Violence and post-traumatic stress disorder in Sao Paulo and Rio de Janeiro, Brazil: the protocol for an epidemiological and genetic survey

Background: violence is a public health major concern, and it is associated with post-traumatic stress disorder and other psychiatric outcomes. Brazil is one of the most violent countries in the world, and has an extreme social inequality. Research on the association between violence and mental health may support public health policy and thus reduce the burden of disease attributable to violence. the main objectives of this project were: to study the association between violence and mental disorders in the Brazilian population; to estimate the prevalence rates of exposure to violence, post-traumatic stress disorder, common metal disorder, and alcohol hazardous use and dependence: and to identify contextual and individual factors, including genetic factors, associated with the outcomes.Methods/design: one phase cross-sectional survey carried out in São Paulo and Rio de Janeiro, Brazil. A multistage probability to size sampling scheme was performed in order to select the participants (3000 and 1500 respectively). the cities were stratified according to homicide rates, and in São Paulo the three most violent strata were oversampled. the measurements included exposure to traumatic events, psychiatric diagnoses (CIDI 2.1), contextual (homicide rates and social indicators), and individual factors, such as demographics, social capital, resilience, help seeking behaviours. the interviews were carried between June/2007 February/2008, by a team of lay interviewers. the statistical analyses will be weight-adjusted in order to take account of the design effects. Standardization will be used in order to compare the results between the two centres. Whole genome association analysis will be performed on the 1 million SNP (single nucleotide polymorphism) arrays, and additional association analysis will be performed on additional phenotypes. the Ethical Committee of the Federal University of São Paulo approved the study, and participants who matched diagnostic criteria have been offered a referral to outpatient clinics at the Federal University of São Paulo and Federal University of Rio de Janeiro

Protocol for investigating genetic determinants of posttraumatic stress disorder in women from the Nurses' Health Study II

<p>Abstract</p> <p>Background</p> <p>One in nine American women will meet criteria for the diagnosis of posttraumatic stress disorder (PTSD) in their lifetime. Although twin studies suggest genetic influences account for substantial variance in PTSD risk, little progress has been made in identifying variants in specific genes that influence liability to this common, debilitating disorder.</p> <p>Methods and design</p> <p>We are using the unique resource of the Nurses Health Study II, a prospective epidemiologic cohort of 68,518 women, to conduct what promises to be the largest candidate gene association study of PTSD to date. The entire cohort will be screened for trauma exposure and PTSD; 3,000 women will be selected for PTSD diagnostic interviews based on the screening data. Our nested case-control study will genotype1000 women who developed PTSD following a history of trauma exposure; 1000 controls will be selected from women who experienced similar traumas but did not develop PTSD.</p> <p>The primary aim of this study is to detect genetic variants that predict the development of PTSD following trauma. We posit inherited vulnerability to PTSD is mediated by genetic variation in three specific neurobiological systems whose alterations are implicated in PTSD etiology: the hypothalamic-pituitary-adrenal axis, the locus coeruleus/noradrenergic system, and the limbic-frontal neuro-circuitry of fear. The secondary, exploratory aim of this study is to dissect genetic influences on PTSD in the broader genetic and environmental context for the candidate genes that show significant association with PTSD in detection analyses. This will involve: conducting conditional tests to identify the causal genetic variant among multiple correlated signals; testing whether the effect of PTSD genetic risk variants is moderated by age of first trauma, trauma type, and trauma severity; and exploring gene-gene interactions using a novel gene-based statistical approach.</p> <p>Discussion</p> <p>Identification of liability genes for PTSD would represent a major advance in understanding the pathophysiology of the disorder. Such understanding could advance the development of new pharmacological agents for PTSD treatment and prevention. Moreover, the addition of PTSD assessment data will make the NHSII cohort an unparalleled resource for future genetic studies of PTSD as well as provide the unique opportunity for the prospective examination of PTSD-disease associations.</p

Cognitive Effects of Intravenous Hydrocortisone in Subjects with PTSD and Healthy Control Subjects

On the basis of peripheral (nonbrain) neuroendocrine findings in subjects with posttraumatic stress disorder (PTSD), it has been hypothesized that these individuals also have a greater central (brain) sensitivity to glucocorticoids. In nonpsychiatric subjects, it has been found that working and declarative memory performance is selectively impaired by acute glucocorticoid administration. We hypothesized that subjects with PTSD, as compared to nonpsychiatric controls, would show greater impairments in verbal declarative memory and working memory, but not attention, following exogenous glucocorticoid administration. These data are part of a larger study using functional neuroimaging and peripheral HPA axis measures in these same subjects. Subjects underwent a 0.5-mg dexamethasone suppression test and measurement of basal cortisol, basal plasma lymphocyte glucocorticoid receptor number, and postdexamethasone cortisol on a separate day. Under double-blind randomized crossover conditions, 17-mg hydrocortisone or placebo was administered by intravenous (i.v.) bolus to 15 medication-free PTSD subjects (4 female) and 12 nonpsychiatric control subjects (4 female) matched by age, sex, and education level. Participants then underwent positron emission tomography (PET) scanning and 90 min after the initial drug/placebo administration, cognitive testing was then performed. By repeated measures ANCOVA (covaried for baseline performance on that neuropsychological test), neither attention tasks of digit span forward nor backward showed significant change. However, there were significant drug (F = 17.644, df = 1,25 P < 0.001), group (F = 4.383, df = 1,25 P = 0.048), and drug by group interactions (F = 4.756, df = 1,25 P = 0.040) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The subject group with PTSD experienced a greater decline in verbal declarative memory performance following hydrocortisone administration. For working memory, there were significant group (F = 6.048, df = 1,25 P = 0.022) and drug by group interactions (F = 6.048, df = 1,25 P = 0.022) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The hydrocortisone administration led to impairment in working memory in the group of subjects with PTSD, but not in the control subject group. Exploratory correlations between percent cortisol suppression following dexamethasone and baseline plasma lymphocyte glucocorticoid receptor number with declarative and working memory measures among subject groups separately and in a combined way revealed a negative correlation between lymphocyte glucocorticoid receptor density and working memory (r = -0.54, df = 25, P = 0.008). Brain sensitivity to glucocorticoids appears to be greater in subjects with PTSD. Heightened vulnerability of declarative memory in subjects with PTSD may indicate hippocampal involvement, whereas working memory vulnerability suggests additional brain regions (prefrontal, cingulate, temporal, and parietal cortices) and neurotransmitter systems (dopamine and serotonin) particularly sensitive to glucocorticoids in persons with PTSD