Nagy A. Youssef

Allopregnanolone levels are reduced in temporal cortex in patients with Alzheimer's disease compared to cognitively intact control subjects.

The neurosteroid allopregnanolone has pronounced neuroprotective actions, increases myelination, and enhances neurogenesis. Evidence suggests that allopregnanolone dysregulation may play a role in the pathophysiology of Alzheimers disease (AD) and other neurodegenerative disorders. Our prior data demonstrate that allopregnanolone is reduced in prefrontal cortex in male patients with AD compared to male cognitively intact control subjects, and inversely correlated with neuropathological disease stage (Braak and Braak). We therefore determined if allopregnanolone levels are also reduced in AD patients compared to control subjects in temporal cortex, utilizing a larger set of samples from both male and female patients. In addition, we investigated if neurosteroids are altered in subjects who are APOE4 allele carriers. Allopregnanolone, dehydroepiandrosterone (DHEA), and pregnenolone levels were determined in temporal cortex postmortem samples by gas chromatography/mass spectrometry, preceded by high performance liquid chromatography (40 subjects with AD/41 cognitively intact control subjects). Allopregnanolone levels are reduced in temporal cortex in patients with AD (median 2.68 ng/g, n=40) compared to control subjects (median 5.64 ng/g, n=41), Mann-Whitney p=0.0002, and inversely correlated with Braak and Braak neuropathological disease stage (Spearman r=-0.38, p=0.0004). DHEA and pregnenolone are increased in patients with AD compared to control subjects. Patients carrying an APOE4 allele demonstrate reduced allopregnanolone levels in temporal cortex (Mann-Whitney p=0.04). In summary, our findings indicate that neurosteroids are altered in temporal cortex in patients with AD and related to neuropathological disease stage. In addition, the APOE4 allele is associated with reduced allopregnanolone levels. Neurosteroids may be relevant to the neurobiology and therapeutics of AD.

Associations of depression, anxiety and antidepressants with histological severity of nonalcoholic fatty liver disease.

Depression and anxiety are common in patients with nonalcoholic fatty liver disease (NAFLD). However, their associations with histological severity of NAFLD are unknown.

Exploration of the influence of childhood trauma, combat exposure, and the resilience construct on depression and suicidal ideation among U.S. Iraq/Afghanistan era military personnel and veterans.

This study evaluated the effect of childhood trauma exposure and the role of resilience on both depressive symptoms and suicidal ideation. The study evaluated 1,488 military personnel and veterans, who served after September 2001, for depressive, suicidal, and PTSD symptoms, combat exposure, childhood trauma exposure, and resiliency. Participants were enrolled as part of an ongoing multicenter study. Outcome measures were depressive symptoms and suicidal ideation. After controlling for the effects of combat exposure and PTSD, results revealed that childhood trauma exposures were significantly associated with depressive symptoms and suicidal ideation. In addition, resilience was negatively associated with depressive symptoms and suicidal ideation, suggesting a potential protective effect. These findings suggest that evaluation of childhood trauma is important in the clinical assessment and treatment of depressive symptoms and suicidal ideation among military personnel and veterans.

Randomized controlled trial of brief cognitive behavioral intervention for depression and anxiety symptoms preoperatively in patients undergoing coronary artery bypass graft surgery

OBJECTIVE The goal of this study was to examine the feasibility, acceptability, and efficacy of a brief, tailored cognitive-behavioral intervention for patients with symptoms of preoperative depression or anxiety before undergoing a coronary artery bypass graft (CABG) operation. METHODS Patients were recruited from a university teaching hospital between February 2007 and May 2009. Patients were randomly assigned to receive treatment as usual (TAU) or a cognitive behavioral therapy (CBT) intervention called Managing Anxiety and Depression using Education and Skills (MADES). A total of 100 subjects were randomized into the study. Length of hospital stay was assessed with a 1-way analysis of variance. Depression, anxiety, and quality of life were assessed with mixed-model repeated measures analyses. RESULTS Overall, the intervention was feasible, and patients had a positive impression of the MADES. Patients in the TAU group stayed longer in the hospital than did those in the MADES group (7.9 days ± 2.6 vs 9.2 days ± 3.5; P = .049). Depressive symptoms increased at time of hospital discharge for the TAU group, whereas the MADES group had a decrease in depressive symptoms at the time of discharge. Quality of life and anxiety symptoms improved in both groups at 3 to 4 weeks of follow-up. However, the MADES group had greater improvements than did the TAU group. CONCLUSIONS This study demonstrated that brief, tailored CBT targeting preoperative depression and anxiety is both feasible and acceptable for patients undergoing CABG surgery. Most important, this intervention improved depressive and anxiety symptoms, as well as quality of life. Moreover, it reduced in-hospital length of stay. This study found that a cognitive-behavioral intervention for patients undergoing CABG surgery for symptoms of preoperative depression/anxiety is both feasible and acceptable. Most important, this intervention improved depressive and anxiety symptoms, as well as quality of life. It also reduced in-hospital length of stay.

Alcohol misuse and psychological resilience among U.S. Iraq and Afghanistan era veterans

OBJECTIVE The present study sought to investigate the longitudinal effects of psychological resilience against alcohol misuse adjusting for socio-demographic factors, trauma-related variables, and self-reported history of alcohol abuse. METHODOLOGY Data were from the National Post-Deployment Adjustment Study (NPDAS) participants who completed both a baseline and one-year follow-up survey (N=1090). Survey questionnaires measured combat exposure, probable posttraumatic stress disorder (PTSD), psychological resilience, and alcohol misuse, all of which were measured at two discrete time periods (baseline and one-year follow-up). Baseline resilience and change in resilience (increased or decreased) were utilized as independent variables in separate models evaluating alcohol misuse at the one-year follow-up. RESULTS Multiple linear regression analyses controlled for age, gender, level of educational attainment, combat exposure, PTSD symptom severity, and self-reported alcohol abuse. Accounting for these covariates, findings revealed that lower baseline resilience, younger age, male gender, and self-reported alcohol abuse were related to alcohol misuse at the one-year follow-up. A separate regression analysis, adjusting for the same covariates, revealed a relationship between change in resilience (from baseline to the one-year follow-up) and alcohol misuse at the one-year follow-up. The regression model evaluating these variables in a subset of the sample in which all the participants had been deployed to Iraq and/or Afghanistan was consistent with findings involving the overall era sample. Finally, logistic regression analyses of the one-year follow-up data yielded similar results to the baseline and resilience change models. CONCLUSIONS These findings suggest that increased psychological resilience is inversely related to alcohol misuse and is protective against alcohol misuse over time. Additionally, it supports the conceptualization of resilience as a process which evolves over time. Moreover, our results underscore the importance of assessing resilience as part of alcohol use screening for preventing alcohol misuse in Iraq and Afghanistan era military veterans.

Autonomic cardiovascular dysregulation as a potential mechanism underlying depression and coronary artery bypass grafting surgery outcomes

BackgroundCoronary artery bypass grafting (CABG) is often used to treat patients with significant coronary heart disease (CHD). To date, multiple longitudinal and cross-sectional studies have examined the association between depression and CABG outcomes. Although this relationship is well established, the mechanism underlying this relationship remains unclear. The purpose of this study was twofold. First, we compared three markers of autonomic nervous system (ANS) function in four groups of patients: 1) Patients with coronary heart disease and depression (CHD/Dep), 2) Patients without CHD but with depression (NonCHD/Dep), 3) Patients with CHD but without depression (CHD/NonDep), and 4) Patients without CHD and depression (NonCHD/NonDep). Second, we investigated the impact of depression and autonomic nervous system activity on CABG outcomes.MethodsPatients were screened to determine whether they met some of the studys inclusion or exclusion criteria. ANS function (i.e., heart rate, heart rate variability, and plasma norepinephrine levels) were measured. Chi-square and one-way analysis of variance were performed to evaluate group differences across demographic, medical variables, and indicators of ANS function. Logistic regression and multiple regression analyses were used to assess impact of depression and autonomic nervous system activity on CABG outcomes.ResultsThe results of the study provide some support to suggest that depressed patients with CHD have greater ANS dysregulation compared to those with only CHD or depression. Furthermore, independent predictors of in-hospital length of stay and non-routine discharge included having a diagnosis of depression and CHD, elevated heart rate, and low heart rate variability.ConclusionsThe current study presents evidence to support the hypothesis that ANS dysregulation might be one of the underlying mechanisms that links depression to cardiovascular CABG surgery outcomes. Thus, future studies should focus on developing and testing interventions that targets modifying ANS dysregulation, which may lead to improved patient outcomes.

The role of epigenetics in depression and suicide: A platform for gene-environment interactions

Epigenetics involves functional modifications of genes. The aim of this paper is to explore if an association exists between epigenetics and depression and/or suicide. MedLine/PubMed searches were performed using both Medical Subject Heading (MeSH) and Non-MeSH terms. Based on pre-specified terms and inclusion criteria, sixteen studies met inclusion criteria by the 3 independent reviewers. Epigenetic changes seem to be important in both depression and suicide. All of the studies reviewed herein found significant epigenetic changes associated with depression and suicide except for two. Several studies showed that hypermethylation of BDNF is involved in suicide. TrkB hypermethylation was also shown to be associated with suicide by several studies, specifically in Brodmanns Areas (BA) 8 and 9. Future research is needed in a larger sample to further characterize these changes.

Neurosteroids and Self-Reported Pain in Veterans Who Served in the U.S. Military after September 11, 2001

OBJECTIVE Nearly half of Operation Enduring Freedom/Operation Iraqi Freedom veterans experience continued pain post-deployment. Several investigations report analgesic effects of allopregnanolone and other neurosteroids in animal models, but few data are currently available focusing on neurosteroids in clinical populations. Allopregnanolone positively modulates GABA(A) receptors and demonstrates pronounced analgesic and anxiolytic effects in rodents, yet studies examining the relationship between pain and allopregnanolone in humans are limited. We thus hypothesized that endogenous allopregnanolone and other neurosteroid levels may be negatively correlated with self-reported pain symptoms in humans. DESIGN We determined serum neurosteroid levels by gas chromatography/mass spectrometry (allopregnanolone, pregnenolone) or radioimmunoassay (dehydroepiandrosterone [DHEA], progesterone, DHEA sulfate [DHEAS]) in 90 male veterans who served in the U.S. military after September 11, 2001. Self-reported pain symptoms were assessed in four areas (low back pain, chest pain, muscle soreness, headache). Stepwise linear regression analyses were conducted to investigate the relationship between pain assessments and neurosteroids, with the inclusion of smoking, alcohol use, age, and history of traumatic brain injury as covariates. SETTING Durham VA Medical Center. RESULTS Allopregnanolone levels were inversely associated with low back pain (P=0.044) and chest pain (P=0.013), and DHEA levels were inversely associated with muscle soreness (P=0.024). DHEAS levels were positively associated with chest pain (P=0.001). Additionally, there was a positive association between traumatic brain injury and muscle soreness (P=0.002). CONCLUSIONS Neurosteroids may be relevant to the pathophysiology of self-reported pain symptoms in this veteran cohort, and could represent future pharmacological targets for pain disorders.

A pilot randomized controlled trial with paroxetine for subthreshold PTSD in Operation Enduring Freedom/Operation Iraqi Freedom era veterans.

Subthreshold posttraumatic stress disorder (PTSD) is associated with increased risk for suicidality, depression, and functional impairment. We thus conducted a small (N=12) pilot randomized controlled trial (RCT) with paroxetine for subthreshold PTSD in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) era veterans. Hospital Anxiety and Depression Scale (HADS) scores improved by 30.4% in the paroxetine group. Paroxetine may have promise for subthreshold PTSD.

Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline.

Compelling evidence suggests that epigenetic mechanisms such as DNA methylation play a role in stress regulation and in the etiologic basis of stress related disorders such as Post traumatic Stress Disorder (PTSD). Here we describe the purpose and methods of an international consortium that was developed to study the role of epigenetics in PTSD. Inspired by the approach used in the Psychiatric Genomics Consortium, we brought together investigators representing seven cohorts with a collective sample size of N = 1147 that included detailed information on trauma exposure, PTSD symptoms, and genome‐wide DNA methylation data. The objective of this consortium is to increase the analytical sample size by pooling data and combining expertise so that DNA methylation patterns associated with PTSD can be identified. Several quality control and analytical pipelines were evaluated for their control of genomic inflation and technical artifacts with a joint analysis procedure established to derive comparable data over the cohorts for meta‐analysis. We propose methods to deal with ancestry population stratification and type I error inflation and discuss the advantages and disadvantages of applying robust error estimates. To evaluate our pipeline, we report results from an epigenome‐wide association study (EWAS) of age, which is a well‐characterized phenotype with known epigenetic associations. Overall, while EWAS are highly complex and subject to similar challenges as genome‐wide association studies (GWAS), we demonstrate that an epigenetic meta‐analysis with a relatively modest sample size can be well‐powered to identify epigenetic associations. Our pipeline can be used as a framework for consortium efforts for EWAS.