Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Patterns of pharmacotherapy for bipolar disorder: A GBC survey.

OBJECTIVES: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well-characterized individuals with BD in North America, Europe, and Australia. METHODS: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta-analyses with generalized linear mixed methods were conducted to identify prescription patterns. RESULTS: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD-I (60%; vs. BD-II = 33%). Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First-generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD-II (47%) compared to BD-I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. CONCLUSIONS: Mood-stabilizing anticonvulsants, second-generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first-generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence-based guidelines to help improve treatment practices in BD.

Association between visceral adipose tissue and major depressive disorder across the lifespan: A scoping review.

OBJECTIVES: Increasing evidence supports a bidirectional relationship between major depressive disorder (MDD) and obesity, but the role of visceral adipose tissue (VAT) as a measure of obesity in relation to MDD is not well understood. Here we review literature investigating the link between MDD and VAT in terms of biomarkers, sex differences, and aging. METHODS: PubMed, EMBASE, PsycINFO, and CINAHL searches were conducted on December 11, 2020. No date or language limits were imposed. Major concepts searched were Depressive Disorder linked with Adipose Tissue, White, Hypothalmo-Hypophyseal System, and Pituitary-Adrenal System in addition to keywords. A final set of 32 items meeting criteria for inclusion. RESULTS: Converging biological evidence suggests a significant bidirectional relationship between VAT and MDD across the lifespan. In adulthood, greater VAT was associated with increased risk for depression, especially in vulnerable groups such as individuals who are overweight/obese, postmenopausal women, and individuals with comorbid medical or psychiatric illness. In older adults, sarcopenia had an impact on the relationship between abnormal VAT and risk of depression. Additionally, sex differences emerged as a potential factor affecting the strength of the association between VAT and depression. CONCLUSIONS: Elucidating the pathophysiological mechanisms associated with increased rates of depression in obese individuals will be crucial for developing specific treatment strategies that seek to improve outcomes in individuals with comorbid depression and obesity. Moreover, identifying age- and sex-specific risk factors may contribute to a more personalized medicine approach, thereby improving the quality of clinical care.

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.

Dysregulated Diurnal Cortisol Pattern and Heightened Night-Time Cortisol in Individuals with Bipolar Disorder.

INTRODUCTION: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may contribute to the symptom burden in bipolar disorder (BD). Further characterization of cortisol secretion is needed to improve understanding of the connection between mood, sleep, and the HPA axis. Here, we observe diurnal cortisol patterns in individuals with BD and healthy controls (HCs) to determine time points where differences may occur. METHODS: Salivary cortisol was measured at 6 time points (wake, 15, 30, and 45 min after wake, between 2:00 and 4:00 p.m. and 10:00 p.m.) for 3 consecutive days in individuals with symptomatic BD (N = 27) and HC participants (N = 31). A general linear model with correlated errors was utilized to determine if salivary cortisol changed differently throughout the day between the 2 study groups. RESULTS: A significant interaction (F = 2.74, df = 5, and p = 0.02) was observed between the time of day and the study group (BD vs. HC) when modeling salivary cortisol over time, indicating that salivary cortisol levels throughout the day significantly differed between the study groups. Specifically, salivary cortisol in BD was elevated compared to HCs at the 10:00 p.m. time point (p = 0.01). CONCLUSION: Significantly higher levels of cortisol in participants with BD in the night-time suggest that the attenuation of cortisol observed in healthy individuals may be impaired in those with BD. Reregulation of cortisol levels may be a target of further study and treatment intervention for individuals with BD.

Total sleep time and kynurenine metabolism associated with mood symptom severity in bipolar disorder.

OBJECTIVE: Chronic, low-level inflammation is associated with symptomatic bipolar disorder (BD) and with chronic insomnia. Disrupted sleep is a feature of episodes of both mania and depression. We examined the effect of neopterin, a marker of cellular immune activation, and kynurenine (KYN), an inflammatory byproduct of the serotonin pathway, on the association between total sleep time and depression severity in BD. METHOD: Twenty-one symptomatic BD participants and 28 healthy controls (HC) were recruited and followed during usual clinical care. At baseline and after symptomatic recovery, total sleep time was objectively measured with actigraphy for 1 week and blood plasma was collected to measure the serotonin precursor tryptophan (TRP), KYN, the KYN/TRP ratio, and neopterin levels. Statistical analyses were conducted using chi-square, independent t tests and hierarchical linear multiple regression models. RESULTS: Total sleep time was correlated positively with depressive severity and negatively with manic severity. TRP was significantly reduced in BD participants compared to HC. KYN, TRP, and the KYN/TRP ratio were associated with depressive severity when total sleep time and body mass index (BMI) were included in the model. The KYN/TRP ratio trended towards a negative association with mania symptoms, controlling for BMI and total sleep time, in acutely symptomatic BD participants. Neopterin was not associated with sleep or mood severity. After usual clinical care, BD participants showed significantly decreased clinical symptoms but no significant differences in sleep phenotype or biomarkers. CONCLUSION: Inflammation, sleep, and mood are closely intertwined. Future research into the effect of inflammation on sleep in BD may lead to clinical markers of outcome.

The effect of aging on facial emotion recognition in bipolar disorder.

OBJECTIVE: Convergent data point to an exaggerated negativity bias in bipolar disorder (BD), and little is known about whether people with BD experience the 'positivity effect' with increasing age. METHOD: This is a cross sectional study of 202 participants with BD aged 18-65, and a sample (n = 53) of healthy controls (HCs). Participants completed the CANTAB Emotion Recognition Task (ERT). Using analysis of variance, we tested for a main effect of age, diagnosis, and an interaction of age x diagnosis on both negative and positive conditions. RESULTS: We observed increased accuracy in identifying positive stimuli in the HC sample as a function of increasing age, a pattern that was not seen in participants with BD. Specifically, there was a significant diagnosis by age cohort interaction on ERT performance that was specific to the identification of happiness, where the Later Adulthood cohort of HCs was more accurate when identifying happy faces relative to the same cohort of BD patients. CONCLUSION: Later life looks different for people with BD. With an aging population globally, gaining a clearer picture of the effects of recurrent mood dysregulation on the brain will be critical in guiding efforts to effectively optimize outcomes in older adults with BD.

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.

The Effects of Peripheral Inflammation on the Brain-A Neuroimaging Perspective.

ABSTRACT: In the field of neuropsychiatry, neuroinflammation is one of the prevailing hypotheses to explain the pathophysiology of mood and psychotic disorders. Neuroinflammation encompasses an ill-defined set of pathophysiological processes in the central nervous system that cause neuronal or glial atrophy or death and disruptions in neurotransmitter signaling, resulting in cognitive and behavioral changes. Positron emission tomography for the brain-based translocator protein has been shown to be a useful tool to measure glial activation in neuropsychiatric disorders. Recent neuroimaging studies also indicate a potential disruption in the choroid plexus and blood-brain barrier, which modulate the transfer of ions, molecules, toxins, and cells from the periphery into the brain. Simultaneously, peripheral inflammatory markers have consistently been shown to be altered in mood and psychotic disorders. The crosstalk (i.e., the communication between peripheral and central inflammatory pathways) is not well understood in these disorders, however, and neuroimaging studies hold promise to shed light on this complex process. In the current Perspectives article, we discuss the neuroimaging insights into neuroimmune crosstalk offered in selected works. Overall, evidence exists for peripheral immune cell infiltration into the central nervous system in some patients, but the reason for this is unknown. Future neuroimaging studies should aim to extend our knowledge of this system and the role it likely plays in symptom onset and recurrence.

C-reactive protein and affective inhibition in bipolar disorder.

BACKGROUND: Individuals with bipolar disorder (BD) experience cognitive and affective processing deficits that often persist beyond the remission of acute mood symptoms. One possible biological mechanism for these deficits involves the potential effects of chronic low-grade peripheral inflammation on brain function. Peripheral inflammation has been associated with reduced executive functioning and memory performance, as well as altered reward processing in BD, but whether it is also implicated in cognitive-affective processing remains unknown. METHOD: Peripheral inflammation was measured by serum C-reactive protein (CRP) in 119 adults with BD I or II, age 18-65. All participants completed the Affective Go/No-Go Task, a measure of cognitive-emotional processing. Correlations of CRP with discrimination of and response times to Negative, Positive, and Neutral words were performed before and after adjustment for severity of residual depressive symptoms and other demographic and clinical characteristics associated with inflammation. RESULTS: Increased CRP was significantly associated with reduced negative target discriminability, which was also significantly reduced compared to positive and neutral target conditions. Additionally, greater CRP was associated with faster response times for both negative hits and commissions, as well as positive commissions. CONCLUSIONS: This study adds to existing research demonstrating associations between inflammation and cognition or reward sensitivity and motivation separately in BD, by raising the possibility that inflammation is also implicated in the integration of cognitive-affective processing. Assessment of these associations over time is warranted to determine involvement of inflammation and cognitive-emotional processing in course of illness and identify critical periods for possible modulation of inflammation.

Defining Heterogeneous Cognitive Trajectories in Bipolar Disorder: A Perspective.

ABSTRACT: Bipolar disorder (BD) is a highly disabling mental illness that affects approximately 1% of the global population. Cognitive capacity is a strong predictor of "everyday" functional outcome in BD and should thus be considered a key treatment target. Interventions to improve cognition have been largely unsuccessful, likely due to the substantial heterogeneity inherent to the illness. It is known that 40%-60% of people with BD have cognitive impairment, yet impairment is not "one size fits all"; in fact, the literature supports discrete cognitive subtypes in BD (e.g., intact, globally impaired, and selectively impaired). Gaining a better understanding of these cognitive subtypes, their longitudinal trajectories, and their biological underpinnings will be essential for improving patient outcomes. The prevailing hypothesis for the development of cognitive impairment in BD postulates a stepwise cumulative effect of repeated mood episodes causing wear-and-tear on the brain. However, a paucity of data supports this idea at the group level. We propose that studying heterogeneity longitudinally will allow for clearer delineation of the natural history of cognitive trajectories in BD. In sum, parsing heterogeneity in BD will allow us to identify causal mechanisms and optimize treatment at the level of the individual.

Cognitive heterogeneity is a key predictor of differential functional outcome in patients with bipolar disorder.

Bipolar disorder (BD) is a complex illness with variability at the level of symptom presentation, clinical course, cognitive capacity, and everyday function. Cognition is a key predictor of functional disability in BD, however, much remains unknown about the development and presentation of cognitive dysfunction in BD. Studies have shown that 30-50% of affectively stable people with BD are indistinguishable from healthy individuals in terms of cognitive presentation. In contrast, many people with BD have moderate to severe cognitive deficits, in some cases on par with what is typically observed in schizophrenia (SZ). Recent research efforts have aimed to parse this cognitive heterogeneity using unsupervised statistical techniques, resulting in more homogeneous subgroups. This method has provided new insights into the clinical and biological predictors of a potentially - neuroprogressive - declinin - gcognitive course in BD. Future studies that include detailed longitudinal follow-up in large BD cohorts hold promise for guiding the development of novel treatments that reach beyond the primary affective symptoms and target functionally relevant outcomes to promote full recovery.

The association between lithium use and neurocognitive performance in patients with bipolar disorder.

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1-5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p < 0.001], CVLT trials 1-5 [F = 29.81; p < 0.001], CVLT delayed recall [F = 15.27; p < 0.001], and TMT-B [F = 6.64, p = 0.012] was detected. The cross-sectional and longitudinal (on a subset of 88 patients) investigations suggest that lithium may be beneficial to neurocognitive functioning in patients with BD and that at the very least it does not seem to significantly impair cognition when used therapeutically.

The Sex-specific Effects of LPS on Depressive-like Behavior and Oxidative Stress in the Hippocampus of the Mouse.

Many human and animal studies have implicated inflammation as a mediator of oxidative stress and a possible contributor to hippocampal atrophy in the pathophysiology of major depressive disorder. We aimed to examine the effect of peripheral, systemic inflammation on oxidative stress and apoptosis in the hippocampi of male and female mice. We hypothesized that (1) lipopolysaccharide (LPS) would induce depressive-like behavior and hippocampal oxidative stress after 1 day in males, and (2) that a single LPS exposure would result in hippocampal apoptosis at 28 days. Further, we predicted that female sex would confer protection from the molecular and behavioral deleterious effects of LPS. Males exhibited depressive-like behavior 24 h after LPS administration compared to the males given saline. Female mice did not exhibit depressive-like behavior after LPS compared to females in the saline group. Males given LPS also had increased levels of superoxide dismutase (SOD) I in the hippocampus by 24 h compared to the saline group. At 28 days, we found decreased levels of brain derived neurotrophic factor (BDNF) protein in males given LPS compared to males given saline. Moreover, males given LPS showed increased apoptosis. Our work will provide insight into the underlying biology in males and females with MDD, and potentially underlying differences between the sexes. Also, our work will hopefully inform optimal clinical treatments that may indeed differ between the sexes.

Peripheral zinc and neopterin concentrations are associated with mood severity in bipolar disorder in a gender-specific manner.

Bipolar disorder (BD) is a recurrent, episodic mood disorder for which there are no current diagnostic, prognostic or theranostic biomarkers. Two peripheral markers of the acute phase immune response, zinc and neopterin, are consistently associated with severity of depression in literature. Given gender differences in clinical presentation of BD and in inflammatory processes, we aimed to explore the interaction between gender and immune biomarkers to predict mood severity in BD. Participants with DSM IV BD I and II were recruited through the Pennsylvania Psychiatric Institute during an acute mood episode. Healthy controls (HC) were recruited through advertisements. Participants fasted for at least 6h when blood was drawn for biomarkers. We found that zinc concentrations were significantly lower in the BD group at baseline (p<.05), and there was also a significant interaction between gender and zinc (p<.05), associated with depression severity. Also, we found a significant interaction between gender and neopterin, associated with mania severity (p<.05). We found that mania severity was associated with neopterin in men, while depression severity was positively associated with zinc in women. Our report bears replication in larger samples and highlights the potential for differences in the underlying pathophysiology between men and women with BD.