Methylation of FKBP5 and SLC6A4 in Relation to Treatment Response to Mindfulness Based Stress Reduction for Posttraumatic Stress Disorder

Mindfulness Based Stress Reduction (MBSR) is an effective non-pharmacologic treatment for veterans with PTSD. Extensive work has identified epigenetic factors related to PTSD disease risk and pathophysiology, but how these factors influence treatment response is unclear. Serotonin signaling and hypothalamic-pituitary-adrenal (HPA) axis functioning may be perturbed in PTSD and are molecular pathways targeted by PTSD treatments. To identify potential biomarkers for treatment response, we utilized genomic DNA isolated from peripheral blood samples from veterans with PTSD who were responders (n = 11) or non-responders (n = 11) to MBSR as part of a clinical trial. We assessed methylation levels at CpG sites in regions of the serotonin transporter (SLC6A4) previously associated with expression and depression outcomes, as well as the Intron 7 region of the FK506 binding protein 5 (FKBP5) containing known glucocorticoid response elements suggested to regulate this gene. Selected subjects were matched across MBSR responder status by baseline symptoms, age, sex, current smoking status, and current antidepressant use. Percent methylation was compared between responders and non-responders at baseline (pre-MBSR treatment). Additionally, percent change in methylation from baseline to post-treatment was compared between responders and non-responders. There was a significant time x responder group interaction for methylation in FKBP5 intron 7 bin 2 [F(1, 19) = 7.492, p = 0.013] whereby responders had a decrease in methylation and non-responders had an increase in methylation from before to after treatment in this region. Analyses of the three CpG sites within bin 2 revealed a significant time x responder group interaction for CpG_35558513 [F(1, 19) = 5.551, p = 0.029] which resides in a known glucocorticoid response element (GRE). Decreases in FKBP5 methylation after treatment in responders as compared to increases in non-responders suggest that effective meditation intervention may be associated with stress-related pathways at the molecular level. These preliminary findings suggest that DNA methylation signatures within FKBP5 are potential indicators of response to meditation treatment in PTSD and require validation in larger cohorts

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Comparative Advertising Wars: An Historical Analysis of Their Causes and Consequences

This historical study contributes to the extensive literature on comparative advertising by examining the causes and consequences of comparative advertising wars; that is, when one advertiser responds to a direct or implied attack by another advertiser. Primary and secondary sources consist of articles published in historic and contemporary marketing and advertising trade journals, such as Printers’ Ink, Advertising & Selling, and Advertising Age. The findings reveal that well-publicized advertising wars occurred frequently between major U.S. advertisers throughout the twentieth century and into the twenty-first, and that they most often occurred in product and service markets characterized by intense competition. Many, if not most, advertisers’ principal motive for responding to a comparative advertising attack has been emotional rather than rational. The findings also reveal that advertising wars often became increasingly hostile, leading to negative consequences for all combatants, as well as a broad and negative social consequence in the form of potentially misleading advertising.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological PsychiatryBackground: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.publishersversionpublishe

Assessing the Clinical Utility of the MMPI-2-RF in Detecting Suicidal Ideation in a High Acuity, Partially-Hospitalized Veteran Sample

© 2020, © 2020 Taylor & Francis Group, LLC. The Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008/2011) has demonstrated utility in suicide risk assessment. Limited research with the MMPI-2-RF in higher acuity populations exists, particularly regarding the impact of possible underreporting on prediction of suicide risk. The current study serves to extend previous findings of the utility of clinically indicated MMPI-2-RF scales and proxy indices in 293 veterans (83.62% White, 85.32% male, and 74.40% with past-week suicide ideation) enrolled in a Veterans Affairs Medical Center partial psychiatric hospitalization program. Differences in self-report indicators and MMPI-2-RF scales and proxy indices relevant in assessing suicide ideation between veterans indicated as possibly underreporting and those who were not and the ability of the scales and proxy indices to predict current suicide ideation were examined. These indicators, scales, and proxy indices, with the exception of SUI, were significantly impacted by underreporting, and none of the examined scales or proxy indices (or their interaction) were consistently associated with self-reported suicide ideation after accounting for SUI. However, SUI was consistently associated with suicide ideation and was less influenced by under-reporting. In acutely ill psychiatric patients, SUI may be the most robust indicator of current suicide ideation

Neurocognitive performance of repeated versus single intravenous subanesthetic ketamine in treatment resistant depression

Background: Ketamine demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). However, evaluation of ketamine's neurocognitive effect in TRD is unclear. We aim to (1) characterize baseline neurocognitive performance as a predictor of the change in severity of depressive symptoms over time, and (2) investigate the association of six versus single intravenous (IV) ketamine and neurocognitive changes from baseline to the end of treatment. Methods: Subjects with TRD were randomized to receive either five IV midazolam followed by a single IV ketamine or six IV ketamine during a 12-day period. Depression symptom assessments occurred prior and 24 h after infusion days using the Montgomery–Åsberg Depression Rating Scale. Neurocognitive tasks were designed to test attention, memory, speed of processing, and set shifting using the CogState battery at baseline and at the end of treatment. Results: Better complex working memory at baseline predicted improvement in MADRS scores of ketamine (vs midazolam) after 5 infusions. Most, but not all, neurocognitive functions remained stable or improved after repeated or single ketamine. There was a greater differential effect of treatment on speed of processing, set shifting, and spatial working memory that favors subjects in the six ketamine group. These cognitive improvements from baseline to the end of treatment were robust when controlling for age and changes in depression severity. Conclusion: The study suggests that six IV ketamine compared to single IV ketamine has a mood independent procognitive effect among TRD patients. Large scale studies are needed to confirm whether ketamine enhances cognitive function in TRD