An Untargeted Metabolomics Analysis of Antipsychotic Use in Bipolar Disorder

BackgroundSecond generation antipsychotic (SGA) use in bipolar disorder is common and has proven effective in short‐term trials. There continues to be a lack of understanding of the mechanisms underlying many of their positive and negative effects in bipolar disorder. This study aimed to describe the metabolite profiles of bipolar subjects treated with SGAs by comparing to metabolite profiles of bipolar subjects treated with lithium, and schizophrenia subjects treated with SGAs.MethodsCross‐sectional, fasting untargeted serum metabolomic profiling was conducted in 82 subjects diagnosed with bipolar I disorder (n = 30 on SGAs and n = 32 on lithium) or schizophrenia (n = 20). Metabolomic profiles of bipolar subjects treated with SGAs were compared to bipolar subjects treated with lithium and schizophrenia subjects treated with SGAs using multivariate methods.ResultsPartial lease square discriminant analysis (PLS‐DA) plots showed separation between bipolar subjects treated with SGAs, bipolar subjects treated with lithium, or schizophrenia subjects treated with SGAs. Top influential metabolite features were associated with several pathways including that of polyunsaturated fatty acids, pyruvate, glucose, and branched chain amino acids.ConclusionsThe findings from this study require further validation in pre‐ and posttreated bipolar and schizophrenia subjects, but suggest that the pharmacometabolome may be diagnosis specific.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115928/1/cts12324.pd

Gene‐specific DNA methylation may mediate atypical antipsychotic‐induced insulin resistance

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134192/1/bdi12422_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134192/2/bdi12422.pd

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Three Commonly Utilized Scholarly Databases and a Social Network Site Provide Different, But Related, Metrics of Pharmacy Faculty Publication

Scholarly productivity is a critical component of pharmacy faculty effort and is used for promotion and tenure decisions. Several databases are available to measure scholarly productivity; however, comparisons amongst these databases are lacking for pharmacy faculty. The objective of this work was to compare scholarly metrics from three commonly utilized databases and a social networking site focused on data from research-intensive colleges of pharmacy and to identify factors associated with database differences. Scholarly metrics were obtained from Scopus, Web of Science, Google Scholar, and ResearchGate for faculty from research-intensive (Carnegie Rated R1, R2, or special focus) United States pharmacy schools with at least two million USD in funding from the National Institutes of Health. Metrics were compared and correlations were performed. Regression analyses were utilized to identify factors associated with database differences. Significant differences in scholarly metric values were observed between databases despite the high correlations, suggestive of systematic variation in database reporting. Time since first publication was the most common factor that was associated with database differences. Google Scholar tended to have higher metrics than all other databases, while Web of Science had lower metrics relative to other databases. Differences in reported metrics between databases are apparent, which may be attributable to the time since first publication and database coverage of pharmacy-specific journals. These differences should be considered by faculty, reviewers, and administrative staff when evaluating scholarly performance

The Influence of Metabolic Syndrome and Sex on the DNA Methylome in Schizophrenia

Introduction. The mechanism by which metabolic syndrome occurs in schizophrenia is not completely known; however, previous work suggests that changes in DNA methylation may be involved which is further influenced by sex. Within this study, the DNA methylome was profiled to identify altered methylation associated with metabolic syndrome in a schizophrenia population on atypical antipsychotics. Methods. Peripheral blood from schizophrenia subjects was utilized for DNA methylation analyses. Discovery analyses (n=96) were performed using an epigenome-wide analysis on the Illumina HumanMethylation450K BeadChip based on metabolic syndrome diagnosis. A secondary discovery analysis was conducted based on sex. The top hits from the discovery analyses were assessed in an additional validation set (n=166) using site-specific methylation pyrosequencing. Results. A significant increase in CDH22 gene methylation in subjects with metabolic syndrome was identified in the overall sample. Additionally, differential methylation was found within the MAP3K13 gene in females and the CCDC8 gene within males. Significant differences in methylation were again observed for the CDH22 and MAP3K13 genes, but not CCDC8, in the validation sample set. Conclusions. This study provides preliminary evidence that DNA methylation may be associated with metabolic syndrome and sex in schizophrenia

Atypical Antipsychotics and the Human Skeletal Muscle Lipidome

Atypical antipsychotics (AAPs) are a class of medications associated with significant metabolic side effects, including insulin resistance. The aim of this study was to analyze the skeletal muscle lipidome of patients on AAPs, compared to mood stabilizers, to further understand the molecular changes underlying AAP treatment and side effects. Bipolar patients on AAPs or mood stabilizers underwent a fasting muscle biopsy and assessment of insulin sensitivity. A lipidomic analysis of total fatty acids (TFAs), phosphatidylcholines (PCs) and ceramides (CERs) was performed on the muscle biopsies, then lipid species were compared between treatment groups, and correlation analyses were performed with insulin sensitivity. TFAs and PCs were decreased and CERs were increased in the AAP group relative to those in the mood stabilizer group (FDR q-value &lt;0.05). A larger number of TFAs and PCs were positively correlated with insulin sensitivity in the AAP group compared to those in the mood stabilizer group. In contrast, a larger number of CERs were negatively correlated with insulin sensitivity in the AAP group compared to that in the mood stabilizer group. The findings here suggest that AAPs are associated with changes in the lipid profiles of human skeletal muscle when compared to mood stabilizers and that these changes correlate with insulin sensitivity

Alterations in Skeletal Muscle Insulin Signaling DNA Methylation: A Pilot Randomized Controlled Trial of Olanzapine in Healthy Volunteers

Antipsychotics are associated with severe metabolic side effects including insulin resistance; however, the mechanisms underlying this side effect are not fully understood. The skeletal muscle plays a critical role in insulin-stimulated glucose uptake, and changes in skeletal muscle DNA methylation by antipsychotics may play a role in the development of insulin resistance. A double-blind, placebo-controlled trial of olanzapine was performed in healthy volunteers. Twelve healthy volunteers were randomized to receive 10 mg/day of olanzapine for 7 days. Participants underwent skeletal muscle biopsies to analyze DNA methylation changes using a candidate gene approach for the insulin signaling pathway. Ninety-seven methylation sites were statistically significant (false discovery rate PPARGC1A) gene, which had 52% lower methylation in the olanzapine group. Antipsychotic treatment in healthy volunteers causes significant changes in skeletal muscle DNA methylation in the insulin signaling pathway. Future work will need to expand on these findings with expression analyses