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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.

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.

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.

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.

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. 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. 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. We conclude that PTSD in a Vietnam veteran father increases the risk specifically for PTSD in his sons and daughters.

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.

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.

Murray and colleagues' confident advice[1][1] to psychiatrists, encouraging them to leave fewer patients with schizophrenia on long-term medication, is based on one of several possible interpretations of a selected literature, and little clinical evidence. We consider that at times Murray and

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.

Contains fulltext : 193179.pdf (Publisher’s version ) (Open Access) The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

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.

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.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.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.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.

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.

It is well established that individuals with schizophrenia demonstrate alterations in auditory perception beginning at the very earliest stages of information processing. However, it is not clear how these impairments in basic information processing translate into high-order cognitive deficits. Auditory scene analysis allows listeners to group auditory information into meaningful objects, and as such provides an important link between low-level auditory processing and higher cognitive abilities. In the present study we investigated whether low-level impairments in the processing of binaural temporal information impact upon auditory scene analysis ability. Binaural temporal processing ability was investigated in 19 individuals with schizophrenia and 19 matched controls. Individuals with schizophrenia showed impaired binaural temporal processing ability on an inter-aural time difference (ITD) discrimination task. In addition, patients demonstrated impairment in two measures of auditory scene analysis. Specifically, patients had reduced ability to use binaural temporal cues to extract signal from noise in a masking level difference paradigm, and to separate the location of a source sound in the presence of an echo in the precedence effect paradigm. These findings demonstrate that individuals with schizophrenia have impairments in the accuracy with which simple binaural temporal information is encoded in the auditory system, and furthermore, this impairment has functional consequences in terms of the use of these cues to extract information in complex auditory environments.

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.

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.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.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.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.

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.

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.

Background: Compared with other leading public health probems, research capacity for schizophrenia and bipolar disorder is grossly under-developed. Also, there are unacceptible delays in applying research discovery to routine clinical practice. Stakeholders have expressed concern with the apparent lack of effect of research upon clinical outcomes. Methods: Interdisciplinary consensus-building processes were supported in order to draft a national psychosis research strategy. Review of the management literature was undertaken to identify an appropriate organisational structure within which to implement the strategy. Results: A translational research framework which linked epidemiological, genetic, neuroscience and drug design research to the development of novel therapeutics and clinical pratice improvement was the preferred research program option and a national collaborative structured network was deemed the optimal governance model. Conclusion: Australia is well-positioned to make a world-leading contribution to finding ways to prevent and cure schizophrenia and bipolar disorder but only with new sources of recurrent funding in the order of $20 million annually.

Introduction: This paper reports on the development of a national recruitment and clinical assessment strategy by the Australian Schizophrenia Research Bank (ASRB). The aim of this strategy is to ensure a representative sample of people with schizophrenia and to collect comprehensive, cross-referenced clinical, cognitive, genetic, brain imaging and linked data. Method: The ASRB recruitment targets are 2000 people with schizophrenia and 2000 healthy, non-psychiatric controls. Using a three pronged approach, schizophrenia subjects will be recruited from various settings. To recruit people in the community, a successful TV and radio community service advertisement campaign was developed and a national 1800 telephone number established. The assessment battery includes the Diagnostic Interview for Psychosis (DIP: Castle et al, 2005), Neurological Evaluation Scale (Buchanan & Heinrichs, 1989), Wechsler Test of Adult Reading (WTAR-Wechsler, 2001), Wechsler Abbreviated Scale of Intelligence (WASI-Wechsler, 1999), Repeatable Battery for Assessment of Neuropsychological Status (RBANS Randolph et al, 1998), Letter Number Sequencing (Wechsler, 1997), Controlled Oral Word Association Test (Spreen & Benton, 1969), Global Assessment of Functioning (GAF-American Psychiatric Association, 2000), and the Schizotypal Personality Questionnaire (Raine et al., 1991). In addition, a blood sample and structural MRI scan are collected. Results: Over 2000 people have registered with the ASRB using the 1800 number. A proportion of these people have been assessed using the ASRB assessment battery. Conclusion: The ASRB is the first Australian research facility to develop a national recruitment and clinical assessment strategy in schizophrenia.

Introduction: Whilst there is robust evidence of excess medical comorbidity in patients with schizophrenia, there are conflicting findings concerning cancer incidence rates in this population.Aim: To carry out a meta-analysis of published studies on the cancer incidence in patients with schizophrenia and their first degree relatives.Method: Meta-analysis was performed on standardised incidence ratios (SIR) of cancer in patients with schizophrenia and first degree relatives compared to general population samples.Results: The pooled overall cancer incidence in patients was notsignificantly increased (SIR1.05, CI 0.951.15). Lung cancer incidence was slightly increased (SIR1.31, CI 1.011.71), but it was reduced after adjusting for smoking prevalence. The incidence of several cancers unrelated to smoking was reduced in patients. The pooled overall cancer incidence in siblings (SIR0.89, CI 0.840.94) and parents (SIR0.90, CI 0.880.93) was significantly reduced.Conclusions: There is direct evidence of a discrepancy between cancer risk exposure and cancer incidence in patients with schizophrenia, and indirect evidence that this discrepancy is unlikely to result from confounding effects of medication or lower detection rates in patients.

The mentalising abilities of schizophrenic patients and normal controls were tested using picture sequencing and story-telling tasks that required subjects to infer causal mental states in story characters, and a recall task that required subjects to dissociate subjective mental states from objective realities. Selective mentalising deficits were found in some patients. For other patients, general sequencing errors, "sensory" mentalising, and poor recall of symbolic representations suggested more profound problems. Task results were best accounted for by dissociable cognitive abnormalities, rather than graded dysfunction of a central mentalising mechanism. Symptom profiles of patient subgroups and correlations between task measures and clinical ratings linked these cognitive abnormalities to specific symptoms. General sequencing difficulty was associated with both poverty symptoms and reality distortion, suggesting that two mechanisms may underpin such errors: one, inability to manipulate symbolic representations, being linked to poverty; the other, failure to critically evaluate plausible cause-and-effect, being linked to reality distortion. There was some evidence that defective self-monitoring underpins thought disorder. Impaired metarepresentation was linked to the autisticlike symptoms of flat affect, social dysfunction, and alogia, rather than reality distortion. Implications of these findings are discussed with respect to theoretical and methodological issues confronting current schizophrenia research.

SummaryThese international clinical practice guidelines were developed with detailed input from 29 invited international consultants, who provided content as well as detailed feedback on draft versions. The final draft of the guidelines was ratified by the Executive of the International Early Psychosis Association and presented and formally endorsed at the Third International Conference on Early Psychosis held in Copenhagen, September 2002. They have been revised slightly to include medications that were not available in 2002, although a fully comprehensive process of update has not yet been conducted. The final version is published in this Supplement with the aim of encouraging further discussion as well as providing practical guidance to clinicians and researchers. A second edition is planned for publication in 2008.

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.

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

Introduction. Poor mentalising in some patients with schizophrenia has been attributed to disruption of a cognitive module dedicated to computing meta - representations (representations of beliefs about propositions) and linked specifically to paranoia. Because meta-representational capacity is needed to infer beliefs but is not needed to judge visual perspectives (which can be done by mentally rotating primary representations of seen objects), this view predicts that patients with selective mentalising deficits will show intact visual perspectivetaking. Method. This study tested that prediction by investigating visual perspective-taking in patients and healthy controls, known to differ in mentalising ability. Item questions (asking locations of array-features) and appearance questions (asking how an array appears from another perspective) were presented with both viewer-rotation instructions (asking subjects to imagine moving themselves relative to an array) and array-rotation instructions (asking subjec...

Introduction: Poor mentalising has been linked to particular psychotic symptoms (e.g., paranoia) and attributed to selective disruption of a mentalising module. Mentalising, executive planning, and disengagement were tested in patients with schizophrenia and healthy controls in order to evaluate this view against nonmodular accounts that attribute poor mentalising to generalised difficulty entertaining any hypothetical state of affairs and/or difficulty inhibiting salient misleading information. Method. Mentalising and disengagement were tested in a picture-sequencing task using false-belief and capture stories - the former require inferences of mental states; the latter test ability to inhibit salient misleading cues. Executive planning was tested using the Tower of London task. Results. Whereas patients as a whole showed impairments of mentalising, executive planning and disengagement, false-belief picture sequencing ability significantly predicted the odds of being a patient, after adjusting for all ot...

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.

The effect of d-amphetamine on selective attention in humans was investigated by measuring event-related potentials (ERPs) during a complex auditory selective attention task (CSAT). The CSAT required subjects to make a button press response to infrequent target tones presented amongst tones that varied in pitch (high vs. low), location (left vs. right ear) and duration (51 ms vs. 102 ms). Healthy subjects completed the CSAT under three conditions: placebo, 10 mg and 20 mg d-amphetamine, at least one week apart. D-amphetamine produced a significant dose response increase in hit-rate and decrease in reaction time without changing false alarm rate. D-amphetamine reduced late PN to location irrelevant stimuli and pitch irrelevant stimuli in both the attended and unattended location. The effect of d-amphetamine was interpreted as a decrease in the maintenance of the attentional trace to irrelevant stimuli. However, these changes were accompanied by some evidence of processing of stimulus features in the unattended location. These results suggest that d-amphetamine improves selective attention, and decreases the maintenance of attention to irrelevant stimuli.

Reliability, specificity, and Validity of three event-related potential (ERP) indices of non-attended and attended auditory information processing [the mismatch negativity (MMN), the novelty-P3a and the target-P3b] were assessed in 21 healthy subjects and 25 schizophrenic patients while performing a Visual discrimination task (Ignore condition) and, subsequently, an auditory discrimination task (Attend condition). Re-test reliability, as measured in a subset of 10 healthy subjects and 9 patients respectively, ranged from r = 0.4 to r = 0.8 In both groups P3a was found to be smaller in the Ignore than in the Attend condition. Patients had significantly larger P3a amplitudes than healthy subjects while their MMN and P3b amplitudes were smaller. Two ERP factors were extracted in healthy subjects: (I) 'novelty reaction' with high loading scores for P3a and (2) 'deviant detection' with high loading scores for MMN. P3b was predominantly loading on the first factor thus confirming partly overlapping P3a and P3b generators. However, considerable variance was also shared by the second factor, particularly in patients. External validity of the ERP factors was confirmed post hoc. Particularly ERP indices of deviant detection were found to be associated with negative symptoms. In order to assess further clinical relevance, therapy response to clozapine was followed-up over 3 yr in a sub-sample of 17 patients. Poor treatment response was associated with high Novelty Factor scores and large P3a amplitudes whereas good response was associated with high Deviant Factor scores and relatively intact MMN. It is concluded that ERP abnormalities provide a severity index of brain impairment and a measure of predicting therapeutic outcome.

This study examines the effect of decreased catecholamine transmission on event-related potential (ERP) indices of selective attention. Intravenous clonidine (1.5 micrograms/kg Catapres), droperidol (15 micrograms/kg Droleptan), or placebo were administered to healthy adult males prior to performance of a multidimensional auditory selective attention task (SAT) in which dichotically presented sequences of tone pips varied on dimensions of location (left or right ear), pitch (high or low), and duration (short or long). Subjects were required to make a button press response to infrequent "target" stimuli that matched a prespecified stimulus on the three dimensions. ERPs were recorded during the task. Clonidine led to a significant increase of processing negativity (PN) over 200-400 ms at the irrelevant location. Droperidol led to a significant increase in reaction time (RT), a significant decrease in hit rate, and an attenuation of PN over the 200- to 400-ms and 400- to 700-ms epochs. Neither substance led to a significant change in P3 amplitude. The role of catecholamines in the selective attention subprocesses of "tuning" and "switching" is discussed.

Objective: The aim of this study was to identify promising elements of best practice relevant to mainstream mental health service (MHS) delivery of early psychosis intervention (EPI) to Indigenous communities. In a companion paper, a comprehensive literature review identified a promising service model with potential for delivering EPI: an Indigenous sub-team embedded within a mainstream health service. Method: This paper describes a consultation process with Indigenous Mental Health Workers (IMHWs) in south eastern Queensland. A case study of the Sunshine Coast Cultural Healing Program (CHP-SC) was carried out during the consultation process. Results: IMHWs agreed that the Australian clinical guidelines for early psychosis were relevant to improving outcomes for Indigenous patients. IMHWs unanimously identified the CHP-SC as a best practice mainstream MHS for delivering EPI. The CHP-SC, which represented an Indigenous sub-team model, was found to be associated with substantially improved engagement of Indigenous young people. Conclusions: We provisionally conclude that specialist EPI could be delivered by specialist Indigenous sub-teams (rather than specialist EPI teams) embedded in mainstream MHSs that incorporate culturally safe practice and are fully integrated with Indigenous primary care services, and recommend that the model be formally evaluated.

This study investigated immune activation, as measured by production of interleukin-2 (IL-2) and soluble interleukin-2 receptors (sIL-2R) from stimulated lymphocytes, in schizophrenia and schizophreniform disorder. The study included 13 neuroleptic-free patients, 13 medicated patients and 13 age- and sex-matched control subjects. Production of IL-2 and sIL-2R by peripheral blood mononuclear cells (PBMCs) was measured after in vitro stimulation with phytohaemagglutinin (PHA). Patients' symptoms were rated on the Scales for Assessment of Positive (SAPS) and Negative Symptoms (SANS) and the Brief Psychiatric Rating Scale (BPRS). IL-2 production by stimulated lymphocytes was significantly elevated in neuroleptic-free patients compared with both medicated patients and control subjects. IL-2 production was inversely correlated with the SAPS subscales of bizarre behaviour and formal thought disorder. The pattern of increased IL-2 production is in contrast to previous findings in patients with schizophrenia. Significant associations with clinical rating scores suggest that IL-2 production may vary in different biological subgroups of schizophrenia and schizophreniform disorder.

Remoxipride, a substituted benzamide, is a selective D-2 antagonist with an atypical neuroleptic profile. Previous studies have demonstrated its antipsychotic efficacy against haloperidol and, more recently, thioridazine. Of the 144 patients enrolled in the Australian remoxipride-thioridazine comparative trial, 28 presented for their first episode of schizophrenia and/or had no previous neuroleptic treatment. These patients form the subject of this paper.

Romney (J. Nerv. Ment. Dis. 178:481-486, 1990) performed a meta-analysis of studies examining psychometrically assessed ''thought disorder'' in the relatives of schizophrenics. He concluded that thought disorder was more prevalent in the relatives of schizophrenics than control subjects. The present review focuses on only those studies that measured ''allusive thinking'' using the Lovibond-Rapaport Object Sorting Test in parents of schizophrenics. Even when the meta-analysis included this more limited number of studies, it demonstrated that the parents of schizophrenics were 2.42 times more likely to obtain high scores on the Object Sorting Test, confirming replication of the original McConaghy (J. Neurol. Neurosurg. Psychiatry 22:243-246, 1959) finding. This effect remained significant when the original study was excluded from the meta-analysis. The predictive strength of parental Object Sorting Test score as a familial risk factor for the development of schizophrenia is discussed.

Loosening of thinking as assessed by the Object Sorting Test (OST) has been found in a percentage of normal subjects but in a higher percentage of schizophrenics, and is familially transmitted in both groups. Loosening of thinking in normal subjects is not associated with evidence of impaired function or increased psychopathology, and in recognition of this, it was termed allusive thinking rather than thought disorder. Both OST-assessed loosening and concreteness of thinking were found to be present independently in a high percentage of schizophrenics, so that both were considered to contribute to schizophrenic thought disorder. The presence of OST-assessed loosening in schizophrenics would, therefore, be predicted to correlate partially rather than totally with measures of schizophrenic thought disorder. It has been suggested that OST-assessed loosening in normal subjects is due to a genetically determined reduction in strength of an inhibitory process that limits the spread of activation of semantic associations and results in a predisposition to schizophrenia. The brain event-related potential P300, which is, in part, under genetic control, may index this inhibitory process. Therefore, it was predicted that in normal subjects, P300 would correlate with OST-assessed loosening of associations. If schizophrenic thought disorder is due to a further weakening of this inhibitory process, it can be predicted that P300 in schizophrenics correlates only weakly with OST-assessed loosening of thinking, but more strongly with schizophrenic thought disorder. In a study in which P300 was elicited using a difficult selective attention task with 15 unmedicated schizophrenics and 22 healthy subjects, all three predictions were supported.

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.

Brain ERPs were recorded in ten unmedicated schizophrenic patients and age- and sex-matched healthy controls during a multidimensional listening task. Patients showed a marked reduction in a long-duration attention-related negative ERP component, termed ‘processing negativity’ (PN), which was elicited by attended stimuli. The amplitude of PN was significantly correlated with SANS and SAPS scores of schizophrenic symptoms. The P300 component was also reduced in amplitude in patients, and was significantly correlated with SANS ratings of negative thought disorder. These findings provide neurophysiological evidence of impairment in the maintenance of selective attention and the cognitive processes associated with target detection among schizophrenic patients. The reduced PN in schizophrenics implicates frontostriatal pathways in the aetiology of attentional deficits in schizophrenia.

Objectives: From 2002 to mid 2003, Royal Brisbane and Women's Hospital Mental Health experienced increased patient – staff aggression and staff injury which resulted in staff conflict and recruitment difficulties. Strategies introduced to reduce the frequency and impact of aggression in the mental health service were evaluated. Method: By mid 2003, incident data indicated increasing aggressive incidents. Based on this, an aggression management strategy was developed which included improved staff communication, new acute pharmacological treatment protocols, mandatory staff aggression management training, personal alarms and aggression risk assessment tools. Results: Following the introduction of the strategy in early 2004, there was a reduction of 40% in aggressive incidents and a 56% reduction in staff injuries in 2005 compared to 2003 levels. A more assertive approach to tranquillisation was not associated with an increased adverse event rate for patients. Conclusions: A co-ordinated strategy can contain and reduce aggressive incidents in acute inpatient mental health settings. These strategies are transferable to other health settings including Emergency Departments.

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.

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.

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.