Gregory H. Cohen

Interaction of the ADRB2 Gene Polymorphism With Childhood Trauma in Predicting Adult Symptoms of Posttraumatic Stress Disorder

IMPORTANCE Posttraumatic stress disorder (PTSD), while highly prevalent (7.6% over a lifetime), develops only in a subset of trauma-exposed individuals. Genetic risk factors in interaction with trauma exposure have been implicated in PTSD vulnerability. OBJECTIVE To examine the association of 3755 candidate gene single-nucleotide polymorphisms with PTSD development in interaction with a history of childhood trauma. DESIGN, SETTING, AND PARTICIPANTS Genetic association study in an Ohio National Guard longitudinal cohort (n = 810) of predominantly male soldiers of European ancestry, with replication in an independent Grady Trauma Project (Atlanta, Georgia) cohort (n = 2083) of predominantly female African American civilians. MAIN OUTCOMES AND MEASURES Continuous measures of PTSD severity, with a modified (interview) PTSD checklist in the discovery cohort and the PTSD Symptom Scale in the replication cohort. RESULTS Controlling for the level of lifetime adult trauma exposure, we identified the novel association of a single-nucleotide polymorphism within the promoter region of the ADRB2 (Online Mendelian Inheritance in Man 109690) gene with PTSD symptoms in interaction with childhood trauma (rs2400707, P = 1.02 × 10-5, significant after correction for multiple comparisons). The rs2400707 A allele was associated with relative resilience to childhood adversity. An rs2400707 × childhood trauma interaction predicting adult PTSD symptoms was replicated in the independent predominantly female African American cohort. CONCLUSIONS AND RELEVANCE Altered adrenergic and noradrenergic function has been long believed to have a key etiologic role in PTSD development; however, direct evidence of this link has been missing. The rs2400707 polymorphism has been linked to function of the adrenergic system, but, to our knowledge, this is the first study to date linking the ADRB2 gene to PTSD or any psychiatric disorders. These findings have important implications for PTSD etiology, chronic pain, and stress-related comorbidity, as well as for both primary prevention and treatment strategies.

The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary–adrenal activity in humans with psychotic major depression

INTRODUCTION Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs). METHODS Fourteen PMDs, 16 NPMDs, and 19 HCs were admitted to the Stanford University Hospital General Clinical Research Center. Serum cortisol levels were sampled at baseline and every hour from 18:00 to 23:00h, when greatest MR activity is expected, on two consecutive nights. On the second afternoon at 16:00h all subjects were given 0.5mg fludrocortisone. Mean cortisol levels pre- and post-fludrocortisone and percent change in cortisol levels were computed. RESULTS There were no significant group differences for cortisol at baseline: F(2,47)=.19, p=.83. There were significant group differences for post-fludrocortisone cortisol: F(2,47)=5.13, p=.01, which were significantly higher in PMDs compared to HCs (p=.007), but not compared to NPMDs (p=.18). There were no differences between NPMDs and HCs (p=.61). Also, PMDs had a lower percent change from baseline in cortisol levels at 2200h than NPMDs (p=.01) or HCs (p=.009). CONCLUSIONS Individuals with psychotic major depression compared to healthy control subjects have diminished feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in response to the mineralocorticoid receptor agonist fludrocortisone. To our knowledge, this is the first study to examine HPA axis response to MR stimulation in major depression (with and without psychosis), and only the third study to demonstrate that exogenously administered fludrocortisone can down-regulate the HPA axis in humans.

Population health in an era of rising income inequality: USA, 1980–2015

Income inequality in the USA has increased over the past four decades. Socioeconomic gaps in survival have also increased. Life expectancy has risen among middle-income and high-income Americans whereas it has stagnated among poor Americans and even declined in some demographic groups. Although the increase in income inequality since 1980 has been driven largely by soaring top incomes, the widening of survival inequalities has occurred lower in the distribution-ie, between the poor and upper-middle class. Growing survival gaps across income percentiles since 2001 reflect falling real incomes among poor Americans as well as an increasingly strong association between low income and poor health. Changes in individual risk factors such as smoking, obesity, and substance abuse play a part but do not fully explain the steeper gradient. Distal factors correlated with rising inequality including unequal access to technological innovations, increased geographical segregation by income, reduced economic mobility, mass incarceration, and increased exposure to the costs of medical care might have reduced access to salutary determinants of health among low-income Americans. Having missed out on decades of income growth and longevity gains, low-income Americans are increasingly left behind. Without interventions to decouple income and health, or to reduce inequalities in income, we might see the emergence of a 21st century health-poverty trap and the further widening and hardening of socioeconomic inequalities in health.

Mental Health Among Reserve Component Military Service Members and Veterans

Since 2001, the US military has increasingly relied on National Guard and reserve component forces to meet operational demands. Differences in preparation and military engagement experiences between active component and reserve component forces have long suggested that the psychiatric consequences of military engagement differ by component. We conducted a systematic review of prevalence and new onset of psychiatric disorders among reserve component forces and a meta-analysis of prevalence estimates comparing reserve component and active component forces, and we documented stage-sequential drivers of psychiatric burden among reserve component forces. We identified 27 reports from 19 unique samples published between 1985 and 2012: 9 studies reporting on the reserve component alone and 10 reporting on both the reserve component and the active component. The pooled prevalence for alcohol use disorders of 14.5% (95% confidence interval: 12.7, 15.2) among the reserve component was higher than that of 11.7% (95% confidence interval: 10.9, 12.6) among the active component, while there were no component differences for depression or post-traumatic stress disorder. We observed substantial heterogeneity in prevalence estimates reported by the reserve component. Published studies suggest that stage-sequential risk factors throughout the deployment cycle predicted alcohol use disorders, post-traumatic stress disorder and, to a lesser degree, depression. Improved and more standardized documentation of the mental health burden, as well as study of explanatory factors within a life-course framework, is necessary to inform mitigating strategies and to reduce psychiatric burden among reserve component forces.

Latent profile analyses of posttraumatic stress disorder, depression and generalized anxiety disorder symptoms in trauma-exposed soldiers

Posttraumatic stress disorder (PTSD) is comorbid with major depressive disorder (MDD; Kessler et al., 1995) and generalized anxiety disorder (GAD; Brown et al., 2001). We aimed to (1) assess discrete patterns of post-trauma PTSD-depression-GAD symptoms using latent profile analyses (LPAs), and (2) assess covariates (gender, income, education, age) in defining the best fitting class solution. The PTSD Checklist (assessing PTSD symptoms), GAD-7 scale (assessing GAD symptoms), and Patient Health Questionnaire-9 (assessing depression) were administered to 1266 trauma-exposed Ohio National Guard soldiers. Results indicated three discrete subgroups based on symptom patterns with mild (class 1), moderate (class 2) and severe (class 3) levels of symptomatology. Classes differed in symptom severity rather than symptom type. Income and education significantly predicted class 1 versus class 3 membership, and class 2 versus class 3. In conclusion, there is heterogeneity regarding severity of PTSD-depression-GAD symptomatology among trauma-exposed soldiers, with income and education predictive of class membership.

Posttraumatic stress disorder׳s dysphoria dimension and relations with generalized anxiety disorder symptoms

The present study investigated symptom relations between two highly comorbid disorders--posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD)--by exploring their underlying dimensions. Based on theory and prior empirical research it was expected that the dysphoria factor of PTSD would be more highly related to GAD. As part of a longitudinal project of mental health among Ohio National Guard Soldiers, 1266 subjects were administered the Posttraumatic Stress Disorder Checklist (PCL) and Generalized Anxiety Disorder-7 scale (GAD-7). Confirmatory factor analyses (CFAs) were conducted to examine two models of PTSD and to determine which PTSD factors were more related to the GAD factor. The results indicate that the GAD factor was significantly more highly correlated with PTSDs dysphoria factor than with all other PTSD factors, including PTSDs reexperiencing factor, avoidance factor, and hyperarousal factor. Results indicate GAD was not significantly more highly correlated with numbing than most other factors of PTSD. The results are consistent with prior research. Implications of the results are discussed in regards to PTSD in DSM-5, comorbidity and diagnostic specificity.

Anger and Posttraumatic Stress Disorder Symptom Severity in a Trauma-Exposed Military Population: Differences by Trauma Context and Gender

Studies have found a stronger association between anger and posttraumatic stress disorder (PTSD) severity in military populations than in nonmilitary populations. Two hypotheses have been proposed to explain this difference: Military populations are more prone to anger than nonmilitary populations, and traumas experienced on deployment create more anger than nondeployment traumas. To examine these hypotheses, we evaluated the association between anger and PTSD severity among never-deployed military service members with nondeployment traumas (n = 226) and deployed service members with deployment traumas (n = 594) using linear regression. We further examined these associations stratified by gender. Bivariate associations between anger and PTSD severity were similar for nondeployment and deployment events; however, gender modified this association. For men, the association for deployment events was stronger than for nondeployment events (β = .18, r = .53 vs. β = .16, r = .37, respectively), whereas the reverse was true for women (deployment: β = .20, r = .42 vs. nondeployment: β = .25, r = .65). Among men, findings supported the hypothesis that deployment traumas produce stronger associations between PTSD and anger and are inconsistent with hypothesized population differences. In women, however, there was not a clear fit with either hypothesis.

Trajectories of posttraumatic stress symptoms after civilian or deployment traumatic event experiences.

Objective: Growth mixture model studies have observed substantial differences in the longitudinal patterns of posttraumatic stress symptom (PTSS) trajectories. This variability could represent chance iterations of some prototypical trajectories or measurable variability induced by some aspect of the source population or traumatic event experience. Testing the latter, the authors analyzed a nationally representative sample of U.S. Reserve and National Guard members to identify the influence of civilian versus deployment trauma on the number of PTSS trajectories, the nature of these trajectories, and the proportion of respondents in each trajectory. Method: Data were collected from 2010 to 2013 and latent class growth analysis was used to identify different patterns of PTSS in persons exposed to both a civilian and a deployment trauma and to test whether respondents’ exposure to civilian trauma developed similar or distinct patterns of response compared to respondents exposed to deployment trauma. Results: PTSS were found to follow 3 trajectories, with respondents predominantly clustered in the lowest symptom trajectory for both trauma types. Covariates associated with each trajectory were similar between the 2 traumas, except number of civilian-related traumatic events; specifically, a higher number of civilian traumatic events was associated with membership in the borderline-stable, compared to low-consistent, trajectory, for civilian traumas and associated with the preexisting chronic trajectory for military traumas. Conclusions: Holding the source population constant, PTSS trajectory models were similar for civilian and deployment-related trauma, suggesting that irrespective of traumatic event experienced there might be some universal trajectory patterns. Thus, the differences in source populations may have induced the heterogeneity observed among prior PTSS trajectory studies.

Weighing the evidence for harm from long-term treatment with antipsychotic medications: A systematic review.

Research findings supporting the use of antipsychotic medication for acute treatment of schizophrenia are relatively consistent and undisputed. However, the rationale for recommending long-term antipsychotic medication treatment-the current standard of care treatment strategy-is unclear. A controversial hypothesis proposed recently suggests people with schizophrenia who are exposed to long-term treatment with antipsychotic medications have worse outcomes than people with schizophrenia who are not exposed to these medications. We tested whether a systematic appraisal of published literature would produce data consistent with this hypothesis. We reviewed the published literature to identify studies of patients with psychotic disorders who were followed for at least 2 years that compared outcomes in patients who received antipsychotic medication during the follow-up with patients who did not receive antipsychotic medication during the follow-up. We included all English language articles published through 2013 in this review. Our process for selecting studies and documenting study findings included a consensus decision of 2 members of the research team. We found the published data to be inadequate to test this hypothesis. By extension, these data were also inadequate to conclusively evaluate whether long-term antipsychotic medication treatment results in better outcomes on average. We conclude that careful reappraisal of existing data is useful to ensure standard of care treatment strategies are indeed evidence-based. In the case of long-term use of antipsychotic medications, new data may be needed to establish a sufficient evidence base to understand its benefit/risk balance for patients with schizophrenia. (PsycINFO Database Record

Lifetime and 12-Month Use of Psychiatric Services Among U.S. Army National Guard Soldiers in Ohio

OBJECTIVE The individual and economic burden of psychiatric illnesses is substantial. Although treatment of psychiatric disorders mitigates the burden of illness, over half of military personnel with disorders do not receive mental health care. However, there is a paucity of research examining the relationship between psychiatric disorder categories and treatment-seeking behavior in representative military populations. This study aimed to document, by psychiatric disorder category, the annualized rate of Guard members who obtained psychiatric services and the factors associated with service utilization. METHODS Face-to-face clinical assessments were conducted between 2008 and 2012 to assess lifetime and current psychiatric disorders and recent psychiatric service use among 528 Ohio Army National Guard soldiers. RESULTS An annualized rate of 31% of persons per year accessed psychiatric services between 2010 and 2012. Persons with substance use disorders had the lowest annualized rate of service use, and these were the only disorders not predictive of accessing services. Current mood disorder, current anxiety disorder, and lifetime history of service use were the strongest predictors of recent service use. There were no socioeconomic or other group predictors of psychiatric service use. CONCLUSIONS About half of the soldiers who could benefit from mental health services used them, yet soldiers with substance use disorders were predominantly going untreated. There were no differences in treatment utilization by group characteristics, suggesting no systematic barriers to care for particular groups. Efforts to encourage broader adoption of treatment seeking, particularly among persons with substance use disorders, are necessary to mitigate psychiatric health burden in this population.