Genomics of Lithium Action and Response

Pickard, Ben

doi:10.1007/s13311-017-0554-7

Cited by 17 publications

(16 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lithium is the first-line treatment for BD, not only for the treatment of acute episodes but also for maintenance and suicide prevention (Cipriani et al ., 2013; Malhi et al ., 2017). However, only about 30% of BD patients fully respond to lithium, it has several adverse side effects, and its mechanisms of action are not well understood (Alda, 2015; Gitlin, 2016; Pickard, 2017). One probable reason for this lack of understanding is the magnitude of lithium's physiological interactions (Roux and Dosseto, 2017).…”

Section: Discussionmentioning

confidence: 99%

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect

et al. 2019

View full text Add to dashboard Cite

Background Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and poorly understood etiology. Previous transcriptomic BD studies have had inconsistent findings due to issues such as small sample sizes and difficulty in adequately accounting for confounders like medication use. Methods We performed a differential expression analysis in a well-characterized BD case-control sample (Nsubjects = 480) by RNA sequencing of whole blood. We further performed co-expression network analysis, functional enrichment, and cell type decomposition, and integrated differentially expressed genes with genetic risk. Results While we observed widespread differential gene expression patterns between affected and unaffected individuals, these effects were largely linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell signaling and immune response functional annotations, among others, and were associated with neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression genetic risk based on information from genome-wide association studies, nor was gene expression associated with polygenic risk scores for BD. Conclusions These findings suggest that BD is associated with minimal changes in whole blood gene expression independent of medication use but emphasize the importance of accounting for medication use and cell type heterogeneity in psychiatric transcriptomic studies. The results of this study add to mounting evidence of lithium's cell signaling and immune-related mechanisms.

show abstract

Section: Discussionmentioning

confidence: 99%

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Lithium is the first-line treatment for BD, not only for the treatment of acute episodes but also for maintenance and suicide prevention 46–47 . However, only about 30% of BD patients fully respond to lithium, it has several adverse side effects, and its mechanisms of action are not well understood 48–50 . One probable reason for this lack of understanding is the magnitude of lithium’s physiological interactions 51 .…”

Section: Discussionmentioning

confidence: 99%

“…One probable reason for this lack of understanding is the magnitude of lithium’s physiological interactions 51 . In pharmacological terms, lithium is a small molecule (the third smallest element in fact) without a defined target 50 . This lack of specificity makes it difficult to discern therapeutic mechanisms from off-target effects, which likely lead to many of lithium’s undesirable side effects and even its toxicity at doses that are too high.…”

Section: Discussionmentioning

confidence: 99%

“…This lack of specificity makes it difficult to discern therapeutic mechanisms from off-target effects, which likely lead to many of lithium’s undesirable side effects and even its toxicity at doses that are too high. Lithium ions (Li+) have a single positive charge and are hypothesized to mimic and disrupt the actions and targets of more ubiquitous metal ions such as magnesium (Mg 2 +) 50 . Theorized therapeutic mechanisms of lithium include its inhibition of the protein GS3Kβ, and its effect on intracellular signaling cascades such as those involving protein kinases and phosphatidylinositol 52, 53 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect

Krebs

Ori

Vreeker

et al. 2018

Preprint

View full text Add to dashboard Cite

23Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and 24 poorly understood etiology. We performed a whole blood transcriptome analysis in a BD case-25 control sample (Nsubjects = 480) by RNA sequencing. While we observed widespread differential 26 gene expression patterns between affected and unaffected individuals, these effects were largely 27 linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD 28 diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell 29 signaling and immune response functional annotations, among others, and were associated with 30 neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered 31 expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression 32 genetic risk based on information from genome-wide association studies, nor was gene 33 expression associated with polygenic risk scores for BD. Our findings suggest that BD is 34 associated with minimal changes in whole blood gene expression independent of medication use 35 but underline the importance of accounting for medication use and cell type heterogeneity in 36 psychiatric transcriptomic studies. The results of our study add to mounting evidence of lithium's 37 cell signaling and immune-related mechanisms. 38 39 strategy for uncovering disease mechanisms. Many such studies have been carried out for BD, 48and in Table 1 we present a summary that reveals a lack of consistency between findings likely 49 owing to clinical heterogeneity, differing study designs, and the low numbers of samples 50 investigated (N ≤ 62 BD subjects) . Moreover, there are many potential confounds that impact 51 gene expression, including medication. 52 Therefore, to explore gene expression changes associated with BD, we generated RNA 53 sequencing data from peripheral whole blood collected in a large, well-characterized case-control 54 cohort from The Netherlands. We examined gene expression differences between groups both at 55 the individual gene level and at the level of gene co-expression. Upon correction for technical and 56 biological variables including the use of lithium, the most widely used prescription drug in our 57 cohort, gene expression differences between subjects with BD and controls were minor. 58Differences in subjects being treated with lithium compared to those who are not, however, were 59 widespread. These differences were partially but not entirely explained by differences in cell-type 60 composition, driven by elevated neutrophil proportions in lithium users. The lithium-associated 61 changes in gene expression were independent of psychiatric genetic risk, though. Our results 62 suggest nominal BD-related gene expression effects in blood but numerous effects related to 63 lithium treatment. This work highlights the importance of accounting for medication use in 64 psychiatric transcriptomic studies and provides insight into lithium's mole...

show abstract

“…Given the complexity of this topic, the first article in this section, by Jacob Michaelson [4], provides an accessible overview of the field along with in-depth discussion of the applicat i o n o f g e n o m i c s t o s t u d y i n g t h e e t i o l o g y o f neurodevelopmental disorders. The second article in this section, by Benjamin Pickard [5], describes modern genomic approaches that are being used to identify and explore key differences between patients that do or do not respond to lithium. This line of research provides one of several examples in this issue of how new approaches are being used to improve classic treatments that were originally based on serendipitous discovery.…”

mentioning

confidence: 99%