Ronald C. Kessler’s research while affiliated with Harvard Medical School and other places

Background Heterogeneity of treatment effects (HTEs) can occur because of either differential treatment compliance or differential treatment effectiveness. This distinction is important, as it has action implications, but it is unclear how to distinguish these two possibilities statistically in precision treatment analysis given that compliance is not observed until after randomization. We review available statistical methods and illustrate a recommended method in secondary analysis in a trial focused on HTE. Methods The trial randomized n = 880 anxious and/or depressed university students to guided internet‐delivered cognitive behavioral therapy (i‐CBT) or treatment‐as‐usual (TAU) and evaluated joint remission. Previously reported analyses documented superiority of i‐CBT but significant HTE. In the reanalysis reported here, we used baseline (i.e., pre‐randomization) covariates to predict compliance among participants randomized to guided i‐CBT, generated a cross‐validated within‐person expected compliance score based on this model in both intervention groups, and then used this expected composite score as a predictor in an expanded HTE analysis. Results The significant intervention effect was limited to participants with high expected compliance. Residual HTE was nonsignificant. Conclusions Future psychotherapy HTE trials should routinely develop and include expected compliance composite scores to distinguish the effects of differential treatment compliance from the effects of differential treatment effectiveness.

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 Illumina HumanMethylation450 or MethylationEPIC (850 K) BeadChips. 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. Out of 9 CpGs annotated to a gene expressed in blood, methylation levels at 5 CpGs showed significant correlations with the expression levels of their respective annotated genes. Conclusions This study identifies 11 PTSD-associated CpGs and 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. Supplementary Information The online version contains supplementary material available at 10.1186/s13073-024-01417-1.

Background: Chronic pain following traumatic stress exposure (TSE) is common. Increasing evidence suggests inflammatory/immune mechanisms are induced by TSE, play a key role in the recovery process versus development of post-TSE chronic pain, and are sex specific. In this study, we tested the hypothesis that the inflammatory marker C-reactive protein (CRP) is associated with chronic pain after TSE in a sex-specific manner. Methods: We utilized blood-plasma samples and pain questionnaire data from men (n=99) and (n=223) women enrolled in AURORA, a multi-site emergency department (ED)-based longitudinal study of TSE survivors. We measured CRP using Ella/ELISA from plasma samples collected in the ED ('peritraumatic CRP', n=322) and six months following TSE (n=322). Repeated measures mixed-effects models were used to assess the relationship between peritraumatic CRP and post-TSE chronic pain. Results: Peritraumatic CRP levels significantly predicted post-TSE chronic pain, such that higher levels of CRP were associated with lower levels of pain over time following TSE, but only in men (men:β=-0.24, p=0.037; women:β=0.05, p=0.470). By six months, circulating CRP levels had decreased by more than half in men, but maintained similar levels in women (t(290)=1.926, p=0.055). More men with a decrease in CRP levels had decreasing pain over time versus women (men:83% women:65%; Z=2.21, p=0.027). Conclusions: In men but not women, we found circulating peritraumatic CRP levels predict chronic pain outcomes following TSE and resolution of CRP levels in men over time might be associated with increased pain recovery. Further studies are needed to validate these results.

Objective Several gaps remain in the understanding of the onset, dynamic transitions, and associated risk factors of adverse posttraumatic neuropsychiatric sequelae (APNS) in the acute post‐trauma window. Based on serial assessments of symptoms from a large cohort study, we identified homogeneous statuses across multiple APNS symptom domains and investigated the dynamic transitions among these statuses during the first 2 months after trauma exposure. Furthermore, we studied how symptom onset and transitions are affected by equity‐relevant characteristics. Methods The analysis was based on 2557 participants enrolled in the Advancing Understanding of RecOvery afteR traumA (AURORA). APNS symptoms comprised pain, depression, sleep discontinuity, nightmares, avoidance, re‐experience, anxiety, hyperarousal, somatic symptoms, and mental fatigue. We identified the homogeneous status of APNS symptoms at baseline, 1 month, and 2 months, and explored transition probabilities among these statuses using latent transition analysis. Equity‐relevant characteristics included gender, race, education, family income, childhood trauma, and area deprivation. Results Three homogeneous statuses–low‐, moderate‐, and severe‐symptom–were identified. While the majority of trauma survivors with severe‐ or moderate‐symptom status maintained the same status over time, some transitioned to a less severe symptom status, particularly within the first month. Specifically, females, non‐whites, and those with higher childhood trauma were associated with a decreased likelihood of transitioning to a less severe symptom status. From one to 2 months, lower income was associated with a decreased likelihood of transitioning from moderate‐to low‐symptom status. Conclusions The findings can inform early intervention strategies for APNS, potentially reducing health disparities among trauma survivors.

Traumatic stress exposures (TSE) are common in life. While most individuals recover following a TSE, a substantial subset develop adverse posttraumatic neuropsychiatric sequelae such as chronic posttraumatic musculoskeletal pain (CPMP). Vulnerability factors for CPMP are poorly understood, which hinders identification of high-risk individuals for targeted interventions. One known vulnerability factor for many pain types is exposure to early life adversity (ELA), but few studies have assessed whether ELA increases risk for CPMP. This study used data from the AURORA study, a prospective human cohort study of TSE survivors, to test the hypothesis that ELA increases risk for CPMP. In addition, in secondary analyses, we assessed which subtypes of ELA (including childhood bullying) were most predictive of CPMP and whether a rat ELA model consisting of neonatal limited bedding (NLB), combined with single prolonged stress (SPS) in adulthood, would accurately model human findings. In AURORA study participants (n=2,480), using multinomial logistic regression modeling of four identified latent pain classes, we found that ELA increased vulnerability to the high unremitting pain class (OR=1.047, p <0.001), the moderate pain class (OR=1.031, p <0.001), and the moderate recovery pain class (OR=1.018, p =0.004), with physical abuse, emotional abuse, and bullying being the strongest predictors of high pain class assignment. Similarly, in male and female Sprague Dawley rats, in comparison to SPS alone NLB combined with SPS caused increased baseline sensitivity and prolonged mechanical hypersensitivity (F(11,197)=3.22, p <0.001). Further studies in animals and humans are needed to understand mechanisms by which ELA confers vulnerability to CPMP. Summary In humans and rats, early life adversity is associated with a greater duration of musculoskeletal pain and mechanical hypersensitivity following traumatic stress exposures during adulthood.