Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

Alcohol milestones and internalizing, externalizing, and executive function: longitudinal and polygenic score associations.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

Non-linear development of EEG coherence in adolescents and young adults shown by the analysis of neurophysiological trajectories and their covariance.

To contribute to the understanding of changes in the factors governing the development of neural connectivity, the developmental structure of EEG coherence in adolescents and young adults was analyzed using the means, variances, and covariances of high alpha frequency band coherence measures from a set of 27 coherence pairs obtained from a sample of 1426 participants from the COGA study with 5006 observations over ages 12 through 31. Means and covariances were calculated at 96 age centers by a LOESS method. In the current study, trajectories of covariance matrices considered as individual units were determined by tensorial analysis: calculation of Riemannian geodesic (non-Euclidean) distances between matrices and application of both linear and non-linear dimension reduction techniques to these distances. Results were evaluated by bootstrap methods. Mean coherence trajectories for males and females were very similar, showing a steady upward trend from ages 12 to 20 which diminishes gradually from 20 to 25 and reaches stability from 25 to 31. In contrast, the individual covariance trajectories of males and female differed, with the male covariance levels becoming greater than that of females during the developmental process. Tensorial determination of the distances from the initial covariance matrix of subsequent covariance matrices to age 20 had the same trajectory as the mean coherence values. Tensorial determination of the trajectories of the covariance matrices of males and females based on their all pairs geodesic distances revealed a non-linear pattern in the multi-dimensional space of each of the trajectories: A steady increase in one dimension is accompanied by deviations from it peaking at age 20 which have both transient and lasting effects. There is a precise temporal parallelism of this pattern of covariance in males and females, while there is a consistent distance between the male and female covariance structures throughout the developmental process. Between region differences (anterior-posterior) within each sex are greater than between sex differences within regions. Examining development using multiple methods provides unique insight into the developmental process.

Prediction of brain age in individuals with and at risk for alcohol use disorder using brain morphological features.

Brain age measures predicted from structural and functional brain features are increasingly being used to understand brain integrity, disorders, and health. While there is a vast literature showing aberrations in both structural and functional brain measures in individuals with and at risk for alcohol use disorder (AUD), few studies have investigated brain age in these groups. The current study examines brain age measures predicted using brain morphological features, such as cortical thickness and brain volume, in individuals with a lifetime diagnosis of AUD as well as in those at higher risk to develop AUD from families with multiple members affected with AUD (i.e., higher family history density (FHD) scores). The AUD dataset included a group of 30 adult males (mean age = 41.25 years) with a lifetime diagnosis of AUD and currently abstinent and a group of 30 male controls (mean age = 27.24 years) without any history of AUD. A second dataset of young adults who were categorized based on their FHD scores comprised a group of 40 individuals (20 males) with high FHD of AUD (mean age = 25.33 years) and a group of 31 individuals (18 males) with low FHD (mean age = 25.47 years). Brain age was predicted using 187 brain morphological features of cortical thickness and brain volume in an XGBoost regression model; a bias-correction procedure was applied to the predicted brain age. Results showed that both AUD and high FHD individuals showed an increase of 1.70 and 0.09 years (1.08 months), respectively, in their brain age relative to their chronological age, suggesting accelerated brain aging in AUD and risk for AUD. Increased brain age was associated with poor performance on neurocognitive tests of executive functioning in both AUD and high FHD individuals, indicating that brain age can also serve as a proxy for cognitive functioning and brain health. These findings on brain aging in these groups may have important implications for the prevention and treatment of AUD and ensuing cognitive decline.

Post-traumatic stress and future substance use outcomes: leveraging antecedent factors to stratify risk.

Background: Post-traumatic stress disorder (PTSD) and substance use (tobacco, alcohol, and cannabis) are highly comorbid. Many factors affect this relationship, including sociodemographic and psychosocial characteristics, other prior traumas, and physical health. However, few prior studies have investigated this prospectively, examining new substance use and the extent to which a wide range of factors may modify the relationship to PTSD. Methods: The Advancing Understanding of RecOvery afteR traumA (AURORA) study is a prospective cohort of adults presenting at emergency departments (N = 2,943). Participants self-reported PTSD symptoms and the frequency and quantity of tobacco, alcohol, and cannabis use at six total timepoints. We assessed the associations of PTSD and future substance use, lagged by one timepoint, using the Poisson generalized estimating equations. We also stratified by incident and prevalent substance use and generated causal forests to identify the most important effect modifiers of this relationship out of 128 potential variables. Results: At baseline, 37.3% (N = 1,099) of participants reported likely PTSD. PTSD was associated with tobacco frequency (incidence rate ratio (IRR): 1.003, 95% CI: 1.00, 1.01, p = 0.02) and quantity (IRR: 1.01, 95% CI: 1.001, 1.01, p = 0.01), and alcohol frequency (IRR: 1.002, 95% CI: 1.00, 1.004, p = 0.03) and quantity (IRR: 1.003, 95% CI: 1.001, 1.01, p = 0.001), but not with cannabis use. There were slight differences in incident compared to prevalent tobacco frequency and quantity of use; prevalent tobacco frequency and quantity were associated with PTSD symptoms, while incident tobacco frequency and quantity were not. Using causal forests, lifetime worst use of cigarettes, overall self-rated physical health, and prior childhood trauma were major moderators of the relationship between PTSD symptoms and the three substances investigated. Conclusion: PTSD symptoms were highly associated with tobacco and alcohol use, while the association with prospective cannabis use is not clear. Findings suggest that understanding the different risk stratification that occurs can aid in tailoring interventions to populations at greatest risk to best mitigate the comorbidity between PTSD symptoms and future substance use outcomes. We demonstrate that this is particularly salient for tobacco use and, to some extent, alcohol use, while cannabis is less likely to be impacted by PTSD symptoms across the strata.

Trauma Exposure and Post-Traumatic Stress Disorder Among Youth in a High-Risk Family Study: Associations with Maternal and Paternal Alcohol Use Disorder.

This study presents findings regarding the prevalence of trauma exposure and Posttraumatic Stress Disorder (PTSD) based on discrete types of trauma (physical, sexual, witnessed violence, and non-assaultive trauma) among 3404 youth in a family study of Alcohol Use Disorder (AUD). Data from the Collaborative Study on the Genetics of Alcoholism (COGA) were used to examine associations of parent AUD with offspring's childhood trauma exposure, and with lifetime diagnosis of DSM-IV PTSD among White and Black participants aged 12-35. Of 3404 youth, 59.7% had parents affected by AUD and 78% experienced ≤1 traumatic events before age 18. AUD in one or both parents was associated with physical, sexual, and witnessed violence among Whites. Among African Americans, maternal AUD was associated with sexual assault. The lifetime PTSD rate among youth exposed to childhood trauma was 8.6%, and mother-only AUD was significantly associated with lifetime PTSD among participants in both groups. PTSD among youth in this study were somewhat higher (7.9% to 8.83%) than those found in general population studies of the same demographic (5% to 6.8%). Maternal AUD appears to be a salient risk factor for sexual assault before age 18 among Black and development of lifetime PTSD among White youth.