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.

Implementing a mentoring program for clinical research professionals: A novel professional development initiative for university health research staff.

Clinical and translational research relies on a well-trained workforce, but mentorship programs designed expressly for this workforce are lacking. This paper presents the development of a mentoring program for research staff and identifies key programmatic outcomes. Research staff participating in this program were matched with a senior mentor. Focus groups were conducted to identify key program outcomes. Surveys were administered throughout the program period to assess participants' experience, gains in skill, and subsequent careers. Analysis of the resultant qualitative and quantitative data are used to characterize the implementation and impact of the program. A total of 47 mentees and 30 mentors participated in program between 2018 and 2023. A comprehensive logic model of short-, intermediate- and long-term outcomes was developed. Participants reported positive valuations of every programmatic outcome assessed including their program experience, learning and research careers. The pool of available mentors also grew as new mentors were successfully recruited for each cohort. This mentorship program developed and implemented by senior research staff successfully provided junior research staff with professional development support, mentorship, and professional development opportunities. Junior and senior health research staff built mentoring relationships that advanced their clinical and translational research careers.

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.

Plasma linoleic acid partially mediates the association of bipolar disorder on self-reported mental health scales.

We have shown that bipolar individuals have reduced quality diets, including lower intake of polyunsaturated fatty acids (PUFA). We have also reported reduced plasma levels of the n-6 PUFA, linoleic acid (LA), and the n-3 PUFA, eicosapentaenoic acid (EPA) in bipolar subjects. In the current analysis we hypothesized that LA and EPA plasma levels would mediate lower self-reported mental health and life functioning scores in bipolar subjects. In a cross-sectional study, we collected a 7-day diet record in bipolar (n = 56) and control subjects (n = 46) followed by a fasted blood draw. We used structured equation modeling path analysis to test for mediating effects of dietary intake and plasma levels of LA and EPA on self-reported mental health questionnaire scores, including the Life Functioning Questionnaire (LFQ), the Patient Health Questionnaire (PHQ9), and the Short Form Health Survey (SF12), extracting the mental health component summary score (SF12-MH). We adjusted for age, gender, psychiatric medication use, body mass index (BMI), and total caloric intake as covariates with bipolar disorder as the primary predictor. We found a significant path association from bipolar disorder to lower plasma LA levels (p = 0.03) and significant paths from plasma LA to PHQ9 (p = 0.05), LFQ (p = 0.01) and SF12-MH (p = 0.05) scores, such that lower plasma LA predicted worse outcomes. We found no significant paths from plasma EPA levels to any of the outcome measures. These findings suggest that plasma LA levels partially mediate the effect of bipolar disorder on self-reported measures of mental health and life functioning.

Dietary intake and plasma metabolomic analysis of polyunsaturated fatty acids in bipolar subjects reveal dysregulation of linoleic acid metabolism.

Polyunsaturated fatty acids (PUFA) profiles associate with risk for mood disorders. This poses the hypothesis of metabolic differences between patients and unaffected healthy controls that relate to the primary illness or are secondary to medication use or dietary intake. However, dietary manipulation or supplementation studies show equivocal results improving mental health outcomes. This study investigates dietary patterns and metabolic profiles relevant to PUFA metabolism, in bipolar I individuals compared to non-psychiatric controls. We collected seven-day diet records and performed metabolomic analysis of fasted plasma collected immediately after diet recording. Regression analyses adjusted for age, gender and energy intake found that bipolar individuals had significantly lower intake of selenium and PUFAs, including eicosapentaenoic acid (EPA) (n-3), docosahexaenoic acid (DHA) (n-3), arachidonic acid (AA) (n-6) and docosapentaenoic acid (DPA) (n-3/n-6 mix); and significantly increased intake of the saturated fats, eicosanoic and docosanoic acid. Regression analysis of metabolomic data derived from plasma samples, correcting for age, gender, BMI, psychiatric medication use and dietary PUFA intake, revealed that bipolar individuals had reduced 13S-HpODE, a major peroxidation product of the n-6, linoleic acid (LA), reduced eicosadienoic acid (EDA), an elongation product of LA; reduced prostaglandins G2, F2 alpha and E1, synthesized from n-6 PUFA; and reduced EPA. These observations remained significant or near significant after Bonferroni correction and are consistent with metabolic variances between bipolar and control individuals with regard to PUFA metabolism. These findings suggest that specific dietary interventions aimed towards correcting these metabolic disparities may impact health outcomes for individuals with bipolar disorder.

Fats and factors: lipid profiles associate with personality factors and suicidal history in bipolar subjects.

Polyunsaturated fatty acids (PUFA) have shown efficacy in the treatment of bipolar disorder, however their specific role in treating the illness is unclear. Serum PUFA and dietary intakes of PUFA associate with suicidal behavior in epidemiological studies. The objective of this study was to assess serum n-3 and n-6 PUFA levels in bipolar subjects and determine possible associations with suicidal risk, including suicidal history and relevant personality factors that have been associated with suicidality. We studied 27 bipolar subjects using the NEO-PI to assess the big five personality factors, structured interviews to verify diagnosis and assess suicidal history, and lipomics to quantify n-3 and n-6 PUFA in serum. We found positive associations between personality factors and ratios of n-3 PUFA, suggesting that conversion of short chain to long chain n-3s and the activity of enzymes in this pathway may associate with measures of personality. Thus, ratios of docosahexaenoic acid (DHA) to alpha linolenic acid (ALA) and the activity of fatty acid desaturase 2 (FADS2) involved in the conversion of ALA to DHA were positively associated with openness factor scores. Ratios of eicosapentaenoic acid (EPA) to ALA and ratios of EPA to DHA were positively associated with agreeableness factor scores. Finally, serum concentrations of the n-6, arachidonic acid (AA), were significantly lower in subjects with a history of suicide attempt compared to non-attempters. The data suggest that specific lipid profiles, which are controlled by an interaction between diet and genetics, correlate with suicidal history and personality factors related to suicidal risk. This study provides preliminary data for future studies to determine whether manipulation of PUFA profiles (through diet or supplementation) can affect personality measures and disease outcome in bipolar subjects and supports the need for further investigations into individualized specific modulations of lipid profiles to add adjunctive value to treatment paradigms.

Association of plasma ω-3 and ω-6 lipids with burden of disease measures in bipolar subjects.

Omega-3 (n-3) fatty acids have been implicated in mood disorders, yet clinical trials supplementing n-3 fats have shown mixed results. However, the predominant focus of this research has been on the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). We used an unbiased approach to assay plasma n-3 and omega-6 (n-6) species that interact at the level of biosynthesis and down-stream processing, to affect brain function and, potentially, mood. We used lipomic technology to assay plasma levels of n-3 and n-6 fatty acids from 40 bipolar and 18 control subjects to investigate differences in plasma levels and associations with the burden of disease markers, neuroticism and global assessment of function (GAF) and mood state (Hamilton Depression Scale (HAM-D)). Most significantly, we found the levels of dihomo-gamma-linolenic acid (DGLA) to positively correlate with neuroticism and HAM-D scores and negatively correlate with GAF scores; and HAM-D to negatively correlate with linoleic acid (LA) and positively correlate with fatty acid desaturase 2 (FADS2) activity, an enzyme responsible for converting LA to gamma-linolenic acid (GLA). These associations remained significant following Bonferroni multiple testing correction. These data suggest that specific n-6 fatty acids and the enzymes that control their biosynthesis may be useful biomarkers in measurements of depressive disorders and burden of disease, and that they should be considered when investigating the roles of n-3s.

Associations between suicide attempts and elevated bedtime salivary cortisol levels in bipolar disorder.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been reported in bipolar disorder and also in suicidal behavior, but few studies have examined the relationship between suicidal behaviors and the HPA axis function in bipolar disorder, attending to and minimizing confounding factors. We compare HPA axis activity in bipolar individuals with and without suicidal behavior and unaffected healthy controls through measurement of salivary cortisol. METHOD: Salivary cortisol was collected for three consecutive days in 29 controls, 80 bipolar individuals without a history of suicide and 56 bipolar individuals with a past history of suicide. Clinical factors that affect salivary cortisol were also examined. RESULTS: A past history of suicide was associated with a 7.4% higher bedtime salivary cortisol level in bipolar individuals. There was no statistical difference between non-suicidal bipolar individuals and controls in bedtime salivary cortisol and awakening salivary cortisol was not different between the three groups. LIMITATIONS: The measure of salivary cortisol was a home based collection by the study subjects and the retrospective clinical data was primarily based on their historical account. CONCLUSIONS: Bipolar individuals with a past history of suicidal behavior exhibit hyperactivity in the HPA axis. This biological marker remains significant regardless of demographic factors, mood state, severity and course of illness. This finding in bipolar disorder is consistent with the evidence for altered HPA axis functioning in suicide and mood disorders and is associated with a clinical subgroup of bipolar patients at elevated risk for suicide based on their history, and in need of further attention and study.