Target trial emulation using cohort studies: estimating the effect of antihypertensive medication initiation on incident dementia.

BACKGROUND: Observational studies link high midlife systolic blood pressure to increased dementia risk. However, synthesis of evidence from randomized controlled trials has not definitively demonstrated that antihypertensive medication use reduces dementia risk. Here, we emulate target trials of antihypertensive medication initiation on incident dementia using three cohort studies, with attention to potential violations of necessary assumptions. METHODS: We emulated trials of antihypertensive medication initiation on incident dementia using data from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Health and Retirement Study (HRS). We used data-driven methods to restrict participants to initiators and non-initiators with overlap in propensity scores and positive control outcomes to look for violations of positivity and exchangeability assumptions. RESULTS: Analyses were limited by the small number of cohort participants who met eligibility criteria. Associations between antihypertensive medication initiation and incident dementia were inconsistent and imprecise (ARIC: HR = 0.30 [0.05, 1.93]; CHS: HR = 0.66 [0.27, 1.64]; HRS: HR = 1.09 [0.75, 1.59]). More stringent propensity score restriction had little effect on findings. Sensitivity analyses using a positive control outcome unexpectedly suggested antihypertensive medication initiation increased risk of coronary heart disease in all three samples. CONCLUSIONS: Positive control outcome analyses suggested substantial residual confounding in effect estimates from our target trials, precluding conclusions about the impact of antihypertensive medication initiation on dementia risk through target trial emulation. Formalized processes for identifying violations of necessary assumptions will strengthen confidence in target trial emulation and avoid inappropriate confidence in emulated trial results.

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Correlates of missed or late versus timely diagnosis of dementia in healthcare settings.

INTRODUCTION: There is limited evidence about factors related to the timeliness of dementia diagnosis in healthcare settings. METHODS: In five prospective cohorts at Rush Alzheimer's Disease Center, we identified participants with incident dementia based on annual assessments and examined the timing of healthcare diagnoses in Medicare claims. We assessed sociodemographic, health, and psychosocial correlates of timely diagnosis. RESULTS: Of 710 participants, 385 (or 54%) received a timely claims diagnosis within 3 years prior to or 1 year following dementia onset. In logistic regressions accounting for demographics, we found Black participants (odds ratio [OR] = 2.15, 95% confidence interval [CI]: 1.21 to 3.82) and those with better cognition at dementia onset (OR = 1.48, 95% CI: 1.10 to 1.98) were at higher odds of experiencing a diagnostic delay, whereas participants with higher income (OR = 0.89, 95% CI: 0.81 to 0.97) and more comorbidities (OR = 0.94, 95% CI: 0.89 to 0.98) had lower odds. DISCUSSION: We identified characteristics of individuals who may miss the optimal window for dementia treatment and support. HIGHLIGHTS: We compared the timing of healthcare diagnosis relative to the timing of incident dementia based on rigorous annual evaluation. Older Black adults with lower income, higher cognitive function, and fewer comorbidities were less likely to be diagnosed in a timely manner by the healthcare system.

Associations of Social Capital with Mental Disorder Prevalence, Severity, and Comorbidity among U.S. Adolescents.

OBJECTIVE: To examine cross-sectional associations between social capital constructs and 1) adolescent lifetime mental disorders, 2) severity of functional impairment, and 3) psychiatric comorbidity. METHOD: Data were from the National Comorbidity Survey Adolescent Supplement, a nationally representative mental health survey of 6,483 U.S. adolescents aged 13-18 years. Information from fully-structured diagnostic interviews, including adolescent and caregiver reports, was used to measure seven social capital constructs and lifetime DSM-IV mental disorders (mood, anxiety, behavior, substance use and eating disorder classes). Disorder severity was divided into severe vs. mild/moderate. Comorbidity was measured as the number of different classes of lifetime mental disorders. RESULTS: Adjusted for socio-demographics and caregivers' mental health, the most consistent associations with adolescent mental disorder were for supportive friendships (any disorder OR = 0.95, 95%CI = 0.91-0.99), family cohesion (OR = 0.81, 95%CI = 0.75-0.86), school bonding (OR = 0.76, 95%CI = 0.71-0.81), and extracurricular participation (OR = 0.90, 95%CI = 0.86-0.95), although results differed by disorder class. Caregiver-reported neighborhood trust and reciprocity and caregiver community involvement were less consistently associated with mental disorder. Medium levels of adolescent-reported affiliation with neighbors was associated with lower odds of mood (OR = 0.81, 95%CI = 0.66-0.98) and anxiety (OR = 0.78, 95%CI = 0.64-0.96) disorder, while high levels were associated with higher odds of behavior disorder (OR = 1.47, 95%CI = 1.16-1.87). Several associations were stronger for severe vs. mild/moderate disorder and with increasing comorbidity. CONCLUSION: Although we cannot infer causality, our findings support the notion that improving actual and/or perceived social capital, especially regarding friendships, family, and school, (e.g., through multimodal interventions) could aid in the prevention and treatment of both individual adolescent mental disorders and psychiatric comorbidity.

Examining the association of familial and social stress, trauma, and support on mood, anxiety, and behavioral symptoms and diagnoses in youth at risk for bipolar disorder and controls.

INTRODUCTION: Youth with a family history of bipolar disorder (At-Risk) have a higher risk of developing psychiatric disorders and experiencing environmental stressors than youth without such family history (Control). We studied the differential associations of familial and environmental factors on developing psychiatric diagnoses and symptoms, in At-Risk and Control youth. METHODS: At-Risk and Control youth (N = 466, ages 9-22) were systematically assessed for severity of symptoms, psychiatric diagnoses, and self-reported measures of stress and social support. We tested the association of family history and measures of stress or support with symptom severity and diagnoses. RESULTS: At-Risk youth had higher symptom severity scores and were more frequently diagnosed with psychiatric disorders (all p values < 0.001). When predicting mood symptom severity, family history had an interaction effect with stressful life events (p < 0.001) and number of distinct traumatic events (p = 0.001). In multivariate models, At-Risk status predicted anxiety disorders (OR = 2.7, CI 1.3-5.4, p = 0.005) and anxiety severity (Coefficient = 0.4, CI 0.2-0.7, p < 0.001) but not mood or behavioral disorder diagnoses or severity. LIMITATIONS: Measures of stress and social support were based on self-report. Not all participants had passed through the period of risk for developing the outcomes under study and the follow up period was variable. We could not fully study the differential impact of physical or sexual abuse due to low frequency of occurrence in controls. CONCLUSION: At-Risk youth exhibit more severe mood symptoms compared to Controls when exposed to similar levels of stress or trauma. At-Risk youth are also more prone to develop anxiety which may be a precursor for bipolar disorder.

Specificity of affective dynamics of bipolar and major depressive disorder.

OBJECTIVE: Here, we examine whether the dynamics of the four dimensions of the circumplex model of affect assessed by ecological momentary assessment (EMA) differ among those with bipolar disorder (BD) and major depressive disorder (MDD). METHODS: Participants aged 11-85 years (n = 362) reported momentary sad, anxious, active, and energetic dimensional states four times per day for 2 weeks. Individuals with lifetime mood disorder subtypes of bipolar-I, bipolar-II, and MDD derived from a semistructured clinical interview were compared to each other and to controls without a lifetime history of psychiatric disorders. Random effects from individual means, inertias, innovation (residual) variances, and cross-lags across the four affective dimensions simultaneously were derived from multivariate dynamic structural equation models. RESULTS: All mood disorder subtypes were associated with higher levels of sad and anxious mood and lower energy than controls. Those with bipolar-I had lower average activation, and lower energy that was independent of activation, compared to MDD or controls. However, increases in activation were more likely to perpetuate in those with bipolar-I. Bipolar-II was characterized by higher lability of sad and anxious mood compared to bipolar-I and controls but not MDD. Compared to BD and controls, those with MDD exhibited cross-augmentation of sadness and anxiety, and sadness blunted energy. CONCLUSION: Bipolar-I is more strongly characterized by activation and energy than sad and anxious mood. This distinction has potential implications for both specificity of intervention targets and differential pathways underlying these dynamic affective systems. Confirmation of the longer term stability and generalizability of these findings in future studies is necessary.

Family environment and polygenic risk in the bipolar high-risk context.

Background: The interaction of polygenic risk (PRS) and environmental effects on development of bipolar disorder (BD) is understudied, as are high-risk offspring perceptions of their family environment (FE). We tested the association of offspring-perceived FE in interaction with BD-PRS on liability for BD in offspring at high or low familial risk for BD. Methods: Offspring of a parent with BD (oBD; n = 266) or no psychiatric disorders (n = 174), aged 12-21 at recruitment, participated in the US and Australia. Empirically-derived profiles of FE classified offspring by their perceived levels of familial cohesion, flexibility, and conflict. Offspring BD-PRS were derived from Psychiatric Genomics Consortium BD-GWAS. Lifetime DSM-IV bipolar disorders were derived from the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. We used a novel stepwise approach for latent class modeling with predictors and distal outcomes. Results: Fifty-two offspring were diagnosed with BD. For those with well-functioning FE (two-thirds of the sample), higher BD-PRS tracked positively with liability for BD. However, for those with high-conflict FEs, the relationship between BD-PRS and liability to BD was negative, with highest risk for BD observed with lower BD-PRS. In exploratory analyses, European-ancestry offspring with BD had elevated history of suicidal ideation in high-conflict FE compared to well-functioning-FE, and of suicide attempt with low-BD-PRS and high-conflict FE. Conclusions: The data suggest that the relationship of BD-PRS and offspring liability for BD differed between well-functioning versus high-conflict FE, potentially in line with a multifactorial liability threshold model and supporting future study of and interventions improving family dynamics.

The association of long-term exposure to criteria air pollutants, fine particulate matter components, and airborne trace metals with late-life brain amyloid burden in the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Studies suggest associations between long-term ambient air pollution exposure and outcomes related to Alzheimer's disease (AD). Whether a link exists between pollutants and brain amyloid accumulation, a biomarker of AD, is unclear. We assessed whether long-term air pollutant exposures are associated with late-life brain amyloid deposition in Atherosclerosis Risk in Communities (ARIC) study participants. METHODS: We used a chemical transport model with data fusion to estimate ambient concentrations of PM2.5 and its components, NO2, NOx, O3 (24-hour and 8-hour), CO, and airborne trace metals. We linked concentrations to geocoded participant addresses and calculated 10-year mean exposures (2002 to 2011). Brain amyloid deposition was measured using florbetapir amyloid positron emission tomography (PET) scans in 346 participants without dementia in 2012-2014, and we defined amyloid positivity as a global cortical standardized uptake value ratio ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and each air pollutant, adjusting for putative confounders. In sensitivity analyses, we considered whether use of alternate air pollution estimation approaches impacted findings for PM2.5, NO2, NOx, and 24-hour O3. RESULTS: At PET imaging, eligible participants (N = 318) had a mean age of 78 years, 56% were female, 43% were Black, and 27% had mild cognitive impairment. We did not find evidence of associations between long-term exposure to any pollutant and brain amyloid positivity in adjusted models. Findings were materially unchanged in sensitivity analyses using alternate air pollution estimation approaches for PM2.5, NO2, NOx, and 24-hour O3. CONCLUSIONS: Air pollution may impact cognition and dementia independent of amyloid accumulation, though whether air pollution influences AD pathogenesis later in the disease course or at higher exposure levels deserves further consideration.

Polygenic Scores and Onset of Major Mood or Psychotic Disorders Among Offspring of Affected Parents.

OBJECTIVE: Family history is an established risk factor for mental illness. The authors sought to investigate whether polygenic scores (PGSs) can complement family history to improve identification of risk for major mood and psychotic disorders. METHODS: Eight cohorts were combined to create a sample of 1,884 participants ages 2-36 years, including 1,339 offspring of parents with mood or psychotic disorders, who were prospectively assessed with diagnostic interviews over an average of 5.1 years. PGSs were constructed for depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuroticism, subjective well-being, p factor, and height (as a negative control). Cox regression was used to test associations between PGSs, family history of major mental illness, and onsets of major mood and psychotic disorders. RESULTS: There were 435 onsets of major mood and psychotic disorders across follow-up. PGSs for neuroticism (hazard ratio=1.23, 95% CI=1.12-1.36), schizophrenia (hazard ratio=1.15, 95% CI=1.04-1.26), depression (hazard ratio=1.11, 95% CI=1.01-1.22), ADHD (hazard ratio=1.10, 95% CI=1.00-1.21), subjective well-being (hazard ratio=0.90, 95% CI=0.82-0.99), and p factor (hazard ratio=1.14, 95% CI=1.04-1.26) were associated with onsets. After controlling for family history, neuroticism PGS remained significantly positively associated (hazard ratio=1.19, 95% CI=1.08-1.31) and subjective well-being PGS remained significantly negatively associated (hazard ratio=0.89, 95% CI=0.81-0.98) with onsets. CONCLUSIONS: Neuroticism and subjective well-being PGSs capture risk of major mood and psychotic disorders that is independent of family history, whereas PGSs for psychiatric illness provide limited predictive power when family history is known. Neuroticism and subjective well-being PGSs may complement family history in the early identification of persons at elevated risk.

Mood and anxiety profiles differentially associate with physical conditions in US adolescents.

BACKGROUND: Mood and anxiety are widely associated with physical conditions, but research and treatment are complicated by their overlap, clinical heterogeneity, and manifestation on a spectrum rather than as discrete disorders. In contrast to previous work relying on threshold-level disorders, we examined the association between empirically-derived profiles of mood and anxiety syndromes with physical conditions in a nationally-representative sample of US adolescents. METHODS: Participants were 2,911 adolescents (aged 13-18) from the National Comorbidity Survey-Adolescent Supplement who provided information on physical conditions and reported at least one lifetime mood-anxiety 'syndrome' based on direct interviews with the Composite International Diagnostic Interview Version 3.0. Mood-anxiety syndromes reflected 3-level ratings from subthreshold to severe distress/impairment, and subtyped mood episodes. Stepwise latent profile analysis identified mood-anxiety profiles and tested associations with physical conditions. RESULTS: Three mood-anxiety profiles were identified: "Mood-GAD" (25.6%)-non-atypical depression, mania, generalized anxiety; "Atypical-Panic" (11.3%)-atypical depression, panic; and "Reference" (63.1%)-lower mood and anxiety except specific phobia. Headaches were more prevalent in Mood-GAD and Atypical-Panic than Reference (47.9%, 50.1%, and 37.7%, respectively; p=0.011). Heart problems were more common in Mood-GAD than Atypical-Panic (7.4% v 2.2%, p=0.004) and Reference, with back/neck pain more prevalent in Mood-GAD than Reference (22.5% v 15.3%, p=0.016). LIMITATIONS: Broad categories of physical conditions without information on specific diagnoses; replication regarding specificity is recommended. CONCLUSIONS: Heart problems and pain-related conditions were differentially associated with specific mood-anxiety profiles. Subtyping depression and anxiety-inclusive of subthreshold syndromes-and their patterns of clustering may facilitate etiologic and intervention work in multimorbidity.

Suicide attempt endophenotypes: Latent profiles of child and adolescent aggression and impulsivity differentially predict suicide attempt in females.

Suicide is a leading cause of death in young adulthood. Identifying early prevention targets to reduce later suicide is a public health priority. Impulsivity and aggression in early childhood may represent actionable early prevention candidate endophenotypes for later suicidal behavior. Our objective is to to understand the association of aggression and impulsivity trajectories with mental health outcomes to inform future prevention efforts. Participants were part of a longitudinal cohort of a preventative intervention trial (n = 597) and predominantly Black. They were assessed for aggressive and impulsive behaviors yearly in 1st-3rd and 6th-12th grades, and provided mental health data via self-report beginning in 6th grade. Longitudinal latent profiles of aggressive and impulsive behaviors were derived for males and females and used to determine whether profiles was associated with lifetime suicide attempt and meeting diagnostic criteria for major depressive disorder. Two impulsivity and aggression classes were found for males, characterized by low behaviors or moderate to high behaviors across development. Three classes were found for females, one of which was characterized by an undulating pattern of behaviors. For females, the class of severe behaviors was associated with significant risk of suicide attempt (Wald = 6.01, p = 0.05). No relationship was found for males or for MDD diagnosis. An endophenotype model of impulsivity and aggression in predicting later suicide attempt was supported in females, but not males. Results underscore the importance of evaluating sex differences in suicide research and the potential identification of females at risk for later suicidal behavior in school settings.

Comorbidity and Coaggregation of Major Depressive Disorder and Bipolar Disorder and Cannabis Use Disorder in a Controlled Family Study.

Importance: Cannabis use disorder (CUD) is increasing in the US. Clarification of the potential mechanisms underlying the comorbidity between mood disorders and CUD may help prevent CUD. Objective: To examine co-occurrence and familial aggregation of CUD and mood disorder subtypes. Design, Setting, and Participants: In this cross-sectional, community-based study in the Washington, DC, metropolitan area, semistructured diagnostic interviews and family history reports assessed lifetime DSM-IV disorders in probands and relatives. Familial aggregation and coaggregation of CUD with mood disorders were estimated via mixed-effects models, adjusting for age, sex, recruitment source, and comorbid mood, anxiety, and other substance use disorders. A total of 586 adult probands (186 with bipolar disorder; 55 with CUD) and 698 first-degree relatives (91 with bipolar disorder; 68 with CUD) were recruited from a community screening of the greater Washington, DC, metropolitan area from May 2004 to August 2020. Inclusion criteria were ability to speak English, and availability and consent to contact at least 2 living first-degree relatives. Main Outcomes and Measures: Lifetime CUD in first-degree relatives. Results: Of 586 probands, 395 (67.4%) were female; among 698 relatives, 437 (62.6%) were female. The mean (SD) age was 47.5 (15.2) years for probands and 49.6 (18.0) years for relatives. In the proband group, 82 participants (14.0%) self-identified as African American or Black, 467 (79.7%) as White, and 37 (6.3%) as American Indian or Alaska Native, Asian, more than one race, or another race or ethnicity or declined to respond. In the relative group, 53 participants (7.6%) self-identified as African American or Black, 594 (85.1%) as White, and 51 (7.3%) as American Indian or Alaska Native, Asian, more than one race, or another race or ethnicity or declined to respond. These groups were combined to protect privacy owing to small numbers. CUD in probands (55 [9.4%]) was associated with an increase in CUD in relatives (adjusted odds ratio [aOR], 2.64; 95% CI, 1.20-5.79; P = .02). Bipolar disorder II (BP-II) in probands (72 [12.3%]) was also associated with increased risk of CUD in relatives (aOR, 2.57; 95% CI, 1.06-6.23; P = .04). However, bipolar disorder I (114 [19.5%]) and major depressive disorder (192 [32.8%]) in probands were not significantly associated with CUD in relatives. Among relatives, CUD was associated with BP-II (aOR, 4.50; 95% CI, 1.72-11.77; P = .002), major depressive disorder (aOR, 3.64; 95% CI, 1.78-7.45; P < .001), and mean (SD) age (42.7 [12.8] years with CUD vs 50.3 [18.3] years without CUD; aOR, 0.98; 95% CI, 0.96-1.00; P = .02). Familial coaggregation of BP-II with CUD was attenuated by the inclusion of comorbid anxiety disorders. Further, rates of CUD were highest in relatives with both a familial and individual history of BP-II (no familial or individual history of BP-II: 41 [7.2%]; familial history but no individual history of BP-II: 13 [19.1%]; individual history but no familial history of BP-II: 10 [22.2%]; familial and individual history of BP-II: 4 [28.6%]; Fisher exact test, P < .001). The onset of mood disorder subtypes preceded CUD in probands and relatives in most cases. Conclusions and Relevance: The findings confirmed a familial aggregation of CUD. The increase in risk of CUD among relatives of probands with BP-II suggests that CUD may share a common underlying diathesis with BP-II. Taken together with the temporal precedence of depression and mania with respect to CUD onset, these findings highlight a potential role for BP-II intervention as CUD prevention.

Comorbidity and familial aggregation of back/neck pain in the NIMH Family Study of Affective Spectrum Disorders.

OBJECTIVE: Back pain is associated with substantial Global Burden of Disease and is highly comorbid with mood and anxiety symptoms and syndromes. However, mechanisms underlying this association have not been well-elucidated. Here we apply data from the NIMH Family Study of Affective Spectrum Disorders to investigate the comorbidity, familial aggregation, and cross-aggregation of back/neck pain with mood disorder subtypes. METHODS: The sample includes 519 probands and 560 interviewed first-degree relatives. Lifetime DSM-IV Bipolar I, Bipolar II, and Major Depressive Disorder [MDD] were derived from semi-structured diagnostic interviews. Lifetime history of back or neck pain and its age of onset were self-reported retrospectively. Familial aggregation and cross-aggregation were estimated via mixed effects models in probands and interviewed first-degree relatives, while heritability and co-heritability (endophenotypic ranking value [ERV]) were estimated using full pedigrees. RESULTS: Over 45% of participants endorsed a history of back/neck pain. Back/neck pain was familial (adjusted odds ratio [aOR] 1.5, p = 0.04; h2 = 0.24, p = 0.009). Back/neck pain in probands was associated with MDD in relatives (aOR 1.5, p = 0.04; ERV = 0.17, p = 0.024), but not with bipolar disorder. Onset of back/neck pain occurred earlier in those with bipolar disorder compared to controls. CONCLUSION: Findings suggest common familial risk factors underlying back/neck pain with MDD, whereas there was within-individual comorbidity of bipolar with back/neck pain. Future studies that identify common factors that lead to either back/neck pain or MDD can inform prevention and interventions.

Trends and Geographic Availability of Emergency Psychiatric Walk-In and Crisis Services in the United States.

OBJECTIVE: Serious mental illness places a considerable burden on the mental health service system in the United States. To date, no research has examined the availability of psychiatric emergency walk-in and crisis services. The goal of this study was to examine temporal trends, geographic variation, and characteristics of psychiatric facilities that provide emergency psychiatric walk-in and crisis services across the United States. METHODS: The authors used cross-sectional, annually collected data covering the 2014-2018 period from the National Mental Health Services Survey (N-MHSS), a representative survey of both public and private mental health treatment facilities in the United States. RESULTS: Overall, 42.6% of all U.S. mental health facilities did not offer any mental health crisis services between 2014 and 2018. A third of all facilities (33.5%) offered emergency psychiatric walk-in services, and just under one-half (48.3%) provided crisis services. When examining population-adjusted estimates, the authors noted a 15.8% (1.52-1.28 per 100,000 U.S. adults) and 7.5% (2.01-1.86 per 100,000 U.S. adults) decrease in walk-in and crisis services, respectively, from 2014 to 2018. Large geographic variation in service availability was also observed. CONCLUSION: A large proportion of psychiatric facilities in the United States do not provide psychiatric walk-in or crisis services. Availability of these services either has stayed flat or is declining. Disparities, particularly around U.S. borders and coasts, suggest policy efforts would be valuable for ensuring equitable service availability.

Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder.

Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk for BD in young people at high familial risk (HR) of BD. Peripheral blood-derived DNA was assayed using Illumina PsychArray, and Methylation-450K or -EPIC BeadChips. Polygenic risk scores (PRS) were calculated using summary statistics from recent genome-wide association studies for BD, major depressive disorder (MDD) and cross-disorder (meta-analysis of eight psychiatric disorders). Unrelated HR participants of European ancestry (n = 103) were stratified based on their BD-PRS score within the HR-population distribution, and the top two quintiles (High-BD-PRS; n = 41) compared against the bottom two quintiles (Low-BD-PRS; n = 41). The High-BD-PRS stratum also had higher mean cross-disorder-PRS and MDD-PRS (ANCOVA p = 0.035 and p = 0.024, respectively). We evaluated DNA methylation differences between High-BD-PRS and Low-BD-PRS strata using linear models. One differentially methylated probe (DMP) (cg00933603; p = 3.54 × 10-7) in VARS2, a mitochondrial aminoacyl-tRNA synthetase, remained significantly hypomethylated after multiple-testing correction. Overall, BD-PRS appeared to broadly impact epigenetic processes, with 1,183 genes mapped to nominal DMPs (p < 0.05); these displayed convergence with genes previously associated with BD, schizophrenia, chronotype, and risk taking. We tested poly-methylomic epigenetic profiles derived from nominal DMPs in two independent samples (n = 54 and n = 82, respectively), and conducted an exploratory evaluation of the effects of family environment, indexing cohesion and flexibility. This study highlights an important interplay between heritable risk and epigenetic factors, which warrant further exploration.

Environmental factors in offspring of parents with mood disorders and their role in parent-child transmission: findings from a 14-year prospective high-risk study.

BACKGROUND: The factors involved in the transmission of mood disorders are only partially elucidated. Aside from genes, the family environment might play a crucial role in parent-child transmission. Our goals were to (1) assess the associations of parental bipolar disorder (BPD) and Major Depressive Disorder (MDD) with individual or shared family environmental factors, including traumatic events in offspring, parental separation, family cohesion and parental attitudes; and 2) test whether these factors were mediators of the association between exposure to parental mood disorders and the onset of these disorders in offspring. METHODS: The sample stems from an ongoing family high-risk study of mood disorders conducted in the French-speaking part of Switzerland. Given the strong impact of the age of onset of parental disorders on their transmission to children, parental disorders were dichotomized according to the onset (cut-off 21 years). Probands with early-onset (n = 30) and later-onset BPD (n = 51), early-onset (n = 21) and later-onset MDD (n = 47) and controls (n = 65), along with their spouses (n = 193) and offspring (n = 388; < 18 years on study inclusion), were assessed over a mean follow-up duration of 14 years (s.d: 4.6). The environmental measures were based on reports by offspring collected before the onset of their first mood episode. RESULTS: Offspring of probands with later-onset BPD and offspring of probands with both early-onset and later-onset MDD reported traumatic events more frequently than comparison offspring, whereas exposure to parental separation was more frequent in all groups of high-risk offspring. Moreover, several familial environment scores including parenting attitudes differed between offspring of probands with BPD and comparison offspring. However, none of these factors were mediators of the parent-child transmission of BPD. Among the environmental factors, traumatic events were shown to be modest mediators of the transmission of early-onset MDD. CONCLUSIONS: Our data do not support the implication of the assessed environmental factors in the parent-child transmission of BPD. In contrast to BPD, traumatic events partially mediate the parent-child transmission of early-onset MDD, which has important implications for intervention and prevention. Early therapeutic efforts in offspring exposed to these events are likely to reduce their deleterious impact on the risk of subsequent MDD.

Parental bipolar disorder, family environment, and offspring psychiatric disorders: A systematic review.

BACKGROUND: Our objective was to systematically review non-experimental studies of parental bipolar disorder (BD), current family environment, and offspring psychiatric disorders to identify characteristics of family environment associated with parental BD and risk for offspring psychiatric disorders. METHODS: CINAHL, Embase, PsycINFO, and PubMed were searched using MeSH terms to identify studies on offspring of BD parents published through September 2017. We followed PRISMA guidelines and used the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS). We calculated prevalence ratios and 95% confidence intervals to compare offspring psychiatric disorders within and across studies. RESULTS: Of 10,454 unique documents retrieved, we included 13 studies. The most consistent finding was lower parent-reported cohesion in families with a BD parent versus no parental psychiatric disorders. Family environment did not differ between BD parents and parents with other disorders. Offspring of BD parents had higher prevalence of psychiatric disorders than offspring of parents without psychiatric disorders but did not differ from offspring of parents with other disorders. Families with a BD child had higher conflict than families without a BD child. LIMITATIONS: Comparisons between studies were qualitative. A single reviewer conducted screening, data extraction, and bias assessment. CONCLUSIONS: Family environment in families with a BD parent is heterogeneous. The pattern of findings across studies also suggests that family problems may be associated with parental psychiatric illness generally rather than parental BD in particular. Few studies included offspring-reported measures. Given the association of family conflict with offspring mood disorders, further study is merited on children's perceptions of the family environment in the BD high-risk context.

Complementary and Alternative Medicine Use in Children with a Developmental Disability and Co-occurring Medical Conditions.

OBJECTIVE: The primary aim of this study was to evaluate differences in the prevalence of complementary and alternative medicine (CAM) usage among children with and without developmental disabilities (DD). Secondarily, the association between CAM usage and comorbid chronic medical conditions was explored among children with DD. DESIGN: Data come from the 2012 Child Complementary and Alternative Medicine Supplement of the National Health Interview Survey, a nationally representative sample of children in the United States between the ages of 4 and 17 (n = 10,218).Main outcome measures Multiple logistical regression models provided insight into the relationships between parent-report CAM usage, DD, and chronic medical conditions. RESULTS: Children with developmental disabilities were more likely to use CAMs compared to their typically developing peers (21% vs 16%). Children with DDs and comorbid chronic medical conditions used CAMs at even higher rates (23% vs 18%). CONCLUSIONS: Results indicated that children with DD, especially those with a co-occurring chronic medical condition, use CAMs more often that typically developing children. Given scarcity of information on safety and effectiveness, clinical providers need to be alert to which children may be more likely to be exposed to CAMs. Communication between parents and providers needs to include discussion of CAM treatments.

Association of Outdoor Artificial Light at Night With Mental Disorders and Sleep Patterns Among US Adolescents.

Importance: Indoor nighttime light exposure influences sleep and circadian rhythms and is known to affect mood-associated brain circuits in animals. However, little is known about the association between levels of nighttime outdoor light and sleep and mental health in the population, especially among adolescents. Objective: To estimate associations of outdoor artificial light at night (ALAN) with sleep patterns and past-year mental disorder among US adolescents. Design, Setting, and Participants: This population-based, cross-sectional study of US adolescents used the National Comorbidity Survey-Adolescent Supplement, a nationally representative cross-sectional survey conducted from February 2001 through January 2004. A probability sample of adolescents aged 13 to 18 years was included. Analyses were conducted between February 2019 and April 2020. Exposures: Levels of outdoor ALAN, measured by satellite, with means calculated within census block groups. ALAN values were transformed into units of radiance (nW/cm2/sr). Main Outcomes and Measures: Self-reported habitual sleep patterns (weeknight bedtime, weeknight sleep duration, weekend bedtime delay, and weekend oversleep) and past-year mood, anxiety, behavior, and substance use disorders, measured via an in-person structured diagnostic interview. Parent-reported information was included in behavior disorder diagnoses. Results: Among 10 123 adolescents (4953 boys [51.3%]; mean [SE] age, 15.2 [0.06] years [weighted]; 6483 for behavior disorder outcomes), ALAN was positively associated with indicators of social disadvantage, such as racial/ethnic minority status (median [IQR] ALAN: white adolescents, 12.96 [30.51] nW/cm2/sr; Hispanic adolescents: 38.54 [47.84] nW/cm2/sr; non-Hispanic black adolescents: 37.39 [51.88] nW/cm2/sr; adolescents of other races/ethnicities: 30.94 [49.93] nW/cm2/sr; P < .001) and lower family income (median [IQR] ALAN by family income-to-poverty ratio ≤1.5: 26.76 [52.48] nW/cm2/sr; >6: 21.46 [34.38] nW/cm2/sr; P = .005). After adjustment for several sociodemographic characteristics, as well as area-level population density and socioeconomic status, this study found that higher ALAN levels were associated with later weeknight bedtime, and those in the lowest quartile of ALAN reported the longest weeknight sleep duration. Those in the highest quartile of ALAN went to bed 29 (95% CI, 15-43) minutes later and reported 11 (95% CI, 19-2) fewer minutes of sleep than those in the lowest quartile. ALAN was also positively associated with prevalence of past-year mood and anxiety disorder: each median absolute deviation increase in ALAN was associated with 1.07 (95% CI, 1.00-1.14) times the odds of mood disorder and 1.10 (95% CI, 1.05-1.16) times the odds of anxiety disorder. Further analyses revealed associations with bipolar disorder (odds ratio [OR], 1.19 [95% CI, 1.05-1.35]), specific phobias (OR, 1.18 [95% CI, 1.11-1.26]), and major depressive disorder or dysthymia (OR, 1.07 [95% CI, 1.00-1.15]). Among adolescent girls, differences in weeknight bedtime by ALAN (third and fourth quartiles vs first quartile) were greater with increasing years since menarche (F3, 8.15; P < .001). Conclusions and Relevance: In this study, area-level outdoor ALAN was associated with less favorable sleep patterns and mood and anxiety disorder in adolescents. Future studies should elucidate whether interventions to reduce exposure to ALAN may positively affect mental and sleep health.

Mood disorders, childhood maltreatment, and medical morbidity in US adults: An observational study.

OBJECTIVE: Mood disorders, child maltreatment, and medical morbidity are associated with enormous public health burden and individual suffering. The effect of mood disorders on medical morbidity, accounting for child maltreatment, has not been studied prospectively in a large, representative sample of community-dwelling US adults. This study tested the effects of mood disorders and child maltreatment on medical morbidity, and variation by subtypes. METHODS: Participants were noninstitutionalized US adults in the National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093 wave 1, N = 34,653 wave 2). Mood disorders included lifetime DSM-IV episodes of depression, dysthymia, mania, or hypomania. Child maltreatment was defined as sexual, physical, or emotional abuse, or physical or emotional neglect before age 18. Survey-weighted zero-inflated poisson regression was used to study effects on medical morbidity, a summary score of 11 self-reported medical conditions. Results were adjusted for age, sex, ethnicity/race, income, substance use disorders, smoking, and obesity. RESULTS: Mood disorders and child maltreatment additively associated with medical morbidity at study entry and three years later, with similar magnitude as obesity and smoking. Mania/hypomania (incidence rate ratio [IRR] 1.06, 95% CI 1.01-1.10) and child sexual (IRR 1.08, 95% CI 1.04-1.11) and emotional (IRR 1.05, 95% CI 1.01-1.10) abuse were associated with higher medical morbidity longitudinally. CONCLUSIONS: Child maltreatment is common, and its long-range negative effect on medical morbidity underscores the importance of trauma-informed care, and consideration of early life exposures. History of mania/hypomania should be considered in medical practice, and physical health must be emphasized in mental health care.