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

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

Cortical similarities in psychiatric and mood disorders identified in federated VBM analysis via COINSTAC.

Structural neuroimaging studies have identified a combination of shared and disorder-specific patterns of gray matter (GM) deficits across psychiatric disorders. Pooling large data allows for examination of a possible common neuroanatomical basis that may identify a certain vulnerability for mental illness. Large-scale collaborative research is already facilitated by data repositories, institutionally supported databases, and data archives. However, these data-sharing methodologies can suffer from significant barriers. Federated approaches augment these approaches by enabling access or more sophisticated, shareable and scaled-up analyses of large-scale data. We examined GM alterations using Collaborative Informatics and Neuroimaging Suite Toolkit for Anonymous Computation, an open-source, decentralized analysis application. Through federated analysis of eight sites, we identified significant overlap in the GM patterns (n = 4,102) of individuals with schizophrenia, major depressive disorder, and autism spectrum disorder. These results show cortical and subcortical regions that may indicate a shared vulnerability to psychiatric disorders.

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.

Total knee arthroplasty: Quality assurance and improved longevity costs less.

Background: There is an accepted variation in the financial cost of total knee arthroplasty (TKA) implants but it is not known whether this cost is reflected by the evidence in support of their use. A cost analysis study was carried out to determine the total cost of consumables of a TKA, and whether this was related to the supporting evidence and survivorship data. Methods: Intra-operative data for all unilateral, cemented, primary TKA over a 13 month period at a high-volume Orthopaedic Centre was collected. Level of evidence for each model was taken from the Orthopaedic Data Evaluation Panel (ODEP) website, and data from the UK National Joint Registry was used to assign survivorship (failure rates). Correlation was calculated using the Spearman rank correlation (r). Results: A total of 1301 TKA were performed at the study centre during the data collection period. The mean cost of consumables for a TKA with patella resurfacing (n = 816) was £1969.08 (range of £1061.46 and £5143.89), and without resurfacing (n = 485) was £1846.62 (range of £1118.98 and £4196.81). There was a negative correlation between price of implant and ODEP rating (r = -0.47), with increasing level of evidence being associated with a lower cost. There was a positive correlation between price of implant and rate of implant failure at the1-, 3- and 5-year time-points (r = 0.55, 0.44, 0.28 respectively), with increasing cost being associated with a higher failure rate. Conclusion: Higher financial cost of TKA prostheses was associated with a weaker level of supporting evidence and a higher failure rate. The increased financial cost of new implants may be justified as more data and evidence becomes available to support an advantage in its use over currently established implants.

Striatal Functional Alterations Link to Distinct Symptomatology Across Mood States in Bipolar Disorder.

BACKGROUND: As a central hub in cognitive and emotional brain circuits, the striatum is considered likely to be integrally involved in the psychopathology of bipolar disorder (BD). However, it remains unclear how alterations in striatal function contribute to distinct symptomatology of BD during different mood states. METHODS: Behavioral assessment (i.e., emotional symptoms and cognitive performance) and neuroimaging data were collected from 125 participants comprising 31 (hypo)manic, 31 depressive, and 31 euthymic patients with BD, and 32 healthy control participants. We compared the functional connectivity (FC) of striatal subregions across BD mood states with healthy control participants and then used a multivariate data-driven approach to explore dimensional associations between striatal connectivity and behavioral performance. Finally, we compared the FC and behavioral composite scores, which reflect the individual weighted representation of the associations, among different mood states. RESULTS: Patients in all mood states exhibited increased FC between the bilateral ventral rostral putamen and ventrolateral thalamus. Bipolar (hypo)mania uniquely exhibited increased ventral rostral putamen connectivity and superior ventral striatum connectivity. One latent component was identified, whereby increased FCs of striatal subregions were associated with distinct psychopathological symptomatology (more manic symptoms, elevated positive mood, less depressive symptoms, and worse cognitive performance). Patients with bipolar (hypo)mania had the highest FC and behavioral composite scores while bipolar patients with depression had the lowest scores. CONCLUSIONS: Our data demonstrated both trait features of BD and state features specific to bipolar (hypo)mania. The findings underscored the fundamental role of the striatum in the pathophysiological processes underlying specific symptomatology across all mood states.

Sensory processing across eating disorders: A systematic review and meta-analysis of self-report inventories.

OBJECTIVE: This review investigated the extant literature regarding the relationship between eating disorder diagnoses and sensory processing as measured by validated and reliable self-report inventories. Increasing evidence highlights the role of sensory processing in cognitive functions. Sensory processing is implicated in mental-ill health, including eating disorders (ED) and body image disturbances. However, the pathophysiological underpinnings of sensory processing, encompassing exteroception and interoception, in relation to ED remain underexplored. METHOD: We included studies involving participants aged 15 years or older with an eating disorder diagnosis confirmed by semi-structured or structured interviews. We further limited inclusion to articles using validated and reliable self-report instruments to measure sensory processing. Our meta-analysis focused on studies using the interoceptive awareness subscale from the second version of the Eating Disorder Inventory. We used the Critical Appraisal checklist for quasi-experimental studies to assess the quality of included articles. RESULTS: There were 19 studies that met our inclusion criteria. Most studies showed moderate-to-high quality. Anorexia nervosa (AN) and bulimia nervosa (BN) were associated with heightened exteroception. Moreover, people with AN reported a heightened sense of taste compared to those with BN. Our meta-analysis comprising 10 studies, 19 samples, and 6382 participants revealed that AN (binge-purge subtype) and BN were associated with increased interoceptive difficulties compared to AN (restrictive subtype) or binge-eating disorder. DISCUSSION: Overall, this review emphasizes the need for a deeper investigation into sensory processing, spanning both exteroception and interoception, in relation to ED. This may prove important for individualizing person-centered care. PUBLIC SIGNIFICANCE: How people process internal, for example, hunger, and external, for example, taste and sensations is known to influence cognition and mental-ill health, including ED and body image disturbances. However, the ways in which sensory processing may contribute to ED are incompletely understood. We found that individuals with AN or BN experienced heightened exteroception, while people with an eating disorder characterized by purging reported increased interoceptive difficulties. These patterns could inform the development of more personalized treatments.

OBJETIVO: Esta revisión investigó la literatura existente sobre la relación entre los diagnósticos de trastornos de conducta alimentaria y el procesamiento sensorial, medido mediante inventarios de autoreporte validados y fiables. Cada vez hay más evidencia que destaca el papel del procesamiento sensorial en las funciones cognitivas. El procesamiento sensorial está implicado en la salud mental, incluidos los trastornos de conducta alimentaria y las alteraciones de la imagen corporal. Sin embargo, los fundamentos fisiopatológicos del procesamiento sensorial, que abarcan la exterocepción y la interocepción, en relación con los trastornos alimentarios permanecen poco explorados. MÉTODO: Incluimos estudios con participantes de 15 años o más con un diagnóstico de trastorno de conducta alimentaria confirmado por entrevistas semiestructuradas o estructuradas. Además, limitamos la inclusión a artículos que utilizaran instrumentos de autoreporte validados y fiables para medir el procesamiento sensorial. Nuestro metaanálisis se centró en estudios que utilizaron la subescala de conciencia interoceptiva de la segunda versión del Inventario de Trastornos de Conducta Alimentaria. Utilizamos la lista de verificación de Evaluación Crítica para estudios cuasiexperimentales para evaluar la calidad de los artículos incluidos. RESULTADOS: Hubo 19 estudios que cumplieron con nuestros criterios de inclusión. La mayoría de los estudios mostraron una calidad moderada a alta. La anorexia nerviosa y la bulimia nerviosa se asociaron con una exterocepción elevada. Además, las personas que padecían anorexia nerviosa reportaron de un sentido del gusto más agudizado en comparación con aquellas que padecían bulimia nerviosa. Nuestro metaanálisis, que comprendió 10 estudios, 19 muestras y 6382 participantes, reveló que la anorexia nerviosa (subtipo atracones­purga) y la bulimia nerviosa se asociaron con dificultades interoceptivas aumentadas en comparación con la anorexia nerviosa (subtipo restrictivo) o el trastorno por atracón. DISCUSIÓN: En general, esta revisión enfatiza la necesidad de una investigación más profunda sobre el procesamiento sensorial, abarcando tanto la exterocepción como la interocepción, en relación con los trastornos de conducta alimentaria. Esto puede ser importante para personalizar la atención centrada en la persona.

Identifying genetic differences between bipolar disorder and major depression through multiple GWAS.

Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

Predictors of Functional Impairment in Bipolar Disorder: Results From 13 Cohorts From Seven Countries by the Global Bipolar Cohort Collaborative.

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. Methods: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. Results: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.Reprinted from Bipolar Disord 2022; 24:709-719, with permission from John Wiley and Sons. Copyright © 2022.