Genetic and Epigenetic Markers of Lithium Response

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.

Actualización en el uso y el manejo del litio en neuropsiquiatría

“…El litio actúa sobre múltiples vías de señalización, aunque no es claro en cuál de ellas se asienta su efectividad clínica. En efecto, se ha sugerido que este ion incrementa la transmisión serotoninérgica, regula los niveles de calcio intracelular, interfiere en la producción de múltiples segundos mensajeros y media corriente abajo la transcripción génica de algunos elementos involucrados en la neuroprogresión, la plasticidad sináptica y/o la regulación de ritmos circadianos (Pisanu et al, 2022).…”

Genomic regulatory sequences in the pathogenesis of bipolar disorder

“…In particular, the article deals with common disease-associated variants discovered in genome-wide association studies (GWASs) and located in the same genomic loci than regulatory sequences implicated in: (a) regulation of gene transcription, (b) post-transcriptional regulation. The topics of pharmacogenetics and pharmacoepigenetics in BD are beyond the scope of the present article, so the reader is referred to other reviews covering these important topics ( 10 – 13 ).…”

A pilot investigation of differential hydroxymethylation levels in patient-derived neural stem cells implicates altered cortical development in bipolar disorder

“…Epigenetic studies of BD, and its treatment with mood stabilizers, have largely focused on DNA methylation profiling in the brain or peripheral blood, identifying both global and regional differential methylation patterns in patients with bipolar disorder versus non-patients, and in patients following treatment with mood stabilizers (9)(10)(11)(12)(13)(14). Further, the disruption of epigenetic regulation by environmental factors during embryonic development, childhood, and adolescence has long-term consequences on adult phenotypes and is thought to contribute to risk for psychiatric disorders (15)(16)(17)(18)(19).…”