Longitudinal studies of bipolar patients and their families: translating findings to advance individualized risk prediction, treatment and research.

BACKGROUND: Bipolar disorder is a broad diagnostic construct associated with significant phenotypic and genetic heterogeneity challenging progress in clinical practice and discovery research. Prospective studies of well-characterized patients and their family members have identified lithium responsive (LiR) and lithium non-responsive (LiNR) subtypes that hold promise for advancement. METHOD: In this narrative review, relevant observations from published longitudinal studies of well-characterized bipolar patients and their families spanning six decades are highlighted. DSM diagnoses based on SADS-L interviews were decided in blind consensus reviews by expert clinicians. Genetic, neurobiological, and psychosocial factors were investigated in subsets of well-characterized probands and adult relatives. Systematic maintenance trials of lithium, antipsychotics, and lamotrigine were carried out. Clinical profiles that included detailed histories of the clinical course, symptom sets and disorders segregating in families were documented. Offspring of LiR and LiNR families were repeatedly assessed up to 20 years using KSADS-PL format interviews and DSM diagnoses and sub-threshold symptoms were decided by expert clinicians in blind consensus reviews using all available clinical and research data. RESULTS: A characteristic clinical profile differentiated bipolar patients who responded to lithium stabilization from those who did not. The LiR subtype was characterized by a recurrent fully remitting course predominated by depressive episodes and a positive family history of episodic remitting mood disorders, and not schizophrenia. Response to lithium clustered in families and the characteristic clinical profile predicted lithium response, with the episodic remitting course being a strong correlate. There is accumulating evidence that genetic and neurobiological markers differ between LiR and LiNR subtypes. Further, offspring of bipolar parents subdivided by lithium response differed in developmental history, clinical antecedents and early course of mood disorders. Moreover, the nature of the emergent course bred true from parent to offspring, independent of the nature of emergent psychopathology. CONCLUSIONS: Bipolar disorders are heterogeneous and response to long-term lithium is associated with a familial subtype with characteristic course, treatment response, family history and likely pathogenesis. Incorporating distinctive clinical profiles that index valid bipolar subtypes into routine practice and research will improve patient outcomes and advance the development and translation of novel treatment targets to improve prevention and early intervention.

Acceptability and utility of digital well-being and mental health support for university students: A pilot study.

AIM: To assess the acceptability and explore the utility of a novel digital platform designed as a student-facing well-being and mental health support. METHODS: An adapted version of i-spero® was piloted as a student-facing well-being support and as part of routine university-based mental health care. In both pathways, student participants completed baseline demographics and brief validated measures of well-being and mental health. Weekly measures of anxiety (GAD-7) and depression (PHQ-9) and a Week 8 Experience Survey were also scheduled. Integrated mixed methods analysis was used to assess acceptability and explore the utility of these platforms. RESULTS: Students in the well-being (n = 120) and care pathways (n = 121) were mostly female and between 19 and 22 years of age. Baseline screen positive rates for anxiety and depression were high in both the well-being (68%) and care pathways (80%). There was a substantial drop in adherence over Week 1 (50% well-being; 40% care) followed by minor attrition up to Week 8. Anxiety and depressive symptom levels improved from baseline in students who dropped out after Week 1 (p ≤ .06). The student experience was that i-spero® improved their emotional self-awareness, understanding of progress in care, and knowledge about when to seek help. Most students agreed (>75%) that i-spero® should form part of regular university student wellness support. CONCLUSIONS: Digital well-being and mental health support seems acceptable to university students; however, engagement and persistence are areas for further development. Such digital tools could make a positive contribution to an evidence-based stepped approach to student well-being and mental health support.

Changes in sleep and the prevalence of probable insomnia in undergraduate university students over the course of the COVID-19 pandemic: findings from the U-Flourish cohort study.

BACKGROUND: Sleep problems associated with poor mental health and academic outcomes may have been exacerbated by the COVID-19 pandemic. AIMS: To describe sleep in undergraduate students during the COVID-19 pandemic. METHOD: This longitudinal analysis included data from 9523 students over 4 years (2018-2022), associated with different pandemic phases. Students completed a biannual survey assessing risk factors, mental health symptoms and lifestyle, using validated measures. Sleep was assessed with the Sleep Condition Indicator (SCI-8). Propensity weights and multivariable log-binomial regressions were used to compare sleep in four successive first-year cohorts. Linear mixed-effects models were used to examine changes in sleep over academic semesters and years. RESULTS: There was an overall decrease in average SCI-8 scores, indicating worsening sleep across academic years (average change -0.42 per year; P-trend < 0.001), and an increase in probable insomnia at university entry (range 18.1-29.7%; P-trend < 0.001) before and up to the peak of the pandemic. Sleep improved somewhat in autumn 2021, when restrictions loosened. Students commonly reported daytime sleep problems, including mood, energy, relationships (36-48%) and concentration, productivity, and daytime sleepiness (54-66%). There was a consistent pattern of worsening sleep over the academic year. Probable insomnia was associated with increased cannabis use and passive screen time, and reduced recreation and exercise. CONCLUSIONS: Sleep difficulties are common and persistent in students, were amplified by the pandemic and worsen over the academic year. Given the importance of sleep for well-being and academic success, a preventive focus on sleep hygiene, healthy lifestyle and low-intensity sleep interventions seems justified.

Practices, knowledge, and attitudes about lithium treatment: Results of online surveys completed by clinicians and lithium-treated patients.

BACKGROUND: Lithium remains the gold-standard medication for acute and prophylactic treatment of bipolar disorder. Understanding clinicians' practices and patients' experiences, knowledge and attitudes about lithium may improve its clinical use. METHODS: Online anonymous surveys collected information about clinician's practices and level of confidence in managing lithium and patients' experiences with lithium treatment and information received about benefits and side effects. Knowledge and attitudes regarding lithium were assessed with the Lithium Knowledge Test (LKT) and the Lithium Attitudes Questionnaire (LAQ). RESULTS: Among 201 clinicians, 64.2% endorsed often treating patients with lithium and reported high levels of confidence in assessing and managing lithium. Practices concerning clinical indications, drug titration, and serum levels were guideline-concordant, but compliance with monitoring recommendations was less frequent. Practitioners were interested in receiving more education about lithium. The patients' survey recruited 219 participants with 70.3% being current lithium users. Most patients (68%) found lithium helpful and 71% reported experiencing any kind of side effect. Most responders did not receive information about side effects or other benefits of lithium. Patients with higher scores on the LKT were more likely to have positive attitudes about lithium. LIMITATIONS: Cross-sectional design with predominantly English-speaking participants from Brazil and North America. CONCLUSIONS: There is a discrepancy between guidelines, clinician confidence and knowledge of lithium use and practice. A deeper understanding of how to monitor, prevent and manage long-term side effects and which patients are most likely to benefit from lithium may narrow the gap between knowledge and use.

The Impact of the COVID-19 Pandemic on the Mental Health of First-Year Undergraduate Students Studying at a Major Canadian University: A Successive Cohort Study.

OBJECTIVE: To examine the impact of the COVID-19 pandemic on first year undergraduate student mental health. METHODS: As part of the Queen's University U-Flourish Student Well-Being and Academic Success study, three successive cohorts of students entering undergraduate studies in 2018 (pre-pandemic), 2019 (transitional), and 2020 (during pandemic) completed electronic surveys at entry and completion of first year. Validated self-report measures were used to assess mental health status including symptom levels of anxiety, depression, and insomnia, self-harm and frequency of substance use. Propensity matching and multivariable log-binomial regression were used in comparisons of mental health indicators across the cohorts. RESULTS: Clinically significant symptoms of depression, anxiety, insomnia, and self-harm were reported more frequently in the 2020-2021 cohort, coincident with remote learning and pandemic restrictions. In female students, screen positive rates for anxiety and depression, and suicidal ideation increased from about one-third to just under one-half in association with the pandemic (χ2, p < .01), while increases in mental health concerns were less pronounced among males. Among females, increases in clinically significant symptoms over first year appeared greatest during the pandemic year, while striking decreases in alcohol consumption in both females and males were reported in that same year. Studying under pandemic conditions had a negative impact on student well-being, social relationships and school connectedness, quality of learning experience, leisure activities, and optimism about future prospects. CONCLUSIONS: Mental health concerns including anxiety, depression and sleep problems increased in first year students during the pandemic, especially among females, while alcohol use declined. These findings highlight the negative mental health impact associated with studying under pandemic restrictions involving remote learning and social distancing.

Childhood Adversity and Mental Health Outcomes Among University Students: A Longitudinal Study.

BACKGROUND: Mental health concerns are common among university students and maybe elevated among those with specific risk exposures. The study examined the association between childhood adversities and mental health outcomes among undergraduate university students and assessed whether psychosocial and behavioral factors mediate those associations. METHODS: The Queen's University Student Well-Being and Academic Success Survey identified two large cohorts of first-year undergraduate students entering university in Fall 2018 and 2019 (n = 5,943). At baseline, students reported sociodemographic information, family-related mental health history, childhood physical abuse, sexual abuse, peer bullying, and parental separation or divorce. Baseline and follow-up surveys in Spring 2019, Fall 2019, and Spring 2020 included validated measures of anxiety (7-item Generalized Anxiety Disorder) and depressive symptoms (9-item Patient Health Questionnaire ), non-suicidal self-harm, and suicidality, along with psychological processes and lifestyle variables. Repeated measures logistic regression using Generalized Estimating Equations was used to characterize the associations between childhood adversities and mental health outcomes and examine potential mediation. RESULTS: Adjusting for age, gender, ethnicity, familial mental illness, and parental education, any childhood abuse (odds ratio: 2.89; 95% confidence interval, 2.58 to 3.23) and parental separation or divorce (odds ratio: 1.29; 95% confidence interval, 1.12 to 1.50) were significantly associated with a composite indicator of mental health outcomes (either 9-item Patient Health Questionnaire score ≥10 or 7-item Generalized Anxiety Disorderscore ≥10 or suicidality or self-harm). The association with childhood abuse weakened when adjusted for perceived stress, self-esteem, and insomnia (odds ratio: 2.05; 95% confidence interval, 1.80 to 2.34), and that with parental divorce weakened when adjusted for self-esteem (odds ratio: 1.17; 95% confidence interval, 1.00 to 1.36). CONCLUSION: Childhood abuse and parental separation or divorce were associated with mental health concerns among university students. Childhood adversities may impact later mental health through an association with stress sensitivity, self-esteem, and sleep problems. The findings suggest that prevention and early intervention focusing on improving sleep, self-esteem, and coping with stress while considering the individual risk profile of help-seeking students may help support student mental health.

Lithium induced hypercalcemia: an expert opinion and management algorithm.

BACKGROUND: Lithium is the gold standard prophylactic treatment for bipolar disorder. Most clinical practice guidelines recommend regular calcium assessments as part of monitoring lithium treatment, but easy-to-implement specific management strategies in the event of abnormal calcium levels are lacking. METHODS: Based on a narrative review of the effects of lithium on calcium and parathyroid hormone (PTH) homeostasis and its clinical implications, experts developed a step-by-step algorithm to guide the initial management of emergent hypercalcemia during lithium treatment. RESULTS: In the event of albumin-corrected plasma calcium levels above the upper limit, PTH and calcium levels should be measured after two weeks. Measurement of PTH and calcium levels should preferably be repeated after one month in case of normal or high PTH level, and after one week in case of low PTH level, independently of calcium levels. Calcium levels above 2.8 mmol/l may require a more acute approach. If PTH and calcium levels are normalized, repeated measurements are suggested after six months. In case of persistent PTH and calcium abnormalities, referral to an endocrinologist is suggested since further examination may be needed. CONCLUSIONS: Standardized consensus driven management may diminish the potential risk of clinicians avoiding the use of lithium because of uncertainties about managing side-effects and consequently hindering some patients from receiving an optimal treatment.

Transitions to campus mental health care in university students: Determinants and predictors.

Background: Access to university mental health services is poorly characterized. Our objectives were to (1) assess patterns of access and (2) explore predictability of contact with student mental health services. Participants: Data derived from the U-Flourish study, which includes a survey of successive cohorts of incoming undergraduate students attending Queen's University, located in Ontario, Canada (Cohort 1: 2018, Cohort 2: 2019). Methods: Survey data sets were deterministically linked to administrative data provided by Student Wellness Services. Analyses included cross-tabulation, logistic and negative binomial regression. Predictive modeling used LASSO regression. Results: Baseline symptoms were robust determinants of access. For example, a PHQ-9 rating in the severe range (≥ 20) was associated with an OR of 9.71 (95% CI: 4.46-21.1). A predictive algorithm did not outperform cut point-based interpretation of PHQ-9 or GAD-7 ratings. Conclusions: Self-reported symptoms are consistently associated with service use, supporting the widespread use of symptom screens.

Smartphone-based interventions in bipolar disorder: Systematic review and meta-analyses of efficacy. A position paper from the International Society for Bipolar Disorders (ISBD) Big Data Task Force.

BACKGROUND: The clinical effects of smartphone-based interventions for bipolar disorder (BD) have yet to be established. OBJECTIVES: To examine the efficacy of smartphone-based interventions in BD and how the included studies reported user-engagement indicators. METHODS: We conducted a systematic search on January 24, 2022, in PubMed, Scopus, Embase, APA PsycINFO, and Web of Science. We used random-effects meta-analysis to calculate the standardized difference (Hedges' g) in pre-post change scores between smartphone intervention and control conditions. The study was pre-registered with PROSPERO (CRD42021226668). RESULTS: The literature search identified 6034 studies. Thirteen articles fulfilled the selection criteria. We included seven RCTs and performed meta-analyses comparing the pre-post change in depressive and (hypo)manic symptom severity, functioning, quality of life, and perceived stress between smartphone interventions and control conditions. There was significant heterogeneity among studies and no meta-analysis reached statistical significance. Results were also inconclusive regarding affective relapses and psychiatric readmissions. All studies reported positive user-engagement indicators. CONCLUSION: We did not find evidence to support that smartphone interventions may reduce the severity of depressive or manic symptoms in BD. The high heterogeneity of studies supports the need for expert consensus to establish ideally how studies should be designed and the use of more sensitive outcomes, such as affective relapses and psychiatric hospitalizations, as well as the quantification of mood instability. The ISBD Big Data Task Force provides preliminary recommendations to reduce the heterogeneity and achieve more valid evidence in the field.

Psychological predictors of insomnia, anxiety and depression in university students: potential prevention targets.

BACKGROUND: Perfectionism, low self-esteem and external locus of control are psychological constructs linked to insomnia, anxiety and depression. Examining how these constructs impact mental health and serve as risk factors for the development of clinically significant symptoms may help direct psychological support resources and preventative measures for university students. AIMS: To longitudinally examine associations between the aforementioned psychological constructs and symptoms of insomnia, anxiety and depression in a large representative sample of first-year university students. METHOD: Electronic surveys including validated measures of the predictors and outcomes were emailed to all first-year undergraduate students at entry to a major Canadian university, and followed up on at conclusion of the academic year. RESULTS: Compared with healthy sleepers, students screening positive for insomnia had lower self-esteem, higher self-evaluative perfectionism and increased external locus of control (all P < 0.001). Self-evaluative perfectionism (standardised ß = 0.13, P < 0.01), self-esteem (ß = -0.30, P < 0.001) and external locus of control (ß = 0.07, P = 0.02) measured at entry were significantly associated with insomnia symptoms at follow-up. Insomnia symptoms at entry were strong predictors of symptoms of depression (ß = 0.15, P < 0.001) and anxiety (ß = 0.16, P < 0.001) at follow-up, even after controlling for baseline symptoms of those disorders. CONCLUSIONS: Perfectionism, low self-esteem and external locus of control may predispose the development of insomnia symptoms in university students. In turn, insomnia symptoms appear to be robust predictors for depressive and anxiety symptoms. Sleep may be an important prevention target in university students.

Impact of the COVID-19 pandemic on the experience and mental health of university students studying in Canada and the UK: a cross-sectional study.

OBJECTIVES: To explore the impact of the COVID-19 pandemic on the experiences and mental health of university students. DESIGN: A cross-sectional study consisting of an electronic survey about students' experiences and concerns during the pandemic and the associated impact. In addition to the quantitative analysis, free-text responses were extracted and analysed using a framework technique. SETTING: Queen's University in Canada and the University of Oxford in the UK. PARTICIPANTS: Undergraduate students at Queen's University and first-year undergraduate students at the University of Oxford were invited to complete the COVID-19 supplement survey. This study included data from 3013 Queen's students as the primary focus and 339 Oxford students as a secondary comparison. RESULTS: Females at Queen's reported greater adherence to government recommendations to prevent the spread of COVID-19 (91.3% vs 86.7%, χ2 p<0.01) and were more likely to self-isolate (63.9% vs 57.0%, χ2 p<0.01) than males. A similar trend was seen among Oxford students. Students' concerns were wide ranging including those related to their learning experience, finances and future academic and career prospects. 78.9% of Queen's students and 50.4% of first-year Oxford students reported worries about the long-term impact on their academic and job prospects. A sizeable proportion of students also reported that the pandemic negatively impacted their plans to continue at university (29.4% of Queen's, 14.2% of Oxford) and disrupted activities important to their mental well-being. Key themes identified in the qualitative component included the negative impacts of social isolation, challenging academic changes and disruption to support services and means of coping. CONCLUSIONS: Overall, findings underscore the importance of addressing areas of student concern and the aspects of student life negatively impacted by the pandemic in order to maintain student well-being and support a successful university experience.

Mental health trajectories in undergraduate students over the first year of university: a longitudinal cohort study.

OBJECTIVE: This study examined the association between candidate psychosocial and lifestyle variables and the trajectories of clinically significant anxiety and depressive symptoms from entry to completion of first-year university. DESIGN: A longitudinal cohort study PARTICIPANTS: First-year undergraduate students METHODS: We analysed the responses of 1686 first-year undergraduate students attending Queen's University who completed electronic surveys at both the beginning and completion of their academic year. Predictors of change in positive anxiety and depressive symptom screens (based on exceeding validated symptom threshold scores) were identified using logistic regression. RESULTS: Increased university connectedness reduced the odds of emergent significant depressive and anxiety symptoms in healthy students and increased the odds of recovery in students who screened positive at the start of university. Students who screened positive for depression or anxiety at university entry were less likely to recover if they had a lifetime history of internalising disorders. Healthy students who increased their drug use over their first year had higher odds of developing significant levels of both anxiety and depressive symptoms by completion of the academic year. CONCLUSIONS: Moderate to severe levels of anxiety and depressive symptoms are common among students at entry to university and persist over the first year. University connectedness may mitigate the risk of persistent or emergent symptoms, whereas drug use appears to increase these risks. Findings have implications for university well-being initiatives.

Development and validation of a risk calculator for major mood disorders among the offspring of bipolar parents using information collected in routine clinical practice.

BACKGROUND: Family history is a significant risk factor for bipolar disorders (BD), but the magnitude of risk varies considerably between individuals within and across families. Accurate risk estimation may increase motivation to reduce modifiable risk exposures and identify individuals appropriate for monitoring over the peak risk period. Our objective was to develop and independently replicate an individual risk calculator for bipolar spectrum disorders among the offspring of BD parents using data collected in routine clinical practice. METHODS: Data from the longitudinal Canadian High-Risk Offspring cohort study collected from 1996 to 2020 informed the development of a 5 and 10-year risk calculator using parametric time-to-event models with a cure fraction and a generalized gamma distribution. The calculator was then externally validated using data from the Lausanne-Geneva High-Risk Offspring cohort study collected from 1996 to 2020. A time-varying C-index by age in years was used to estimate the probability that the model correctly classified risk. Bias corrected estimates and 95% confidence limits were derived using a jackknife resampling approach. FINDINGS: The primary outcome was age of onset of a major mood disorder. The risk calculator was most accurate at classifying risk in mid to late adolescence in the Canadian cohort (n = 285), and a similar pattern was replicated in the Swiss cohort (n = 128). Specifically, the time-varying C-index indicated that there was approximately a 70% chance that the model would correctly predict which of two 15-year-olds would be more likely to develop the outcome in the future. External validation within a smaller Swiss cohort showed mixed results. INTERPRETATION: Findings suggest that this model may be a useful clinical tool in routine practice for improved individualized risk estimation of bipolar spectrum disorders among the adolescent offspring of a BD parent; however, risk estimation in younger high-risk offspring is less accurate, perhaps reflecting the evolving nature of psychopathology in early childhood. Based on external validation with a Swiss cohort, the risk calculator may not be as predictive in more heterogenous high-risk populations. FUNDING: The Canadian High-Risk Study has been funded by consecutive operating grants from the Canadian Institutes for Health Research, currently CIHR PJT Grant 152796 he Lausanne-Geneva high-risk study was and is supported by five grants from the Swiss National Foundation (#3200-040,677, #32003B-105,969, #32003B-118,326, #3200-049,746 and #3200-061,974), three grants from the Swiss National Foundation for the National Centres of Competence in Research project "The Synaptic Bases of Mental Diseases" (#125,759, #158,776, and #51NF40 - 185,897), and a grant from GlaxoSmithKline Clinical Genetics.

Predicting the risk and timing of major mood disorder in offspring of bipolar parents: exploring the utility of a neural network approach.

BACKGROUND: Bipolar disorder onset peaks over early adulthood and confirmed family history is a robust risk factor. However, penetrance within families varies and most children of bipolar parents will not develop the illness. Individualized risk prediction would be helpful for identifying those young people most at risk and to inform targeted intervention. Using prospectively collected data from the Canadian Flourish High-risk Offspring cohort study available in routine practice, we explored the use of a neural network, known as the Partial Logistic Artificial Neural Network (PLANN) to predict the time to diagnosis of major mood disorders in 1, 3 and 5-year intervals. RESULTS: Overall, for predictive performance, PLANN outperformed the more traditional discrete survival model for 3-year and 5-year predictions. PLANN was better able to discriminate or rank individuals based on their risk of developing a major mood disorder, better able to predict the probability of developing a major mood disorder and better able to identify individuals who would be diagnosed in future time intervals. The average AUC achieved by PLANN for 5-year prediction was 0.74, which indicates good discrimination. CONCLUSIONS: This evaluation of PLANN is a useful step in the investigation of using neural networks as tools in the prediction of mood disorders in at-risk individuals and the potential that neural networks have in this field. Future research is needed to replicate these findings in a separate high-risk offspring sample.

Consensus on nomenclature for clinical staging models in bipolar disorder: A narrative review from the International Society for Bipolar Disorders (ISBD) Staging Task Force.

OBJECTIVES: Clinical staging is widely used in medicine to map disease progression, inform prognosis, and guide treatment decisions; in psychiatry, however, staging remains a hypothetical construct. To facilitate future research in bipolar disorders (BD), a well-defined nomenclature is needed, especially since diagnosis is often imprecise with blurred boundaries, and a full understanding of pathophysiology is lacking. METHODS: Under the auspices of the International Society of Bipolar Disorders, a Task Force of international experts was convened to review, discuss, and integrate findings from the scientific literature relevant to the development of a consensus staging model and standardize a terminology that could be used to advance future research including staging of BD and related disorders. RESULTS: Consensus opinion and areas of uncertainty or difference were identified in regard to terms referring to staging as it may apply to BD, to at-risk status and subthreshold stages, and to various clinical stages of BD as it is currently diagnosed. CONCLUSION: The use of a standardized nomenclature about the clinical stages of BD will facilitate communication about research on clinical and pathological components of this heterogeneous group of disorders. The concepts presented are based on current evidence, but the template provided allows for further refinements as etiological advances come to light.