Abstract
The mood stabilizer lithium represents a cornerstone in the long term treatment of bipolar disorder (BD), although with substantial interindividual variability in clinical response. This variability appears to be modulated by genetics, which has been significantly investigated in the last two decades with some promising findings. In addition, recently, the interest in the role of epigenetics has grown significantly, since the exploration of these mechanisms might allow the elucidation of the gene–environment interactions and explanation of missing heritability. In this article, we provide an overview of the most relevant findings regarding the pharmacogenomics and pharmacoepigenomics of lithium response in BD. We describe the most replicated findings among candidate gene studies, results from genome-wide association studies (GWAS) as well as post-GWAS approaches supporting an association between high genetic load for schizophrenia, major depressive disorder or attention deficit/hyperactivity disorder and poor lithium response. Next, we describe results from studies investigating epigenetic mechanisms, such as changes in methylation or noncoding RNA levels, which play a relevant role as regulators of gene expression. Finally, we discuss challenges related to the search for the molecular determinants of lithium response and potential future research directions to pave the path towards a biomarker guided approach in lithium treatment.
Highlights
Bipolar disorder (BD) is a group of severe and disabling psychiatric disorders characterized by the recurrence of depressive and manic or hypomanic episodes, alternating with intervals of wellbeing [1]
This study reported that genetic variants previously associated with lithium response in genome-wide association studies (GWAS) showed concordance with regulatory elements annotated by the Epigenome roadmap consortium, suggesting that genetic determinants of lithium response might interfere with regulatory and epigenetic mechanisms
Despite the fact that the new technological strategies and bioinformatic approaches allowed a great step forward compared to the early stages of pharmacogenetic research, overall only few targets have been replicated across studies
Summary
Bipolar disorder (BD) is a group of severe and disabling psychiatric disorders characterized by the recurrence of depressive and manic or hypomanic episodes, alternating with intervals of wellbeing [1]. In the last few years, studies have largely shifted from the assessment of candidate genes to the genome-wide approach, which is, still limited by several challenges related to the necessity of collecting large cohorts of patients with a deep clinical characterization. In this sense, international efforts, such as the International Consortium on Lithium Genetics (ConLiGen) [8], can provide a crucial contribution towards the identification of reliable markers of lithium response and the development of precision medicine approaches
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have