Candidate risks indicators for bipolar disorder:early intervention opportunities in high-risk youth

Background: Psychiatric illnesses like bipolar disorder are increasingly understood to be neurodevelopmental disorders with clinical, psychological, and biological indicators recognizable long before the emergence of the full-blown syndromes. Methods: This paper is a selective review of findings from studies of high-risk children of affected parents that inform the knowledge of illness risk and development markers of bipolar disorder. We specifically focus on candidate clinical, biological, and psychological risk indicators that could serve as targets for future early intervention and prevention studies. Results: There is convergent evidence from prospective studies that bipolar disorder typically debuts as depressive episodes after puberty. In some high-risk children, sleep and anxiety disorders precede mood disorders by several years and reflect an increased vulnerability. An association between early exposure to adversity (eg, exposure to parental illness, neglect from mother) and increased risk of psychopathology may be mediated through increased stress reactivity evident at both behavioral and biological levels. Inter-related psychological processes including reward sensitivity, unstable self-esteem, rumination, and positive self-appraisal are risk factors for mood disorders. Disturbances in circadian rhythm and immune dysfunction are associated with mood disorders and may be vulnerability markers influenced by these other risk factors. Conclusions: There is accruing evidence of a number of measurable and potentially modifiable markers of vulnerability and developing illness in youth at familial risk for bipolar disorder. Longitudinal studies of multiple biological and psychological risk processes in high-risk offspring, both individually and together, will improve our understanding of illness onset and lead to the development of specific early interventions

Unlocking stress and forecasting its consequences with digital technology

Chronic stress is a major underlying origin of the top leading causes of death, globally. Yet, the mechanistic explanation of the association between stress and disease is poorly understood. This stems from the inability to adequately measure stress in its naturally occurring state and the extreme heterogeneity by inter and intraindividual characteristics. The growth and availability of digital technologies involving wearable devices and mobile phone apps afford the opportunity to dramatically improve measurement of the biological stress response in real time. In parallel, the advancement and capabilities of artificial intelligence (AI) and machine learning could discern heterogeneous, multidimensional information from individual signs of stress, and possibly inform how these signs forecast the downstream consequences of stress in the form of end-organ damage. The marriage of these tools could dramatically enhance the field of stress research contributing to impactful and empowering interventions for individuals bridging knowledge to practice, and intervention to real-world use. Here we discuss this potential, anticipated challenges, and emerging opportunities

Multi-state models for investigating possible stages leading to bipolar disorder

BACKGROUND: It has been proposed that bipolar disorder onsets in a predictable progressive sequence of clinical stages. However, there is some debate in regard to a statistical approach to test this hypothesis. The objective of this paper is to investigate two different analysis strategies to determine the best suited model to assess the longitudinal progression of clinical stages in the development of bipolar disorder. METHODS: Data previously collected on 229 subjects at high risk of developing bipolar disorder were used for the statistical analysis. We investigate two statistical approaches for analyzing the relationship between the proposed stages of bipolar disorder: 1) the early stages are considered as time-varying covariates affecting the hazard of bipolar disorder in a Cox proportional hazards model, 2) the early stages are explicitly modelled as states in a non-parametric multi-state model. RESULTS: We found from the Cox model thatthere was evidence that the hazard of bipolar disorder is increased by the onset of major depressive disorder. From the multi-state model, in high-risk offspring the probability of bipolar disorder by age 29 was estimated as 0.2321. Cumulative incidence functions representing the probability of bipolar disorder given major depressive disorder at or before age 18 were estimated using both approaches and found to be similar. CONCLUSIONS: Both the Cox model and multi-state model are useful approaches to the modelling of antecedent risk syndromes. They lead to similar cumulative incidence functions but otherwise each method offers a different advantage

The association between self-reported and clinically determined hypomanic symptoms and the onset of major mood disorders

BACKGROUND Hypomanic symptoms may be a useful predictor of mood disorder among young people at high risk for bipolar disorder. AIMS To determine whether hypomanic symptoms differentiate offspring of parents with bipolar disorder (high risk) and offspring of well parents (control) and predict the development of mood episodes. METHOD High-risk and control offspring were prospectively assessed using semi-structured clinical interviews annually and completed the Hypomania Checklist-32 Revised (HCL-32). Clinically significant sub-threshold hypomanic symptoms (CSHS) were coded. RESULTS HCL-32 total and active or elated scores were higher in control compared with high-risk offspring, whereas 14% of high-risk and 0% of control offspring had CSHS. High-risk offspring with CSHS had a fivefold increased risk of developing recurrent major depression (P=0.0002). The median onset of CSHS in high-risk offspring was 16.4 (6-31) years and was before the onset of major mood episodes. CONCLUSIONS CSHS are precursors to major mood episodes in high-risk offspring and could identify individuals at ultra-high risk for developing bipolar disorder. DECLARATION OF INTEREST None. COPYRIGHT AND USAGE © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license

Repeated salivary daytime cortisol and onset of mood episodes in offspring of bipolar parents

BACKGROUND: Differences in cortisol secretion may differentiate individuals at high compared to low genetic risk for bipolar disorder (BD) and predict the onset or recurrence of mood episodes. The objectives of this study were to determine if salivary cortisol measures are: (1) different in high-risk offspring of parents with BD (HR) compared to control offspring of unaffected parents (C), (2) stable over time, (3) associated with the development of mood episode onset/recurrence, and (4) influenced by comorbid complications. METHODS: Fifty-three HR and 22 C completed salivary cortisol sampling annually for up to 4 years in conjunction with semi-structured clinical interviews. The cortisol awakening response (CAR), daytime cortisol [area under the curve (AUC)], and evening cortisol (8:00 p.m.) were calculated. RESULTS: There were no differences in baseline CAR, AUC and evening cortisol between HR and C (p = 0.38, p = 0.30 and p = 0.84), respectively. CAR, AUC and evening cortisol were stable over yearly assessments in HR, while in Cs, evening cortisol increased over time (p = 0.008), and CAR and AUC remained stable. In HR, AUC and evening cortisol increased the hazard of a new onset mood disorder/recurrence by 2.7 times (p = 0.01), and 3.5 times (p = 0.01), respectively, but this was no longer significant after accounting for multiple comparisons. CONCLUSIONS: Salivary cortisol is stable over time within HR offspring. However, between individuals, basal salivary cortisol is highly variable. More research is needed, with larger samples of prospectively studied HR youth using a more reliable method of cortisol measurement, to determine the potential role of cortisol in the development of mood disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40345-016-0053-5) contains supplementary material, which is available to authorized users

Validation of UK Biobank data for mental health outcomes : a pilot study using secondary care electronic health records

The study was funded by the MRC Pathfinder Grant (MC_PC_17215); the National Institute for Health Research’s (NIHR) Oxford Health Biomedical Research Centre (BRC-1215-20005) and the Virtual Brain Cloud from European Commission (grant no. H2020SC1-DTH-2018-1). This work was supported by the UK Clinical Record Interactive Search (UK-CRIS) system funded by the National Institute for Health Research (NIHR) and the Medical Research Council, with the University of Oxford, using data and systems of the NIHR Oxford Health Biomedical Research Centre (BRC-1215-20005).UK Biobank (UKB) is widely employed to investigate mental health disorders and related exposures; however, its applicability and relevance in a clinical setting and the assumptions required have not been sufficiently and systematically investigated. Here, we present the first validation study using secondary care mental health data with linkage to UKB from Oxford - Clinical Record Interactive Search (CRIS) focusing on comparison of demographic information, diagnostic outcome, medication record and cognitive test results, with missing data and the implied bias from both resources depicted. We applied a natural language processing model to extract information embedded in unstructured text from clinical notes and attachments. Using a contingency table we compared the demographic information recorded in UKB and CRIS. We calculated the positive predictive value (PPV, proportion of true positives cases detected) for mental health diagnosis and relevant medication. Amongst the cohort of 854 subjects, PPVs for any mental health diagnosis for dementia, depression, bipolar disorder and schizophrenia were 41.6%, and were 59.5%, 12.5%, 50.0% and 52.6%, respectively. Self-reported medication records in UKB had general PPV of 47.0%, with the prevalence of frequently prescribed medicines to each typical mental health disorder considerably different from the information provided by CRIS. UKB is highly multimodal, but with limited follow-up records, whereas CRIS offers a longitudinal high-resolution clinical picture with more than ten years of observations. The linkage of both datasets will reduce the self-report bias and synergistically augment diverse modalities into a unified resource to facilitate more robust research in mental health.Peer reviewe

High blood pressure and risk of dementia : a two-sample Mendelian randomization study in the UK biobank

This work was supported by Janssen Research and Development , LLC (of Johnson & Johnson).Background: Findings from randomized controlled trials have yielded conflicting results on the association between blood pressure (BP) and dementia traits. We tested the hypothesis that a causal relationship exists between systolic BP (SBP) and/or diastolic BP (DBP) and risk of Alzheimer's disease (AD). Methods: We performed a generalized summary Mendelian randomization (GSMR) analysis using summary statistics of a genome-wide association study meta-analysis of 299,024 individuals of SBP or DBP as exposure variables against three different outcomes: 1) AD diagnosis (International Genomics of Alzheimer's Project), 2) maternal family history of AD (UK Biobank), and 3) paternal family history of AD (UK Biobank). Finally, a combined meta-analysis of 368,440 individuals that included these three summary statistics was used as final outcome. Results: GSMR applied to the International Genomics of Alzheimer's Project dataset revealed a significant effect of high SBP lowering the risk of AD (βGSMR = −0.19, p =.04). GSMR applied to the maternal family history of AD UK Biobank dataset (SBP [βGSMR = −0.12, p =.02], DBP [βGSMR = −0.10, p =.05]) and to the paternal family history of AD UK Biobank dataset (SBP [βGSMR = −0.16, p =.02], DBP [βGSMR = −0.24, p = 7.4 × 10−4]) showed the same effect. A subsequent combined meta-analysis confirmed the overall significant effect for the other SBP analyses (βGSMR = −0.14, p =.03). The DBP analysis in the combined meta-analysis also confirmed a DBP effect on AD (βGSMR = −0.14, p =.03). Conclusions: A causal effect exists between high BP and a reduced late-life risk of AD. The results were obtained through careful consideration of confounding factors and the application of complementary MR methods on independent cohorts.Peer reviewe

YOUTH SUICIDE-RELATED THOUGHTS AND ATTEMPTS IN CANADA: EXPLAINING THE ROLE OF CHILDHOOD EXPOSURE TO MATERNAL DEPRESSION

Objectives: Objectives of this thesis were to: 1) determine the cumulative incidence of suicide-related thoughts (SRT) and attempts (SA) in Canadian youth and young adults; 2) estimate the association between exposure to maternal depressive symptoms during the first decade of life and subsequent SRT and SA; and 3) identify possible moderators (sex, family structure, maternal social support and social cohesion) and mediators (child psychiatric symptoms) of this association in Canadian youth and young adults. Methods: A cohort was constructed by linking all cycles from the National Longitudinal Survey of Children and Youth, a nationally representative survey, from 1994-2009 in respondents 0-25 years. Exposure to maternal-reported depressive symptoms and moderators were measured when offspring were between 0-10 years, while mediators were measured when offspring were between 6-10 years. Offspring self-reported incident and recurrent SRT and SA were measured between 11-25 years. Time-to-event models under a counting process framework were used to estimate cumulative incidence, measures of associations and 95% confidence intervals (CI). Results: The incidence of SRT between 11-25 years was 29% (95% CI: 26-31%) in females and 19% (95% CI: 16-23%) in males, and the incidence of SA between 11-25 years was 16% (95% CI: 14-19%) in females and 7% (95% CI: 6-8%) in males. The risk of incident and recurrent SRT and SA was significantly elevated among females exposed to maternal depressive symptoms, but not in males. Hyperactivity/inattention and psychiatric comorbidity were significant mediators, explaining 60% of the association with SRT and SA, and 50% of the association with SA, respectively. Conclusions: These findings have implications for earlier age implementation of suicide prevention programs and upstream selective approaches. Family-based preventions targeting families where a mother is depressed, prenatal screening, and clinician monitoring of high-risk families could reduce the risk of entering the trajectory towards suicide.Ph.D

YOUTH SUICIDE-RELATED THOUGHTS AND ATTEMPTS IN CANADA: EXPLAINING THE ROLE OF CHILDHOOD EXPOSURE TO MATERNAL DEPRESSION

Objectives: Objectives of this thesis were to: 1) determine the cumulative incidence of suicide-related thoughts (SRT) and attempts (SA) in Canadian youth and young adults; 2) estimate the association between exposure to maternal depressive symptoms during the first decade of life and subsequent SRT and SA; and 3) identify possible moderators (sex, family structure, maternal social support and social cohesion) and mediators (child psychiatric symptoms) of this association in Canadian youth and young adults. Methods: A cohort was constructed by linking all cycles from the National Longitudinal Survey of Children and Youth, a nationally representative survey, from 1994-2009 in respondents 0-25 years. Exposure to maternal-reported depressive symptoms and moderators were measured when offspring were between 0-10 years, while mediators were measured when offspring were between 6-10 years. Offspring self-reported incident and recurrent SRT and SA were measured between 11-25 years. Time-to-event models under a counting process framework were used to estimate cumulative incidence, measures of associations and 95% confidence intervals (CI). Results: The incidence of SRT between 11-25 years was 29% (95% CI: 26-31%) in females and 19% (95% CI: 16-23%) in males, and the incidence of SA between 11-25 years was 16% (95% CI: 14-19%) in females and 7% (95% CI: 6-8%) in males. The risk of incident and recurrent SRT and SA was significantly elevated among females exposed to maternal depressive symptoms, but not in males. Hyperactivity/inattention and psychiatric comorbidity were significant mediators, explaining 60% of the association with SRT and SA, and 50% of the association with SA, respectively. Conclusions: These findings have implications for earlier age implementation of suicide prevention programs and upstream selective approaches. Family-based preventions targeting families where a mother is depressed, prenatal screening, and clinician monitoring of high-risk families could reduce the risk of entering the trajectory towards suicide.Ph.D