Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity.

Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.

A Novel Unsupervised Machine Learning Approach to Assess Postural Dynamics in Euthymic Bipolar Disorder.

Bipolar disorder (BD) is a mood disorder with different phases alternating between euthymia, manic or hypomanic episodes, and depressive episodes. While motor abnormalities are commonly seen during depressive or manic episodes, not much attention has been paid to postural abnormalities during periods of euthymia and their association with illness burden. We collected 24-hour posture data in 32 euthymic participants diagnosed with BD using a shirt-based wearable. We extracted a set of nine time-domain features, and performed unsupervised participant clustering. We investigated the association between posture variables and 12 clinical characteristics of illness burden. Based on their postural dynamics during the daytime, evening, or nighttime, participants clustered in three clusters. Higher illness burden was associated with lower postural variability, in particular during daytime. Participants who exhibited a mostly upright sitting/standing posture during the night with frequent nighttime postural transitions had the highest number of lifetime depressive episodes. Euthymic participants with BD exhibit postural abnormalities that are associated with illness burden, especially with the number of depressive episodes. Our results contribute to understanding the role of illness burden on posture changes and sleep consolidation in periods of euthymia.

Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a multifactorial psychiatric illness affecting ∼1% of the global adult population. Lithium (Li), is the most effective mood stabilizer for BD but works only for a subset of patients and its mechanism of action remains largely elusive. METHODS: In the present study, we used iPSC-derived neurons from patients with BD who are responsive (LR) or not (LNR) to lithium. Combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics were employed to provide mechanistic insights into neuronal hyperactivity in BD, investigate Li's mode of action, and identify alternative treatment strategies. FINDINGS: We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na+ conductance. Whole transcriptome sequencing in BD neurons revealed altered gene expression pathways related to glutamate transmission, alterations in cell signalling and ion transport/channel activity. We found altered Akt signalling as a potential therapeutic effect of Li in LR neurons from patients with BD, and that Akt activation mimics Li effect in LR neurons. Furthermore, the increased neural network activity observed in both LR & LNR neurons from patients with BD were reversed by AMP-activated protein kinase (AMPK) activation. INTERPRETATION: These results suggest potential for new treatment strategies in BD, such as Akt activators in LR cases, and the use of AMPK activators for LNR patients with BD. FUNDING: Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation.

Differential contributions of circadian clock genes to cell survival in bipolar disorder patient derived neuronal progenitor cells distinguishes lithium responders and non-responders.

Bipolar disorder (BD) is characterized by disrupted circadian rhythms and neuronal loss. Lithium is neuroprotective and used to treat BD, but outcomes are variable. Past research identified that circadian rhythms in BD patient neurons are associated with lithium response (Li-R) or non-response (Li-NR). However, the underlying cellular mechanisms remain unknown. To study interactions among circadian clock genes and cell survival, and their role in BD and predicting lithium response, we tested selected genes (PER1, BMAL1 and REV-ERBα) and small molecule modulators of ROR/REV-ERB nuclear receptors in models of cell survival using mouse neurons and stem-cell derived neuronal progenitor cells (NPC) from BD patients and controls. In apoptosis assays using staurosporine (STS), lithium was neuroprotective. Knockdown of PER1, BMAL1 and REV-ERBα modified cell survival across models. In NPCs, reduced expression of PER1 and BMAL1 led to more extensive cell death in Li-NR vs. Li-R. Reduced REV-ERBα expression caused more extensive cell death in BD vs. control NPCs, without distinguishing Li-R and Li-NR. In IMHN, The REV-ERB agonist GSK4112 had strong effects on circadian rhythm amplitude, and was neuroprotective in mouse neurons and control NPCs, but not in BD NPCs. Expression of cell survival genes following STS and GSK4112 treatments revealed BD-associated, and Li-R associated differences in expression profiles. We conclude that the neuroprotective response to lithium is similar in NPCs from Li-R and Li-NR. However, knockdown of circadian clock genes or stimulation of REV-ERBs reveal distinct contributions to cell death in BD patient NPCs, some of which distinguish Li-R and Li-NR.

Not missing at random: Missing data are associated with clinical status and trajectories in an electronic monitoring longitudinal study of bipolar disorder.

There is limited information on the association between participants' clinical status or trajectories and missing data in electronic monitoring studies of bipolar disorder (BD). We collected self-ratings scales and sensor data in 145 adults with BD. Using a new metric, Missing Data Ratio (MDR), we assessed missing self-rating data and sensor data monitoring activity and sleep. Missing data were lowest for participants in the midst of a depressive episode, intermediate for participants with subsyndromal symptoms, and highest for participants who were euthymic. Over a mean ± SD follow-up of 246 ± 181 days, missing data remained unchanged for participants whose clinical status did not change throughout the study (i.e., those who entered the study in a depressive episode and did not improve, or those who entered the study euthymic and remained euthymic). Conversely, when participants' clinical status changed during the study (e.g., those who entered the study euthymic and experienced the occurrence of a depressive episode), missing data for self-rating scales increased, but not for sensor data. Overall missing data were associated with participants' clinical status and its changes, suggesting that these are not missing at random.

Phenotypic clustering of bipolar disorder supports stratification by lithium responsiveness over diagnostic subtypes.

INTRODUCTION: The aim of this study was to determine whether the clinical profiles of bipolar disorder (BD) patients could be differentiated more clearly using the existing classification by diagnostic subtype or by lithium treatment responsiveness. METHODS: We included adult patients with BD-I or II (N = 477 across four sites) who were treated with lithium as their principal mood stabilizer for at least 1 year. Treatment responsiveness was defined using the dichotomized Alda score. We performed hierarchical clustering on phenotypes defined by 40 features, covering demographics, clinical course, family history, suicide behaviour, and comorbid conditions. We then measured the amount of information that inferred clusters carried about (A) BD subtype and (B) lithium responsiveness using adjusted mutual information (AMI) scores. Detailed phenotypic profiles across clusters were then evaluated with univariate comparisons. RESULTS: Two clusters were identified (n = 56 and n = 421), which captured significantly more information about lithium responsiveness (AMI range: 0.033 to 0.133) than BD subtype (AMI: 0.004 to 0.011). The smaller cluster had disproportionately more lithium responders (n = 47 [83.8%]) when compared to the larger cluster (103 [24.4%]; p = 0.006). CONCLUSIONS: Phenotypes derived from detailed clinical data may carry more information about lithium responsiveness than the current classification of diagnostic subtype. These findings support lithium responsiveness as a valid approach to stratification in clinical samples.

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

A pilot study examining the impact of lithium treatment and responsiveness on mnemonic discrimination in bipolar disorder.

INTRODUCTION: Mnemonic discrimination (MD), the ability to discriminate new stimuli from similar memories, putatively involves dentate gyrus pattern separation. Since lithium may normalize dentate gyrus functioning in lithium-responsive bipolar disorder (BD), we hypothesized that lithium treatment would be associated with better MD in lithium-responsive BD patients. METHODS: BD patients (N = 69; NResponders = 16 [23 %]) performed the Continuous Visual Memory Test (CVMT), which requires discriminating between novel and previously seen images. Before testing, all patients had prophylactic lithium responsiveness assessed over ≥1 year of therapy (with the Alda Score), although only thirty-eight patients were actively prescribed lithium at time of testing (55 %; 12/16 responders, 26/53 nonresponders). We then used computational modelling to extract patient-specific MD indices. Linear models were used to test how (A) lithium treatment, (B) lithium responsiveness via the continuous Alda score, and (C) their interaction, affected MD. RESULTS: Superior MD performance was associated with lithium treatment exclusively in lithium-responsive patients (Lithium x AldaScore ß = 0.257 [SE 0.078], p = 0.002). Consistent with prior literature, increased age was associated with worse MD (ß = -0.03 [SE 0.01], p = 0.005). LIMITATIONS: Secondary pilot analysis of retrospectively collected data in a cross-sectional design limits generalizability. CONCLUSION: Our study is the first to examine MD performance in BD. Lithium is associated with better MD performance only in lithium responders, potentially due to lithium's effects on dentate gyrus granule cell excitability. Our results may influence the development of behavioural probes for dentate gyrus neuronal hyperexcitability in BD.

Cognitive behavioural therapy for social anxiety disorder in people with bipolar disorder: a case series.

BACKGROUND: Social anxiety disorder increases the likelihood of unfavourable outcomes in people with bipolar disorder. Cognitive behavioural therapy (CBT) is the first-line treatment for social anxiety disorder. However, people with bipolar disorder have been excluded from the studies that this recommendation is based on.  METHOD: We completed a case series to obtain initial data on whether CBT is an acceptable, safe, and effective treatment for social anxiety disorder in people with bipolar disorder. RESULTS: Eleven euthymic participants with bipolar disorder attended up to sixteen treatment and three follow-up sessions of CBT for social anxiety disorder. Participants attended on average 95% of the offered CBT sessions. No adverse events were reported. Participants' mean score on the Social Phobia Inventory decreased from 46.5 (SD 6.6) before the treatment to 19.8 (SD 11.9) at the end of the sixteen-session intervention and further to 15.8 (SD 10.3) by the end of the 3-month follow-up. This degree of improvement is equivalent to the effect observed in studies of CBT for social anxiety disorder in people without severe mental illness. CONCLUSIONS: This case series provides preliminary evidence that CBT is acceptable, safe, and effective for treating social anxiety disorder in people with bipolar disorder during euthymia. A randomized controlled trial is needed to confirm these findings, and to establish whether treatment for social anxiety disorder improves the course of bipolar disorder.

Depressive symptoms in youth before and during the COVID-19 pandemic: longitudinal investigation of patterns dependent on age, sex, and family history of mental illness.

BACKGROUND: Cross-sectional studies report high levels of depressive symptoms during the COVID-19 pandemic, especially in youth and females. However, longitudinal research comparing depressive symptoms before and during the pandemic is lacking. Little is known about how the pandemic affected individuals with familial history of mental illness. The present study examines the impact of the pandemic on youth depressive symptoms, including offspring of parents with major mood and psychotic disorders. METHODS: Between March 2018 and February 2020, we measured depressive symptoms in 412 youth aged 5-25 years. We measured depressive symptoms again in 371 (90%) of these youth between April 2020 and May 2022. Two thirds (249) participants had a biological parent with a major mood or psychotic disorder. We tested the effect of the pandemic by comparing depression symptoms before and after March 2020. We examined age, sex, and family history as potential moderators. RESULTS: We found an overall small increase in youth depressive symptoms (b = 0.07, 95% CI -0.01 to 0.15, p = 0.062). This was driven by an increase in female youth without familial history of mental illness (b = 0.35, 95% CI 0.14 to 0.56, p = 0.001). There was no change in depressive symptoms among offspring of parents with mental illness or males. CONCLUSIONS: Our results provide reassurance about the wellbeing of children of parents with mental illness during a period of restricted access to resources outside the family. Rather than increasing symptoms in established risk groups, the pandemic led to a redistribution of depression burden towards segments of the youth population that were previously considered to be low-risk.

Challenges in defining treatment-resistant mania in adults: A systematic review.

OBJECTIVES: To review the definitions of treatment-resistant mania (TRM) in the literature and propose criteria for an operationalized definition. METHODS: A systematic search of five databases (MEDLINE, EMBASE, PsychInfo, Cochrane Central, and CINAHL) and data extraction of eligible articles. RESULTS: In total, 47 articles addressing the concept of TRM were included, comprising 16 case reports, 11 case series, 3 randomized clinical trials, 8 open-label clinical trials, 1 experimental study, 7 narrative reviews, and 1 systematic review. While reviews discussed several challenges in defining TRM, definitions varied substantially based on different criteria for severity of mania, duration of mania, and use of specific therapeutic agents with minimal dosages and duration of treatment. Only a handful of the reviewed articles operationalized these criteria. CONCLUSION: While the concept of TRM has been discussed in the literature for over three decades, we could not find an agreed-upon operationalized definition based on specific criteria. We propose and discuss a possible definition that could be used by clinicians to guide their practice and by researchers to assess the prevalence of TRM and develop and test interventions targeting TRM.

Developmental Trajectory of Body Weight in Youths at Risk for Major Mood Disorders.

Importance: Mood disorders are associated with increased body weight, especially in females, but it remains unknown when the weight increase starts. Objectives: To examine sex-specific weight trajectories associated with familial mood disorder risk and determine the age at which youth at familial risk for mood disorders begin to diverge in weight from controls. Design, Setting, and Participants: This community-based, single-center, acceleration cohort study of youth at familial risk for mood disorders and controls with yearly follow-ups (mean [SD], 5 [2.1] years) from January 1, 2014, to December 31, 2022, assessed 394 unaffected female and male offspring (aged 3 to 20 years) of parents with or without a mood disorder. Parents with mood (depressive or bipolar) disorders were recruited through adult mental health services. Parents of control participants were matched on age and socioeconomic factors and recruited through acquaintance referrals or schools. Exposures: The youth in the familial mood risk group had at least 1 parent with a major mood disorder, whereas control youth did not have a parent with a mood disorder. Main Outcomes and Measures: Body mass indexes (BMIs) were calculated as weight in kilograms divided by height in meters squared from measured weight and height at annual assessments and then converted to age- and sex-adjusted z scores (zBMIs). Repeated-measure regressions examined the association between zBMI and age in youth at familial risk of mood disorders and controls while accounting for sex. Sensitivity analyses accounted for socioeconomic status, prematurity, and birth weight. Results: Of 394 participants (mean [SD] age, 11.5 [3.6] years; 203 [51.5%] female), youths at familial risk for mood disorders showed overall no difference in body weight (ß = 0.12; 95% CI, 0.01-0.24) from controls. A sex-specific difference was detected, with females at familial risk showing a rapid peripubertal increase in body weight, leading to significantly increased zBMIs at 12 years and older compared with controls (ß = 0.57; 95% CI, 0.31-0.82) independent of socioeconomic status, prematurity, or birth weight. Males did not differ from controls at any age. Conclusions and Relevance: In this cohort study, females with a family history of mood disorders were prone to weight gain starting around puberty and predating mood disorder onset. Early interventions aiming to prevent adverse mental and physical outcomes in this vulnerable group need to start in childhood.

Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Longitudinal Digital Mood Charting in Bipolar Disorder: Experiences with ChronoRecord Over 20 Years.

INTRODUCTION: Longitudinal study is an essential methodology for understanding disease trajectories, treatment effects, symptom changes, and long-term outcomes of affective disorders. Daily self-charting of mood and other illness-related variables is a commonly recommended intervention. With the widespread acceptance of home computers in the early 2000s, automated tools were developed for patient mood charting, such as ChronoRecord, a software validated by patients with bipolar disorder. The purpose of this study was to summarize the daily mood, sleep, and medication data collected with ChronoRecord, and highlight some of the key research findings. Lessons learned from implementing a computerized tool for patient self-reporting are also discussed. METHODS: After a brief training session, ChronoRecord software for daily mood charting was installed on a home computer and used by 609 patients with affective disorders. RESULTS: The mean age of the patients was 40.3±11.8 years, a mean age of onset was 22±11.2 years, and 71.4% were female. Patients were euthymic for 70.8% of days, 15.1% had mild depression, 6.6% had severe depression, 6.6% had hypomania, and 0.8% had mania. Among all mood groups, 22.4% took 1-2 medications, 37.2% took 3-4 medications, 25.7 took 5-6 medications, 11.6% took 7-8 medications, and 3.1% took >8 medications. CONCLUSION: The daily mood charting tool is a useful tool for increasing patient involvement in their care, providing detailed patient data to the physician, and increasing understanding of the course of illness. Longitudinal data from patient mood charting was helpful in both clinical and research settings.

Immunoglobulin genes expressed in lymphoblastoid cell lines discern and predict lithium response in bipolar disorder patients.

Bipolar disorder (BD) is a neuropsychiatric mood disorder manifested by recurrent episodes of mania and depression. More than half of BD patients are non-responsive to lithium, the first-line treatment drug, complicating BD clinical management. Given its unknown etiology, it is pertinent to understand the genetic signatures that lead to variability in lithium response. We discovered a set of differentially expressed genes (DEGs) from the lymphoblastoid cell lines (LCLs) of 10 controls and 19 BD patients belonging mainly to the immunoglobulin gene family that can be used as potential biomarkers to diagnose and treat BD. Importantly, we trained machine learning algorithms on our datasets that predicted the lithium response of BD subtypes with minimal errors, even when used on a different cohort of 24 BD patients acquired by a different laboratory. This proves the scalability of our methodology for predicting lithium response in BD and for a prompt and suitable decision on therapeutic interventions.

Differential characteristics of bipolar I and II disorders: a retrospective, cross-sectional evaluation of clinical features, illness course, and response to treatment.

BACKGROUND: The distinction between bipolar I and bipolar II disorder and its treatment implications have been a matter of ongoing debate. The aim of this study was to examine differences between patients with bipolar I and II disorders with particular emphasis on the early phases of the disorders. METHODS: 808 subjects diagnosed with bipolar I (N = 587) or bipolar II disorder (N = 221) according to DSM-IV criteria were recruited between April 1994 and March 2022 from tertiary-level mood disorder clinics. Sociodemographic and clinical variables concerning psychiatric and medical comorbidities, family history, illness course, suicidal behavior, and response to treatment were compared between the bipolar disorder types. RESULTS: Bipolar II disorder patients were more frequently women, older, married or widowed. Bipolar II disorder was associated with later "bipolar" presentation, higher age at first (hypo)mania and treatment, less frequent referral after a single episode, and more episodes before lithium treatment. A higher proportion of first-degree relatives of bipolar II patients were affected by major depression and anxiety disorders. The course of bipolar II disorder was typically characterized by depressive onset, early depressive episodes, multiple depressive recurrences, and depressive predominant polarity; less often by (hypo)mania or (hypo)mania-depression cycles at onset or during the early course. The lifetime clinical course was more frequently rated as chronic fluctuating than episodic. More patients with bipolar II disorder had a history of rapid cycling and/or high number of episodes. Mood stabilizers and antipsychotics were prescribed less frequently during the early course of bipolar II disorder, while antidepressants were more common. We found no differences in global functioning, lifetime suicide attempts, family history of suicide, age at onset of mood disorders and depressive episodes, and lithium response. CONCLUSIONS: Differences between bipolar I and II disorders are not limited to the severity of (hypo)manic syndromes but include patterns of clinical course and family history. Caution in the use of potentially mood-destabilizing agents is warranted during the early course of bipolar II disorder.

Exploratory study of ultraviolet B (UVB) radiation and age of onset of bipolar disorder.

BACKGROUND: Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. METHODS: Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. RESULTS: The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. CONCLUSION: UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

Associations of active and passive smartphone use with measures of youth mental health during the COVID-19 pandemic.

Smartphone use provides a significant amount of screen-time for youth, and there have been growing concerns regarding its impact on their mental health. While time spent in a passive manner on the device is frequently considered deleterious, more active engagement with the phone might be protective for mental health. Recent developments in mobile sensing technology provide a unique opportunity to examine behaviour in a naturalistic manner. The present study sought to investigate, in a sample of 451 individuals (mean age 20.97 years old, 83% female), whether the amount of time spent on the device, an indicator of passive smartphone use, would be associated with worse mental health in youth and whether an active form of smartphone use, namely frequent checking of the device, would be associated with better outcomes. The findings highlight that overall time spent on the smartphone was associated with more pronounced internalizing and externalizing symptoms in youth, while the number of unlocks was associated with fewer internalizing symptoms. For externalizing symptoms, there was also a significant interaction between the two types of smartphone use observed. Using objective measures, our results suggest interventions targeting passive smartphone use may contribute to improving the mental health of youth.

Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder.

Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from non-responders (Li-NR). The circadian clock regulates molecular pathways involved in apoptosis and cell survival, but how this overlap impacts BD and/or lithium responsiveness is unknown. In primary fibroblasts from Li-R/Li-NR BD patients and controls, we found patterns of co-expression among circadian clock and cell survival genes that distinguished BD vs. control, and Li-R vs. Li-NR cells. In cellular models of apoptosis using staurosporine (STS), lithium preferentially protected fibroblasts against apoptosis in BD vs. control samples, regardless of Li-R/Li-NR status. When examining the effects of lithium treatment of cells in vitro, caspase activation by lithium correlated with period alteration, but the relationship differed in control, Li-R and Li-NR samples. Knockdown of Per1 and Per3 in mouse fibroblasts altered caspase activity, cell death and circadian rhythms in an opposite manner. In BD cells, genetic variation in PER1 and PER3 predicted sensitivity to apoptosis in a manner consistent with knockdown studies. We conclude that distinct patterns of coordination between circadian clock and cell survival genes in BD may help predict lithium response.