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.

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.

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.

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.

Cortical similarities in psychiatric and mood disorders identified in federated VBM analysis via COINSTAC.

Structural neuroimaging studies have identified a combination of shared and disorder-specific patterns of gray matter (GM) deficits across psychiatric disorders. Pooling large data allows for examination of a possible common neuroanatomical basis that may identify a certain vulnerability for mental illness. Large-scale collaborative research is already facilitated by data repositories, institutionally supported databases, and data archives. However, these data-sharing methodologies can suffer from significant barriers. Federated approaches augment these approaches by enabling access or more sophisticated, shareable and scaled-up analyses of large-scale data. We examined GM alterations using Collaborative Informatics and Neuroimaging Suite Toolkit for Anonymous Computation, an open-source, decentralized analysis application. Through federated analysis of eight sites, we identified significant overlap in the GM patterns (n = 4,102) of individuals with schizophrenia, major depressive disorder, and autism spectrum disorder. These results show cortical and subcortical regions that may indicate a shared vulnerability to psychiatric disorders.

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.

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.

Appraising evidence for intervention effectiveness in early psychosis: conceptual framework and review of evaluation approaches.

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.

Factors associated with civilian mortality in Australian Vietnam veterans three decades after the war.

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

Family emotional climate in childhood and risk of PTSD in adult children of Australian Vietnam veterans.

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.

The physical and mental health of Australian Vietnam veterans 3 decades after the war and its relation to military service, combat, and post-traumatic stress disorder.

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

Trauma, PTSD, and physical health: an epidemiological study of Australian Vietnam veterans.

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.

The mental health of sons and daughters of Australian Vietnam veterans.

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