Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts.

BACKGROUND: Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. METHODS: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. RESULTS: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. CONCLUSION: The inclusion of exposure variables adds to the predictive power of MRS. Classification-based MRS may be useful in predicting risk of future PTSD in populations with anticipated trauma exposure. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting PTSD and, relatedly, improve their performance in independent cohorts.

Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: A meta-analysis of 23 military and civilian cohorts.

Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.

DNA methylation GrimAge acceleration in US military veterans with PTSD.

Epigenetic alterations in DNA methylation might mediate gene expression effects of trauma underlying PTSD symptoms, or effects of PTSD on related health problems. PTSD is associated with all-cause morbidity and premature mortality, suggesting accelerated biological aging. We measured genome-wide DNA methylation (Illumina MethylationEPIC BeadChip) in whole blood in a treatment study for combat-related PTSD - "PROGrESS", a multisite RCT comparing sertraline plus enhanced medication management (SERT + EMM), prolonged exposure (PE) therapy plus placebo (PE + PLB), and the combination (SERT + PE). DNA methylation was measured in 140 US military veterans who served in Iraq and/or Afghanistan (112 current PTSD cases enrolled in a PTSD treatment study and 28 veterans without PTSD history controls), and also 59 non-trauma exposed controls at baseline posttreatment (24 weeks after baseline). Increased DNA methylation GrimAge acceleration (p = 8.8e-09) was observed in patients with PTSD compared to a pooled control group (trauma exposed and non-trauma exposed), suggesting a higher risk of premature mortality in those with PTSD. There was no difference in GrimAge acceleration between combat trauma and non-trauma exposed controls. No treatment-related changes in GrimAge acceleration were found in within-subject comparisons of PTSD patients pre- to post-treatment.

Rare copy number variation in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.

Stressful life events and trajectories of depression symptoms in a U.S. military cohort.

Depression is a common mental disorder that may comprise distinct, underlying symptom patterns over time. Associations between stressful life events throughout the civilian lifecourse-including during childhood-and adult depression have been documented in many populations, but are less commonly assessed in military samples. We identified different trajectories of depression symptoms across four years in a military cohort using latent class growth analysis, and investigated the relationship between these trajectories and two domains of civilian life experiences: childhood adversity (e.g., being mistreated during childhood) and more proximal stressful experiences (e.g., divorce). A four-group depression model was identified, including a symptom-free group (62%), an increasing symptom group (13%), a decreasing symptom group (16%), and a "chronic" symptom group (9%). Compared to the symptom-free group, soldiers with childhood adversity were more likely to be in the chronic depression, decreasing, and increasing symptom groups. Time-varying adult stressors had the largest effect on depression symptoms for the increasing symptom group compared to other groups, particularly in the last two years of follow-up. This study indicates the importance of considering events from throughout the lifecourse-not only those from deployment-when studying the mental health of servicemembers.

Oxytocin receptor gene, post-traumatic stress disorder and dissociation in a community sample of European American women.

The aims of this study were: (a) to examine associations of oxytocin receptor gene (OXTR) single nucleotide polymorphisms (SNPs) with post-traumatic stress disorder (PTSD) and dissociative symptoms and (b) to investigate gene-environment (G × E) interaction with childhood maltreatment. Salivary DNA samples from 228 women of European ancestry were analysed. Two SNPs, rs237895 and rs237897, were associated with dissociative symptoms but not PTSD diagnosis. Another SNP (rs2254298) was associated with dissociation when interacting with history of childhood maltreatment. These results contribute to theorising and evidence suggesting that the oxytocin system and its genetics may be associated with risk for dissociation among European American women, including those with maltreatment history. Replication with larger patient samples, including men and other ancestry groups, is needed.

A Machine Learning Approach to Predicting New-onset Depression in a Military Population.

OBJECTIVE: Depression is one of the most common mental disorders in the United States in both civilian and military populations, but few prospective studies assess a wide range of predictors across multiple domains for new-onset (incident) depression in adulthood. Supervised machine learning methods can identify predictors of incident depression out of many different candidate variables, without some of the assumptions and constraints that underlie traditional regression analyses. The objectives of this study were to identify predictors of incident depression across 5 years of follow-up using machine learning, and to assess prediction accuracy of the algorithms. METHODS: Data were from a cohort of Army National Guard members free of history of depression at baseline (n = 1951 men and 298 women), interviewed once per year for probable depression. Classification trees and random forests were constructed and cross-validated, using 84 candidate predictors from the baseline interviews. RESULTS: Stressors and traumas such as emotional mistreatment and adverse childhood experiences, demographics such as being a parent or student, and military characteristics including paygrade and deployment location were predictive of probable depression. Cross-validated random forest algorithms were moderately accurate (68% for women and 73% for men). CONCLUSIONS: Events and characteristics throughout the life course, both in and outside of deployment, predict incident depression in adulthood among military personnel. Although replication studies are needed, these results may help inform potential intervention targets to reduce depression incidence among military personnel. Future research should further refine and explore interactions between identified variables.

Cohort profile: the Ohio Army National Guard Mental Health Initiative (OHARNG-MHI).

PURPOSE: Rates of mental disorders in the United States military have increased in recent years. National Guard members may be particularly at risk for mental disorders, given their dual role as citizen-soldiers and their increased involvement in combat deployments during recent conflicts. The Ohio Army National Guard Mental Health Initiative (OHARNG-MHI) was launched to assess the prevalence, incidence, and potential causes and consequences of mental disorders in this unique population. METHODS: OHARNG-MHI is a decade-long dynamic cohort study that followed over 3,000 National Guard members yearly through structured telephone interviews. RESULTS: Findings thus far have applied a pre-, peri-, post-deployment framework, identifying factors throughout the life course associated with mental disorders, including childhood events and more recent events, both during and outside of deployment. An estimated 61% of participants had at least one mental disorder in their lifetime, the majority of which initiated prior to military service. Psychiatric comorbidity was common, as were alcohol use and stressful events. Latent class growth analyses revealed four distinct trajectory paths of both posttraumatic stress and depression symptoms across four years. Only 37% of soldiers with probable past-year mental disorders accessed mental health services in the subsequent year, with substance use disorders least likely to be treated. CONCLUSION: Strengths of this study include a large number of follow-up interviews, detailed data on both military and non-military experiences, and a clinical assessment subsample that assessed the validity of the telephone screening instruments. Findings, methods, and procedures of the study are discussed, and collaborations are welcome.

Interdependent self-construal predicts increased gray matter volume of scene processing regions in the brain.

Interdependent self-construal (SC) is thought to lead to a more holistic cognitive style that emphasizes the processing of the background scene of a focal object. At present, little is known about whether the structural properties of the brain might underlie this functional relationship. Here, we examined the gray matter (GM) volume of three cortical regions involved in scene processing -- a cornerstone of contextual processing. Study 1 tested 78 European American non-student adults and found that interdependent (vs. independent) SC predicts higher GM volume in the parahippocampal place area (PPA), one of the three target regions. Testing both European American and East Asian college students (total N = 126), Study 2 replicated this association. Moreover, the GM volume of all the three target regions was greater for East Asians than for European Americans. Our findings suggest that there is a structural neural underpinning for the cultural variation in cognitive style.

Cortical volume abnormalities in posttraumatic stress disorder: an ENIGMA-psychiatric genomics consortium PTSD workgroup mega-analysis.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

Associations between resting-state functional connectivity and treatment response in a randomized clinical trial for posttraumatic stress disorder.

BACKGROUND: Alterations in resting-state functional connectivity (rsFC) have been reported in posttraumatic stress disorder (PTSD). Here, we examined pre- and post-treatment rsFC during a randomized clinical trial to characterize alterations and examine predictors of treatment response. METHODS: Sixty-four combat veterans with PTSD were randomly assigned to prolonged exposure (PE) plus placebo, sertraline plus enhanced medication management, or PE plus sertraline. Symptom assessment and resting-state functional magnetic resonance imaging (fMRI) scans occurred before and after treatment. Twenty-nine trauma-exposed combat veterans without PTSD served as a control group at intake. Seed-based and region of interest (ROI)-to-ROI connectivities, as well as an exploratory connectome-based approach were used to analyze rsFC patterns. Based on previously reported findings, analyses focused on Salience Network (SN) and Default-Mode Network (DMN). RESULTS: At intake, patients with PTSD showed greater DMN-dorsal attention network (DAN) connectivity (between ventromedial prefrontal cortex and superior parietal lobule; family-wise error corrected p = .011), greater SN-DAN connectivity (between insula and middle frontal gyrus; corrected p = .003), and a negative correlation between re-experiencing symptoms and within-DMN connectivity (between posterior cingulate cortex (PCC) and middle temporal gyrus; corrected p < .001). We also found preliminary evidence for associations between rsFC and treatment response. Specifically, high responders (≥50% PTSD symptom improvement), compared with low responders, had greater SN-DMN segregation (i.e., less pre-treatment amygdala-PCC connectivity; p = .011) and lower pre-treatment global centrality (p = .042). CONCLUSIONS: Our findings suggest neural abnormalities in PTSD and may inform future research examining neural biomarkers of PTSD treatment response.

Neural correlates of emotional reactivity and regulation associated with treatment response in a randomized clinical trial for posttraumatic stress disorder.

Posttraumatic Stress Disorder (PTSD) is a debilitating condition often associated with difficulty in emotion regulation, including reappraising negative emotions. This study assessed neural mechanisms associated with emotion regulation in veterans prior to and following treatment for PTSD. Participants with PTSD and combat exposed controls (CC) completed diagnostic evaluation and underwent fMRI scanning while completing Emotion Regulation Task (ERT) and Emotional Faces Assessment Task (EFAT). Participants with PTSD were randomly assigned to Prolonged Exposure plus placebo (PE+PLB), Sertraline plus enhanced medication management (SERT+EMM), or PE plus SERT (PE+SERT) and repeated diagnostic evaluation and MRI scanning following treatment. The amygdala, dmPFC, and dlPFC were examined as regions of interest. On ERT, veterans with PTSD showed significantly less dmPFC activation than CCs during reappraisal vs emotional maintenance. Within the PTSD group, results demonstrated a significant association between less activation in the dmPFC during emotion reappraisal vs maintenance trials before treatment and greater reductions in symptoms from pre- to post-treatment. During the EFAT, there were no group differences between participants with PTSD and CCs in brain activation, and no relationships between brain function and PTSD symptoms. These findings suggest that less emotional reactivity might potentially reflect less need for recruitment of prefrontal regions when reappraising negative emotion, and is an individual factor associated with better treatment outcome.

The gray matter volume of the temporoparietal junction varies across cultures: a moderating role of the dopamine D4 receptor gene (DRD4).

Prior work shows that compared to European Americans, East Asians show an enhanced propensity to take the perspective of another person. In the current work, we tested whether this cultural difference might be reflected in the gray matter (GM) volume of the temporoparietal junction (TPJ), a brain region selectively implicated in perspective taking and mentalizing. We also explored whether the cultural difference in the TPJ GM volume might be moderated by dopamine D4 receptor gene (DRD4) exon 3 variable-number tandem repeat polymorphism. Structural magnetic resonance imaging of 66 European Americans and 66 East Asian-born Asians were subjected to voxel-based morphometry. It was observed that the GM volume of the right TPJ was greater among East Asians than among European Americans. Moreover, this cultural difference was significantly more pronounced among carriers of the 7- or 2-repeat allele of DRD4 than among the non-carriers of these alleles. Our findings contribute to the growing evidence that culture can shape the brain.

Neural function during emotion processing and modulation associated with treatment response in a randomized clinical trial for posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with exaggerated threat processing and deficits in emotion modulation circuitry. It remains unknown how neural circuits are associated with response to evidence-based treatments for PTSD. METHOD: We examined associations between PTSD symptoms and indicators of neural response in key emotion processing and modulation regions. Fifty-six military Veterans with PTSD were randomly assigned to one of three evidence-based treatments (prolonged exposure, sertraline, and PE plus sertraline) in a randomized clinical trial ("PROGrESS"; 2018, Contemp Clin Trials, 64, 128-138). Twenty-seven combat-exposed controls (CCs) served as a comparison group at pretreatment. Before and after PTSD treatment, functional magnetic resonance imaging was used to assess brain activation and connectivity during the validated Shifted Attention Emotion Appraisal Task (2003, J Neurosci, 23, 5627-5633; 2013, Biol Psychiatry, 73, 1045-1053). RESULTS: Greater activation in emotion processing (anterior insula) and modulation (prefrontal cortex) regions and increased connectivity between attentional control (dorsolateral prefrontal cortex and superior parietal cortex) and emotion processing (amygdala) regions, at pretreatment, were associated with subsequent PTSD symptom improvement. CONCLUSIONS: This study is one of the first to examine task-based activation and functional connectivity in a PTSD treatment trial, and provides evidence to suggest that activation in and connectivity between emotion processing and modulation regions are important predictors of treatment response.

Neural Mechanisms of Spatial Attention Deficits in Trauma.

BACKGROUND: Survival requires effective shifting of attention from one stimulus to another as goals change. It has been consistently demonstrated that posttraumatic stress disorder (PTSD) is associated with both faster orienting of attention toward and slower disengagement of attention from affective stimuli. Prior work, however, suggests that attention abnormalities in PTSD may extend beyond the affective domain. METHODS: We used the Attention Network Test-modified to include invalid spatial cues-in conjunction with functional magnetic resonance imaging to examine the neurocognitive underpinnings of visuospatial attention in participants with PTSD (n = 31) and control participants who were (n = 20) and were not (n = 21) exposed to trauma. RESULTS: We observed deficits in the utilization of spatial information in the group with PTSD. Specifically, compared with the non-trauma-exposed group, participants with PTSD showed a smaller reaction time difference between invalidly and validly cued targets, demonstrating that they were less likely to use spatial cues to inform subsequent behavior. We also found that in both the PTSD and trauma-exposed control groups, utilization of spatial information was positively associated with activation of attentional control regions (e.g., right precentral gyrus, inferior and middle frontal gyri) and negatively associated with activation in salience processing regions (e.g., right insula). CONCLUSIONS: This pattern suggests that both trauma exposure and psychopathology may be associated with alterations of spatial attention. Overall, our findings suggest that both attention- and salience-network abnormalities may be related to altered attention in trauma-exposed populations. Treatments that target these neural networks could therefore be a new avenue for PTSD research.

Associations between oxytocin receptor gene (OXTR) polymorphisms, childhood trauma, and parenting behavior.

Maternal oxytocin is connected to aspects of parenting including sensitivity, warmth, positive affect, and affectionate touch. Oxytocin receptor gene (OXTR) polymorphisms are associated with circulating oxytocin levels, altered brain activity, and parenting behaviors. This study aimed to replicate prior work on OXTR single-nucleotide polymorphisms (SNPs) rs1042778 and rs53576 in relation to maternal sensitivity, explore associations with other aspects of parenting (i.e., negative parenting), evaluate observational and self-report measures of parenting in relation to OXTR SNPs, and examine whether childhood trauma exposure moderates the relation between OXTR SNPs and parenting. Mothers (N = 100) were observed during 2 teaching interaction tasks with their 7-month-old infant, completed questionnaire and interview measures related to parenting and trauma history, and provided saliva specimens to derive OXTR genotypes. Mothers with OXTR rs1042778 TT genotypes demonstrated lower behavioral sensitivity, lower engagement, higher intrusiveness, and more frequent frightened/frightening behavior than mothers with TG or GG genotypes. Genotype interacted with childhood trauma history such that mothers who had experienced childhood trauma were more likely to demonstrate frightened/frightening behavior if they had the TT genotype on rs1042778 relative to the TG or GG genotype; however, small cell sizes for this interaction suggest replication is warranted. Contrary to expectations, mothers with the TT genotype on rs1042778 self-reported that they had less impaired bonding than mothers with TG or GG genotypes. Results are discussed with respect to prior work with oxytocin in lower versus higher risk samples, and the potential role of mothers' self-awareness in explaining discrepancies between results from observational versus self-report measures of parenting. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A neurobehavioral account for decentering as the salve for the distressed mind.

Distress is commonly characterized by prolonged internal suffering that can range from self-focused processing of negative emotions and stressors, to highly intensely aversive and prolonged emotional states, thereby, worsening or complicating emotional and physical conditions. Decentering represents a metacognitive capacity thought to reflect three interrelated processes: meta-awareness, disidentification from internal experience, and reduced reactivity to thought content-which is reliably increased with mindfulness-based interventions. In this essay, we seek to link the clinical presentation of distress disorders to known or hypothesized disruptions in neural networks that underlie emotion, cognition, and goal directed behavior, and offer a neurobehavioral account for how and why treatments imbued with mindfulness meditation might ameliorate these conditions, in part through increases in decentering.

Efficacy of Prolonged Exposure Therapy, Sertraline Hydrochloride, and Their Combination Among Combat Veterans With Posttraumatic Stress Disorder: A Randomized Clinical Trial.

Importance: Meta-analyses of treatments for posttraumatic stress disorder (PTSD) suggest that trauma-focused psychotherapies produce greater benefits than antidepressant medications alone. Objective: To determine the relative efficacy of prolonged exposure therapy plus placebo, prolonged exposure therapy plus sertraline hydrochloride, and sertraline plus enhanced medication management in the treatment of PTSD. Design, Setting, and Participants: The Prolonged Exposure and Sertraline Trial was a randomized, multisite, 24-week clinical trial conducted at the Veterans Affairs Ann Arbor Healthcare System, Veterans Affairs San Diego Healthcare System, Ralph H. Johnson Veterans Affairs Medical Center, and Massachusetts General Hospital Home Base Veterans Program between January 26, 2012, and May 9, 2016. Participants and clinicians were blinded to pill condition, and outcome evaluators were blinded to assignment. Participants completed assessments at weeks 0 (intake), 6, 12, 24, and 52 (follow-up). Participants (N = 223) were service members or veterans of the Iraq and/or Afghanistan wars with combat-related PTSD and significant impairment (Clinician-Administered PTSD Scale score, ≥50) of at least 3 months' duration. Analyses were on an intent-to-treat basis. Intervention: Participants completed up to thirteen 90-minute sessions of prolonged exposure therapy by week 24. Sertraline dosage was titrated during a 10-week period and continued until week 24; medication management was manualized. Main Outcomes and Measures: The primary outcome was symptom severity of PTSD in the past month as assessed by the Clinician-Administered PTSD Scale score at week 24. Results: Of 223 randomized participants, 149 completed the study at 24 weeks, and 207 (180 men and 27 women; mean [SD] age, 34.5 [8.3 years]) were included in the intent-to-treat analysis. Modified intent-to-treat analysis using a mixed model of repeated measures showed that PTSD symptoms decreased significantly during the 24 weeks (sertraline plus enhanced medication management, 33.8 points; prolonged exposure therapy plus sertraline, 32.7 points; and prolonged exposure therapy plus placebo, 29.4 points; ß,-9.39; 95% CI, -11.62 to -7.16; P < .001); however, slopes did not differ by treatment group (prolonged exposure therapy plus placebo group, -9.39; sertraline plus enhanced medication management group, -10.37; and prolonged exposure therapy plus sertraline group, -9.99; P = .81). Conclusions and Relevance: No difference in change in PTSD symptoms or symptom severity at 24 weeks was found between sertraline plus enhanced medication management, prolonged exposure therapy plus placebo, and prolonged exposure therapy plus sertraline. Trial Registration: ClinicalTrials.gov Identifier: NCT01524133.

Prenatal intimate partner violence exposure predicts infant biobehavioral regulation: Moderation by the brain-derived neurotrophic factor (BDNF) gene.

The ability to regulate stress is a critical developmental milestone of early childhood that involves a set of interconnected behavioral and physiological processes and is influenced by genetic and environmental stimuli. Prenatal exposure to traumatic stress and trauma, including intimate partner violence (IPV), increases risk for offspring biobehavioral regulation problems during childhood and adolescence. Although individual differences in susceptibility to prenatal stress have been largely unexplored, a handful of studies suggest children with specific genetic characteristics are most vulnerable to prenatal stress. We evaluated the brain-derived neurotrophic factor Val66Met gene (BDNF) as a moderator of the effect of prenatal IPV exposure on infant temperamental and cortisol regulation in response to a psychosocial challenge. Ninety-nine mother-infant dyads recruited from the community were assessed when infants (51% female) were 11 to 14 months. Maternal reports of IPV during pregnancy and infant temperament were obtained, and infant saliva was collected for genotyping and to assess cortisol reactivity (before and after the Strange Situation Task). Significant genetic moderation effects were found. Among infants with the BDNF Met allele, prenatal IPV predicted worse temperamental regulation and mobilization of the cortisol response, while controlling for infant postnatal exposure to IPV, other maternal traumatic experiences, and infant sex. However, prenatal IPV exposure was not associated with temperamental or cortisol outcomes among infant carriers of the Val/Val genotype. Findings are discussed in relation to prenatal programming and biological susceptibility to stress.