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AimTo evaluate the longitudinal association of sedentary behavior, light and moderate-to-vigorous physical activity (MVPA) participation with depressive symptoms and whether their possible association changed depending on the pandemic phase.MethodsThis longitudinal study conducted secondary analysis from the Spanish cohort of the Remote Assessment of Disease and Relapse – Major Depressive Disorder (RADAR-MDD) study. Depressive symptoms were assessed by the Patient Health Questionnaire (PHQ-8). Sedentary behavior and physical activity were estimated via wrist-worn devices. Linear mixed models evaluated the longitudinal associations of sedentary behavior and physical activity (light and moderate-to-vigorous intensities) with depressive symptoms.ResultsIn total, 95 participants (67.5% women, 53.0 [±10.5] years of age on average) were monitored pre-COVID-19 and included in the analyses. Pre-COVID-19, 73.7% of participants presented depression, and, on average, participated in 13.2 (±1.08) hours/day of sedentary behavior, 2.42 (±0.90) hours/day of light physical activity and 23.6 (±19.80) minutes/day of MVPA. Considering all the observations (from November 2019 to October 2020), an additional hour/day of sedentary behavior was longitudinally associated with higher depressive symptoms [βstd = 0.06, 95% confidence interval (CI) 0.10 to 0.47], whereas an additional hour/day in light physical activity was associated with lower depressive symptoms (βstd = −0.06, 95% CI −0.59 to −0.15). Time in MVPA was not associated with depressive symptomatology. The association of sedentary behavior and light physical activity with depressive symptoms was significant only during pre-COVID-19 and COVID-19 relaxation periods, whereas during the strictest periods of the pandemic with regards to the restrictions (lockdown and de-escalation), the association was not observed.ConclusionSedentary behavior and light physical activity were longitudinally associated with depressive symptoms in participants with a history of MDD. The incorporation of light physical activity should be stimulated in adults with a history of MDD. Neither sedentary behavior nor light physical activity were associated with depressive symptoms during the most restrictive COVID-19 phases, whereas sedentary behavior (positively) and light physical activity (negatively) were associated with depressive symptoms in persons with MDD before and after the COVID-19 pandemic.

Abstract Background Tailoring antidepressant drugs (AD) to patients’ genetic drug-metabolism profile is promising. However, literature regarding associations of ADs’ treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses. Methods Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann–Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses. Results No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects. Conclusions We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.

Background One of the most robust risk factors for developing a mood disorder is having a parent with a mood disorder. Unfortunately, mechanisms explaining the transmission of mood disorders from one generation to the next remain largely elusive. Since timely intervention is associated with a better outcome and prognosis, early detection of intergenerational transmission of mood disorders is of paramount importance. Here, we describe the design of the Mood and Resilience in Offspring (MARIO) cohort study in which we investigate: 1. differences in clinical, biological and environmental (e.g., psychosocial factors, substance use or stressful life events) risk and resilience factors in children of parents with and without mood disorders, and 2. mechanisms of intergenerational transmission of mood disorders via clinical, biological and environmental risk and resilience factors. Methods MARIO is an observational, longitudinal cohort study that aims to include 450 offspring of parents with a mood disorder (uni- or bipolar mood disorders) and 100-150 offspring of parents without a mood disorder aged 10-25 years. Power analyses indicate that this sample size is sufficient to detect small to medium sized effects. Offspring are recruited via existing Dutch studies involving patients with a mood disorder and healthy controls, for which detailed clinical, environmental and biological data of the index-parent (i.e., the initially identified parent with or without a mood disorder) is available. Over a period of three years, four assessments will take place, in which extensive clinical, biological and environmental data and data on risk and resilience are collected through e.g., blood sampling, face-to-face interviews, online questionnaires, actigraphy and Experience Sampling Method assessment. For co-parents, information on demographics, mental disorder status and a DNA-sample are collected. Discussion The MARIO cohort study is a large longitudinal cohort study among offspring of parents with and without mood disorders. A unique aspect is the collection of granular data on clinical, biological and environmental risk and resilience factors in offspring, in addition to available parental data on many similar factors. We aim to investigate the mechanisms underlying intergenerational transmission of mood disorders, which will ultimately lead to better outcomes for offspring at high familial risk.

Abstract X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Abstract Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.

Abstract Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Recently the 1/f signal of human electroencephalography has attracted attention, as it could potentially reveal a quantitative measure of neural excitation and inhibition in the brain, that may be relevant in a clinical setting. The purpose of this short article is to show that the 1/f signal depends on the vigilance state of the brain in both humans and mice. Therefore, proper labelling of the EEG signal is important as improper labelling may obscure disease-related changes in the 1/f signal. We demonstrate this by comparing EEG results from a longitudinal study in a genetic mouse model for synaptic dysfunction in schizophrenia and autism spectrum disorders to results from a large European cohort study with schizophrenia and mild Alzheimer's disease patients. The comparison shows when the 1/f is corrected for vigilance state there is a difference between groups, and this effect disappears when vigilance state is not corrected for. In conclusion, more attention should be paid to the vigilance state during analysis of EEG signals regardless of the species.

Abstract Depression shows a metabolomic signature overlapping with that of cardiometabolic conditions. Whether this signature is linked to specific depression profiles remains undetermined. Previous research suggested that metabolic alterations cluster more consistently with depressive symptoms of the atypical spectrum related to energy alterations, such as hyperphagia, weight gain, hypersomnia, fatigue and leaden paralysis. We characterized the metabolomic signature of an “atypical/energy-related” symptom (AES) profile and evaluated its specificity and consistency. Fifty-one metabolites measured using the Nightingale platform in 2876 participants from the Netherlands Study of Depression and Anxiety were analyzed. An ‘AES profile’ score was based on five items of the Inventory of Depressive Symptomatology (IDS) questionnaire. The AES profile was significantly associated with 31 metabolites including higher glycoprotein acetyls (β = 0.13, p = 1.35*10-12), isoleucine (β = 0.13, p = 1.45*10-10), very-low-density lipoproteins cholesterol (β = 0.11, p = 6.19*10-9) and saturated fatty acid levels (β = 0.09, p = 3.68*10-10), and lower high-density lipoproteins cholesterol (β = −0.07, p = 1.14*10-4). The metabolites were not significantly associated with a summary score of all other IDS items not included in the AES profile. Twenty-five AES-metabolites associations were internally replicated using data from the same subjects (N = 2015) collected at 6-year follow-up. We identified a specific metabolomic signature—commonly linked to cardiometabolic disorders—associated with a depression profile characterized by atypical, energy-related symptoms. The specific clustering of a metabolomic signature with a clinical profile identifies a more homogenous subgroup of depressed patients at higher cardiometabolic risk, and may represent a valuable target for interventions aiming at reducing depression’s detrimental impact on health.

Background Despite growing concerns about mental health during the COVID-19 pandemic, particularly in people with pre-existing mental health disorders, research has shown that symptoms of depression and anxiety were generally quite stable, with modest changes in certain subgroups. However, individual differences in cumulative exposure to COVID-19 stressors have not been yet considered. Aims We aimed to quantify and investigate the impact of individual-level cumulative exposure to COVID-19-pandemic-related adversity on changes in depressive and anxiety symptoms and loneliness. In addition, we examined whether the impact differed among individuals with various levels of pre-pandemic chronicity of mental health disorders. Method Between April 2020 and July 2021, 15 successive online questionnaires were distributed among three psychiatric case–control cohorts that started in the 2000s (N = 1377). Outcomes included depressive and anxiety symptoms and loneliness. We developed a COVID-19 Adversity Index (CAI) summarising up to 15 repeated measures of COVID-19-pandemic-related exposures (e.g. exposure to COVID-19 infection, negative economic impact and quarantine). We used linear mixed linear models to estimate the effects of COVID-19-related adversity on mental health and its interaction with pre-pandemic chronicity of mental health disorders and CAI. Results Higher CAI scores were positively associated with higher increases in depressive symptoms, anxiety symptoms and loneliness. Associations were not statistically significantly different between groups with and without (chronic) pre-pandemic mental health disorders. Conclusions Individual differences in cumulative exposure to COVID-19-pandemic-related adversity are important predictors of mental health, but we found no evidence for higher vulnerability among people with (chronic) pre-pandemic mental health disorders.

Abstract Background Childhood maltreatment is associated with depression and cardiometabolic disease in adulthood. However, the relationships with these two diseases have so far only been evaluated in different samples and with different methodology. Thus, it remains unknown how the effect sizes magnitudes for depression and cardiometabolic disease compare with each other and whether childhood maltreatment is especially associated with the co-occurrence (“comorbidity”) of depression and cardiometabolic disease. This pooled analysis examined the association of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity in adulthood. Methods We carried out an individual participant data meta-analysis on 13 international observational studies (N = 217,929). Childhood maltreatment comprised self-reports of physical, emotional, and/or sexual abuse before 18 years. Presence of depression was established with clinical interviews or validated symptom scales and presence of cardiometabolic disease with self-reported diagnoses. In included studies, binomial and multinomial logistic regressions estimated sociodemographic-adjusted associations of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity. We then additionally adjusted these associations for lifestyle factors (smoking status, alcohol consumption, and physical activity). Finally, random-effects models were used to pool these estimates across studies and examined differences in associations across sex and maltreatment types. Results Childhood maltreatment was associated with progressively higher odds of cardiometabolic disease without depression (OR [95% CI] = 1.27 [1.18; 1.37]), depression without cardiometabolic disease (OR [95% CI] = 2.68 [2.39; 3.00]), and comorbidity between both conditions (OR [95% CI] = 3.04 [2.51; 3.68]) in adulthood. Post hoc analyses showed that the association with comorbidity was stronger than with either disease alone, and the association with depression was stronger than with cardiometabolic disease. Associations remained significant after additionally adjusting for lifestyle factors, and were present in both males and females, and for all maltreatment types. Conclusions This meta-analysis revealed that adults with a history of childhood maltreatment suffer more often from depression and cardiometabolic disease than their non-exposed peers. These adults are also three times more likely to have comorbid depression and cardiometabolic disease. Childhood maltreatment may therefore be a clinically relevant indicator connecting poor mental and somatic health. Future research should investigate the potential benefits of early intervention in individuals with a history of maltreatment on their distal mental and somatic health (PROSPERO CRD42021239288).

Abstract Background Major Depressive Disorder (MDD) is a heterogenous brain disorder, with potentially multiple psychosocial and biological disease mechanisms. This is also a plausible explanation for why patients do not respond equally well to treatment with first- or second-line antidepressants, i.e., one-third to one-half of patients do not remit in response to first- or second-line treatment. To map MDD heterogeneity and markers of treatment response to enable a precision medicine approach, we will acquire several possible predictive markers across several domains, e.g., psychosocial, biochemical, and neuroimaging. Methods All patients are examined before receiving a standardised treatment package for adults aged 18–65 with first-episode depression in six public outpatient clinics in the Capital Region of Denmark. From this population, we will recruit a cohort of 800 patients for whom we will acquire clinical, cognitive, psychometric, and biological data. A subgroup (subcohort I, n = 600) will additionally provide neuroimaging data, i.e., Magnetic Resonance Imaging, and Electroencephalogram, and a subgroup of patients from subcohort I unmedicated at inclusion (subcohort II, n = 60) will also undergo a brain Positron Emission Tomography with the [11C]-UCB-J tracer binding to the presynaptic glycoprotein-SV2A. Subcohort allocation is based on eligibility and willingness to participate. The treatment package typically lasts six months. Depression severity is assessed with the Quick Inventory of Depressive Symptomatology (QIDS) at baseline, and 6, 12 and 18 months after treatment initiation. The primary outcome is remission (QIDS ≤ 5) and clinical improvement (≥ 50% reduction in QIDS) after 6 months. Secondary endpoints include remission at 12 and 18 months and %-change in QIDS, 10-item Symptom Checklist, 5-item WHO Well-Being Index, and modified Disability Scale from baseline through follow-up. We also assess psychotherapy and medication side-effects. We will use machine learning to determine a combination of characteristics that best predict treatment outcomes and statistical models to investigate the association between individual measures and clinical outcomes. We will assess associations between patient characteristics, treatment choices, and clinical outcomes using path analysis, enabling us to estimate the effect of treatment choices and timing on the clinical outcome. Discussion The BrainDrugs-Depression study is a real-world deep-phenotyping clinical cohort study of first-episode MDD patients. Trial Registration Registered at clinicaltrials.gov November 15th, 2022 (NCT05616559).

Abstract Recent growth in digital technologies has enabled the recruitment and monitoring of large and diverse populations in remote health studies. However, the generalizability of inference drawn from remotely collected health data could be severely impacted by uneven participant engagement and attrition over the course of the study. We report findings on long-term participant retention and engagement patterns in a large multinational observational digital study for depression containing active (surveys) and passive sensor data collected via Android smartphones, and Fitbit devices from 614 participants for up to 2 years. Majority of participants (67.6%) continued to remain engaged in the study after 43 weeks. Unsupervised clustering of participants’ study apps and Fitbit usage data showed 3 distinct engagement subgroups for each data stream. We found: (i) the least engaged group had the highest depression severity (4 PHQ8 points higher) across all data streams; (ii) the least engaged group (completed 4 bi-weekly surveys) took significantly longer to respond to survey notifications (3.8 h more) and were 5 years younger compared to the most engaged group (completed 20 bi-weekly surveys); and (iii) a considerable proportion (44.6%) of the participants who stopped completing surveys after 8 weeks continued to share passive Fitbit data for significantly longer (average 42 weeks). Additionally, multivariate survival models showed participants’ age, ownership and brand of smartphones, and recruitment sites to be associated with retention in the study. Together these findings could inform the design of future digital health studies to enable equitable and balanced data collection from diverse populations.

Abstract Background Major depressive disorder (MDD) is a common, recurrent mental disorder and a leading cause of disability worldwide. A large part of adult MDD patients report a history of childhood trauma (CT). Patients with MDD and CT are assumed to represent a clinically and neurobiologically distinct MDD subtype with an earlier onset, unfavorable disease course, stress systems’ dysregulations and brain alterations. Currently, there is no evidence-based treatment strategy for MDD that specifically targets CT. Given the central role of trauma in MDD patients with CT, trauma-focused therapy (TFT), adjunctive to treatment as usual (TAU), may be efficacious to alleviate depressive symptoms in this patient population. Methods The RESET-psychotherapy study is a 12-week, single-blind, randomized controlled trial testing the efficacy of TFT in 158 adults with moderate to severe MDD, as a ‘stand-alone’ depression diagnosis or superimposed on a persistent depressive disorder (PDD), and CT. TFT (6–10 sessions of Eye Movement Desensitization and Reprocessing and/or imagery rescripting) + TAU is compared to TAU only. Assessments, including a wide range of psychological/psychiatric and biological characteristics, take place before randomization (T0), during treatment (T1), at post-treatment (T2) and at 6-month follow-up (T3). Pre-post treatment stress-related biomarkers in hair (cortisol) and blood (epigenetics and inflammation) will be assessed to better understand working mechanisms of TFT. A subgroup of 60 participants will undergo structural and functional Magnetic Resonance Imaging (MRI) assessments to determine pre-post treatment brain activity. The primary outcome is self-reported depression symptom severity at post-treatment, measured with the 30-item Inventory of Depressive Symptomatology – Self Report (IDS-SR). Discussion If adjunctive TFT efficaciously alleviates depressive symptoms in MDD patients with CT, this novel treatment strategy could pave the way for a more personalized and targeted MDD treatment. Trial registration ClinicalTrials.gov, registered at 08–12-2021, number of identification: NCT05149352.

Abstract Background The spread of unvetted scientific information about COVID-19 presents a significant challenge to public health, adding to the urgency for increased understanding of COVID-19 information-seeking preferences that will allow for the delivery of evidence-based health communication. This study examined factors associated with COVID-19 information-seeking behavior. Methods An online survey was conducted with US adults (N = 1800) to identify key interpersonal (e.g., friends, health care providers) and mediated (e.g., TV, social media) sources of COVID-19 information. Logistic regression models were fitted to explore correlates of information-seeking. Results Study findings show that the first sought and most trusted sources of COVID-19 information had different relationships with sociodemographic characteristics, perceived discrimination, and self-efficacy. Older adults had greater odds of seeking information from print materials (e.g., newspapers and magazines) and TV first. Participants with less educational attainment and greater self-efficacy preferred interpersonal sources first, with notably less preference for mass media compared to health care providers. Those with more experiences with discrimination were more likely to seek information from friends, relatives, and co-workers. Additionally, greater self-efficacy was related to increased trust in interpersonal sources. Conclusion Study results have implications for tailoring health communication strategies to reach specific subgroups, including those more vulnerable to severe illness from COVID-19. A set of recommendations are provided to assist in campaign development.

Abstract Despite advances in identifying the genetic basis of psychiatric and neurological disorders, fundamental questions about their evolutionary origins remain elusive. Here, introgressed variants from archaic humans such as Neandertals can serve as an intriguing research paradigm. We compared the number of associations for Neandertal variants to the number of associations of frequency-matched non-archaic variants with regard to human CNS disorders (neurological and psychiatric), nervous system drug prescriptions (as a proxy for disease), and related, non-disease phenotypes in the UK biobank (UKBB). While no enrichment for Neandertal genetic variants were observed in the UKBB for psychiatric or neurological disease categories, we found significant associations with certain behavioral phenotypes including pain, chronotype/sleep, smoking and alcohol consumption. In some instances, the enrichment signal was driven by Neandertal variants that represented the strongest association genome-wide. SNPs within a Neandertal haplotype that was associated with smoking in the UKBB could be replicated in four independent genomics datasets. Our data suggest that evolutionary processes in recent human evolution like admixture with Neandertals significantly contribute to behavioral phenotypes but not psychiatric and neurological diseases. These findings help to link genetic variants in a population to putative past beneficial effects, which likely only indirectly contribute to pathology in modern day humans

BackgroundMajor depressive disorder (MDD) affects millions of people worldwide, but timely treatment is not often received owing in part to inaccurate subjective recall and variability in the symptom course. Objective and frequent MDD monitoring can improve subjective recall and help to guide treatment selection. Attempts have been made, with varying degrees of success, to explore the relationship between the measures of depression and passive digital phenotypes (features) extracted from smartphones and wearables devices to remotely and continuously monitor changes in symptomatology. However, a number of challenges exist for the analysis of these data. These include maintaining participant engagement over extended time periods and therefore understanding what constitutes an acceptable threshold of missing data; distinguishing between the cross-sectional and longitudinal relationships for different features to determine their utility in tracking within-individual longitudinal variation or screening individuals at high risk; and understanding the heterogeneity with which depression manifests itself in behavioral patterns quantified by the passive features. ObjectiveWe aimed to address these 3 challenges to inform future work in stratified analyses. MethodsUsing smartphone and wearable data collected from 479 participants with MDD, we extracted 21 features capturing mobility, sleep, and smartphone use. We investigated the impact of the number of days of available data on feature quality using the intraclass correlation coefficient and Bland-Altman analysis. We then examined the nature of the correlation between the 8-item Patient Health Questionnaire (PHQ-8) depression scale (measured every 14 days) and the features using the individual-mean correlation, repeated measures correlation, and linear mixed effects model. Furthermore, we stratified the participants based on their behavioral difference, quantified by the features, between periods of high (depression) and low (no depression) PHQ-8 scores using the Gaussian mixture model. ResultsWe demonstrated that at least 8 (range 2-12) days were needed for reliable calculation of most of the features in the 14-day time window. We observed that features such as sleep onset time correlated better with PHQ-8 scores cross-sectionally than longitudinally, whereas features such as wakefulness after sleep onset correlated well with PHQ-8 longitudinally but worse cross-sectionally. Finally, we found that participants could be separated into 3 distinct clusters according to their behavioral difference between periods of depression and periods of no depression. ConclusionsThis work contributes to our understanding of how these mobile health–derived features are associated with depression symptom severity to inform future work in stratified analyses.

Abstract The use of remote measurement technologies (RMTs) across mobile health (mHealth) studies is becoming popular, given their potential for providing rich data on symptom change and indicators of future state in recurrent conditions such as major depressive disorder (MDD). Understanding recruitment into RMT research is fundamental for improving historically small sample sizes, reducing loss of statistical power, and ultimately producing results worthy of clinical implementation. There is a need for the standardisation of best practices for successful recruitment into RMT research. The current paper reviews lessons learned from recruitment into the Remote Assessment of Disease and Relapse- Major Depressive Disorder (RADAR-MDD) study, a large-scale, multi-site prospective cohort study using RMT to explore the clinical course of people with depression across the UK, the Netherlands, and Spain. More specifically, the paper reflects on key experiences from the UK site and consolidates these into four key recruitment strategies, alongside a review of barriers to recruitment. Finally, the strategies and barriers outlined are combined into a model of lessons learned. This work provides a foundation for future RMT study design, recruitment and evaluation.

Abstract The serotonin-transporter-linked promoter region (5-HTTLPR) has been widely investigated as contributing to depression vulnerability. Nevertheless, empirical research provides wide contrasting findings regarding its involvement in the etiopathogenesis of the disorder. Our hypothesis was that such discrepancy can be explained considering time as moderating factor. We explored this hypothesis, exploiting a meta analytic approach. We searched PubMed, PsychoINFO, Scopus and EMBASE databases and 1096 studies were identified and screened, resulting in 22 studies to be included in the meta-analyses. The effect of the 5-HTTLPR x stress interaction on depression risk was found to be moderated by the following temporal factors: the duration of stress (i.e. chronic vs. acute) and the time interval between end of stress and assessment of depression (i.e. within 1 year vs. more than 1 year). When stratifying for the duration of stress, the effect of the 5-HTTLPR x stress interaction emerged only in the case of chronic stress, with a significant subgroup difference (p = 0.004). The stratification according to time interval revealed a significant interaction only for intervals within 1 year, though no difference between subgroups was found. The critical role of time interval clearly emerged when considering only chronic stress: a significant effect of the 5-HTTLPR and stress interaction was confirmed exclusively within 1 year and a significant subgroup difference was found (p = 0.01). These results show that the 5-HTTLPR x stress interaction is a dynamic process, producing different effects at different time points, and indirectly confirm that s-allele carriers are both at higher risk and more capable to recover from depression. Overall, these findings expand the current view of the interplay between 5-HTTLPR and stress adding the temporal dimension, that results in a three-way interaction: gene x environment x time.

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.

Abstract Background Major Depressive Disorder (MDD) is prevalent, often chronic, and requires ongoing monitoring of symptoms to track response to treatment and identify early indicators of relapse. Remote Measurement Technologies (RMT) provide an opportunity to transform the measurement and management of MDD, via data collected from inbuilt smartphone sensors and wearable devices alongside app-based questionnaires and tasks. A key question for the field is the extent to which participants can adhere to research protocols and the completeness of data collected. We aimed to describe drop out and data completeness in a naturalistic multimodal longitudinal RMT study, in people with a history of recurrent MDD. We further aimed to determine whether those experiencing a depressive relapse at baseline contributed less complete data. Methods Remote Assessment of Disease and Relapse – Major Depressive Disorder (RADAR-MDD) is a multi-centre, prospective observational cohort study conducted as part of the Remote Assessment of Disease and Relapse – Central Nervous System (RADAR-CNS) program. People with a history of MDD were provided with a wrist-worn wearable device, and smartphone apps designed to: a) collect data from smartphone sensors; and b) deliver questionnaires, speech tasks, and cognitive assessments. Participants were followed-up for a minimum of 11 months and maximum of 24 months. Results Individuals with a history of MDD (n = 623) were enrolled in the study,. We report 80% completion rates for primary outcome assessments across all follow-up timepoints. 79.8% of people participated for the maximum amount of time available and 20.2% withdrew prematurely. We found no evidence of an association between the severity of depression symptoms at baseline and the availability of data. In total, 110 participants had > 50% data available across all data types. Conclusions RADAR-MDD is the largest multimodal RMT study in the field of mental health. Here, we have shown that collecting RMT data from a clinical population is feasible. We found comparable levels of data availability in active and passive forms of data collection, demonstrating that both are feasible in this patient group.

Background Little is known about the reasons for suicidal behaviour in Africa, and communities’ perception of suicide prevention. A contextualised understanding of these reasons is important in guiding the implementation of potential suicide prevention interventions in specific settings. Aims To understand ideas, experiences and opinions on reasons contributing to suicidal behaviour in the Coast region of Kenya, and provide recommendations for suicide prevention. Method We conducted a qualitative study with various groups of key informants residing in the Coast region of Kenya, using in-depth interviews. Audio-recorded interviews were transcribed and translated from the local language before thematic inductive content analysis. Results From the 25 in-depth interviews, we identified four key themes as reasons given for suicidal behaviour: interpersonal and relationship problems, financial and economic difficulties, mental health conditions and religious and cultural influences. These reasons were observed to be interrelated with each other and well-aligned to the suggested recommendations for suicide prevention. We found six key recommendations from our thematic content analysis: (a) increasing access to counselling and social support, (b) improving mental health awareness and skills training, (c) restriction of suicide means, (d) decriminalisation of suicide, (e) economic and education empowerment and (f) encouraging religion and spirituality. Conclusions The reasons for suicidal behaviour are comparable with high-income countries, but suggested prevention strategies are more contextualised to our setting. A multifaceted approach in preventing suicide in (coastal) Kenya is warranted based on the varied reasons suggested. Community-based interventions will likely improve and increase access to suicide prevention in this study area.

Our long-term goal is to foster genetically informed reproductive health knowledge and behaviors among young adults with sickle cell disease (SCD) or sickle cell trait (SCT) with a web-based, tailored, multimedia intervention called CHOICES. CHOICES is designed to help young adults with SCD or SCT preconception to gain knowledge of genetic inheritance, specify their reproductive health intentions (their parenting plan), and engage in reproductive health behaviors concordant with their parenting plan. In a previous study, we found high acceptability of both the e-Book (usual care control) and CHOICES interventions. We also found sustained (24 months), significant effects on knowledge but not on behavior, most likely because half of the recruited group was not at risk for their children inheriting SCD. Hence, we propose an adequately powered randomized controlled trial with the CHOICES intervention and an e-Book control to compare their effects on genetic inheritance knowledge and at-risk reproductive health behaviors (immediate posttest and at 6, 12, 18, and 24 months). We will conduct subgroup analyses to provide insight into the baseline knowledge and behavior as well as the intervention effects in different demographic or acceptability groups. Given the scalability and low cost of CHOICES, if proved to be effective, it can reach the affected population at low cost.

BackgroundPsychotic disorders increase the risk for premature mortality with up to 40% of this mortality attributable to suicide. Although suicidal ideation (SI) and suicidal behavior (SB) are high in persons with psychotic disorders in sub-Saharan Africa, there is limited data on the risk of suicide and associated factors among persons with psychotic disorders.MethodsWe assessed SI and SB in persons with psychotic disorders, drawn from a large case-control study examining the genetics of psychotic disorders in a Kenyan population. Participants with psychotic disorders were identified using a clinical review of records, and the diagnosis was confirmed with the Mini-International Neuropsychiatric Interview (MINI). We conducted bivariate and multivariate logistic (for binary suicide outcomes) or linear regression (for suicide risk score) analysis for each of the suicide variables, with demographic and clinical variables as determinants.ResultsOut of 619 participants, any current SI or lifetime suicidal attempts was reported by 203 (32.8%) with psychotic disorders, of which 181 (29.2%) had a lifetime suicidal attempt, 60 (9.7%) had SI in the past month, and 38 (20.9%) had both. Family history of suicidality was significantly associated with an increased risk of suicidality across all the following four outcomes: SI [OR = 2.56 (95% CI: 1.34–4.88)], suicidal attempts [OR = 2.01 (95% CI: 1.31–3.06)], SI and SB [OR = 2.00 (95% CI: 1.31–3.04)], and suicide risk score [beta coefficient = 7.04 (2.72; 11.36), p = 0.001]. Compared to persons aged

Abstract Background Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. Methods Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. Results Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99–1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96–1.04; p value 0.59). Conclusions Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk.

Abstract Background Although the burden of impaired renal function is rising in sub-Saharan Africa (SSA), little is known about correlates of impaired renal function in the region. We determined factors associated with estimated glomerular filtration rate (eGFR) and impaired renal function in HIV-infected and HIV-uninfected adults. Methods We undertook cross-sectional analysis of data from 1947 adults at enrolment for a cohort study on diabetes and associated complications in HIV patients in Mwanza, north-western Tanzania. A structured questionnaire was used to collect data on sociodemography, smoking, alcohol, physical activity, antiretroviral therapy (ART) and anthropometry. We measured blood pressure, tested blood samples for creatinine, glucose and HIV, and performed Kato Katz for Schistosoma mansoni. Correlates of eGFR (mL/min/1.73 m2) and impaired renal function (eGFR

BackgroundGait is an essential manifestation of depression. However, the gait characteristics of daily walking and their relationships with depression have yet to be fully explored. ObjectiveThe aim of this study was to explore associations between depression symptom severity and daily-life gait characteristics derived from acceleration signals in real-world settings. MethodsWe used two ambulatory data sets (N=71 and N=215) with acceleration signals collected by wearable devices and mobile phones, respectively. We extracted 12 daily-life gait features to describe the distribution and variance of gait cadence and force over a long-term period. Spearman coefficients and linear mixed-effects models were used to explore the associations between daily-life gait features and depression symptom severity measured by the 15-item Geriatric Depression Scale (GDS-15) and 8-item Patient Health Questionnaire (PHQ-8) self-reported questionnaires. The likelihood-ratio (LR) test was used to test whether daily-life gait features could provide additional information relative to the laboratory gait features. ResultsHigher depression symptom severity was significantly associated with lower gait cadence of high-performance walking (segments with faster walking speed) over a long-term period in both data sets. The linear regression model with long-term daily-life gait features (R2=0.30) fitted depression scores significantly better (LR test P=.001) than the model with only laboratory gait features (R2=0.06). ConclusionsThis study indicated that the significant links between daily-life walking characteristics and depression symptom severity could be captured by both wearable devices and mobile phones. The daily-life gait patterns could provide additional information for predicting depression symptom severity relative to laboratory walking. These findings may contribute to developing clinical tools to remotely monitor mental health in real-world settings.

Abstract Background The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes a clinical illness Covid-19, has had a major impact on mental health globally. Those diagnosed with major depressive disorder (MDD) may be negatively impacted by the global pandemic due to social isolation, feelings of loneliness or lack of access to care. This study seeks to assess the impact of the 1st lockdown – pre-, during and post – in adults with a recent history of MDD across multiple centres. Methods This study is a secondary analysis of an on-going cohort study, RADAR-MDD project, a multi-centre study examining the use of remote measurement technology (RMT) in monitoring MDD. Self-reported questionnaire and passive data streams were analysed from participants who had joined the project prior to 1st December 2019 and had completed Patient Health and Self-esteem Questionnaires during the pandemic (n = 252). We used mixed models for repeated measures to estimate trajectories of depressive symptoms, self-esteem, and sleep duration. Results In our sample of 252 participants, 48% (n = 121) had clinically relevant depressive symptoms shortly before the pandemic. For the sample as a whole, we found no evidence that depressive symptoms or self-esteem changed between pre-, during- and post-lockdown. However, we found evidence that mean sleep duration (in minutes) decreased significantly between during- and post- lockdown (− 12.16; 95% CI − 18.39 to − 5.92; p

Abstract Background Notwithstanding the firmly established cross-sectional association of happiness with psychiatric disorders and their symptom severity, little is known about their temporal relationships. The goal of the present study was to investigate whether happiness is predictive of subsequent psychiatric disorders and symptom severity (and vice versa). Moreover, it was examined whether changes in happiness co-occur with changes in psychiatric disorder status and symptom severity. Methods In the Netherlands Study of Depression and Anxiety (NESDA), happiness (SRH: Self-Rated Happiness scale), depressive and social anxiety disorder (CIDI: Composite Interview Diagnostic Instrument) and depressive and anxiety symptom severity (IDS: Inventory of Depressive Symptomatology; BAI: Beck Anxiety Inventory; and FQ: Fear Questionnaire) were measured in 1816 adults over a three-year period. Moreover, we focused on occurrence and remittance of 6-month recency Major Depressive Disorder (MDD) and Social Anxiety Disorders (SAD) as the two disorders most intertwined with subjective happiness. Results Interindividual differences in happiness were quite stable (ICC of .64). Higher levels of happiness predicted recovery from depression (OR = 1.41; 95% CI = 1.10–1.80), but not social anxiety disorder (OR = 1.31; 95%CI = .94–1.81), as well as non-occurrence of depression (OR = 2.41; 95%CI = 1.98–2.94) and SAD (OR = 2.93; 95%CI = 2.29–3.77) in participants without MDD, respectively SAD at baseline. Higher levels of happiness also predicted a reduction of IDS depression (sr = − 0.08; 95%CI = -0.10 - -0.04), and BAI (sr = − 0.09; 95%CI = -0.12 - -0.05) and FQ (sr = − 0.06; 95%CI = -0.09 - -0.04) anxiety symptom scores. Conversely, presence of affective disorders, as well as higher depression and anxiety symptom severity at baseline predicted a subsequent reduction of self-reported happiness (with marginal to small sr values varying between −.04 (presence of SAD) to −.17 (depression severity on the IDS)). Moreover, changes in happiness were associated with changes in psychiatric disorders and their symptom severity, in particular with depression severity on the IDS (sr = − 0.46; 95%CI = −.50 - -.42). Conclusions Results support the view of rather stable interindividual differences in subjective happiness, although level of happiness is inversely associated with changes in psychiatric disorders and their symptom severity, in particular depressive disorder and depression severity.

Abstract Depression and anxiety are common and often comorbid mental health disorders that represent risk factors for aging-related conditions. Brain aging has shown to be more advanced in patients with major depressive disorder (MDD). Here, we extend prior work by investigating multivariate brain aging in patients with MDD, anxiety disorders, or both, and examine which factors contribute to older-appearing brains. Adults aged 18–57 years from the Netherlands Study of Depression and Anxiety underwent structural MRI. A pretrained brain-age prediction model based on >2000 samples from the ENIGMA consortium was applied to obtain brain-predicted age differences (brain PAD, predicted brain age minus chronological age) in 65 controls and 220 patients with current MDD and/or anxiety. Brain-PAD estimates were associated with clinical, somatic, lifestyle, and biological factors. After correcting for antidepressant use, brain PAD was significantly higher in MDD (+2.78 years, Cohen’s d = 0.25, 95% CI −0.10-0.60) and anxiety patients (+2.91 years, Cohen’s d = 0.27, 95% CI −0.08-0.61), compared with controls. There were no significant associations with lifestyle or biological stress systems. A multivariable model indicated unique contributions of higher severity of somatic depression symptoms (b = 4.21 years per unit increase on average sum score) and antidepressant use (−2.53 years) to brain PAD. Advanced brain aging in patients with MDD and anxiety was most strongly associated with somatic depressive symptomatology. We also present clinically relevant evidence for a potential neuroprotective antidepressant effect on the brain-PAD metric that requires follow-up in future research.

Background Mental health was only modestly affected in adults during the early months of the COVID-19 pandemic on the group level, but interpersonal variation was large. Aims We aim to investigate potential predictors of the differences in changes in mental health. Method Data were aggregated from three Dutch ongoing prospective cohorts with similar methodology for data collection. We included participants with pre-pandemic data gathered during 2006–2016, and who completed online questionnaires at least once during lockdown in The Netherlands between 1 April and 15 May 2020. Sociodemographic, clinical (number of mental health disorders and personality factors) and COVID-19-related variables were analysed as predictors of relative changes in four mental health outcomes (depressive symptoms, anxiety and worry symptoms, and loneliness), using multivariate linear regression analyses. Results We included 1517 participants with (n = 1181) and without (n = 336) mental health disorders. Mean age was 56.1 years (s.d. 13.2), and 64.3% were women. Higher neuroticism predicted increases in all four mental health outcomes, especially for worry (β = 0.172, P = 0.003). Living alone and female gender predicted increases in depressive symptoms and loneliness (β = 0.05–0.08), whereas quarantine and strict adherence with COVID-19 restrictions predicted increases in anxiety and worry symptoms (β = 0.07–0.11).Teleworking predicted a decrease in anxiety symptoms (β = −0.07) and higher age predicted a decrease in anxiety (β = −0.08) and worry symptoms (β = −0.10). Conclusions Our study showed neuroticism as a robust predictor of adverse changes in mental health, and identified additional sociodemographic and COVID-19-related predictors that explain longitudinal variability in mental health during the COVID-19 pandemic.

BackgroundThis paper describes the research protocol for a randomized controlled trial of a self-management intervention for adults diagnosed with sickle cell disease (SCD). People living with SCD experience lifelong recurrent episodes of acute and chronic pain, which are exacerbated by stress. ObjectiveThis study aims to decrease stress and improve SCD pain control with reduced opioid use through an intervention with self-management relaxation exercises, named You Cope, We Support (YCWS). Building on our previous findings from formative studies, this study is designed to test the efficacy of YCWS on stress intensity, pain intensity, and opioid use in adults with SCD. MethodsA randomized controlled trial of the short-term (8 weeks) and long-term (6 months) effects of YCWS on stress, pain, and opioid use will be conducted with 170 adults with SCD. Patients will be randomized based on 1:1 ratio (stratified on pain intensity [≤5 or >5]) to be either in the experimental (self-monitoring of outcomes, alerts or reminders, and use of YCWS [relaxation and distraction exercises and support]) or control (self-monitoring of outcomes and alerts or reminders) group. Patients will be asked to report outcomes daily. During weeks 1 to 8, patients in both groups will receive system-generated alerts or reminders via phone call, text, or email to facilitate data entry (both groups) and intervention use support (experimental). If the participant does not enter data after 24 hours, the study support staff will contact them for data entry troubleshooting (both groups) and YCWS use (experimental). We will time stamp and track patients’ web-based activities to understand the study context and conduct exit interviews on the acceptability of system-generated and staff support. This study was approved by our institutional review board. ResultsThis study was funded by the National Institute of Nursing Research of the National Institutes of Health in 2020. The study began in March 2021 and will be completed in June 2025. As of April 2022, we have enrolled 45.9% (78/170) of patients. We will analyze the data using mixed effects regression models (short term and long term) to account for the repeated measurements over time and use machine learning to construct and evaluate prediction models. Owing to the COVID-19 pandemic, the study was modified to allow for mail-in consent process, internet-based consent process via email or Zoom videoconference, devices delivered by FedEx, and training via Zoom videoconference. ConclusionsWe expect the intervention group to report reductions in pain intensity (primary outcome; 0-10 scale) and in stress intensity (0-10 scale) and opioid use (Wisepill event medication monitoring system), which are secondary outcomes. Our study will contribute to advancing the use of nonopioid therapy such as guided relaxation and distraction techniques for managing SCD pain. Trial RegistrationClinicalTrials.gov NCT04484272; https://clinicaltrials.gov/ct2/show/NCT04484272 International Registered Report Identifier (IRRID)PRR1-10.2196/33818

Abstract Background Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD)[95% confidence interval (CI) − 0.12, − 0.03] in AMV and − 0.03SD [− 0.07, − 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (− 0.04SD [− 0.08, 0.00] in AMV and − 0.05SD [− 0.09, − 0.02] in MR), and lower phospholipids in very large HDL particles (− 0.04SD [− 0.08, 0.002] in AMV and − 0.05SD [− 0.08, − 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. Conclusions Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Purpose Our specific aim was to develop and assess the consensus-based validity of common measures for understanding health behaviors and ancestry in Florida’s population subgroups and establish the feasibility of wide-scale implementation of the measures and biospecimen collection within three cancer centers’ catchment areas. Methods Using the National Cancer Institute’s Grid-Enabled Measures web-based platform and an iterative process, we developed the Florida Health and Ancestry Survey (FHAS). We then used three sampling approaches to implement the FHAS: community-engaged, panel respondent, and random digit dialing (RDD). We asked a subset of participants to provide a saliva sample for future validation of subjective ancestry report with DNA-derived ancestry markers. Results This process supported the FHAS content validity. As an indicator of feasibility, the goals for completed surveys by sampling approach were met for two of the three cancer centers, yielding a total of 1438 completed surveys. The RDD approach produced the most representative sample. The panel sampling approach produced inadequate representation of older individuals and males. The community-engaged approach along with social media recruitment produced extreme underrepresentation only for males. Two of the cancer centers mailed biospecimen kits, whereas one did not due to resource constraints. On average, the community engaged approach was more productive in obtaining returned biospecimen samples (80%) than the panel approach (48%). Conclusions We successfully developed and implemented the FHAS as a common measure to show its feasibility for understanding cancer health disparities in Florida. We identified sampling approach successes and challenges to obtaining biospecimens for ancestry research.

Abstract Neuronal surface autoantibodies (NSAbs) against various antigens cause autoimmune encephalitis. Some of these antigens are also involved in the pathology of depression and anxiety. To study whether NSAbs are more common in plasma of individuals with depression and anxiety than in controls, and to investigate if NSAbs correlate with disease status, plasma samples of 819 individuals with a current diagnosis of depression and/or anxiety, 920 in remission and 492 individuals without these disorders were included in this study. Samples were tested by a combination of immunohistochemistry (IHC), staining on live rat hippocampus neurons and cell-based assay (CBA). By IHC, 50 (2.2%) samples showed immunoreactivity to rat brain tissue, with no significant differences between the aforementioned groups (22/819 vs 18/920 vs 11/492, P > 0.99). In addition, eight IHC positive samples were positive for NSAbs on live neurons (7/819 vs 0/920 vs 1/492, P = 0.006). The IHC-staining patterns of these eight samples were atypical for autoimmune encephalitis and accordingly, they tested negative for known NSAbs by CBA. No obvious difference in the clinical characteristics between individuals with or without NSAbs was observed. In conclusion, novel NSAbs were rare but predominately found in patients with current anxiety or depression indicating they might affect mental health in a small group of patients.

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in over 5% of the parenchyma in the absence of excessive alcohol consumption. It is more prevalent in patients with diverse mental disorders, being part of the comorbidity driving loss of life expectancy and quality of life, yet remains a neglected entity. NAFLD can progress to non-alcoholic steatohepatitis (NASH) and increases the risk for cirrhosis and hepatic carcinoma. Both NAFLD and mental disorders share pathophysiological pathways, and also present a complex, bidirectional relationship with the metabolic syndrome (MetS) and related cardiometabolic diseases. Main text This review compares the demographic data on NAFLD and NASH among the global population and the psychiatric population, finding differences that suggest a higher incidence of this disease among the latter. It also analyzes the link between NAFLD and psychiatric disorders, looking into common pathophysiological pathways, such as metabolic, genetic, and lifestyle factors. Finally, possible treatments, tailored approaches, and future research directions are suggested. Conclusion NAFLD is part of a complex system of mental and non-communicable somatic disorders with a common pathogenesis, based on shared lifestyle and environmental risks, mediated by dysregulation of inflammation, oxidative stress pathways, and mitochondrial function. The recognition of the prevalent comorbidity between NAFLD and mental disorders is required to inform clinical practice and develop novel interventions to prevent and treat these complex and interacting disorders.

Abstract Background Comorbidity between depressive and anxiety disorders is common. A hypothesis of the network perspective on psychopathology is that comorbidity arises due to the interplay of symptoms shared by both disorders, with overlapping symptoms acting as so-called bridges, funneling symptom activation between symptom clusters of each disorder. This study investigated this hypothesis by testing whether (i) two overlapping mental states “worrying” and “feeling irritated” functioned as bridges in dynamic mental state networks of individuals with both depression and anxiety as compared to individuals with either disorder alone, and (ii) overlapping or non-overlapping mental states functioned as stronger bridges. Methods Data come from the Netherlands Study of Depression and Anxiety (NESDA). A total of 143 participants met criteria for comorbid depression and anxiety (65%), 40 participants for depression-only (18.2%), and 37 for anxiety-only (16.8%) during any NESDA wave. Participants completed momentary assessments of symptoms (i.e., mental states) of depression and anxiety, five times a day, for 2 weeks (14,185 assessments). First, dynamics between mental states were modeled with a multilevel vector autoregressive model, using Bayesian estimation. Summed average lagged indirect effects through the hypothesized bridge mental states were compared between groups. Second, we evaluated the role of all mental states as potential bridge mental states. Results While the summed indirect effect for the bridge mental state “worrying” was larger in the comorbid group compared to the single disorder groups, differences between groups were not statistically significant. The difference between groups became more pronounced when only examining individuals with recent diagnoses (

Abstract Background Exercise may be a promising target for depression interventions. However, evidence for a beneficial effect of exercise interventions on the prevention of depression differs substantially across different studies. Methods A systematic search was performed up to July 2018 using PubMed, Embase, PsycINFO, and Cochrane. Articles were included if a meta-analysis of randomized controlled trials was performed that examined the effect of exercise interventions on the onset of depression or depressive symptoms in the general population. Meta-analyses focusing on treatment of diagnosed depression were excluded. Two authors independently screened the articles and graded the quality of included meta-analyses using AMSTAR 2. Results Eight meta-analyses were included that showed little overlap in 134 included studies. All meta-analyses reported on depressive symptoms rather than onset of depression. Five of these were rated as moderate quality and three of low quality. Six meta-analyses found significant effects, and two found non-significant effects of exercise interventions in reducing depressive symptoms in children, adolescents, adults and the elderly (effect sizes ranging from − 0.10 to − 0.81). Scarce evidence did not allow to draw conclusions about the role of sex and characteristics of exercise on depression. However, some findings suggest that low intensity exercise was as effective as high intensity exercise. Heterogeneity among primary studies was high, likely caused by differences in study quality and exercise characteristics. Conclusions The evidence from this study suggests that exercise interventions have a beneficial effect on depressive symptoms in the general population across a wide age-range.

Rationale & Objective: Surrogate outcomes for end-stage kidney disease often assume linear changes, which may not reflect true estimated glomerular filtration rate (eGFR) trajectories. This study’s objective was to characterize nonlinear eGFR trajectories in nephrotic syndrome. Study Design: Observational cohort study. Setting & Participants: Nephrotic Syndrome Study Network (NEPTUNE) is a multicenter study of adult and pediatric patients with proteinuria enrolled at clinically indicated kidney biopsy or initial presentation of disease (pediatric only). Predictors: Patient demographic, clinical, and pathology variables at study enrollment and follow-up time. Outcome: eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (patients ≥ 18 years old) or modified Chronic Kidney Disease in Children Study–Schwartz (patients < 18 years) formulas. The probability of nonlinearity (PNL) was calculated for individual eGFR trajectories. Analytical Approach: Associations between predictors and PNL were assessed using multivariable linear regression. Results: 453 patients with ≥3 eGFR measurements and 1 or more year of follow-up were included (median follow-up, 3.6 years). Median PNL was 0.052; 56% and 16% had PNL < 10% and >50%, respectively. In both adults and pediatric patients, higher baseline eGFR was associated with higher PNL, whereas longer follow-up time was associated with lower PNL. Higher urine protein-creatinine ratio and steroid use were also associated with higher PNL in adults. Higher percentages of tubular atrophy and foot-process effacement were associated with lower and higher PNLs, respectively, in adults. Limitations: Relatively short follow-up time, inability to assess acute kidney injury events, and variable eGFR measurement frequency across patients. Conclusions: Although increasing follow-up time resulted in more linear trajectories, nonlinear eGFR trajectories were common in this cohort. Future studies in nephrotic syndrome should consider novel outcomes that do not rely on linearity assumptions.

Introduction: Childhood-onset nephrotic syndrome has a variable clinical course. Improved predictive markers of long-term outcomes in children with nephrotic syndrome are needed. This study tests the association between baseline urinary epidermal growth factor (uEGF) excretion and longitudinal kidney function in children with nephrotic syndrome. Methods: The study evaluated 191 participants younger than 18 years enrolled in the Nephrotic Syndrome Study Network, including 118 with their first clinically indicated kidney biopsy (68 minimal change disease; 50 focal segmental glomerulosclerosis) and 73 with incident nephrotic syndrome without a biopsy. uEGF was measured at baseline for all participants and normalized by the urine creatinine (Cr) concentration. Renal epidermal growth factor (EGF) mRNA was measured in the tubular compartment microdissected from kidney biopsy cores from a subset of patients. Linear mixed models were used to test if baseline uEGF/Cr and EGF mRNA expression were associated with change in estimated glomerular filtration rate (eGFR) over time. Results: Higher uEGF/Cr at baseline was associated with slower eGFR decline during follow-up (median follow-up = 30 months). Halving of uEGF/Cr was associated with a decrease in eGFR slope of 2.0 ml/min per 1.73 m2 per year (P < 0.001) adjusted for age, race, diagnosis, baseline eGFR and proteinuria, and APOL1 genotype. In the biopsied subgroup, uEGF/Cr was correlated with EGF mRNA expression (r = 0.74; P < 0.001), but uEGF/Cr was retained over mRNA expression as the stronger predictor of eGFR slope after multivariable adjustment (decrease in eGFR slope of 1.7 ml/min per 1.73 m2 per year per log2 decrease in uEGF/Cr; P < 0.001). Conclusion: uEGF/Cr may be a useful noninvasive biomarker that can assist in predicting the long-term course of kidney function in children with incident nephrotic syndrome. Keywords: disease progression, epidermal growth factor, focal segmental glomerulosclerosis, nephrotic syndrome, pediatrics

Abstract Background Hemodialysis sessions frequently become unstable from complications such as intradialytic hypotension and untoward symptoms. Previous patient safety initiatives promote prevention of treatment complications; yet, they have placed little specific focus on avoidable session instability. A patient-centered definition of session instability grounded in patient experiences, and an understanding of patient perceptions of causes and solutions to instability, may enable such efforts. Methods Twenty-five participants participated in three focus groups and/or a survey. They were purposively sampled for variation in region of residence, and sensitivity to patient well-being. Focus group recordings were analyzed using descriptive coding, in vivo coding, and thematic analysis. Results Patients define unstable sessions (“bad runs”) as those in which they experience severe discomfort or unanticipated events that interfere with their ability to receive therapy. Bad runs were characterized primarily by cramping, low blood pressure (“crashing”), cannulation-related difficulties (“bad sticks”), and clotting of the dialysis circuit or vascular access. Patients believed that cramping and crashing could be explained by both patient and clinician behavior: patient fluid consumption and providers’ fluid removal goals. Patients felt that the responsibility for cannulation-related problems lay with dialysis staff, and they asked for different staff or self-cannulated as solutions. Clotting was viewed as an idiosyncratic issue with one’s body, and perceived solutions were clinician-driven. Patients expressed concern about “bad runs” on their ability to achieve fluid balance. Conclusions Findings point to novel priorities for efforts to enhance hemodialysis session stability, and areas in which patients can be supported to become involved in such efforts.

Background Social functioning is often impaired in schizophrenia (SZ) and Alzheimer’s disease (AD). However, commonalities and differences in social dysfunction among these patient groups remain elusive. Materials and methods Using data from the PRISM study, behavioral (all subscales and total score of the Social Functioning Scale) and affective (perceived social disability and loneliness) indicators of social functioning were measured in patients with SZ (N = 56), probable AD (N = 50) and age-matched healthy controls groups (HC, N = 29 and N = 28). We examined to what extent social functioning differed between disease and age-matched HC groups, as well as between patient groups. Furthermore, we examined how severity of disease and mood were correlated with social functioning, irrespective of diagnosis. Results As compared to HC, both behavioral and affective social functioning seemed impaired in SZ patients (Cohen’s d’s 0.81–1.69), whereas AD patients mainly showed impaired behavioral social function (Cohen’s d’s 0.65–1.14). While behavioral indices of social functioning were similar across patient groups, SZ patients reported more perceived social disability than AD patients (Cohen’s d’s 0.65). Across patient groups, positive mood, lower depression and anxiety levels were strong determinants of better social functioning (p’s Conclusions AD and SZ patients both exhibit poor social functioning in comparison to age- and sex matched HC participants. Social dysfunction in SZ patients may be more severe than in AD patients, though this may be due to underreporting by AD patients. Across patients, social functioning appeared as more influenced by mood states than by severity of disease.

We present a methodology for subtyping of persons with a common clinical symptom complex by integrating heterogeneous continuous and categorical data. We illustrate it by clustering women with lower urinary tract symptoms (LUTS), who represent a heterogeneous cohort with overlapping symptoms and multifactorial etiology. Data collected in the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN), a multi-center observational study, included self-reported urinary and non-urinary symptoms, bladder diaries, and physical examination data for 545 women. Heterogeneity in these multidimensional data required thorough and non-trivial preprocessing, including scaling by controls and weighting to mitigate data redundancy, while the various data types (continuous and categorical) required novel methodology using a weighted Tanimoto indices approach. Data domains only available on a subset of the cohort were integrated using a semi-supervised clustering approach. Novel contrast criterion for determination of the optimal number of clusters in consensus clustering was introduced and compared with existing criteria. Distinctiveness of the clusters was confirmed by using multiple criteria for cluster quality, and by testing for significantly different variables in pairwise comparisons of the clusters. Cluster dynamics were explored by analyzing longitudinal data at 3- and 12-month follow-up. Five clusters of women with LUTS were identified using the developed methodology. None of the clusters could be characterized by a single symptom, but rather by a distinct combination of symptoms with various levels of severity. Targeted proteomics of serum samples demonstrated that differentially abundant proteins and affected pathways are different across the clusters. The clinical relevance of the identified clusters is discussed and compared with the current conventional approaches to the evaluation of LUTS patients. The rationale and thought process are described for the selection of procedures for data preprocessing, clustering, and cluster evaluation. Suggestions are provided for minimum reporting requirements in publications utilizing clustering methodology with multiple heterogeneous data domains.

Background: The prevalence of insomnia and hypersomnia in depressed individuals is substantially higher than that found in the general population. Unfortunately, these concurrent sleep problems can have profound effects on the disease course. Although the full biology of sleep remains to be elucidated, a recent genome-wide association (GWAS) of insomnia, and other sleep traits in over 1 million individuals was recently published and provides many promising hits for genetics of insomnia in a population-based sample.Methods: Using data from the largest available GWAS of insomnia and other sleep traits, we sought to test if sleep variable PRS scores derived from population-based studies predicted sleep variables in samples of depressed cases [Psychiatric Genomics Consortium - Major Depressive Disorder subjects (PGC MDD)]. A leave-one-out analysis was performed to determine the effects that each individual study had on our results.Results: The only significant finding was for insomnia, where p-value threshold, p = 0.05 was associated with insomnia in our PGC MDD sample (R2 = 1.75−3, p = 0.006).Conclusion: Our results reveal that

Abstract Objectives Psychosocial factors have been hypothesized to increase the risk of cancer. This study aims (1) to test whether psychosocial factors (depression, anxiety, recent loss events, subjective social support, relationship status, general distress, and neuroticism) are associated with the incidence of any cancer (any, breast, lung, prostate, colorectal, smoking‐related, and alcohol‐related); (2) to test the interaction between psychosocial factors and factors related to cancer risk (smoking, alcohol use, weight, physical activity, sedentary behavior, sleep, age, sex, education, hormone replacement therapy, and menopausal status) with regard to the incidence of cancer; and (3) to test the mediating role of health behaviors (smoking, alcohol use, weight, physical activity, sedentary behavior, and sleep) in the relationship between psychosocial factors and the incidence of cancer. Methods The psychosocial factors and cancer incidence (PSY‐CA) consortium was established involving experts in the field of (psycho‐)oncology, methodology, and epidemiology. Using data collected in 18 cohorts (N = 617,355), a preplanned two‐stage individual participant data (IPD) meta‐analysis is proposed. Standardized analyses will be conducted on harmonized datasets for each cohort (stage 1), and meta‐analyses will be performed on the risk estimates (stage 2). Conclusion PSY‐CA aims to elucidate the relationship between psychosocial factors and cancer risk by addressing several shortcomings of prior meta‐analyses.

BackgroundResearch in mental health has found associations between depression and individuals’ behaviors and statuses, such as social connections and interactions, working status, mobility, and social isolation and loneliness. These behaviors and statuses can be approximated by the nearby Bluetooth device count (NBDC) detected by Bluetooth sensors in mobile phones. ObjectiveThis study aimed to explore the value of the NBDC data in predicting depressive symptom severity as measured via the 8-item Patient Health Questionnaire (PHQ-8). MethodsThe data used in this paper included 2886 biweekly PHQ-8 records collected from 316 participants recruited from three study sites in the Netherlands, Spain, and the United Kingdom as part of the EU Remote Assessment of Disease and Relapse-Central Nervous System (RADAR-CNS) study. From the NBDC data 2 weeks prior to each PHQ-8 score, we extracted 49 Bluetooth features, including statistical features and nonlinear features for measuring the periodicity and regularity of individuals’ life rhythms. Linear mixed-effect models were used to explore associations between Bluetooth features and the PHQ-8 score. We then applied hierarchical Bayesian linear regression models to predict the PHQ-8 score from the extracted Bluetooth features. ResultsA number of significant associations were found between Bluetooth features and depressive symptom severity. Generally speaking, along with depressive symptom worsening, one or more of the following changes were found in the preceding 2 weeks of the NBDC data: (1) the amount decreased, (2) the variance decreased, (3) the periodicity (especially the circadian rhythm) decreased, and (4) the NBDC sequence became more irregular. Compared with commonly used machine learning models, the proposed hierarchical Bayesian linear regression model achieved the best prediction metrics (R2=0.526) and a root mean squared error (RMSE) of 3.891. Bluetooth features can explain an extra 18.8% of the variance in the PHQ-8 score relative to the baseline model without Bluetooth features (R2=0.338, RMSE=4.547). ConclusionsOur statistical results indicate that the NBDC data have the potential to reflect changes in individuals’ behaviors and statuses concurrent with the changes in the depressive state. The prediction results demonstrate that the NBDC data have a significant value in predicting depressive symptom severity. These findings may have utility for the mental health monitoring practice in real-world settings.

Abstract Background Depressive and anxiety disorders have shown to be associated to premature or advanced biological aging and consequently to adversely impact somatic health. Treatments with antidepressant medication or running therapy are both found to be effective for many but not all patients with mood and anxiety disorders. These interventions may, however, work through different pathophysiological mechanisms and could differ in their impact on biological aging and somatic health. This study protocol describes the design of an unique intervention study that examines whether both treatments are similarly effective in reducing or reversing biological aging (primary outcome), psychiatric status, metabolic stress and neurobiological indicators (secondary outcomes). Methods The MOod Treatment with Antidepressants or Running (MOTAR) study will recruit a total of 160 patients with a current major depressive and/or anxiety disorder in a mental health care setting. Patients will receive a 16-week treatment with either antidepressant medication or running therapy (3 times/week). Patients will undergo the treatment of their preference and a subsample will be randomized (1:1) to overcome preference bias. An additional no-disease-no-treatment group of 60 healthy controls without lifetime psychopathology, will be included as comparison group for primary and secondary outcomes at baseline. Assessments are done at week 0 for patients and controls, and at week 16 and week 52 for patients only, including written questionnaires, a psychiatric and medical examination, blood, urine and saliva collection and a cycle ergometer test, to gather information about biological aging (telomere length and telomerase activity), mental health (depression and anxiety disorder characteristics), general fitness, metabolic stress-related biomarkers (inflammation, metabolic syndrome, cortisol) and genetic determinants. In addition, neurobiological alterations in brain processes will be assessed using structural and functional Magnetic Resonance Imaging (MRI) in a subsample of at least 25 patients per treatment arm and in all controls. Discussion This intervention study aims to provide a better understanding of the impact of antidepressant medication and running therapy on biological aging, metabolic stress and neurobiological indicators in patients with depressive and anxiety disorders in order to guide a more personalized medicine treatment. Trial registration Trialregister.nl Number of identification: NTR3460, May 2012.