Search

Structural neuroimaging studies have identified a combination of shared and disorder-specific patterns of gray matter (GM) deficits across psychiatric disorders. Pooling large data allows for examination of a possible common neuroanatomical basis that may identify a certain vulnerability for mental illness. Large-scale collaborative research is already facilitated by data repositories, institutionally supported databases, and data archives. However, these data-sharing methodologies can suffer from significant barriers. Federated approaches augment these approaches by enabling access or more sophisticated, shareable and scaled-up analyses of large-scale data. We examined GM alterations using Collaborative Informatics and Neuroimaging Suite Toolkit for Anonymous Computation, an open-source, decentralized analysis application. Through federated analysis of eight sites, we identified significant overlap in the GM patterns ( n  = 4,102) of individuals with schizophrenia, major depressive disorder, and autism spectrum disorder. These results show cortical and subcortical regions that may indicate a shared vulnerability to psychiatric disorders., Competing Interests: The authors declare no competing interests.

Objective: Schizophrenia is a multifaceted disorder associated with structural brain heterogeneity. Despite its relevance for identifying illness subtypes and informative biomarkers, structural brain heterogeneity in schizophrenia remains incompletely understood. Therefore, the objective of this study was to provide a comprehensive insight into the structural brain heterogeneity associated with schizophrenia., Methods: This meta- and mega-analysis investigated the variability of multimodal structural brain measures of white and gray matter in individuals with schizophrenia versus healthy controls. Using the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6139 individuals for a given brain measure, we examined variability in cortical thickness, surface area, folding index, subcortical volume and fractional anisotropy., Results: We found that individuals with schizophrenia are distinguished by higher heterogeneity in the frontotemporal network with regard to multimodal structural measures. Moreover, individuals with schizophrenia showed higher homogeneity of the folding index, especially in the left parahippocampal region., Conclusions: Higher multimodal heterogeneity in frontotemporal regions potentially implies different subtypes of schizophrenia that converge on impaired frontotemporal interaction as a core feature of the disorder. Conversely, more homogeneous folding patterns in the left parahippocampal region might signify a consistent characteristic of schizophrenia shared across subtypes. These findings underscore the importance of structural brain variability in advancing our neurobiological understanding of schizophrenia, and aid in identifying illness subtypes as well as informative biomarkers.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Background: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life., Methods: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed., Results: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth., Conclusions: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Schizophrenia has a heritability of 60-80% 1 , much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The mechanisms of intergenerational transmission of posttraumatic stress disorder (PTSD) from parent to child are not yet known. We hypothesised that the mechanisms involved in trauma transmission may be dependent upon sex specific caregiver-child dyads and these dyads may have a differential impact on post-traumatic stress disorder (PTSD). A non-clinical sample of adult offspring (N = 306) of Australian Vietnam veterans was interviewed in-person to assess the relationship between family emotional climate and caregiver attachment with the offspring's adult experience of post-traumatic stress disorder (PTSD). Attachment to the veteran father was not associated with sons' PTSD, but was for daughters. Attachment to mother was associated with PTSD and depression for both sons and daughters, with positive and warm attachment related to reduced PTSD diagnosis and its symptom clusters. A less positive family emotional environment was related to increased PTSD symptoms in daughters, while for sons a negative relationship style with their mother was related to increased frequency and severity of numbing/avoidance behaviours and hyperarousal symptoms. The findings suggest that sex-related differences in caregiver-child dyads do have a differential impact on PTSD symptom domains and may be one environmental mechanism by which trauma is transmitted across generations., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The present study examined the course of diagnosed alcohol use disorders (AUDs) in a cohort of Australian veterans of the Vietnam War (N = 388) who were assessed 22 and 36 years after returning home. Standardized interviews provided data on AUDs, posttraumatic stress disorder (PTSD), other psychiatric diagnoses, and combat exposure. Overall, 148 veterans (38.1%) had no history of alcohol-related diagnoses, 151 veterans (38.9%) had a past AUD diagnosis that was not current at the second assessment point, and 89 veterans (22.9%) had a current AUD diagnosis at the second assessment. Less education, lower intelligence test scores, and misconduct were individual risk factors for AUDs, as were first-interview diagnoses of PTSD, antisocial personality disorder, generalized anxiety, and dysthymia, but not depression; these variables were all nonsignificant after controlling for combat exposure and PTSD. Multinomial regression was used to assess the relative contributions of combat exposure and PTSD to the course of AUDs. Combat exposure and PTSD had different patterns of association with AUDs whereby combat exposure, but not PTSD, was associated with a history of AUDs, odds ratio (OR) = 1.02, but not with current AUDs, whereas PTSD, but not combat exposure, was associated with current AUDs, OR = 3.37. Current numbing and avoidance symptoms were associated with current AUDs, OR = 4.48. The results do not support a mutual maintenance model of PTSD and AUDs but are consistent with a self-medication model, which suggests treatment for PTSD may have beneficial effects on AUDs., (© 2020 International Society for Traumatic Stress Studies.)

Objectives: Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. To further investigate loci, genes and pathways associated more specifically in the well-characterized Australian Schizophrenia Research Bank cohort, we applied genome-wide single-nucleotide polymorphism analysis in these three annotation categories., Methods: We performed a case-control genome-wide association study in 429 schizophrenia samples and 255 controls. Post-genome-wide association study analyses were then integrated with genomic annotations to explore the enrichment of variation at the gene and pathway level. We also examine candidate single-nucleotide polymorphisms with potential function within expression quantitative trait loci and investigate overall enrichment of variation within tissue-specific functional regulatory domains of the genome., Results: The strongest finding ( p  = 2.01 × 10 -6 , odds ratio = 1.82, 95% confidence interval = [1.42, 2.33]) in genome-wide association study was with rs10252923 at 7q21.13, downstream of FZD1 (frizzled class receptor 1). While this did not stand alone after correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance ( p  = 2.78 × 10 -6 )., Conclusion: The identification of FZD1 , as an independent association signal at the gene level, supports the hypothesis that the Wnt signalling pathway is altered in the pathogenesis of schizophrenia and may be an important target for therapeutic development.

A non-clinical sample of male Australian Vietnam veterans, their wives, and adult offspring were interviewed in-person in a national epidemiological study to assess the relationship between the mental ill-health of veterans and the emotional climate of the family while the children were growing up. Veterans were assessed 17 years before their children using standardised psychiatric diagnostic interviews. Family emotional climate was assessed using offspring ratings of parental attachment, and codings of positive and negative family relationship styles based on five minute speech samples provided by the offspring. Sons and daughters had different views of their mothers and fathers, and were less positive towards their fathers particularly if he had posttraumatic stress disorder (PTSD). Veteran PTSD and depression significantly negatively impacted the family emotional climate, while mothers' mental health was not related. Veteran PTSD symptoms were lowest in secure attachment to the veteran and highest in inconsistent attachment for both sons and daughters, but were not related to attachment to the mother. Veteran PTSD was related to daughters' but not sons' perceptions of family emotional climate. The impact of veterans' PTSD on their families' emotional climate is more marked for daughters than sons., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Whether trauma exposure itself or consequent posttraumatic stress disorder (PTSD) is primarily responsible for smoking and failure to quit remains unclear., Methods: A cohort of male Australian Vietnam veterans (N = 388) was interviewed twice, 22 and 36 years after their return to Australia using standardized psychiatric diagnostic and health interviews and assessment of combat exposure. The smoking trajectory over time revealed a spectrum of outcomes (never smoked, early quitters, late quitters, and continuing smokers). Analysis used multivariate statistics to assess the relative contributions of combat trauma exposure and PTSD while controlling for potential confounders., Results: The trajectory of smoking over time revealed that 21.9% of veterans had never smoked, 45.1% had quit smoking by the time of wave 1, 16.2% were current smokers at wave 1 who had quit by the time of wave 2, 2.8% were late adopters who were current smokers, and 13.9% were continuing smokers. Smoking was associated in single-predictor models with demographics, intelligence, combat exposure, PTSD symptom clusters and diagnosis, and alcohol disorders. Multivariate analysis revealed that PTSD, combat, and intelligence were related to the smoking spectrum but, after adding demographics and other Axis I psychiatric diagnoses, only combat remained significant. No PTSD symptom cluster uniquely predicted smoking status., Conclusions: The results suggest that trauma exposure in the form of military combat may be a more robust predictor of smoking status over time than PTSD. It may be stress itself, rather than poststress disorder, that is more germane to smoking and failure to quit., Implications: Exposure to traumatic stress and development of PTSD have been implicated separately in the maintenance of smoking. This longitudinal cohort study of smoking in war veterans up to three decades postwar enabled evaluation of traumatic stress exposure in combat and the course of PTSD in smoking and quitting while controlling for intelligence, background disadvantage, and other psychiatric conditions. Combat rather than PTSD emerged as more significant to smoking status, suggesting that it may be the traumatic stress itself rather than the development of a poststress disorder that is more germane to smoking in war veterans.

Background: War service increases the risk of post-traumatic stress disorder (PTSD) to combatants, and has been shown to increase the risk of PTSD in their offspring. The extent to which there is an excess compared with the general population is not yet established, nor whether PTSD increases the risk of other psychiatric problems., Methods: A national sample of 133 sons and 182 daughters of a cohort of 179 Australian Vietnam veterans' families were assessed in person, using structured psychiatric interviews. The prevalence of trauma exposures, DSM-IV (Diagnostic and Statistical Manual of Mental Disorders Fourth Edition) diagnoses and suicidality were compared with the Australian Bureau of Statistics' 2007 National Survey of Mental Health and Wellbeing data matched for age and sex. The risk of mental health problems potentially attributable to PTSD was also assessed., Results: Sons and daughters were more likely than population expectations to report exposures to natural disasters, fire or explosions and transport accidents, and sons more likely to report exposure to toxic chemicals whereas daughters were more likely to report sexual assault. Sons and daughters had higher prevalences of alcohol and other substance dependence, depression and anxiety, and PTSD, and children's PTSD was associated with substance dependence, depression and suicidal ideation. There were strong associations between children's PTSD and comorbid conditions of substance use disorders, depression and anxiety., Conclusions: Higher rates of mental health problems in veterans' families, together with comorbidity with PTSD and the link between veterans' and children's PTSD, suggest that the effects of trauma may continue into subsequent generations.

Objective: In response to evidence of deteriorating outcomes of people with schizophrenia we recently published a critical review in the journal concerning why outcomes for schizophrenia are not improving. A published commentary on our review raised criticisms that we aim to address herein., Method: Published data related to four issues raised in the commentary were reviewed., Results: There is a body of evidence that supports the possibility of dramatic improvements in treatment effectiveness, presented in our critical review, and these can be achieved within existing financial resources and present day understanding of the pathophysiology of schizophrenia. However, the commentary leads us to highlight four current obstacles to improving treatment effectiveness: (1) the belief of many psychiatrists that long-term antipsychotic medication raises the cardiovascular mortality rate in schizophrenia when the opposite is almost certainly the case; (2) the need to improve psychiatrist training in diagnostic and communication skills, especially with first episode presentations; (3) the requirement for comprehensive and structured assessment of the highly prevalent deficits in insight and decision making capacity associated with schizophrenia; and (4) the need for improved intervention design to minimise the impact of these deficits on treatment choice and refusal., Conclusion: With a sense of professional urgency, a genuinely respectful and caring partnership between clinicians, affected individuals and their families, and researchers, with relative little innovation, we conclude that the standard of care can definitely be raised now in the treatment of schizophrenia.

Objective: To assess the association between parental post-traumatic stress disorder (PTSD) and offspring PTSD and its specificity for other disorders in a non-clinical epidemiological cohort of Australian Vietnam veterans, their partners and their sons and daughters., Method: Veterans were interviewed twice, in 1992-1994 and 2005-2006; partners were interviewed in 2006-2007, and their offspring in 2012-2014. A total of 125 sons and 168 daughters were interviewed from 197 families, 137 of which also included partners who were the mothers of the children. Statistical analysis used multi-level modelling to compute odds ratios and 95% confidence intervals while controlling for clustering effects within families. Parent PTSD diagnoses were examined for associations with offspring trauma exposure, PTSD and other psychiatric diagnoses., Results: Veteran PTSD increased the risk of PTSD and no other disorder in both sons and daughters; partner PTSD did not. Veteran depression was also a risk factor for sons' PTSD, and alcohol disorder was linked to alcohol dependence in sons and PTSD in daughters, but not when controlling for veteran PTSD., Conclusion: We conclude that PTSD in a Vietnam veteran father increases the risk specifically for PTSD in his sons and daughters., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

White matter abnormalities associated with schizophrenia have been widely reported, although the consistency of findings across studies is moderate. In this study, neuroimaging was used to investigate white matter pathology and its impact on whole-brain white matter connectivity in one of the largest samples of patients with schizophrenia. Fractional anisotropy (FA) and mean diffusivity (MD) were compared between patients with schizophrenia or schizoaffective disorder (n = 326) and age-matched healthy controls (n = 197). Between-group differences in FA and MD were assessed using voxel-based analysis and permutation testing. Automated whole-brain white matter fiber tracking and the network-based statistic were used to characterize the impact of white matter pathology on the connectome and its rich club. Significant reductions in FA associated with schizophrenia were widespread, encompassing more than 40% (234ml) of cerebral white matter by volume and involving all cerebral lobes. Significant increases in MD were also widespread and distributed similarly. The corpus callosum, cingulum, and thalamic radiations exhibited the most extensive pathology according to effect size. More than 50% of cortico-cortical and cortico-subcortical white matter fiber bundles comprising the connectome were disrupted in schizophrenia. Connections between hub regions comprising the rich club were disproportionately affected. Pathology did not differ between patients with schizophrenia and schizoaffective disorder and was not mediated by medication. In conclusion, although connectivity between cerebral hubs is most extensively disturbed in schizophrenia, white matter pathology is widespread, affecting all cerebral lobes and the cerebellum, leading to disruptions in the majority of the brain's fiber bundles., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Australian male Vietnam veterans (N = 388) were assessed 22 and 36 years after their return to Australia using standardized diagnostic interviews, with added data from Army records and self-report questionnaires. Among veterans who ever had posttraumatic stress disorder (PTSD), 50.3% had a current diagnosis at the second assessment; of those who had a current diagnosis at Wave 1, 46.9% were also current at Wave 2. Late onset occurred for 19.0% of veterans, of whom 60.8% were current at Wave 2. Multivariate analysis compared veterans with no history of PTSD (n = 231) with veterans who had ever had PTSD (n = 157) to assess risk factors for PTSD incidence; and veterans with a history, but not current PTSD (n = 78) with veterans who had current PTSD at the second assessment (n = 79) to assess risk factors for failure to remit. Incidence was associated with lower education, shorter Army training predeployment, higher combat, excess drinking, and help-seeking after return to Australia. Prevalence was associated with having a father who saw combat in World War II, being injured in battle, having a lower intelligence test score, experiencing higher combat, and having a diagnosis of phobia at the first assessment. Only combat was common to incidence and prevalence., (Copyright © 2017 International Society for Traumatic Stress Studies.)

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10 -15 ), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10 -6 ). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10 -11 ) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10 -5 ). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Objective: There is evidence that over time health outcomes of people with schizophrenia are deteriorating rather than improving both in terms of mortality rate and levels of morbidity, even in Australia where service resourcing is substantial. Our objective was to examine the evidence of whether poor outcomes reflect decreases in treatment effectiveness and, if so, what are the barriers to improving standards of care. This review will argue that the confidence of clinicians to diagnose schizophrenia early, and provide assertive and long-term care, may be being undermined by a series of controversies in the published literature and discrepancies in clinical practice guidelines., Method: A critical review was conducted of the evidence regarding six issues of high clinical relevance to the treatment of schizophrenia formulated as questions: (1) Is schizophrenia a progressive disease? (2) Does relapse contribute to disease progression and treatment resistance? (3) When should the diagnosis of schizophrenia be made? (4) Should maintenance antipsychotic medication be discontinued in fully remitted first-episode patients? (5) Do antipsychotic medications cause deleterious reductions in cortical grey matter volumes? and (6) Are long-acting injectable antipsychotics more effective in reducing relapse rate compared to oral formulations?, Results: There is reliable evidence for schizophrenia being a progressive disease with emergent treatment resistance in most cases, that relapse contributes to this treatment resistance, that maintenance antipsychotic medication should not be discontinued in remitted first-episode patients, that antipsychotic medication does not appear to cause deleterious grey matter volume changes, that maintenance antipsychotic medication reduces the mortality rate in schizophrenia and that long-acting injectable antipsychotics are more effective in preventing relapse than oral formulations., Conclusion: There is an urgent need to re-engineer the early management of schizophrenia and to routinely evaluate this type of innovation within practice-based research networks. A proposal for an assertive treatment algorithm is included., (© The Royal Australian and New Zealand College of Psychiatrists 2016.)

Importance: Cognitively distinct subgroups of schizophrenia have been defined based on premorbid and current IQ, but little is known about the neuroanatomical differences among these cognitive subgroups., Objectives: To confirm previous findings related to IQ-based subgroups of patients with schizophrenia in an independent sample and extend those findings to determine the extent to which brain volumetric differences correspond to the IQ-based subgroups., Design, Setting, and Participants: A total of 183 participants were assessed at the outpatient settings of Neuroscience Research Australia and Lyell McEwin Hospital from September 22, 2009, to August 1, 2012. Patients were classified using cluster analysis on the basis of current and premorbid IQ differences. Regional magnetic resonance imaging (MRI) brain volumes were compared among the IQ-based subgroups using analysis of covariance with intracranial volume and age as covariates., Main Outcomes and Measures: Wechsler Adult Intelligence Scale, third edition, scores; Wechsler Test of Adult Reading scores; Positive and Negative Syndrome Scale scores; and MRI brain volumes., Results: Ninety-six outpatients (mean [SD] age, 35.7 [8.4] years; age range, 18-51 years; 59 men) with schizophrenia or schizoaffective disorder and 87 healthy controls (mean [SD] age, 31.9 [8.4] years; age range, 20-50 years; 46 men) were studied. Sixty-two patients and 67 healthy controls underwent structural MRI of the brain. Cluster analyses revealed 25 putatively preserved patients (26%), 33 moderately deteriorated patients (34%), 27 severely deteriorated patients (28%), and 11 compromised patients (12%). Negative symptom scores were significantly worse in the severely deteriorated group relative to the putatively preserved group (F2,82 = 13.8, P < .001, effect size [ES] = 1.40). Patient subgroups analyzed revealed significantly reduced inferior parietal volume relative to controls (F3,113 = 9.7, P < .001, ES = 0.85-1.24). The severely deteriorated group had significantly reduced total hippocampal (mean [SEM], 8309.6 [175.0] vs 9024.0 [145.5]; P = .01), lingual gyrus (mean [SEM], 11 996.0 [531.5] vs 13 838.1 [441.9]; P = .05), and superior temporal sulcus (mean [SEM], 4697.8 [192.0] vs 5446.0 [159.6]; P = .05) gray matter volumes relative to the putatively preserved group (ES = 0.91-1.10)., Conclusions and Relevance: Using an independent sample, we obtained proportions in each IQ-based subgroup that were similar to our previous work. Inferior parietal volume reduction was characteristic of schizophrenia relative to controls, and the severely deteriorated IQ group had widespread volumetric reductions. Classifying cognitive heterogeneity in schizophrenia provides a platform to better characterize the neurobiological underpinnings of the illness and its treatment.

Previous studies on schizophrenia have detected elevated cytokines in both brain and blood, suggesting neuroinflammation may contribute to the pathophysiology in some cases. We aimed to determine the extent to which elevated peripheral cytokine messenger RNA (mRNA) expression: (1) characterizes a subgroup of people with schizophrenia and (2) shows a relationship to cognition, brain volume and/or symptoms. Forty-three outpatients with schizophrenia or schizoaffective disorder and matched healthy controls were assessed for peripheral cytokine mRNAs (interleukin (IL)-1β, IL-2, IL-6, IL-8 and IL-18), intelligence quotient, memory and verbal fluency, symptom severity and cortical brain volumes integral to language (that is, Broca's and Wernicke's areas). IL-1β mRNA levels were 28% increased in schizophrenia compared with controls (t(82)=2.64, P<0.01). Using a two-step clustering procedure, we identified a subgroup of people displaying relatively elevated cytokine mRNA levels (17/43 people with schizophrenia and 9/42 controls). Individuals with schizophrenia in the elevated cytokine subgroup performed significantly worse than the low-cytokine subgroup on verbal fluency (F(1,40)=15.7, P<0.001). There was a 17% volume reduction of the left pars opercularis (POp) (Broca's area) in patients with elevated cytokines compared with patients with lower cytokines (F(1,29)=9.41, P=0.005). Negative linear relationships between IL-1β mRNA levels and both verbal fluency and left POp volume were found in schizophrenia. This study is among the first to link blood biomarkers of inflammation with both cognitive deficits and brain volume reductions in people with schizophrenia, supporting that those with elevated cytokines represent a neurobiologically meaningful subgroup. These findings raise the possibility that targeted anti-inflammatory treatments may ameliorate cognitive and brain morphological abnormalities in some people with schizophrenia.

Evidence suggests that anomalous mismatch negativity (MMN) in schizophrenia is related to glutamatergic abnormalities, possibly involving N-methyl-D-aspartate (NMDA) receptors. Decreased cortical expressions of NMDA receptor subunits have been observed in schizophrenia, though not consistently. To aid with integration and interpretation of previous work, we performed a meta-analysis of effect sizes of mRNA or protein levels of the obligatory NR1 subunit in prefrontal cortex from people with schizophrenia. In schizophrenia compared to unaffected controls the pooled effect size was -0.64 (95% confidence interval: -1.08 to -0.20) for NR1 mRNA reduction and -0.44 (95% confidence interval: -0.80 to -0.07) for NR1 protein reduction. These results represent the first step to a deeper understanding of the region-specific, cell-specific, and stage-specific NMDA receptor hypofunction in schizophrenia, which could be linked to mismatch negativity deficits via transgenic and pharmacological animal models., (Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.)

People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

Growing evidence suggests that testosterone may play a role in the pathophysiology of schizophrenia given that testosterone has been linked to cognition and negative symptoms in schizophrenia. Here, we determine the extent to which serum testosterone levels are related to neural activity in affective processing circuitry in men with schizophrenia. Functional magnetic resonance imaging was used to measure blood-oxygen-level-dependent signal changes as 32 healthy controls and 26 people with schizophrenia performed a facial emotion identification task. Whole brain analyses were performed to determine regions of differential activity between groups during processing of angry versus non-threatening faces. A follow-up ROI analysis using a regression model in a subset of 16 healthy men and 16 men with schizophrenia was used to determine the extent to which serum testosterone levels were related to neural activity. Healthy controls displayed significantly greater activation than people with schizophrenia in the left inferior frontal gyrus (IFG). There was no significant difference in circulating testosterone levels between healthy men and men with schizophrenia. Regression analyses between activation in the IFG and circulating testosterone levels revealed a significant positive correlation in men with schizophrenia (r=.63, p=.01) and no significant relationship in healthy men. This study provides the first evidence that circulating serum testosterone levels are related to IFG activation during emotion face processing in men with schizophrenia but not in healthy men, which suggests that testosterone levels modulate neural processes relevant to facial emotion processing that may interfere with social functioning in men with schizophrenia., (Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.)

Lifetime suicidality was assessed in a cohort of 448 ageing Australian Vietnam veterans and 237 female partners during in-person structured psychiatric interviews that permitted direct comparison with age-sex matched Australian population statistics. Relative risks for suicidal ideation, planning and attempts were 7.9, 9.7 and 13.8 times higher for veterans compared with the Australian population and for partners were 6.2, 3.5 and 6.0 times higher. Odds ratios between psychiatric diagnoses and suicidality were computed using multivariate logistic regression, and suicidality severity scores were assigned from ideation, planning and attempt, and analysed using ordinal regression. PTSD, depression alcohol disorders, phobia and agoraphobia were prominent predictors of ideation, attempts and suicidal severity among veterans, while depression, PTSD, social phobia and panic disorder were prominent predictors among partners. For veterans and their partners, PTSD is a risk factor for suicidality even in the presence of other psychiatric disorders, and is stronger in Vietnam veterans than their partners., (Copyright © 2015. Published by Elsevier Ltd.)

Aim: A deficit in theory of mind--the ability to infer and reason about the mental states of others - might underpin the poor social functioning of patients with psychosis. Unfortunately, however, there is considerable variation in how such a deficit is assessed. The current study compared three classic tests of theory of mind in terms of their ability to detect impairment in patients in the early stages of psychosis., Methods: Twenty-three patients within 2 years of their first psychotic episode and 19 healthy controls received picture-sequencing, joke-appreciation and story-comprehension tests of theory of mind., Results: Whereas the picture-sequencing and joke-appreciation tests successfully detected a selective theory-of-mind deficit in patients, the story-comprehension test did not., Conclusions: The findings suggest that tests that place minimal demands on language processing and involve indirect, rather than explicit, instructions to assess theory of mind might be best suited to detecting theory-of-mind impairment in early stages of psychosis., (© 2013 Wiley Publishing Asia Pty Ltd.)

Introduction: Patients with delusions typically seek less information when making decisions than controls ("jumping-to-conclusions", JTC) and paradoxically over-adjust to counter-evidence on probabilistic reasoning tasks. Previous studies have examined JTC bias across the delusion-prone continuum, but have not considered the co-occurrence of both biases at early stages of psychosis. This was our aim., Method: Twenty-three early psychosis patients and 19 healthy controls completed two versions of the probabilistic reasoning task: a "draws-to-decision" version (to assess JTC) and a "graded-estimates" version (to assess over-adjustment). Both versions have been used previously with clinically delusional people with schizophrenia. IQ, memory and executive function were also examined., Results: Patients took fewer trials to reach a decision in the draws-to-decision version and showed greater over-adjustment to counter-evidence in the graded-estimates version than controls. Across groups, those who jumped to conclusions showed greater over-adjustment. Poor executive function predicted more extreme biases in controls but not in patients. Task performances were unrelated to memory. Similar results were evident in patient and control subgroups matched on IQ, and years of formal education., Conclusions: A jumping-to-conclusions bias and an over-adjustment bias co-occurred in the early psychosis patients. Implications are discussed concerning the role of such biases in delusion-proneness.

Objectives: Attributional biases to externalize blame for negative events (externalizing bias) and to target other people for blame (personalizing bias) may constitute a vulnerability to psychosis. However, most research to date has only examined attributional biases in chronic patients. We examined attributional style, paranoia, and depression in early psychosis patients to assess the primacy of attributional biases in psychosis., Design: A quasi-experimental design was adopted to compare the attributional style of patients and controls. Correlates of attributional style were also examined., Methods: Early psychosis patients and age- and gender-matched healthy controls completed the 'Internal, Personal and Situational Attributions Questionnaire'. Paranoid tendencies, suspiciousness, and depression were also assessed in both groups, while severity of current symptoms was assessed in patients., Results: A high proportion of patients had persecutory delusions. These patients, however, did not differ from controls in externalizing or personalizing bias. Whereas suspiciousness and persecutory delusions in patients associated with externalizing bias, no bias measures associated with paranoid tendencies in either patients or controls. Counter to the pattern seen for endogenous depression, depression in patients was associated with an increased tendency to attribute events to self and a decreased tendency to attribute events to circumstances., Conclusions: These preliminary findings raise doubts about the primacy of attributional biases in psychosis. The novel findings with regard to depression warrant further investigation and suggest that young people, who develop depression after the onset of psychosis, may experience a need to re-establish a sense of personal control over life events that appear unpredictable., (© 2013 The British Psychological Society.)

Blockade of N-methyl-D-aspartate receptors (NMDARs) produces behavior in healthy people that is similar to the psychotic symptoms and cognitive deficits of schizophrenia and can exacerbate symptoms in people with schizophrenia. However, an endogenous brain disruption of NMDARs has not been clearly established in schizophrenia. We measured mRNA transcripts for five NMDAR subunit mRNAs and protein for the NR1 subunit in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control (n=74) brains. Five NMDAR single-nucleotide polymorphisms (SNPs) previously associated with schizophrenia were tested for association with NMDAR mRNAs in postmortem brain and for association with cognitive ability in an antemortem cohort of 101 healthy controls and 48 people with schizophrenia. The NR1 subunit (mRNA and protein) and NR2C mRNA were decreased in postmortem brain from people with schizophrenia (P=0.004, P=0.01 and P=0.01, respectively). In the antemortem cohort, the minor allele of NR2B rs1805502 (T5988C) was associated with significantly lower reasoning ability in schizophrenia. In the postmortem brain, the NR2B rs1805502 (T5988C) C allele was associated with reduced expression of NR1 mRNA and protein in schizophrenia. Reduction in NR1 and NR2C in the DLPFC of people with schizophrenia may lead to altered NMDAR stoichiometry and provides compelling evidence for an endogenous NMDAR deficit in schizophrenia. Genetic variation in the NR2B gene predicts reduced levels of the obligatory NR1 subunit, suggesting a novel mechanism by which the NR2B SNP may negatively influence other NMDAR subunit expression and reasoning ability in schizophrenia.

Sex steroids affect cognitive function as well as emotion processing and regulation. They may also play a role in the pathophysiology of schizophrenia. However, the effects of sex steroids on cognition and emotion-related brain activation in schizophrenia are poorly understood. Our aim was to determine the extent to which circulating testosterone relates to brain activation in men with schizophrenia compared to healthy men during cognitive-emotional processing. We assessed brain activation in 18 men with schizophrenia and 22 age-matched healthy men during an emotional go/no-go task using fMRI and measured total serum testosterone levels on the same morning. We performed an ROI analysis to assess the relationship between serum testosterone and brain activation, focusing on cortical regions involved the emotional go/no-go task. Slower RT and reduced accuracy was observed when participants responded to neutral stimuli, while inhibiting responses to negative stimuli. Healthy men showed a robust increase in activation of the middle frontal gyrus when inhibiting responses to negative stimuli, but there was no significant association between activation and serum testosterone level in healthy men. Men with schizophrenia showed a less pronounced increase in activation when inhibiting responses to negative stimuli; however, they did show a strong inverse association between serum testosterone level and activation of the bilateral middle frontal gyrus and left insula. Additionally, increased accuracy during inhibition of response to negative words was associated with both higher serum testosterone levels and decreased activation of the middle frontal gyrus in men with schizophrenia only. We conclude that endogenous hormone levels, even within the normal range, may play an enhanced modulatory role in determining the neural and behavioural response during cognitive-emotional processing in schizophrenia.

The model of mismatch negativity (MMN) as a simple index of change detection has been superseded by a richer understanding of how this event-related potential (ERP) reflects the representation of the sound environment in the brain. Our conceptualization of why the MMN is altered in certain groups must also evolve along with a better understanding of the activities reflected by this component. The detection of change incorporates processes enabling an automatic registration of "sameness", a memory for such regularities and the application of this recent acoustic context to interpreting the present and future state of the environment. It also includes "weighting" the importance of this change to an organism's behaviour. In this light, the MMN has been considered a prediction error signal that occurs when the brain detects that the present state of the world violates a context-driven expectation about the environment. In this paper we revisit the consistent observation of reduced MMN amplitude in patients with schizophrenia. We review existing data to address whether the apparent deficit might reflect problems in prediction error generation, estimation or salience. Possible interpretations of MMN studies in schizophrenia are linked to dominant theories about the neurobiology of the illness., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: Cancer incidence in schizophrenia is not increased commensurate with higher rates of risk exposures. Here we report an investigation of the DNA damage response, an anti-tumorigenic defence, in immortalised lymphoblasts from patients with schizophrenia., Methods: Unirradiated and irradiated (5Gy) lymphoblasts from schizophrenia patients (n = 28) and healthy controls (n = 28) were immunostained for the phosphorylated histone variant H2AX (γH2AX), an index of DNA double-strand breaks. Flow cytometry was used to assess cell cycle distribution and γH2AX immunofluorescence. Rate of DNA repair was quantified by determining the temporal change in γH2AX values following irradiation., Results: In unirradiated lymphoblasts, γH2AX levels were significantly increased in the schizophrenia group compared with controls (effect size = 0.86). This increase was most evident in patients with cognitive deficits. In irradiated lymphoblasts, peak radiation-induced γH2AX levels were significantly reduced in patients. No differences between patients and controls were found in the rate of DNA repair or in cell cycle distribution., Conclusions: The significant differences in DNA damage response signalling observed involve modification of histone variant H2AX and thereby implicate regulatory processes determining chromatin structure in dividing lymphoblasts from patients with schizophrenia. The role that aberrant DNA damage response signalling plays in protecting patients from cancer is unclear.

OBJECTIVES. Olfactory hallucinations (OHs) are underrepresented in conventional clinical instruments, infrequently researched, and poorly understood. To advance understanding of OHs, we examined their past-month prevalence and co-occurring symptoms in two datasets. DESIGN. One dataset comprised categorical codes and was examined using homogeneity analysis and logistic regression; the other dataset comprised numeric ratings and was examined using principal components analyses and linear regression. METHOD. The two datasets included: (1) 962 cases with Present State Examination - 9th Edition (PSE-9), codes (recoded present/absent) from the World Health Organization 10 Country (WHO-10) Study and (2) 265 cases with ratings on Scales for Assessing Positive/Negative Symptoms of Schizophrenia (SAPS/SANS). Two PSE-9 items (external- and self-smells) were recoded into a single OH item to examine consistency with the SAPS/SANS dataset, which contained a single OH item. RESULTS. Prevalence of OHs and hallucinations in other modalities differed according to the WHO-10 international centre. Across centres, OHs were present in 13% of the WHO-10 dataset, similar to the 17% prevalence rate in the SAPS/SANS dataset. Referential/control delusions and other hallucinations (particularly, somatic/tactile/gustatory hallucinations) were significant independent correlates of OHs in both datasets. OHs also co-occurred with social anxiety and depression in the WHO-10 dataset, with self-smells being particularly associated with self-depreciation. CONCLUSIONS. Sociocultural factors may modulate the self-reporting and/or detection of OHs and hallucinations in other modalities. Referential/control delusions promote the generation and/or maintenance of OHs independent of factors shared with other hallucinations. OHs and hallucinations of taste, touch, and bodily sensation frequently co-occur. Self-smells warrant sensitive probing., (©2010 The British Psychological Society.)

Aim: Clinical practice improvement carried out in a quality assurance framework relies on routinely collected data using clinical indicators. Herein we describe the development, minimum training requirements, and inter-rater agreement of indicators that were used in an Australian multi-site evaluation of the effectiveness of early psychosis (EP) teams., Methods: Surveys of clinician opinion and face-to-face consensus-building meetings were used to select and conceptually define indicators. Operationalization of definitions was achieved by iterative refinement until clinicians could be quickly trained to code indicators reliably. Calculation of percentage agreement with expert consensus coding was based on ratings of paper-based clinical vignettes embedded in a 2-h clinician training package., Results: Consensually agreed upon conceptual definitions for seven clinical indicators judged most relevant to evaluating EP teams were operationalized for ease-of-training. Brief training enabled typical clinicians to code indicators with acceptable percentage agreement (60% to 86%). For indicators of suicide risk, psychosocial function, and family functioning this level of agreement was only possible with less precise 'broad range' expert consensus scores. Estimated kappa values indicated fair to good inter-rater reliability (kappa > 0.65). Inspection of contingency tables (coding category by health service) and modal scores across services suggested consistent, unbiased coding across services., Conclusions: Clinicians are able to agree upon what information is essential to routinely evaluate clinical practice. Simple indicators of this information can be designed and coding rules can be reliably applied to written vignettes after brief training. The real world feasibility of the indicators remains to be tested in field trials.

This study assessed psychiatric diagnoses in female partners of Australian Vietnam veterans, compared these with national Australian population statistics, and assessed their relationship with veterans' military service and mental health. Independent assessments of 240 veteran-partner couples used standardized physical and psychiatric diagnostic interviews that permitted comparison with Australian population data. Multivariate regression modeling examined associations of veterans' war service, combat, and psychiatric status with women's mental health. Anxiety disorders and severe recurrent depression were among 11 of 17 psychiatric diagnoses that were significantly in excess of population expectations. Veterans' combat and post-traumatic stress disorder were significant predictors of women's depressive disorder, particularly severe depression. We conclude that veterans' war service and mental health sequelae including post-traumatic stress disorder are associated with higher rates of mental disorder in their female partners 3 decades after the war.

The literature that is relevant to evaluation of treatment effectiveness is large, scattered and difficult to assemble for appraisal. This scoping review first develops a conceptual framework to help organize the field, and second, uses the framework to appraise early psychosis intervention (EPI) studies. Literature searches were used to identify representative study designs, which were then sorted according to evaluation approach. The groupings provided a conceptual framework upon which a map of the field could be drawn. Key words were cross-checked against definitions in dictionaries of scientific terms and the National Library of Medicine Medical Subject Headings (MeSH) browser. Using the final list of key words as search terms, the EPI evaluation literature was appraised. Experimental studies could be grouped into two classes: efficacy and effectiveness randomized controlled trials. Non-experimental studies could be subgrouped into at least four overlapping categories: clinical epidemiological; health service evaluations; quality assurance studies; and, quasi-experimental assessments of treatment effects. Applying this framework to appraise EPI studies indicated promising evidence for the effectiveness of EPI irrespective of study design type, and a clearer picture of where future evaluation efforts should be focused. Reliance on clinical trials alone will restrict the type of information that can inform clinical practice. There is convergent evidence for the benefits of specialized EPI service functions across a range of study designs. Greater investment in health services research and quality assurance approaches in evaluating EPI effectiveness should be made, which will involve scaling up of study sizes and development of an EPI programme fidelity rating template. The degree of complexity of the evaluation field suggests that greater focus on research methodology in the training of Australasian psychiatrists is urgently needed.

A prospective cohort study of a random sample of 1,000 Australian Army Vietnam veterans analyzed risk factors for postwar mortality using information from Army records and personal interview assessments of physical and mental health measured approximately 15 years earlier. This enabled examination of the role of combat, military service, and psychiatric status including post-traumatic stress disorder (PTSD) on postwar civilian mortality. Factors predicting mortality were identified using multivariate statistical methods including logistic and Cox regression. Mortality was associated principally with age, enlistment route (regular vs. national service conscripts), and conduct while in service in the whole cohort. Additional analysis using interview data revealed that mortality was predicted by age, smoking status, chronic diabetes, bronchitis and blood diseases, and treatment for cancer and heart disease. Psychiatric status including PTSD diagnosis was not associated with mortality. Veterans' mortality risk may be reduced by attention to smoking and alcohol both in-service and postservice.

Aim: Expert opinion holds that the rate of implementation of specialist services for first presentation psychosis in Australia is much too slow. We aimed to collect evidence regarding this view from the first national survey of adult public mental health services about their self-reported efforts to implement specialist early psychosis intervention (EPI)., Methods: Using a purpose-designed Census form for assessing EPI implementation, adult public mental health service directors throughout Australia were asked about EPI-relevant local service activities., Results: Sixty Census forms were returned (response rate = 61%), representing a total catchment population of 12.5 million people. A minority of services reported high levels of EPI implementation, which varied widely between area services and across state and territory jurisdictions. Rural and remote services were overrepresented in the lowest levels of reported EPI implementation. Only one service characteristic, the value of identifiable funding committed specifically to EPI, was predictive of level of reported EPI implementation., Conclusions: The disturbingly high levels of variability in EPI implementation across jurisdictions suggest a pressing need for a set of nationally agreed uniform EPI implementation standards. Additional specific strategies for rural and remote mental health services may be needed for these services to implement EPI.

The reported reduction in cancer risk in those suffering from schizophrenia may be because antipsychotic medications have antineoplastic effects. In this study, 6 antipsychotic agents with a range of structural and pharmacological properties (reserpine, chlorpromazine, haloperidol, pimozide, risperidone and olanzapine), were screened for their effect on the viability of cell lines derived from lymphoblastoma, neuroblastoma, non-small cell lung cancer and breast adenocarcinoma. We aimed to determine if antipsychotic drugs in general possess cancer-specific cytotoxic potential, and whether it can be attributed to a common mode of action. With the exception of risperidone, all drugs tested displayed selective inhibition of the viability of cancer cell lines compared with normal cells. Using Affymetrix expression microarrays and quantitative real-time polymerase chain reaction, we found that for the antipsychotic drugs, olanzapine and pimozide, cytotoxicity appeared to be mediated via effects on cholesterol homeostasis. The role of cholesterol metabolism in the selective cytotoxicity of these drugs was supported by demonstration of their increased lethality when coadministered with a cholesterol synthesis inhibitor, mevastatin. Also, pimozide and olanzapine showed accelerating cytotoxic effects from 12 to 48 hr in time course studies, mirroring the time-dependent onset of cytotoxicity induced by the amphiphile, U18666A. On the basis of these results, we concluded that the Class II cationic amphiphilic properties of antipsychotic drugs contribute to their cytotoxic effects by acting on cholesterol homeostasis and altering the biophysical properties of cellular membranes, and that drugs affecting membrane-related cholesterol pathways warrant further investigation as potential augmentors of standard cancer chemotherapy.

The long-term health consequences of war service remain unclear, despite burgeoning scientific interest. A longitudinal cohort study of a random sample of Australian Vietnam veterans was designed to assess veterans' postwar physical and mental health 36 years after the war (2005-2006) and to examine its relation to Army service, combat, and post-traumatic stress disorder (PTSD) assessed 14 years previously (1990-1993). Prevalences in veterans (n = 450) were compared with those in the Australian general population. Veterans' Army service and data from the first assessments were evaluated using multivariate logistic regression prediction modeling. Veterans' general health and some health risk factors were poorer and medical consultation rates were higher than Australian population expectations. Of 67 long-term conditions, the prevalences of 47 were higher and the prevalences of 4 were lower when compared with population expectations. Half of all veterans took some form of medication for mental well-being. The prevalence of psychiatric diagnoses exceeded Australian population expectations. Military and war service characteristics and age were the most frequent predictors of physical health endpoints, while PTSD was most strongly associated with psychiatric diagnoses. Draftees had better physical health than regular enlistees but no better mental health. Army service and war-related PTSD are associated with risk of illness in later life among Australian Vietnam veterans.

Objective: Controversy concerning cancer incidence in schizophrenia exists because of heterogeneous study findings., Method: A meta-analysis was performed on standardized incidence ratios (SIR) of cancer in patients with schizophrenia and first-degree relatives and compared with general population samples., Results: The pooled overall cancer incidence in patients was not significantly increased (SIR = 1.05, CI 0.95-1.15). Lung cancer incidence was slightly increased (SIR = 1.31, CI 1.01-1.71), but was reduced after adjusting for smoking prevalence. The incidence of several cancers unrelated to smoking was reduced in patients. Breast cancer rates were significantly increased in female patients. The pooled overall cancer incidence in siblings (SIR = 0.89, CI 0.84-0.94) and parents (SIR = 0.90, CI 0.88-0.93) was significantly reduced. A meta-regression detected a significant relationship between cancer risk in the general population and relative risk in patients., Conclusion: The meta-analysis aided exploration of inconsistent study findings. There is a discrepancy between cancer risk exposure and cancer incidence in schizophrenia consistent with a protective effect.

Objective: This study aimed to examine the relative contributions to physical health of combat trauma exposure and posttraumatic stress disorder (PTSD), which have both been implicated separately in poorer physical health but whose unconfounded effects have not been teased out., Methods: Data from an epidemiological study of Australian Vietnam veterans, which used personal interviews and standardized physical and psychiatric health assessments, provided the means to assess the independent and joint effects of psychological trauma exposure and PTSD on a wide range of self-reported measures of physical health. Trauma exposure was measured by published scales of combat exposure and peritraumatic dissociation. Logistic regression modeling was used to assess the relative importance of trauma exposure and PTSD to health while controlling for a set of potential confounders including standardized psychiatric diagnoses., Results: Greater health service usage and more recent health actions were associated more strongly with PTSD, which was also associated with a range of illness conditions coded by the World Health Organization International Classification of Diseases, 9th Edition (asthma, eczema, arthritis, back and other musculoskeletal disorders, and hypertension) both before and after controlling for potential confounders. In contrast, combat exposure and peritraumatic dissociation were more weakly associated with a limited number of unconfounded physical health outcomes., Conclusions: This study provided evidence that PTSD, rather than combat exposure and peritraumatic dissociation, is associated with a pattern of physical health outcomes that is consistent with altered inflammatory responsiveness.

Objective: To review the first 10 years of operation of the Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD), Australia's first virtual research institute., Method: Narrative description of the evolution of NISAD., Results: Since inception in 1996, NISAD has developed a wide range of activities to enhance existing efforts and develop new initiatives in schizophrenia research, initially throughout New South Wales, but increasingly on a national scale. This involved the initial development of critical research infrastructure to provide the foundation, with the subsequent focus on developing a multidisciplinary programme of schizophrenia research, across the basic to applied research spectrum. While the primary focus has been the scientific domain, NISAD has also played a leading role in increasing public awareness of schizophrenia as a disease amenable to scientific investigation., Conclusion: NISAD has succeeded in building a framework to apply the latest developments in neuroscience to the study of schizophrenia and has formed a multidisciplinary network of clinicians and neuroscientists who are actively collaborating on a range of research initiatives. The 'virtual institute' structure of NISAD has proven cost-efficient and consistent with innovative thinking about research resource management.

The purpose of the present study was to determine antipsychotic doses that achieve 80% striatal dopamine D2-receptor occupancy for haloperidol, risperidone and olanzapine in rats. Wistar rats were treated with normal saline vehicle (controls), haloperidol (0.25 and 0.5 mg/kg/day), risperidone (3, 5 and 6 mg/kg/day) and olanzapine (5 and 10 mg/kg/day) for 7 days via osmotic minipumps. Striatal and cerebellar tissue were collected and in vivo dopamine D2-receptor occupancies were determined using 3H-raclopride. The doses required to achieve dopamine D2-receptor occupancy of 80% in 11- and 24-week old rats were: haloperidol 0.25 mg/kg/day, risperidone 5 mg/kg/day and olanzapine 10 mg/kg/day.

Introduction: The aim of this study was to investigate whether there is an increased susceptibility to apoptosis in cultured fibroblasts from patients with schizophrenia., Method: Dermal fibroblasts were collected and cultured from three groups: patients with schizophrenia, patients with non-schizophrenic psychosis, and healthy comparison subjects. Susceptibility to apoptosis was measured at the level of degradation product (proportion of cells in the sub-G0 cell cycle fraction in which apoptotic bodies accumulate), pro-apoptotic effector (activated caspase-3), and molecular regulators (P53, Bax and Bcl-2). Cell lines were studied under both basal culture and cycloheximide (an apoptotic inducer) exposure conditions., Results: Consistent with increased susceptibility to apoptosis, the proportion of sub-G0 cells under basal conditions was significantly larger in the schizophrenia group, compared to the non-schizophrenic psychosis group. However when apoptosis was stimulated with cycloheximide, the schizophrenia group showed an attenuated caspase-3 response. The pattern of correlations between regulators, caspase-3 and the proportion of sub-G0 cells was different in the schizophrenia group, consistent with group-specific apoptotic pathway dysregulation., Conclusion: The study demonstrated anomalous apoptotic mechanisms in schizophrenia, which appear not to affect non-schizophrenia psychosis patients. The detection of these anomalies in fibroblasts suggests that altered apoptosis may be observable in all somatic cell types in schizophrenia.

Background: Although there is evidence that post-mortem interval (PMI) is not a major contributor to reduced overall RNA integrity, it may differentially affect a subgroup of gene transcripts that are susceptible to PMI-related degradation. This would particularly have ramifications for microarray studies that include a broad spectrum of genes., Method: Brain tissue was removed from adult mice at 0, 6, 12, 18, 24, 36 and 48 h post-mortem. RNA transcript abundance was measured by hybridising RNA from the zero time point with test RNA from each PMI time point, and differential gene expression was assessed using cDNA microarrays. Sequence and ontological analyses were performed on the group of RNA transcripts showing greater than two-fold reduction., Results: Increasing PMI was associated with decreased tissue pH and increased RNA degradation as indexed by 28S/18S ribosomal RNA ratio. Approximately 12% of mRNAs detected on the arrays displayed more than a two-fold decrease in abundance by 48 h post-mortem. An analysis of nucleotide composition provided evidence that transcripts with the AUUUA motif in the 3' untranslated region (3'UTR) were more susceptible to PMI-related RNA degradation, compared to transcripts not carrying the 3'UTR AUUUA motif. Consistent with this finding, ontological analysis showed transcription factors and elements to be over-represented in the group of transcripts susceptible to degradation., Conclusion: A subgroup of mammalian mRNA transcripts are particularly susceptible to PMI-related degradation, and as a group, they are more likely to carry the 3'UTR AUUUA motif. PMI should be controlled for in human and animal model post-mortem brain studies, particularly those including a broad spectrum of mRNA transcripts.

Background: Disturbed speech in schizophrenia may reflect pragmatic deficits of expressive language. Pragmatic comprehension deficits also occur in schizophrenia. This study investigated whether poor 'mind-reading' (i.e. a general difficulty with inferring and monitoring other people's thoughts) causes pragmatic language impairments of both expression and comprehension in patients with schizophrenia., Method: Mind-reading (or theory of mind) was tested in patients with schizophrenia and in healthy controls using a false-belief picture-sequencing task. Pragmatic comprehension skills were assessed using a test of non-literal speech interpretation. Clinical ratings of formal thought disorder (FTD) indexed the expressive language deficits of patients. To control for possible contributory effects of executive dysfunction, inhibitory control was tested using capture picture-sequences and executive-planning was tested using the Tower of London task., Results: False-belief picture-sequencing, understanding of irony and understanding of metaphors were all selectively impaired in the patients. Poor mind-reading (indexed by high error rate in sequencing false-belief stories) was associated with poor understanding of irony, but was unrelated to poor understanding of metaphors. Whereas poor appreciation of irony and poor mind-reading were associated with high ratings of positive formal thought disorder, high ratings of negative formal thought disorder were associated with poor understanding of metaphors and executive dysfunction., Conclusions: Whereas poor mind-reading may contribute to positive aspects of formal thought disorder and impaired appreciation of irony in patients with schizophrenia; negative features of formal thought disorder and poor understanding of metaphors appear better explained by abnormal semantics. Overall, the findings of this study support the view that the functional basis of formal thought disorder in schizophrenia is not unitary.

Objective: To evaluate measures of schizotypy as familial risk factors for schizophrenia with the aim of making recommendations for assessing schizotypy as part of screening procedures for identifying people at risk of schizophrenia., Method: Published studies using self-report and interview-based measures of schizotypy to assess relatives of patients with schizophrenia are reviewed. A parent study is reported evaluating the diagnostic accuracy of parental schizotypy as assessed by three questionnaire-based measures: the Chapman Perceptual Aberration and Physical Anhedonia Scales, and the Eysenck Psychoticism Scale. Group scores for these self-report ratings of 23 parent-pairs of patients with schizophrenia, 20 parent-pairs of patients with chronic nonpsychotic psychiatric disorder, and 19 parent-pairs of healthy comparison subjects are compared., Results: Consistent with published evidence that self-report measures of psychosis-proneness and schizotypy do not consistently reflect familial risk factors that are specific for schizophrenia, scores on questionnaire measures of schizotypy did not distinguish the parents of patients with schizophrenia from the parents in the other two groups., Conclusions: Interview-based assessments of schizotypy better assess familial risk factors than self-report measures of schizotypy. Questionnaire measures of schizotypy should be supplemented by interview-based assessments when screening for individuals at risk of schizophrenia.

This paper reviews the six published incidence studies of the relative risk of cancer in patients with schizophrenia compared with the general population. These studies used: incidence data, register case ascertainment, and controlled for age and sex. It is concluded that schizophrenia is associated with a lower risk of developing cancer. The role of apoptosis (programmed cell death) in cancer and brain development is briefly described. The possibility is explored that increased apoptosis may account for neurodevelopmental abnormalities as well as tumour resistance associated with schizophrenia. The authors propose that p53, a tumour suppressor gene central to regulation of apoptosis, should be investigated as a candidate susceptibility gene in schizophrenia.