Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

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.

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Military Combat, Posttraumatic Stress Disorder, and the Course of Alcohol Use Disorders in a Cohort of Australian Vietnam War Veterans.

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.

Combat, Posttraumatic Stress Disorder, and Smoking Trajectory in a Cohort of Male Australian Army Vietnam Veterans.

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.

Raising the standard of care in the treatment of schizophrenia: Yes we can!

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.

The Course and Correlates of Combat-Related PTSD in Australian Vietnam Veterans in the Three Decades After the War.

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.

The treatment of schizophrenia: Can we raise the standard of care?

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.

Theory of mind and neurocognition in early psychosis: a quasi-experimental study.

BACKGROUND: People with chronic psychosis often display theory of mind impairments that are not fully accounted for by other, more general neurocognitive deficits. In these patients, both theory of mind and neurocognitive deficits contribute to poor functioning, independently of psychotic symptoms. In young people with recent-onset psychosis, however, it is unclear the extent to which theory of mind impairment is independent of neurocognitive deficits. The primary aim of this study was to examine the evidence for specific theory of mind impairments in early psychosis. A secondary aim was to explore the relations between theory of mind, neurocognition, symptom severity, and functional outcomes. METHODS: Twenty-three patients who were within two years of their first psychotic episode and 19 healthy controls completed theory of mind and neurocognitive batteries. Social functioning, quality of life, and symptom severity were also assessed in patients. RESULTS: Patients demonstrated deficits in tasks assessing theory of mind and neurocognition relative to controls. Patients' deficits in theory of mind were evident even after adjusting for their deficits in neurocognition. Neither theory of mind nor neurocognition predicted social functioning or quality of life in this early psychosis sample. Severity of negative symptoms, however, was a significant predictor of both outcomes. CONCLUSIONS: While a specific theory of mind impairment was evident in this early psychosis sample, severity of negative symptoms emerged as the best predictor of poor functional outcome. Further early psychosis research is needed to examine the longitudinal progression of theory of mind impairments - independent of neurocognitive deficits - and their impact on psychosocial function.

Jumping to delusions in early psychosis.

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.

Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Attributional biases, paranoia, and depression in early psychosis.

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.

Best practice in early psychosis intervention for Australian indigenous communities: indigenous worker consultation and service model description.

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.

Estimating multimodal brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study.

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.

Virtual Ontogeny of Cortical Growth Preceding Mental Illness.

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.

Clinical indicators for routine use in the evaluation of early psychosis intervention: development, training support and inter-rater reliability.

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.

Clinical correlates of olfactory hallucinations in schizophrenia.

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.

Cytotoxic effects of antipsychotic drugs implicate cholesterol homeostasis as a novel chemotherapeutic target.

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 mental health of partners of Australian Vietnam veterans three decades after the war and its relation to veteran military service, combat, and PTSD.

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.