case/control design with 416 methamphetamine abusing subjects and 435 normal controls. All subjects were Han Chinese from Taiwan. We found an excess of the high activity Val158 allele in the methamphetamine abuser group, consistent with several previous reports of association of this allele with drug abuse. The 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene itself did not show significant association with methamphetamine abuse. However, analysis of the 120-bp VNTR polymorphism and the exon 3 VNTR in the dopamine D4 receptor as a haplotype showed significant association with methamphetamine abuse, which gave an empirical P value 0.0034 for a heterogeneity model. Moreover, there were significant interactive effects between polymorphisms in the catechol-O-methyltransferase and dopamine D4 genes. The evidence of interaction between COMT 158 Val/Met and DRD4 48-bp VNTR polymorphisms (P = 0.0003, OR = 1.45, 95% CI: 1.148-1.77), and between COMT 158 Val/Met and DRD4 120 bp promoter polymorphisms (P = 0.01, OR = 1.10, 95% CI: 1.10-1.18) were significant but the latter was weak. We conclude that genetic variation in the dopamine system may encode an additive effect on risk of becoming a methamphetamine abuser.

The association of inequality with the incidence of schizophrenia--an ecological study.

Abstract: Socio–economic factors are known to be associated with schizophrenia, but no studies have investigated the effect of inequality on incidence rates of schizophrenia. The aim of the study was to determine whether those electoral wards with greater inequality have a higher incidence of schizophrenia. An ecological study was carried out involving a retrospective case record study to calculate the incidence of schizophrenia across wards in Camberwell, South London for the period 1988–1997, and an index of inequality within each ward was calculated. There was no significant effect of inequality overall. However, in the group of deprived wards, the incidence of RDC schizophrenia increased as inequality increased (IRR 3.79, 95 %CI 1.25.11.49 p = 0.019 after adjusting for age, sex, absolute deprivation, ethnicity, proportion of ethnic minorities and the interaction between individual ethnicity and proportion of ethnic minorities. Increased inequality is associated with increasing incidence of schizophrenia, but only in the most deprived areas. This is independent of other known social risk factors.

Reliability of brain volumes from multicenter MRI acquisition: A calibration study

Abstract: Multicenter studies can provide additional information over single center studies because of their increased statistical power. Because similar acquisition protocols are being used internationally for structural magnetic resonance imaging (MRI) studies of the human brain, volumetric MRI data studies seem suitable for this purpose. Possible systematic differences between sites should be avoided, however, particularly when subtle differences in tissue volume are being searched for, such as in neuropsychiatric diseases. In this calibration study, the brains of six healthy volunteers were (re)scanned with MR scanners from four different manufacturers at five different sites, using the local acquisition protocols. The images were segmented at a central reference site. The intraclass correlation coefficient (ICC) was determined for the whole brain, gray and white matter, cerebellum, and lateral and third ventricle volumes. When required, the processing algorithms were calibrated for each site. Calibration of the histogram analysis was needed for segmentation of total brain volume at one site and for gray and white matter volume at all sites. No (additional) calibration was needed for cerebellum and ventricle volumes. The ICCs were ≥0.96 for total brain, ≥0.92 for cerebellum, ≥0.96 for lateral ventricle, ≥0.21 for third ventricle, ≥0.84 for gray matter, and ≥0.78 for white matter volume. Calibration of segmentation procedures allows morphologic MRI data acquired at different research sites to be combined reliably in multicenter studies. Hum. Brain Mapping 22:312–320, 2004. © 2004 Wiley-Liss, Inc.

Persecutory delusions and the determination of self-relevance: an fMRI investigation.

Abstract: Background People with persecutory delusions regard ambiguous data in the social domain as self-relevant and selectively attend to threatening information. This study aimed to characterize these social cognitive biases in functional neuroanatomical terms. Method Eight schizophrenic patients with active persecutory delusions and eight matched normal controls underwent functional magnetic resonance imaging while determining the self-relevance of ambiguous self-relevant or unambiguous other-relevant neutral and threatening statements. Results In determining self-relevance, the deluded subjects showed a marked absence of rostral-ventral anterior cingulate activation together with increased posterior cingulate gyrus activation in comparison to the normal subjects. The influence of threat on self-relevance determination did not yield statistically significant differences between deluded and normal subjects. Conclusions Abnormalities of cingulate gyrus activation while determining self-relevance suggest impaired self-reflection in the persecutory deluded state. This may contribute to persecutory belief formation and maintenance.

Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population.

Abstract: Haploinsufficiency for or mutation in at least one gene from the velocardiofacial syndrome (VCFS) region at chromosome 22q11 is implicated in psychosis. Linkage disequilibrium mapping of the region in patients identified a segment containing two genes, proline dehydrogenase (PRODH) and DGCR6, as candidates [Liu et al., 2002a] and by analysis of additional polymorphisms the PRODH gene was associated with schizophrenia in adult and early onset patients. In the present study we provide additional evidence in support of genetic association between PRODH and schizophrenia in a Chinese population. We analyzed the PRODH gene in a samples of schizophrenic patients and their families from Sichuan, SW China consisting of 528 family trios and sibling pairs. We genotyped six SNPs, PRODH*1195C T, PRODH*1482C T, PRODH*1483A G, PRODH*1766A G, PRODH*1852G A PRODH*1945T C, two of which (PRODH*1483A G and PRODH*1852G A) have not been previously reported. We found association with schizophrenia for two haplotypes consisting of PRODH*1945T C and PRODH*1852G A (Global P = 0.006), and PRODH*1852G A and PRODH*1766A G (Global P = 0.01) which include one of the newly identified markers. After six-fold Bonferroni correction for multiple testing the PRODH*1945T-C/PRODH*1852G-A haplotypes remained significant. This is a sub-haplotype of the PRODH haplotype previously associated with schizophrenia and it also maps to the 3′ region of the gene, indicating that this is the region most likely to contain the underlying risk alleles. Overall this finding supports a role for the PRODH locus in schizophrenia. © 2004 Wiley-Liss, Inc.

A prospective study of impairment in glucose control caused by clozapine without changes in insulin resistance.

Abstract: OBJECTIVE: This prospective study examines the effect of clozapine on glucose control and insulin sensitivity. METHOD: Glucose homeostasis was measured in nine female and 11 male patients with schizophrenia (mean age=30.5 years, SD=7.4) before clozapine treatment and after a mean of 2.5 months (SD=0.95) of clozapine treatment. Oral glucose tolerance and insulin levels were measured. Insulin resistance level was measured by the homeostasis model assessment. RESULTS: Eleven (55%) of the patients developed abnormal glucose control; the mean age of these patients was 30.2 (SD=7.1), and five were women. Patients’ insulin resistance at baseline (mean insulin resistance level=3.88, SD=2.93) was unaffected by clozapine. Mean fasting and 2-hour glucose levels significantly increased by 0.55 mmol/liter and 1.4 mmol/liter, respectively. There was no correlation between change in body mass index and change in fasting glucose levels. CONCLUSIONS: Clozapine impairs glucose control within 4 months of treatment, independ...

Neurodevelopment and schizophrenia

Abstract: 1. Genes and brain development Timothy A. Klempan, Pierandrea Muglia and James L. Kennedy 2. Brain development in healthy children and adolescents: magnetic resonance imaging studies Jay N. Giedd, Michael A. Rosenthal, A. Blythe Rose, Jonathan D. Blumenthal, Elizabeth Molloy, Richard R. Dopp, Liv S. Clasen, Daniel J. Fridberg and Nitin Gogtay 3. Cognitive development: fMRI studies Beatriz Luna and John Sweeney 4. Cognitive development in adolescence: cerebral underpinnings, neural trajectories and the impact of aberrations Stephen J. Wood, Cinzia R. DeLuca, Vicki Anderson and Christos Pantelis 5. Brain plasticity and long-term function after early cerebral insult: the example of very preterm birth Matthew Allin, Chiara Nosarti, Larry Rifkin and Robin M. Murray 6. Do degenerative changes operate across diagnostic boundaries? The case for glucocorticoids involvement in major psychiatric disorders Carmine M. Pariante and David Cotter 7. Velo-cardio-facial syndrome (deletion 22q11.2): a homogeneous neurodevelopmental model for schizophrenia Stephan Eliez and Carl Feinstein 8. Can structural MRI provide an alternative phenotype for genetic studies of schizophrenia? Colm McDonald and Robin M. Murray 9. Nutritional factors and schizophrenia Sahebarao P. Mahadik 10. Schizophrenia, neurodevelopment, and epigenetics Arturas Petronis 11. Early environmental risk factors for schizophrenia Mary Cannon, Kimberlie Dean and Peter B. Jones 12. Transcriptomes in schizophrenia: assessing altered gene expression with microarrays David A. Lewis, Karoly Mirnics and Pat Levitt 13. Is there a role for social factors in a comprehensive development model for schizophrenia? Jane Boydell, Jim Van Os and Robin M. Murray 14. How does drug abuse interact with familial and developmental factors in the aetiology of schizophrenia? Chih-Ken Chen and Robin M. Murray 15. Developmental dysregulation of the dopamine system and the pathophysiology of schizophrenia Anthony A. Grace 16. The development of 'mis-wired' limbic lobe circuitry in schizophrenia and bipolar disorder Francine M. Benes 17. Development of thalamocortical circuitry and the pathophysiology of schizophrenia Darlene S. Melchitzky and David A. Lewis 18. X chromosome, estrogen, and brain development, implications for schizophrenia Michael Craig, William Cutter, Ray Norbury and Declan Murphy 19. Premorbid structural abnormalities in schizophrenia Stephen M. Lawrie 20. Neurodegenerative models of schizophrenia L. Fredrik Jarskog, John H. Gilmore and Jeffrey A. Lieberman 21. Does disordered brain development cut across diagnostic boundaries? Christian W. Kreipke, David R. Rosenberg and Matcheri S. Keshavan 22. Can one identify preschizophrenic children? Eugenia Kravariti, Paola Dazzan, Paul Fearon and Robin M. Murray 23. High risk studies, brain development and schizophrenia Matcheri S. Keshavan 24. Developmental models and hypotheses-driven early interventions in schizophrenia Matcheri S. Keshavan and Barbara A. Cornblatt.