Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

Does Despair Really Kill? A Roadmap for an Evidence-Based Answer.

Two seemingly associated demographic trends have generated considerable interest: income stagnation and rising premature mortality from suicides, drug poisoning, and alcoholic liver disease among US non-Hispanic Whites with low education. Economists interpret these population-level trends to indicate that despair induced by financial stressors is a shared pathway to these causes of death. Although we now have the catchy term "deaths of despair," we have yet to study its central empirical claim: that conceptually defined and empirically assessed "despair" is indeed a common pathway to several causes of death. At the level of the person, despair consists of cognitive, emotional, behavioral, and biological domains. Despair can also permeate social relationships, networks, institutions, and communities. Extant longitudinal data sets feature repeated measures of despair-before, during, and after the Great Recession-offering resources to test the role that despair induced by economic decline plays in premature morbidity and mortality. Such tests must also focus on protective factors that could shield individuals. Deaths of despair is more than a phrase; it constitutes a hypothesis that deserves conceptual mapping and empirical study with longitudinal, multilevel data.

How Does Household Income Affect Child Personality Traits and Behaviors?

We examine the effects of a quasi-experimental unconditional household income transfer on child emotional and behavioral health and personality traits. Using longitudinal data, we find that there are large beneficial effects on children's emotional and behavioral health and personality traits during adolescence. We find evidence that these effects are most pronounced for children who start out with the lowest initial endowments. The income intervention also results in improvements in parental relationships which we interpret as a potential mechanism behind our findings.

Childhood bullying involvement predicts low-grade systemic inflammation into adulthood.

Bullying is a common childhood experience that involves repeated mistreatment to improve or maintain one's status. Victims display long-term social, psychological, and health consequences, whereas bullies display minimal ill effects. The aim of this study is to test how this adverse social experience is biologically embedded to affect short- or long-term levels of C-reactive protein (CRP), a marker of low-grade systemic inflammation. The prospective population-based Great Smoky Mountains Study (n = 1,420), with up to nine waves of data per subject, was used, covering childhood/adolescence (ages 9-16) and young adulthood (ages 19 and 21). Structured interviews were used to assess bullying involvement and relevant covariates at all childhood/adolescent observations. Blood spots were collected at each observation and assayed for CRP levels. During childhood and adolescence, the number of waves at which the child was bullied predicted increasing levels of CRP. Although CRP levels rose for all participants from childhood into adulthood, being bullied predicted greater increases in CRP levels, whereas bullying others predicted lower increases in CRP compared with those uninvolved in bullying. This pattern was robust, controlling for body mass index, substance use, physical and mental health status, and exposures to other childhood psychosocial adversities. A child's role in bullying may serve as either a risk or a protective factor for adult low-grade inflammation, independent of other factors. Inflammation is a physiological response that mediates the effects of both social adversity and dominance on decreases in health.

The Great Smoky Mountains Study: developmental epidemiology in the southeastern United States.

AIMS: To describe the Great Smoky Mountains Study (GSMS). METHODS: GSMS is a longitudinal study of child psychiatric disorders that began in 1992 to look at need for mental health services in a rural area of the USA. Over 20 years it has expanded its range to include developmental epidemiology more generally, not only the development of psychiatric and substance abuse problems but also their correlates and predictors: family and environmental risk, physical development including puberty, stress and stress-related hormones, trauma, the impact of poverty, genetic markers, and epigenetics. Now that participants are in their 30s the focus has shifted to adult outcomes of childhood psychopathology and risk, and early physical, cognitive, and psychological markers of aging. RESULTS: This paper describes the results from over 11,000 interviews, examples of the study's contributions to science and policy, and plans for the future. CONCLUSIONS: Longitudinal studies can provide insights that aid in policy planning.

Early Detection and Prevention of Mental Health Problems: Developmental Epidemiology and Systems of Support.

This article reviews the role of developmental epidemiology in the prevention of child and adolescent mental disorders and the implications for systems of support. The article distinguishes between universal or primary prevention, which operates at the level of the whole community to limit risk exposure before the onset of symptoms, and secondary or targeted prevention, which operates by identifying those at high risk of developing a disorder. It discusses different aspects of time as it relates to risk for onset of disease, such as age at first exposure, duration of exposure, age at onset of first symptoms, and time until treatment. The study compares universal and targeted prevention, describing the systems needed to support each, and their unintended consequences.

Annual research review: Optimal outcomes of child and adolescent mental illness.

BACKGROUND: 'Optimal outcomes' of child and adolescent psychiatric disorders may mean the best possible outcome, or the best considering a child's history. Most research into the outcomes of child and adolescent psychiatric disorder concentrates on the likelihood of adult illness and disability given an earlier history of psychopathology. METHODS: In this article, we review the research literature (based on a literature search using PubMed, RePORT and Google Advanced Scholar databases) on including optimal outcomes for young people with a history of anxiety, depression, attention-deficit/hyperactivity disorder, conduct disorder, oppositional defiant disorder, or substance use disorders in childhood or adolescence. We consider three types of risks that these children may run later in development: future episodes of the same disorder, future episodes of a different disorder, and functional impairment. The impact of treatment or preventative interventions on early adult functioning is briefly reviewed. RESULTS: We found that very few studies enabled us to answer our questions with certainty, but that in general about half of adults with a psychiatric history were disorder-free and functioning quite well in their 20s or 30s. However, their chance of functioning well was less than that of adults without a psychiatric history, even in the absence of a current disorder. CONCLUSIONS: Among adults who had a psychiatric disorder as a child or adolescent, about half can be expected to be disorder-free as young adults, and of these about half will be free of significant difficulties in the areas of work, health, relationships, and crime. Optimal outcomes are predicted by a mixture of personal characteristics and environmental supports.

Estimating the causal effect of conduct disorder on the time from first substance use to substance use disorders using g-estimation.

BACKGROUND: The effect of conduct disorder (CD) as a major risk factor of substance use disorder (SUD), controlling for other psychiatric problems, has been well established in the literature. However, other psychiatric problems are associated as confounders with an increased risk of SUD. When confounding exists, the use of the standard survival analysis approach would lead to a biased estimate of the effect of a time-varying exposure on the time to event. METHODS: The authors used a G-estimation approach to estimate the causal effect of CD while controlling for time-varying confounders. RESULTS: The present study (N = 1420) found a substantial difference in the estimated hazard ratio of CD (4.49 vs. 1.93) when the results from G-estimation and Cox regression were compared. CONCLUSIONS: G-estimation fixed the problem of underestimating the hazard ratio of conduct disorder (CD) while controlling for all measured covariates.

Children with both asthma and depression are at risk for heightened inflammation.

OBJECTIVE: To test whether children and adolescents with co-occurring asthma and depression are at risk for elevated inflammation-concurrently and at the next assessment. STUDY DESIGN: Up to 6 yearly assessments per person from the prospective, population-based Great Smoky Mountains Study (N = 1420) were used, covering children in the community aged 10-16 years old. High-sensitivity C-reactive protein (CRP) was assayed from annual bloodspot collections and provided indicators of elevated inflammation at CRP > 1, CRP > 2, and CRP > 3 mg/L. Depression was assessed with the Child and Adolescent Psychiatric Assessment. Asthma was assessed using a form adapted from the Centers for Disease Control and Prevention National Health Interview Survey. RESULTS: Controlling common covariates of CRP, the co-occurrence of asthma and depression predicted heightened CRP-concurrently and at the next assessment. In turn, elevated CRP was relatively stable from one assessment to the next. CONCLUSIONS: The co-occurrence of asthma and depression in childhood poses a risk for substantially elevated inflammation concurrently and over time, which could contribute to pathophysiological processes involved in the development of additional chronic diseases and also to asthma--related morbidity and mortality.

Impact of bullying in childhood on adult health, wealth, crime, and social outcomes.

Bullying is a serious problem for schools, parents, and public-policymakers alike. Bullying creates risks of health and social problems in childhood, but it is unclear if such risks extend into adulthood. A large cohort of children was assessed for bullying involvement in childhood and then followed up in young adulthood in an assessment of health, risky or illegal behavior, wealth, and social relationships. Victims of childhood bullying, including those that bullied others (bully-victims), were at increased risk of poor health, wealth, and social-relationship outcomes in adulthood even after we controlled for family hardship and childhood psychiatric disorders. In contrast, pure bullies were not at increased risk of poor outcomes in adulthood once other family and childhood risk factors were taken into account. Being bullied is not a harmless rite of passage but throws a long shadow over affected people's lives. Interventions in childhood are likely to reduce long-term health and social costs.

Diagnostic transitions from childhood to adolescence to early adulthood.

BACKGROUND: Quantifying diagnostic transitions across development is needed to estimate the long-term burden of mental illness. This study estimated patterns of diagnostic transitions from childhood to adolescence and from adolescence to early adulthood. METHODS: Patterns of diagnostic transitions were estimated using data from three prospective, longitudinal studies involving close to 20,000 observations of 3,722 participants followed across multiple developmental periods covering ages 9-30. Common DSM psychiatric disorders were assessed in childhood (ages 9-12; two samples), adolescence (ages 13-18; three samples), and early adulthood (ages 19 to age 32; three samples) with structured psychiatric interviews and questionnaires. RESULTS: Having a disorder at an early period was associated with at least a threefold increase in odds for having a disorder at a later period. Homotypic and heterotypic transitions were observed for every disorder category. The strongest evidence of continuity was seen for behavioral disorders (particularly ADHD) with less evidence for emotional disorders such as depression and anxiety. Limited evidence was found in adjusted models for behavioral disorders predicting later emotional disorders. Adult substance disorders were preceded by behavioral disorders, but not anxiety or depression. CONCLUSIONS: Having a disorder in childhood or adolescence is a potent risk factor for a range of psychiatric problems later in development. These findings provide further support for prevention and early life intervention efforts and suggest that treatment at younger ages, while justified in its own right, may also have potential to reduce the risk for disorders later in development.

Genes, environments, and developmental research: methods for a multi-site study of early substance abuse.

The importance of including developmental and environmental measures in genetic studies of human pathology is widely acknowledged, but few empirical studies have been published. Barriers include the need for longitudinal studies that cover relevant developmental stages and for samples large enough to deal with the challenge of testing gene-environment-development interaction. A solution to some of these problems is to bring together existing data sets that have the necessary characteristics. As part of the National Institute on Drug Abuse-funded Gene-Environment-Development Initiative, our goal is to identify exactly which genes, which environments, and which developmental transitions together predict the development of drug use and misuse. Four data sets were used of which common characteristics include (1) general population samples, including males and females; (2) repeated measures across adolescence and young adulthood; (3) assessment of nicotine, alcohol, and cannabis use and addiction; (4) measures of family and environmental risk; and (5) consent for genotyping DNA from blood or saliva. After quality controls, 2,962 individuals provided over 15,000 total observations. In the first gene-environment analyses, of alcohol misuse and stressful life events, some significant gene-environment and gene-development effects were identified. We conclude that in some circumstances, already collected data sets can be combined for gene-environment and gene-development analyses. This greatly reduces the cost and time needed for this type of research. However, care must be taken to ensure careful matching across studies and variables.

Socioeconomic status and adolescent mental disorders.

OBJECTIVES: Although previous research has shown that low socioeconomic status (SES) is associated with mental illness, it is unclear which aspects of SES are most important. We investigated this issue by examining associations between 5 aspects of SES and adolescent mental disorders. METHODS: Data came from a national survey of US adolescents (n = 6483). Associations among absolute SES (parental income and education), relative SES (relative deprivation, subjective social status), and community level income variation (Gini coefficient) with past-year mental disorders were examined. RESULTS: Subjective social status (mean 0, variance 1) was most consistently associated with mental disorder. Odds ratios with mood, anxiety, substance, and behavior disorders after controlling for other SES indicators were all statistically significant and in the range of 0.7 to 0.8. Associations were strongest for White adolescents. Parent education was associated with low risk for anxiety disorder, relative deprivation with high risk for mood disorder, and the other 2 indicators were associated with none of the disorders considered. CONCLUSIONS: Associations between SES and adolescent mental disorders are most directly the result of perceived social status, an aspect of SES that might be more amenable to interventions than objective aspects of SES.

Long-term Outcomes of Childhood Family Income Supplements on Adult Functioning.

Importance: During an ongoing longitudinal cohort study, a casino opening created a natural cash transfer experiment. Some participating families received income supplements, and others did not. The children in this study are now adults. Objective: To assess the long-term outcomes of family income supplements received in childhood. Design, Setting, and Participants: This community-representative longitudinal cohort study set in western North Carolina assessed 1266 participants aged 9, 11, and 13 years at intake up to 11 times up to age 30 years from January 1993 to December 2015. Data were analyzed from January to December 2021. Exposures: In 1996, a southeastern American Indian tribe implemented a cash transfer program of approximately $5000 annually per person for tribal members. Participants were compared on whether their family ever received the cash transfers (American Indian vs non-American Indian), the duration of the transfers, and annual amount based on the number of parents. Main Outcomes and Measures: Participants were followed up at ages 25 and 30 years to assess mental health symptoms, substance use symptoms, and functional outcomes (physical health, risky or illegal behaviors, and financial and social functioning). Results: Of 1266 included participants, 320 (25.3%) were American Indian and 581 (49.7%) were female. Participants whose families received cash transfers during childhood reported fewer anxiety symptoms (relative risk [RR], 0.33; 95% CI, 0.25-0.44), depressive symptoms (RR, 0.51; 95% CI, 0.42-0.62), and cannabis symptoms (RR, 0.47; 95% CI, 0.27-0.82). They also reported improved physical health (RR, 0.66; 95% CI, 0.55-0.80) and financial functioning (RR, 0.78; 95% CI, 0.67-0.89) and fewer risky or illegal behaviors (RR, 0.57; 95% CI, 0.46-0.72) compared with those who did not receive the cash transfer. This pattern was supported by a series of heterogeneity analyses in which children whose families received the transfers for the longest duration and whose families received the largest transfer (due to having multiple American Indian parents) had the lowest levels of symptoms and the highest levels of functioning. Conclusions and Relevance: In this natural experiment, a family cash transfer in childhood was associated with positive adult functioning 20 years later. The findings support programs like the child tax credit or universal basic income that provide cash directly to families with children.

Trends in psychopathology across the adolescent years: what changes when children become adolescents, and when adolescents become adults?

BACKGROUND: Little is known about changes in the prevalence of psychiatric disorders between childhood and adolescence, and adolescence and adulthood. METHODS: We reviewed papers reporting prevalence rates of psychiatric disorders separately for childhood, adolescence, and early adulthood. Both longitudinal and cross-sectional papers published in the past 15 years were included. RESULTS: About one adolescent in five has a psychiatric disorder. From childhood to adolescence there is an increase in rates of depression, panic disorder, agoraphobia, and substance use disorders (SUD), and a decrease in separation anxiety disorder (SAD) and attention-deficit hyperactivity disorder (ADHD). From adolescence to early adulthood there is a further increase in panic disorder, agoraphobia, and SUD, and a further decrease in SAD and ADHD. Other phobias and disruptive behavior disorders also fall. CONCLUSIONS: Further study of changes in rates of disorder across developmental stages could inform etiological research and guide interventions.

Association of family income supplements in adolescence with development of psychiatric and substance use disorders in adulthood among an American Indian population.

CONTEXT: In a natural experiment in which some families received income supplements, prevalence of adolescent behavioral symptoms decreased significantly. These adolescents are now young adults. OBJECTIVE: To examine the effects of income supplements in adolescence and adulthood on the prevalence of adult psychiatric disorders. DESIGN: Quasi-experimental, longitudinal. POPULATION AND SETTING: A representative sample of children aged 9, 11, or 13 years in 1993 (349 [25%] of whom are American Indian) were assessed for psychiatric and substance use disorders through age 21 years (1993-2006). Of the 1420 who participated in 1993, 1185 were interviewed as adults. From 1996, when a casino opened on the Indian reservation, every American Indian but no non-Indians received an annual income supplement that increased from $500 to around $9000. MAIN OUTCOME MEASURES: Prevalence of adult psychiatric disorders and substance use disorders based on the Diagnostic and Statistical Manual of Mental Disorders in 3 age cohorts, adjusted for age, sex, length of time in the family home, and number of Indian parents. RESULTS: As adults, significantly fewer Indians than non-Indians had a psychiatric disorder (106 Indians [weighted 30.2%] vs 337 non-Indians [weighted 36.0%]; odds ratio [OR], 0.46; 95% confidence interval [CI], 0.30-0.72; P = .001), particularly alcohol and cannabis abuse, dependence, or both. The youngest age-cohort of Indian youth had the longest exposure to the family income. Interactions between race/ethnicity and age cohort were significant. Planned comparisons showed that fewer of the youngest Indian age-cohort had any psychiatric disorder (31.4%) than the Indian middle cohort (41.7%; OR, 0.43; 95% CI, 0.24-0.78; P = .005) or oldest cohort (41.3%; OR, 0.69; 95% CI, 0.51-0.94; P = .01) or the youngest non-Indian cohort (37.1%; OR, 0.66; 95% CI, 0.48-0.90; P = .008). Study hypotheses were not upheld for nicotine or other drugs, or emotional or behavioral disorders. The income supplement received in adulthood had no impact on adult psychopathology. CONCLUSION: Lower prevalence of psychopathology in American Indian youth following a family income supplement, compared with the nonexposed, non-Indian population, persisted into adulthood.

Income dividends and subjective survival in a Cherokee Indian cohort: a quasi-experiment.

Persons with high temporal discounting tend to value immediate gratification over future gains. Low self-reported lifespan (SRL)-an individual's assessment of a relatively short future lifespan-concentrates in low-income populations and may reflect high temporal discounting. We use casino-based cash dividends among the Eastern Band of Cherokee Indians (EBCI) as a quasi-experiment to test whether large income gains among EBCI members translate into increased SRL. We used SRL data for EBCI and White youth, aged 19 to 28, participating in two waves of the Life Time Trajectory of Youth (LTI-Y) survey from 2000 to 2010. We controlled for unobserved confounding across individuals, time, and region through a longitudinal design using a difference-in-difference analytic approach (N = 294). We conducted all analyses separately by gender and by quartile of socioeconomic status. Cash dividends correspond with a 15.23 year increase in SRL among EBCI men below the lowest socio-economic quartile at baseline relative to Whites (standard error = 5.39, p < .01). Results using other socio-economic cut-points support improved SRL among EBCI men (but not women). The large magnitude of this result among EBCI men indicates that a non-trivial cash dividend to a low-income population may confer long-term benefits on perceptions of future lifespan and, in turn, reduce temporal discounting.Abbreviations: EBCI: Eastern Band of Cherokee Indians; SES: Socioeconomic Status; LTI-Y: Life Trajectory Interview for Youth; GSMS: Great Smoky Mountains Study; SRL: Self-Reported Lifespan; SSS: Subjective Social Status.

Associations of Despair With Suicidality and Substance Misuse Among Young Adults.

Importance: Deaths of despair is a term that has recently been used to describe the increases in premature mortality from suicides, drug overdoses (particularly from opiates), and alcohol-related liver disease among US adults. Despite the use of the term despair, its role in these causes of premature death has not been empirically tested. Objective: To test whether despair among young adults is associated with suicidal thoughts and behavior, alcohol misuse, and drug misuse. Design, Setting, and Participants: The Great Smoky Mountains Study is a Southeastern, mixed urban-rural population-based cohort study conducted from November 10, 1992, to September 22, 2015. A total of 1420 participants originally 9, 11, and 13 years of age were followed up 11 times to 30 years of age (11 230 person-observations). A total of 1154 of 1400 living participants (82.4%) were assessed at 30 years of age. Statistical analysis was performed from May 7, 2019, to April 10, 2020. Exposures: Participants were assessed with structured interviews for indicators of despair (eg, hopelessness, helplessness, low self-worth, and feeling unloved). Despair was assessed with items from structured interviews: the Child and Adolescent Psychiatric Assessment and the Young Adult Psychiatric Assessment. Main Outcomes and Measures: Structured interviews were used to assess suicidal thoughts and behavior, substance use, and Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) alcohol use disorder and drug use disorder (including opioids) in young adulthood (2424 observations of 1266 individuals between 25 and 30 years of age). Results: This study included 1420 individuals (790 male individuals). During young adulthood (25 and 30 years of age), the 3-month weighted prevalence of any despair was 19.5% (476 of 2424 observations) with 7.6% of participants (201 of 2424 observations) reporting 2 or more despair items. In longitudinal, lagged models, despair scores (range, 0-3) were associated with more suicidal thoughts and behaviors (odds ratio [OR], 1.5; 95% CI, 1.1-2.0), illicit drug use (OR, 1.7; 95% CI, 1.2-2.5), and opioid use (OR, 1.9; 95% CI, 1.1-3.3) but not alcohol use disorder (OR, 0.8; 95% CI, 0.6-1.2). These associations persisted after accounting for sociodemographic factors (eg, poverty and educational level), lagged outcome status, and lagged depression status. The associations between despair and study outcomes were stronger in models accounting for long-term measures of despair extending back to childhood. There was no consistent pattern of moderation by sociodemographic factors. Conclusions and Relevance: This study's findings suggest an empirical basis for longitudinal associations between despair and several, but not all, precursors of "deaths of despair" in rural Appalachia. Individual despair should be studied as a potential factor associated with morbidity and impairment in young adulthood.